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

  1. Sebastiaan L Knijnenburg1,*,
  2. Renée L Mulder2,
  3. Antoinette YN Schouten-Van Meeteren2,
  4. Arend Bökenkamp3,
  5. Hester Blufpand3,
  6. Eline van Dulmen-den Broeder4,
  7. Margreet A Veening4,
  8. Leontien CM Kremer2,
  9. Monique WM Jaspers1

Editorial Group: Cochrane Childhood Cancer Group

Published Online: 8 OCT 2013

Assessed as up-to-date: 20 MAY 2012

DOI: 10.1002/14651858.CD008944.pub2


How to Cite

Knijnenburg SL, Mulder RL, Schouten-Van Meeteren AYN, Bökenkamp A, Blufpand H, van Dulmen-den Broeder E, Veening MA, Kremer LCM, Jaspers MWM. Early and late renal adverse effects after potentially nephrotoxic treatment for childhood cancer. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD008944. DOI: 10.1002/14651858.CD008944.pub2.

Author Information

  1. 1

    Academic Medical Center, Medical Informatics, Amsterdam, Netherlands

  2. 2

    Emma Children's Hospital/Academic Medical Center, Department of Paediatric Oncology, Amsterdam, Netherlands

  3. 3

    VU University Medical Center, Department of Pediatric Nephrology, Amsterdam, Netherlands

  4. 4

    VU University Medical Center, Department of Pediatrics, Division of Oncology/Hematology, Amsterdam, Netherlands

*Sebastiaan L Knijnenburg, Medical Informatics, Academic Medical Center, P.O. Box 22660, Amsterdam, 1100 DD, Netherlands. sebastiaan.knijnenburg@gmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 8 OCT 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Aronson 2011

MethodsCross-sectional cohort study


ParticipantsN 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


InterventionsN 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


OutcomesChronic 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


ParticipantsN 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)


InterventionsN 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


OutcomesChronic 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR: 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


ParticipantsAll 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


InterventionsN 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


OutcomesComposite 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


ParticipantsN 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


InterventionsN 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


OutcomesChronic 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


ParticipantsN 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


InterventionsN 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


OutcomesGlomerular 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


ParticipantsN 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


InterventionsN 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


OutcomesBlood 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


NotesUnclear 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR: 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


ParticipantsN 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


InterventionsN 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


OutcomesChronic 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


ParticipantsN 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


InterventionsN 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


OutcomesProteinuria 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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)


OutcomesBlood 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


ParticipantsN 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


InterventionsN 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)


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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)


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesProteinuria 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


ParticipantsN 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


InterventionsN 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


OutcomesChronic 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


ParticipantsN 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


InterventionsN 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


OutcomesChronic 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


ParticipantsN 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


InterventionsN 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


OutcomesEstimated 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


ParticipantsAll 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


InterventionsN 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


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesBlood 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


ParticipantsN 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


InterventionsN 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


OutcomesEstimated 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


ParticipantsN 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


InterventionsN 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


OutcomesChronic 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


ParticipantsN 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


InterventionsN 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


OutcomesComposite 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


ParticipantsN 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


InterventionsN 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)


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesEstimated 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


ParticipantsN 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


InterventionsN 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


OutcomesEstimated 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


ParticipantsN 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


InterventionsN 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


OutcomesSerum 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesChronic 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesEstimated 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


ParticipantsN 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


InterventionsN 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


OutcomesEstimated 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


ParticipantsN 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


InterventionsN 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


OutcomesEstimated 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


ParticipantsN 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


InterventionsN 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


OutcomesEstimated 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


ParticipantsN 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


InterventionsN 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


OutcomesTubular 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


NotesCI: 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


ParticipantsN 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


InterventionsN 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


OutcomesTubular 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


ParticipantsN 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


InterventionsN 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


OutcomesChronic 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR 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


ParticipantsN 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


InterventionsN 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


OutcomesEstimated 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


NotesRegarding 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


ParticipantsN 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


InterventionsN 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


OutcomesEstimated 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


ParticipantsN 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


InterventionsN 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


OutcomesChronic 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


ParticipantsAll 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


InterventionsN 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)


OutcomesComposite 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


ParticipantsN 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


InterventionsN 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)


OutcomesEstimated 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR, 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


ParticipantsN 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


InterventionsN 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


OutcomesBlood 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


ParticipantsN 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


InterventionsN 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)


OutcomesGlomerular 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


ParticipantsN 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


InterventionsN 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


OutcomesEstimated 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


ParticipantsN 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


InterventionsN 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


OutcomesGFR 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


ParticipantsTumour 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


InterventionsN 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


OutcomesRenal/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

MethodsCross-sectional cohort study


ParticipantsN 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)


InterventionsN 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


OutcomesGFR 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

ParticipantsN 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

OutcomesChronic 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

ParticipantsN 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

InterventionsN 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

OutcomesUnclear 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

ParticipantsN 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

ParticipantsN 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

OutcomesEstimated 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

ParticipantsN 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

ParticipantsN 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

InterventionsN 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

ParticipantsN 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

ParticipantsN 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

ParticipantsN 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

ParticipantsN 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

InterventionsN 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

OutcomesGFR 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

ParticipantsN 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

OutcomesChronic 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

ParticipantsN 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

ParticipantsN 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

InterventionsN 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

MethodsRetrospective cohort study

ParticipantsN 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

InterventionsN 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

 
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 authors10Prevalence (Random, 95% CI)Totals not selected

    1.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    1.2 Carboplatin, ifosfamide, radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    1.3 Ifosfamide, radiotherapy and/or nephrectomy
3Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    1.4 Radiotherapy and/or nephrectomy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    1.5 Unilateral nephrectomy for Wilms' tumour
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    1.6 Unilateral nephrectomy for Wilms' tumour (Denys-Drash syndrome)
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    1.7 Unilateral nephrectomy for Wilms' tumour (WAGR syndrome)
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    1.8 Unilateral nephrectomy for Wilms' tumour (genitourinary anomalies)
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    1.9 Bilateral (partial) nephrectomy for Wilms' tumour
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    1.10 Bilateral (partial) nephrectomy for Wilms' tumour (Denys-Drash syndrome)
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    1.11 Bilateral (partial) nephrectomy for Wilms' tumour (WAGR syndrome)
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    1.12 Bilateral (partial) nephrectomy for Wilms' tumour (genitourinary anomalies)
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

 2 (Estimated) glomerular filtration rate < 90 mL/min/1.73m212Prevalence (Random, 95% CI)Totals not selected

    2.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    2.2 Cisplatin, carboplatin, ifosfamide and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    2.3 Cisplatin, carboplatin and/or radiotherapy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    2.4 Cisplatin, ifosfamide, radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    2.5 Cisplatin and/or ifosfamide
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    2.6 Carboplatin
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    2.7 Carboplatin, ifosfamide, radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    2.8 Ifosfamide and/or radiotherapy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    2.9 Ifosfamide and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    2.10 Ifosfamide
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    2.11 Radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

 3 (Estimated) glomerular filtration rate < 80 mL/min/1.73m27Prevalence (Random, 95% CI)Totals not selected

    3.1 Cisplatin, ifosfamide, radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Cisplatin, ifosfamide and/or nephrectomy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    3.3 Cisplatin and/or ifosfamide
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    3.4 Cisplatin
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    3.5 Radiotherapy and/or nephrectomy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

 4 (Estimated) glomerular filtration rate < 70 mL/min/1.73m21Prevalence (Random, 95% CI)Totals not selected

    4.1 Radiotherapy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

 5 (Estimated) glomerular filtration rate < 50 mL/min/1.73 m21Prevalence (Random, 95% CI)Totals not selected

    5.1 Radiotherapy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

 6 Proteinuria as defined by authors17Prevalence (Random, 95% CI)Totals not selected

    6.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy
3Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    6.2 Cisplatin, carboplatin, ifosfamide and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    6.3 Cisplatin, carboplatin and/or ifosfamide
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    6.4 Cisplatin, carboplatin, radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    6.5 Cisplatin, ifosfamide, radiotherapy and/or nephrectomy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    6.6 Cisplatin and/or ifosfamide
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    6.7 Carboplatin, ifosfamide, radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    6.8 Carboplatin
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    6.9 Ifosfamide and/or radiotherapy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    6.10 Radiotherapy and/or nephrectomy
4Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    6.11 Nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

 7 Serum phosphate / hypophoshataemia as defined by the authors7Prevalence (Random, 95% CI)Totals not selected

    7.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    7.2 Cisplatin, carboplatin and/or ifosfamide
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    7.3 Cisplatin, carboplatin, radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    7.4 Ifosfamide and/or radiotherapy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    7.5 Radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    7.6 Radiotherapy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

 8 Tubular phosphate regulation parameters as defined by the authors11Prevalence (Random, 95% CI)Totals not selected

    8.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    8.2 Cisplatin, ifosfamide, radiotherapy and/or nephrectomy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    8.3 Cisplatin, ifosfamide and/or nephrectomy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    8.4 Cisplatin and/or ifosfamide
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    8.5 Carboplatin
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    8.6 Ifosfamide and/or radiotherapy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    8.7 Ifosfamide
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

 9 Serum magnesium / hypomagnesaemia as defined by the authors7Prevalence (Random, 95% CI)Totals not selected

    9.1 Cisplatin, carboplatin, ifosfamide and/or radiotherapy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    9.2 Cisplatin, carboplatin and/or ifosfamide
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    9.3 Cisplatin
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    9.4 Carboplatin
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    9.5 Ifosfamide and/or radiotherapy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    9.6 Radiotherapy and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

 10 Blood pressure24Prevalence (Random, 95% CI)Totals not selected

    10.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    10.2 Cisplatin, carboplatin, and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    10.3 Cisplatin, ifosfamide, radiotherapy and/or nephrectomy
3Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    10.4 Carboplatin, ifosfamide, radiotherapy and/or nephrectomy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    10.5 Carboplatin
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    10.6 Ifosfamide, radiotherapy and/or nephrectomy
2Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    10.7 Ifosfamide and/or nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    10.8 Radiotherapy and/or nephrectomy
10Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    10.9 Radiotherapy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

    10.10 Nephrectomy
1Prevalence (Random, 95% CI)0.0 [0.0, 0.0]

 
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 controls4Mean Difference (Random, 95% CI)Totals not selected

    1.1 Cisplatin, carboplatin, ifosfamide, radiotherapy and/or nephrectomy
2Mean Difference (Random, 95% CI)0.0 [0.0, 0.0]

    1.2 Cisplatin, carboplatin, ifosfamide and/or nephrectomy
1Mean Difference (Random, 95% CI)0.0 [0.0, 0.0]

    1.3 Radiotherapy and/or nephrectomy
1Mean Difference (Random, 95% CI)0.0 [0.0, 0.0]

 
Table 1. Risk of bias assessment criteria for observational studies

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

 *: 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.
 
Table 2. Treatment subgroups

Treatments included in studyAmount of studiesIncluded studies

Cisplatin, carboplatin, ifosfamide, radiotherapy and nephrectomy5Bardi 2004; Bolling 2010; Laverdiere 2005; Patzer 2001; Schell 1995

Cisplatin, carboplatin, ifosfamide and radiotherapy2Stohr 2007; Stohr 2007a

Cisplatin, carboplatin, ifosfamide and nephrectomy1Stefanowicz 2009

Cisplatin, carboplatin and ifosfamide1Fujieda 2009

Cisplatin, carboplatin, radiotherapy and nephrectomy2Mancini 1996; Skinner 2009

Cisplatin, carboplatin and radiotherapy1Trahair 2007

Cisplatin, ifosfamide, radiotherapy and nephrectomy6Cardous-Ubbink 2010; Chevallier 1997; Di Tullio 1996; Loebstein 1999; Rossi 1993; Rossi 1999

Cisplatin, ifosfamide and nephrectomy2Rossi 1994; Rossi 1994a

Cisplatin and ifosfamide3Ferrari 2005; Rossi 1994b; von Schweinitz 1997

Cisplatin1Brock 1991

Carboplatin, ifosfamide, radiotherapy and nephrectomy3Stefanowicz 2011; Trobs 2001; Weirich 2004

Carboplatin2English 1999; Bergeron 2005

Ifosfamide, radiotherapy and nephrectomy4Geenen 2010; Hamilton 2011; Paulino 2000; Sasso 2010

Ifosfamide and radiotherapy2Oberlin 2009; Skinner 2010

Ifosfamide and nephrectomy1Kubiak 2004

Ifosfamide2Prasad 1996; Rossi 1997

Radiotherapy and nephrectomy13Aronson 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

Nephrectomy3Breslow 2005; Cosentino 1993; Cozzi 2005

Radiotherapy3Frisk 2002; Frisk 2007; Van Why 1991

 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.
 
Table 3. Risk factors from multivariable analyses on diminished (estimated) glomerular filtration rate

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)

 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.
 
Table 4. Risk factors from multivariable analyses on impaired tubular phosphate regulation parameters

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

 Abbreviations: CI: confidence interval; g/m2: gram/meter2; n/m: not mentioned; OR: odds ratio; SD: standard deviation.
 
Table 5. Risk factors from multivariable analyses on serum magnesium / hypomagnesaemia

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

 Abbreviations: mmol/L: millimols/litre; n/m: not mentioned; vs: versus.
 
Table 6. Risk factors from multivariable analyses on blood pressure

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

 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.