Early and late renal adverse effects after potentially nephrotoxic treatment for childhood cancer

  • Review
  • Intervention

Authors


Abstract

Background

Great improvements in diagnostics and treatment for malignant disease in childhood have led to a major increase in survival. However, childhood cancer survivors (CCS) are at great risk for developing adverse effects caused by multimodal treatment for their malignancy. Nephrotoxicity is one of these known (acute) side effects of several treatments, including cisplatin, carboplatin, ifosfamide, radiotherapy and nephrectomy, and can cause glomerular filtration rate impairment, proteinuria, tubulopathy and hypertension. However, evidence about the long-term effects of these treatments on renal function remains inconclusive. To reduce the number of (long-term) nephrotoxic events in CCS, it is important to know the risk of, and risk factors for, early and late renal adverse effects, so that ultimately treatment and screening protocols can be adjusted.

Objectives

To evaluate existing evidence on the effects of potentially nephrotoxic treatment modalities on the prevalence of and associated risk factors for renal dysfunction in survivors treated for childhood cancer with a median or mean survival of at least one year after cessation of treatment, where possible in comparison with healthy controls or CCS treated without potentially nephrotoxic treatment.

Search methods

We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2011), MEDLINE/PubMed (from 1945 to December 2011) and EMBASE/Ovid (from 1980 to December 2011).

Selection criteria

With the exception of case reports, case series and studies including fewer than 20 participants, we included studies with all study designs that reported on renal function (one year or longer after cessation of treatment) in children and adults who were treated for a paediatric malignancy (aged 18 years or younger at diagnosis) with cisplatin, carboplatin, ifosfamide, radiation including the kidney region and/or a nephrectomy.

Data collection and analysis

Two review authors independently performed study selection, risk of bias assessment and data extraction using standardised data collection forms. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.

Main results

The search strategy identified 5504 studies, of which 5138 were excluded on the basis of title and/or abstract. The full-text screening of the remaining 366 articles resulted in the inclusion of 57 studies investigating the prevalence of and sometimes also risk factors for early and late renal adverse effects of treatment for childhood cancer. The 57 studies included at least 13,338 participants of interest for this study, of whom at least 6516 underwent renal function testing. The prevalence of renal adverse effects ranged from 0% to 84%. This variation may be due to diversity in included malignancies, prescribed treatments, reported outcome measurements and the methodological quality of available evidence.

Chronic kidney disease/renal insufficiency (as defined by the authors of the original studies) was reported in 10 of 57 studies. The prevalence of chronic kidney disease ranged between 0.5% and 70.4% in the 10 studies and between 0.5% and 18.8% in the six studies that specifically investigated Wilms' tumour survivors treated with a unilateral nephrectomy.

A decreased (estimated) glomerular filtration rate was present in 0% to 50% of all assessed survivors (32/57 studies). Total body irradiation; concomitant treatment with aminoglycosides, vancomycin, amphotericin B or cyclosporin A; older age at treatment and longer interval from therapy to follow-up were significant risk factors reported in multivariate analyses. Proteinuria was present in 0% to 84% of all survivors (17/57 studies). No study performed multivariate analysis to assess risk factors for proteinuria.

Hypophosphataemia was assessed in seven studies. Reported prevalences ranged between 0% and 47.6%, but four of seven studies found a prevalence of 0%. No studies assessed risk factors for hypophosphataemia using multivariate analysis. The prevalence of impairment of tubular phosphate reabsorption was mostly higher (range 0% to 62.5%; 11/57 studies). Higher cumulative ifosfamide dose, concomitant cisplatin treatment, nephrectomy and longer follow-up duration were significant risk factors for impaired tubular phosphate reabsorption in multivariate analyses.

Treatment with cisplatin and carboplatin was associated with a significantly lower serum magnesium level in multivariate analysis, and the prevalence of hypomagnesaemia ranged between 0% and 37.5% in the eight studies investigating serum magnesium.

Hypertension was investigated in 24 of the 57 studies. Reported prevalences ranged from 0% to 18.2%. A higher body mass index was the only significant risk factor noted in more than one multivariate analysis. Other reported factors that significantly increased the risk of hypertension were use of total body irradiation, abdominal irradiation, acute kidney injury, unrelated or autologous stem cell donor type, growth hormone therapy and older age at screening. Previous infection with hepatitis C significantly decreased the risk of hypertension.

Because of the profound heterogeneity of the studies, it was not possible to perform any meta-analysis.

Authors' conclusions

The prevalence of renal adverse events after treatment with cisplatin, carboplatin, ifosfamide, radiation therapy involving the kidney region and/or nephrectomy ranged from 0% to 84%. With currently available evidence, it was not possible to draw any conclusions with regard to prevalence of and risk factors for renal adverse effects. Future studies should focus on adequate study design and reporting and should deploy multivariate risk factor analysis to correct for possible confounding. Until more evidence becomes available, CCS should be enrolled into long-term follow-up programmes to monitor their renal function and blood pressure.

Résumé scientifique

Des effets indésirables rénaux précoces et tardifs après un traitement potentiellement néphrotoxiques pour cancer infantile

Contexte

Une grande amélioration dans le diagnostique et le traitement des maladies malignes chez l'enfant ont conduit à une augmentation importante dans la survie. Cependant, les survivants d'un cancer de l'enfant (SCI) présentent un risque important pour le développement d'effets indésirables causés par un traitement multimodal de leur cancer. La néphrotoxicité est l'un de ces effets secondaires connus (aigus) de plusieurs traitements, notamment la cisplatine, la carboplatine, l'ifosfamide, la radiothérapie et la néphrectomie, et peuvent entraîner une détérioration du taux de filtration glomérulaire, une protéinurie, une tubulopathie et de l'hypertension. Cependant, les preuves concernant les effets à long terme de ces traitements sur la fonction rénale ne sont pas concluants. Pour réduire le nombre d'événements néphrotoxiques (à long terme) des SCI, il est important de connaître le risque et les facteurs de risque d’effets indésirables précoces et tardifs, de sorte que les protocoles de traitement et le dépistage puissent être adaptés.

Objectifs

Évaluer les preuves existantes concernant les effets des modalités de traitement potentiellement néphrotoxiques sur la prévalence et des facteurs de risque associés pour le dysfonctionnement rénal chez les survivants traités pour un cancer infantile avec une survie moyenne d'au moins un an après l'arrêt du traitement, lorsque cela était possible, en comparaison avec les témoins ou SCI en bonne santé traités sans traitement potentiellement néphrotoxiques.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans les bases de données électroniques suivantes: Le registre Cochrane des essais contrôlés (CENTRAL) ( La Bibliothèque Cochrane , numéro 4, 2011), MEDLINE/PubMed (de 1945 à décembre 2011) et EMBASE/Ovid (de 1980 à décembre 2011).

Critères de sélection

À l'exception de rapports de cas, les séries de cas et les études incluant moins de 20 participants, nous avons inclus des études avec tous les plans d'étude qui avaient rendu compte de la fonction rénale (un an ou plus après l'arrêt du traitement) chez les enfants et les adultes qui étaient traités pour une malignité pédiatrique (âgés de 18 ans ou moins, au moment du diagnostic) à la cisplatine, la carboplatine, l’ifosfamide, y compris la radiothérapie dans la région rénale et/ou une néphrectomie.

Recueil et analyse des données

Deux auteurs de la revue ont effectué indépendamment la sélection des études, l'évaluation du risque de biais et l'extraction des données à l'aide de formulaires de collecte de données standardisés. Des analyses ont été effectuées conformément aux recommandations du Livre de poche de revues d’intervention systématiques Cochrane .

Résultats principaux

La stratégie de recherche documentaire a identifié 5504 études, dont 5138 ont été exclues sur la base du titre et/ou de résumé. L'examen complet de 366 articles restants a entraîné l'inclusion de 57 études portant sur la prévalence et parfois aussi des facteurs de risque d’effets indésirables rénaux précoces et tardifs du traitement pour cancer infantile. Les 57 études incluaient au moins 13 338 participants de jugement pour cette étude, dont au moins 6516 avec un test de la fonction rénale. La prévalence des effets indésirables rénaux était comprise entre 0% à 84%. Cette variation peut être due à la diversité des tumeurs malignes incluses, les traitements prescrits, les mesures de résultats rapportées et la qualité méthodologique de preuves disponibles.

Une maladie/insuffisance rénale chronique (telle que définie par les auteurs des études originales) a été signalée dans 10 de 57 études. La prévalence de la maladie rénale chronique était comprise entre 0,5 et 70,4% dans les 10 études et entre 0,5 et 18,8% dans les six études qui avaient spécifiquement étudié la tumeur de Wilms des survivants traités avec une néphrectomie unilatérale.

Une diminution du taux de filtration glomérulaire (estimée) était présente chez 0% à 50% de tous les essais évaluant les survivants (32/57 études). L’irradiation corporelle totale; un traitement concomitant avec des aminosides, vancomycine, amphotéricine B ou cyclosporine A; un âge plus avancé au moment du traitement et plus d’intervalle entre la thérapie et le suivi à long terme ont été des facteurs de risque significatifs rapportés dans des analyses multivariés. Une protéinurie était présente dans 0% à 84% de tous les survivants (17/57 études). Aucune étude n’a fait une analyse multifactorielle pour évaluer les facteurs de risque de protéinurie.

L'hypophosphatémie a été évaluée dans sept études. La prévalence était rapportée en termes compris entre 0% et 47,6%, mais quatre des sept études rapportaient une prévalence de 0%. Aucune étude n'a évalué les facteurs de risque d'hypophosphatémie à l'aide d’une analyse multifactorielle. La prévalence de la dégradation de la réabsorption tubulaire de phosphate était généralement plus élevée (plage de 0 à 62,5%; 11/57 études). La dose cumulée supérieure d'ifosfamide, concomitante à un traitement par cisplatine, la néphrectomie et une plus longue durée de suivi étaient de facteurs de risque significatifs de retard réabsorption tubulaires de phosphate dans des analyses multivariées.

Le traitement par cisplatine et carboplatine était associée à un niveau significativement plus faible de concentrations sériques de magnésium dans l'analyse multifactorielle, et la prévalence d'hypomagnésémie était comprise entre 0% et 37,5% dans les huit études examinant le magnésium sérique.

L'hypertension était étudiée dans les 24 des 57 études. Les prévalences rapportées en termes était de 0 à 18,2%. Une augmentation de l'indice de masse corporelle était le seul facteur de risque majeur noté dans plus d'une analyse multivariée. Un autre facteur rapporté qui a augmenté significativement le risque d'hypertension était utilisation d'irradiation corporelle totale, irradiation abdominale, l'insuffisance rénale aiguë, l’autogreffe sans lien de parenté ou de cellules souches, le traitement par hormone de croissance et l’âge plus avancé au dépistage. Un antécédent d’infection par l'hépatite C a significativement réduit le risque d'hypertension.

En raison de la profonde hétérogénéité des études, il n'a pas été possible de réaliser une méta-analyse.

Conclusions des auteurs

La prévalence des événements indésirables rénaux après le traitement par cisplatine, la carboplatine, de l'ifosfamide, la radiothérapie sur la région rénale et/ou la néphrectomie est entre 0 et 84%. Avec les preuves actuellement disponibles, il n'a pas été possible de tirer des conclusions quant à la prévalence de et des facteurs de risque pour les effets indésirables. Des études devraient se concentrer sur la conception et rapport adéquat et devraient déployer des facteurs de risque en analyse multivariée pour corriger des possibles confusions. En attendant que davantage de preuves soient disponibles, les SCI devraient être inclus dans les programmes de suivi à long terme pour contrôler leur fonction rénale et leur pression artérielle.

Notes de traduction

Translated by: French Cochrane Centre

Translation supported by: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux; pour la France : Minist�re en charge de la Sant�

Plain language summary

Treatment-related early and late side effects on the kidney in survivors of childhood cancer

Over the past few decades, great improvements in diagnostics and treatment have resulted in a major increase in survival rates of childhood cancer. However, childhood cancer survivors (CCS) are at great risk of developing adverse effects as a result of their cancer treatment. One of the potential adverse effects of childhood cancer treatment is kidney damage. Renal adverse effects are common during and just after treatment, but very little evidence is available on the frequency of renal function impairment in long-term CCS and on what the risk factors are. Survivors with impaired renal function due to childhood cancer treatment are usually symptom free. The kidneys are remarkably well able to compensate for problems in their functioning. However, when renal late adverse events become symptomatic, survivors can experience a range of symptoms, depending on the kidney functions that are damaged. This systematic review aimed to assess the magnitude of asymptomatic and symptomatic early and late renal adverse events in long-term CCS and to identify which risk factors contribute to impaired renal function.

After thoroughly searching the literature, we were able to include 57 studies in this review. These 57 studies included at least 13,338 participants of interest for this study, of whom at least 6516 underwent renal function testing. Wide variation was noted in the percentage of participants who suffered from renal impairment after treatment for childhood cancer, ranging from 0% to 84%. Variation in the study population, received treatments, outcome measurements and study quality may explain the variation in reported percentages. All included studies suffered from methodological issues. More and especially higher quality research is needed to gain better insight into renal adverse events and related risk factors.

Résumé simplifié

Effets secondaires précoces et tardifs sur le rein dus aux traitements chez des enfants survivants d'un cancer

Des dernières décennies, des grandes améliorations dans le diagnostique et le traitement ont entraîné une augmentation importante dans les taux de survie de cancer de l'enfant. Cependant, les survivants d'un cancer de l'enfant (SCI) présentent un risque important de développer des effets indésirables en relation avec le traitement d’un cancer. L'un des effets indésirables potentiels du traitement d'un cancer de l'enfant sont des lésions rénales. Des effets indésirables rénaux sont courants pendant et après le traitement, mais très peu de preuves sont disponibles sur la fréquence des troubles de la fonction rénale à long terme des SCI et sur les facteurs de risque. Les survivants d’une détérioration de la fonction rénale en raison d'un traitement d'un cancer de l'enfant sont généralement asymptomatiques. Les reins sont en mesure de compenser des problèmes dans leur état fonctionnel d’une manière remarquable. Cependant, lorsque les événements indésirables tardifs rénaux deviennent symptomatiques, les survivants peuvent ressentir un éventail de symptômes, selon la fonction rénale atteinte. Cette revue systématique visait à évaluer l'ampleur d’événements indésirables symptomatiques et asymptomatiques précoces et tardifs rénaux à long terme des SCI et à identifier les facteurs de risque contribuant à une altération de la fonction rénale.

Après des recherches exhaustives dans la littérature, nous avons pu inclure 57 études dans cette revue. Ces 57 études comprenaient au moins 13 338 participants pour cette étude, dont au moins 6516 avec tests de la fonction rénale. Une ample variation était observée dans le pourcentage de participants ayant souffert d'insuffisance rénale après un traitement pour cancer infantile, allant de 0 à 84%. Les variations dans la population étudiée, les traitements reçus, les mesures de résultats et la qualité des études pourraient expliquer la variation des pourcentages rapportés. Toutes les études incluses présentaient de problèmes méthodologiques. D’avantage de recherches en particulier de haute qualité sont nécessaires afin d'obtenir une meilleure compréhension des événements indésirables rénaux et ses facteurs de risque.

Notes de traduction

Translated by: French Cochrane Centre

Translation supported by: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux; pour la France : Minist�re en charge de la Sant�

Background

Great improvements in diagnostics and treatment for malignant disease in childhood have led to a major increase in survival, with five-year survival reaching 80% in Europe (Gatta 2009). Despite this rise in five-year survival, childhood cancer survivors (CCS) are at high risk of developing late effects caused by their cancer therapies. Three large cohort studies found that up to 88% of all survivors suffer from at least one long-term effect after follow-up of 30, 17 and 7 years, respectively (Oeffinger 2006; Geenen 2007; Wasilewski-Masker 2010).

Nephrotoxicity is a known side effect of certain childhood cancer therapies, resulting in a decline in glomerular filtration rate (GFR), deterioration of tubular function, development of albuminuria and/or (renovascular) hypertension during or after treatment (Jones 2008). Potentially nephrotoxic agents include ifosfamide and the platinum compounds cisplatin and carboplatin (Womer 1985; English 1999; Rossi 1999; Jones 2008). Recent studies have shown that ifosfamide and platinum toxicities persist during follow-up even up to 10 years after treatment, with prevalence of renal adverse effects ranging from 0% to 45% depending on the study group and the measured outcome variable (Oberlin 2009; Skinner 2009). Abdominal and total body irradiation may cause radiation nephropathy, characterised by hypertension, a decline in GFR and (intermittent) proteinuria (Breitz 2004). Kidney surgery may also play a role in the long-term course of renal function, for example, by causing hyperfiltration in unilateral nephrectomised survivors, which may ultimately lead to hypertension and glomerular impairment (Schell 1995; De Graaf 1996).

Several risk factors for the development of late renal effects have been mentioned in the literature, but these effects were often examined in small, selected study populations and produced inconsistent results. Risk factors such as cumulative chemotherapy and radiotherapy doses, age at diagnosis, duration of follow-up and infusion schemes have all been investigated, but conclusive evidence is missing. For example, both Pietilä et al and Loebstein et al reported the cumulative cisplatin dose to be a risk factor for impaired renal function, whereas Brock et al and Schell et al did not find any relationship (Brock 1991; Schell 1995; Loebstein 1999; Pietilä 2005). The use of multimodal nephrotoxic cancer treatment may also increase the risk of renal dysfunction: In one study, glomerular function of nephrectomised Wilms' tumour (WT) survivors was significantly lower among participants who received radiation therapy and chemotherapy in comparison with those given chemotherapy alone (De Graaf 1996). Systematic review and meta-analysis of the literature may elucidate which risk factors are associated with renal impairment and which are not.

In 2008, Jones et al published an evidence summary for the American Childhood Oncology Group (COG), delineating exposure-based risks of potentially nephrotoxic treatment modalities accompanied by health screening recommendations and considerations for the treatment/management of associated late effects (Jones 2008). The focus of management of nephrotoxicity lies in blood pressure control, electrolyte supplementation and, when needed, consultation with or referral to the nephrologist. The COG evidence summary served as a basis for the COG Long-Term Follow-up Guidelines. Skinner published two overviews of the literature regarding nephrotoxicity during and after treatment for childhood cancer (Skinner 2010a; Skinner 2011). To reduce the number of (long-term) nephrotoxic events in CCS, treatment and screening protocols should be adjusted. A systematic review of the literature is required to gain evidence-based insight into the role of these treatments in early and long-term function of the kidneys.

Objectives

To evaluate existing evidence on the effects of potentially nephrotoxic treatment modalities on the prevalence of and associated risk factors for renal dysfunction in survivors treated for childhood cancer with a median or mean survival of at least one year after cessation of treatment, where possible in comparison with healthy controls or CCS treated without potentially nephrotoxic treatment.

Methods

Criteria for considering studies for this review

Types of studies

All study designs, except case reports and case series, examining the effects of (multimodal) treatment of childhood cancer on renal adverse effects.

Types of participants

CCS diagnosed between the ages of 0 and 18 years with a mean or median survival of at least one year after the end of treatment and related healthy controls, if available. If no follow-up time after the end of treatment was stated, at least 90% of the study group had to be off treatment. Studies had to include at least 20 survivors who received potentially nephrotoxic therapies.

Types of interventions

Treatment with cisplatin, carboplatin, ifosfamide, radiotherapy involving the kidney including total body irradiation and/or surgery involving the kidney.

Types of outcome measures

We decided to limit included outcome measures to those reported most often and that were most consistent and had the greatest clinical relevance. Included outcome measurements were chronic kidney disease (CKD)/renal insufficiency, (estimated) GFR, proteinuria, serum phosphate/hypophosphataemia, tubular phosphate regulation parameters (tubular phosphate threshold and fractional phosphate excretion), serum magnesium/hypomagnesaemia and finally blood pressure. We did not impose any restrictions on the outcome definitions. Studies that reported on composite outcome measures that included one of the aforementioned outcomes were included. Studies investigating blood pressure as part of a cardiovascular assessment or metabolic syndrome were excluded.

Search methods for identification of studies

The objective of the literature search was to identify all studies reporting on renal adverse effects of potentially nephrotoxic treatment modalities in CCS, with the exception of case reports and case series; hence randomised controlled trials, case control studies and cohort studies were included.

We did not impose language restrictions.

Electronic searches

We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2011), MEDLINE/PubMed (from 1945 to December 2011) and EMBASE/Ovid (from 1980 to December 2011).

We provide the search strategies for the different electronic databases (using a combination of controlled vocabulary and text words) in the appendices (Appendix 1, Appendix 2, Appendix 3).

Data collection and analysis

Selection of studies

After performing the search strategy described previously, two review authors independently selected studies meeting the inclusion criteria on the basis of title and/or abstract. Full-text papers were obtained for closer inspection of any study that seemed to meet the inclusion criteria on the basis of title and/or abstract. We resolved discrepancies between review authors by consensus. If this proved impossible, final resolution was achieved by consulting a third review author. Details of reasons for exclusion of any study considered for this review are provided in the Characteristics of excluded studies.

Data extraction and management

Two review authors performed data extraction independently using standardised data extraction forms. We retrieved data on the following items.

  1. Study characteristics.

    1. Study design;

    2. Number of participants in the original cohort;

    3. Number of participants in the described study group;

    4. Number of participants in the study group of interest;

    5. Number of participants tested for renal adverse effects; and

    6. Number of controls.

  2. Study participants.

    1. Age at diagnosis or at treatment;

    2. Time period diagnosis/treatment;

    3. Age at follow-up;

    4. Duration of follow-up;

    5. Completion of follow-up;

    6. Sex; and

    7. Tumour type.

  3. Interventions.

    1. Number of participants treated with ifosfamide, cisplatin and carboplatin;

    2. Cumulative doses of ifosfamide, cisplatin and carboplatin;

    3. Number of participants treated with other types of chemotherapy;

    4. Number of participants treated with radiotherapy including the kidney region;

    5. Cumulative radiotherapy dose; and

    6. Number of participants treated with (partial) unilateral or bilateral nephrectomy.

  4. Outcome measurements as defined by the authors of the original studies.

  5. Risk factors for nephrotoxicity as defined by the authors of the original studies.

The participants in the original cohort represent the whole group of CCS. The described study group encompasses CCS from the original cohort included in the study. The study group of interest consists of the CCS within the original cohort who received potentially nephrotoxic treatment. Finally, the study group tested for renal adverse effects is made up of the CCS who were assessed for renal function as well.

In cases of disagreement, both review authors re-assessed the abstracts and full-text articles and discussed until consensus was achieved. If consensus was not achieved, we consulted a third review author for resolution.

Assessment of risk of bias in included studies

The risk of bias assessment was based on earlier described checklists for observational studies based on evidence-based medicine criteria (Grimes 2002; Laupacis 1994), as adapted by Mulder 2010. Two review authors independently assessed all included studies on the risk of bias related to the composition of the study population, the follow-up assessments and the outcome assessments, as well as the methods used to assess risk factors for nephrotoxicity in each study. The criteria for the risk of bias assessment are presented in Table 1. To ensure a well-defined study group, chemotherapy and radiotherapy dosages were assessed as relevant when a study explicitly stated that potentially nephrotoxic therapy was part of the study's treatment protocol. For the risk of bias assessment in case control studies, we used adapted criteria related to the selection of cases and controls: Selection of cases and controls had to be based on similar participant characteristics (i.e. age, sex and cancer treatment). For randomised controlled trials (RCTs) and non-randomised controlled trials (CCTs), we will use the criteria put forth by the Childhood Cancer Group (Module CCG).

Table 1. Risk of bias assessment criteria for observational studies
  1. *: if studies presented more than one follow-up measurement in time, the follow-up measurement with the highest percentage of follow-up was used to assess attrition bias.

Study group

Reporting bias (well-defined: yes/no):

  • if the treatment regimen was specified, including relevant cumulative chemotherapy and radiotherapy doses

Selection bias (representative: yes/no):

  • if the described study group consisted of more than 90% of the original cohort of childhood cancer survivors

  • or if the described study group was a random sample of the original cohort with respect to treatment

Follow-up

Reporting bias (well-defined: yes/no):

  • if the duration of follow-up was mentioned

Attrition bias (adequate: yes/no)*:

  • if the outcome was assessed for more than 90% of the study group of interest (++)

  • or if the outcome was assessed for 60% to 90% of the study group of interest (+)

Outcome

Reporting bias (well-defined: yes/no):

  • if the outcome definitions were objective and precise, that is, if the upper or lower limits of normal for renal function tests were described in the definition of renal late adverse effects for more than 50% of the included outcomes

Detection bias (blind: yes/no):

  • if the outcome assessors were blinded to the investigated determinant

Risk estimation

Analysis (well-defined: yes/no):

  • if a risk ratio, odds ratio, attributable risk, linear or logistic regression model, mean difference, Chi2 or any other relevant risk measure was calculated for more than 90% of the study group

Confounding (adjustment for other factors: yes/no):

  • if important prognostic factors (i.e. age, sex, co-treatment, follow-up duration) were taken adequately into account

In cases of disagreement between two review authors, both re-assessed the abstracts and full-text articles to achieve consensus. If this proved impossible, a third review author was consulted for resolution.

Measures of treatment effect

Prevalence, cumulative incidence, mean difference, risk ratio, odds ratio, attributable risk and other associated risk measures.

Assessment of heterogeneity

Heterogeneity was assessed by visual inspection of the forest plots and by the I2 statistic-the formal statistical test for heterogeneity. Substantial heterogeneity was defined as I² > 50% (Higgins 2011). Cases of substantial heterogeneity were reported.

Assessment of reporting biases

We planned to make funnel plots to assess possible publication bias. Heterogeneity prevented us from performing any meta-analysis; therefore, it was not possible to construct any funnel plot.

Data synthesis

Data were entered into Review Manager 5 and were analysed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We used random-effects models throughout the review. We used the generic inverse variance function of RevMan to analyse the prevalence of renal adverse effects. Pooling was not possible, so we provided descriptive results of the studies. Because of the substantial heterogeneity, it was not feasible to perform multivariate meta-regression analyses on any of the outcome variables. We had planned to perform subgroup analyses of studies based on age at diagnosis and follow-up duration and of studies that reported on a single treatment modality (cisplatin, carboplatin, ifosfamide, nephrectomy or radiotherapy). However, it was not feasible to perform these analyses, again because of the high degree of heterogeneity and the variety of treatment regimens given within the included studies.

Sensitivity analysis

Pooling of study outcomes was not possible for any of the included outcomes; therefore, sensitivity analysis was not performed.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

We identified 5504 references by searches of the electronic databases of CENTRAL, MEDLINE (PubMed) and EMBASE (Ovid). After initial screening of the titles and abstracts, we excluded 5138 references that clearly did not meet all inclusion criteria defined for this systematic review. We obtained 366 articles in full text for further screening. Of these 366, another 293 were excluded for not meeting the inclusion criteria. The reasons for exclusion are described in the Characteristics of excluded studies section. Another sixteen studies are not yet classified because we are awaiting the translation, because we were not able to retrieve the full-text study, or because no full-text study was available yet (Cohen 2010; Cozzi 2010; D'Angio 1978; Eckstein 2010; Janda 1993; Kieran 2010; Li 2006; Madden 2010; Matsuyama 2002; Pugachev 2004; Radvansky 2010; Sakellari 2010; Schwartz 2001; Sierota 2005; Stronska 2003; Terenziani 2010). The details of these studies can be found in the Characteristics of studies awaiting classification table. As a result, we were able to include 57 studies on renal adverse effects after potentially nephrotoxic treatment for childhood cancer. The characteristics of these studies are summarised below and are provided in the Characteristics of included studies table. One other study was added to the Characteristics of studies awaiting classification section during the review process because it was suggested by a review author. This study will be included in the first update of the review. Based on the author lists and study and treatment characteristics, readers should take note that there may be potential overlap of participants in the studies of Geenen 2010, Van Dijk 2010, Aronson 2011 and Cardous-Ubbink 2010; the studies of Stefanowicz 2009, Stefanowicz 2010 and Stefanowicz 2011; the studies of Frisk 2002 and Frisk 2007; the studies of Di Tullio 1996 and Indolfi 2001 and all studies of Rossi and colleagues (Rossi 1993; Rossi 1994; Rossi 1994a; Rossi 1994b; Rossi 1997; Rossi 1999).

A total of 23 prospective cohort studies were identified, as well as 12 retrospective cohort studies, 13 cross-sectional cohort studies and 7 cohort studies for which the direction of inclusion was unclear. Additionally, one nested case control study (Cardous-Ubbink 2010) and one medical record linkage study (Breslow 2005) were obtained. Diagnosis or treatment periods of included participants started as early as 1931 (Kantor 1989) and went on until 2009 (Bolling 2010), with a median enrolment period of 15 years per study. Thirteen studies did not report the diagnosis or treatment period of included participants. The earliest study was published in 1986 (Wikstad 1986) and the latest ones in 2011 (Aronson 2011; Hamilton 2011; Stefanowicz 2011).

The total number of participants of interest described in 55 studies was 13,338, and the numbers were not mentioned in two studies (Bardi 2004; Cardous-Ubbink 2010). Of these 13,338 participants of interest, at least 6516 participants from 50 studies underwent renal function testing. In seven studies, the number of participants who underwent renal function tests was not mentioned (Breslow 2005; Cosentino 1993; Hamilton 2011; Laverdiere 2005; Loebstein 1999; Van Dijk 2010; Weirich 2004). Study sizes ranged from 23 (English 1999; Kubiak 2004; Trahair 2007 ) to 5910 participants (Breslow 2005). Twenty-six studies included only survivors of unilateral or bilateral WT (Aronson 2011; Breslow 2005; Chevallier 1997; Cosentino 1993; Cozzi 2005; de Graaf 1996; Di Tullio 1996; Finklestein 1993; Geenen 2010; Hamilton 2011; Indolfi 2001; Kantor 1989; Kubiak 2004; Makipernaa 1991; Mancini 1996; Mpofu 1992; Othman 2002; Paulino 2000; Sasso 2010; Srinivas 1998; Stefanowicz 2010; Stefanowicz 2011; Trobs 2001; Van Dijk 2010; Weirich 2004; Wikstad 1986). Furthermore, seven studies included only survivors with a sarcoma (Ferrari 2005; Oberlin 2009; Prasad 1996; Rossi 1997; Skinner 2010; Stohr 2007; Stohr 2007a), three studies included only participants with neuroblastoma (Bergeron 2005; Laverdiere 2005; Trahair 2007), one study included only participants with hepatoblastoma (von Schweinitz 1997), two studies included only participants with leukaemia and/or lymphoma (Frisk 2002; Frisk 2007) and 17 studies included participants with diagnoses of miscellaneous tumours. One study did not mention the types of tumours that were included (Rossi 1993).

Fifty studies mentioned the median or mean participant age at diagnosis, which ranged from 4.7 months (Bergeron 2005) to 16 years (Ferrari 2005). Median or mean participant age at follow-up was reported in only 24 studies and ranged from 3.6 years (de Graaf 1996) to 29 years (Kantor 1989). Follow-up duration of survivors also varied widely, from a median less than 1 year (Schell 1995) up to 25 years (Kantor 1989). Follow-up duration was better reported than participant age at follow-up: all but three studies mentioned the follow-up duration. The sex distribution was reported in 41 studies. The percentage of included male participants ranged from 28% to 69%, but the median percentage of male participants in the 41 studies that reported sex was 52%.

Treatment

In 23 of 57 studies, participants were treated with cisplatin, in 21 studies it was clear that participants did not receive cisplatin and in 13 studies it was unclear whether participants did or did not receive cisplatin. At least 1049 participants were treated with cisplatin. The percentage of participants treated with cisplatin varied widely from 2% (Mancini 1996) to 100% (Brock 1991; Ferrari 2005; von Schweinitz 1997); one study did not mention the exact number of participants treated with cisplatin (Bardi 2004). Median or mean doses were reported in 18 of the 23 studies including cisplatin and ranged from 80 mg/m2 (Trahair 2007) to 4000 mg/m2 (Loebstein 1999), although most studies reported a mean or median cumulative cisplatin dose prescription of between 300 and 500 mg/m2 (Brock 1991; Fujieda 2009; Rossi 1993; Rossi 1994; Rossi 1994a; Rossi 1994b; Rossi 1999; Schell 1995; Skinner 2009; Stohr 2007; Stohr 2007a).

Carboplatin was used in 16 studies for at least 447 participants. Twenty-six studies did not use carboplatin and 15 studies did not mention carboplatin usage. The average percentage of participants treated with carboplatin was 36%, although this varied widely from 3% (Mancini 1996) to 100% (Bergeron 2005; English 1999) and was not reported in three studies (Bardi 2004; Stefanowicz 2011; Trobs 2001). Cumulative carboplatin dose was reported in all but four studies (Bardi 2004; Stefanowicz 2011; Trobs 2001; Weirich 2004). Median carboplatin cumulative doses ranged from 267 mg/m2 to 2590 mg/m2.

Thirty-one of the 57 studies reported prescription of ifosfamide for at least 2147 participants, 16 studies did not use ifosfamide and in 10 studies ifosfamide usage was unclear. In 13 of the 31 ifosfamide studies, all participants received ifosfamide (Ferrari 2005; Fujieda 2009; Loebstein 1999; Oberlin 2009; Prasad 1996; Rossi 1994; Rossi 1994a; Rossi 1994b; Rossi 1997; Rossi 1999; Skinner 2010; Stohr 2007; von Schweinitz 1997). Median cumulative dose varied between 10 g/m2 (Patzer 2001) and 106 g/m2 (Skinner 2010) in 19 studies and was not reported in 12 studies.

Radiotherapy was used in the treatment regimen of at least 1736 participants and in 41 of the 57 studies. Four studies did not include participants who received radiotherapy, and prescription of radiotherapy was unclear in 12 studies. Radiotherapy included solely total body irradiation (TBI) in 5 studies (Frisk 2002; Frisk 2007; Patzer 2001; Trahair 2007; Van Why 1991) and solely abdominal irradiation in 25 studies. Four studies included both participants treated with TBI and participants treated with abdominal irradiation (Skinner 2010; Hoffmeister 2010; Laverdiere 2005; Schell 1995), and the field was not mentioned in seven other studies. Median doses ranged between 7.5 Gy and 13.2 Gy for the TBI group and between 15 Gy and 45 Gy for the abdominal irradiation group. Eighteen studies did not report the radiation dose.

A total of 40 studies included nephrectomised participants, 10 studies did not and in seven studies, this information was unclear. In most (24) of the 40 studies, 100% of the included participants were treated with a nephrectomy (Aronson 2011; Breslow 2005; Chevallier 1997; Cozzi 2005; de Graaf 1996; Di Tullio 1996; Finklestein 1993; Geenen 2010; Indolfi 2001; Kantor 1989; Kubiak 2004; Makipernaa 1991; Mancini 1996; Mpofu 1992; Othman 2002; Paulino 2000; Schell 1995; Srinivas 1998; Stefanowicz 2010; Stefanowicz 2011; Trobs 2001; Van Dijk 2010; Weirich 2004; Wikstad 1986). In all but one of these 24 studies, nephrectomy was performed for WT. Eight studies mentioned that they also included participants who underwent bilateral surgery in cases of bilateral disease (Aronson 2011; Breslow 2005; Hamilton 2011; Kantor 1989; Mancini 1996; Paulino 2000; Trobs 2001; Weirich 2004).

In 45 of the 57 studies, other chemotherapeutics were described; 12 studies did not report on other treatments. Types of other chemotherapy varied widely between studies; detailed descriptions per study can be found in the Characteristics of included studies.

We divided the included studies into subgroups on the basis of the combination of treatments described in the paper, as the five different included treatments can be given in various combinations. When a study included at least one participant who was given a certain treatment, we considered the study to include participants with that treatment. When it was unclear whether a study prescribed a certain treatment, we considered the study to exclude participants with that treatment. The subgroups and the studies per subgroup are provided in Table 2.

Table 2. Treatment subgroups
  1. Studies had to include at least one participants with a certain treatment to be considered, including participants with that specific treatment. When it was unclear whether a study prescribed, a certain treatment we considered the study to exclude participants with that treatment.

Treatments included in studyAmount of studiesIncluded studies
Cisplatin, carboplatin, ifosfamide, radiotherapy and nephrectomy5 Bardi 2004; Bolling 2010; Laverdiere 2005; Patzer 2001; Schell 1995
Cisplatin, carboplatin, ifosfamide and radiotherapy2 Stohr 2007; Stohr 2007a
Cisplatin, carboplatin, ifosfamide and nephrectomy1 Stefanowicz 2009
Cisplatin, carboplatin and ifosfamide1 Fujieda 2009
Cisplatin, carboplatin, radiotherapy and nephrectomy2 Mancini 1996; Skinner 2009
Cisplatin, carboplatin and radiotherapy1 Trahair 2007
Cisplatin, ifosfamide, radiotherapy and nephrectomy6 Cardous-Ubbink 2010; Chevallier 1997; Di Tullio 1996; Loebstein 1999; Rossi 1993; Rossi 1999
Cisplatin, ifosfamide and nephrectomy2 Rossi 1994; Rossi 1994a
Cisplatin and ifosfamide3 Ferrari 2005; Rossi 1994b; von Schweinitz 1997
Cisplatin1 Brock 1991
Carboplatin, ifosfamide, radiotherapy and nephrectomy3 Stefanowicz 2011; Trobs 2001; Weirich 2004
Carboplatin2 English 1999; Bergeron 2005
Ifosfamide, radiotherapy and nephrectomy4 Geenen 2010; Hamilton 2011; Paulino 2000; Sasso 2010
Ifosfamide and radiotherapy2 Oberlin 2009; Skinner 2010
Ifosfamide and nephrectomy1 Kubiak 2004
Ifosfamide2 Prasad 1996; Rossi 1997
Radiotherapy and nephrectomy13 Aronson 2011; de Graaf 1996; Finklestein 1993; Hoffmeister 2010; Indolfi 2001; Kantor 1989; Makipernaa 1991; Mpofu 1992; Othman 2002; Srinivas 1998; Stefanowicz 2010; Van Dijk 2010; Wikstad 1986
Nephrectomy3 Breslow 2005; Cosentino 1993; Cozzi 2005
Radiotherapy3 Frisk 2002; Frisk 2007; Van Why 1991

Outcome definitions

A total of 225 adverse renal outcomes were reported in the 57 studies. As profound heterogeneity was noted in the reported outcome measurements, we limited this review to the following outcome parameters: CKD/renal insufficiency, (estimated) GFR, proteinuria, serum phosphate, tubular phosphate parameters, serum magnesium and blood pressure. Even in these selected outcome measurements, great differences were observed in defined cut-off points for abnormal test results. Also, studies differed in reporting dichotomous or continuous outcome variables.

Chronic kidney disease/renal insufficiency
Ten studies reported only the prevalence of (chronic) renal insufficiency or end-stage renal disease without specifying the cut-off value used to assess the GFR (Aronson 2011; Bardi 2004; Breslow 2005; Cosentino 1993; Geenen 2010; Hamilton 2011; Laverdiere 2005; Paulino 2000; Sasso 2010; Stefanowicz 2011).

(Estimated) glomerular filtration rate
(Estimated) GFR was the most frequently assessed outcome parameter (32 studies). However, great methodological variation was noted in the assessment of this outcome parameter. Studies assessed the GFR directly by 51Cr-EDTA clearance (Brock 1991; English 1999; Frisk 2002; Frisk 2007; Makipernaa 1991; Skinner 2009; Skinner 2010), inulin clearance (Chevallier 1997; Patzer 2001; Schell 1995; Wikstad 1986), Tc-99m clearance (Srinivas 1998; Stefanowicz 2011) or 125-I-iothalamate clearance (de Graaf 1996), or they used GFR estimation formulae, including the Schwartz formula (Bergeron 2005; Hoffmeister 2010; Kubiak 2004; Mpofu 1992; Oberlin 2009; Rossi 1993; Rossi 1994; Rossi 1994a; Rossi 1994b; Stefanowicz 2009; Stefanowicz 2010; Stefanowicz 2011; Stohr 2007a), the Cockroft-Gault formula (Oberlin 2009), the Modification of Diet in Renal Disease (MDRD) formula (Hoffmeister 2010), the Filler formula (Stefanowicz 2009; Stefanowicz 2011) or the Counahan formula (Bardi 2004). Two studies used more than one method to assess the GFR: Stefanowicz 2009 compared the Schwartz and Filler formulae for GFR estimation, whereas Stefanowicz 2011 compared Tc-99m clearance with the Filler formula, the old Schwartz formula and the new Schwartz formula. Five studies investigated the GFR but did not mention the assessment methods used (Di Tullio 1996; Ferrari 2005; Indolfi 2001; Mancini 1996; von Schweinitz 1997). Studies also varied in the defined cut-off point for glomerular dysfunction: values of 90, 80 and 70 mL/min/1.73m2 were used.

Proteinuria
Proteinuria was reported in 19 manuscripts and was investigated by a variety of urinary protein measurements. Five studies reported on microalbuminuria (Bardi 2004; Di Tullio 1996; Indolfi 2001; Mancini 1996; Srinivas 1998) and used cut-off points of 20 mg/24 h (Di Tullio 1996; Indolfi 2001), 30 mg/24 h (Srinivas 1998) or 20 mg/L (Bardi 2004; Mancini 1996). Seven studies reported urinary albumin-to-creatinine ratios (Bergeron 2005; Chevallier 1997; Cozzi 2005; Mpofu 1992; Rossi 1994b; Stefanowicz 2009; Stefanowicz 2011) and used cut-off points of 2 g/mol (Bergeron 2005; Chevallier 1997; Cozzi 2005), 20 mg/mmol (Mpofu 1992), 30 mg/g (Stefanowicz 2011) and 38 mg/g (Rossi 1994b). One study did not mention a cut-off value for the urinary albumin-to-creatinine ratio (Stefanowicz 2009). Four studies reported urinary albumin levels (Makipernaa 1991; Patzer 2001; Stefanowicz 2011; Wikstad 1986). Makipernaa 1991 used a cut-off value of 20 mg/24 h, Stefanowicz 2011 used 20 mg/L, Patzer 2001 used age-specific reference values and Wikstad 1986 did not present a cut-off value. Two studies reported more than one proteinuria measure: Bardi 2004 reported on urine dipsticks and microalbuminuria in 24-hour urine samples, whereas Stefanowicz 2011 reported on the urinary albumin-to-creatinine ratio and the urinary albumin level. Four studies did not further specify how proteinuria was measured (Fujieda 2009; Laverdiere 2005; Oberlin 2009; Schell 1995), and two studies did not provide a prevalence for proteinuria (Patzer 2001; Wikstad 1986).

Serum phosphate/hypophosphataemia
Seven studies reported on serum phosphate levels (Frisk 2007; Fujieda 2009; Mancini 1996; Oberlin 2009; Othman 2002; Schell 1995; Skinner 2010). The cut-off value for hypophosphataemia was age-dependent in two studies (Frisk 2007; Oberlin 2009), < 0.90 mmol/L in one study (Skinner 2010) and < 2.9 mg/dL in one study (Fujieda 2009); it was not mentioned in the last three (Mancini 1996; Othman 2002; Schell 1995).

Tubular phosphate regulation parameters
Eleven studies reported on an outcome measure related to tubular phosphate regulation. Four studies reported on the renal tubular phosphate threshold (Bergeron 2005; Ferrari 2005; Oberlin 2009; Skinner 2010). The low cut-off value for the renal tubular phosphate threshold was < 1.0 mmol/L in two studies (Bergeron 2005; Ferrari 2005) and < 0.99 mmol/L in one study (Skinner 2010), and in another study a cut-off value of < -2 standard deviations (SD) below the expected tubular phosphate threshold for age was used (Oberlin 2009). Seven studies reported the fractional phosphate reabsorption (Chevallier 1997; Rossi 1993; Rossi 1994; Rossi 1994a; Rossi 1994b; Rossi 1997; Rossi 1999). Two studies compared the fractional phosphate reabsorption with previously established normal data (Rossi 1993; Rossi 1994), two studies used < 1.07 mmol/L as a cut-off value (Rossi 1994a; Rossi 1994b), one study used < 1.0 mmol/L (Rossi 1999) and two studies did not report a cut-off value (Chevallier 1997; Rossi 1997).

Serum magnesium/hypomagnesaemia
Hypomagnesaemia was assessed by serum magnesium measurements in 8 studies (Bergeron 2005; Brock 1991; English 1999; Fujieda 2009; Oberlin 2009; Othman 2002; Skinner 2009; Stohr 2007a). Two studies used an age-dependent cut-off to define hypomagnesaemia (Brock 1991; Skinner 2009), two studies used a cut-off of < 0.70 mmol/L (Oberlin 2009; Stohr 2007a), Fujieda 2009 used < 1.9 mg/dL, Othman 2002 used < 0.80 mmol/L and two studies did not report the used cut-off value (Bergeron 2005; English 1999).

Blood pressure
Twenty-six studies investigated the blood pressure of CCS (Bergeron 2005; Cardous-Ubbink 2010; Chevallier 1997; Cozzi 2005; Di Tullio 1996; Finklestein 1993; Geenen 2010; Hoffmeister 2010; Indolfi 2001; Kantor 1989; Kubiak 2004; Laverdiere 2005; Makipernaa 1991; Mancini 1996; Mpofu 1992; Paulino 2000; Sasso 2010; Schell 1995; Srinivas 1998; Stefanowicz 2009; Stefanowicz 2010; Stefanowicz 2011; Trobs 2001; Van Dijk 2010; Van Why 1991; Wikstad 1986). Twenty-four studies reported hypertension prevalence, and the other two studies provided only mean/median blood pressure measurements (Mancini 1996; Wikstad 1986).

Composite outcome measures
Five studies reported on composite outcome measures that included at least one of the six outcome measures mentioned previously (Bolling 2010; Loebstein 1999; Stohr 2007; Weirich 2004; von Schweinitz 1997). Three of those used a composite outcome to capture general renal function by defining their own grading system (Bolling 2010; Loebstein 1999) or by using a set of predefined criteria (Weirich 2004). Two studies used a composite outcome to report on renal tubular function (Stohr 2007; von Schweinitz 1997). Both studies used their own definitions, combining hypophosphataemia, glycosuria and proteinuria (Stohr 2007) or tubular phosphate reabsorption and amino acid reabsorption (von Schweinitz 1997). Detailed descriptions of the composite outcome measures can be found in the Characteristics of included studies table.

Risk of bias in included studies

Data on the risk of bias of the included studies are reported in the Characteristics of included studies section and are summarised in Figure 1 and Figure 2. The criteria for the risk of bias assessment are listed in Table 1.

Figure 1.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

To determine the internal validity of the included studies, we assessed the risks of selection bias, attrition bias, detection bias and confounding.

Risk of selection bias was low in only 19 of the 57 (33.3%) included studies (Bolling 2010; Chevallier 1997; de Graaf 1996; Finklestein 1993; Frisk 2002; Geenen 2010; Hamilton 2011; Kubiak 2004; Loebstein 1999; Paulino 2000; Rossi 1999; Sasso 2010; Skinner 2009; Skinner 2010; Trahair 2007; Van Dijk 2010; Van Why 1991; von Schweinitz 1997; Weirich 2004). These studies provided enough information for the review authors to conclude that they consisted of a representative study group, including > 90% of the original cohort or a random sample of the original cohort. Twenty studies (35.1%) included < 90% of the original cohort, and this group did not represent a random sample, and the other 18 studies (31.6%) did not report the size of their original cohort, so the risk of selection bias could not be assessed for these studies.

Most included studies (46/57; 80.7%) had good follow-up, defined as assessment of outcome parameters in > 90% of the study group. For four additional studies (7%), follow-up was adequate and was defined as an outcome assessment for 60% to 90% of the study group (Bolling 2010; Finklestein 1993; Indolfi 2001; von Schweinitz 1997). No study assessed the outcome parameter in < 60% of the study group. The risk of attrition bias was unclear in seven other studies (12.3%) that did not mention the size of the study group or the number of participants who underwent an outcome assessment (Breslow 2005; Cosentino 1993; Hamilton 2011; Laverdiere 2005; Loebstein 1999; Van Dijk 2010; Weirich 2004).

The risk of detection bias, defined as outcomes assessment by blinded investigators, could not be determined in any of the 57 studies (0%). Although most of the reported outcomes were not at risk for detection bias, as they represent only objective laboratory measurements, some outcomes (e.g. blood pressure, echographic measurements) could have been influenced by non-blinded outcome assessors.

Forty-three studies assessed possible risk factors for the development of early or late renal adverse effects (75.4%). Only 11 of these 43 studies (25.6%) adjusted their risk factor analyses for potential confounders (Cardous-Ubbink 2010; Frisk 2002; Geenen 2010; Hoffmeister 2010; Kantor 1989; Oberlin 2009; Rossi 1994a; Stohr 2007; Stohr 2007a; Van Dijk 2010; Van Why 1991). One of these 11 studies did not report potential risk factors but did adjust for potential confounders in their analysis (Van Why 1991). Thirty-one of the 43 studies (72.1%) that did perform some risk factor analysis did not adjust for possible confounders and hence were scored as having a high risk of potential bias. For only one of the 43 studies (2.3%) that assessed potential risk factors, it was unclear whether the analyses were adjusted for confounders (English 1999). The remaining fourteen studies did not assess and hence could not correct for confounding (Breslow 2005; Cosentino 1993; Frisk 2007; Hamilton 2011; Kubiak 2004; Laverdiere 2005; Loebstein 1999; Othman 2002; Paulino 2000; Srinivas 1998; Trahair 2007; Trobs 2001; von Schweinitz 1997; Weirich 2004). This means that the risk for confounding could not be excluded for 46 of 57 studies (80.7%).

To determine the external validity, we assessed four aspects of possible reporting bias in the included studies.

As a first requirement, studies had to adequately describe the treatment regimen, including cumulative doses of the chemotherapeutic agents of interest (cisplatin, carboplatin and/or ifosfamide), as well as (cumulative) doses of radiotherapy, as long as these therapies were part of the study's main treatment protocol. Thirty-one studies (54.4%) met this criterion. Twenty-six studies (45.6%) provided partial or no information on the treatment regimen provided and were regarded to have a high risk of reporting bias regarding the included study group (Aronson 2011; Bardi 2004; Bolling 2010; Breslow 2005; Cardous-Ubbink 2010; Cosentino 1993; Finklestein 1993; Fujieda 2009; Geenen 2010; Hamilton 2011; Kantor 1989; Kubiak 2004; Mancini 1996; Mpofu 1992; Othman 2002; Prasad 1996; Rossi 1994b; Sasso 2010; Srinivas 1998; Stefanowicz 2010; Stefanowicz 2011; Trobs 2001; Van Dijk 2010; Van Why 1991; von Schweinitz 1997; Weirich 2004).

The second requirement was mention of the follow-up duration for the study group of interest. This was reported better than the treatment regimen, with only four studies (7.0%) not reporting the follow-up period (Cosentino 1993; Finklestein 1993; Othman 2002; Trobs 2001). All of the other 53 studies (93.0%) mentioned a minimum, a median or a mean follow-up period.

Outcome definitions had to be objective and precise and had to include a description of the upper or lower limits of the reported outcome. Studies had to provide their outcome definitions for more than 50% of their included outcomes. Although the outcome definitions were highly heterogeneous, outcomes were described objectively and precisely in 38 of the 57 studies (66.7%). The other 19 studies (33.3%) did not provide outcome definitions for most of their included outcomes, or the given definitions were not objective and precise (Bardi 2004; Bolling 2010; Chevallier 1997; Cosentino 1993; De Graaf 1996; English 1999; Hamilton 2011; Indolfi 2001; Loebstein 1999; Mancini 1996; Othman 2002; Paulino 2000; Rossi 1997; Sasso 2010; Schell 1995; Stohr 2007; Trobs 2001; von Schweinitz 1997; Wikstad 1986).

The last criterion for the external validity assessment was that studies had to provide relevant risk measures for more than 90% of the study group. Forty-three studies (75.4%) investigated potential risk factors for the development of early or late renal adverse effects. Of these 43 studies, seven failed to provide any relevant risk measure for the assessed risk factors (Bergeron 2005; Bolling 2010; Ferrari 2005; Finklestein 1993; Rossi 1993; Sasso 2010; Wikstad 1986). One other study did perform multivariate logistic regression but did not present any relevant risk measures (Van Why 1991). This means that 35 studies (61.4%) had a well-defined risk estimation and eight studies (14.0%) had a high risk of bias regarding the definition of their statistical analyses. Fourteen studies (24.6%) did not investigate potential risk factors and hence were scored as having an unclear risk of bias.

Effects of interventions

Chronic kidney disease/renal insufficiency

Chronic renal disease (or renal insufficiency) was reported by ten studies (Aronson 2011; Bardi 2004; Breslow 2005; Cosentino 1993; Geenen 2010; Hamilton 2011; Laverdiere 2005; Paulino 2000; Sasso 2010; Stefanowicz 2011). Six studies specifically evaluated renal function in WT survivors treated with a unilateral nephrectomy and found prevalences ranging from 0.5% to 18.8% (Breslow 2005; Cosentino 1993; Geenen 2010; Paulino 2000; Sasso 2010; Stefanowicz 2011). The study by Geenen et al also assessed CKD/renal insufficiency in 63 healthy siblings of survivors and found a prevalence of 0% (Geenen 2010). Three studies investigated renal function after a bilateral WT and reported a prevalence range for renal insufficiency of 10.7% to 32% (Aronson 2011; Breslow 2005; Hamilton 2011). Breslow et al also investigated the prevalence of end-stage renal disease (ESRD) in unilateral and bilateral nephrectomised WT survivors with specific tumour disposition syndromes and genitourinary malformations, which ranged from 3.2% to 70% (Breslow 2005). The study by Laverdiere et al reported on CKD as defined by the Common Terminology Criteria for Adverse Events (CTCAE) criteria in 63 survivors of neuroblastoma and found only 1 participant with mild CKD (Laverdiere 2005). The study by Bardi et al reported that one of the 115 included survivors had been put on chronic haemodialysis for end-stage renal failure (Bardi 2004). Pooling of data regarding CKD/renal insufficiency proved not feasible because of the high heterogeneity (I2 = 94%). See also Analysis 1.1 and Figure 3.

Figure 3.

Forest plot of comparison: 1 Prevalence of renal dysfunction, outcome: 1.1 Chronic kidney disease/renal insufficiency as defined by authors.

(Estimated) glomerular filtration rate
Twelve studies used a cut-off value of 90 mL/min/1.73 m2 to assess the (estimated) GFR. Reported prevalences ranged from 2.3% in CCS treated with cisplatin, carboplatin, ifosfamide or nephrectomy (Stefanowicz 2009) up to 50% in CCS treated with ifosfamide and radiotherapy involving the kidney region (Skinner 2010). Because of profound heterogeneity (I2 = 91%) pooling of study results was not feasible. Only Oberlin et al investigated possible risk factors for glomerular dysfunction defined as GFR < 90 in multivariate analyses (Oberlin 2009). They showed that older age at treatment and longer follow-up duration were significantly associated with glomerular dysfunction, whilst no relationship could be established between GFR and higher cumulative ifosfamide dose. See also Analysis 1.2, Figure 4 and Table 3.

Figure 4.

Forest plot of comparison: 1 Prevalence of renal dysfunction, outcome: 1.2 (Estimated) glomerular filtration rate < 90 ml/min/1.73m2. The outcome presented for Stefanowicz 2009 is the estimated GFR using the Schwartz formula, for Stefanowicz 2011 the GFR measured by Tc-99m clearance.

Table 3. Risk factors from multivariable analyses on diminished (estimated) glomerular filtration rate
  1. Abbreviations: 51-Cr: 51-chromium; BMT: bone marrow transplant; CI: confidence interval; CTCAE: Common Terminology Criteria for Adverse Events; GFR: glomerular filtration rate; n/m: not mentioned; RR: relative risk; TBI: total body irradiation.

StudyStudy populationOutcome definitionRisk factorP < 0.05Extent of the effect
Frisk 2002Survivors treated with TBIGFR by 51-Cr clearanceConcomitant treatment with aminoglycosides and vancomycin+Beta: -32 mL/min/1.73 m2 (95% CI: -54 to -10)
 Survivors treated with TBIGFR by 51-Cr clearanceAge-n/m
 Survivors treated without TBIGFR by 51-Cr clearanceConcomitant treatment with aminoglycosides and vancomycin-n/m
Van Why 1991Bone marrow transplant survivorsRenal insufficiency defined as doubling of baseline serum creatinine concentration OR creatinine clearance <50 mL/min/1.73 m2 (Schwartz formula)Cyclosporin A use beyond day 60, amphotericin B use, conditioning with TBI+n/m
 Bone marrow transplant survivorsRenal insufficiency defined as doubling of baseline serum creatinine concentration OR creatinine clearance <50 mL/min/1.73 m2 (Schwartz formula)Conditioning with chemotherapy, renal insufficiency in first 60 days post-BMT-n/m
Oberlin 2009Survivors treated with ifosfamideGFR < 90 mL/min/1.73 m2Higher cumulative ifosfamide dose-RR: 1.02 (95% CI 0.99 to 1.04)
 Survivors treated with ifosfamideGFR < 90 mlL/min/1.73 m2Older age at treatment (per year)+RR: 1.08 (95% CI 1.00 to 1.17)
 Survivors treated with ifosfamideGFR < 90 mL/min/1.73 m2Longer interval from therapy to investigation (per year)+RR: 1.09 (95% CI 1.01 to 1.19)

Seven studies used a cut-off value of 80 mL/min/1.73 m2 to assess the GFR. Reported prevalences ranged from 0.0% in CCS treated with nephrectomy and radiotherapy involving the kidney region (Srinivas 1998) to 42.5% in CCS treated with cisplatin (Brock 1991). Heterogeneity made it impossible to pool these study results as well (I2 = 79%). See also Analysis 1.3 and Figure 5.

Figure 5.

Forest plot of comparison: 1 Prevalence of renal dysfunction, outcome: 1.3 (Estimated) glomerular filtration rate < 80 mL/min/1.73 m2.

Only one study used a cut-off value of 70 mL/min/1.73 m2 to assess GFR. Frisk et al found a prevalence of 27% in 26 survivors treated with TBI as a conditioning regimen for an autologous bone marrow transplantation (Frisk 2002). Combined treatment with aminoglycosides and intravenous vancomycin was significantly related to the decrease in GFR among survivors treated with TBI, whereas age had no influence. In survivors treated without TBI, no relationship was observed between concomitant treatment with aminoglycosides and intravenous vancomycin and a lower GFR. See also Analysis 1.4, Figure 6 and Table 3.

Figure 6.

Forest plot of comparison: 1 Prevalence of renal dysfunction, outcome: 1.4 (Estimated) glomerular filtration rate < 70 mL/min/1.73 m2.

One other study used a GFR cut-off value of 50 mL/min/1.73 m2. Van Why et al investigated survivors treated with a bone marrow transplant and found a prevalence of 14% (Van Why 1991). In this study, treatment with TBI, amphotericin B and cyclosporin A after 60 days was an independent predictor of late renal insufficiency, whilst early renal insufficiency and chemotherapy conditioning had no predictive value. See also Analysis 1.5, Figure 7 and Table 3.

Figure 7.

Forest plot of comparison: 1 Prevalence of renal dysfunction, outcome: 1.5 (Estimated) glomerular filtration rate < 50 mL/min/1.73 m2.

One study did not report any exact cut-off values for GFR but used the CTCAE v3 grading criteria to assess glomerular function impairment in sarcoma survivors treated with cisplatin and/or carboplatin (Stohr 2007a). However, estimation of the GFR using the Schwartz formula proved to be inappropriate in this cohort, especially during the first year after treatment, as > 40% of all survivors had an estimated GFR above the upper limit of normal, indicating considerable overestimation of the GFR.

Four studies reported a mean GFR at follow-up in comparison with controls (Bardi 2004; Schell 1995; Stefanowicz 2009; Wikstad 1986). All four studies investigated WT survivors who received a unilateral nephrectomy. The most profound decrease in GFR was note by Bardi et al after a median follow-up of 7 years (Bardi 2004). WT survivors had a mean GFR of 71 mL/min/1.73 m2 at follow-up-a decrease of 61 mL/min/1.73 m2 in comparison with healthy controls (P < 0.05). Schell et al used a control group of only six children who received a unilateral nephrectomy for non-malignant disease, and found an insignificant difference of 6 mL/min/1.73 m2 (Schell 1995). In the study by Stefanowicz et al, it was possible to compare survivors with oncohaematological disease treated without potentially nephrotoxic therapy with survivors treated for WT or other solid tumours treated with potentially nephrotoxic therapy, who had a mean difference in GFR of -20.0 mL/min/1.73 m2(Stefanowicz 2009). Wikstad et al reported a similar difference between WT survivors and healthy controls (-18.9 mL/min/1.73 m2), as well as a significant difference between WT survivors and children nephrectomised for hydronephrosis (-10.6 mL/min/1.73 m2; Wikstad 1986). Pooling of these study results was not feasible (I2 = 86%). See also Analysis 2.1 and Figure 8.

Figure 8.

Forest plot of comparison: 2 Mean glomerular filtration rate in mL/min/1.73 m2 at least 1 year after diagnosis, outcome: 2.1 Mean (estimated) GFR in studies that included internal or healthy controls. The outcome presented for Stefanowicz 2009 is the estimated GFR using the Schwartz formula.

Three studies investigated risk factors for glomerular dysfunction whilst correcting for possible confounders (Frisk 2002; Oberlin 2009; Van Why 1991). Table 3 gives an overview of which risk factors were investigated and which were or were not significantly associated with GFR in multivariate analyses.

Proteinuria
The prevalence of proteinuria was reported in 17 studies (Bardi 2004; Bergeron 2005; Chevallier 1997; Cozzi 2005; Di Tullio 1996; Fujieda 2009; Indolfi 2001; Laverdiere 2005; Makipernaa 1991; Mancini 1996; Mpofu 1992; Oberlin 2009; Rossi 1994b; Schell 1995; Srinivas 1998; Stefanowicz 2009; Stefanowicz 2011). The lowest prevalence (0%) was found in a study focusing on carboplatin nephrotoxicity (Bergeron 2005), the highest prevalence (84%) in a study on renal function after nephrectomy for WT (Srinivas 1998). It should be noted that the 16 studies that reported proteinuria used 5 different methods of proteinuria assessment. Median follow-up duration varied from 1 to 19.2 years, and median age at follow-up varied widely, from 6 to 21.8 years. Because of high heterogeneity, it was not possible to pool results (I2 = 93%). No studies investigated risk factors for proteinuria whilst correcting for possible confounders. See also Analysis 1.6 and Figure 9.

Figure 9.

Forest plot of comparison: 1 Prevalence of renal dysfunction, outcome: 1.6 Proteinuria as defined by authors.

Serum phosphate/hypophosphataemia
Seven studies investigated serum phosphate levels (Frisk 2007; Fujieda 2009 Mancini 1996; Oberlin 2009; Othman 2002; Schell 1995; Skinner 2010). In four studies, the prevalence of hypophosphataemia was 0% (Frisk 2007; Mancini 1996; Othman 2002; Schell 1995). The studies by Oberlin et al and Skinner et al specifically evaluated ifosfamide toxicity after a follow-up duration of approximately 10 years and reported prevalences of 1.1% and 8.0%, respectively (Oberlin 2009; Skinner 2010). Fujieda et al also reported hypophosphataemia prevalence of 47.6% after ifosfamide (in combination with cisplatin or carboplatin) but after a much shorter median follow-up period of 14 months (Fujieda 2009). All hypophosphataemia prevalences are presented in Analysis 1.7 and Figure 10. No study used multivariate analysis to assess possible risk factors for hypophosphataemia. Again, variation in outcome definitions, study populations and follow-up durations resulted in profound heterogeneity (I2 = 90%), making pooling of results not feasible.

Figure 10.

Forest plot of comparison: 1 Prevalence of renal dysfunction, outcome: 1.7 Serum phosphate/hypophoshataemia as defined by the authors.

Tubular phosphate regulation parameters
Eleven studies investigated the phosphate reabsorption capacity of the renal tubuli, using fractional phosphate reabsorption or the tubular phosphate threshold as an outcome measure. Two studies found a relatively low prevalence of impaired tubular function of 3.3% and 0% (Bergeron 2005; Chevallier 1997). All other studies found a prevalence between 24.4% and 62.5% (see Analysis 1.8 and Figure 11). It should be noted that the five studies investigating tubular phosphate function by Rossi et al may have included the same participants in multiple studies (Rossi 1994; Rossi 1994a; Rossi 1994b; Rossi 1997; Rossi 1999). Again, variation in outcome definitions, study populations and follow-up durations resulted in profound heterogeneity (I2 = 90%), making pooling of results not feasible.

Figure 11.

Forest plot of comparison: 1 Prevalence of renal dysfunction, outcome: 1.8 Tubular phosphate regulation parameters as defined by the authors.

Two studies used multivariate regression analysis to analyse possible risk factors for tubular dysfunction (Oberlin 2009; Rossi 1994a). Oberlin et al found that the cumulative ifosfamide dose and the follow-up duration were significant predictors of the tubular phosphate threshold, whilst age at treatment was not significant (Oberlin 2009). Rossi et al performed stepwise logistic regression on a combined outcome (low phosphate reabsorption AND low amino acid reabsorption) in survivors treated with ifosfamide and found that concomitant treatment with cisplatin and a nephrectomy were significant risk factors (Rossi 1994a). Methotrexate, gentamicin, mesna and age had no influence. See Table 4 for additional details on the multivariate analyses.

Table 4. Risk factors from multivariable analyses on impaired tubular phosphate regulation parameters
  1. Abbreviations: CI: confidence interval; g/m2: gram/meter2; n/m: not mentioned; OR: odds ratio; SD: standard deviation.

StudyStudy populationOutcome definitionRisk factorP < 0.05Extent of the effect
Oberlin 2009Survivors treated with ifosfamideTubular phosphate thresholdHigher cumulative ifosfamide dose in g/m2+Beta: -0.0028 (SD 0.0012)
 Survivors treated with ifosfamideTubular phosphate thresholdLonger follow-up duration in years+Beta: -0.013 (SD 0.0036)
 Survivors treated with ifosfamideTubular phosphate thresholdOlder age at treatment in yearsBeta: -0.0047 (SD 0.0033)
Rossi 1994aSurvivors treated with ifosfamideLow phosphate reabsorption AND low amino acid reabsorptionConcomitant cisplatin+OR: 6.4 (95% CI 2.2 to 18.9)
 Survivors treated with ifosfamideLow phosphate reabsorption AND low amino acid reabsorptionNephrectomy+OR: 6.4 (95% CI 1.3 to 30.9)
 Survivors treated with ifosfamideLow phosphate reabsorption AND low amino acid reabsorptionMethothrexate, gentamycin, mesna, agen/m

Serum magnesium/hypomagnesaemia
Hypomagnesaemia prevalences in CCS were reported in eight studies (Bergeron 2005; Brock 1991; English 1999; Fujieda 2009; Oberlin 2009; Othman 2002; Stohr 2007a; Skinner 2009), as shown in Analysis 1.9 and Figure 12. The study of Skinner 2009 could not be included in Figure 12 because the number of tested participants was missing. Six of these eight studies included survivors treated with cisplatin and/or carboplatin (Bergeron 2005; Brock 1991; English 1999; Fujieda 2009; Stohr 2007a; Skinner 2009). The studies of Bergeron et al and English et al investigated survivors treated only with carboplatin as a potentially nephrotoxic agent and found prevalences of 0% and 4.4% after follow-up durations of 7 years and 1 year, respectively (Bergeron 2005; English 1999). The carboplatin-only subgroup of the study by Stohr et al revealed a similar prevalence of 3.3% after 1.9 years (Stohr 2007a), whilst Skinner et al reported a prevalence of 17% ten years after treatment (Skinner 2009). The studies by Stohr et al and Skinner et al also reported the prevalence of hypomagnesaemia in survivors treated with both cisplatin and carboplatin, which was 9% in both studies (Stohr 2007a; Skinner 2009). Hypomagnesaemia in survivors treated only with cisplatin was reported to be 2.3% (Stohr 2007a), 32% (Skinner 2009) and 29% (Brock 1991).

Figure 12.

Forest plot of comparison: 1 Prevalence of renal dysfunction, outcome: 1.7 Serum magnesium/hypomagnesaemia as defined by the authors. The study of Skinner 2009 was not included in the figure due to missing numbers of included survivors.

Two additional studies investigated serum magnesium as an outcome measure for tubular function in participants treated without cisplatin and/or carboplatin (Oberlin 2009; Othman 2002). Oberlin et al investigated the nephrotoxic effects of ifosfamide and found 2 of 171 survivors (1.2%) to be hypomagnesaemic (Oberlin 2009). Othman et al investigated serum magnesium in WT survivors treated with nephrectomy and radiotherapy (in 15/31 survivors only) and found a prevalence of 25.8% (Othman 2002). As with all other outcomes, it was not possible to pool the results of these studies because of heterogeneity (I2 = 79%).

Only one study investigated possible risk factors for hypomagnesaemia whilst taking into account appropriate measures to prevent confounding (Stohr 2007a). Investigators found that sarcoma survivors treated with carboplatin (P = 0.0102) and/or cisplatin (P = 0.0005) had significantly lower serum magnesium levels than sarcoma survivors treated without these therapies. They did not find a significant effect of abdominal radiotherapy, ifosfamide or follow-up duration nor any interaction of these risk factors with time (see also Table 5).

Table 5. Risk factors from multivariable analyses on serum magnesium / hypomagnesaemia
  1. Abbreviations: mmol/L: millimols/litre; n/m: not mentioned; vs: versus.

StudyStudy populationOutcome definitionRisk factorP < 0.05Extent of the effect
Stohr 2007aSarcoma survivorsSerum magnesiumCisplatin treatment+Mean serum magnesium: 0.86 vs 0.82 mmol/L
   Carboplatin treatment+Mean serum magnesium: 0.86 vs 0.82 mmol/L
   Abdominal irradiationMean serum magnesium: 0.84 vs 0.84 mmol/L
   Longer follow-up durationn/m
   Ifosfamide treatmentn/m

Blood pressure
Twenty-four studies reported the prevalence of hypertension (high blood pressure as defined by the authors) in survivors treated with potentially nephrotoxic therapy (Bergeron 2005; Cardous-Ubbink 2010; Chevallier 1997; Cozzi 2005; Di Tullio 1996; Finklestein 1993; Geenen 2010; Hoffmeister 2010; Indolfi 2001; Kantor 1989; Kubiak 2004; Laverdiere 2005; Makipernaa 1991; Mpofu 1992; Paulino 2000; Sasso 2010; Schell 1995; Srinivas 1998; Stefanowicz 2009; Stefanowicz 2010; Stefanowicz 2011; Trobs 2001; Van Dijk 2010; Van Why 1991). Prevalence of hypertension ranged from 0% (Chevallier 1997; Di Tullio 1996; Indolfi 2001; Schell 1995; Srinivas 1998) to 18.2% (Kubiak 2004). Especially studies that included only radiotherapy and nephrectomy as potentially nephrotoxic treatments investigated hypertension (see Analysis 1.10 and Figure 13). One study compared hypertension prevalence between 62 WT survivors and 69 healthy sibling controls and found that survivors treated with radiotherapy and chemotherapy had a significantly higher hypertension prevalence than their siblings (prevalence 21.6% vs 1.4%; Geenen 2010). Overall the differences in outcome definition, study population and follow-up duration caused profound heterogeneity, making it impossible to pool the results (I2 = 89%).

Figure 13.

Forest plot of comparison: 1 Prevalence of renal dysfunction, outcome: 1.10 Blood pressure.

Four studies reported risk factors for hypertension as a result of multivariate analysis (Cardous-Ubbink 2010; Geenen 2010; Hoffmeister 2010; Kantor 1989). Table 6 lists the risk factors reported in these studies. Two studies that investigated a higher body mass index in relation to hypertension found it to be a significant risk factor (Cardous-Ubbink 2010; Hoffmeister 2010). All other investigated risk factors were assessed in a single study only, or inconsistent results were reported between studies. One determinant significantly decreased the risk of hypertension: previous hepatitis C infection (hazard ratio 0.52, 95% confidence interval (CI) 0.3 to 0.9; Hoffmeister 2010). All other significant risk factors increased the risk of hypertension.

Table 6. Risk factors from multivariable analyses on blood pressure
  1. Abbreviations: (a/c)GVHD: (acute/chronic) graft versus host disease; ALL: acute lymphoblastic leukaemia; BMI: body mass index; BP: blood pressure; CCS: childhood cancer survivors; CI: confidence interval; CTCAE: Common Terminology Criteria for Adverse Events; HCT: hematopoietic stem cell transplant; HLA: human leukocyte antigen; HR: hazard ratio; kg/m2: kilogram/meter2; mmHg: millimetre mercury; n/m: not mentioned; OR: odds ratio; RT: radiotherapy; SOS: sinusoidal obstruction syndrome.

StudyStudy populationOutcome definitionRisk factorP < 0.05Extent of the effect
Cardous-Ubbink 2010Overall cohort of long-term CCSSystolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg at least at three consecutive visitsBody mass index ≥ 25+OR 3.95 (95% CI 1.71 to 9.09)
 Overall cohort of long-term CCSSystolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg at least at three consecutive visitsCisplatin, cyclophosphamide, ifosfamide, other chemotherapy, abdominal RT, cranial RT 
Hoffmeister 2010Long-term HCT survivorsSystolic or diastolic BP ≥ 140/90 mmHg for adults or > 95th percentile for age, sex and height in childrenAcute kidney injury+HR 2.53 (95% CI: 1.7 to 3.7)
 Long-term HCT survivorsSystolic or diastolic BP ≥ 140/90 mmHg for adults or > 95th percentile for age, sex and height in childrenTotal body irradiation+HR 2.06 (95% CI 1.3 to 3.3)
 Long-term HCT survivorsSystolic or diastolic BP ≥ 140/90 mmHg for adults or > 95th percentile for age, sex and height in childrenHepatitis C infection+HR 0.52 (95% CI: 0.3 to 0.9)
 Long-term HCT survivorsSystolic or diastolic BP >= 140/90 mmHg for adults or > 95th percentile for age, sex and height in childrenStam cell donor type+

Related: HR 1.00

Unrelated: HR 1.79 (95% CI 1.0 to 3.2)

Autologous: HR 2.39 (95% CI 1.3 to 4.4)

 Long-term HCT survivorsSystolic or diastolic BP >= 140/90 mmHg for adults or > 95th percentile for age, sex and height in childrenObesity (BMI >= 30 kg/m2 for adults and >= 95th percentile of normal for children)+HR 3.98 (95% CI 2.3 to 6.8)
 Long-term HCT survivorsSystolic or diastolic BP >= 140/90 mmHg for adults or > 95th percentile for age, sex and height in children.Growth hormone therapy+HR 1.58 (95% 1.0 to 2.5)
 Long-term HCT survivorsSystolic or diastolic BP >= 140/90 mmHg for adults or > 95th percentile for age, sex and height in childrenSex, race/ethnicity, family history of hypertension, single kidney, cranial and abdominal irradiation, pretransplant nephrotoxic chemotherapy agents, age at transplantation, diagnosis at transplantation, degree of HLA-antigen mismatching between donor and recipient, SOS, cyclosporine (CsA)/tacrolimus for aGVHD prophylaxis, aGVHD grade (0 to I vs II to IV), cGVHD, cGVHD therapy, duration of cGVHD therapy, smoking history, diabetes and growth hormone deficiency 
Kantor 1989Long-term survivors of a renal tumour160 mmHg systolic or > 95 mmHg diastolic or receiving treatment for hypertensionRadiation dose, use dactinomycin or a combination of the two 
Geenen 2010Long-term survivors of Wilms' tumour and ALLSystolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHgOlder age at screening (per year)+OR 1.30 (95% CI 1.09 to 1.54)
 Long-term survivors of Wilms' tumour and ALLSystolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHgAbdominal irradiation+OR 30.14 (95% CI 3.98 to 228.44)
 Long-term survivors of Wilms' tumour and ALLSystolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHgSex, family history of premature cardiovascular disease, cranial radiotherapy, alkylating agents, anthracyclines 

Composite outcome measures
Three studies reported on the prevalence of renal toxicity by using a composite outcome that incorporated one of the included outcome measures for this review (Bolling 2010; Loebstein 1999; Weirich 2004). Bolling et al assessed radiation nephropathy in 74 survivors and found 5 of 74 (6.8%) survivors with signs of renal toxicity (Bolling 2010). The study by Loebstein et al investigated ifosfamide toxicity in 174 participants after a mean follow-up duration of 5.3 years (Loebstein 1999); 7 of 174 had developed severe nephrotoxicity, of whom 2 survivors showed progressive deterioration of GFR followed by ESRD. One study used the CTCAE v2 criteria to assess renal and urinary dysfunction and found 28 of 385 (7.2%) WT survivors with toxicity. Fifteen survivors (3.9%) needed treatment for renal or urinary system impairment (Weirich 2004). Two studies used a composite outcome measure to report on renal tubular function. Stohr et al assessed ifosfamide toxicity in 593 German sarcoma survivors and reported on the prevalence of tubular dysfunction, defined as having at least two of the three following criteria: hypophosphataemia, glycosuria and/or proteinuria (Stohr 2007). Eighteen of the 593 survivors (30.4%) were diagnosed with a tubulopathy after a median follow-up period of 12.6 months. Von Schweinitz et al defined a tubulopathy as impaired tubular phosphate reabsorption and/or impaired amino acid reabsorption (von Schweinitz 1997), although cut-off values for both measurements were not stated. Of 41 assessed hepatoblastoma survivors, five had a mild tubulopathy (12%) and two had a more severe tubulopathy (5%) after a median follow-up duration of 5.3 years.

Discussion

In this systematic review of the literature, we evaluated all available evidence on the prevalence of and risk factors for renal dysfunction in CCS treated with potentially nephrotoxic treatments (i.e. ifosfamide, carboplatin, cisplatin, radiotherapy involving the kidney region and nephrectomy). We were able to include 57 studies. The prevalence of renal adverse effects ranged from 0% to 84%. This variation can be explained in part by variation in included malignancies, variation in prescribed treatments, variation in reported outcome measurements and variation in the methodological quality of available evidence. Gaps in evidence remain regarding which specific nephrotoxic treatments put CCS at greatest risk of developing early or late renal adverse effects.

The prevalence of CKD/renal insufficiency was low, ranging between 0.5% and 3% in unilaterally nephrectomised WT survivors without specific syndromes or genitourinary congenital malformations. When survivors received a bilateral (partial) nephrectomy or suffered from syndromes such as Denys-Drash or WAGR, the prevalence was higher (11% to 71%). Follow-up in these studies ranged from 7 to 25 years. The studies that investigated an impaired (estimated) GFR (regardless of the used cut-off value) showed higher prevalences, ranging from 0% to 50%. This raises the suspicion that glomerular function, with renal insufficiency as the ultimate stage, deteriorates slowly over time. The decline in GFR is a physiological process as well: During the normal aging process, glomerular function slowly declines. However, a GFR below 90 mL/min/1.73 m2 usually does not manifest until late adulthood (Hoang 2003), whilst most of the included studies show an increased prevalence of impaired GFR in a relatively very young population. No evidence indicates which nephrotoxic treatments place CCS at greatest risk for glomerular dysfunction. Very long-term follow-up (> 25 years) studies have not yet been performed, in part because of the low survival rates for paediatric malignancies up until 25 years ago. Future studies should assess glomerular function in these aging survivors over time, especially in relation to glomerular function in the normal population.

A matter of concern was the large variation in the methods used to determine or estimate the GFR. The studies included in this review used more than ten different measures to express the GFR by obtaining renal clearance measurements or by estimating the GFR using estimation formulae. Two studies by Stefanowicz et al showed that there may be large differences in the GFR that are based on which method or formula is used (Stefanowicz 2009; Stefanowicz 2011). Depending on the method, these differences were as large as 35.6 mL/min/1.73 m2, causing variation in the prevalence of participants with a GFR < 90 mL/min/1.73 m2 between 0% and 43.8% in the same study. Effort should be put into (international) guideline harmonisation for the follow-up of glomerular function after childhood cancer to facilitate comparability between studies.

Proteinuria is one of the early and sensitive markers for CKD, and it is an independent predictor of mortality in the general population (Matsushita 2010; National Kidney Foundation 2002). In the sixteen studies that measured proteinuria, prevalence ranged between 0% and 84%. This heterogeneity may have been caused by several measurements that were available to assess proteinuria: The sixteen studies reported at least five different proteinuria measurements. Because of this heterogeneity and the fact that no study corrected its proteinuria analyses for potential confounders, it was not possible to draw any conclusions regarding prevalence or risk factors for proteinuria. More valid research is needed regarding proteinuria in CCS, as it is can be a valuable and cheap tool for screening purposes.

Hypophosphataemia in CCS is most often associated with impairment of proximal tubular reabsorption of phosphate caused by ifosfamide toxicity. Hypomagnesaemia and hypokalaemia are associated with renal phosphate wasting and phosphate depletion as well (Liamis 2010). Impairment of proximal tubular phosphate reabsorption may be accompanied by impaired reabsorption of bicarbonate, glucose, amino acids and uric acid, possibly resulting in metabolic acidosis, hypouricaemia, aminoaciduria and/or glycosuria (Pratt 1991). Hypophosphataemia prevalence ranged between 1.1% and 8.0% 10 years after diagnosis in survivors treated with ifosfamide (Oberlin 2009; Skinner 2010). Impaired tubular phosphate regulation parameters were more prevalent in these two studies, with prevalences of 24.4% and 62.5%, respectively. The prevalence of impaired tubular phosphate regulation parameters in all other studies that solely investigated ifosfamide survivors ranged between these two percentages. The difference between the prevalence of hypophosphataemia and impaired phosphate reabsorption may be explained by sufficient dietary intake or adequate phosphate supplementation. Still, the high prevalence of impaired tubular phosphate regulation parameters emphasises the need for longitudinal follow-up to prevent the development of hypophosphataemia, loss of bone mineral density and ultimately hypophosphataemic rickets. Especially survivors treated with higher cumulative ifosfamide doses and with ifosfamide in combination with cisplatin or a nephrectomy should be considered for follow-up.

Damage to the proximal and distal tubulus of the kidney, associated with platinum toxicity caused by cisplatin and/or carboplatin treatment, can cause (chronic) tubular magnesium wasting, leading to hypomagnesaemia (Lajer 1999). The prevalence of hypomagnesaemia among participants in the included studies varied between 0% and 29%. The variation in prevalence was not consistent with the variation in treatment modality or the time between cancer diagnosis and serum magnesium testing at follow-up; nor did it reflect the definitions of abnormal values provided. The only way to gain valid insight into potential risk factors for hypomagnesaemia is to perform multivariate analysis to control for potential confounders such as cumulative chemotherapy dose, follow-up duration and age at diagnosis. Only Stöhr et al used appropriate measures to prevent confounding and found that treatment with cisplatin and carboplatin significantly reduced serum magnesium, whereas abdominal irradiation and duration of follow-up had no significant influence (Stohr 2007a). Longitudinal studies with repeated serum magnesium measurements, preferably in a cohort of CCS that included all malignancies and treatments, would provide the opportunity for investigators to assess in greater detail risk factors for hypomagnesaemia and its course.

Uncontrolled hypertension is the number one risk factor associated with high mortality rates throughout the world, as high blood pressure is closely correlated with coronary heart disease and stroke (Beevers 2007; World Health Organization 2002). Many CCS are already at risk for cardiovascular disease, for example, that due to anthracycline- or radiation-induced cardiotoxicity (Kremer 2002; van Dalen 2006; van der Pal 2012). In the studies included in this review, the prevalence of renal-related hypertension varied between 0% and 18.2%. Substantial heterogeneity among studies prevented us from performing a meta-analysis. The studies that corrected for possible confounders for hypertension were not concordant either: Only two of the four studies showed a significant negative effect of radiation therapy, whilst the two other studies could not confirm this effect. The study by Hoffmeister et al reported that survivors with hepatitis C virus (HCV) infection were almost 50% less likely to develop hypertension than their HCV-negative counterparts (Hoffmeister 2010). Although they did not have an explanation for this phenomenon, investigators in a large study of 171,665 veterans reported a similar finding (Butt 2009). Two studies that performed multivariate analyses showed that higher body mass index (BMI) was a significant risk factor for hypertension in CCS (Cardous-Ubbink 2010; Hoffmeister 2010). Targeting obesity and its related life-style factors may be an important approach in preventing cardiovascular events and subsequently renal late adverse effects in this population. Additionally, future studies should always correct for BMI when assessing treatment-related risk factors for hypertension in CCS.

The risk of bias assessment of all included studies showed that all studies suffered from methodological limitations. Not a single study stated that investigators blinded the outcome assessor to the treatment exposure. Of course this may not be applicable to simple laboratory tests, but assessment of blood pressure or renal ultrasound would be susceptible to detection bias, for example. Apart from this bias, the methodological quality of studies varied widely. Only one study had a low risk of bias on all seven remaining criteria (Frisk 2002). In addition, eight studies had a low risk of bias when only six items were taken into account (Geenen 2010; Hoffmeister 2010; Oberlin 2009; Rossi 1994a; Rossi 1999; Skinner 2009; Skinner 2010; Stohr 2007a). One study had an unclear or high risk of bias on all eight criteria (Cosentino 1993).

We assessed the internal validity of the included studies by applying criteria for selection bias, attrition bias, detection bias and confounding. Selection bias could not be excluded in 67% of the studies. Selection bias may lead to distortion of the observed effects in a study in relationship to the 'real' effect. When a study includes only a non-random subsample of the original cohort, the risk that selection of survivors is based on factors related to the specific outcome of interest is substantial. The results of these studies should be interpreted with caution, as reported prevalences and risk factors may overestimate or underestimate the real prevalence. If selection bias can be ruled out, attrition bias (incomplete follow-up) poses an additional threat to the validity of the study. The risk for attrition bias was low in all but seven studies.

The last criterion related to the internal validity of studies was confounding: Did studies take important (confounding) variables into account in the analysis of possible risk factors for renal adverse outcomes? For most studies, the answer was no; only 11 studies used multivariate analysis to correct for possible confounders. This poses a problem for the interpretation of risk factor analyses in the other 46 studies. Without control for potential confounders, the results of (univariate) risk factor analysis may overestimate or underestimate the real effect.

To a considerable extent, external validity determines the generalisability of study results to other populations or to individual participants. We assessed external validity by applying four criteria of study reporting: the characteristics of the study group, the follow-up duration, the outcome definition and the statistical analysis. Although the follow-up duration was mentioned in most studies, reporting of the other three items was limited. If substantial information is missing regarding the treatment that participants received, the definition of the outcome measured or the statistical relevance of the results, it is difficult to interpret the results of the study correctly. To improve the external validity of studies, authors should adhere to published guidelines regarding high-quality reporting, such as the STROBE statement (von Elm 2007).

This systematic review may have some limitations as well. Although we used a comprehensive search strategy, because of time constraints we were unable to comply with Cochrane guidelines on handsearching conference proceedings, reference lists of included studies and reference lists of relevant reviews. As a result, we cannot affirm that we did not miss certain relevant studies for inclusion, and we must state that selection bias based on the search strategy may be present. Additionally, we are still awaiting translation of some of the relevant studies that were not published in English. These language limitations may have resulted in language bias, as it is known that authors of studies are more likely to publish in English if their results are significant (Egger 1997). Selection of outcome measurements that had the highest clinical relevance and were reported most often and most consistently also may have introduced reporting bias, as reporting of a certain outcome may be related to the nature and direction of study results. This may have caused selection of outcome measures that show the most desirable or significant results. However, selection of the outcome measures for this review was based predominantly on clinical relevance and existing screening guidelines for renal function in childhood cancer survivors, such as the guidelines of Skinner 1991.

In conclusion, this systematic review shows that the prevalence of renal adverse effects after treatment for childhood cancer varies widely, from 0% to 84%. Variations in study populations, outcome measurements, follow-up duration and methodological quality may explain this heterogeneity. New research projects should focus particularly on complete data collection and well-defined outcome measurements and especially on multivariate analysis methods. Evidence on renal adverse effects is not conclusive; therefore, all CCS treated with cisplatin, carboplatin, ifosfamide, kidney or TBI and/or nephrectomy should be included in prospective, longitudinal follow-up programmes to allow researchers to gain insight into the prevalence of, and especially the risk factors for, kidney disease.

Authors' conclusions

Implications for practice

This systematic review shows that childhood cancer survivors (CCS) are at risk for developing early and late renal adverse effects, including chronic kidney disease/renal insufficiency, impaired (estimated) glomerular filtration rate, proteinuria, hypomagnesaemia, hypophosphataemia, impaired tubular phosphate regulation and hypertension. CCS should be screened for these adverse effects, preferably according to systematic, prespecified protocols based on the treatment modalities provided. Because current evidence is not conclusive regarding possible risk factors for renal adverse effects, we believe that all CCS who receive potentially nephrotoxic therapy should receive renal function testing at fixed time intervals. Increasing follow-up duration was a risk factor in several studies; therefore, regardless of the investigated outcome, screening should continue during adulthood. However, recommendations about the exact time interval for renal function surveillance cannot be made on the basis of current evidence. When additional evidence becomes available, treatment regimens and follow-up protocols can be adjusted. Until then, alternatives for nephrotoxic treatment should be explored without compromising the high childhood cancer survival rates. CCS should receive life-style counselling on topics such as avoidance of tobacco use, excessive non-steroidal anti-inflammatory drug (NSAID) use, excessive alcohol use and dehydration, to minimise the risk of developing kidney disease and/or hypertension (Jones 2008; Nathan 2009).

Implications for research

All studies included in this review showed methodological limitations. Future research on the prevalence of and risk factors for renal dysfunction after childhood cancer should be designed as prospective cohort studies, preferably in large and complete cohorts with large and complete study groups. Very little evidence is available on the development of renal function over time in CCS. Study investigators should perform longitudinal analyses of renal function and, if possible, should include an age-matched control population (preferably siblings) because normative data on glomerular and tubular function in healthy children and in young adults are scarce. As the development of renal adverse effects after childhood cancer can have several causes and pathways, studies should always use multivariate analysis to assess risk factors and to correct for possible confounders. As the reporting quality of many of the included studies was inadequate, we recommend that all authors adhere to one of the existing reporting guidelines for clinical studies, such as the STROBE checklist (von Elm 2007).

Acknowledgements

We would like to thank Edith Leclercq for developing and running the search strategies for the different databases, and peer reviewers R. Skinner, E. Bárdi and D.P. Jones for their constructive comments on the manuscript.

The editorial base of the Cochrane Childhood Cancer Group is funded by Kinderen Kankervrij (KiKa).

Data and analyses

Download statistical data

Comparison 1. Prevalence of renal dysfunction
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Chronic kidney disease / renal insufficiency as defined by authors10 Prevalence (Random, 95% CI)Totals not selected
1.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
1.2 Carboplatin, ifosfamide, radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
1.3 Ifosfamide, radiotherapy and/or nephrectomy3 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
1.4 Radiotherapy and/or nephrectomy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
1.5 Unilateral nephrectomy for Wilms' tumour2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
1.6 Unilateral nephrectomy for Wilms' tumour (Denys-Drash syndrome)1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
1.7 Unilateral nephrectomy for Wilms' tumour (WAGR syndrome)1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
1.8 Unilateral nephrectomy for Wilms' tumour (genitourinary anomalies)1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
1.9 Bilateral (partial) nephrectomy for Wilms' tumour1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
1.10 Bilateral (partial) nephrectomy for Wilms' tumour (Denys-Drash syndrome)1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
1.11 Bilateral (partial) nephrectomy for Wilms' tumour (WAGR syndrome)1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
1.12 Bilateral (partial) nephrectomy for Wilms' tumour (genitourinary anomalies)1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2 (Estimated) glomerular filtration rate < 90 mL/min/1.73m212 Prevalence (Random, 95% CI)Totals not selected
2.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2.2 Cisplatin, carboplatin, ifosfamide and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2.3 Cisplatin, carboplatin and/or radiotherapy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2.4 Cisplatin, ifosfamide, radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2.5 Cisplatin and/or ifosfamide1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2.6 Carboplatin1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2.7 Carboplatin, ifosfamide, radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2.8 Ifosfamide and/or radiotherapy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2.9 Ifosfamide and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2.10 Ifosfamide1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2.11 Radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
3 (Estimated) glomerular filtration rate < 80 mL/min/1.73m27 Prevalence (Random, 95% CI)Totals not selected
3.1 Cisplatin, ifosfamide, radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
3.2 Cisplatin, ifosfamide and/or nephrectomy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
3.3 Cisplatin and/or ifosfamide1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
3.4 Cisplatin1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
3.5 Radiotherapy and/or nephrectomy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
4 (Estimated) glomerular filtration rate < 70 mL/min/1.73m21 Prevalence (Random, 95% CI)Totals not selected
4.1 Radiotherapy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
5 (Estimated) glomerular filtration rate < 50 mL/min/1.73 m21 Prevalence (Random, 95% CI)Totals not selected
5.1 Radiotherapy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
6 Proteinuria as defined by authors17 Prevalence (Random, 95% CI)Totals not selected
6.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy3 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
6.2 Cisplatin, carboplatin, ifosfamide and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
6.3 Cisplatin, carboplatin and/or ifosfamide1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
6.4 Cisplatin, carboplatin, radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
6.5 Cisplatin, ifosfamide, radiotherapy and/or nephrectomy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
6.6 Cisplatin and/or ifosfamide1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
6.7 Carboplatin, ifosfamide, radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
6.8 Carboplatin1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
6.9 Ifosfamide and/or radiotherapy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
6.10 Radiotherapy and/or nephrectomy4 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
6.11 Nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
7 Serum phosphate / hypophoshataemia as defined by the authors7 Prevalence (Random, 95% CI)Totals not selected
7.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
7.2 Cisplatin, carboplatin and/or ifosfamide1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
7.3 Cisplatin, carboplatin, radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
7.4 Ifosfamide and/or radiotherapy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
7.5 Radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
7.6 Radiotherapy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
8 Tubular phosphate regulation parameters as defined by the authors11 Prevalence (Random, 95% CI)Totals not selected
8.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
8.2 Cisplatin, ifosfamide, radiotherapy and/or nephrectomy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
8.3 Cisplatin, ifosfamide and/or nephrectomy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
8.4 Cisplatin and/or ifosfamide2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
8.5 Carboplatin1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
8.6 Ifosfamide and/or radiotherapy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
8.7 Ifosfamide1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
9 Serum magnesium / hypomagnesaemia as defined by the authors7 Prevalence (Random, 95% CI)Totals not selected
9.1 Cisplatin, carboplatin, ifosfamide and/or radiotherapy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
9.2 Cisplatin, carboplatin and/or ifosfamide1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
9.3 Cisplatin1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
9.4 Carboplatin2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
9.5 Ifosfamide and/or radiotherapy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
9.6 Radiotherapy and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
10 Blood pressure24 Prevalence (Random, 95% CI)Totals not selected
10.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
10.2 Cisplatin, carboplatin, and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
10.3 Cisplatin, ifosfamide, radiotherapy and/or nephrectomy3 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
10.4 Carboplatin, ifosfamide, radiotherapy and/or nephrectomy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
10.5 Carboplatin1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
10.6 Ifosfamide, radiotherapy and/or nephrectomy2 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
10.7 Ifosfamide and/or nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
10.8 Radiotherapy and/or nephrectomy10 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
10.9 Radiotherapy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
10.10 Nephrectomy1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 Prevalence of renal dysfunction, Outcome 1 Chronic kidney disease / renal insufficiency as defined by authors.

Analysis 1.2.

Comparison 1 Prevalence of renal dysfunction, Outcome 2 (Estimated) glomerular filtration rate < 90 mL/min/1.73m2.

Analysis 1.3.

Comparison 1 Prevalence of renal dysfunction, Outcome 3 (Estimated) glomerular filtration rate < 80 mL/min/1.73m2.

Analysis 1.4.

Comparison 1 Prevalence of renal dysfunction, Outcome 4 (Estimated) glomerular filtration rate < 70 mL/min/1.73m2.

Analysis 1.5.

Comparison 1 Prevalence of renal dysfunction, Outcome 5 (Estimated) glomerular filtration rate < 50 mL/min/1.73 m2.

Analysis 1.6.

Comparison 1 Prevalence of renal dysfunction, Outcome 6 Proteinuria as defined by authors.

Analysis 1.7.

Comparison 1 Prevalence of renal dysfunction, Outcome 7 Serum phosphate / hypophoshataemia as defined by the authors.

Analysis 1.8.

Comparison 1 Prevalence of renal dysfunction, Outcome 8 Tubular phosphate regulation parameters as defined by the authors.

Analysis 1.9.

Comparison 1 Prevalence of renal dysfunction, Outcome 9 Serum magnesium / hypomagnesaemia as defined by the authors.

Analysis 1.10.

Comparison 1 Prevalence of renal dysfunction, Outcome 10 Blood pressure.

Comparison 2. Mean (estimated) glomerular filtration rate in mL/min/1.73m2 at least 1 year after diagnosis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mean (estimated) glomerular filtration rate in studies that included internal or healthy controls4 Mean Difference (Random, 95% CI)Totals not selected
1.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy2 Mean Difference (Random, 95% CI)0.0 [0.0, 0.0]
1.2 Cisplatin, carboplatin, ifosfamide and/or nephrectomy1 Mean Difference (Random, 95% CI)0.0 [0.0, 0.0]
1.3 Radiotherapy and/or nephrectomy1 Mean Difference (Random, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Mean (estimated) glomerular filtration rate in mL/min/1.73m2 at least 1 year after diagnosis, Outcome 1 Mean (estimated) glomerular filtration rate in studies that included internal or healthy controls.

Appendices

Appendix 1. Search strategy for Cochrane Central Register of Controlled Trials (CENTRAL)

1. ForIfosfamide the following text words were used:

ifosfamide OR iphosphamide OR iso-endoxan OR iso endoxan OR isophosphamide OR isofosfamide OR holoxan OR asta z 4942 OR NSC-109,724 OR NSC 109,724 OR NSC109,724 OR NSC 109724 OR NSC-109724 OR NSC109724 OR cyclic p-oxides OR ethylamines OR oxazines OR ifosfa* OR iphospha* OR isofosfa* OR isophospha* OR “br cl fosfamide” OR cyfos OR ifex OR “ifo-cell” OR ifolem OR ifomide OR ifosfamidum OR ifosforamide mustard OR ifoxan OR ipambr OR iphosphamid OR isophosphoramide bromide mustard OR isophosphoramide mustard OR mitoxana OR mjf 9325 OR naxamide OR seromida OR tronoxal OR z 4942

2. ForCarboplatin and cisplatin the following text words were used:

Platinum OR Platinum Compounds OR cis-diamminedichloroplatinum* OR cis-platinum OR cis platinum OR biocisplatinum OR dichlorodiammineplatinum OR nsc-119875 or NSC 119875 or NSC119875 OR platidiam OR platino OR platinol OR platinum* OR CDDP OR CACP OR cisplatin OR carboplatin OR abiplatin OR paraplatin OR CBDCA OR cis-DDP OR neoplatin OR platidiam OR cis-Diamminedichloroplatinum OR cis Diamminedichloroplatinum OR cis-Dichlorodiammineplatinum(II) OR platinum diamminodichloride OR Platinum Diamminodichloride OR 15663-27-1 OR cis-Diammine(cyclobutanedicarboxylato)platinum II OR Carbosin OR Pharmachemie Brand of Carboplatin OR Carbotec OR Columbia Brand of Carboplatin OR Ercar OR Almirall Brand of Carboplatin OR JM-8 OR JM 8 OR JM8 OR Neocarbo OR Neocorp Brand of Carboplatin OR NSC-241240 OR NSC 241240 OR NSC241240 OR Bristol-Myers Squibb Brand of Carboplatin OR Carboplat OR Paraplatine OR Platinwas OR Chiesi Brand of Carboplatin OR Ribocarbo OR ribosepharm Brand of Carboplatin OR Blastocarb OR Lemery Brand of Carboplatin OR Nealorin OR Prasfarma Brand of Carboplatin OR 41575-94-4

3. ForRadiotherapy the following text words were used:

Radiotherapy OR radiotherapies OR Targeted Radiotherapies OR Targeted Radiotherapy OR radiother* OR (radiation AND therapy) OR "radiation therapy" OR "x ray therapy" OR ("x-ray" AND therapy) OR total body irradiation OR TBI OR whole-body irradiation OR Whole Body Irradiation OR Whole-Body Radiation OR Whole Body Radiation OR Whole-Body Radiations OR Total Body Irradiations OR Whole-Body Irradiations

4. ForNephrectomy the following text words were used:

Nephrectomy OR nephrectomies OR nephrect* OR nephron-sparing surgery

5. ForChildren the following text words were used:

infant OR infan* OR newborn OR newborn* OR new-born* OR baby OR baby* OR babies OR neonat* OR perinat* OR postnat* OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar* OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric* OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school* OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy

6. For Childhood cancer the following text words were used:

leukemia OR leukemi* OR leukaemi* OR childhood ALL OR AML OR lymphoma OR lymphom* OR hodgkin OR hodgkin* OR T-cell OR B-cell OR non-hodgkin OR sarcoma OR sarcom* OR Ewing* OR osteosarcoma OR osteosarcom* OR wilms tumor OR wilms* OR nephroblastom* OR neuroblastoma OR neuroblastom* OR rhabdomyosarcoma OR rhabdomyosarcom* OR teratoma OR teratom* OR hepatoma OR hepatom* OR hepatoblastoma OR hepatoblastom* OR PNET OR medulloblastoma OR medulloblastom* OR PNET* OR primitive neuroectodermal tumors OR retinoblastoma OR retinoblastom* OR meningioma OR meningiom* OR glioma OR gliom* OR pediatric oncology OR paediatric oncology OR childhood cancer OR childhood tumor OR childhood tumors OR brain tumor* OR brain tumour* OR brain neoplasms OR central nervous system neoplasm OR central nervous system neoplasms OR central nervous system tumor* OR central nervous system tumour* OR brain cancer* OR brain neoplasm* OR intracranial neoplasm* OR acute lymphocytic leukemia

7. ForCancer the following text words were used:

cancer OR oncology OR oncolog* OR neoplasms OR neoplas* OR carcinoma OR carcinom* OR tumor OR tumour OR tumor* OR tumour* OR cancer* OR malignan* OR hematooncological OR hemato oncological OR hemato-oncological OR hematologic neoplasms OR hematolo* OR bone marrow transplantation OR bone marrow transplant* OR leukemia OR leukaemia OR lymphoma

8. ForNephrotoxicity the following text words were used:

glomerular filtration rate OR GFR OR Glomerular Filtration Rates OR glomerular OR glomerul* OR tubular OR tubula* OR renal tubular acidosis OR RTA OR Distal Renal Tubular Acidosis OR Classic Distal Renal Tubular Acidosis OR Proximal Renal Tubular Acidosis OR Type II Renal Tubular Acidosis OR renal acidosis OR renal insufficiency OR Renal Insufficiencies OR Kidney Insufficiency OR Kidney Insufficiencies OR microalbuminuria OR microalbumin*OR hypophosphatemia OR hypophosphataemia OR hypophospha* OR hypomagnes* OR hypomagnesemia OR hypomagnesaemia OR magnesium OR 7439-95-4 OR phosphate OR phosphates OR Inorganic Phosphates OR Phosphates, Inorganic OR Orthophosphate OR phosphorus OR Hyponatremia OR Hyponatremias OR hyponatraemia OR hyponatraemias OT hyponatrem* OR hyponatraem* OR Hypocitraturia OR Hypocitraturias OR Hypocitraturi* OR Potassium OR Potassium Ion Level OR Ion Level, Potassium OR Level, Potassium Ion OR 7440-09-7 OR Hypokalemia OR Hypokalemias OR Hypopotassemia OR Hypopotassemias OR hypokalemic OR hypokalem* OR hypokalaemic OR hypokalaem* OR Hypocalcemia OR hypocalcemias OR hypocalciuria OR hypocalciuri* OR hypocalcem* OR hypocalc* OR “hypocarbia” OR Proteinuria OR proteinurias OR proteinuri* OR albuminuria OR albuminurias OR albuminuri* OR Aminoaciduria OR Renal Aminoaciduria OR Renal Aminoacidurias OR Aminoacidurias, Renal OR Aminoaciduria, Renal OR aminoacidur* OR Glucosuria OR glucosurias OR glucosur* OR glycosuria OR glycosurias OR glycosuria, renal OR Fanconi syndrome OR Syndrome, Fanconi OR Renal Fanconi Syndrome OR Proximal Renal Tubular Dysfunction OR Fanconi Renotubular Syndrome OR Syndrome, Fanconi Renotubular OR De Toni-Debre-Fanconi Syndrome OR De Toni Debre Fanconi Syndrome OR Syndrome, De Toni-Debre-Fanconi OR Lignac-Fanconi Syndrome OR Lignac Fanconi Syndrome OR Syndrome, Lignac-Fanconi OR low molecular weight OR LMW OR alpha 1 microglobulin OR a1 microglobulin OR beta 2 microglobulin OR b2 microglobulin OR 2-Microglobulin, beta OR Thymotaxin OR retinol binding protein OR RBP OR Retinol Binding Proteins OR Binding Proteins, Retinol OR Retinoid Binding Proteins OR Binding Proteins, Retinoid OR Retinoid Binding Protein, F-Type OR Retinoid Binding Protein, F Type OR creatinine OR Krebiozen OR Creatinine Sulfate Salt OR Salt, Creatinine Sulfate OR Sulfate Salt, Creatinine OR 60-27-5 OR inulin OR 9005-80-5 OR "(51) Cr EDTA" OR 51chromium edetic acid OR “(99) Tc DTPA” OR Tc DTPA OR 65454-61-7[rn] OR Technetium Tc 99m Pentetate OR (99m)Tc-DMSA OR 99mTc(V)DMSA OR DMSA OR dimercaptosuccinic acid OR Technetium Tc 99m Dimercaptosuccinic Acid OR 65438-08-6 OR 99Tc-Succimer OR 99Tc Succimer OR 99mTc-Dimercaptosuccinate OR 99mTc Dimercaptosuccinate OR renal scan OR “kidney size” OR cystatin c OR gamma-Trace OR gamma Trace OR Post-gamma-Globulin OR Post gamma Globulin OR Cystatin 3 OR Neuroendocrine Basic Polypeptide OR Basic Polypeptide, Neuroendocrine OR CST3 gene OR cystatins OR cystatin* OR renal failure OR kidney failure OR Failure, Kidney OR Failures, Kidney OR Kidney Failures OR Failure, Renal OR Failures, Renal OR Renal Failures OR renal plasma flow OR Plasma Flow, Renal OR Flow, Renal Plasma OR RPF OR ERPF OR Renal clearance OR reabsorption OR re-absorption OR nephrotoxicity OR nephrotox* OR rickets OR rickets* OR Hypertension OR hypertens* OR hypertension, renal OR Hypertensions, Renal OR Renal Hypertension OR Renal Hypertensions OR Blood Pressure, High OR Blood Pressures, High OR High Blood Pressure OR High Blood Pressures OR blood pressure OR blood pressures OR blood pressur* OR diastolic pressure OR systolic pressure

9. Final search (1 or 2 or 3 or 4) and 5 and (6 or 7) and 8

The search was performed in title, abstract or keywords

[* = 1 or more characters]

Appendix 2. Search strategy for MEDLINE/PubMed

1. ForIfosfamide the following MeSH headings and text words were used:

ifosfamide OR iphosphamide OR iso-endoxan OR iso endoxan OR isophosphamide OR isofosfamide OR holoxan OR asta z 4942 OR NSC-109,724 OR NSC 109,724 OR NSC109,724 OR NSC 109724 OR NSC-109724 OR NSC109724 OR cyclic p-oxides OR ethylamines OR oxazines OR ifosfa* OR iphospha* OR isofosfa* OR isophospha* OR “br cl fosfamide” OR cyfos OR ifex OR “ifo-cell” OR ifolem OR ifomide OR ifosfamidum OR ifosforamide mustard OR ifoxan OR ipambr OR iphosphamid OR isophosphoramide bromide mustard OR isophosphoramide mustard OR mitoxana OR mjf 9325 OR naxamide OR seromida OR tronoxal OR z 4942

2. For Carboplatin and cisplatin the following MeSH headings and text words were used:

Platinum OR Platinum Compounds OR cis-diamminedichloroplatinum* OR cis-platinum OR cis platinum OR biocisplatinum OR dichlorodiammineplatinum OR nsc-119875 or NSC 119875 or NSC119875 OR platidiam OR platino OR platinol OR platinum* OR CDDP OR CACP OR cisplatin OR carboplatin OR abiplatin OR paraplatin OR CBDCA OR cis-DDP OR neoplatin OR platidiam OR cis-Diamminedichloroplatinum OR cis Diamminedichloroplatinum OR cis-Dichlorodiammineplatinum(II) OR platinum diamminodichloride OR Platinum Diamminodichloride OR Diamminodichloride, Platinum OR 15663-27-1 OR cis-Diammine(cyclobutanedicarboxylato)platinum II OR Carbosin OR Pharmachemie Brand of Carboplatin OR Carbotec OR Columbia Brand of Carboplatin OR Ercar OR Almirall Brand of Carboplatin OR JM-8 OR JM 8 OR JM8 OR Neocarbo OR Neocorp Brand of Carboplatin OR NSC-241240 OR NSC 241240 OR NSC241240 OR Bristol-Myers Squibb Brand of Carboplatin OR Carboplat OR Paraplatine OR Platinwas OR Chiesi Brand of Carboplatin OR Ribocarbo OR ribosepharm Brand of Carboplatin OR Blastocarb OR Lemery Brand of Carboplatin OR Nealorin OR Prasfarma Brand of Carboplatin OR 41575-94-4

3. ForRadiotherapy the following MeSH headings and text words were used:

Radiotherapy OR radiotherapy[sh] OR radiotherapies OR Radiotherapy, Targeted OR Radiotherapies, Targeted OR Targeted Radiotherapies OR Targeted Radiotherapy OR radiother* OR ("radiation"[All Fields] AND "therapy"[All Fields]) OR "radiation therapy"[All Fields] OR "x ray therapy"[All Fields] OR "x-ray therapy"[MeSH Terms] OR ("x-ray"[All Fields] AND "therapy"[All Fields]) OR "x-ray therapy"[All Fields] OR total body irradiation OR TBI OR whole-body irradiation OR Whole Body Irradiation OR Radiation, Whole-Body OR Radiation, Whole Body OR Whole-Body Radiation OR Radiations, Whole-Body OR Whole Body Radiation OR Whole-Body Radiations OR Irradiation, Total Body OR Irradiations, Total Body OR Total Body Irradiations OR Irradiation, Whole-Body OR Irradiation, Whole Body OR Irradiations, Whole-Body OR Whole-Body Irradiations

4. ForNephrectomy the following MeSH headings and text words were used:

Nephrectomy OR nephrectomies OR nephrect* OR nephron-sparing surgery

5. For Children the following MeSH headings and text words were used:

infant OR infan* OR newborn OR newborn* OR new-born* OR baby OR baby* OR babies OR neonat* OR perinat* OR postnat* OR child OR child* OR schoolchild* OR schoolchild OR school child OR school child* OR kid OR kids OR toddler* OR adolescent OR adoles* OR teen* OR boy* OR girl* OR minors OR minors* OR underag* OR under ag* OR juvenil* OR youth* OR kindergar* OR puberty OR puber* OR pubescen* OR prepubescen* OR prepuberty* OR pediatrics OR pediatric* OR paediatric* OR peadiatric* OR schools OR nursery school* OR preschool* OR pre school* OR primary school* OR secondary school* OR elementary school* OR elementary school OR high school* OR highschool* OR school age OR schoolage OR school age* OR schoolage* OR infancy OR schools, nursery OR infant, newborn

6. For Childhood cancer the following MeSH headings and text words were used:

leukemia OR leukemi* OR leukaemi* OR ALL OR AML OR lymphoma OR lymphom* OR hodgkin OR hodgkin* OR T-cell OR B-cell OR non-hodgkin OR sarcoma OR sarcom* OR sarcoma, Ewing's OR Ewing* OR osteosarcoma OR osteosarcom* OR wilms tumor OR wilms* OR nephroblastom* OR neuroblastoma OR neuroblastom* OR rhabdomyosarcoma OR rhabdomyosarcom* OR teratoma OR teratom* OR hepatoma OR hepatom* OR hepatoblastoma OR hepatoblastom* OR PNET OR medulloblastoma OR medulloblastom* OR PNET* OR neuroectodermal tumors, primitive OR retinoblastoma OR retinoblastom* OR meningioma OR meningiom* OR glioma OR gliom* OR pediatric oncology OR paediatric oncology OR childhood cancer OR childhood tumor OR childhood tumors OR brain tumor* OR brain tumour* OR brain neoplasms OR central nervous system neoplasm OR central nervous system neoplasms OR central nervous system tumor* OR central nervous system tumour* OR brain cancer* OR brain neoplasm* OR intracranial neoplasm* OR leukemia lymphocytic acute OR leukemia, lymphocytic, acute[mh]

7. For Cancer the following MeSH headings and text words were used:

cancer OR cancers OR cancer* OR oncology OR oncolog* OR neoplasm OR neoplasms OR neoplasm* OR carcinoma OR carcinom* OR tumor OR tumour OR tumor* OR tumour* OR tumors OR tumours OR malignan* OR malignant OR hematooncological OR hemato oncological OR hemato-oncological OR hematologic neoplasms OR hematolo*

8. For Nephrotoxicity the following MeSH headings and text words were used:

glomerular filtration rate OR GFR OR Filtration Rate, Glomerular OR Filtration Rates, Glomerular OR Glomerular Filtration Rates OR Rate, Glomerular Filtration OR Rates, Glomerular Filtration OR glomerular OR glomerul* OR tubular OR tubula* OR renal tubular acidosis OR RTA OR Acidosis, Renal Tubular OR Renal Tubular Acidosis, Type I OR Type I Renal Tubular Acidosis OR Distal Renal Tubular Acidosis OR Acidosis, Renal Tubular, Type I OR Classic Distal Renal Tubular Acidosis OR Renal Tubular Acidosis, Distal, Autosomal Dominant OR Renal Tubular Acidosis, Type II Acidosis, Renal Tubular, Type II OR Renal Tubular Acidosis, Proximal, with Ocular Abnormalities OR Proximal Renal Tubular Acidosis OR Type II Renal Tubular Acidosis OR renal acidosis OR renal insufficiency OR Renal Insufficiencies OR Kidney Insufficiency OR Insufficiency, Kidney OR Kidney Insufficiencies OR microalbuminuria OR microalbumin* OR hypophosphatemia OR hypophosphataemia OR hypophospha* OR hypomagnes* OR hypomagnesemia OR hypomagnesaemia OR magnesium OR 7439-95-4[rn] OR phosphate OR phosphates OR Inorganic Phosphates OR Phosphates, Inorganic OR Orthophosphate OR phosphorus OR Hyponatremia OR Hyponatremias OR hyponatraemia OR hyponatraemias OR hyponatrem* OR hyponatraem* OR Hypocitraturia OR Hypocitraturias OR Hypocitraturi* OR Potassium OR Potassium Ion Level OR Ion Level, Potassium OR Level, Potassium Ion OR 7440-09-7[rn] OR Hypokalemia OR Hypokalemias OR Hypopotassemia OR Hypopotassemias OR hypokalemic OR hypokalem* OR hypokalaemic OR hypokalaem* OR Hypocalcemia OR hypocalcemias OR hypocalciuria OR hypocalciuri* OR hypocalcem* OR hypocalc* OR “hypocarbia” OR Proteinuria OR proteinurias OR proteinuri* OR albuminuria OR albuminurias OR albuminuri* OR Aminoaciduria OR Renal Aminoaciduria OR Renal Aminoacidurias OR Aminoacidurias, Renal OR Aminoaciduria, Renal OR aminoacidur* OR Glucosuria OR glucosurias OR glucosur* OR glycosuria OR glycosurias OR glycosuria, renal OR Fanconi syndrome OR Syndrome, Fanconi OR Renal Fanconi Syndrome OR Proximal Renal Tubular Dysfunction OR Fanconi Renotubular Syndrome OR Syndrome, Fanconi Renotubular OR De Toni-Debre-Fanconi Syndrome OR De Toni Debre Fanconi Syndrome OR Syndrome, De Toni-Debre-Fanconi OR Lignac-Fanconi Syndrome OR Lignac Fanconi Syndrome OR Syndrome, Lignac-Fanconi OR low molecular weight OR LMW OR alpha 1 microglobulin OR a1 microglobulin OR beta 2 microglobulin OR b2 microglobulin OR 2-Microglobulin, beta OR Thymotaxin OR retinol binding protein OR RBP OR Retinol Binding Proteins OR Binding Proteins, Retinol OR Retinoid Binding Proteins OR Binding Proteins, Retinoid OR Retinoid Binding Protein, F-Type OR Retinoid Binding Protein, F Type OR creatinine OR Krebiozen OR Creatinine Sulfate Salt OR Salt, Creatinine Sulfate OR Sulfate Salt, Creatinine OR 60-27-5[rn] OR inulin OR 9005-80-5[rn] OR "(51) Cr EDTA" OR 51chromium edetic acid OR “(99) Tc DTPA” OR Tc DTPA OR 65454-61-7[rn] OR Technetium Tc 99m Pentetate OR (99m)Tc-DMSA OR 99mTc(V)DMSA OR DMSA OR dimercaptosuccinic acid OR Technetium Tc 99m Dimercaptosuccinic Acid OR 65438-08-6[rn] OR 99Tc-Succimer OR 99Tc Succimer OR 99mTc-Dimercaptosuccinate OR 99mTc Dimercaptosuccinate OR renal scan OR “kidney size” OR cystatin c OR gamma-Trace OR gamma Trace OR Post-gamma-Globulin OR Post gamma Globulin OR Cystatin 3 OR Neuroendocrine Basic Polypeptide OR Basic Polypeptide, Neuroendocrine OR CST3 gene OR cystatins OR cystatin* OR renal failure OR kidney failure OR Failure, Kidney OR Failures, Kidney OR Kidney Failures OR Failure, Renal OR Failures, Renal OR Renal Failures OR renal plasma flow OR Plasma Flow, Renal OR Flow, Renal Plasma OR RPF OR ERPF OR Renal clearance OR reabsorption OR re-absorption OR nephrotoxicity OR nephrotox* OR rickets OR rickets* OR Hypertension OR hypertens* OR hypertension, renal OR Hypertensions, Renal OR Renal Hypertension OR Renal Hypertensions OR Blood Pressure, High OR Blood Pressures, High OR High Blood Pressure OR High Blood Pressures OR blood pressure OR blood pressures OR blood pressur* OR diastolic pressure OR systolic pressure

9. Final search (1 OR 2 OR 3 OR 4) AND 5 AND (6 OR 7) AND 8

[* = 1 or more characters; mh = MeSH heading; rn = registry number]

Appendix 3. Search strategy for Embase (OVID)

1. ForIfosfamide the following Emtree terms and text words were used:

1. exp ifosfamide/
2. (ifosfamide or iphosphamide or iso-endoxan or iso endoxan or isophosphamide or isofosfamide or holoxan or asta z 4942 or NSC-109,724 or NSC 109,724 or NSC109,724 or NSC 109724 or NSC-109724 or NSC109724 or cyclic p-oxides or ethylamines or oxazines or ifosfa$ or iphospha$ or isofosfa$ or isophospha$).mp.
3. (br cl fosfamide or cyfos or ifex or ifo-cell or ifolem or ifomide or ifosfamidum or ifosforamide mustard or ifoxan or ipambr or iphosphamid or isophosphoramide bromide mustard or isophosphoramide mustard or mitoxana or mjf 9325 or naxamide or seromida or tronoxal or z 4942).mp.
4. 3778-73-2.rn.
5. or/1-4

2. ForCarboplatin and cisplatin the following Emtree terms and text words were used:

1. exp platinum/ or platinum.mp.
2. Platinum Compounds.mp. or exp platinum derivative/
3. (cis-diamminedichloroplatinum or cis diamminedichloroplatinum or cis-diamminedichloroplatinum$).mp.
4. cis-diamminedichloroplatinum II.mp. or exp cisplatin/
5. (cis-platinum or cis platinum or biocisplatinum).mp.
6. (dichlorodiammineplatinum or NSC-119875 or NSC 119875 or NSC119875).mp.
7. (platidiam or platino or platinol or platinum$).mp.
8. (CDDP or CACP or CBDCA or cis-DDP).mp.
9. (cisplatin or carboplatin or abiplatin or paraplatin or neoplatin or platidiam).mp.
10. (platinum diamminodichloride or Platinum Diamminodichloride).mp.
11. 15663-27-1.rn.
12. (cis-Diammine cyclobutanedicarboxylato platinum II or Carbosin).mp.
13. (carbotec or ercar or JM-8 or JM 8 or JM8 or neocarbo or NSC-241240 or NSC 241240 or NSC241240 or carboplat or paraplatine or platinwas or blastocarb or nealorin).mp.
14. 41575-94-4.rn.
15. or/1-14

3. ForRadiotherapy the following Emtree terms and text words were used:

1. exp radiotherapy/ or exp cancer radiotherapy/ or radiotherapy.mp.
2. radiotherapy.sh.
3. (radiotherapies or targeted radiotherapies or targeted radiotherapy or radiother$).mp.
4. ((radiation and therapy) or (radiation and x ray therapy)).mp.
5. (x ray therapy or (x ray and therapy)).mp
6. (total body irradiation or TBI).mp.
7. whole-body irradiation.mp. or exp whole body radiation/
8. (whole body irradiation or whole body radiation).mp.
9. (whole-body radiation or whole-body radiations or whole body radiations).mp.
10. (whole-body irradiations or Total Body Irradiation or Total Body Irradiations).mp.
11. or/1-10

4. ForNephrectomy the following Emtree terms and text words were used:

1. exp partial nephrectomy/ or exp nephrectomy/ or nephrectomy.mp.
2. (nephrectomies or nephrect$).mp.
3. nephron sparing surgery.mp. or exp nephron sparing surgery/
4. or/1-3

5. ForChildren the following Emtree terms and text words were used:

1. infant/ or infancy/ or newborn/ or baby/ or child/ or preschool child/ or school child/
2. adolescent/ or juvenile/ or boy/ or girl/ or puberty/ or prepuberty/ or pediatrics/
3. primary school/ or high school/ or kindergarten/ or nursery school/ or school/
4. or/1-3
5. (infant$ or newborn$ or (new adj born$) or baby or baby$ or babies or neonate$ or perinat$ or postnat$).mp.
6. (child$ or (school adj child$) or schoolchild$ or (school adj age$) or schoolage$ or (pre adj school$) or preschool$).mp.
7. (kid or kids or toddler$ or adoles$ or teen$ or boy$ or girl$).mp.
8. (minors$ or (under adj ag$) or underage$ or juvenil$ or youth$).mp.
9. (puber$ or pubescen$ or prepubescen$ or prepubert$).mp.
10. (pediatric$ or paediatric$ or peadiatric$).mp.
11. (school or schools or (high adj school$) or highschool$ or (primary adj school$) or (nursery adj school$) or (elementary adj school) or (secondary adj school$) or kindergar$).mp.
12. or/5-11
13. 4 or 12

6. ForChildhood cancer the following Emtree terms and text words were used:

1. (leukemia or leukemi$ or leukaemi$ or (childhood adj ALL) or acute lymphocytic leukemia).mp.
2. (AML or lymphoma or lymphom$ or hodgkin or hodgkin$ or T-cell or B-cell or non-hodgkin).mp.
3. (sarcoma or sarcom$ or Ewing$ or osteosarcoma or osteosarcom$ or wilms tumor or wilms$).mp.
4. (nephroblastom$ or neuroblastoma or neuroblastom$ or rhabdomyosarcoma or rhabdomyosarcom$ or teratoma or teratom$ or hepatoma or hepatom$ or hepatoblastoma or hepatoblastom$).mp.
5. (PNET or medulloblastoma or medulloblastom$ or PNET$ or neuroectodermal tumors or primitive neuroectodermal tumor$ or retinoblastoma or retinoblastom$ or meningioma or meningiom$ or glioma or gliom$).mp.
6. (pediatric oncology or paediatric oncology).mp.
7. ((childhood adj cancer) or (childhood adj tumor) or (childhood adj tumors) or childhood malignancy or (childhood adj malignancies) or childhood neoplasm$).mp.
8. ((pediatric adj malignancy) or (pediatric adj malignancies) or (paediatric adj malignancy) or (paediatric adj malignancies)).mp.
9. ((brain adj tumor$) or (brain adj tumour$) or (brain adj neoplasms) or (brain adj cancer$) or brain neoplasm$).mp.
10. (central nervous system tumor$ or central nervous system neoplasm or central nervous system neoplasms or central nervous system tumour$).mp.
11. intracranial neoplasm$.mp.
12. LEUKEMIA/ or LYMPHOMA/ or brain tumor/ or central nervous system tumor/ or teratoma/ or sarcoma/ or osteosarcoma/
13. nephroblastoma/ or neuroblastoma/ or rhabdomyosarcoma/ or hepatoblastoma/ or medulloblastoma/ or neuroectodermal tumor/ or retinoblastoma/ or meningioma/ or glioma/ or childhood cancer/
14. or/1-13

7. ForCancer the following Emtree terms and text words were used:

1. (cancer or cancers or cancer$).mp.
2. (oncology or oncolog$).mp. or exp oncology/
3. (neoplasm or neoplasms or neoplasm$).mp. or exp neoplasm/
4. (carcinoma or carcinom$).mp. or exp carcinoma/
5. (tumor or tumour or tumor$ or tumour$ or tumors or tumours).mp. or exp tumor/
6. (malignan$ or malignant).mp.
7. (hematooncological or hemato oncological or hemato-oncological or hematologic neoplasms or hematolo$).mp. or exp hematologic malignancy/
8. or/1-7

8. For Nephrotoxicity the following Emtree terms and text words were used:

1. glomerular filtration rate.mp. or exp glomerulus filtration rate/
2. (GFR or glomerular filtration rates).mp.
3. (glomerular or glomerul$).mp.
4. (tubular or tubula$).mp.
5. exp tubular dysfunction/ or tubular.mp.
6. renal tubular acidosis.mp. or exp kidney tubule acidosis/
7. (RTA or renal tubular acidosis or type I renal tubular acidosis or distal renal tubular acidosis or classic distal renal tubular acidosis).mp.
8. (type II renal tubular acidosis or proximal renal tubular acidosis or renal acidosis).mp.
9. renal insufficiency.mp.
10. (renal insufficiencies or kidney insufficiency or kidney insufficiencies).mp.
11. (microalbuminuria or microalbumin$).mp.
12. exp microalbuminuria/
13. hypophosphatemia.mp. or exp hypophosphatemia/
14. (hypophosphataemia or hypophospha$).mp.
15. hypomagnesemia.mp. or exp hypomagnesemia/
16. (hypomagnes$ or hypomagnesaemia or magnesium).mp. or 7439-95-4.rn.
17. phosphate.mp. or exp phosphate/
18. (phosphates or inorganic phosphates or orthophosphate or phosphorus).mp.
19. Hyponatremia.mp. or exp hyponatremia/
20. (hyponatremias or hyponatraemia or hyponatraemias or hyponatrem$ or hyponatraem$).mp.
21. exp hypocitraturia/ or hypocitraturia.mp.
22. (hypocitraturias or hypocitraturi$).mp.
23. exp potassium/ or Potassium.mp.
24. Potassium Ion Level.mp. or 7440-09-7.rn.
25. Hypokalemia.mp. or exp hypokalemia/
26. (hypokalemias or hypopotassemia or hypopotassemias or hypokalemic or hypokalem$ or hypokalaemic or hypokalaem$).mp.
27. Hypocalcemia.mp. or exp hypocalcemia/
28. (hypocalcemias or hypocalciuria or hypocalciuri$ or hypocalcem$ or hypocalc$ or hypocarbia).mp.
29. Proteinuria.mp. or exp proteinuria/
30. (proteinurias or proteinuri$).mp.
31. albuminuria.mp. or exp albuminuria/
32. (albuminurias or albuminuri$).mp.
33. aminoaciduria.mp. or exp aminoaciduria/
34. (Renal Aminoaciduria or Renal Aminoacidurias or aminoacidur$).mp.
35. glucosuria.mp. or exp glucosuria/
36. (glucosurias or glucosur$ or glycosuria or glycosurias).mp.
37. Fanconi syndrome.mp. or exp Fanconi renotubular syndrome/
38. (renal Fanconi syndrome or proximal renal tubular dysfunction or Fanconi renotubular syndrome).mp.
39. (De Toni-Debre-Fanconi Syndrome or De Toni Debre Fanconi Syndrome or Lignac-Fanconi Syndrome or Lignac Fanconi Syndrome).mp.
40. (low molecular weight or LMW or alpha 1 microglobulin or a1 microglobulin or beta 2 microglobulin or b2 microglobulin or thymotaxin).mp.
41. retinol binding protein.mp. or exp retinol binding protein/
42. (RBP or retinol binding proteins or retinoid binding proteins or F type retinoid binding protein).mp.
43. creatinine.mp. or exp creatinine/
44. (krebiozen or creatinine sulfate salt).mp. or 60-27-5.rn.
45. exp inulin clearance/ or exp inulin/ or inulin.mp. or 9005-80-5.rn.
46. (51 Cr EDTA or 51chromium edetic acid or 99 Tc DTPA or Tc DTPA).mp. or 65454-61-7.rn.
47. Technetium Tc 99m Pentetate.mp. or exp pentetate technetium tc 99m/
48. exp succimer tc 99m/ or exp succimer/ or (99m Tc-DMSA or 99mTc V DMSA or DMSA).mp.
49. (dimercaptosuccinic acid or Technetium Tc 99m Dimercaptosuccinic Acid).mp. or 65438-08-6.rn.
50. (99Tc-Succimer or 99Tc Succimer or 99mTc-Dimercaptosuccinate or 99mTc Dimercaptosuccinate).mp.
51. (renal scan or kidney size).mp.
52. cystatin.mp. or exp cystatin/
53. (gamma-Trace or gamma Trace or Post-gamma-Globulin or Post gamma Globulin or Cystatin 3 or Neuroendocrine Basic Polypeptide).mp.
54. (CST3 gene or cystatins or cystatin$).mp.
55. renal failure.mp. or exp kidney failure/
56. (kidney failure or kidney failures or renal failures).mp.
57. renal plasma flow.mp. or exp kidney plasma flow/
58. (RPF or ERPF or Renal clearance or reabsorption or re-absorption or nephrotoxicity or nephrotox$ or rickets or rickets$).mp.
59. exp hypertension/ or (Hypertension or hypertens$).mp.
60. (Renal Hypertension or Renal Hypertensions or Renal Hypertension$).mp. or exp renovascular hypertension/
61. (High Blood Pressure or High Blood Pressures or High Blood Pressure$).mp.
62. (blood pressure or blood pressures or blood pressure$).mp. or exp blood pressure/
63. (diastolic pressure or systolic pressure).mp.
64. or/1-63

9. Final search (1 or 2 or 3 or 4) and 5 and (6 or 7) and 8

[mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name; rn = registry number; $ = 1 or more characters; / = Emtree term]

What's new

Last assessed as up-to-date: 20 May 2012.

DateEventDescription
14 April 2016AmendedContact details updated.

Contributions of authors

Sebastiaan Knijnenburg designed the study and wrote the protocol. He identified studies meeting the inclusion criteria (both by initial screening of the titles and abstract and by screening of the full-text articles). He performed data extraction and the risk of bias assessment of included studies, analysed the data and interpreted the results. He wrote and revised the manuscript.

Renée L Mulder designed the study and critically reviewed the protocol. She identified studies meeting the inclusion criteria (part of the initial screening and all full-text articles). She performed data extraction and the risk of bias assessment of included studies. She critically revised the manuscript.

Antoinette Schouten-Van Meeteren critically reviewed the protocol. She identified parts of studies that met the inclusion criteria. She critically reviewed the manuscript.

Arend Bökenkamp critically reviewed the protocol. He identified parts of studies that met the inclusion criteria. He critically reviewed the manuscript.

Hester Blufpand identified parts of studies that met the inclusion criteria. She critically reviewed the manuscript.

Eline van Dulmen-den Broeder identified parts of studies that met the inclusion criteria. She critically reviewed the manuscript.

Margreet A Veening identified parts of studies that met the inclusion criteria. She critically reviewed the manuscript.

Leontien CM Kremer designed the study and critically reviewed the protocol. She identified parts of studies that met the inclusion criteria and contributed to the interpretation of results. She critically reviewed the manuscript.

Monique WM Jaspers critically reviewed the protocol. She identified parts of studies that met the inclusion criteria. She critically reviewed the manuscript.

All authors approved the final version of the manuscript.

Declarations of interest

Leontien CM Kremer is author of several studies included in this review.

Sources of support

Internal sources

  • Dutch Cochrane Centre, Netherlands.

External sources

  • Tom Voûte Fund, Netherlands.

    Financial support

Differences between protocol and review

The protocol stated that we would include all renal outcome measurements as reported by the authors. During the data synthesis of this review, it became clear that the heterogeneity in reported outcomes of all included studies was very high. After careful deliberation about whether it would be useful to report on all these outcomes, we decided that this would add too little information. Instead, we focused on outcomes that were reported most often and that had the highest clinical relevance. We added a sentence to state that we included studies reporting on composite outcome measures covering one of the included outcomes. Additionally, we included only studies investigating hypertension when they had a clear focus on renal function, to prevent the inclusion of studies focusing on metabolic abnormalities.

In the Data Extraction section, we removed two points in comparison with the protocol: The number of participants treated with a specific combination of potentially nephrotoxic treatment (point 3.f. in the protocol) and the number of participants treated with potentially nephrotoxic antibiotics (point 3.g. in the protocol) were both reported so sporadically that systematic extraction had no use.

Some changes regarding the risk of bias assessment were made. We added the word "relevant" to the definition of a well-defined study group in Table 1: "if the treatment regimen was specified, including relevant cumulative chemotherapy and radiotherapy doses." Chemotherapy and radiotherapy dosages were assessed as relevant when a study explicitly stated that that potentially nephrotoxic therapy was part of the study's treatment protocol. For the definition of a well-defined outcome, we added "for more than 50% of the included outcomes."

We stated that we would (hand)search the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2005 to 2010), the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (from 2004 to 2010) and the European Symposium on Late Complications After Childhood Cancer 2009 (from 2007 to 2009). We also started to search for information about trials not registered in MEDLINE, EMBASE or CENTRAL, published or unpublished, by searching the reference lists of relevant articles and review articles and by scanning the International Standard Randomised Controlled Trials Number (ISRCTN) register and the National Institutes of Health (NIH) register for ongoing trials: http://www.controlled-trials.com. However, because of the sheer volume of references retrieved from the online databases, we did not have resources available to search the aforementioned sources.

We adapted the risk of bias assessment criteria for an adequate follow-up and for a well-defined outcome. The original definition of low risk of follow-up bias was as follows: if the outcome was assessed at the end date of the study for 60% to 90% of the study group, or if the outcome was assessed for more than 90% of the study group but with an unknown end date. Because no straightforward definition is available for the end date of the study, we decided to change this risk of bias item. The new definition of low risk of follow-up bias is as follows: if the outcome was assessed for more than 90% of the study group of interest (++), or if the outcome was assessed for 60% to 90% of the study group of interest (+). In the protocol we had not yet specified the definition of a well-defined outcome. The definition is as follows: if the outcome definition was objective and precise, that is, if the upper or lower limits of normal for renal function tests were described in the definition of renal adverse effects.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Aronson 2011

MethodsCross-sectional cohort study
Participants

N of participants in original cohort: 29; N of participants described study group: 25; N of participants in study group of interest: 25; N of participants with renal function tests: 25

Tumour: Bilateral Wilms tumour: 25/25 (100%). Time period diagnosis/treatment: 1967-2007. %M/F: 28%/72%

Age at diagnosis: median: 1.03 years (range 0.27 to 5.35 years); Age at follow-up: Median: 15.0 years (range 5.4 to 34.0 years); Follow-up duration: median: 10.5 years (range 5.5 to 34 years); Completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: n/m; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: n/m; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 25/25 (100%); nephrectomy details: bilateral total nephrectomy: 3/25 (12%); unilateral total nephrectomy + contralateral partial nephrectomy: 14/25 (56%); bilateral partial nephrectomy: 8/25 (32%)

N of participants radiotherapy including the kidney region: 5/25 (20%); radiotherapy field: n/m; radiation dose: n/m

Outcomes

Chronic kidney disease/renal insufficiency

Definition of renal adverse effect
Serum creatinine > 1.2 mg/100 mL

Observed values of renal adverse effects
Median: 0.7 mg/100 mL (range 0.5 to 2.8)

N of participants with renal adverse effect
8/25 (32%), of whom 5 received a renal transplant (3 after bilateral nephrectomy, 2 for ESRD), and 3 with mild renal insufficiency (creatinine > 1.2)

Risk factors (univariate analyses)
Mean creatinine values were significantly lower after bilateral nephron sparing surgery (partial nephrectomy or enucleation) as compared with other types of surgery (P < 0.0001). Mean creatinine values showed lower trend in participants treated without radiotherapy (NS)

NotesPossible overlap between the study groups of Geenen 2010, Van Dijk 2010, Aronson 2011 and Cardous-Ubbink 2010
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskRelevant chemotherapy and radiotherapy regimens were not specified
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was no random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskFollow-up duration was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definition was objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Bardi 2004

MethodsProspective cohort study
Participants

N of participants original cohort: n/m; N of participants described study group: 115; N of participants study group of interest: unclear; N of participants with renal function tests: 115

Tumour: leukaemia/lymphoma: 60/115 (52%), Wilms' tumour: 22/115 (19%), (other) solid tumours: 33/115 (29%). Time period diagnosis/treatment: 1984-2001. %M/F: 57%/43%

Age at diagnosis: median: 5 years (range 0.3 to 20); age at follow-up: median: 13 years (range 3 to 24); Follow-up duration: median: 7 years (range 2 to 23); completion of follow-up: 100%

Controls: 86 children with no renal or urinary tract disease (46 males/40 females; median age 10 years; age range: 2 to 20 years)

Interventions

N of participants ifosfamide: Wilms' tumour: 4/22; other tumours: n/m; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m, but possibly given to solid tumour participants; cisplatin cumulative dose: n/m
N of participants carboplatin: Wilms' tumour: 4/22 (18%); other tumours: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: HD MTX, cyclophosphamide (N = 60), vincristine, dactinomycin (N = 18); other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 22/115 (19%, or 100% of all Wilms' tumour participants); nephrectomy details: 21/22 heminephrectomy, 1/22 polar resection

N of participants radiotherapy including the kidney region: Wilms' tumour: 11/22 (50%); radiotherapy field: flank radiation; radiation dose: n/m

Outcomes

Chronic kidney disease/renal insufficiency

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
1/115 (0.9%)

Risk factors
n/m

GFR: estimated glomerular filtration rate by Counahan formula

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Mean GFR (SD):
Overall: 102 mL/min/1.73 m2

Controls: 132 (79) mL/min/1.73 m2

Wilms tumour: 71 (27) mL/min/1.73 m2 (P < 0.05 vs controls)

N of participants with renal adverse effect
n/m

Risk factors

n/m

Proteinuria (gross) by dipstick

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
At first measurement: 30/115 (26.1%); twelve months after first measurement: 10/115 (8.7%); three years after first measurement: 3/115 (2.6%); of the 10/115 with persistent gross proteinuria, five had glomerular and five had glomerular/tubular proteinuria

Risk factors
n/m

Proteinuria measured by microalbuminuria in 24-hour urine

Definition of renal adverse effect
> 20 mg/L

Observed values of renal adverse effects
Mean (SD) in mg/L: leukaemia/lymphoma: 16.4 (2.1); Wilms' tumour: 16.6 (2.4); solid tumour: 24.9 (2.7); controls: 15.8 (1.2); P < 0.05 for solid tumours vs controls

N of participants with renal adverse effect
Leukaemia/lymphoma: 12; Wilms' tumour: 1; solid tumour: 7; controls: n/m

Risk factors
n/m

NotesExact number of participants treated with nephrotoxic treatments is unclear. However, 100% of the Wilms' tumour group received a nephrectomy (N = 22), and all other participants received cisplatin, carboplatin, ifosfamide or high-dose methotrexate
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskRelevant cumulative chemotherapy and radiotherapy doses were not specified
Representative study groupUnclear riskOriginal cohort size was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskOutcome definition was not mentioned for 2 of 3 outcome measures
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Bergeron 2005

MethodsProspective cohort study
Participants

N of participants original cohort: 46; N of participants described study group: 30; N of participants study group of interest: 30; N of participants with renal function tests: 30

Tumour: neuroblastoma. Time period diagnosis/treatment: 1990-1994. %M/F: 63%/37%

Age at diagnosis: median 4.7 months (range 0 to 10 months); age at follow-up: median 6 years (range 4.5 to 9.2); follow-up duration: median time since diagnosis: 7 years (range 4.5 to 9.5); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 0/30 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 0/30 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 30/30 (100%); carboplatin cumulative dose: median 267 mg (102 to 700)

Other types of chemotherapy: etoposide, vincristine, cyclophosphamide, doxorubicin; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: n/m; nephrectomy details: n/m

N of participants radiotherapy including the kidney region: n/m; radiotherapy field: n/m; radiation dose: n/m

Outcomes

GFR: estimated glomerular filtration rate by the Schwartz formula

Definition of renal adverse effect
eGFR < 90 mL/min/1.73 m2

Observed values of renal adverse effects
Mean GFR: 114 mL/min/1.73 m2 (SD 13; range 87 to 145)

N of participants with renal adverse effect
1/30 (3%)

Risk factors (all univariate analyses)
No relation between GFR and cumulative carboplatin dose

Proteinuria measured by urinary albumin/creatinine ratio

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Mean: 0.4 mmol/mmol (SD 0.2; range 0.1 to 0.7)

N of participants with renal adverse effect
0/25 (0%)

Risk factors
n/m

Tubular phosphate regulation parameters measured by renal tubular phosphate threshold

Definition of renal adverse effect
< 1 mmol/L or > 1.7 mmol/L

Observed values of renal adverse effects
Mean: 1.3 mmol/L (SD 0.1; range 1.0 to 1.6)

N of participants with renal adverse effect
1/30 (3%)

Risk factors
n/m

Serum magnesium/hypomagnesaemia

Definition of renal adverse effect
Serum magnesium < local normal values

Observed values of renal adverse effects
Mean: 0.82 mmol/L (SD 0.06; range 0.68 to 0.99)

N of participantswith renal adverse effect
0/25 (0%)

Risk factors
n/m

Blood pressure

Definition of renal adverse effect
Systolic and/or diastolic blood pressure > 97.5th percentile for age and sex

Observed values of renal adverse effects
n/a

N of participants with renal adverse effect
4/30 (13%) with borderline hypertension (97.5th percentile)

Risk factors                 
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definition was objective and precise for 4/5 of reported outcome measures
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisHigh riskNo risk measurements were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Bolling 2010

MethodsProspective cohort study
Participants

All tumour- and age-related characteristics were described for the 126 participants in the described study group

N of participants original cohort: 1086; N of participants described study group: 126; N of participants study group of interest: 126; N of participants with renal function tests: 74

Tumour: Ewing sarcoma: 31/126 (25%), Hodgkin’s disease 31/126 (25%), neuroblastoma 23/126 (18%), nephroblastoma 17/126 (13%), soft tissue sarcoma 10/126 (8%), other tumours 14/126 (11%). Time period diagnosis/treatment: 2001-May 2009. %M/F: n/m

Age at diagnosis: median 10.2 yr (range 1.7 to 28) at radiotherapy; age at follow-up: n/m; follow-up duration: median 28.5 months (range 4 to 88 months); completion of follow-up: 76/126 (60%)

Controls: n/a

Interventions

N of participants ifosfamide: n/m, but at least one; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m, but at least one; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m, but at least one; carboplatin cumulative dose: n/m

Other types of chemotherapy: additional chemotherapy for 126/126, including carboplatin, cisplatin, ifosfamide and/or methotrexate in 81/126 (64%); other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 20/126 (16%); nephrectomy details: unilateral nephrectomy (N = 18), partial nephrectomy (N = 2)

N of participants radiotherapy including the kidney region: 126/126 (100%); radiotherapy field: n/m; radiation dose: detailed dosimetry per participants

Outcomes

Composite outcome including creatinine clearance, proteinuria, haematuria and serum creatinine

Definition of renal adverse effect

Grading system based on RTOG/EORTC criteria:
Grade 1: serum creatinine > upper normal limit OR creatinine clearance < 90 mL/min/1.73 m2 OR proteinuria < 3 g/L OR haematuria as microscopic hematuria or more; and
Grade 2: serum creatinine > 1.5 upper normal limit OR creatinine clearance < 60 mL/min/1.73 m2 OR proteinuria < 10 g/L OR haematuria as macroscopic haematuria without clot passage

Observed values of renal adverse effects
n/a

N of participantswith renal adverse effect
Maximal grade of toxicity during follow-up:
Grade 1: 7/74 (9%)
Grade 2: 2/74 (3%)

Last grade of late toxicity:
Grade 1: 4/74 (5%)
Grade 2: 1/74 (1%)

Risk factors (univariate analyses)
More toxicity in participants treated with higher exposed kidney volumes (kidney volume exposed to 20 Gy: P = 0.031; kidney volume exposed to 30 Gy: P = 0.003). No significant differences in the comparison of organ volumes exposed to all other doses: 5, 10, 15, 40, 50 Gy

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskRelevant numbers of participants and cumulative chemotherapy and radiotherapy doses were not specified
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for 60% of the study group of interest (+)
Well-defined outcomeHigh riskOutcome definition objective but not precise: multiple outcomes combined into one
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisHigh riskNo risk measurements were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Breslow 2005

MethodsRecord linkage study
Participants

N of participants original cohort: 5910; N of participants described study group: 5910; N of participants study group of interest: 5910; N of participants with renal function tests: n/a (cases were ascertained using medical record linkage between the NTWS and the United States Renal Data System)

Tumour: unilateral Wilms' tumour: 5526; bilateral Wilms' tumour: 450 (384 at diagnosis and 66 participants with unilateral disease who later developed a metachronous tumour in the contralateral kidney). Time period diagnosis/treatment: October 1969 to September 1994. %M/F: n/m

Age at diagnosis: n/m; age at follow-up: n/m; follow-up duration: mean 11.5 years; completion of follow-up: n/m

Controls: n/a

Interventions

N of participants ifosfamide: n/m; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: NTWS-protocols 1-4; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: not explicitly mentioned. 41/53 (77%) of survivors with ESRD had bilateral nephrectomy or unilateral + partial nephrectomy with < 25% tissue remaining; Nephrectomy details: n/m

N of participants radiotherapy including the kidney region: n/m; radiotherapy field: n/m; radiation dose: n/m

Outcomes

Chronic kidney disease/renal insufficiency

Definition of renal adverse effect
Treatment with chronic dialysis or kidney transplant

Observed values of renal adverse effects
n/a

N of participants with renal adverse effect:
N affected/N total (prevalence/cumulative incidence ESRD with death as competing risk)

Unilateral Wilms' tumour (N = 5526):

Denys Drash syndrome: 12/17 (70.6%/74%)

WAGR syndrome: 11/37 (29.7%/36%)

Genitourinary anomalies: 4/125 (3.2%/6.7%)

No congenital malformations: 25/5347 (0.5%/0.6%)

 

Bilateral Wilms' tumour (N = 450):

Denys-Drash syndrome: 3/6 (50%/50%)

WAGR syndrome: 5/10 (50%/90%)

Genitourinary anomalies: 8/25 (32%/25%)

No congenital malformations: 44/409 (10.8%/11.5%)

Risk factors

n/m

NotesChildren with a metachronous bilateral tumour were included in the analyses of both unilateral and bilateral disease
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo chemotherapy and radiotherapy regimens were specified
Representative study groupUnclear riskUnclear because of the nature of the record linkage study
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentUnclear riskUnclear because of the nature of the record linkage study
Well-defined outcomeLow riskOutcome definition was objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analysis was performed
Adjustment for important confoundersUnclear riskNo analysis was performed

Brock 1991

MethodsProspective cohort study
Participants

N of participants original cohort: 55; N of participants described study group: 40; N of participants study group of interest: 40; N of participants with renal function tests: 40

Tumour: neuroblastoma: 27/40 (68%), germ cell tumour: 8/40 (20%), hepatoblastoma: 3/40 (8%), osteogenic sarcoma: 2/40 (5%). Time period diagnosis/treatment: 1979-1988. %M/F: 62%/38%

Age at diagnosis: median: 15 months (range 13 days to 13 years 8 months); age at follow-up: n/m; follow-up duration: median: 2.5 years (range 1.5 to 7); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 0/40 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 40/40 (100%); cisplatin cumulative dose: median: 500 mg/m2 (range 120 to 1860)
N of participants carboplatin: 0/40 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: neuroblastoma: cyclophosphamide, vincristine, teniposide-etoposide and high-dose melphalan; germ cell tumour: bleomycin, vinblastine-etoposide; hepatoblastoma: doxorubicin; osteosarcoma: doxorubicin and methotrexate; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 0/40 (0%); nephrectomy details: n/a

N of participants radiotherapy including the kidney region: 0/40 (0%); radiotherapy field: n/a; radiation dose: n/a

Outcomes

Glomerular filtration rate by 51Cr-EDTA clearance

Definition of renal adverse effect
GFR < 80 mL/min/1.73 m2

Observed values of renal adverse effects
Median GFR in mL/min/1.73 m2 (range)

End of treatment: 74 (13 to 184)

At follow-up: 90 (27 to 135)

N of participants with renal adverse effect
End of treatment: 13/40 (33%) 60 to 80 mL/min/1.73 m2; 11/40 (28%) < 60 mL/min/1.73 m2

At follow-up: 15/40 (38%) 60 to 80 mL/min/1.73 m2; 2/40 (5%) < 60 mL/min/1.73 m2

Risk factors (all univariate analyses)
GFR significantly improved from end of treatment at 1-, 2- and 4-year follow-up (P < 0.05)

Children with an end-of-treatment GFR of 60 to 80 mL/min/1.73 m2 had a significantly better chance to regain a GFR of at least 80 mL/min/1.73 m2 than those who had a GFR < 60 mL/min/1.73 m2 (P < 0.01)

At end-of-treatment, no significant correlation between GFR and cumulative cisplatin dose, age, sex, tumour type or associated nephrotoxic medications

No significant correlation between GFR recovery and cumulative cisplatin dose

Serum magnesium/hypomagnesaemia

Definition of renal adverse effect
Age-specific reference values

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
6/21 (29%)

Risk factors (univariate analyses)No correlation was found with GFR

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definition was objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Cardous-Ubbink 2010

MethodsNested case control study
Participants

N of participants original cohort: 1362; N of participants described study group: 1080; N of participants study group of interest: unclear; N of participants with renal function tests: 1080. All following data represent the 44 cases and 123 matched controls (N = 167)

Tumour: leukaemia: 26/167 (15.6%), lymphoma: 44/167 (26.3%), Wilms' tumour: 47/167 (28.1%), brain/CNS: 18/167 (10.8%), bone: 9/167 (5.4%), soft tissue sarcoma: 16/167 (9.6%), other: 7/167 (4.2%). Time period diagnosis/treatment: 1966-1996. %M/F: 56%/44%

Age at diagnosis: median 7.7 years; Age at follow-up: median 28.0 years; follow-up duration: median 20.4 years; completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 9/167 (5.4%); ifosfamide cumulative dose: n/m
N of participants cisplatin: 7/167 (4.2%); cisplatin cumulative dose: n/m
N of participants carboplatin: 0/167 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: any chemotherapy: 146/167 (87.4%). Chemo besides cisplatin/ifosfamide: 134/167 (80.2%); other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 47/167 (28.1%); nephrectomy details: n/m

N of participants radiotherapy including the kidney region: any radiotherapy: 102/167 (61.1%); radiotherapy field: abdominal RT: 54/167 (32.3%); radiation dose: n/m

Outcomes

Blood pressure

Definition of renal adverse effect
Blood pressure systolic ≥ 140 mmHg or diastolic ≥90 mmHg at least at three consecutive visits

Observed values of renal adverse effects
-

N of participants with renal adverse effect
44/1080 (4.1%). Unclear how many of the 1080 were treated with potentially nephrotoxic treatment

Risk factors (multivariate analyses)
Multivariate logistic regression:

Significant: BMI ≥ 25 kg/m2: OR: 3.95 (95% CI: 1.71 to 9.09), P = 0.001

Not significant: cisplatin, cyclophosphamide, ifosfamide, other chemotherapy, abdominal radiation, cranial radiation

Notes

Unclear how many of the 1080 described survivors were originally treated with nephrotoxic treatment, so the prevalence of 4.2% cannot be interpreted regarding potentially nephrotoxic treatment.

Possible overlap between the study groups of Geenen 2010, Van Dijk 2010, Aronson 2011 and Cardous-Ubbink 2010

Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskCumulative chemotherapy and radiotherapy doses were not specified
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed in 100% of all described participants, which included the study group of interest (++)
Well-defined outcomeLow riskOutcome definition was objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersLow riskImportant prognostic factors were taken into account using multivariate logistic regression

Chevallier 1997

MethodsProspective cohort study
Participants

N of participants original cohort: 30; N of participants described study group: 30; N of participants study group of interest: 30; N of participants with renal function tests: 30

Tumour: Wilms' tumour 30/30 (100%). Time period diagnosis/treatment: 1986-1993. %M/F: n/m

Age at diagnosis: mean 3.4 years (SD 2.5); age at follow-up: n/m; follow-up duration: mean 4.6 years (SD 3.1); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 2/30 (6.6%); ifosfamide cumulative dose: 60 g/m2 and 3.3 g
N of participants cisplatin: 1/30 (3.3%); cisplatin cumulative dose: 35 mg
N of participants carboplatin: 0/30 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: vincristine, actinomycin and adriamycin (28/30) and other regimens in 2/30; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 30/30 (100%); nephrectomy details: unilateral nephrectomy

N of participants radiotherapy including the kidney region: 6/30 (20%); radiotherapy field: abdomen; radiation dose: 15 Gy + 20 Gy boost to the tumour

Outcomes

GFR: glomerular filtration rate by inulin clearance

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Mean GFR 93 mL/min/1.73 m2 (SD 13)

N of participants with renal adverse effect
n/m

Risk factors (univariate analyses)
No difference between < 4 and ≥ 4 years' follow-up. No difference between nephrectomised before or after age of 2

Proteinuria measured by urinary albumin/creatinine ratio

Definition of renal adverse effect
> 2 g/mol

Observed values of renal adverse effects
Mean (SD): 2.8 g/mol (2.2 g/mol)

N of participants with renal adverse effect
14/30 (47%) had a urinary albumin-to-creatinine ratio > 2 g/mol

Risk factors (univariate analyses)
No difference between < 4 and ≥ 4 years' follow-up. No difference between nephrectomised before or after age of 2

Tubular phosphate regulation parameters measured by fractional phosphate reabsorption

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Mentioned only for subgroups

N of participants with renal adverse effect
0/30 (0%)

Risk factors (univariate analyses)
No difference between < 4 and ≥ 4 years' follow-up. No difference between nephrectomised before or after age of 2

Blood pressure

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
0/30 (0%)

Risk factors (univariate analyses)
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcomes were assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskOutcome definition was objective but not precise; no cut-off values were mentioned for 3/4 outcomes
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Cosentino 1993

MethodsRetrospective cohort study
Participants

N of participants original cohort: unclear; N of participants described study group: 234; N of participants study group of interest: 234; N of participants with renal function tests: n/m

Tumour: Wilms' tumour 234/234 (100%). Time period diagnosis/treatment: 1965-1989. %M/F: 54%/46%

Age at diagnosis: mean: 40 months (range 3 days to 145 months); age at follow-up: n/m; follow-up duration: n/m; completion of follow-up: unclear

Controls: n/a

Interventions

N of participants ifosfamide: n/m; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: n/m; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 234/234 (100%); nephrectomy details: n/m

N of participants radiotherapy including the kidney region: n/m; radiotherapy field: n/m; radiation dose: n/m

Outcomes

Chronic kidney disease/renal insufficiency

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
7/234 (3.0%)

Risk factors
5/7 needed haemodialysis. All five received a nephrectomy followed by a subsequent partial nephrectomy

NotesSurvivors treated according to NWTS study protocols
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo description of chemotherapy and radiotherapy was provided
Representative study groupUnclear riskSize of original cohort was not mentioned
Well-defined follow-upHigh riskNo duration of follow-up was mentioned
Complete follow-up assessmentUnclear riskNumber of participants with renal tests was not mentioned
Well-defined outcomeHigh riskOutcome definition was not mentioned
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analysis was performed
Adjustment for important confoundersUnclear riskNo analysis was performed

Cozzi 2005

MethodsCross-sectional cohort study
Participants

N of participants original cohort: 30; N of participants described study group: 26; N of participants study group of interest: 26; N of participants with renal function tests: 26

Tumour: Wilms' tumour. Time period diagnosis/treatment: 1992-2003. %M/F: 35%/65%

Age at diagnosis: mean (SD): NP: 60.0 months (40.7); NSS: 42.7 months (42.0); age at follow-up: n/m; follow-up duration: mean (SD): NP: 71.9 months (41.0); NSS: 65.3 months (38.6); completion of follow-up: 100%

Group 1: nephrectomy (NP, 16/26)

Group 2: nephron sparing surgery (NSS, 10/26)

Controls: n/a

Interventions

N of participants ifosfamide: 0/26 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 0/26 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/26 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: NP (12/16): vincristine + actinomycin D (N = 2); vincristine + actinomycin D + epirubicin (N = 10); NSS (7/10): vincristine + actinomycin D (N = 2); vincristine + actinomycin D + epirubicin (N = 5); other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 26/26 (100%); nephrectomy details: group 1: unilateral nephrectomy (NP, N = 16); group 2: nephron sparing surgery (NSS, N = 10)

N of participants radiotherapy including the kidney region: 0/26 (0%); radiotherapy field: n/a; radiation dose: n/a

Outcomes

Proteinuria measured by urinary albumin-to-creatinine ratio (in mg/mmol)

Definition of renal adverse effect
> 20 mg/mmol

Observed values of renal adverse effects
Mean (SD) in mg/mmol: NP: 12.6 (9.38); NSS: 11.02 (5.46); P = 0.63

N of participants with renal adverse effect
NP: 2/16 (12.5%); NSS: 0/10 (0%)

Risk factors
n/m

Blood pressure

Definition of renal adverse effect
Blood pressure > 2 standard deviations of expected mean for age and sex

Observed values of renal adverse effects
Mean (SD) in mmHg: systolic NP: 112.5 (8.6); systolic NSS: 100.0 (9.1) P < 0.001; diastolic NP: 72.5 (8.4); diastolic NSS: 63.5 (7.1) P < 0.001; systolic SDS NP: 0.72 (0.74); systolic SDS NSS: -0.10 (0.92) P = 0.01; diastolic SDS NP: 0.87 (0.77); diastolic SDS NSS: 0.19 (0.62) P = 0.01

N of participants with renal adverse effect
NP: 2/16 (12.5%) with a systolic SDS > 2 SD; NSS: 0/10 (0%) with a systolic SD S >2SD

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

de Graaf 1996

MethodsProspective cohort study
Participants

N of participants original cohort: 48; N of participants described study group: 41; N of participants study group of interest: 41; N of participants with renal function tests: 41

Tumour: Wilms' tumour: 41/41 (100%). Time period diagnosis/treatment: n/m. %M/F: 39%/61%

Age at diagnosis: median: 3 years 3 months (range 5 months to 9 year 9 months); age at follow-up: median (range): radiated group: 62 months (25 to 125); no-radiation group: 43 months (18 to 139); follow-up duration: median: 13 months (range 11 to 22); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 0/41 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 0/41 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/41 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: vincristine, actinomycin D: 41/41 (100%)

Doxorubicin: 12/41 (29%); other chemotherapy cumulative doses: median doxorubicin dose: 300 mg/m2 (range 150 to 480). n/m for vincristine and actinomycin D

N of participants nephrectomy: 41/41 (100%); nephrectomy details: unilateral nephrectomy

N of participants radiotherapy including the kidney region: 12/41 (29%); radiotherapy field: fields including the kidney region; radiation dose: range: 1000 to 2250 cGy

Outcomes

GFR using 125-I-iothalamate clearance, expressed as standard deviation scores

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Mean GFR (SD):

All participants: -0.57 (1.74)

No-radiation group: -0.27 (1.82)

Irradiated group: -1.51 (1.05)

P = 0.022 for non-radiated versus irradiated participants

Percentage of GFR for normal age-match children

No irradiation: 94.6%

Radiation: 72.7%

N of participants with renal adverse effect
n/m

Risk factors (univariate analyses)
GFR was significantly lower in the irradiated group than in the non-irradiated group (P = 0.022, Mann-Whitney U-test)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupLow riskDescribed study group consisted of only 85% of the original cohort but was a random sample with respect to treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskOutcome definition was objective but not precise, with no cut-off values mentioned
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Di Tullio 1996

MethodsRetrospective cohort study
Participants

N of participants original cohort: unclear; N of participants described study group: 34; N of participants study group of interest: 34; N of participants with renal function tests: 34.

Tumour: Wilms' tumour: 34/34 (100%). Time period diagnosis/treatment: n/m. %M/F: 35%/65%

Age at diagnosis: n/m; age at follow-up: mean: 12.1 years (range 2.1 to 19.6); follow-up duration: mean: 8.6 years (range 2.7 to 15.8); completion of follow-up: 34/34 (100%)

Controls: n/a

Interventions

N of participants ifosfamide: 1/34 (3%); ifosfamide cumulative dose: 18 g/m2
N of participants cisplatin: 1/34 (3%); cisplatin cumulative dose: 180 mg/m2
N of participants carboplatin: 0/34 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: actinomycin D + vincristine (+ adriamycin); other chemotherapy cumulative doses: actinomycin D: 15 mcg/g per course; vincristine: 1.5 mg/m2 per course; adriamycin: 50 mg/m2

N of participants nephrectomy: 34/34 (100%); nephrectomy details: unilateral nephrectomy in all cases

N of participants radiotherapy including the kidney region: 23/34 (68%); radiotherapy field: tumour bed and/or abdomen, with shielding for contralateral kidney; radiation dose: 15 to 35 Gy

Outcomes

GFR using creatinine clearance, method not mentioned

Definition of renal adverse effect
< 80 mL/min/1.73 m2

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
1/34 (3%)

Risk factors
This was the only child treated with additional cisplatin and ifosfamide

Proteinuria measured by microalbuminuria

Definition of renal adverse effect
Urinary albumin excretion > 20 mg/24 h

Observed values of renal adverse effects
Mean microalbuminuria: 48 mg/24 h (SD 94)

N of participants with renal adverse effect                     
11/34 (32%) with urinary albumin > 20 mg/24 h

4/34 (12%) with proteinuria (> 4 mg/m2/h)

Risk factors (univariate analyses)

Mean microalbuminuria was related to time from nephrectomy (rs 0.39; P = 0.026)

Blood pressure

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
0/34 (0%)

Risk factors
n/m

NotesSame study group as Indolfi 2001
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupUnclear riskSize of original cohort was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definition was given for two of the three outcomes
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

English 1999

MethodsProspective cohort study
Participants

N of participants original cohort: n/m; N of participants described in the study group: 23; N of participants study group of interest: 23; N of participants with renal function tests: 23

Tumour: glioma: 2/23 (9%); dysgerminoma 1/23 (4%); astrocytoma: 1/23(4%); PNET: 5/23 (22%); sacrococcygeal teratoma: 2/23 (9%); neuroblastoma: 1/23 (4%); retinoblastoma: 1/23 (4%); hypothalamic teratoma: 3/23 (13%); pineal teratoma: 1/23 (4%); low-grade astrocytoma: 3/23 (13%); teratoma: 2/23 (9%); pineal dysgerminoma: 1/23 (4%). Time period diagnosis/treatment: 1988-1994. %M/F: 57%/43%

Age at diagnosis: n/m; age at follow-up: n/m; follow-up duration: measurements at 1 year and 2 years post-treatment, not further specified; Completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 0/23 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 0/23 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 23/23 (100%); carboplatin cumulative dose: median: 2590 mg/m2 (range 1364 to 7133)

Other types of chemotherapy: HD methotrexate: 3/23 (13%), not mentioned otherwise; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: n/m; nephrectomy details: n/m

N of participants radiotherapy including the kidney region: n/m; radiotherapy field: n/m; radiation dose: n/m

Outcomes

GFR using 51Cr-EDTA clearance

Definition of renal adverse effect
GFR < 90 mL/min/1.73 m2

Observed values of renal adverse effects
Only fall in GFR from pretreatment to mean post-treatment value reported: mean -22 mL/min/1.73 m2 (95% CI 5 to 38; P = 0.012)

N of participants with renal adverse effect
n/m

Risk factors (univariate analyses)
Cumulative dose and cumulative AUC were not related to GFR after treatment, nor was change in GFR from before to after treatment. GFR did not change significantly over the 2 years after completion of treatment

Serum magnesium/hypomagnesaemia

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Difference in serum Mg between pretreatment and post-treatment: mean -0.17 mmol/L (95% CI 0.06 to 0.28 L; P = 0.0077)

N of participants with renal adverse effect
1/23 (4%) with symptomatic hypomagnesaemia 1 year after completion of carboplatin treatment

Risk factors (univariate analyses)
Magnesium did not change significantly over the 2 years after completion of treatment. Higher carboplatin dose was related to lower serum magnesium post-treatment (P = 0.031). Higher carboplatin dose was related to reduction in serum magnesium over time (P < 0.001). Carboplatin dose intensity was not related to serum magnesium levels nor to change in levels over time. Cumulative carboplatin AUC was related to lower serum magnesium post-treatment (P = 0.004)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupUnclear riskOriginal cohort size was not mentioned
Well-defined follow-upLow riskDuration of follow-up was mentioned for each individual participant
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskOutcome definitions were objective and precise for one of the two outcome measurements
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersUnclear riskUnclear whether univariate or multivariate linear regression was used

Ferrari 2005

MethodsProspective cohort study
Participants

N of participant original cohort: unclear; N of participant described study group: 43; N of participant study group of interest: 28; N of participant with renal function tests: 28

Tumour: osteosarcoma: 43/43 (100%). Time period diagnosis/treatment: n/m. %M/F: n/m

Age at diagnosis (n = 43): median 16 years (range 4 to 34) (<19 years: n = 28); age at follow-up: n/m; follow-up duration (n = 43): median 16 months (range 9 to 49); completion of follow-up (n = 43): 100%

Controls: n/a

Interventions

N of participant ifosfamide: 28/28 (100%); ifosfamide cumulative dose: median 73.5 g/m2
N of participant cisplatin: 28/28 (100%); cisplatin cumulative dose: median 598 mg/m2
N of participant carboplatin: 0/28 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: HD-MTX: 28/28 (100%); doxorubicin: 28/28 (100%); other chemotherapy cumulative doses: HD-MTX: median 60.1 g/m2; doxorubicin: n/m

N of participant nephrectomy: n/m; nephrectomy details: n/m

N of participant radiotherapy including the kidney region: n/m; radiotherapy field: n/m; radiation dose: n/m

Outcomes

GFR using creatinine clearance

Definition of renal adverse effect
< 90 mL/min/1.73 m2

Observed values of renal adverse effects
Not mentioned for late renal function assessment

N of participants with renal adverse effect
21/43 (49%) < 90 mL/min/1.73 m2

Risk factors (univariate analyses)
No statistically significant relationship was found between creatinine clearance and excretion of albumin or A1M

Tubular phosphate regulation parameters measured by renal tubular phosphate threshold (TmP/GFR)

Definition of renal adverse effect
TmP/GFR < 1 mmol/L

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
Paediatric survivors: 13/28 (46%)

Risk factors (univariate analyses)
No statistically significant relationship was found between TmP/GFR and excretion of albumin or A1M

Notes28 of the 43 described survivors were children at diagnosis. All data are presented for the described study group, with the exception of the renal tubular phosphate threshold, which was presented separately for children
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupUnclear riskSize of original cohort was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisHigh riskNo risk measurements were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Finklestein 1993

MethodsRetrospective cohort study
Participants

N of participant original cohort: 2243; N of participant described study group: 2243; N of participant study group of interest: 2243; N of participant with renal function tests: 1528

Tumour: unilateral Wilms' tumour. Time period diagnosis/treatment: 1969 to n/m. %M/F: at first measurement: 48%/52%

Age at diagnosis: n/m; age at follow-up: n/m; follow-up duration: at least 5 years; completion of follow-up: 68%

Controls: n/a

Interventions

N of participant ifosfamide: 0/2243 (0%); ifosfamide cumulative dose: n/a
N of participant cisplatin: 0/2243 (0%); cisplatin cumulative dose: n/a
N of participant carboplatin: 0/2243 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: NWTS-1, NWTS-2 and NWTS-3 regimens (including actinomycin-D, vincristine, doxorubicin, cyclophosphamide); other chemotherapy cumulative doses: n/m

N of participant nephrectomy: 2243/2243(100%); nephrectomy details: unilateral nephrectomy

N of participant radiotherapy including the kidney region: at least 48 of 62 with high blood pressure; radiotherapy field: n/m; radiation dose: median 25 Gy (10 to 40 Gy)

Outcomes

Blood pressure (diastolic)

Definition of renal adverse effect
> 95th percentile for age and sex

Observed values of renal adverse effects
n/a

N of participants with renal adverse effect
Overall: 62/1528 with diastolic pressure > 90 mmHg (4.1%) at any time point (Table 2); first measurement after 5 years > 95th percentile for age and sex: 83/1171 (7.1%)

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskChemotherapy doses were not described, and no radiotherapy information was provided for the whole cohort, only for those with hypertension
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upHigh riskNo length of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for 68% of the study group of interest (+)
Well-defined outcomeLow riskOutcome definition was objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisHigh riskNo risk estimates were provided, only P values, and not for > 90% of the cohort
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Frisk 2002

MethodsProspective cohort study
Participants

N of participant original cohort: 44; N of participant described study group: 40; N of participant study group of interest: 26; N of participant with renal function tests: 26

Tumour: acute lymphoblastic leukaemia, acute myeloid leukaemia, lymphoblastic lymphoma, large cell anaplastic lymphoma and Hodgkin's disease. Time period diagnosis/treatment: October 1985 to August 1997. %M/F: +TBI: 62%/38%; -TBI: 64%/36%

Age at diagnosis: +TBI: median 8.4 years (range 3.6 to 17.7); -TBI: 13.2 years (range 1.9 to 17.9); age at follow-up: n/m; follow-up duration: median: +TBI 120 months; -TBI 54 months; completion of follow-up: 100%

N of participant +TBI group: 26. N of participant -TBI group: 14

Controls: n/a

Interventions

N of participant ifosfamide: 0/40 (0%); ifosfamide cumulative dose: n/a
N of participant cisplatin: 0/40 (0%); cisplatin cumulative dose: n/a
N of participant carboplatin: 0/40 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: +TBI group: prednisolone, teniposide, daunorubicin, vincristine, cyclophosphamide and cytarabine; -TBI group: BCNU, etoposide, cytarabine and cyclophosphamide; other chemotherapy cumulative doses: n/m

N of participant nephrectomy: 0/40 (0%); nephrectomy details: n/a

N of participant radiotherapy including the kidney region: 26/40 (65%); radiotherapy field: total body irradiation; radiation dose: 7.5 Gy (N = 22); 12 Gy (N = 4)

Outcomes

GFR using 51Cr-EDTA clearance

Definition of renal adverse effect
Chronic renal impairment defined as GFR < 70 mL/min/1.73 m2

Observed values of renal adverse effects
Mean GFR before BMT (95% CI): 

+TBI: 124 (114 to 134); -TBI: 129 (117 to 143)

Mean GFR 6 months after BMT (95% CI):

+TBI: 99 (82 to 115) (P < 0.001); -TBI: 121 (105 to 136)

After 6 months GFR stabilised

N of participants with renal adverse effect
+TBI: 7/26 (27%) had a GFR < 70 mL/min/1.73 m2 after 6 months. After 60 months, mean GFR for this group was 76 mL/min/1.73 m2 (range 67 to 85)

Risk factors (multivariate analyses)
Only combined treatment with aminoglycosides and intravenous vancomycin significantly contributed to the decrease in GFR in the +TBI group in multivariate regression (B: -32 (95% CI: -54 to -10; P < 0.01). Age was not significantly related to GFR

NotesPossible overlap with the study group of Frisk 2007
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskDetails of relevant treatments were provided
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest
Well-defined outcomeLow riskOutcome definition was objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersLow riskImportant prognostic factors were taken into account

Frisk 2007

MethodsCohort study with unclear direction
Participants

N of participant original cohort: 40; N of participant described study group: 35; N of participant study group of interest: 23; N of participant with renal function tests: 23

Tumour: AML 7/35 (20%), LCAL 2/35 (6%), Hodgkin's disease 3/35 (9%), ALL 21/35 (60%), LBL 2/35 (6%). Time period diagnosis/treatment: October 1985 to August 1997. %M/F: non-TBI group: 75%/25%; TBI group: 65%/35%

Age at diagnosis: median age at BMT: non-TBI: 13.2 years (range 1.9 to 17.0); TBI: 8.6 years (range 3.6 to 17.7); age at follow-up: n/m; follow-up duration: median non-TBI: 2 years (0.5 to 5.0); TBI: 4 years (0.5 to 9.0); completion of follow-up: 100%

N of participant TBI group: 23. N of participant non-TBI group: 12

Controls: n/a

Interventions

N of participant ifosfamide: 0/23 (0%); ifosfamide cumulative dose: n/a
N of participant cisplatin: 0/23 (0%); cisplatin cumulative dose: n/a
N of participant carboplatin: 0/23 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: miscellaneous, including busulphan, cyclophosphamide, BCNU, etoposide, cytarabine, teniposide, daunorubicin, vincristine, prednisolone; other chemotherapy cumulative doses: n/m

N of participant nephrectomy: 0/23 (0%); nephrectomy details: n/a

N of participant radiotherapy including the kidney region: 23/23 (100%); radiotherapy field: TBI; radiation dose: 7.5 Gy single fraction (N = 20); 12 Gy in six fractions (N = 3)

Outcomes

GFR using 51Cr-EDTA clearance or endogenous creatinine clearance

Definition of renal adverse effect
Mean laboratory reference value for GFR was 119 (SD 9) mL/min/1.73 m2

Observed values of renal adverse effects
GFR (mL/min/1.73 m2) before BMT was 130 (SD 24) in non-TBI group and 119 (SD: 20) in TBI group

GFR decreased five years after BMT to 119 (SD 25) in non-TBI group (P = 0.028) and to 101 (SD 20) in TBI group (P = 0.029)

GFR, which was also measured in 16 participants 10 years after BMT in TBI group: 104 (SD 19)

N of participants with renal adverse effect
n/m

Risk factors                                                      
n/m

Serum phosphate/hypophosphataemia

Definition of renal adverse effect
Reference normal ranges: 1.1 to 2.0 mmol/L from 1 to 3 years of age, 1.0 to 1.8 mmol/L from 4 to 6 years of age, 0.9 to 1.8 mmol/L from 7 to 10 years of age, 0.8 to 1.6 mmol/L from 11 to 15 years of age and 0.74 to 1.54 mmol/L in adult participants

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
"There were sporadic cases of mild hyperphosphataemia, but no case of hypophosphataemia"

Risk factors
n/m

NotesPossible overlap with the study group of Frisk 2002
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analysis was performed
Adjustment for important confoundersUnclear riskNo analysis was performed

Fujieda 2009

MethodsRetrospective cohort study
Participants

N of participants original cohort: n/m; N of participants described study group: 28; N of participants study group of interest: 28; N of participants with renal function tests: 28

Tumour: brain tumour: 20/28 (71.4%), Wilms' tumour: 2/28 (7.1%), osteosarcoma: 2/28 (7.1%), rhabdomyosarcoma: 1/28 (3.6%), Hodgkin's disease: 2/28 (7.1%), non-Hodgkin's lymphoma: 1/28 (3.6%). Time period diagnosis/treatment: n/m. %M/F: n/m

Age at diagnosis: median 8 years (range 1 to 19); age at follow-up: n/m; follow-up duration: median: 14 months (range 2 to 54); completion of follow-up: 28/28 (100%)

Controls: n/a

Interventions

N of participants ifosfamide: 28/28 (100%); ifosfamide cumulative dose: hypouricaemia group: mean 25.5 g/m2 (SD 4.6g/m2); non-hypouricaemia: mean 25.9 g/m2 (SD 7.9 g/m2)
N of participants cisplatin: 3/28 (10.7%); cisplatin cumulative dose: mean: 300 mg/m2 (SD 100 mg/m2)
N of participants carboplatin: 25/28 (89.3%); carboplatin cumulative dose: hypouricaemia group: mean 2300 mg/m2 (SD 1600 mg/m2); non-hypouricaemia: mean 2500 mg/m2 (SD 600 mg/m2)

Other types of chemotherapy: etoposide; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: n/m; nephrectomy details: n/m

N of participants radiotherapy including the kidney region: n/m; radiotherapy field: n/m; radiation dose: n/m

Outcomes

Proteinuria measured by urine dipsticks

Definition of renal adverse effect
Dipstick > 1+

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
8/28 (28.6%)

Risk factors
n/m

Serum phosphate/hypophosphataemia

Definition of renal adverse effect
Serum phosphate < 2.9 mg/dL

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
10/21 (47.6%)

Risk factors
n/m

Serum magnesium/hypomagnesaemia

Definition of renal adverse effect
Serum magnesium < 1.9 mg/dL

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
6/16 (37.5%)

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskInformation on surgery and radiotherapy was missing (at least for the 2 participants with Wilms' tumour)
Representative study groupUnclear riskSize of original study group was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Geenen 2010

MethodsCross-sectional cohort study
Participants

N of participants original cohort: 308; N of participants described study group: 141; N of participants study group of interest: 62; N of participants with renal function tests: 62

Tumour: Wilms' tumour: 62/62 (100%). Time period diagnosis/treatment: 1966-1991. %M/F (N = 141): 45%/55%

Age at diagnosis: RT+CT: mean 3.7 years (SD 2.3); CT: mean 3.6 years (SD 2.2); age at follow-up: RT+CT: mean 28.3 years (SD 5.2); CT: mean 23.5 years (SD 4.0); follow-up duration: RT+CT: mean 24.7 years (SD 5.6); CT: mean 19.9 years (SD 5.0); completion of follow-up: 100%

N of participants RT+CT group: 37/62 (59.7%); CT group: 25/62 (40.3%)

Controls: 69 siblings of survivors

Interventions

N of participants ifosfamide: unclear, but 5/62 (8%) treated with alkylating agents, including ifosfamide; ifosfamide cumulative dose: n/m
N of participants cisplatin: 0/62 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/62 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: anthracyclines: 16/62 (26%); dactinomycin: 58/62 (94%); vincristine: 53/62 (85%); other chemotherapy cumulative doses: n/m

N of participants nephrectomy: not mentioned, but supposedly 62/62 (100%); nephrectomy details: n/m

N of participants radiotherapy including the kidney region: 31/62 (50%); radiotherapy field: abdomen: 31/31 (100%); radiation dose: n/m

Outcomes

Chronic kidney disease/renal insufficiency

Definition of renal adverse effect
Receiving renal replacement therapy, kidney transplantation or a GFR < 50 mL/min/1.73 m2

Observed values of renal adverse effects
n/a

N of participants with renal adverse effect
Total: 3/62 (4.8%). RT+CT: 3/37 (8.1%); CT: 0/25; controls: 0/69. P = 0.016 for RT+CT vs controls. P = 0.14 for RT+CT vs CT

Risk factors
No analysis performed

Blood pressure

Definition of renal adverse effect
Systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg

Observed values of renal adverse effects
Mean (SD) systolic BP in mmHg: RT+CT: 126 (14.6); CT: 120 (10.2); controls: 120 (10). P < 0.05 for RT+CT vs controls

Mean (SD) diastolic BP in mmHg: RT+CT: 79 (9.2); CT: 78 (8.4); controls: 73 (8). P < 0.05 for RT+CT vs controls and CT vs controls

N of participants with renal adverse effect
Total cohort: 9/62 (14.5%). RT+CT: 8/37 (21.6%); CT: 1/25 (4%); controls: 1/69 (1.4%). P < 0.001 for RT+CT vs controls. P = 0.45 for CT vs controls. P = 0.053 for RT+CT vs CT

Risk factors (multivariate analyses)
Multivariate logistic regression (on complete study population, including ALL survivors treated without potentially nephrotoxic treatment). Significant risk factors with OR (95% CI): age at screening: 1.30 (1.09 to 1.54); abdominal irradiation: 30.14 (3.98 to 228.44). Non-significant risk factors: sex, family history of premature cardiovascular disease, cranial radiotherapy, alkylating agents, anthracyclines

NotesPossible overlap between the study groups of Geenen 2010, Van Dijk 2010, Aronson 2011 and Cardous-Ubbink 2010
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskSpecific types of treatment and cumulative doses of chemotherapy and radiotherapy were not mentioned
Representative study groupLow riskStudy group consisted of only 50% of the original cohort but was a random sample of the original cohort
Well-defined follow-upLow riskFollow-up duration was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersLow riskImportant prognostic factors were taken into account using multivariate logistic regression analysis

Hamilton 2011

MethodsProspective cohort study
Participants

N of participants original cohort: 188; N of participants described study group: 188; N of participants study group of interest: 188; N of participants with renal function tests: unclear

Tumour: bilateral Wilms' tumour: 188/188 (100%). Time period diagnosis/treatment: 1986-1994. %M/F: 39%/61%

Age at diagnosis: median: 32 months (range 1 to 127 months); age at follow-up: not mentioned; follow-up duration: median: 13.9 years (range 0 to 19.8 years) for non-failure participants; completion of follow-up: unclear

Controls: n/a

Interventions

N of participants ifosfamide: at least 7/188 (3.7%); ifosfamide cumulative dose: n/m
N of participants cisplatin: 0/188 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/188 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: EE-4A (vincristine+dactinomycin): 129/188 (68.6%); DD-4A (vincristine+dactinomycin+doxorubicin): 55/188 (29.3%); other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 164/188 (87.2%); nephrectomy details: bilateral complete nephrectomy: 6/188 (3%); unilateral complete+contralateral partial nephrectomy: 53/188 (27%); unilateral nephrectomy: 57/188 (30%); bilateral partial nephrectomy: 35/188 (19%); unilateral partial nephrectomy: 13/188 (6%)

N of participants radiotherapy including the kidney region: 64/188 (34.0%); radiotherapy field: kidney/abdomen; radiation dose: n/m

Outcomes

Chronic kidney disease/renal insufficiency

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/a

N of participants with renal adverse effect
23/188 (12.2%). Median time from diagnosis to ESRD: 2.9 years (range 0.5 to 18.4)

Risk factors
n/m

NotesUnclear whether all 188 participants in the original study cohort survived their malignancy. The study reported an 8-year event-free survival of 70% and an overall survival of 84%.
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskTypes of treatment and doses of relevant chemotherapy and radiotherapy were not mentioned
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskFollow-up duration was mentioned
Complete follow-up assessmentUnclear riskNumber of participants with renal tests at follow-up was not mentioned
Well-defined outcomeHigh riskOutcome definition was not mentioned
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analysis was performed
Adjustment for important confoundersUnclear riskNo analysis was performed

Hoffmeister 2010

MethodsRetrospective cohort study
Participants

N of participants original cohort: 789; N of participants described study group: 689; N of participants study group of interest: 480; N of participants with renal function tests: 480

Tumour: ALL: 204/689 (30%); AML: 157/689 (23%); aplastic anaemia: 106/689 (15%); CML: 55/689 (8%); neuroblastoma: 39/689 (6%); other: 128/689 (19%). Time period diagnosis/treatment: 1969-2004. %M/F (n = 689): 59%/41%

Age at diagnosis: median age at bone marrow transplant (n = 689): 9.2 years (range 0.3 to 18.0); age at follow-up: age at onset of hypertension (N = 120): median: 25 years (range 3 to 46) Follow-up duration (n = 689): median 16 years (range 5 to 36); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 0/689 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 0/689 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/689 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: cyclophosphamide, busulphan, fludarabine, methotrexate; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 13/689 (2%); nephrectomy details: n/m

N of participants radiotherapy including the kidney region: single fraction TBI: 79/689 (11%); fractionated TBI: 356/689 (52%); low-dose TBI: 10/689 (1%); pre-HCT abdominal radiation: 22/689 (3%); radiotherapy field: TBI: 445/689 (65%); abdominal: 22/689 (3%); radiation dose: single fraction: 10 Gy; fTBI: 12 to 15.75 Gy; low-dose: 2 to 6 Gy. Abdominal: n/m

Outcomes

Estimated GFR using the Schwartz formula for children and the MDRD formula for adults

Definition of renal adverse effect
eGFR < 90 mL/min/1.73 m2

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
23/72 hypertensive survivors (32%)

Risk factors

Blood pressure

Definition of renal adverse effect
In participants < 18 years: systolic or diastolic blood pressure ≥ 95th percentile according to age, sex and height. In adult participants: systolic blood pressure ≥ 140 mmHg or diastolic ≥90 mmHg (participants with diabetes: 130/80). Onset of hypertension was defined as having high blood pressure at two consecutive readings OR at start of drug therapy for hypertension

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
Overall: 120/689 (17.4%); TBI: 92/445 (20.7%); abdominal RT: 4/22 (18%); single kidney: 4/13 (30%)

Risk factors (multivariate analyses)
Risk factors among participants in the described study group (N = 689): more hypertension after acute kidney injury (doubling of serum creatinine in first 100 days after transplant): hypertension group: 51/109 (47%) vs non-hypertension group: 176/547 (32%); P = 0.004

Significant risk factors for development of hypertension in multivariate analysis (hazard ratio): acute kidney injury (2.53), TBI (2.06), hepatitis C infection (0.52), donor type: autologous (2.39), unrelated (1.79), related 1.0; obesity (3.98), diabetes (6.59), growth hormone therapy (1.58)

NotesExtracted study characteristics under participants and interventions are from the described study group as no separate data were available for the study group of interest
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersLow riskImportant prognostic factors were taken into account using multivariate Cox regression analysis

Indolfi 2001

MethodsProspective cohort study
Participants

All tumour and age-related characteristics were described for the 27 participants with renal function tests

N of participants original cohort: unclear; N of participants described study group: 34; N of participants study group of interest: 34; N of participants with renal function tests: 27

Tumour: Wilms' tumour 27/27 (100%). Time period diagnosis/treatment: n/m. %M/F: 33%/66%

Age at diagnosis: mean 3.4 years (SD 2.7); age at follow-up: n/m; follow-up duration: 1: mean 8.5 years (3.5); 2: mean 14.5 years (SD 3.5); completion of follow-up: 79%

Controls: n/a

Interventions

N of participants ifosfamide: 0/27 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 0/27 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/27 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: n/m; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 27/27 (100%); nephrectomy details: 27/27 unilateral nephrectomy

N of participants radiotherapy including the kidney region: 19/27 (70%); radiotherapy field: abdominal, contralateral kidney shielded when > 12 Gy; radiation dose: range: 1500 to 3000 cGy

Outcomes

GFR using creatinine clearance

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Creatine clearance mean values (SD) in mL/min/1.73 m2

after mean follow-up of 8.5 years: 117 (46); after mean follow-up of 14.5 years: 118 (34)

N of participants with renal adverse effect
0/27 survivors with a low clearance

Risk factors (univariate analyses)
No significant difference between first and second measurements (P = 0.67)

Proteinuria measured by microalbuminuria

Definition of renal adverse effect
> 20 mg/24 h

Observed values of renal adverse effects
Mean values (SD) in mg/24 h: measurement 1: 42 (79); measurement 2: 47 (81)

N of participants with renal adverse effect
Measurement 1: 8/34 (24%); measurement 2: 10/27 (37%)

Risk factors (univariate analyses)
No difference between the groups in terms of radiotherapy: yes/no. No significant difference between first measurement and follow-up (P = 0.83)

Blood pressure

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
0/27 survivors with hypertension

Risk factors
n/m

NotesSame study group as Di Tullio 1996
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupUnclear riskSize of original cohort was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for 79% of the study group of interest (+)
Well-defined outcomeHigh riskOutcome definition was objective and precise for only one of the three outcome measures
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Kantor 1989

MethodsCross-sectional cohort study
Participants

N of participants original cohort: 152; N of participants described study group: 119; N of participants study group of interest: 119; N of participants with renal function tests: 119

Tumour: Wilms' tumour (116/119, 97.5%); renal cell carcinoma (3/119, 2.5%). Time period diagnosis/treatment: 1931-1972. %M/F: 43%/57%

Age at diagnosis: n/m; age at follow-up: median: 29 years (range 18 to 58); follow-up duration: median: 25 years (range 14 to 53); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: n/m; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: dactinomycin alone or with other drugs: 80/119 (67%); other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 119/119 (100%); nephrectomy details: unilateral nephrectomy (plus partial nephrectomy in case of bilateral disease)

N of participants radiotherapy including the kidney region: 91/119 (76%); radiotherapy field: whole or partial abdominal irradiation; radiation dose: n/m

Outcomes

Blood pressure measured by a physician/nurse, taken from recent medical records or by personal recall from a recent visit

Definition of renal adverse effect
Definite hypertension: > 160 mmHg systolic or > 95 mmHg diastolic or receiving treatment for hypertension

Borderline hypertension: 140 to 160 mmHg systolic or 90 to 95 mmHg diastolic, no medication

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
Definite hypertension: 18/119 (15%), significantly more than expected from normal population

Borderline hypertension: 6/119 (5%)

Risk factors (multivariate analyses)
Via case comparison study: no influence of radiation dose, dactinomycin or a combination of the two

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskChemotherapy and radiotherapy regimens were not specified
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definition was objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersLow riskImportant prognostic factors were taken into account

Kubiak 2004

MethodsRetrospective cohort study
Participants

N of participants original cohort: 25; N of participants described study group: 23; N of participants study group of interest: 23; N of participants with renal function tests: 23

Tumour: bilateral Wilms' tumour 23/23 (100%). Time period diagnosis/treatment: 1973-2002. %M/F: 30%/70%

Age at diagnosis: median 19 months (range 5 to 65); age at follow-up: n/m; follow-up duration: median 57 months (range 12.5 to 297); completion of follow-up: 23/23 (100%)

Controls: n/a

Interventions

N of participants ifosfamide: 1/23 (4.3%); ifosfamide cumulative dose: n/m
N of participants cisplatin: 0/23 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/23 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: vincristine, actinomycin D, etoposide, cyclophosphamide, doxorubicin; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 23/23 (100%); nephrectomy details: 18/46 kidneys in 23 participants nephrectomised

28/46 kidneys salvaged (21 excisions, 5 enucleations, 2 bench surgical procedures with autotransplantation)

N of participants radiotherapy including the kidney region: n/m; radiotherapy field: n/m; radiation dose: n/m

Outcomes

Estimated GFR using the Schwartz formula

Definition of renal adverse effect
< 90 mL/min/1.73 m2

Observed values of renal adverse effects
Median: 101.5 mL/min/m2 (range 60 to 169 mL/min/m2) in 20/20 survivors without renal failure

N of participants with renal adverse effect
6/22 (27%) including 2 with renal failure

Risk factors
n/m

Blood pressure

Definition of renal adverse effect
Mean systolic and/or diastolic pressure was ≥ 95th percentile in relation to age and sex

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
4/22 (18.2%)

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo chemotherapy doses and radiotherapy regimens were mentioned
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analysis was performed
Adjustment for important confoundersUnclear riskNo analysis was performed

Laverdiere 2005

MethodsRetrospective cohort study
Participants

N of participants original cohort: 98; N of participants described study group: 63; N of participants study group of interest: 63; N of participants with renal function tests: unclear

Tumour: stage III/IV neuroblastoma 63/63 (100%). Time period diagnosis/treatment: 1991-2003. %M/F: 49%/51%

Age at diagnosis: median 3.0 years (range 0.07 to 23.5); age at follow-up: median 11.6 (range 4 to 30); follow-up duration: off-treatment: median 6.0 years (range 0.1 to 24.9); since diagnosis: 7.1 (1.9 to 25.5); completion of follow-up: unclear

Controls: n/a

Interventions

N of participants ifosfamide: at least one; ifosfamide cumulative dose: n/m
N of participants cisplatin: 56/63 (89%); cisplatin cumulative dose: mean 514 mg/m2 (range 123 to 1324)
N of participants carboplatin: 17/63 (27%); carboplatin cumulative dose: mean 948 mg (range 540 to 1496)

Other types of chemotherapy: cyclophosphamide: 63/63 (100%), doxorubicin: 61/63 (97%), etoposide: 54/63 (86%); other chemotherapy cumulative doses: cyclophosphamide: mean 9.5 g (range 1.5 to 30.8), doxorubicin: mean 258 g/m2 (range 75 to 554), etoposide: mean 1162 mg (range 153 to 3450)

N of participants nephrectomy: 6/63 (9%); nephrectomy details: n/m

N of participants radiotherapy including the kidney region: 52/63 (83%); radiotherapy field: abdominal (46/63); TBI (6/63); radiation dose: abdominal: mean 2174 cGy; TBI: mean 1075 cGy

Outcomes

Chronic kidney disease/renal insufficiency

Definition of renal adverse effect
As defined by CTCAE 3.0

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect

1/63 (2%) (1 grade 1/2)

Risk factors
n/m

Chronic proteinuria/hematuria not further specified

Definition of renal adverse effect
As defined by CTCAE 3.0

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect

2/63 (3%) (2 grade 1/2)

Risk factors
n/m

Blood pressure

Definition of renal adverse effect
As defined by CTCAE 3.0

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect

1/63 (3%) (1 grade 3/4)

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentUnclear riskNumber of participants with renal function tests was not mentioned
Well-defined outcomeLow riskOutcome definitions met CTCAE v3 criteria
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analysis was performed
Adjustment for important confoundersUnclear riskNo analysis was performed

Loebstein 1999

MethodsRetrospective cohort study
Participants

N of participants original cohort: 192; N of participants described study group: 174; N of participants study group of interest: 174; N of participants with renal function tests: unclear

Tumour: brain tumour: 65/174 (37%); Ewing's sarcoma: 21/174 (12%); osteogenic sarcoma: 26/174 (15%); rhabdomyosarcoma: 39/174 (22%); other tumours: 23/174 (13%). Time period diagnosis/treatment: 1984-1996. %M/F: n/m

Age at diagnosis: median 8.7 years (range 0.4 to 21.2); age at follow-up: n/m; follow-up duration: mean: 5.3 years (range 2 to 12); completion of follow-up: unclear

Controls: n/a

Interventions

N of participants ifosfamide: 174/174 (100%); ifosfamide cumulative dose: median: 45.5 g/m2 (range 12.4 to 76.6)
N of participants cisplatin: 123/174 (70.7%); cisplatin cumulative dose: median: 4 g/m2 (range 1.7 to 10.6)
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: n/m; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 2/174 (1.1%); nephrectomy details: unilateral nephrectomy

N of participants radiotherapy including the kidney region: 2/174 (1.1%); radiotherapy field: kidney included in the field; radiation dose: n/m

Outcomes

Composite outcome: ifosfamide-induced abnormal tubular or glomerular function, measured by these criteria:

1) Hypophosphataemia < 2 SD for age;

2) Hypocarbia together with acidosis;

3) Glycosuria;

4) Proteinuria (>1 g/L); and

5) GFR < 80 mL/min/1.73 m2 (Schwartz formula).

Definition of renal adverse effect
Mild nephrotoxicity: one abnormal criterion

Moderate: nephrotoxicity: two to three abnormal criteria

Severe nephrotoxicity: four to five abnormal criteria

Observed values of renal adverse effectsn/a

N of participants with renal adverse effect
Severe nephrotoxicity: 7/174 (4.0%). Four developed hypophosphataemic rickets, 2 had progressive deterioration of GFR followed by ESRD

Moderate nephrotoxicity: 4/174 (2.3%). Two developed hypophosphataemic rickets, 2 had gradual deterioration of GFR

Mild nephrotoxicity: n/m

Risk factors

n/a

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentUnclear riskNumber of participants with renal tests at follow-up was not mentioned
Well-defined outcomeHigh riskOutcome definition objective but not precise: composite outcome
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analysis was performed for long-term follow-up
Adjustment for important confoundersUnclear riskNo analysis was performed for long-term follow-up

Makipernaa 1991

MethodsCross-sectional cohort study
Participants

N of participants original cohort: 34; N of participants described study group: 30; N of participants study group of interest: 30; N of participants with renal function tests: 30

Tumour: Wilms' tumour: 30/30 (100%). Time period diagnosis/treatment: 1960-1976. %M/F: 50%/50%

Age at diagnosis: mean 2.6 years (range 0.3 to 7.2); age at follow-up: mean 21.8 years (range 12.2 to 29.6); follow-up duration: mean 19.2 years (range 10.8 to 27.7); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 0/30 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 0/30 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/30 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: dactinomycin: 26/30 (86.7%), cyclophosphamide: 3/30 (10%), vincristine: 3/30 (10%); other chemotherapy cumulative doses: dactinomycin: 15 microgram/kg daily in 5-day courses. One course: 6/26; six to eight courses: 7/26; nine or more courses: 13/26. Not mentioned for cyclophosphamide and vincristine

N of participants nephrectomy: 30/30 (100%); nephrectomy details: unilateral nephrectomy

N of participants radiotherapy including the kidney region: 27/30 (90%); radiotherapy field: abdominal radiation (27/30) but excluding the remaining kidney; radiation dose: median: 30 Gy (range 20 to 49)

Outcomes

GFR using 51-Cr-EDTA clearance

Definition of renal adverse effect
No cut-off mentioned

Observed values of renal adverse effects
Mean GFR 108 mL/min/1.73 m2 (range 74 to 151) in 27/30

N of participants with renal adverse effect
n/m

Risk factors (univariate analyses)
GFR was independent of age at diagnosis and radiation dose

Proteinuria measured by urinary albumin excretion

Definition of renal adverse effect
Urinary albumin excretion > 20 mg/24 h

Observed values of renal adverse effects
Normal: 25/30 (83.3%); 10 to 20 mg/24 h: 2/30 (6.7%); > 20 mg/24 h: 3/30 (10%)

N of participants with renal adverse effect
Overall: 3/30 (10%)

Risk factors (univariate analyses)
Urinary albumin excretion was independent of age at diagnosis, follow-up time, age at follow-up and dactinomycin

Blood pressure

Definition of renal adverse effect
Blood pressure above 140 mmHg systolic and/or 90 mmHg diastolic

Observed values of renal adverse effects
In normotensive participants, mean blood pressure was 110/75 mmHg (range 100/70 to 140/85 mmHg)

N of participants with renal adverse effect
5/30 (16.7%)

Risk factors (univariate analyses)
No correlation of blood pressure with the radiation dose was noted.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskObjective and precise outcome definitions were given for two of the three outcome measurements
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Mancini 1996

MethodsProspective cohort study
Participants

N of participants original cohort: 89; N of participants described study group: 60; N of participants study group of interest: 60; N of participants with renal function tests: 60

Tumour: Wilms' tumour: 60/60 (100%). Time period diagnosis/treatment: 1973-1992. %M/F: 48%/52%

Age at diagnosis: median: 3.1 years (range 0.7 to 10.8); age at follow-up: median: 13.4 years (range 4.2 to 22.7); follow-up duration: median: 9.3 years (range 1.7 to 21.1); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 0/60 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 1/60 (2%); cisplatin cumulative dose: 800 mg/m2
N of participants carboplatin: 2/60 (3%); carboplatin cumulative dose: 2000 and 3000 mg/m2

Other types of chemotherapy: actinomycin D only: 1/60 (2%); actinomycin D+vincristine: 38/60 (63%); actinomycin D+vincristine+adriamycin: 15/60 (25%); cyclophosphamide: 2/60 (3%); other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 60/60 (100%); nephrectomy details: 59/60 (98%) unilateral nephrectomy, 1/60 (2%) bilateral nephrectomy

N of participants radiotherapy including the kidney region: 29/60 (48%); radiotherapy field: 21 on renal bed, 5 abdomen, 3 other; radiation dose: n/m

Outcomes

GFR using creatinine clearance, no further method specified

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Mean GFR: 97.6 mL/min/1.73 m2 (SD 12.4, range 67.6 to 134.6)

N of participants with renal adverse effect
n/m

Risk factors (univariate analyses)
GFR was significantly lower for survivors treated > 10 years before with a nephrectomy than for those treated < 10 years ago (GFR 94.0 vs 100.7; P = 0.035)

No significant influence on GFR of sex, age at nephrectomy, bilateral disease, radiotherapy on the remaining kidney, chemotherapy duration and type of chemotherapy

Proteinuria measured by microalbuminuria

Definition of renal adverse effect
> 20 mcg/mL

Observed values of renal adverse effects
Mean: 15.2 mcg/mL (SD 23.4)

N of participants with renal adverse effect
7/60 (12%)

Risk factors (univariate analyses)
No significant influence of time since nephrectomy (< 10 years vs > 10 years; P = 0.57)

Serum phosphate/hypophosphataemia

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
0/60 (0%)

Risk factors
n/m

Blood pressure

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Mean systolic blood pressure: 113.9 mmHg (SD 12.9)

Mean diastolic blood pressure: 71.9 mmHg (SD 12.3)

N of participants with renal adverse effect
n/m

Risk factors (univariate analyses)
Blood pressure was higher in survivors treated > 10 years ago with nephrectomy than in those treated < 10 years ago: systolic BP 120.4 vs 108.2; P = 0.007; diastolic BP 75.5 vs 68.6; P = 0.008

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskRadiotherapy doses not specified
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskOutcome definition was mentioned for only one of the four outcome measures
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Mpofu 1992

MethodsCross-sectional cohort study
Participants

N of participants original cohort: n/m; N of participants described study group: 76; N of participants study group of interest: 76; N of participants with renal function tests: 76

Tumour: Wilms' tumour: 76/76 (100%). Time period diagnosis/treatment: 1970-1989. %M/F: 47%/53%

Age at diagnosis: mean: 3.41 years; age at follow-up: n/m; follow-up duration: mean 9.0 years (range 2 to 23); completion of follow-up: 76/76 (100%)

Controls: n/a

Interventions

N of participants ifosfamide: n/m; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: n/m; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 76/76 (100%); nephrectomy details: n/m

N of participants radiotherapy including the kidney region: 41/76 (54%); radiotherapy field: renal bed only: 31/76; whole abdomen: 7/76; other: 3/76; radiation dose: with proteinuria: 2820 cGy; without proteinuria: 2000 cGy

Outcomes

Estimated GFR using the Schwartz formula (or 51Cr-EDTA clearance in 4 participants)

Definition of renal adverse effect
GFR < 80 mL/min/1.73 m2

Observed values of renal adverse effects
EMU p/c > 20 mg/mmol group:

Mean GFR (range): 88.6 (39.0 to 121.6)

EMU p/c < 20 mg/mmol group:

Mean GFR (range): 104.5 (96.0 to 132.4)

N of participants with renal adverse effect
3/55 (5%), all 3 had EMU p/c > 20 mg/mmol

Risk factors (univariate analyses)
A significant correlation was noted between early morning urine protein/creatinine index and glomerular filtration rate (Pearson's correlation coefficient: -0.61)

Proteinuria measured by urinary albumin-to-creatinine ratio (in early morning urine)

Definition of renal adverse effect
EMU albumin-to-creatinine ratio > 20 mg/mmol

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
11/76 (14.5%)

Risk factors (univariate analyses)
No significant difference regarding age at nephrectomy and radiation dose

Blood pressure in standard deviations from normal (derived from the Second Task Force on Blood Pressure in Children)

Definition of renal adverse effect
Receiving treatment for hypertension

Observed values of renal adverse effects
Mean systolic BP (SD): 0.72 (1.29); median: 0.77

Mean diastolic BP (SD): 0.48 (1.14); median: 0.54

N of participants with renal adverse effect
2/76 (2.6%)

Risk factors

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo chemotherapy regimens were mentioned
Representative study groupUnclear riskSize of original cohort was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Oberlin 2009

MethodsCohort study with unclear direction
Participants

N of participants original cohort: 255; N of participants described study group: 183; N of participants study group of interest: 183; N of participants with renal function tests: 183

Tumour: rhabdomyosarcoma 77/183 (42%), Ewing's sarcoma 39/183 (21%), soft tissue sarcoma 39/183 (21%), osteosarcoma 28/183 (15%). Time period diagnosis/treatment: 1984-2000. %M/F: 55%/45%

Age at diagnosis: median 9.3 years (range 0.4 to 27.2) at start of ifosfamide; age at follow-up: median 18.3 years (range 7.1 to 44.2); follow-up duration: median 10.3 years (range 5.0 to 20.7); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 183/183 (100%); ifosfamide cumulative dose: median 54 g/m2 (range 18 to 117)
N of participants cisplatin: 0/183 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/183 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: several other drugs, including high-dose methotrexate, vincristine, dactinomycin and etoposide; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 0/183 (0%); nephrectomy details: n/a

N of participants radiotherapy including the kidney region: 1/183 (0,5%); radiotherapy field: kidney: 1/183 (0.5%); radiation dose: n/m

Outcomes

Estimated GFR using the Schwartz formula for children and the Cockroft-Gault formula for adults

Definition of renal adverse effect
GFR < 90 mL/min/1.73 m2

Observed values of renal adverse effects
Median GFR: 104 mL/min/1.73 m2 (range 50 to 196)

N of participants with renal adverse effect
39/181 (21.5%)

Risk factors (multivariate analyses)
Multivariate logistic regression analysis on GFR < 90 mL/min

Risk factor: odds ratio (95% CI; P value)

Age at treatment in years: 1.08 (1.00 to 1.17; P = 0.05)

Ifosfamide dose in g/m2: 1.02 (0.99 to 1.04; P = 0.3)

Follow-up duration in years: 1.09 (1.01 to 1.19; P = 0.03)

Univariate logistic regression:

Use of methotrexate: 0.76 (0.27 to 2,15; P = 0.6)

Proteinuria in 24-hour urine

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
19/168 (11.3%)

Risk factors
n/m

Tubular phosphate regulation parameters measured by the renal tubular phosphate threshold (TmP/GFR)

Definition of renal adverse effect
Ratio of observed versus expected TmP/GFR for age < -2 SD

Observed values of renal adverse effects
Median (range): 1.02 (0.49 to 1.66)

N of participants with renal adverse effect
38/156 (24%)

Risk factors (multivariate analyses)
Linear multivariate regression analysis:

Risk factor: coefficient (standard error; P value)

Age at treatment in years: -0.0047 (0.0033; P = 0.2)

Ifosfamide dose in g/m2: -0.0028 (0.0012; P = 0.02)

Follow-up duration in years: -0.013 (0.0036; P = 0.0005)

Univariate linear regression:

Use of methotrexate: 0.0048 (0.046; P = 0.9)

Serum phosphate/hypophosphataemia

Definition of renal adverse effect
Serum phosphate: 6 to 12 years < 1 mmol/L; 13 to 16 years: < 0.9 mmol/L; adults < 0.77 mmol/L

Observed values of renal adverse effects
Median (range) in mmol/L: 1.19 (0.77 to 1.76)

N of participants with renal adverse effect
2/178 (1.1%)

Risk factors
n/m

Serum magnesium/hypomagnesaemia

Definition of renal adverse effect
Serum magnesium < 0.7 mmol/L

Observed values of renal adverse effects
Median (range) in mmol/L: 0.86 (0.60 to 2.07)

N of participants with renal adverse effect
2/171 (1.1%)

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definition was objective and precise for four of the five outcome measures
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersLow riskImportant prognostic factors were taken into account

Othman 2002

MethodsCross-sectional cohort study
Participants

N of participants original cohort: 49; N of participants described study group: 31; N of participants study group of interest: 31; N of participants with renal function tests: 31

Tumour: Wilms' tumour: 31/31 (100%). Time period diagnosis/treatment: n/m. %M/F: 35%/65%

Age at diagnosis: mean: 3.6 years; median: 3 years (range 0.75 to 9); age at follow-up: mean: 13.7 years; median: 13 years (range 4 to 32); follow-up duration: n/m; completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: n/m; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: n/m; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 31/31 (100%); nephrectomy details: n/m

N of participants radiotherapy including the kidney region: 15/31 (48%); radiotherapy field: abdomen: 15/31; radiation dose: n/m

Outcomes

Serum phosphate/hypophosphataemia

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Mean: 1.41 mmol/L (SD 0.38 mmol/L)

N of participants with renal adverse effect
0/31 (0%)

Risk factors
n/m

Serum magnesium/hypomagnesaemia

Definition of renal adverse effect
< 0.80 mmol/L

Observed values of renal adverse effects
Mean serum magnesium: 0.83 mmol/L (SD 0.14 mmol/L)

N of participants with renal adverse effect
8/31 (25.8%)

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo chemotherapy regimens were mentioned, and no radiotherapy doses were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upHigh riskLength of follow-up was not mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskOutcome definitions were not mentioned for one of the two outcomes
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analysis was performed
Adjustment for important confoundersUnclear riskNo analysis was performed

Patzer 2001

MethodsProspective cohort study
Participants

N of participants original cohort: 55; N of participants described study group: 44; N of participants study group of interest: 44; N of participants with renal function tests: 1 year: max 43; 2 year: max 36

Tumour: acute lymphoblastic leukaemia: 13/44 (30%); acute non-lymphoblastic leukaemia: 9/44 (20%); chronic myeloid leukaemia: 4/44 (9%); Hodkin's lymphoma: 4/44 (9%); other tumours: 11/44 (25%). Time period diagnosis/treatment: 1992-1998. %M/F: n/m

Age at diagnosis: median age at HSCT: 13.6 years (range 3.9 to 42); age at follow-up: n/m; follow-up duration: follow-up at 1 year and 2 years; completion of follow-up: 1-year: 43/44 (97%); 2-year: 36/44 (82%)

Controls: n/a

Interventions

N of participants ifosfamide: 26/44 (59%); ifosfamide cumulative dose: median: 10 g/m2 (range 2 to 86 g/m2)
N of participants cisplatin: 4/44 (9%); cisplatin cumulative dose: n/m
N of participants carboplatin: 2/44 (5%); carboplatin cumulative dose: 5.2 g/m2 and 1.8 g/m2

Other types of chemotherapy: different conditioning regimens including busulphan, cyclophosphamide, melphalan, etoposide, thiotepa, antithymocyte globulin, carboplatin, Ara-C, carmustine, ALG; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 3/44 (7%); nephrectomy details: unilateral nephrectomy

N of participants radiotherapy including the kidney region: 14/44 (32%); radiotherapy field: fractionated total body irradiation; radiation dose: 6×2 Gy

Outcomes

GFR using inulin clearance

Definition of renal adverse effect
< 90 mL/min/1.73 m2

Observed values of renal adverse effects
Median GFR (range): before HSCT: 130 mL/min/1.73 m2 (73 to 217); after 1 year: 123 mL/min/1.73 m2 (68 to 185) (P < 0.05 compared with before); after 2 years: 105 mL/min/1.73 m2 (81 to 177) (P < 0.01 compared with before)

N of participants with renal adverse effect
Before HSCT: 3/33 (9%); after 1 year: 4/28 (14.3%); after 2 years: 4/16 (25%)

Risk factors (univariate analyses)
No significant differences in GFR were noted with regard to the initial disease, use of fTBI, use of ifosfamide, type of HSCT, acute renal failure within 30 days of HSCT or the presence of GVHD

Proteinuria measured by urinary albumin excretion

Definition of renal adverse effect
Age-specific reference values

Observed values of renal adverse effects
Median albumin excretion (range) in mg/mmol: before HSCT: 1.13 (0.37 to 15.36); after 1 year: 1.02 (0.38 to 15.4); after 2 years: 1.13 (0.37 to 12.39)

N of participants with renal adverse effect
n/m

Risk factors
n/m

Tubular phosphate regulation parameters measured by tubular phosphate reabsorption

Definition of renal adverse effect
< 1.07 mmol/L

Observed values of renal adverse effects
Median phosphate reabsorption (range) in mmol/L: before HSCT: 1.21 (0.51 to 1.75); after 1 year: 1.11 (0.56 to 1.64) (P < 0.05 compared with before); after 2 years: 1.08 (0.53 to 1.44) (P < 0.005 compared with before)

N of participants with renal adverse effect
Before HSCT: 14/44 (32%); after 1 year: 18/42 (43%); after 2 years: 15/36 (42%)

Risk factors (univariate analyses)
No significant difference in phosphate reabsorption was noted with respect to earlier ifosfamide treatment, fTBI, type of HSCT, acute renal failure within 30 days of HSCT and presence of GVHD

A positive correlation was seen between TP/Cr at 1 and 2 years (Spearman-Rho: 0.41, P < 0.05)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for 97% of the study group of interest (++) at 1 year follow-up and for 82% of the study group of interest at 2 years' follow-up (+)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Paulino 2000

MethodsProspective cohort study
Participants

N of participants original cohort: 42; N of participants described study group: 42; N of participants study group of interest: 42; N of participants with renal function tests: 42

Tumour: Wilms' tumour: 42/42 (100%). Time period diagnosis/treatment: 1968-1994. %M/F: 40%/60%

Age at diagnosis: median: 48 months (range 7 to 126); age at follow-up: median (range) in years: A: 13.7 (6.7 to 20.0); B: 19.9 (13.3 to 28.9); C: 19.7 (9.3 to 27.1); follow-up duration: median: 181 months (range 60 to 306); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: at least 1; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: actinomycin D/vincristine/adriamycin: 13/42 (31%); actinomycin D/vincristine: 18/42 (43%); other: n/m; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 42/42 (100%); nephrectomy details: unilateral nephrectomy: 41/42 (97.6%); bilateral partial nephrectomy: 1/42 (2.4%)

N of participants radiotherapy including the kidney region: 42/42 (100%); radiotherapy field: 36/42 (86%): hemiabdomen or tumour bed. 6/42 (14%): whole abdomen; radiation dose: A: 12/42: 1000 to 1200 cGy; B: 11/42: 1201 to 2399 cGy; C: 19/42: 2400 to 4000 cGy

Outcomes

Chronic kidney disease/renal insufficiency

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
1/42 (2%) with chronic renal insufficiency

Risk factors
n/m

Blood pressure

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
3/42 (7.1%)

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskOutcome definitions were not mentioned
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analyses were performed
Adjustment for important confoundersUnclear riskNo analyses were performed

Prasad 1996

MethodsRetrospective cohort study
Participants

N of participants original cohort: 59; N of participants described study group: 37; N of participants study group of interest: 37; N of participants with renal function tests: 37

Tumour: rhabdomyosarcoma: 14/37 (38%), Ewing's sarcoma: 10/37 (27%), PNET: 5/37 (14%), other: 8/37 (22%). Time period diagnosis/treatment: 1986 to n/m. %M/F: 43%/57%

Age at diagnosis: median: 8.1 years (range 0.8 to 14.6); age at follow-up: median: 10.8 years (range 3.3 to 18.5); follow-up duration: median: 29 months (range 6 to 68); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 37/37 (100%); ifosfamide cumulative dose: median: 54 g/m2 (range 9 to 135)
N of participants cisplatin: n/m; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: n/m; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: n/m; nephrectomy details: n/m

N of participants radiotherapy including the kidney region: n/m; radiotherapy field: n/m; radiation dose: n/m

Outcomes

GFR using 51Cr-EDTA clearance

Definition of renal adverse effect
GFR < 90 mL/min

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
6/35 (17%). All 6 had coexistent tubulopathy, but this was not tested in the other 29 children

Risk factors (univariate analyses)
Only follow-up duration was significantly longer in the affected group: 41.5 vs 19 months; P = 0.04

No significant difference in glomerular toxicity was noted with regard to age at study, age at treatment, cumulative ifosfamide dose, infusion schedule, pretreatment nephrectomy, pretreatment renal tract disease, other nephrotoxic anticancer agents, amphotericin B/acyclovir, aminoglycoside toxicity or abdominal radiotherapy

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskTypes of treatment and cumulative doses of relevant surgery, chemotherapy and radiotherapy were not mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definition was objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Rossi 1993

MethodsProspective cohort study
Participants

N of participants original cohort: unclear; N of participants described study group: 79; N of participants study group of interest: 79; N of participants with renal function tests: 79

Tumour: n/m. Time period diagnosis/treatment: n/m. %M/F: n/m

Age at diagnosis: n/m; age at follow-up: n/m; follow-up duration: range 3 to 134 months; completion of follow-up: 79/79 (100%)

Controls: n/a

Interventions

N of participants ifosfamide: 74/79 (94%); ifosfamide cumulative dose: median: 8 g/m2 for 15/79, 30 g/m2 for 30/79 and 67 g/m2 for 29/79
N of participants cisplatin: 40/79 (51%); cisplatin cumulative dose: median: 200 mg/m2 for 10/79 and 480 mg/m2 for 30/79
N of participants carboplatin: 0/79 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: n/m; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: at least 3/79; nephrectomy details: n/m

N of participants radiotherapy including the kidney region: at least 2/79; radiotherapy field: n/m; radiation dose: n/m

Outcomes

Estimated GFR using the Schwartz formula

Definition of renal adverse effect
GFR < 80 mL/min/1.73 m2

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
8/76 (10.5%)

Risk factors (univariate analyses)
No correlation between GFR and cumulative ifosfamide dose

Tubular phosphate regulation parameters measured by fractional phosphate reabsorption

Definition of renal adverse effect
Results were compared with previously established normal values. The accepted range of variation included the 2 SD band for the parameters of tubular reabsorption

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
38/67 (56.7%)

Risk factors (univariate analyses)
No correlation between fractional phosphate excretion and cumulative ifosfamide dose

NotesPossible overlap with the study group of Rossi 1994, Rossi 1994a, Rossi 1994b, Rossi 1997 and Rossi 1999
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes and cumulative doses of relevant chemotherapy were mentioned
Representative study groupUnclear riskSize of original cohort not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisHigh riskCorrelations performed regarding ifosfamide cumulative dose but not presented
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Rossi 1994

MethodsCohort study with unclear direction
Participants

N of participants original cohort: n/m; N of participants described study group: 72; N of participants study group of interest: 72; N of participants with renal function tests: 72

Tumour: Ewing's/soft tissue sarcoma: 22/72 (30.5%), osteosarcoma: 18/72 (25%), ALL/B-NHL: 15/72 (20.8%), neuroblastoma: 3/72 (4.2%), Wilms' tumour: 3/72 (4.2%), other: 11/72 (15.3%). Time period diagnosis/treatment: n/m. %M/F: n/m

Age at diagnosis: n/m; age at follow-up: median: 13.4 years (range 1.7 to 16.9); follow-up duration: median: 15.8 months (range 3.5 to 123); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 72/72 (100%); ifosfamide cumulative dose: < 15 g/m2: 8/72; 15 to 40 g/m2: 30/72; > 40 g/m2: 27/72
N of participants cisplatin: 33/72 (45.8%); cisplatin cumulative dose: 100 to 300 mg/m2: 8/72; > 300 mg/m2: 25
N of participants carboplatin: 0/72 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: n/m; other chemotherapy cumulative doses: n/a

N of participants nephrectomy: 5/72 (6.9%); nephrectomy details: unilateral nephrectomy

N of participants radiotherapy including the kidney region: 0/72 (0%); radiotherapy field: n/a; radiation dose: n/a

Group definitions:

Group 1: low-dose ifosfamide (N = 15, < 15 g/m2, median 8 g/m2)

Group 2: medium-dose ifosfamide (N = 20, 15 to 40 g/m2, median 27 g/m2) and cisplatin > 300 mg/m2

Group 3: high-dose ifosfamide (N = 21, > 40 g/m2, median > 68 g/m2) but no cisplatin

Outcomes

Estimated GFR using the Schwartz formula

Definition of renal adverse effect
eGFR < 80 mL/min/1.73 m2

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
6/69 (8.7%)

Risk factors
Reduced GFR occurred only in group 2 (2/20 participants) and group 3 (3/21 participants), not in group 1

Tubular phosphate regulation parameters measured by fractional phosphate reabsorption

Definition of renal adverse effect
Normal TP/Cr: mean 1.50 micromol/mL

TP/Cr < -2 SD: < 1.07 micromol/mL

TP/Cr < -3 SD: < 0.84 micromol/mL

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
TP/Cr between -2 SD and -3 SD: 15/64 (23.4%)

TP/Cr < -3 SD: 6/64 (9.4%)

Repeat measurement 8 months after first measurement (N = 28):

All normal (14) stayed normal; 11/14 abnormal showed further deterioration; 3/14 abnormal regained normal phosphate reabsorption

Risk factors (univariate analyses)
All participants treated with ifosfamide showed a significant reduction of the phosphate reabsorption. Group 1 participant reduction was low, and all participants were still within normal ranges. Group 3 showed a further decrease, with 4/19 (21%) below normal. Group 2 had the most severe depletion of phosphate reabsorption, with 10/16 (62.5%) below normal, even though ifosfamide dose was intermediate. No linear relationship was observed between cumulative ifosfamide dose and phosphate reabsorption

Greater impairment of phosphate reabsorption was seen in participants who were older at the time of diagnosis

NotesPossible overlap with the study groups of Rossi 1993, Rossi 1994a, Rossi 1994b, Rossi 1997 and Rossi 1999
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupUnclear riskSize of original cohort was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Rossi 1994a

MethodsCohort study with unclear direction
Participants

N of participants original cohort: n/m; N of participants described study group: 120; N of participants study group of interest: 120; N of participants with renal function tests: 120

Tumour: Ewing's/soft tissue sarcoma: 33/120 (27.5%), osteosarcoma: 24/120 (20%), neuroblastoma: 11/120 (9%), Wilms' tumour: 6/120 (5%), B-NHL: 17/120 (14%), ALL: 13/120 (11%), miscellaneous: 16/120 (13.3%). Time period diagnosis/treatment: n/m. %M/F: n/m

Age at diagnosis: median: 11 years (range 0 to 23); age at follow-up: n/m; follow-up duration: median: 13 months (range 3 to 123); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 120/120 (100%); ifosfamide cumulative dose: median: 30 g/m2 (range 2 to -95)
N of participants cisplatin: 51/120 (42.5%); cisplatin cumulative dose: median: 400 mg/m2 (range 97 to 900)
N of participants carboplatin: 0/120 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: methotrexate: 57/120 (47.5%), gentamicin: 68/120 (56.7%); other chemotherapy cumulative doses: MTX: median: 30 g/m2 (range 0.2 to 102), gentamicin: median: 35 mg/kg (range 1 to 217)

N of participants nephrectomy: 10/120 (8.3%); nephrectomy details: unilateral nephrectomy

N of participants radiotherapy including the kidney region: n/m; radiotherapy field: n/m ; radiation dose: n/m

Outcomes

Estimated GFR using the Schwartz formula

Definition of renal adverse effect
eGFR < 80 mL/min/1.73 m2

Observed values of renal adverse effect
n/m

N of participants with renal adverse effect
10/118 (8.5%)

Risk factors
n/m

Tubular phosphate regulation parameters measured by fractional phosphate reabsorption

Definition of renal adverse effect
TP/Cr < 1.07 micromol/mL

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
46/120 (38.3%)

Risk factors (multivariate regression)
Significant linear inverse correlation between cumulative ifosfamide dose and fractional phosphate reabsorption

Stepwise logistic regression on low phosphate reabsorption AND low amino acid reabsorption gave:

Concomitant cisplatin: OR 6.4 (range 2.2 to 18.9); P < 0.01

Nephrectomy: OR 6.4 (range 1.3 to 30.9); P < 0.01

Not significant: methotrexate, gentamicin, mesna, age

NotesPossible overlap with the study group of Rossi 1993, Rossi 1994, Rossi 1994b, Rossi 1997 and Rossi 1999
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy were mentioned
Representative study groupUnclear riskSize of original cohort was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersLow riskImportant prognostic factors were taken into account

Rossi 1994b

MethodsCross-sectional cohort study
Participants

N of participants original cohort: n/m; N of participants described study group: 64; N of participants study group of interest: 64; N of participants with renal function tests: 64

Tumour: Ewing's/soft tissue sarcoma: 22/64 (34%); osteosarcoma: 15/64 (23%); acute leukaemia: 13/64 (20%); Wilms' tumour: 3/64 (5%); neuroblastoma: 3/64 (5%); miscellaneous: 8/64 (13%) Time period diagnosis/treatment: n/m. %M/F: n/m

Age at diagnosis: n/m; age at follow-up: median: 14 years (range 1.9 to 24.7); follow-up duration: median: 1 year; completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 64/64 (100%); ifosfamide cumulative dose: IFO only: median: 51 g/m2; IFO+CISP: median: 30 g/m2
N of participants cisplatin: 27/64 (42%); cisplatin cumulative dose: median: 480 mg/m2
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: n/m; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: n/m; nephrectomy details: n/m

N of participants radiotherapy including the kidney region: n/m; radiotherapy field: n/m; radiation dose: n/m

Treatments were divided into 3 groups:

Group 1: low-dose IFOS only: < 15 g/m2, N = 13

Group 2: intermediate-dose IFOS+CISP 15 to 40 g/m2 + > 300 mg/m2, N = 15

Group 3: high-dose IFOS only: > 40 g/m2, N = 20

Outcomes

Estimated GFR using the Schwartz formula

Definition of renal adverse effect
<80 mL/min/1.73 m2

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
7/64 (11%)

Risk factors
n/m

Proteinuria measured by the urinary albumin/creatinine ratio

Definition of renal adverse effect
> 38 mg/g creatinine

Observed values of renal adverse effects
For the 19/64 (30%) with pathological results:

Median: 62.2 mg/g creatinine (range 40.3 to 266.7)

N of participants with renal adverse effect
19/64 (30%)

Risk factors
n/m

Tubular phosphate regulation parameters measured by fractional phosphate reabsorption in micromol/mL

Definition of renal adverse effect
< 1.07 micromol/mL

Observed values of renal adverse effects
Median in micromol/mL: group 1: 1.40; group 2: 0.99 (P < 0.01 with group 1); group 3: 1.22; ifosfamide only: 1.25; Ifosfamide+cisplatin: 0.99 (not significant)

N of participants with renal adverse effect
Overall: 35%; group 1: 0%; group 2: 69% (P < 0.01 with group1, P < 0.05 with group 3); group 3: 26% (P < 0.01 with group 1)

Ifosfamide only: 27%; ifosfamide+cisplatin: 60% (P < 0.05 with ifosfamide only)

Risk factors
n/m

NotesPossible overlap with the study groups of Rossi 1993, Rossi 1994, Rossi 1994a, Rossi 1997 and Rossi 1999
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo treatment regimen was described apart from ifosfamide/cisplatin
Representative study groupUnclear riskSize of original cohort was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Rossi 1997

MethodsCohort study with unclear direction
Participants

N of participants original cohort: n/m; N of participants described study group: 51; N of participants study group of interest: 51; N of participants with renal function tests: 51

Tumour: sarcoma (soft tissue or Ewing's): 51/51 (100%). Time period diagnosis/treatment: n/m. %M/F: n/m

Age at diagnosis: median (range): CI: 14 years (0 to 19); SI: 12 years (2 to 19); age at follow-up: n/m; follow-up duration: median: CI: 4.5 years; SI: 1.5 years; completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 51/51 (100%); ifosfamide cumulative dose: median (range) in g/m2: CI: 67 (36 to 81); SI: 69 (37 to 92)
N of participants cisplatin: 0/51 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/51 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: adriamycin, actinomycin D and vincristine; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 0/51 (0%); nephrectomy details: n/a

N of participants radiotherapy including the kidney region: n/m; radiotherapy field: n/m; radiation dose: n/m

Outcomes

Tubular phosphate regulation parameters measured by fractional phosphate reabsorption

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
18 months off-therapy: continuous infusion: 2/14 (14%); short infusion: 6/27 (22%) (P = NS). Continuous infusion: 12/23 (52%); short infusion: 8/28 (29%) (P = NS)

Risk factors
n/m

Notes

CI: Continuous infusion of ifosfamide (48 hours)

SI: Short infusion (3× 3 hours in 3 days)

Possible overlap with the study groups of Rossi 1993, Rossi 1994, Rossi 1994a, Rossi 1994b and Rossi 1999

Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy were mentioned
Representative study groupUnclear riskSize of original cohort was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskOutcome definition was not mentioned
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Rossi 1999

MethodsProspective cohort study
Participants

N of participants original cohort: 75; N of participants described study group: 75; N of participants study group of interest: 75; N of participants with renal function tests: 75

Tumour: sarcoma: 49/75 (65%), recurrent lymphoma/leukaemia: 13/75 (17%), neuroblastoma: 6/75 (8%), brain tumour: 5/75 (7%), other: 2/75 (3%). Time period diagnosis/treatment: n/m. %M/F: n/m

Age at diagnosis: median age at completion of chemotherapy: 12.1 years (range 1.1 to 24.1); age at follow-up: n/m; follow-up duration: median 31 months (range 12 to 71); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 75/75 (100%); ifosfamide cumulative dose: median: 30 g/m2 (range 2 to 95)
N of participants cisplatin: 35/75 (47%); cisplatin cumulative dose: median: 402 mg/m2 (range 97 to 600)
N of participants carboplatin: 0/75 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: methotrexate: 35/75 (47%), gentamicin: 46/75 (61%); other chemotherapy cumulative doses: MTX: median 88.4 g/m2 (range 3 to 168), gentamicin: median 32.5 mg/kg (range 4 to 217)

N of participants nephrectomy: 3/75 (4%); nephrectomy details: unilateral nephrectomy (3/3)

N of participants radiotherapy including the kidney region: 3/75 (4%); radiotherapy field: abdominal RT; radiation dose: n/m

Outcomes

Tubular phosphate regulation parameters measured by fractional phosphate reabsorption in micromol/mL

Definition of renal adverse effect
Mild phosphaturia: < 1.0 micromol/mL

Severe phosphaturia: < 0.84 micromol/mL

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
Mild phosphaturia: 44.6% (no N reported)

Severe phosphaturia: 13/75 (17.3%)

Risk factors (univariate analyses)
All participants with Fanconi syndrome had severe phosphaturia. Mean cumulative ifosfamide dose was significantly higher in survivors with phosphaturia than in survivors without phosphaturia (55 g/m2 vs 27 g/m2; P < 0.05)

NotesPossible overlap with the study groups of Rossi 1993, Rossi 1994, Rossi 1994a, Rossi 1994b and Rossi 1997
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definition was objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Sasso 2010

MethodsCohort study with unclear direction
Participants

N of participants original cohort: 34; N of participants described study group: 34; N of participants study group of interest: 34; N of participants with renal function tests: 34

Tumour: Wilms' tumour 34/34 (100%). Time period diagnosis/treatment: April 1981 to April 2000. %M/F: 41%/59%

Age at diagnosis: median 48 months (range 2 to 151); age at follow-up: not mentioned; follow-up duration: median 181 months (range 60 to 264); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: n/m, but at least 6; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: neoadjuvant chemotherapy: not defined (6/34, 18%); other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 33/34 (97%); nephrectomy details: all 33 unilateral nephrectomy

N of participants radiotherapy including the kidney region: 34/34 (100%); radiotherapy field: whole abdomen only (17/34), hemiabdomen only (9/34), other (8/34); radiation dose: range: 15 to 35 Gray

Outcomes

Chronic kidney disease/renal insufficiency

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/a

N of participants with renal adverse effect
Chronic renal failure: 1/34 (3%)

Risk factors (univariate analyses)

n/m

Blood pressure

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/a

N of participants with renal adverse effect
4/34 (12%)

Risk factors (univariate analyses)

n/m

NotesAll 5 survivors with renal toxicity were treated with Ifosfamide and > 12 Gy radiotherapy to the unaffected kidney (P < 0.05)
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo chemotherapy regimens were mentioned
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskNo outcome definitions were given
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisHigh riskNo risk measurements were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Schell 1995

MethodsCohort study with unclear direction
Participants

N of participants original cohort: 57; N of participants described study group: 34; N of participants study group of interest: 34; N of participants with renal function tests: 34

Tumour: neuroblastoma: 13/34 (38%), Wilms' tumour: 21/34 (62%). Time period diagnosis/treatment: 1986-1992. %M/F: n/m

Age at diagnosis: NB: mean 41 months (SD 40); WT: mean 42 months (SD 39); age at follow-up: n/m; follow-up duration: NB: median 9 months (range 3 to 70); WT: median 12 months (range 2 to 60); completion of follow-up: 100%

Control group: 6 children who underwent nephrectomy for a non-malignant disease, without radiological and ultrasound evidence of abnormalities in the contralateral kidney

Interventions

N of participants ifosfamide: NB: 2/13 (15%); WT: 4/21 (19%); ifosfamide cumulative dose: n/m
N of participants cisplatin: NB: 13/13 (100%); WT: 1/21 (5%); cisplatin cumulative dose: NB: median 300 mg/m2 (range 0 to 600); WT: 400 mg/m2
N of participants carboplatin: NB: 13/13 (100%); WT: 1/21 (5%); carboplatin cumulative dose: NB: median 1250 mg/m2 (range 0 to 5400); WT: 1750 mg/m2

Other types of chemotherapy: NB: carmustine 5/13 (38%); other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 34/34 (100%); nephrectomy details: unilateral nephrectomy

N of participants radiotherapy including the kidney region: NB: 7/13 (54%);  WT: 7/21 (33%); radiotherapy field: NB: TBI; WT: local irradiation; radiation dose: n/m

Outcomes

GFR using inulin clearance

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Mean GFR (SD) in mL/min/1.73 m2: NB: 90 (24); WT: 85 (17); controls: 93 (13)

N of participants with renal adverse effect
n/m

Risk factors (univariate analyses)
No correlation was noted between GFR and cisplatin dose, age at nephrectomy, follow-up duration, bone marrow transplantation in NB participants or nephrotoxic drug administration in WT participants. No significant differences were observed between NB, WT and controls

Proteinuria not further specified

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
NB: 2/13 (15%) with mild proteinuria; WT: 1/21 (5%) with mild proteinuria

Risk factors
n/m

Serum phosphate/hypophosphataemia

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
0/34 (0%), all levels were normal in all children

Risk factors
n/m

Blood pressure

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
0/34 (0%)

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample with respect to treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskOutcome definitions were not mentioned
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Skinner 2009

MethodsProspective cohort study
Participants

N of participants original cohort: 68; N of participants described study group: 63; N of participants study group of interest: 63; N of participants with renal function tests: 63

Tumour: miscellaneous. Time period diagnosis/treatment: 1981-1996. %M/F: 54%/46%

Age at diagnosis: median years (range): cisplatin group: 7.7 (0.6 to 17.8); carboplatin group: 4.4 (0.4 to 15.8); combination group: 1.9 (0.1 to 6.2); age at follow-up: n/m; follow-up duration: median 1 year: 1.1 (range 0.7 to 2.3); 10 year: 10.3 (9.0 to 12.3); completion of follow-up: 63/63 (100%)

Controls: n/a

Interventions

N of participants ifosfamide: 0/63 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 27/63 cisplatin only (43%), 12/63 combined with carboplatin (19%); cisplatin cumulative dose: cis-only: 500 mg/m2 (300 to 960); combination: 473 mg/m2 (240 to 739)
N of participants carboplatin: 24 carboplatin only (38%), 12 combined with cisplatin (19%); carboplatin cumulative dose: carbo-only: 2400 mg/m2 (560 to 8800); combination: 1500 mg/m2 (750 to 4200)

Other types of chemotherapy: high-dose Melphalan (9/63), high- or intermediate-dose methotrexate (8/63), other: actinomycin D, bleomycin, cyclophosphamide, doxorubicin, etoposide, 5-fluorouracil, teniposide and vincristine; other chemotherapy cumulative doses: melphalan: 180 to 200 mg/m2, MTX: 1 or 8 g/m2

N of participants nephrectomy: 1/63 (1.5%); nephrectomy details: unilateral nephrectomy: 1/63

N of participants radiotherapy including the kidney region: 8/63 (12.7%); radiotherapy field: small area of kidney: 3; scatter: 5; radiation dose: n/m

Outcomes

GFR using 51Cr-EDTA clearance

Definition of renal adverse effect
GFR < 90 mL/min/1.73 m2

Observed values of renal adverse effects
Median in mL/min/1.73 m2 (range):

Cisplatin alone, end of treatment: 84 (18 to 197)
Cisplatin alone, 1 year post-treatment: 98 (25 to 130)
Cisplatin alone, 10 years post-treatment: 96 (29 to 142)
Carboplatin alone, end of treatment: 120 (68 to 207)
Carboplatin alone, 1 year post-treatment: 109 (63 to 161)
Carboplatin alone, 10 years post-treatment: 110 (66 to 171)
Combination, end of treatment: 91 (45 to 160)
Combination, 1 year post-treatment: 93 (55 to 131)
Combination, 10 years post-treatment: 92 (66 to 135)

N of participants with renal adverse effect
Cisplatin alone, end of treatment: 60%

Cisplatin alone, 1 year post-treatment: 38%

Cisplatin alone, 10 years post-treatment: 40%

Carboplatin alone, end of treatment: 20%

Carboplatin alone, 1 year post-treatment: 19%

Carboplatin alone, 10 years post-treatment: 21%

Combination, end of treatment: 20%

Combination, 1 year post-treatment: 25%

Combination, 10 years post-treatment: 45%

Risk factors (univariate analyses)
Cisplatin alone:

Older age at treatment correlated with lower GFR at 10 years' follow-up (P < 0.001). A 5-year increase in age at treatment lowered GFR at 10 years' follow-up with 13.0 (4.5 to 21.5) mL/min/1.73 m2.

Carboplatin alone:

Older age at treatment correlated with lower GFR at end of treatment, 1 year and 10 years' follow-up (P = 0.018, P = 0.025 and P = 0.011). A 5-year increase in age at treatment lowered GFR with 17.5 (3.5 to 31.5) mL/min/1.73 m2 at end of treatment and 13.8 (3.3 to 24.3) mL/min/1.73 m2 at 10 years' follow-up

Serum magnesium/hypomagnesaemia

Definition of renal adverse effect
Serum magnesium < 0.75 mmol/L for children < 2 years; serum magnesium < 0.70 mmol/L for everyone else

Observed values of renal adverse effects
Median (range) in mmol/L:

Cisplatin alone, end of treatment: 0.68 (0.32 to 0.93)

Cisplatin alone, 1 year post-treatment: 0.70 (0.44 to 0.95)

Cisplatin alone, 10 years post-treatment: 0.73 (0.37 to 0.83)

Carboplatin alone, end of treatment: 0.77 (0.42 to 0.89)

Carboplatin alone, 1 year post-treatment: 0.78 (0.51 to 0.90)

Carboplatin alone, 10 years post-treatment: 0.77 (0.54 to 0.94)

Combination, end of treatment: 0.74 (0.62 to 0.98)

Combination, 1 year post-treatment: 0.80 (0.68 to 0.89)

Combination, 10 years post-treatment: 0.81 (0.68 to 0.92)

N of participants with renal adverse effect
Cisplatin alone, end of treatment: 52%

Cisplatin alone, 1 year post-treatment: 50%

Cisplatin alone, 10 years post-treatment: 32%

Carboplatin alone, end of treatment: 26%

Carboplatin alone, 1 year post-treatment: 27%

Carboplatin alone, 10 years post-treatment: 17%

Combination, end of treatment: 45%

Combination, 1 year post-treatment: 8%

Combination, 10 years post-treatment: 9%

Risk factors (univariate analyses)
Cisplatin only:

Children with an abnormal Mg were older at treatment than those with a normal Mg: 10.9 vs 4.8 years; P = 0.006

Carboplatin only:

Children with an abnormal Mg were older at treatment than those with a normal Mg: 11.4 vs 4.2 years; P = 0.008. Higher cumulative carboplatin dose was correlated with a lower Mg at 1 year post-treatment (P = 0.001). Higher cumulative carboplatin dose also significantly correlated with Mg at end of treatment (P = 0.037), but the magnitude of the effect was very small: a dose increase of 600 mg/m2 leads to a Mg fall of 0.015 mmol/L

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Skinner 2010

MethodsProspective cohort study
Participants

N of participants original cohort: 29; N of participants described study group: 25; N of participants study group of interest: 25; N of participants with renal function tests: 25

Tumour: rhabdomyosarcoma 12/25 (48%), soft tissue sarcoma 6/25 (24%), Ewing's sarcoma 6/25 (24%), PNET 1/25 (4%). Time period diagnosis/treatment: 1986-1996. %M/F: 64%/36%

Age at diagnosis: median: 6.0 years (range 0.6 to 17.7); age at follow-up: n/m; follow-up duration: 1 year: median 1.1 years (range 0.9 to 2.1); 10 year: median 10.5 years (range 9.3 to 11.4); completion of follow-up: 21/25 to 25/25 (92%/100%), depending on time point and outcome

Controls: n/a

Interventions

N of participants ifosfamide: 25/25 (100%); ifosfamide cumulative dose: median 106 g/m2 (range 12 to 153)
N of participants cisplatin: 0/25 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/25 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: melphalan (N = 2), actinomycin D, cyclophosphamide, doxorubicin, etoposide and vincristine (N = n/m); other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 0/25 (0%); nephrectomy details: n/a

N of participants radiotherapy including the kidney region: 3/25 (12%); radiotherapy field: kidney (N = 2), TBI (N = 1); radiation dose: kidney: n/m; TBI: 12 Gy

Outcomes

GFR using 51Cr-EDTA clearance

Definition of renal adverse effect
Age-related reference ranges for subclinical nephrotoxicity, < 60 mL/min/1.73 m2 for clinical nephrotoxicity

Observed values of renal adverse effects
Median (range) in mL/min/1.73 m2:
End of treatment: 101 (65 to 147); 1 year post-treatment: 82 (59 to 131); 10 years post-treatment: 88 (40 to 151)

N of participants with renal adverse effect
End of treatment: 26%; 1 year post-treatment: 72%; 10 years post-treatment: 50%

GFR < 60 mL/min/1.73 m2: end of treatment: 0%; 1 year post-treatment: 4%; 10 years post-treatment: 13%

Risk factors (univariate analyses)
No correlation found between cumulative ifosfamide dose or age at treatment and GFR at any time point

Serum phosphate/hypophosphataemia

Definition of renal adverse effect
< 0.90 mmol/L

Observed values of renal adverse effects
Median (range) in mmol/L:
End of treatment: 1.20 (0.43 to 1.61); 1 year post-treatment: 1.19 (0.57 to 1.62); 10 years post-treatment: 1.07 (0.74 to 1.58)

N of participants with renal adverse effect
End of treatment: 22%; one year post-treatment: 28%; 10 years post-treatment: 8%

Risk factors (univariate analyses)
At end of treatment, higher cumulative ifosfamide dose gave a lower serum phosphate (0.14 mmol/L per 36 g/m2; P = 0.03). At one year post-treatment, higher cumulative ifosfamide dose gave a lower serum phosphate (0.14 mmol/L per 36 g/m2; P = 0.02). At 10 years post-treatment, no relation between ifosfamide and serum phosphate was found. No relation was noted between age at diagnosis and serum phosphate at any time point

Tubular phosphate regulation parameters measured by the renal tubular phosphate threshold (Tmp/GFR)

Definition of renal adverse effect
< 0.99 mmol/L

Observed values of renal adverse effects
Median (range) in mmol/L:
End of treatment: 0.90 (0.19 to 1.41); 1 year post-treatment: 0.85 (0.01 to 1.46); 10 year post-treatment: 0.85 (0.43 to 1.49)

N of participants with renal adverse effect
End of treatment: 48%; 1 year post-treatment: 50%; 10 years post-treatment: 62%

Risk factors (univariate analyses)
At end of treatment, no relation between ifosfamide and Tmp/GFR was found. At 1 year post-treatment, a higher cumulative ifosfamide dose gave a lower Tmp/GFR (P = 0.008). At 10 years post-treatment, no relation between ifosfamide and Tmp/GFR was found. No relation was noted between age at diagnosis and Tmp/GFR at any time point

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupLow riskDescribed study group consisted of 86% of the original cohort but was a random sample with respect to treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Srinivas 1998

MethodsProspective cohort study
Participants

N of participants original cohort: 56; N of participants described study group: 25; N of participants study group of interest: 25; N of participants with renal function tests: 25

Tumour: Wilms' tumour: 25/25 (100%). Time period diagnosis/treatment: 1985-1995. %M/F: 56%/44%

Age at diagnosis: mean: 2.8 years (SD 1.9 years); age at follow-up: mean: 7.7 years (range 2 to 20); follow-up duration: mean: 4.9 years (range 1 to 15); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: n/m; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: n/m; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 25/25 (100%); nephrectomy details: 25/25 (100%) unilateral nephrectomy

N of participants radiotherapy including the kidney region: 6/25 (24%); radiotherapy field: n/m; radiation dose: n/m

Outcomes

GFR using Tc-99m DTPA clearance

Definition of renal adverse effect
< 80 mL/min/1.73 m2

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
0/25 (0%)

Risk factors
n/m

Proteinuria measured by microalbuminuria

Definition of renal adverse effect
> 30 mg/24 h urinary albumin

Observed values of renal adverse effects
Mean urinary albumin/creatinine ratio: 28.82 (SD 10.08)

N of participants with renal adverse effect
Overal: 21/25 (84%)

30 to 100 mg/24 h: 15/25 (60%)

> 100 mg/24 h: 6/25 (24%)

Risk factors
n/m

Blood pressure

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
0/25 (0%)

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo chemotherapy regimens were specified, and no radiotherapy doses were specified
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample with respect to treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise for two of the three outcome measures
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analyses were performed
Adjustment for important confoundersUnclear riskNo analyses were performed

Stefanowicz 2009

MethodsCross-sectional cohort study
Participants

N of participants original cohort: unclear; N of participants described study group: 127; N of participants study group of interest: 69; N of participants with renal function tests: 69

Tumour: group 1: nephroblastoma 34/127 (27%), group 2: onco-haematological disease 58/127 (46%), group 3: other solid tumours 35/127 (28%). Time period diagnosis/treatment: n/m. %M/F (n = 127): 46%/54%

Age at diagnosis (n = 127): median 11 years (range 2.3 to 20.4); age at follow-up: n/m; follow-up duration: group 1: 6 years (range 0.4 to 16.4); 2: 3.6 (0.3 to 12.2); 3: 3.1 (0.3 to 12).; completion of follow-up: 100%

Controls: group 2 did not receive any of the included treatments for this review and was used as an internal control population

Interventions

N of participants ifosfamide: 69/127 (54.3%); ifosfamide cumulative dose: range 6 to 80.4 g/m2
N of participants cisplatin: 35/127 (27.6%); cisplatin cumulative dose: range 0.3 to 0.8 g/m2
N of participants carboplatin: 69/127 (54.3%); carboplatin cumulative dose: range 0.6 to 3.6 g/m2

Other types of chemotherapy: HD-MTX: 58/127 (45.7%), cyclophosphamide: 83/127 (65.4%); other chemotherapy cumulative doses: HD-MTX: range 1 to 22 g/m2, cyclophosphamide: range 1.8 to 12.6 g/m2

N of participants nephrectomy: n/m, but at least 34 Wilms' tumours; nephrectomy details: n/m

N of participants radiotherapy including the kidney region: n/m; radiotherapy field: n/m; radiation dose: n/m

Outcomes

Estimated GFR using the Schwartz formula

Definition of renal adverse effect
GFR < 90 mL/min/1.73 m2

Observed values of renal adverse effects
Group 1: mean 118.2 mL/min/1.73 m2 (SD 20.3); group 2: mean 137.4 mL/min/1.73 m2 (SD 19.4); group 3: mean 116.6 mL/min/1.73 m2 (SD 22.4)

N of participants with renal adverse effect
Group 1: 1/34 (2.9%); group 2: 0/58 (0%); group 3: 2/35 (5.7%)

Risk factors (univariate analyses)
Groups 1 and 3 are significantly lower than group 2 (P < 0.001)

Estimated GFR using the Filler formula

Definition of renal adverse effect
GFR < 90 mL/min/1.73 m2

Observed values of renal adverse effects
Group 1: mean 99.0 mL/min/1.73 m2 (SD 17.1); group 2: mean 121.1 mL/min/1.73 m2 (SD 17.9); group 3: mean 103.9 mL/min/1.73 m2 (SD 21.4)

N of participants with renal adverse effect
Group 1: 9/34 (26.5%); group 2: 2/58 (3.4%); group 3: 9/35 (25.7%)

Risk factors (univariate analyses)

Median values and incidence percentages in groups 1 and 3 are significantly higher than in group 2 (P < 0.001 for medians, P = 0.009 for percentages).

Proteinuria measured by albumin/creatinine ratio

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Group 1: median 9.7 mg/g (range 0 to 84.79); group 2:  median 12.1 mg/g (range 2.7 to 140.9); group 3:  median 38.7 mg/g (range 0 to 1756.3)

N of participants with renal adverse effect
Group 1: 7/34 (20.6%); group 2: 7/58 (12.1%); group 3: 14/35 (40%)

Risk factors (univariate analyses)
Mean values were significantly higher in group 3 compared with groups 1 and 2 (P = 0.0007 and P = 0.004 respectively). Incidence was significantly different for the three groups (P = 0.007). In all participants, a correlation existed between albuminuria and the time elapsed from the end of treatment. In the general population for P < 0.05, r =–0.21; in group 3 for P < 0.05, r = –0.55

Blood pressure

Definition of renal adverse effect
Systolic/diastolic blood pressure > 95th percentile for age/sex

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
1/127 (0.8%)

Risk factors
n/m

Notes

Regarding treatment: numbers of participants per treatment were based on the number of participants in each tumour group

No other signs of tubulopathy (including hypophosphataemia, hypokalaemia, hypomagnesaemia or acidosis) were found

There may be overlap between the studies of Stefanowicz 2009, Stefanowicz 2010 and Stefanowicz 2011

Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupUnclear riskOriginal cohort size was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise for three of the four outcome measures
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Stefanowicz 2010

MethodsCross-sectional cohort study
Participants

N of participants original cohort: unclear; N of participants described study group: 26; N of participants study group of interest: 26; N of participants with renal function tests: 26

Tumour: nephroblastoma stage 1 7/26 (27%), stage 2N- 9/26 (34%), stage 2N+ 3/26 (12%) and stage 3 7/26 (27%). Time period diagnosis/treatment: 1992-2007. %M/F: 50%/50%

Age at diagnosis: n/m; age at follow-up: mean 11.2 years (SD 4.8; range 2.3 to 20.4); follow-up duration: mean 7.1 years (SD 4.8 range 0.4 to 16.4); completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: 0/26 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 0/26 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/26 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: 5/26 treated with nephrotoxic chemotherapy not further specified; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 26/26 (100%); nephrectomy details: unilateral nephrectomy

N of participants radiotherapy including the kidney region: 11/26 (42.3%); radiotherapy field: n/m; radiation dose: n/m

Outcomes

Estimated GFR using the Schwartz formula

Definition of renal adverse effect
< 90 mL/min/1.73 m2

Observed values of renal adverse effects
Normal CysC group: median 120 mL/min/1.73 m2 (range 102 to 165)

High CysC group: median 102 mL/min/1.73 m2 (range 74 to 142)

N of participants with renal adverse effect
1/26 (4%)

Risk factors
n/m

Blood pressure

Definition of renal adverse effect
Mean systolic/diastolic blood pressure compared with sex/age/height corrected reference values

Observed values of renal adverse effect
n/m

N of participants with renal adverse effect
1/26 (4%)

Risk factors

n/m

NotesThere may be overlap between the studies of Stefanowicz 2009, Stefanowicz 2010 and Stefanowicz 2011
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo chemotherapy was specified, no cumulative doses, no radiotherapy doses
Representative study groupUnclear riskSize of original cohort was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Stefanowicz 2011

MethodsCross-sectional cohort study
Participants

N of participants original cohort: unclear; N of participants described study group: 32; N of participants study group of interest: 32; N of participants with renal function tests: 32

Tumour: Wilms' tumour: 32/32 (100%). Time period diagnosis/treatment: 1987-2008. %M/F: 59%/41%

Age at diagnosis: mean: 8.5 years (SD 5.7 years); median: 2.9 years (range 0.08 to 11.4); age at follow-up: mean: 13 years (SD 5.4 years); median: 12.2 years (range 3.6 to 24.3); follow-up duration: mean: 9.3 years (SD 5.4 years); median: 7.75 years (range 0.3 to 20.6); completion of follow-up: 100%.

Controls: n/a

Interventions

N of participants ifosfamide: unclear, maximum: 7/32 (22%); ifosfamide cumulative dose: n/m
N of participants cisplatin: 0/32 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: unclear, maximum: 7/32 (22%); carboplatin cumulative dose: n/m

Other types of chemotherapy: n/m; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 32/32 (100%); nephrectomy details: unilateral nephrectomy: 32/32 (100%)

N of participants radiotherapy including the kidney region: 12/32 (37.5%); radiotherapy field: tumour bed or total abdomen: 9/32 (28%); remnant kidney: 3/32 (9%); radiation dose: n/m

Outcomes

Chronic kidney disease/renal insufficiency

Definition of renal adverse effect
Chronic kidney disease staging according to National Kidney Foundation guidelines

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
CKD stage I: GFR > 90 mL/min/1.73 m2 with no signs of kidney damage: 8/32 (25%); GFR > 90 mL/min/1.73 m2 with signs of kidney damage: 10/32 (32%). CKD stage II: GFR 60 to 89 mL/min/1.73 m2 with no signs of kidney damage: 8/32 (25%); GFR 60 to 89 mL/min/1.73 m2 with signs of kidney damage: 6/32 (19%)

Risk factors       

Not mentioned

GFR using 99Tc-DTPA clearance

Definition of renal adverse effect
GFR < 90 mLl/min/1.73 m2

Observed values of renal adverse effects
Mean: 94.3 mL/min/1.73 m2 (SD 10.24). Mean GFR nephrotoxic chemo (N = 7): 92.7 (SD 8.7); mean GFR non-nephrotoxic chemo (N = 25): 88.9 (SD 18.3) (P = 0.43)

N of participants with renal adverse effects
14/32 (44%)

Risk factors
Not mentioned

Estimated GFR using the old Schwartz formula

Definition of renal adverse effect
eGFR < 90 mL/min/1.73 m2

Observed values of renal adverse effects
Mean: 122.3 mL/min/1.73 m2 (SD 19.92)

N of participants with renal adverse effect
1/32 (3%)

Risk factors
Not mentioned

Estimated GFR using the new Schwartz formula

Definition of renal adverse effect
eGFR < 90 mL/min/1.73 m2

Observed values of renal adverse effects
Mean: 94.3 mL/min/1.73 m2 (SD 10.2)

N of participants with renal adverse effect
11/32 (34%)

Risk factors
Not mentioned

Estimated glomerular filtration rate by the Filler formula

Definition of renal adverse effect
eGFR < 90 mL/min/1.73 m2

Observed values of renal adverse effects
Mean: 129.8 mL/min/1.73 m2 (SD 23.9)

N of participants with renal adverse effect
0/32 (0%)

Risk factors
Not mentioned

Proteinuria measured by urinary albumin to creatinine ratio

Definition of renal adverse effect
Albumin-to-creatinine ratio > 30 mg/g

Observed values of renal adverse effects
Not mentioned

N of participants with renal adverse effect
7/32 (22%)

Risk factors
Not mentioned

Proteinuria measured by urinary albumin concentration

Definition of renal adverse effect
Urinary albumin concentration > 20 mg/L

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
6/32 (19%)

Risk factors
Not mentioned

Blood pressure

Definition of renal adverse effect
Arterial or diastolic blood pressure > 95th percentile

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
4/32 (12.5%)

Risk factors       

Not mentioned

NotesThere may be overlap between the studies of Stefanowicz 2009, Stefanowicz 2010 and Stefanowicz 2011
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo chemotherapy was specified, no cumulative doses, no radiotherapy doses
Representative study groupUnclear riskSize of original cohort was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Stohr 2007

MethodsProspective cohort study
Participants

All tumour and age-related characteristics were described for the 593 participants with renal function tests

N of participants original cohort: 754; N of participants described study group: 648; N of participants study group of interest: 648; N of participants with renal function tests: 593

Tumour: Ewing's sarcoma 154/593 (26%), osteosarcoma 217/593 (37%), soft tissue sarcoma 222/593 (37%). Time period diagnosis/treatment: 01-01-1998 to 07-01-2002. %M/F: 55%/45%

Age at diagnosis: median 11.7 years (range 0.4 to 17.6); age at follow-up: n/m; follow-up duration: median 19 months (IQR 8 to 36) after end of therapy; completion of follow-up: 92%

Controls: n/a

Interventions

N of participants ifosfamide: 593/593 (100%); ifosfamide cumulative dose: 51 g/m2 (range 6 to 105)
N of participants cisplatin: 217/593 (37%); cisplatin cumulative dose: 360 mg/m2 (range 120 to 960)
N of participants carboplatin: 84/593 (14%); carboplatin cumulative dose: 1.5 g/m2 (range 0.5 to 4.2)

Other types of chemotherapy: variable combinations of actinomycin D, doxorubicin, epirubicin, etoposide, methotrexate, or vincristine according to the appropriate protocols; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 0/593 (0%); nephrectomy details: n/a

N of participants radiotherapy including the kidney region: 63/593 (11%); radiotherapy field: abdominal (tumour) field; radiation dose: median cumulative dose: 45 Gray (range 27 to 59)

Outcomes

Composite outcome: tubulopathy, including hypophosphataemia, glucosuria, proteinuria, at least at two consecutive examinations 4 weeks apart

Definition of renal adverse effect
Having met at least 2 of the 3 above-mentioned criteria

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
27/593 (4.6%), of which 9/27 were diagnosed during therapy and 18/27 after cessation of therapy (median follow-up 12.6 months (range 0 to 22.6))

Risk factors (univariate and multivariate analyses)
Univariate analyses:

Ifosfamide cumulative dose:

< 24 g/m2: 1/229 (0.4%)

24 to 60 g/m2: 14/214 (6.5%)

> 60 g/m2: 12/150 (8.0%)

Age:

Younger participants presented significantly more often with tubulopathy compared with older participants, with an incidence of 14.7% in children < 5 years in comparison with 2.4, 1.4 and 4.2% in the age classes 5 to 9.9, 10 to 14.9 and 15 years (P < 0.001). This difference remained significant after stratification for the cumulative ifosfamide dose

Multivariate proportional hazards model:

Younger age and higher cumulative ifosfamide dose significantly decreased time to tubulopathy. Children < 4 years at diagnosis had a 8.7-fold risk of tubulopathy compared with older participants (P < 0.001). In comparison with cumulative ifosfamide dose < 24 g/m2, risk was 5.6-fold higher for 24 to 60 g/m2 (P = 0.11) and 18.6-fold higher for > 60 g/m2 (P = 0.005). No independent effect of carboplatin or abdominal irradiation was found, nor any interaction with age at diagnosis or ifosfamide dosage

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and no random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskOutcome definition was objective but not precise: composite outcome
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersLow riskImportant prognostic factors were taken into account

Stohr 2007a

MethodsProspective cohort study
Participants

N of participants original cohort: 757; N of participants described study group: 651; N of participants study group of interest: 651; N of participants with renal function tests: Mg: 435. GFR: 618

Tumour: in the magnesium analyses (N = 435): osteosarcoma 139/435 (32%), soft tissue sarcoma 167/435 (38%), Ewing's sarcoma 109/435 (25%). In the GFR analyses (N = 618): osteosarcoma 212/618 (34%), soft tissue sarcoma 258/618 (42%), Ewing's sarcoma 148/618 (24%). Time period diagnosis/treatment: January 1998 to January 2002. %M/F: in the magnesium analyses: 56%/44%. In the GFR analyses: 57%/43%

Age at diagnosis: in the magnesium analyses: median 11.6 years (IQR 6.5 to 14.9). In the GFR analyses: "similar to Mg group"; age at follow-up: n/m; follow-up duration: In the magnesium analyses: median 23 months (range 0 to 59). In the GFR analyses: "similar to Mg group"; completion of follow-up: Mg: 67%. GFR: 95%

Controls: n/a

Interventions

N of participants ifosfamide: in the magnesium analyses: 410/435 (94%). In the GFR analyses: "similar to Mg group"; ifosfamide cumulative dose: in the magnesium analyses: median 51 g/m2 (range 6 to 105). In the GFR analyses: "similar to Mg group"
N of participants cisplatin: in the magnesium analyses: 158/435 (36%). In the GFR analyses: 234/618 (38%); cisplatin cumulative dose: in the magnesium analyses: median 360 mg/m2 (range 120 to 600). In the GFR analyses: "similar to Mg group"
N of participants carboplatin: in the magnesium analyses: 60/435 (14%). In the GFR analyses: 114/618 (18%); carboplatin cumulative dose: in the magnesium analyses: median 1.5 g/m2 (range 0.5 to 4.2). In the GFR analyses: "similar to Mg group"

Other types of chemotherapy: actinomycin D, busulphan, doxorubicin, epirubicin, etoposide, melphalan, methotrexate or vincristine; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 0/618 (0%); nephrectomy details: n/a

N of participants radiotherapy including the kidney region: in the magnesium analyses: 53/435 (12%). In the GFR analyses: "similar to Mg group"; radiotherapy field: abdominal; radiation dose: median 45 Gy (IQR 36 to 51)

Outcomes

Estimated GFR using the Schwartz formula

Definition of renal adverse effect
Grade 1 : < 75% to 50% lower limits of normal (LLN); grade 2: < 50% to 25% LLN; grade 3 < 25% LLN, long-term dialysis not indicated; grade 4: long-term dialysis or renal transplant indicated; grade 5: death

Observed values of renal adverse effect
n/m

N of participants with renal adverse effect
n/m

Risk factors (multivariate analyses)
No analyses were performed on glomerular function because the GFR estimation by the Schwartz formula seemed unreliable in the study population, especially in the first year after therapy, when more than 40% of all included participants had an estimated GFR above the upper limit of normal

Serum magnesium/hypomagnesaemia

Definition of renal adverse effect
Serum magnesium < 0.7 mmol/L or receiving magnesium supplementation

Observed values of renal adverse effects
After  6 months (mean (SD)): no platinum: 0.85 (0.09); only cisplatin: 0.80 (0.09); only carboplatin: 0.81 (0.15); cisplatin+carboplatin: 0.74 (0.09)

Last examination (mean (SD)): no platinum: 0.88 (0.09); only cisplatin: 0.84 (0.08); only carboplatin: 0.86 (0.09); cisplatin+carboplatin: 0.81 (0.11)

N of participants with renal adverse effect
After  6 months: overall: 30/339 (8.9%); no platinum: 8/177 (4.5%); only cisplatin: 14/116 (12.1%); only carboplatin: 5/32 (15.6%); cisplatin+carboplatin: 3/14 (21.4%)

Last examination: overall: 9/286 (3.1%); no platinum: 5/156 (3.2%); only cisplatin: 2/86 (2.3%); only carboplatin: 1/33 (3.0%); cisplatin+carboplatin: 1/11 (9.1%)

Risk factors (multivariate analyses)
ANOVA: significant lower serum magnesium when treated with cisplatin (mean serum Mg 0.82 vs 0.86 mmol/L; P = 0.0005) and carboplatin (mean serum Mg 0.82 vs 0.86 mmol/L; P = 0.0102), no significant effect of length of follow-up and abdominal irradiation. None of these factors had a significant interaction effect with time

Neither in bivariate or multivariate analyses, any significant influence of ifosfamide on serum magnesium could be found. However, almost all included survivors received ifosfamide

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskGFR was assessed in 95% of the study group of interest (++), serum magnesium was assessed in 67% of the study group of interest (+)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersLow riskImportant prognostic factors were taken into account

Trahair 2007

MethodsRetrospective cohort study
Participants

N of participants original cohort: 23; N of participants described study group: 23; N of participants study group of interest: 23; N of participants with renal function tests: 21

Tumour: neuroblastoma 23/23 (100%). Time period diagnosis/treatment: June 1985 to December 2003. %M/F (n = 40, including 17 deceased participants): 65%/35%

Age at diagnosis (n = 40, including 17 deceased participants): median: 2.7 years (range 0.0 to 10.8); age at follow-up: n/m; follow-up duration (n = 23): median 4.6 years (range 0.6 to 17.8) from diagnosis; completion of follow-up: for renal evaluation: 21/23 (91%)

Controls: n/a

Interventions

N of participants ifosfamide: 0/23 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 19/23 (83%); cisplatin cumulative dose: 80 mg/m2
N of participants carboplatin: 3/23 (13%); carboplatin cumulative dose: 1700 mg/m2

Other types of chemotherapy: included teniposide, adriamycin, melphalan, thiotepa, cyclophosphamide; other chemotherapy cumulative doses: teniposide 130 mg/m2, adriamycin 30 mg/m2, melphalan 120 or 210 mg/m2, thiotepa 810 mg/m2, etoposide 1800 or 1352 mg/m2, cyclophosphamide 200 mg/kg

N of participants nephrectomy: 0/23 (0%); nephrectomy details: n/a

N of participants radiotherapy including the kidney region: 19/23 (83%); radiotherapy field: TBI; radiation dose: 12 Gy in 6 fractions

Outcomes

GFR, method n/m or serum creatinine

Definition of renal adverse effect
GFR < 90 mL/min/1.73 m2 or persistent elevated creatinine

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
10/21 (47%)

Two participants have been dialysed and one subsequently received a living related donor kidney transplant. One participant with mild renal impairment was treated for recurrent gout before death. Of the remaining seven participants with renal complications, two were diagnosed with post-transplant nephropathy, one with an obstructive uropathy secondary to the tumour arising in the pelvic retroperitoneum, one with a combination of post-infectious glomerulonephritis and tubular dysfunction, one with recurrent urinary tract infections complicated by pyelonephritis and one with an unknown cause of renal impairment. The study did not mention the details of the seventh participants with renal complications

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatment and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definition was objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analysis was performed
Adjustment for important confoundersUnclear riskNo analysis was performed

Trobs 2001

MethodsRetrospective cohort study
Participants

N of participants original cohort: 54; N of participants described study group: 49; N of participants study group of interest: 49; N of participants with renal function tests: 49

Tumour: Wilms' tumour 54/54 (100%). Time period diagnosis/treatment: 1974-1996. %M/%F: 57%/43%

Age at diagnosis: median 2.6 years (range 0 to 12); age at follow-up: n/m; follow-up duration: n/m; completion of follow-up: 49/54 (90.7%)

Controls: n/a

Interventions

N of participants ifosfamide: n/m, but was included in at least one of the given protocols; ifosfamide cumulative dose: n/m
N of participants cisplatin: 0/49 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: n/m, but was included in at least one of the given protocols; carboplatin cumulative dose: n/m

Other types of chemotherapy: cyclophosphamide, actinomycin D, vincristine, doxurubicin, VP16; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 49/49 (100%); nephrectomy details: 6 bilateral nephrectomies, other unilateral

N of participants radiotherapy including the kidney region: n/m, but was included in at least one of the given protocols; radiotherapy field: n/m; radiation dose: range 15 to 35 Gy

Outcomes

Blood pressure

Definition of renal adverse effect
Hypertension requiring medication

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
2/49 survivors had arterial hypertension

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo relevant chemotherapy regimens were specified, no cumulative doses, no number of participants treated with radiotherapy
Representative study groupHigh riskDescribed study group consisted of less than 90% of the original cohort and was not a random sample of the original cohort with respect to cancer treatment
Well-defined follow-upHigh riskLength of follow-up was not mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskOutcome definition was not precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analysis was performed
Adjustment for important confoundersUnclear riskNo analysis was performed

Van Dijk 2010

MethodsCross-sectional cohort study
Participants

N of participants original cohort: 185; N of participants described study group: 185; N of participants study group of interest: 185; N of participants with renal function tests: unclear

Tumour: Wilms' tumour: 185/185 (100%). Time period diagnosis/treatment: 1966-1996. %M/F: 52%/48%

Age at diagnosis: median: 3.7 years (range 0.3 to 16.5); age at follow-up: median: 22.9 years (range 6.8 to 42.0); follow-up duration: median: 18.9 years (range 5.0 to 36.7); completion of follow-up: 181/185 (98%) for overall follow-up, but unclear how many were tested for renal function

Controls: n/a

Interventions

N of participants ifosfamide: n/m; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: anthracyclines, alkylating agents, vincristine, vinblastine, dactinomycin; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: 185/185 (100%); nephrectomy details: n/m

N of participants radiotherapy including the kidney region: 78/185 (42%); flank only: 53/78 (68%); abdomen only: 12/78 (15%); flank + abdomen: 13/78 (17%); radiation dose: median EQD2 for flank/abdomen: 27.7 Gy (range 11.6 to 39.0)

Outcomes

Glomerular function

Definition of renal adverse effect
As defined by the CTCAE 3.0, not explicitly mentioned

Observed values of renal adverse effect
n/m

N of participants with renal adverse effect
Overall: 12/181 (6.6%). Survivors treated with RT: grade 1: 3/12; grade 2: 2/12; grade 3,4,5: 2/12. Survivors treated without RT: grade 1: 2/12; grade 2: 0/12; grade 3,4,5: 3/12

Risk factors (multivariate analyses)
Multivariate logistic regression analysis did not find any significant risk factors for nephrological adverse events (including hypertension, glomerular dysfunction not further specified and tubular dysfunction not further specified). Risk factors included in the model: sex, age at diagnosis, radiotherapy doses, chemotherapy

Blood pressure

Definition of renal adverse effect
As defined by the CTCAE 3.0, not explicitly mentioned

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
Overall: 18/181 (9.9%). Survivors treated with RT: grade 1: 2/18; grade 2: 8/18; grade 3,4,5: 0/18. Survivors treated without RT: grade 1: 1/18; grade 2: 7/18; grade 3,4,5: 0/18

Risk factors (multivariate analyses)
Multivariate logistic regression analysis did not find any significant risk factors for nephrological adverse events (including hypertension, glomerular dysfunction not further specified and tubular dysfunction not further specified). Risk factors included in the model: sex, age at diagnosis, radiotherapy doses, chemotherapy

NotesPossible overlap between the study groups of Geenen 2010, Van Dijk 2010, Aronson 2011 and Cardous-Ubbink 2010
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo chemotherapy was specified and no cumulative doses of chemotherapy
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskFollow-up duration was mentioned
Complete follow-up assessmentUnclear riskNumber of participants who underwent renal function tests was not mentioned
Well-defined outcomeLow riskOutcome definitions as defined by the CTCAE v3 criteria
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisLow riskRelevant risk measures were provided
Adjustment for important confoundersLow riskImportant prognostic factors were taken into account

Van Why 1991

MethodsRetrospective cohort study
Participants

N of participants original cohort: 64; N of participants described study group: 64; N of participants study group of interest: 39; N of participants with renal function tests: 39

Tumour: haematological malignancies 36/64 (56%), solid tumours 5/64 (8%), immunodeficiency/other non-malignancies 23/64 (36%). Time period diagnosis/treatment: 1975-1988. %M/F: n/m

Age at diagnosis (n = 64): mean age 7.6 years (range 1 month to 18 years); age at follow-up: n/m; follow-up duration (n = 64): mean 17 months (range 2 months to 11 years); Completion of follow-up: 100%

Controls: n/a

Interventions

N of participants ifosfamide: n/m; ifosfamide cumulative dose: n/m
N of participants cisplatin: n/m; cisplatin cumulative dose: n/m
N of participants carboplatin: n/m; carboplatin cumulative dose: n/m

Other types of chemotherapy: 53/64 any conditioning chemotherapy regimen; other chemotherapy cumulative doses: n/m

N of participants nephrectomy: n/m; nephrectomy details: n/m

N of participants radiotherapy including the kidney region: 39/64 (61%); radiotherapy field: TBI; radiation dose: 1320 cGy in 8 fractions

Outcomes

Estimated GFR using the Schwartz formula OR serum creatinine concentration

Definition of renal adverse effect
eGFR < 50 mLl/min/1.73 m2 OR doubling of baseline serum creatinine concentration

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
Overall: 18/64 (28%) with late renal insufficiency (> 60 days post-transplant)

TBI group: 17/39 (43.6%) with late renal insufficiency (> 60 days post-transplant)

9/64 (14%) with persistent renal insufficiency (range 3 months to 3 years)

Risk factors (multivariate analyses)
Stepwise logistical regression on late renal insufficiency:

Independent predictors: cyclosporin A use beyond day 60, amphotericin B use and conditioning with TBI

Not predictive: chemotherapy as conditioning regimen and renal insufficiency in first 60 days post-BMT

Blood pressure

Definition of renal adverse effect
Blood pressure > 95th percentile for age

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
10/64 (16%) > 60 days post-BMT

Risk factors (univariate analyses)
Early hypertension (< 60 days post-BMT) was not predictive of late hypertension (> 60 days post-BMT). 9/10 had concomitant cyclosporin A treatment and 8/10 had concomitant renal insufficiency

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskNo chemotherapy and nephrectomy data were given
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeLow riskOutcome definitions were objective and precise
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisHigh riskMultivariate logistic regression was performed, but the results were not presented
Adjustment for important confoundersLow riskImportant prognostic factors were taken into account

von Schweinitz 1997

MethodsProspective cohort study
Participants

N of participants original cohort: 56; N of participants described study group: 54; N of participants study group of interest: 54; N of participants with renal function tests: 41

Tumour: hepatoblastoma: 54/54 (100%). Time period diagnosis/treatment: 1988-1993. %M/F (n = 72, including 18 deceased participants): 66%/34%

Age at diagnosis (n = 72, including 18 deceased participants): median: 12 months (range 1 day to 11 years); age at follow-up: n/m; follow-up duration: median: 64 months (range 28 to 82 months); completion of follow-up: 41/54 (76%)

Controls: n/a

Interventions

N of participants ifosfamide: 54/54 (100%); ifosfamide cumulative dose: n/m (0.5 g/m2 bolus + 3.0 g/m2 over 72 h per cycle)
N of participants cisplatin: 54/54 (100%); cisplatin cumulative dose: n/m (20 mg/m2 × 5 per cycle)
N of participants carboplatin: 0/54 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: doxorubicin: 54/54 (100%); other chemotherapy cumulative doses: 60 mg/m2 over 48 h per cycle

N of participants nephrectomy: 0/54 (0%); nephrectomy details: n/a

N of participants radiotherapy including the kidney region: 0/54 (0%); radiotherapy field: n/a; radiation dose: n/a

Outcomes

GFR using creatinine clearance, method not specified

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
0/41 (0%) had an abnormal clearance at follow-up

Risk factors
n/m

Renal tubular function as a composite outcome of tubular phosphate reabsorption and amino acid reabsorption

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
7/41 (17%) with a subclinical renal tubulopathy of which:

5/41 (12%) with mild tubulopathy

2/41 (5%) with more severe tubulopathy

Risk factors                         
n/m

NotesAll participants received at least 2 cycles of chemotherapy
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskChemotherapy dosages given only per cycle, no cumulative doses
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for 76% of the study group of interest (+)
Well-defined outcomeHigh riskNo outcome definitions were given for the outcome measurements
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analyses were performed
Adjustment for important confoundersUnclear riskNo analyses were performed

Weirich 2004

MethodsProspective cohort study
Participants

Tumour and age-related characteristics were described for all 392 participants without tumour- or therapy-related death. All other characteristics related to the 385/392 participants with a follow-up duration > 5 years

N of participants original cohort: 385; N of participants described study group: 385; N of participants study group of interest: 385; N of participants with renal function tests: unclear

Tumour: unilateral Wilms tumour: 369/392 (94.1%), bilateral Wilms' tumour: 23/392 (5.9%). Time period diagnosis/treatment: 1989-1994. %M/F: n/m for follow-up cohort

Age at diagnosis: median 2.9 years; mean 3.5 years; age at follow-up: 157/392 (40.1%) > 13 years; follow-up duration: > 5 years in 385/392 (98.2%). Median: 8 years (range 0.25 to 12.6); completion of follow-up: unclear, mailed questionnaires

Controls: n/a

Interventions

N of participants ifosfamide: 25/385 (6.4%); ifosfamide cumulative dose: range 24 to 30 g/m2
N of participants cisplatin: 0/385 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 26/385 (6.7%); carboplatin cumulative dose: n/m

Other types of chemotherapy: adriamycin: 204/385 (52.9%), etoposide 26/385 (6.7%); other chemotherapy cumulative doses: adriamycin: range 250 to 400 mg/m2

N of participants nephrectomy: 385/385 (100%); nephrectomy details: bilateral surgery with >50% loss of renal tissue: 11/385 (2.8%)

Unilateral surgery: 374/385 (97.1%)

N of participants radiotherapy including the kidney region: 84/385 (21.8%); radiotherapy field: abdominal irradiation; radiation dose: n/m

Outcomes

Renal/urinary dysfunction

Definition of renal adverse effect
According to CTCAE v2 criteria

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
Overall: 28/385 (7.2%)

Mild: 13/385 (3.4%)

Moderate: 7/385 (1.8%)

Severe: 5/385 (1.3%)

Disabling: 3/385 (0.8%)

15/385 (3.9%) needed treatment for renal or urinary system impairment

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupHigh riskCarboplatin and radiotherapy cumulative dose was not specified
Representative study groupLow riskDescribed study group consisted of more than 90% of the original cohort
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentUnclear riskOutcomes were reported only if apparent, unclear how many survivors received renal tests
Well-defined outcomeLow riskOutcome definitions as defined by the CTCAE v2 criteria
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisUnclear riskNo analysis was performed
Adjustment for important confoundersUnclear riskNo analysis was performed

Wikstad 1986

  1. a

    Abbreviations: %M/F: Percentage males/females; 24h: 24 hour; 51Cr-EDTA: 51-chromium-ethylenediaminetetraacetic acid; A1M: alpha-1-microglobulin; ALL: acute lymphoblastic leukaemia; AML: acute myeloid leukaemia; ANOVA: analysis of variance; Ara-C: cytarabine; BCNU: carmustine; BMI: body mass index; BMT: bone marrow transplantation; BP: blood pressure; Carbo: Carboplatin; cGy: centiGray; CI: confidence interval; CI: continuous infusion; CISP: cisplatin; CKD: chronic kidney disease; CML: chronic myeloid leukaemia; CNS: central nervous system; CT: chemotherapy; CTCAE: Common Terminology Criteria for Adverse Events; CysC: cystatin C; DD-4A: vincristine+dactinomycin+doxorubicin); EE-4A: vincristine+dactinomycin; eGFR: estimated glomerular filtration rate; EMU p/c: early morning urine protein-to-creatinine ratio; EQD2: equivalent dose in 2 Gray fractions; ESRD: end-stage renal disease; fTBI: fractioned total body irradiation; GFR: glomerular filtration rate; GVHD: graft versus host disease; Gy: Gray; H(S)CT: hematopoietic (stem) cell transplant; HD: high-dose; Hn: hydronephrosis; IFO: ifosfamide; IQR: interquartile range; i.v.: intravenous; kg: kilogram; L: litre; LBL: lymphoblastic lymphoma; LCAL: large cell anaplastic lymphoma; LDH: lactate dehydrogenase; LLN: lower limit of normal; m: metre; mcg: microgram; MDRD: modification of diet in renal disease; Mg: magnesium; mg: milligram; min: minute; ml: millilitre; mmHg: millimetre mercury; mmol: millimols; MTX: methotrexate; N-NHL: B-cell non-Hodgkin lymphoma; n/a: not applicable; n/m: not mentioned; N: number; NB: neuroblastoma; NCI: National Cancer Institute; NP: nephrectomy; NS: not significant; NSS: nephron sparing surgery; NWTS: National Wilms' Tumour Study; OR: odds ratio; PNET: primitive neuroectodermal tumour; RT: radiotherapy; RTOG/EORTC: Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer; SD: standard deviation; SDS: standard deviation score; SI: short infusion; TBI: total body irradiation; Tc-99m DTPA: technetium-99m diethylenetriaminepentaacetic acid; TmP/GFR: renal tubular phosphate threshold; TP/Cr: fractional tubular phosphate reabsorption (tubular phosphate/creatinine ratio); VP16: etoposide; vs: versus; WT: Wilms' tumour; y: year.

MethodsCross-sectional cohort study
Participants

N of participants original cohort: n/m; N of participants described study group: 37 (22 Wilms' tumour survivors (WT) + 15 hydronephrosis (Hn)); N of participants study group of interest: 22; N of participants with renal function tests: 22

Tumour: Wilms' tumour 22/22 (100%). Time period diagnosis/treatment: 1950-1978. %M/F: Wt: 50%/50%; Hn: 40%/60%

Age at diagnosis: WT: mean 2.6 years (SD 0.4); Hn: mean 7.9 years (SD 1.2); age at follow-up: WT: mean 16.2 years (SD 1.8); Hn: mean: 25 years (SD 2.7); follow-up duration: WT: mean 13.2 years (SD 1.7); Hn: mean: 17.1 years (SD 2.5); completion of follow-up: 100%

Controls: 6 healthy participants (3 male); mean age 35 years (SD 3 years)

Interventions

N of participants ifosfamide: 0/22 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 0/22 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/22 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: actinomycin D: 18/22; other chemotherapy cumulative doses: actinomycin D: 70 microgram/kg i.v. 3 to 7 times in 11/18 and once in 7/18

N of participants nephrectomy: WT: 22/22 (100%); Hn :15/15 (100%); nephrectomy details: all unilateral nephrectomies

N of participants radiotherapy including the kidney region: 22/22 (100%); radiotherapy field: abdominal radiation; radiation dose: 5 to 15 Gray to the contralateral kidney

Outcomes

GFR using inulin clearance

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Mean (SD)

WT: 85.6 mL/min/1.73 m2 (3.4)

Hn: 96.2 mL/min/1.73 m2 (3.6)

Controls: 104.5 mL/min/1.73 m2 (3.6)

P < 0.05 between WT and Hn

N of participants with renal adverse effect
n/m

Risk factors (univariate analyses)
There was no relationship between GFR and duration of follow-up

Proteinuria measured by urinary albumin excretion

Definition of renal adverse effect
n/m

Observed values of renal adverse effect
Mean (SD): WT: 16.7 microgram/min (11.9); Hn: 72.9 microgram/min (23.1); controls: 17.2 microgram/min (3.7); P < 0.05 for WT vs Hn; no difference between WT and controls, neither when corrected for body surface area

N of participants with renal adverse effects
n/m

Risk factors
n/m

Blood pressure

Definition of renal adverse effect
n/m

Observed values of renal adverse effects
Mean systolic pressure in mmHg (SD):

WT: 117 (2); Hn: 125 (3); controls: 122 (6)

Mean diastolic blood pressure in mmHg (SD): WT: 76 (2); Hn: 81 (2); controls: 81 (2) No significant differences between the subgroups

N of participants with renal adverse effect
n/m

Risk factors
n/m

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Well-defined study groupLow riskTypes of treatments and cumulative doses of relevant chemotherapy and radiotherapy were mentioned
Representative study groupUnclear riskNumber of participants in original cohort was not mentioned
Well-defined follow-upLow riskLength of follow-up was mentioned
Complete follow-up assessmentLow riskOutcome was assessed for more than 90% of the study group of interest (++)
Well-defined outcomeHigh riskNo outcome definitions were given for the outcome measurements
Blinded outcome assessorUnclear riskUnclear whether outcome assessors were blinded to the investigated determinant
Well-defined analysisHigh riskNo risk measurements were provided
Adjustment for important confoundersHigh riskImportant prognostic factors were not taken into account

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Abboud 2009No distinction between nephrotoxic therapy and other therapy
Abd-El-Aal 2005No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Abedi 1990No childhood cancer survivors
Aksnes 2009No distinction between nephrotoxic therapy and other therapy
Aleksa 2001Review
Aleksa 2004No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Amato 1995No childhood cancer survivors
Anderson 1979No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Anderson 2010Editorial
Antman 1989No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Arai 1998No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Arakelyan 2010No childhood cancer survivors
Argueso 1992Less than 20 childhood cancer survivors
Ariceta 1997Less than 20 patients tested for early or late effects
Arjmandi-Rafsanjani 2008No distinction between nephrotoxic therapy and other therapy
Arndt 1997No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Arndt 1999No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Arriagada 2009Review
Ashraf 1994Less than 20 patients tested for early or late effects
Bacci 2002No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Baker 2010Review
Barahmani 2009No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Bardi 2004aNo evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Bardi 2007No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Bashir 2007Case report
Baudoin 1993Less than 20 childhood cancer survivors
Berg 2006Case report
Beyzadeoglu 2008No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Bhatia 2003Review
Bhisitkul 1991Less than 20 childhood cancer survivors
Boddy 1996Less than 20 childhood cancer survivors
Bodei 2008No childhood cancer survivors
Bonsib 2010Review
Bosl 1988No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Brade 1991Review
Bradley 1998No distinction between nephrotoxic therapy and other therapy
Brock 1992Less than 20 childhood cancer survivors with early or long-term follow-up as defined in our inclusion criteria
Bunjes 2002No childhood cancer survivors
Burk 1990Less than 20 childhood cancer survivors
Bürger 1985Review
Cachat 1996Review
Cai 2010No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Carlson 1993No childhood cancer survivors
Castleberry 1991No nephrotoxicity
Chen 2007No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Cheng 2008Review
Chow 2007No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Chow 2010No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Chow 2011No distinction between nephrotoxic therapy and other therapy
Cohen 1995Case series
Cohen 2008No childhood cancer survivors
Cole 1994No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Conn 1972No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Cosset 1994Review
Couto-Silva 2001No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Coze 1997No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Cozzi 1997Letter to the editor
Cozzi 2001No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Cozzi 2007No relevant outcome measures
Crist 2001No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Crom 1981No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Culine 1994No childhood cancer survivors
Curigliano 2009No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
D'Angio 1976No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
D'Aoust 1979No childhood cancer survivors
De Gislain 1990No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
de Kraker 1989No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Delpassand 2008No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Demchak 1991No childhood cancer survivors
Detaille 2007Review
Dhaliwal 1980Case report
Diavolitsis 2010No childhood cancer survivors
Dome 1993Review
Doz 1994Review
Druley 2009No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Dunkel 2007No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Edgar 2009Review
Eghbali 1994No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Ehrlich 1974Case report
Eklof 1976No relevant outcome measures
Emminger 1992No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
England 2011No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Escobar 2006No distinction between nephrotoxic therapy and other therapy
Esiashvili 2009No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Feig 2009Review
Ferrari 2005aNo evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Feusner 2008No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Feyer 1989No distinction between childhood and adult cancer survivors
Flentje 1998No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Fouladi 2009No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Friedman 2007Case report
Gallegos-Castorena 2007No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Galsky 2007No childhood cancer survivors
Garaventa 1994No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Gaynon 1994Review
Geenen 2007No distinction between nephrotoxic therapy and other therapy
Gerke 2000No childhood cancer survivors
Gerstein 2009No relevant outcome measures
Gillis 2007No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Gobel 1993No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Goren 1986Less than 20 childhood cancer survivors
Goren 2003Review
Goyal 2011No childhood cancer survivors
Graf 2003Review
Gratton 2006Review
Green 1995Review
Green 2008Review
Gronroos 2008No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Gunes 2010No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Haddy 2009No distinction between nephrotoxic therapy and other therapy
Hadley 2006No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Hanly 2009Review
Hanna 2008No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Hartmann 2000No childhood cancer survivors
Hayashi 2009No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Hayes-Jordan 2010No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Hazar 2009No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Hegde 2009Review
Heikens 1998Review
Heikens 2000No distinction between nephrotoxic therapy and other therapy
Helenglass 1988Less than 20 childhood cancer survivors
Henderson 2008Review
Hingorani 2008Review
Horwich 1991Less than 20 childhood cancer survivors
Hovi 1989Nephrotoxic treatment given in <20 patients
Hudson 2008Review
Iida 2008No childhood cancer survivors
Ippolito 2006No childhood cancer survivors
Janeway 2010Review
Jereb 1997Review
Jones 1995Review
Jones 2008Review
Kantarjian 1996No childhood cancer survivors
Katzenstein 2009No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Keaney 2005Review
Kenney 2010No nephrotoxic treatment
Kibirige 1988No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Kim 1980No childhood cancer survivors
Kim 2009No distinction between nephrotoxic therapy and other therapy
Kirch 1997Review
Kist-van Holthe 2002No distinction between nephrotoxic therapy and other therapy
Kist-van Holthe 2005No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Koren 2007Review
Kourti 2005No distinction between nephrotoxic therapy and other therapy
Kremens 2002No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Kremers 2003Review
Kumar 1996Less than 20 patients tested for early or late effects
Kung 1995No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Kurt 2008Review
Kusumi 2008No childhood cancer survivors
Landier 2008Review
Langer 2004No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Le Bourgeois 1979No distinction between childhood and adult cancer survivors
Leahey 1999No distinction between nephrotoxic therapy and other therapy
Lee 2001Early or late nephrotoxicity as defined in our inclusion criteria in <20 patients
Levi 1993No childhood cancer survivors
Liesner 1994Nephrotoxic treatment given in <20 patients
Lonnerholm 1991No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Ludwig 1992No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Macklis 1991No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Macleod 1988No childhood cancer survivors
Majhail 2009No distinction between nephrotoxic chemotherapy and other therapy
Makari 2010Review
Mandell 1999No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Marina 1994No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Marina 2000No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Marina 2004Review
Mashhadi 2011No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Massimi 2007Review
McCune 2004No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
McCune 2009No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
McDonald 1993No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Meacham 2010No nephrotoxic therapy
Meadows 1985Review
Meck 2006Review
Mendez 2006No childhood cancer survivors
Mertens 1997No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Meyer 2006No childhood cancer survivors
Millar 2011Less than 20 childhood cancer survivors
Miralbell 1996No childhood cancer survivors
Miralbell 2004No childhood cancer survivors
Mitchell 2009Review
Moghrabi 1998No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Mohammadianpanah 2004Case report
Morris 1991Review
Naguib 2008No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Nath 2007No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Niethammer 1998Review
Nieto 2005Less than 20 survivors with nephrotoxic treatment
Nogueira 1998Less than 20 childhood cancer survivors
Nunez 2007Review
Oeffinger 2001No nephrotoxic therapy
Oeffinger 2009No nephrotoxic therapy
Ota 1993Review of cisplatin studies in adults
Pahernik 2007No childhood cancer survivors
Parigi 2003No distinction between nephrotoxic therapy and other therapy
Parisi 1999Review
Patte 1991No nephrotoxic treatment
Patzer 1997No distinction between nephrotoxic therapy and other therapy
Paulides 2008Review
Pectasides 2010No childhood cancer survivors
Pentheroudakis 2007Review
Pereira 2005No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Petersen 1992No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Petersen 1999No childhood cancer survivors
Phillips 2008Review
Pietila 2005Less than 20 childhood cancer survivors
Pietila 2009No distinction between nephrotoxic therapy and other therapy
Pinter 2003No distinction between nephrotoxic therapy and other therapy
Plowman 1999Review
Pochedly 1973Review
Ponisch 2006Review
Poon 2007No childhood cancer survivors
Pratt 1981No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Pratt 1991No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Pratt 1996Review
Raney 1994No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Regazzoni 1998No childhood cancer survivors
Reisi 2009No nephrotoxic therapy
Renal tumours and hypertensionReview/editorial
Ritchey 1996No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Ritchey 2008Review
Roback 1971Case report
Robert 1995Review
Romanini 1981No childhood cancer survivors
Rossi 1999aReview
Saddadi 2009No childhood cancer survivors
Saez 1995No childhood cancer survivors
Sagerman 1969Case serie
Sagstuen 2005No childhood cancer survivors
Sakellari 2010aDuplicate study of Sakellari 2010
Sastry 2005Review
Schenkein 1994No childhood cancer survivors
Schiff 1977No childhood cancer survivors
Schmidt 2010Review
Schmoll 2003No childhood cancer survivors
Schwartz 2007No childhood cancer survivors
Shamash 2000No childhood cancer survivors
Shirasaki 2004No childhood cancer survivors
Shirasaki 2004aNo childhood cancer survivors
Shnorhavorian 2009Review
Sieber 2004No childhood cancer survivors
Silberzweig 1992Case report
Simpson 2002No childhood cancer survivors
Skinner 1991Review
Skinner 1992No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Skinner 1993Review
Skinner 2000No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Skinner 2003Less than 20 childhood cancer survivors
Skinner 2010aReview
Skinner 2011Review
Sloetjes 2000No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Smith 1998Case serie
Sonn 2008Review
Spira 2009No childhood cancer survivors
Springate 1997Review
Stava 2007Review
Steinbach 1995Review
Stern 2002No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Suarez 1991No relevant outcome measures
Sukarochana 1972No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Talvensaari 1996No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Talvensaari 1997Review
Tamaro 1997Review
Taylor 1997No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Taylor 2003No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Tefft 1977No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Thomas 1983No relevant outcome measures
Tichelli 1991Review
Tokuc 1997No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Trimis 2007No nephrotoxic therapy
Turna 2008No childhood cancer survivors
van Waas 2010Review
van Waas 2010aNo nephrotoxic therapy
Veringa 2011No nephrotoxic treatment
Vio 1970Review
Von Der Weid 1999Less than 20 patients treated with nephrotoxic therapy
Voute 1992Review
Voute 1996Review
Weijl 2004No childhood cancer survivors
Welch 1987No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Wistow 1979No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Womer 1985No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Wright 2009Review
Wu 2005Review
Yanagisawa 2009No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Yao 1997No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Yaris 2005No nephrotoxic therapy
Yoshimura 1997No childhood cancer survivors
Zagars 1987No childhood cancer survivors
Zerin 1996No relevant outcome measures
Zielinska 2003No evaluation of early or late nephrotoxicity as defined in our inclusion criteria
Zorn 2007No childhood cancer survivors

Characteristics of studies awaiting assessment [ordered by study ID]

Bailey 2002

MethodsPopulation-based cohort study
Participants

N of participants original cohort: 58; N of participants described study group: 40; N of participants study group of interest: 40; N of participants with renal function tests: 40

Tumour: Wilms' tumour (40/40). Time period diagnosis/treatment: 1966-1998. %M/F: 40%/60%

Age at diagnosis: median 4.3 years (range 3 months to 11.8 years); age at follow-up: n/m; follow-up duration: median 8.8 years (range 0.06 to 27.5 years); completion of follow-up: 40/58 (69%)

InterventionsRadiotherapy: 19/40 (48%); chemotherapy: 40/40 (100%); nephrectomy: 40/40 (100%)
OutcomesGlomerular filtration rate by 51Cr-EDTA plasma clearance, serum phosphate, serum magnesium, renal tubular phosphate threshold (TmP/GFR), urine albumin excretion and blood pressure
NotesStudy suggested by an expert after reviewing will be included in the next update of this review

Cohen 2010

MethodsRandomised clinical study
ParticipantsAdults and children undergoing hematopoietic stem cell transplant (HSCT) for which total body irradiation (TBI) was used in pre-HSCT conditioning; further information unclear from the currently available information
InterventionsTBI
Outcomes

Chronic kidney disease/renal insufficiency

Further information unclear from the currently available information

NotesThis study has not been published in full text (as of December 2011) but has been presented at the European Society for Therapeutic Radiology and Oncology, ESTRO 29, Barcelona, Spain (abstract S109). From currently available data, it is unclear whether this study is eligible for inclusion in this review

Cozzi 2010

MethodsCross-sectional cohort study
Participants

N of participants original cohort: unclear from the currently available information; N of participants described study group: 25; N of participants study group of interest: 25; N of participants with renal function tests: 25

Tumour: unilateral renal tumour. Time period diagnosis/treatment: unclear from the currently available information. %M/F: unclear from the currently available information

Age at diagnosis: unclear from the currently available information; age at follow-up: n/m; follow-up duration: mean 12 years; completion of follow-up: unclear from the currently available information

Controls: unclear from the currently available information

Interventions

N of participants ifosfamide: unclear from the currently available information; ifosfamide cumulative dose: unclear from the currently available information
N of participants cisplatin: unclear from the currently available information; cisplatin cumulative dose: unclear from the currently available information
N of participants carboplatin: unclear from the currently available information; carboplatin cumulative dose: unclear from the currently available information

Other types of chemotherapy: unclear from the currently available information; other chemotherapy cumulative doses: unclear from the currently available information

N of participants nephrectomy: 25/25 (100%); nephrectomy details: group 1: unilateral nephrectomy (NP, N = 15); group 2: nephron sparing surgery (NSS, N = 10)

N of participants radiotherapy including the kidney region: unclear from the currently available information; radiotherapy field: unclear from the currently available information; radiation dose: unclear from the currently available information

Outcomes

Unclear from the currently available information

Only serum creatinine SDS presented in abstract

NotesThis study has not been published in full text (as of December 2011) but has been presented at the 42nd Congress of the International Society of Pediatric Oncology, SIOP 2010, Boston, MA, United States (abstract 793). From currently available data, it is unclear whether this study is eligible for inclusion in this review

D'Angio 1978

MethodsUnclear from the currently available information
ParticipantsTumour: Wilms' tumour (based on title)
InterventionsUnclear from the currently available information
OutcomesUnclear from the currently available information
NotesNo abstract available online, awaiting delivery of the full-text version of manuscript. Based on the currently available information, it is unclear whether this study meets all inclusion criteria

Eckstein 2010

MethodsProspective cohort study
Participants

N of participants original cohort: 32; N of participants described study group: 32; N of participants study group of interest: unclear from the currently available information; N of participants with renal function tests: unclear from the currently available information

Tumour: craniospinal tumours: 32/32 (100%). Time period diagnosis/treatment: 2002-2009. %M/F: 47%/53%

Age at diagnosis: median 66 months; age at follow-up: unclear from the currently available information; follow-up duration: median 502 days; completion of follow-up: unclear from the currently available information

Controls: unclear from the currently available information

InterventionsConditioning regimens included carboplatin/thio-tepa/etoposide (61%), carboplatin/thiotepa (21%), carboplatin/ thiotepa/etoposide (5%), thiotepa/etoposide (5%) and other (8%). Furthermore, unclear from the currently available information
OutcomesUnclear from the currently available information, but abstract reports hypertension and renal failure
NotesThis study has not been published in full text (as of December 2011) but has been presented at the 2010 BMT Tandem Meetings Orlando, FL, United States (abstract S247). From currently available data, it is unclear whether this study is eligible for inclusion in this review

Janda 1993

MethodsCross-sectional cohort study
Participants

N of participants original cohort: unclear from the currently available information; N of participants described study group: 20; N of participants study group of interest: 20; N of participants with renal function tests: 20

Tumour: unilateral Wilms' tumour: 20/20 (100%). Time period diagnosis/treatment: unclear from the currently available information. %M/F: 45%/55%

Age at diagnosis: unclear from the currently available information; age at follow-up: mean 15.5 years (range 8 to 25 years); follow-up duration: mean 11.1 years (range 3 to 24 years); completion of follow-up: 20/20 (100%)

Controls: number unknown, participants with a solitary kidney due to agenesis or nephrectomy due to other causes than Wilms' tumour

InterventionsUnclear from the currently available information. At least 20/20 (100%) with a unilateral nephrectomy
Outcomes

Estimated GFR using the Schwartz formula

Definition of renal adverse effect
< 1.33 mL/sec/1.73 m2

Observed values of renal adverse effects
Mean 1.66 mL/sec/1.73 m2 (SD 0.27)

N of participants with renal adverse effect
1/20 (5%)

Risk factors (univariate analyses)
n/m

Proteinuria measured by biuret reaction

Definition of renal adverse effect
> 100 mg/m2/24 h

Observed values of renal adverse effects
Mean 34.7 mg/m2/24 h (SD 145)

N of participants with renal adverse effect
1/20 (5%)

Risk factors (univariate analyses)
n/m

Proteinuria measured by microalbuminuria

Definition of renal adverse effect
> 10 mg/m2/24 h

Observed values of renal adverse effect
Mean 16.8 mg/m2/24 h (SD 30.1)

N of participants with renal adverse effect
7/20 (35%)

Risk factors (univariate analyses)
n/m

Blood pressure

Definition of renal adverse effect
Systolic or diastolic blood pressure above 97th percentile according to the 2nd Task Force report on hypertension in children

Observed values of renal adverse effects
n/m

N of participants with renal adverse effect
Systolic blood pressure: 1/20 (5%)

Diastolic blood pressure: 4/20 (20%)

Risk factors (univariate analyses)
n/m

NotesThe study is written in Czech. We are awaiting the translation. On the basis of currently available information, it is unclear whether this study meets all inclusion criteria

Kieran 2010

MethodsRetrospective cohort study
Participants

N of participants original cohort: unclear from the currently available information; N of participants described study group: 72; N of participants study group of interest: unclear from the currently available information; N of participants with renal function tests: unclear from the currently available information

Tumour: 40 (55.6%) leukaemia, 8 (11.1%) lymphoma, 15 (20.8%) central nervous system tumours, and 9 (12.5%) other solid tumours. Time period diagnosis/treatment: 2004-2009. %M/F: 56%/44%

Age at diagnosis: mean: 8.3 years (range: 0.7 - 18.9 years); Age at follow-up:mean 19.5 (range: 1.2 to 46.7) years; Follow-up duration: unclear from the currently available information; Completion of follow-up: unclear from the currently available information.

Controls: n/a.

Interventions35 (48.6%) participants received chemotherapy, 4 (5.6%) received radiation, 31 (43.1%) received both, and 2 (2.8%) participants were treated with surgical resection alone, furthermore unclear from the currently available information.
OutcomesUnclear from the currently available information, but including serum creatinine, serum electrolytes and urine electrolytes.
NotesThis study has not been published in full text (as of December 2011), but has been presented at the 2010 Annual Meeting of the American Urological Association, AUA San Francisco, CA United States (abstract e409). From currently available data it is unclear if this study is eligible for inclusion in this review

Li 2006

MethodsProspective cohort study
Participants

N of participants original cohort: 62; N of participants described study group: 62; N of participants study group of interest: 62; N of participants with renal function tests: unclear from the currently available information

Tumour: Wilms' tumour: 62/62 (100%). Time period diagnosis/treatment: 1993-2002. %M/F: unclear from the currently available information

Age at diagnosis: mean: 3.2 years (range 5 months to 10 years); age at follow-up: unclear from the currently available information; follow-up duration: unclear from the currently available information; completion of follow-up: unclear from the currently available information

Controls: n/a

Interventions

N of participants ifosfamide: 0/62 (0%); ifosfamide cumulative dose: n/a
N of participants cisplatin: 0/62 (0%); cisplatin cumulative dose: n/a
N of participants carboplatin: 0/62 (0%); carboplatin cumulative dose: n/a

Other types of chemotherapy: including actinomycin D, vincristine and epirubicin, but numbers unclear from the currently available information; other chemotherapy cumulative doses: unclear from the currently available information

N of participants nephrectomy: 62/62 (100%); nephrectomy details: n/m

N of participants radiotherapy including the kidney region: unclear from the currently available information; radiotherapy field: unclear from the currently available information; radiation dose: unclear from the currently available information

OutcomesUnclear from the currently available information
NotesThe study is written in Chinese. We are awaiting the translation. On the basis of currently available information, it is unclear whether this study meets all inclusion criteria

Madden 2010

MethodsProspective cohort study
Participants

N of participants original cohort: 47; N of participants described study group: 44; N of participants study group of interest: 44; N of participants with renal function tests: unclear from the currently available information

Tumour: medulloblastoma: 49/49 (100%). Time period diagnosis/treatment: 1994-2009. %M/F: unclear from the currently available information

Age at diagnosis: unclear from the currently available information; age at follow-up: unclear from the currently available information; follow-up duration: unclear from the currently available information; completion of follow-up: unclear from the currently available information

Controls: unclear from the currently available information

InterventionsCisplatin, lomustine, vincristine alternating with cyclophosphamide, vincristine, no further details specified
OutcomesUnclear from the currently available information, but the abstract mentions long-term renal insufficiency
NotesThis study has not been published in full text (as of December 2011) but has been presented at the 14th International Symposium on Pediatric Neuro-Oncology, Vienna, Austria (abstract ii111). From currently available data, it is unclear whether this study is eligible for inclusion in this review

Matsuyama 2002

MethodsProspective cohort study
Participants

N of participants original cohort: 123; N of participants described study group: 123; N of participants study group of interest: unclear from the currently available information; N of participants with renal function tests: unclear from the currently available information

Tumour: acute lymphoblastic leukaemia: 123/123 (100%). Time period diagnosis/treatment: unclear from the currently available information. %M/F: unclear from the currently available information

Age at diagnosis: unclear from the currently available information; age at follow-up: unclear from the currently available information; follow-up duration: unclear from the currently available information; completion of follow-up: unclear from the currently available information

Controls: unclear from the currently available information

InterventionsApart from 40/123 (33%) of included participants treated with total body irradiation: unclear from the currently available information
OutcomesUnclear from the currently available information
NotesThe study is written in Japanese. We are awaiting delivery of the full-text version of manuscript. On the basis of currently available information, it is unclear whether this study meets all inclusion criteria

Pugachev 2004

MethodsUnclear from the currently available information
Participants

N of participants original cohort: 58; N of participants described study group: 58; N of participants study group of interest: unclear from the currently available information; N of participants with renal function tests: unclear from the currently available information

Tumour: unclear from the currently available information. Time period diagnosis/treatment: unclear from the currently available information. %M/F: unclear from the currently available information

Age at diagnosis: unclear from the currently available information; age at follow-up: unclear from the currently available information; follow-up duration: unclear from the currently available information; completion of follow-up: unclear from the currently available information

Controls: number of controls unclear from the currently available information

InterventionsN of participants nephrectomy: 58/58 (100%). All other intervention information: unclear from the currently available information
OutcomesUnclear from the currently available information
NotesThe study is written in Russian. We are awaiting the translation. On the basis of currently available information, it is unclear whether this study meets all inclusion criteria

Radvansky 2010

MethodsCross-sectional cohort study
Participants

N of participants original cohort: unclear from currently available information; N of participants described study group: 151; N of participants study group of interest: unclear from the currently available information; N of participants with renal function tests: unclear from the currently available information

Tumour: Wilms' tumour: 151/151 (100%). Time period diagnosis/treatment: 1980-2001. %M/F: 45%/55%

Age at diagnosis: mean 3.7 years (SD 2.7 years); age at follow-up: mean 19.4 years (SD 5.8 years); follow-up duration: unclear from the currently available information; completion of follow-up: unclear from the currently available information

Interventions

N of participants ifosfamide: unclear from the currently available information; ifosfamide cumulative dose: n/a
N of participants cisplatin: unclear from the currently available information; cisplatin cumulative dose: n/a
N of participants carboplatin: unclear from the currently available information; carboplatin cumulative dose: n/a

Other types of chemotherapy: including anthracyclines: 25.9%; other chemotherapy cumulative doses: unclear from the currently available information

N of participants nephrectomy: unclear from the currently available information; nephrectomy details: n/m

N of participants radiotherapy including the kidney region: 34.2%; radiotherapy field: unclear from the currently available information; radiation dose: unclear from the currently available information

Controls: n/a

Outcomes

GFR using creatinine clearance

Definition of renal adverse effect
Unclear from the currently available information

Observed values of renal adverse effect
Mean (SD): 1.56 mL/sec/1.73 m2 (SD 0.56)

N of participants with renal adverse effect
Unclear from the currently available information

Risk factors (univariate analyses)
Unclear from the currently available information

Proteinuria, method unclear from the currently available information

Definition of renal adverse effect
> 1 g/24 h

Observed values of renal adverse effect
Mean 0.18 g/24 h/m2 (SD 0.30)

N of participants with renal adverse effect
3/151 (2.0%) with proteinuria and normal glomerular function and serum albumin

Risk factors (univariate analyses)

Unclear from the currently available information

Blood pressure

Definition of renal adverse effect
Systolic blood pressure > 135 mmHg, diastolic blood pressure above 90 mmHg or receiving treatment for hypertension

Observed values of renal adverse effect
Unclear from the currently available information

N of participants with renal adverse effect
Systolic blood pressure: 8.3%

Diastolic blood pressure: 10.2%

Treatment for hypertension: 8.6% of participants (of which 6% treated by pharmacotherapy)

Risk factors (univariate analyses)
Unclear from the currently available information

NotesThe study is written in Czech. We are awaiting the translation. On the basis of currently available information, it is unclear whether this study meets all inclusion criteria

Sakellari 2010

MethodsRetrospective cohort study
Participants

N of participants original cohort: 164; N of participants described study group: 164; N of participants study group of interest: unclear from the currently available information; N of participants with renal function tests: unclear from the currently available information

Tumour: haematological disease, not further specified. Time period diagnosis/treatment: unclear from the currently available information. %M/F: unclear from the currently available information

Age at diagnosis: range 9 to 65 years; age at follow-up: unclear from the currently available information; follow-up duration: median 23.5 months; completion of follow-up: unclear from the currently available information

Controls: unclear from the currently available information

InterventionsUnclear from the currently available information but including hyperfractionated TBI, administration of thiotepa or fludarabine
Outcomes

Chronic kidney disease/renal insufficiency and estimated GFR using the MDRD or the Schwartz formula

Definition of renal adverse effect
< 60 mL/min/1.73 m2

Observed values of renal adverse effects
The mean value of pre-HCT GFR was within normal limits (111.5 ± 26) for participants who did not develop CKD and 97.21 ± -19 for those who developed CKD, while the GFR at 12 months post-transplant was 108 ± 28 and 54.7 ± 5.4 (mL/min/1.73 m2), respectively. The course of CKD was asymptomatic until end-stage disease, when 3 participants were on dialysis and 1 participant received a renal transplant from his mother

N of participants with renal adverse effect
Unclear from the currently available information

Risk factors (univariate analyses)
On univariate analyses, the probability of developing CKD was 25% at 18 months for participants with 0 or 1 event of kidney injury versus 60% for those with two to five preceding events (P = 0.006). On the other hand, the type of conditioning, hyperfractionated TBI, administration of thiotepa or fludarabine, acute or chronic GVHD and the toxicity of antiviral or antifungal treatment did not correlate with the CKD. Calcineurin inhibitors were not included as risk factors because of their universal administration as prophylaxis and because of their toxicity with long-term treatment. On multivariate analysis, the only predictive factors were older age (P = 0.01), the number of preceded events of acute kidney injury and the in vivo T cell depletion with antithymocyte globulin or alemtuzumab (0.013)

NotesThis study has not been published in full text (as of December 2011) but has been presented at the 36th Annual Meeting of the European Group for Blood and Marrow Transplantation, EBMT 2010, Vienna, Austria (abstract S107). From currently available data, it is unclear whether this study is eligible for inclusion in this review

Schwartz 2001

MethodsProspective cohort study
Participants

N of participants original cohort: 104; N of participants described study group: 101; N of participants study group of interest: unclear from currently available information; N of participants with renal function tests: unclear from currently available information

Tumour: retinoblastoma: 24, nephroblastoma: 19, Hodgkin’s disease: 14, sarcoma: 12, neuroblastoma: 11, non-Hodgkin's lymphoma: 11, Langerhans cell histiocytosis: 5, gonadal germ cell tumours: 4, osteosarcoma: 2, Ewing's sarcoma: 2. Time period diagnosis/treatment: 1965-1986. %M/F: unclear from the currently available information

Age at diagnosis: unclear from the currently available information; age at follow-up: unclear from the currently available information; follow-up duration: unclear from the currently available information; completion of follow-up: unclear from the currently available information

Controls: unclear from the currently available information

InterventionsUnclear from the currently available information
OutcomesUnclear from the currently available information
NotesThe study is written in Spanish. We are awaiting the translation. On the basis of currently available information, it is unclear whether this study meets all inclusion criteria

Sierota 2005

MethodsUnclear from the currently available information
Participants80 children treated for Wilms' tumour; furthermore unclear from the currently available information
InterventionsUnclear from the currently available information
OutcomesUnclear from the currently available information but includes renal insufficiency, proteinuria and hypertension
NotesThe study is written in Polish. We are awaiting the translation. On the basis of currently available information, it is unclear whether this study meets all inclusion criteria

Stronska 2003

MethodsCross-sectional cohort study
Participants

N of participants original cohort: 40; N of participants described study group: 40; N of participants study group of interest: 40; N of participants with renal function tests: 40

Tumour: Wilms' tumour: 40/40 (100%). Time period diagnosis/treatment: unclear from the currently available information. %M/F: unclear from the currently available information

Age at diagnosis: mean: 3.42 years (SD 2.5 years); age at follow-up: mean: 12.2 years (SD 5 years); follow-up duration: unclear from the currently available information; completion of follow-up: 40/40 (100%)

Controls: 24 age-matched persons furthermore unclear from the currently available information

Interventions

N of participants ifosfamide: unclear from the currently available information; ifosfamide cumulative dose: n/a
N of participants cisplatin: unclear from the currently available information; cisplatin cumulative dose: n/a
N of participants carboplatin: unclear from the currently available information; carboplatin cumulative dose: n/a

Other types of chemotherapy: unclear from the currently available information; other chemotherapy cumulative doses: unclear from the currently available information

N of participants nephrectomy: 40/40 (100%); nephrectomy details: unilateral nephrectomy: 40/40 (100%)

N of participants radiotherapy including the kidney region: 24/40 (60%); radiotherapy field: unclear from the currently available information; radiation dose: unclear from the currently available information

OutcomesEndogenous creatinine clearance and serum phosphate: details unclear from the currently available information
NotesThe study is written in Polish. We are awaiting the translation

Terenziani 2010

  1. a

    Abbreviations: BMT: bone marrow transplantation; CKD: chronic kidney disease; g: gram; GFR: glomerular filtration rate; GVHD: graft versus host disease; H(S)CT: hematopoietic (stem) cell transplant; M/F: males/females; MDRD: modification of diet in renal disease; mg/m2: milligram per square meter; mL/s: milliliters per second; n/a: not applicable; n/m: not mentioned; N: number; NP: nephrectomy; NSS: nephron sparing surgery; SD: standard deviation; SDS: standard deviation score; TBI: total body irradiation.

MethodsRetrospective cohort study
Participants

N of participants original cohort: 27; N of participants described study group: 27; N of participants study group of interest: 27; N of participants with renal function tests: unclear from the currently available information

Tumour: bilateral Wilms' tumour: 27/27 (100%). Time period diagnosis/treatment: unclear from the currently available information. %M/F: 33%/66%

Age at diagnosis: median 30 months (range 11 to 86 months); age at follow-up: unclear from the currently available information; follow-up duration: median 31 months (range 3 to 76 months); completion of follow-up: unclear from the currently available information

Controls: unclear from the currently available information

Interventions

N of participants ifosfamide: unclear from the currently available information; ifosfamide cumulative dose: n/a
N of participants cisplatin: unclear from the currently available information; cisplatin cumulative dose: n/a
N of participants carboplatin: unclear from the currently available information; carboplatin cumulative dose: n/a

Other types of chemotherapy: vincristine and dactinomycin: 27/27 (100%); other chemotherapy cumulative doses: unclear from the currently available information

N of participants nephrectomy: 27/27 (100%); nephrectomy details: bilateral partial nephrectomy: 9/27 (33%). Combined partial and complete nephrectomy: 12/27 (44%). Data missing or too early for surgery: 6/27 (23%)

N of participants radiotherapy including the kidney region: 24/40 (60%); radiotherapy field: unclear from the currently available information; radiation dose: unclear from the currently available information

OutcomesUnclear from the currently available information
NotesThis study has not been published in full text (as of December 2011) but has been presented at the 42nd Congress of the International Society of Pediatric Oncology, SIOP 2010, Boston, MA, United States (abstract 883). From currently available data, it is unclear whether this study is eligible for inclusion in this review