Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for preserving residual kidney function in peritoneal dialysis patients

  • Review
  • Intervention

Authors


Abstract

Background

Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are widely used in peritoneal dialysis (PD) patients, yet controversy exists about their impact on residual kidney function.

Objectives

This review aimed to evaluate the benefits and harms of ACEis and ARBs for preserving residual kidney function in PD patients.

Search methods

The Cochrane Renal Group's specialised register, Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE (OvidSP interface), Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI) and other resources were searched by applying a prespecified comprehensive search strategy. Date of last search: 01 May 2014.

Selection criteria

Randomised controlled trials (RCTs) and quasi-RCTs comparing ACEis or ARBs with placebo, other antihypertensive drugs or each other in PD patients were included.

Data collection and analysis

Screening, selection, data extraction and quality assessments for each retrieved article were carried out by two authors using standardised forms. Authors were contacted when published data were incomplete. Statistical analyses were performed using the random effects model and results expressed as risk ratio (RR) with 95% confidence intervals (CI). Heterogeneity among studies was explored using the Cochran Q statistic and the I² test, subgroup analyses and random effects meta-regression.

Main results

Six open-label studies (257 patients) were identified. One study compared ACEi with other antihypertensive drugs, three compared ARBs with other antihypertensive drugs, and two studies compared an ARB with an ACEi. Long-term use (≥ 12 months) of an ARB showed significantly benefit of preserving residual kidney function in continuous ambulatory PD (CAPD) patients (MD 1.11 mL/min/1.73 m², 95% CI 0.38 to 1.83), although there was no significant benefit when an ARB were used short-term (≤ six months). One study showed that compared with other antihypertensive drugs, long-term use (12 months) of the ACEi ramipril showed a significant reduction in the decline of residual kidney function in patients on CAPD (MD -0.93 mL/min/1.73m², 95% CI -0.75 to -0.11), and delayed the progression to complete anuria (RR 0.64, 95% CI 0.41 to 0.99). There was no significant difference in serum potassium, urinary protein excretion, Kt/V, weekly creatinine clearance and blood pressure for ARBs versus other antihypertensive drugs. Compared with other antihypertensive drugs, ramipril showed no difference in mortality and cardiovascular events. Compared with an ACEi, ARBs did not show any difference in residual kidney function.

The selection bias assessment was low in four studies and unclear in two. Five studies were open-label; however the primary outcome (residual kidney function) was obtained objectively from laboratory tests, and were not likely to be influenced by the lack of blinding. Reporting bias was unclear in all six studies.

Authors' conclusions

Compared with other antihypertensive drugs, long-term use (≥ 12 months) of ACEis or ARBs showed additional benefits of preserving residual kidney function in CAPD patients. There was no significant difference on residual kidney function preservation between ARBs and ACEis. However, limited by the small number of RCTs enrolling small number of participants, there is currently insufficient evidence to support the use of an ACEi or an ARB as first line antihypertensive therapy in PD patients.

Résumé scientifique

Les inhibiteurs de l'enzyme de conversion de l'angiotensine et les antagonistes des récepteurs de l'angiotensine pour préserver la fonction rénale résiduelle chez les patients sous dialyse péritonéale

Contexte

Les inhibiteurs de l'enzyme de conversion de l'angiotensine (IEC) et les antagonistes des récepteurs de l'angiotensine (ARA) sont largement utilisés chez les patients sous dialyse péritonéale (DP), mais leur impact sur la fonction rénale résiduelle est controversée.

Objectifs

Cette revue visait à évaluer les bénéfices et les inconvénients des IEC et des ARA pour préserver la fonction rénale résiduelle chez les patients sous DP.

Stratégie de recherche documentaire

Le registre spécialisé du groupe Cochrane sur la néphrologie, le registre Cochrane des essais contrôlés (CENTRAL), MEDLINE, EMBASE (interface OvidSP), Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI) et d'autres ressources ont fait l'objet de recherches en appliquant une stratégie de recherche exhaustive prédéfinie. Date de la dernière recherche : le 1er mai 2014.

Critères de sélection

Ont été inclus les essais contrôlés randomisés (ECR) et quasi-ECR comparant un IEC ou un ARA à un placebo, à d'autres médicaments antihypertenseurs ou les uns par rapport aux autres chez des patients sous DP.

Recueil et analyse des données

Le criblage, la sélection, l'extraction des données et l'évaluation de la qualité de chaque article sélectionné ont été effectués par deux auteurs de la revue à l'aide de formulaires standardisés. Les auteurs ont été contactés lorsque les données publiées étaient incomplètes. Les analyses statistiques ont été réalisées en utilisant le modèle à effets aléatoires et les résultats ont été exprimés sous la forme de risque relatif (RR) avec des intervalles de confiance (IC) à 95 %. L'hétérogénéité entre les études a été explorée en utilisant la statistique Cochran Q et le test I², les analyses de sous-groupes et la méta-régression à effets aléatoires.

Résultats principaux

Six études ouvertes (257 patients) ont été identifiées. Une étude comparait un IEC à d'autres médicaments antihypertenseurs, trois comparaient un ARA à d'autres médicaments antihypertenseurs et deux études un ARA à un IEC. L'utilisation à long terme (≥ 12 mois) d'un ARA a montré qu'il y avait un avantage significatif dans la préservation d'une fonction rénale résiduelle de patients en DP continue ambulatoire (DPCA) (DM 1,11 ml/min/1,73m², IC à 95 % de 0,38 à 1,83), alors qu'il n'y avait pas de bénéfice significatif lorsqu'un ARA était utilisé à court terme (≤ six mois). Une étude a montré que, en comparaison avec d'autres médicaments antihypertenseurs, l'utilisation à long terme (12 mois) de l'IEC ramipril montrait une réduction significative dans le déclin de la fonction rénale résiduelle chez des patients sous DPCA (DM -0,93 ml/min/1,73m²,IC à 95 % de -0,75 à -0,11), et retardait la progression vers une anurie totale (RR 0,64, IC à 95 % de 0,41 à 0,99). Il n'y avait pas de différence significative dans le potassium sérique, l'excrétion de protéines dans les urines, le Kt/V, la clairance de la créatinine hebdomadaire et la pression artérielle entre les ARA et d'autres médicaments antihypertenseurs. Par rapport à d'autres médicaments antihypertenseurs, le ramipril n'a pas montré de différence dans la mortalité et les événements cardio-vasculaires. En comparaison avec un IEC, les ARA n'ont montré aucune différence dans la fonction rénale résiduelle.

Le biais de sélection a été évalué comme faible dans quatre études et incertain dans deux. Cinq études étaient ouvertes ; cependant, le critère de jugement principal (la fonction rénale résiduelle) a été obtenu objectivement par des examens de laboratoire et n'était pas susceptible d'être influencé par le manque de masquage. Le biais de notification était imprécis dans les six études.

Conclusions des auteurs

Par rapport à d'autres médicaments antihypertenseurs, l'utilisation à long terme (≥ 12 mois) des IEC ou des ARA a montré des bénéfices supplémentaires dans la préservation de la fonction rénale résiduelle chez les patients sous DPCA. Il n'y avait aucune différence significative entre les ARA et les IEC dans la préservation de la fonction rénale résiduelle. Toutefois, en raison du petit nombre d'ECR portant sur un petit nombre de participants, les preuves sont actuellement insuffisantes pour recommander l'utilisation d'un IEC ou d'un ARA comme traitement antihypertenseur de première intention chez les patients sous DP.

Plain language summary

Angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers for preserving residual kidney function in peritoneal dialysis patients

Residual kidney function plays a key role in the health and quality of life of patients on peritoneal dialysis (PD). Better preservation of residual kidney function is associated with decreased mortality, even at 1 mL/min of residual glomerular filtration rate (GFR), which is associated with a nearly 50% reduction in mortality rate. Two kinds of antihypertensive drugs, angiotensin-converting enzyme inhibitors (ACEis) and angiotensin-II receptor blockers (ARBs), are frequently prescribed for PD patients (primarily to control hypertension or heart failure), and could provide significant cardiovascular benefit for ESKD patients. Nowadays, while ACEis and ARBs use is advocated in PD patients, the supporting evidence is still unclear. However studies have focused on heart protection rather than residual kidney function. The aim of this review was to assess the benefits and harms of ACEis and ARBs therapy for preserving residual kidney function in PD patients. Six studies (257 patients) were included (three ARB studies, one ACEi study and ACEi versus ARB studies). Long-term use (12 months or more) of an ARB showed a significant benefit in preserving residual kidney function in continuous ambulatory PD (CAPD) patients compared with other antihypertensive drugs, although there was no significant benefit when an ARB were used for less than six months). One study showed that compared with other antihypertensive drugs, long-term use of the ACEi ramipril showed a significant reduction in the decline of residual kidney function in patients on CAPD as well as anuria rate. While dizziness and cough are the main adverse events when an ACEi is used, only one study comparing an ARB with an ACEi reported this outcome and no significant difference between the two groups were found. While the use of an ARB or an ACEi may both be useful in preserving residual kidney function, the small number of studies and small number of patients enrolled means there is currently insufficient evidence to support the use of an ACEi or an ARB as first line antihypertensive therapy in PD patients.

Résumé simplifié

Les inhibiteurs de l'enzyme de conversion de l'angiotensine et les antagonistes des récepteurs de l'angiotensine II pour préserver la fonction rénale résiduelle chez les patients sous dialyse péritonéale

La fonction rénale résiduelle joue un rôle essentiel dans la santé et la qualité de vie des patients sous dialyse péritonéale (DP). Une meilleure préservation de la fonction rénale résiduelle est associée à une diminution de la mortalité, même un débit de filtration glomérulaire (DFG) réduit à 1 ml/min est associé à une réduction de près de 50 % du taux de mortalité. Deux types de médicaments antihypertenseurs, les inhibiteurs de l'enzyme de conversion de l'angiotensine (IEC) et les antagonistes des récepteurs de l'angiotensine II (ARA) sont souvent prescrits chez les patients sous DP (principalement pour contrôler l'hypertension ou l'insuffisance cardiaque) et pourraient apporter des bénéfices cardiovasculaires significatifs pour les patients en insuffisance rénale terminale (IRT). Actuellement, bien que les IEC et les ARA soient préconisés chez les patients sous DP, les preuves pour étayer leur utilisation sont encore incertaines. Toutefois, les études se sont centrées sur la protection cardiaque plutôt que sur la fonction rénale résiduelle. L'objectif de cette revue était d'évaluer les avantages et les inconvénients du traitement par les IEC et les ARA pour préserver la fonction rénale résiduelle chez les patients sous DP. Six études (257 patients) ont été incluses (trois études concernaient un ARA, une un IEC et deux un IEC versus un ARA). L'utilisation à long terme (12 mois ou plus) d'un ARA a montré un bénéfice significatif pour préserver la fonction rénale résiduelle des patients en dialyse péritonéale continue ambulatoire (DPCA) par rapport à d'autres médicaments antihypertenseurs, bien qu'il n'y ait pas eu de bénéfice significatif lorsqu'un ARA était utilisé moins de six mois. Une étude a montré que, en comparaison avec d'autres médicaments antihypertenseurs, l'utilisation à long terme de l'IEC ramipril entrainait une réduction significative du déclin de la fonction rénale résiduelle chez les patients sous DPCA ainsi que du taux d'anurie. Bien que les étourdissements et la toux soient les principaux événements indésirables lorsqu'un IEC est utilisé, une seule étude comparant un ARA avec un IEC a rapporté des résultats les concernant et aucune différence significative entre les deux groupes n'a été trouvée. Bien que l'utilisation d'un ARA ou d'un IEC pourrait être utile pour préserver la fonction rénale résiduelle, le petit nombre d'études et le petit nombre de patients recrutés signifie qu'il n'y a actuellement pas suffisamment de données probantes pour recommander l'utilisation d'un IEC ou d'un ARA comme traitement antihypertenseur de première intention chez les patients sous DP.

Notes de traduction

Traduit par: French Cochrane Centre 9th October, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Резюме на простом языке

Ингибиторы ангиотензин-превращающего фермента и блокаторы рецепторов ангиотензина-II для сохранения остаточной функции почек у больных, находящихся на перитонеальном диализе

Остаточная функция почек играет ключевую роль в здоровье и качестве жизни пациентов, находящихся на перитонеальном диализе (ПД). Лучшее сохранение остаточной функции почек связано со снижением смертности, даже при скорости остаточной клубочковой фильтрации (СКФ) 1 мл/мин, что связано с почти 50%-ным снижением смертности. Два вида антигипертензивных препаратов, ингибиторы ангиотензин-превращающего фермента (ИАПФ) и блокаторы рецепторов ангиотензина-II (БРА), часто назначают пациентам, находящимся на ПД (в первую очередь для контроля гипертонии или сердечной недостаточности), и могут обеспечить существенную сердечно-сосудистую пользу для пациентов в терминальной стадии болезни почек (ТСБП). На сегодняшний день, в то время как ИАПФ и БРА применяются у пациентов, находящихся на ПД, подтверждающие доказательства до сих пор неясны. Однако, исследования были посвящены вопросу защиты сердца, а не остаточной функции почек. Цель этого обзора заключалась в оценке пользы и вреда от терапии ИАПФ и БРА для сохранения остаточной функции почек у пациентов, находящихся на ПД. Шесть исследований (257 пациентов) были включены (три исследования БРА, одно исследование ИАПФ и исследование ИАПФ в сравнении с БРА). Длительное использование (12 месяцев и более) БРА показало значительное преимущество в сохранении остаточной функции почек при непрерывном амбулаторном ПД (НАПД) пациентов по сравнению с другими антигипертензивными средствами, хотя не было значительного преимущества, когда БРА применялись менее шести месяцев). Одно исследование показало, что по сравнению с другими антигипертензивными средствами, длительное применение ИАПФ рамиприла показало значительное снижение в уменьшении остаточной функции почек у пациентов при непрерывном амбулаторном ПД, а также частоты развития анурии. В то время, как головокружение и кашель являются основными нежелательными явлениями при использовании ИАПФ, только одно исследование, сравнивающее БРА с ИАПФ, сообщило об этом результате и существенного различия между двумя группами не было обнаружено. В то время как применение БРА или ИАПФ может быть полезным для сохранения остаточной функции почек, небольшое число исследований и небольшое число включенных пациентов означает, что в настоящее время недостаточно доказательств в поддержку использования ИАПФ или БРА в качестве антигипертензивной терапии первой линии у пациентов, находящихся на ПД.

Заметки по переводу

Перевод: Титаренко Альбина Фаритовна. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Казанский федеральный университет. По вопросам, связанным с этим переводом, пожалуйста, свяжитесь с нами по адресу: lezign@gmail.com

Summary of findings(Explanation)

Summary of findings for the main comparison. Angiotensin receptor blockers (ARBs) versus conventional therapy for preserving residual kidney function in peritoneal dialysis patients
ARBs versus conventional therapy for preserving residual kidney function in peritoneal dialysis patients

Patient or population: patients receiving PD

Settings: outpatient

Intervention: ARB

Comparison: Conventional therapy

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Conventional therapyARBs
Residual kidney function (3 months)Mean across control group was 3.06 mL/min/1.73 m²Mean was on average 0.44 mL/min/1.73 m² lower (95% Cl -1.53 to 0.65) in the ARB group 44 (1)⊕⊕⊕⊝
moderate
 
Residual kidney function (6 months)Mean across control group was 2.26 mL/min/1.73 m²Mean was on average 0.20 mL/min/1.73 m² lower (95% Cl -1.01 to 0.61) in the ARB group 44 (1)⊕⊕⊕⊝
moderate
 
Residual kidney function (≥ 12 months)Mean across control groups ranged from 1.04 to 2.8 mL/min/1.73 m²Mean was on average 1.11 mL/min/1.73 m² lower (95% Cl 0.38 to 1.83) in the ARB groups 110 (3)⊕⊕⊕⊝
moderate
 
Residual kidney function (12 months)Mean across control group was 1.04 mL/min/1.73 m²Mean was on average 0.64 mL/min/1.73 m² higher (95% Cl 0.19 to 1.19) in the ARB group 44 (1)⊕⊕⊕⊝
moderate
 
Residual kidney function (24 months)Mean across control groups ranged from 2.57 to 2.8 mL/min/1.73 m²Mean was on average1.49 mL/min/1.73 m² higher (95% Cl 1.12 to 1.86) in the ARB groups 66 (2)⊕⊕⊕⊝
moderate
 
Urinary protein excretionMean across control groups ranged from 1.12 to 2.97 g/24 hMean was on average0.01 g/24 h lower (95% Cl -0.09 to 0.06) in the ARB groups 66 (2)⊕⊕⊝⊝
low
 
Kt/VMean Kt/V across control groups ranged from 1.69 to 1.98Mean was on average0.1 higher (95% Cl -0.02 to 0.22) in the ARB groups 76 (2)⊕⊕⊕⊝
moderate
 
Weekly creatinine clearanceMean across control groups from 31.4 to 71.5 L/wk/1.73 m²Mean was on average9.06 L/wk/1.73 m² higher (95% Cl -2.77 to 20.90) in the ARB groups 110 (3)⊕⊕⊝⊝
low
 
Systolic BPMean across control groups ranged from 129 to 137 mm HgMean was on average-0.67 mm Hg higher (95% Cl -2.77 to 1.42) in the ARB groups 110 (3)⊕⊕⊕⊝
moderate
 
Diastolic BPMean across control groups ranged from 129 to 137 mm HgMean was on average-0.70 mm Hg higher (95% Cl -2.14 to 0.74) in the ARB groups 110 (3)⊕⊕⊕⊝
moderate
 
Serum potassiumMean across control group was 4.06 mmol/LMean was on average0.13 mmol/L higher (95% Cl -0.12 to 0.38) in the ARB group 44 (1)⊕⊕⊝⊝
low
 
Adverse events (episodes of peritonitis) High risk population RR 0.67 (0.18 to 2.54)34 (1)⊕⊕⊝⊝
low
 
250 per 1000 167 per 1000
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Angiotensin-converting enzyme inhibitors (ACEi) versus conventional therapy for preserving residual kidney function in peritoneal dialysis patients

Summary of findings 2. Angiotensin-converting enzyme inhibitors (ACEi) versus conventional therapy for preserving residual kidney function in peritoneal dialysis patients
ACEi versus conventional therapy for preserving residual kidney function in peritoneal dialysis patients

Patient or population: patients receiving PD

Settings: outpatient

Intervention: ACEi

Comparison: Conventional therapy

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Conventional therapy ACEi
Decline in residual kidney function (12 months)Mean across the control group was 1.86 mL/min/1.73 m²Mean was 0.93 mL/min/1.73 m² lower(95% Cl -1.75 to -0.11) in the ACEi group 60 (1)⊕⊕⊕⊝
moderate
 
Anuria

High risk population

733 per 1000

467 per 1000

RR 0.32

(0.11 to 0.94)

60 (1)⊕⊕⊕⊝
moderate
 
Mortality High risk population

RR 1.50

(0.27 to 8.34)

60 (1)⊕⊕⊕⊝
moderate
 
67 per 1000 100 per 1000
Cardiac events High risk population

RR 1.0

(0.37 to 3.21)

60 (1)⊕⊕⊕⊝
moderate
 
83 per 1000 83 per 1000
Cardiac events (fatal) High risk population

RR 1.0

(0.15 to 6.64)

60 (1)⊕⊕⊕⊝
moderate
 
67 per 1000 67 per 1000
Cardiac events (non fatal) High risk population

RR 1.0

(0.31 to 3.27)

60 (1)⊕⊕⊕⊝
moderate
 
100 per 1000 100 per 1000
Adverse events (episodes of peritonitis) High risk population

RR 1.13

(0.47 to 2.71)

60 (1)⊕⊕⊕⊝
moderate
 
133 per 1000 150 per 1000
Adverse events (episodes of peritonitis) - treated with an aminoglycoside High risk population

RR 1.20

(0.41 to 3.51)

60 (1)⊕⊕⊕⊝
moderate
 
167 per 1000 200 per 1000
Adverse events (episodes of peritonitis) - not treated with an aminoglycoside High risk population

RR 1.00

(0.22 to 4.56)

60 (1)⊕⊕⊕⊝
moderate
 
100 per 1000 100 per 1000
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 Angiotensin receptor blockers (ARBs) versus angiotensin-converting enzyme inhibitors (ACEis) for preserving residual kidney function in peritoneal dialysis patients

Summary of findings 3. Angiotensin receptor blockers (ARBs) versus angiotensin-converting enzyme inhibitors (ACEis) for preserving residual kidney function in peritoneal dialysis patients
ARBs compared with ACEis for preserving residual kidney function in peritoneal dialysis patients

Patient or population: patients receiving PD

Settings: outpatient

Intervention: ARB

Comparison: ACEi

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ACEiARB
Residual kidney function (4 weeks)Mean across ACEi group was 2.28 mL/min/1.73 m²Mean was 0.47 mL/min/1.73 m² lower (95% Cl -2.73 to 1.79) in the ARB group 20 (1)⊕⊕⊝⊝
low
 
Residual kidney function (12 months)Mean across ACEi group was 2.36 mL/min/1.73 m²Mean was 0.18 mL/min/1.73 m² higher (95% Cl -0.04 to 0.40) in the ARB group 60 (1)⊕⊕⊕⊝
moderate
 
Anuria

High risk population

367 per 1000

400 per 1000 RR 1.15 (0.41 to 3.26)60 (1)⊕⊕⊕⊝
moderate
 
Cardiovascular events (non-fatal)

High risk population

100 per 1000

133 per 1000 RR 1.33 (0.33 to 5.45)60 (1)⊕⊕⊕⊝
moderate
 
Serum potassiumMean across ACEi group was 4.42 mmol/LMean was 0.05 mmol/L lower (95% Cl -2.73 to 1.79) in the ARB group 42 (1)⊕⊕⊕⊝
moderate
 
Systolic BPMean across ACEi group was 141.95 mm HgMean was 0.48 mm Hg higher (95% Cl -7.76 to 8.72) in the ARB group 42 (1)⊕⊕⊕⊝
moderate
 
Diastolic BPMean across ACEi group was 84.19 mm HgMean was 0.38 mm Hg higher (95% Cl -6.76 to 7.52) in the ARB group 42 (1)⊕⊕⊕⊝
moderate
 
Cough

High risk population

67 per 1000

100 per 1000

RR 1.56

(0.24 to 10.05)

60 (1)⊕⊕⊕⊝
moderate
 
Hyperkalaemia

High risk population

69 per 1000

83 per 1000 RR 1.23 (0.35 to 4.40)144 (2)⊕⊕⊕⊝
moderate
 
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Peritoneal dialysis (PD) has been established for more than 30 years as a form of renal replacement therapy (RRT). Improvements in continuous ambulatory/cyclic PD (CAPD/CCPD) have resulted in its widespread adoption for treating end-stage kidney disease (ESKD). Cost comparisons between PD and haemodialysis (HD) show that PD is less expensive than HD (Blake 2001). In the United States, 8% of the ESKD population is on PD (USRDS 2003), but it is more prevalent in other countries: Canada (20% to 30%) (Schaubel 2000); Denmark (33%) (Heaf 2002); Netherlands (39%) (Termorshuizen 2003); Hong Kong (80%) (Li 1999); and Mexico (81%) (Cueto-Manzano 2003). Some epidemiological studies have shown an adjusted survival advantage for PD compared with HD during the first two years of dialysis (Fenton 1997; Heaf 2002), and several studies have also suggested that CAPD is equivalent to HD or may even be superior for certain subgroups (Gokal 1999; Suzuki 2003a).

Residual kidney function is better preserved with PD than with HD (Cancarini 1986) because HD causes substantial haemodynamic disturbance and activates inflammation, which may accelerate the loss of residual kidney function. Patients treated with PD have been shown to have a 65% lower risk for losing residual kidney function than patients receiving HD (Moist 2000). This better preservation, which has been attributed to an effect of residual function on both total solute clearance and fluid status (Bargman 2001), may be an important factor for choosing PD and an important determinant of mortality and morbidity (Bargman 2001; Szeto 2000). Better preservation is associated with decreased mortality, even at a low level (Blake 2001; Shemin 2000) with some studies showing that each 1 mL/min of residual glomerular filtration rate (GFR) is associated with a nearly 50% reduction in mortality rate (Szeto 2000; Maiorca 1995). It has also been estimated that each 1 mL/min of renal clearance can be translated into a Kt/V of 0.25 to 0.3/wk in a 70 kg man (Li 2001a; Venkataraman 2000). One, 2 L dialysis exchange/d could be spared by preserving 1 mL/min of residual GFR, which could improve quality of life and decrease costs substantially (Li 2001b). However, the initial survival advantage of PD compared with HD may change to a disadvantage after long-term PD (Termorshuizen 2003) because of the decrease of residual GFR and the development of peritoneal membrane alterations (Williams 2002). As a result, measures to preserve residual kidney function and peritoneal membrane are an important target in the treatment of patients receiving PD.

Description of the intervention

Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are frequently prescribed in PD patients, primarily for the control of hypertension or heart failure, which could provide significant cardiovascular benefit in ESKD patients. A double blind randomised controlled study (RCT) (Suzuki 2003b) showed that the ARB valsartan had a beneficial effect on left ventricular hypertrophy in patients on CAPD. Use of an ACEi has also been independently associated with a decreased risk for loss of residual kidney function (Moist 2000).

How the intervention might work

Many studies confirm that both ARBs and ACEis are effective in the prevention of progressive chronic kidney disease and reduction of proteinuria. Recently, some clinical studies have demonstrated positive effects of an ACEi or an ARB on preserving residual kidney function in PD patients (Li 2003; Suzuki 2004; Zhong 2007a). In addition, the results of a recent study show that ACEis and ARBs were likely to have a membrane protective effect by preventing the increase in small solute transport that often occurs in long term PD which is possibly related to a larger number of perfused peritoneal microvessels (Kolesnyk 2007).

Why it is important to do this review

A recent systematic review concluded that ACEis and ARBs slow the loss of residual kidney function based on two RCTs enrolling a total of 94 participants (Akbari 2009). A more comprehensive systematic review is warranted since only studies published in English were included and it did not provide details on other parameters of great clinical significance such as peritoneal function, changes in blood pressure and quality of life.

Objectives

This review aimed to evaluate the benefits and harms of ACEis and ARBs for preserving residual kidney function in PD patients.

Methods

Criteria for considering studies for this review

Types of studies

All RCTs and quasi-RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) investigating the benefits and harms of ACEi and ARBs for preserving residual kidney function in PD were considered eligible for inclusion, whether or not residual kidney function was set as the primary outcome. However, studies that did not assess residual kidney function were not included.

Types of participants

Inclusion criteria

ESKD patients with residual kidney function receiving any type of PD regardless of age, primary diseases and clinical medical course. The definition of remaining or losing residual kidney function applied by each study was accepted.

Exclusion criteria
  1. Acute kidney injury: abrupt (within 48 hours) reduction in kidney function, currently defined as an absolute increase in serum creatinine (SCr) (≥ 0.3 mg/dL or ≥ 26.5 μmol/L), a percentage increase in SCr of ≥ 50% (1.5-fold from baseline) or a reduction in urine output (documented oliguria of < 0.5 mL/kg/h for > 6 hours) despite adequate fluid resuscitation when applicable. Patients receiving both PD and HD.

Types of interventions

Any ACEi or ARB used for ESKD patients receiving PD, regardless of dosage, mode of administration or duration of treatment. The comparisons were as follows:

  1. ACEi or ARB or both + routine treatment versus routine treatment + placebo

  2. ACEi or ARB or both + routine treatment versus routine treatment

  3. ACEi or ARB or both+ routine treatment versus routine treatment + other drugs (antihypertensive drugs).

  4. ACEi + routine treatment versus ARB + routine treatment

Routine treatment: PD and supportive treatment.

Supportive treatment can include approaches to treat underlying kidney or medical diseases and to improve other disorders linked to kidney failure, such as anaemia, calcium and phosphate imbalance, and dyslipidaemia. Supportive treatment should be comparable between study and control groups.

Types of outcome measures

Primary outcomes

Residual kidney function (as measured by GFR or endogenous creatinine clearance (CrCl).

Secondary outcomes
  1. All-cause mortality

  2. Cardiovascular mortality (deaths caused by heart failure, myocardial infarction, stroke or cardiac arrest)

  3. Non-fatal cardiovascular events (non-fatal myocardial infarction, angina pectoris, stroke and arrhythmia)

  4. Urinary albumin/protein excretion rate

  5. Anuria

  6. Peritoneal function: dialysis adequacy (Kt/V, weekly CrCl), peritoneal membrane transport

  7. The number of patients changing from PD to HD or increasing PD dose due to declining of residual kidney function

  8. Blood pressure (mm Hg)

  9. Quality of life (validated scale/s are required)

  10. Adverse events: cough, potassium, hyperkalaemia, hypotension, angioedema and peritonitis.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Renal Group's Specialised Register (to 15 May 2014) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. The Cochrane Renal Group’s Specialised Register contains studies identified from the following sources.

  1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of renal-related journals and the proceedings of major renal conferences

  4. Searching of the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected renal journals

  6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Renal Group.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

  1. Chinese Biomedical Literature Database (CBM)

  2. China National Knowledge Infrastructure (CNKI)

  3. Reference lists of clinical practice guidelines, review articles and relevant studies

  4. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The review was undertaken by four authors. The search strategy described was used to obtain titles and abstracts of studies that might be relevant to the review. The titles and abstracts were screened independently by two authors, who discarded studies that were not applicable, however studies and reviews that might include relevant data or information on studies were retained initially. Two authors independently assessed retrieved abstracts (and if necessary the full text) to determine which studies satisfied the inclusion criteria.

Data extraction and management

Data extraction was carried out independently by two authors using standard data extraction forms. Studies reported in non-English or Non-Chinese language journals were translated before assessment. Where more than one publication of one study exists, reports were grouped together and the most recent or most complete data set were used. Any discrepancy between published versions were highlighted. Disagreements were resolved in consultation with the other authors.

Assessment of risk of bias in included studies

The following items were assessed using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?

    • Participants and personnel

    • Outcome assessors

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (mortality, complications of treatment and cardiovascular events) results were expressed as risk ratios (RR) with 95% confidence intervals (CI). Where continuous scales of measurement was used to assess the effects of treatment (e.g. residual kidney function, peritoneal function, blood pressure, proteinuria and urine volume), the mean difference (MD) were used, or the standardised mean difference (SMD) if different scales had been used.

Dealing with missing data

Any further information required from the original author was requested by written correspondence and any relevant information obtained in this manner was included in the review.

Assessment of heterogeneity

Heterogeneity was analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.

Assessment of reporting biases

Although we had planned to create funnel plots to assess for the potential existence of small study bias (Higgins 2011), the small number of included studies meant that this was not possible.

Data synthesis

Data were pooled using the random-effects model but the fixed-effect model was also applied to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

We performed subgroup analysis to identify possible sources of heterogeneity. Differences in participants (ethnicity, age and underlying kidney diseases) and disparities related to intervention (i.e. the type and dose of ACEi or ARB or both, modality and dose of PD and duration of therapy) might be attributed to heterogeneity. The following subgroup analyses were planned to investigate any observed heterogeneity.

  1. Different underlying kidney diseases (i.e. diabetic kidney disease or non-diabetic kidney diseases)

  2. Different type and dose of ACEi and or ARB

  3. Different modalities of PD (i.e. CAPD, CCPD or automated PD)

  4. Different durations of therapy and follow-up.

Adverse effects were tabulated and assessed with descriptive techniques, as they are likely to be different for the various drugs used. Where possible, the risk difference (RD) with 95% CI was calculated for each adverse effect, either compared to no treatment or to another agent.

Sensitivity analysis

Where possible, we performed sensitivity analyses to evaluate the effect on the overall result of removing studies with low methodological quality. Studies with inadequate allocation concealment; achieving inadequate follow-up and unblinded outcome assessment, or blinding of outcome assessment uncertain, were considered as being of low methodological quality.

Results

Description of studies

Results of the search

After searching the Cochrane Renal Group's Specialised Register (59 records), CENTRAL (13), EMBASE (22), and Chinese databases (15) we identified 109 records. After duplicate removal and removing irrelevant records 26 reports were retained for full-text assessment. Full-text assessment identified revealed six eligible studies (seven reports) (Li 2003; Suzuki 2004; Wang 2005d; Zhong 2007a; Phakdeekitcharoen 2004; Reyes-Marin 2012) with a total of 257 participants. Two of these studies were published in Chinese (Wang 2005d; Zhong 2007a). Two reports were classified as ongoing studies (NCT00721773; NCT01041963, one conference abstract is awaiting classification (Medcalf 2000), and nine studies (16 reports) were excluded (Cioni 2010; Favazza 1992; Huang 2002; Kolesnyk 2011; Nakamoto 2004; PERFECT Study 1997; Rojas-Campos 2005; Shigenaga 2009; Suzuki 2003). A flow chart for our study selection procedure is presented as Figure 1.

Figure 1.

Study flow diagram.

Included studies

Three studies investigated the influence of an ARB on residual kidney function in CAPD patients (Suzuki 2004; Wang 2005d; Zhong 2007a). Based on prospective calculation of sample size, Suzuki 2004 enrolled 34 patients (male/female: 21/13; mean age: 63.5 years) and compared the effects of valsartan (40 to 80 mg/d) with other antihypertensive drugs (except an ACEi or an ARB). An antihypertensive regimen was proposed to achieve the target blood pressure (BP) of 130/80 mm Hg. Patients used 1.5 to 2.5 L of 2.5% dextrose dialysate/exchange for 3 to 5 exchanges/d for CAPD. Zhong 2007a enrolled 48 patients (male/female: 31/17; mean age: 44 years) and compared the effects of irbesartan (300 mg/d) with other antihypertensive drugs (except an ACEi or an ARB). An antihypertensive regimen was proposed to achieve the target BP of 12070 to 135/85 mm Hg. It was reported 1.5% or 2.5% dextrose dialysate was used, but detailed CAPD schedule was not available. In Wang 2005d, valsartan (40 to 80 mg/d) and other antihypertensive drugs were compared in 32 patients (male/female: 21/11; mean age: 42 years). Target BP was set at 130/80 mm Hg. Detailed CAPD schedule was not available.

Li 2003 assessed changes in residual kidney function in CAPD patients treated with the ACEi, ramipril (5 mg/d). On the basis of sample size estimation, 60 patients were included (male/female: 38/22; mean age: 58.6 years). Antihypertensive drugs other than an ACEi were allowed in both study and control groups to maintain target BP of 135/85 mm Hg. CAPD protocol was not provided.

Two studies compared an ARB with an ACEi for preservation of residual kidney function in PD patients (Phakdeekitcharoen 2004; Reyes-Marin 2012). Phakdeekitcharoen 2004 was a cross-over study, which enrolled 21 patients (male/female: 14/7; mean age: 44.8 years) and compared the effects of candesartan (8 mg/d) with enalapril (10 mg/d) for four weeks (short-term use). Reyes-Marin 2012 enrolled 60 patients (male/female: 36/24) and compared the effects of losartan (50 mg/d) with enalapril (50 mg/d) for 12 months (long-term use). Target BP was set at 130/85 mm Hg.

See Characteristics of included studies.

Excluded studies

Of the 18 studies (26 reports) identified, nine studies (16 reports) were excluded. One study was not randomised (Kolesnyk 2011); one study enrolled ineligible patients (not all PD patients) (PERFECT Study 1997), and seven studies provided no information about residual kidney function (Cioni 2010; Huang 2002; Nakamoto 2004; Shigenaga 2009; Suzuki 2003; Favazza 1992; Rojas-Campos 2005). See Characteristics of excluded studies.

Risk of bias in included studies

Details of the assessment of risk of bias of included studies are presented in Figure 2 and Figure 3.

Figure 2.

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

Figure 3.

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

Allocation

Two studies provided detailed allocation list generation methods (computer generated) and applied adequate allocation concealment (Li 2003; Suzuki 2004), the remaining four studies did not provide details of allocation (Phakdeekitcharoen 2004; Reyes-Marin 2012; Wang 2005d; Zhong 2007a). The methods used in the studies by Wang 2005d and Zhong 2007a were obtained through corresponding with the original authors. They used computer software to generate the sequence, but allocation concealment was not used.

Blinding

One study did not provide any information about blinding (Reyes-Marin 2012), while the other five studies were open-label. The primary outcome (residual kidney function) assessed in the review was obtained from laboratory tests, and it was judged as unlikely to be influenced by the status of blinding. BP measurements in four studies (Suzuki 2004; Phakdeekitcharoen 2004; Wang 2005d; Zhong 2007a) however might be influenced.

Incomplete outcome data

Suzuki 2004 and Reyes-Marin 2012 did not report detailed information of patients lost to follow-up. In Zhong 2007a, two patients withdrew from the study, and two patients were lost to follow-up with no reason identified. Wang 2005d reported that two patients withdrew from the study but reasons were not provided. In Li 2003, five deaths occurred and 2 patients withdrew due to kidney transplantation; but it was noteworthy that five patients in the ACEi group discontinued ramipril due to persistent dizziness or cough, which are common side effects of ACEis. In Phakdeekitcharoen 2004, eight patients (27.6%) withdraw and reasons were provided.

Selective reporting

None of the included studies reported details of the study protocols or prespecified outcomes. There were insufficient data available to enable an assessment of selective reporting to be made.

Other potential sources of bias

Two studies did not provide detailed antihypertensive protocols (other than ACEis and ARBs) (Wang 2005d; Zhong 2007a), and PD schedules were not provided by four studies (Li 2003; Reyes-Marin 2012; Wang 2005d; Zhong 2007a).

Effects of interventions

See: Summary of findings for the main comparison Angiotensin receptor blockers (ARBs) versus conventional therapy for preserving residual kidney function in peritoneal dialysis patients; Summary of findings 2 Angiotensin-converting enzyme inhibitors (ACEi) versus conventional therapy for preserving residual kidney function in peritoneal dialysis patients; Summary of findings 3 Angiotensin receptor blockers (ARBs) versus angiotensin-converting enzyme inhibitors (ACEis) for preserving residual kidney function in peritoneal dialysis patients

Residual kidney function

Three studies reported the effect of ARBs versus other antihypertensive drugs on residual kidney function at various time points. Zhong 2007a reported no significant difference between ARBs and other antihypertensive therapies in reducing the decline of residual kidney function at three months (Analysis 1.1.1 (1 study, 44 participants): MD -0.44 mL/min/1.73m², 95% CI -1.53 to 0.65) or six months (Analysis 1.1.2 (1 study, 44 participants): MD -0.20 mL/min/1.73 m², 95%CI -1.01 to 0.61); however ARBs significantly reduced the decline of residual kidney function at 12 months (Analysis 1.1.3 (1 study, 44 participants): MD 0.64 mL/min/1.73 m², 95% CI 0.19 to 1.09). At 24 months ARBs significantly reduced the decline in residual kidney function compared to other antihypertensive regimens (Analysis 1.1.4 (2 studies; 66 participants): MD 1.49 mL/min/1.73 m², 95% CI 1.12 to 1.86; I² = 0%). Long-term use (≥ 12 months) of ARBs can benefit residual kidney function in PD patients (Analysis 1.3 MD 1.11 mL/min/1.73 m², 95% CI 0.38 to 1.83).

Li 2003 reported over 12 months ACEis significantly reduced the decline of residual kidney function compared with other antihypertensive drugs (Analysis 2.1 (1 study, 60 participants): MD -0.93 mL/min/1.73 m², 95% CI -1.75 to -0.11).

Phakdeekitcharoen 2004 and Reyes-Marin 2012 reported no significant differences in residual kidney function preservation between ARBs and ACEis in short-term (four weeks) (Analysis 3.1.1 (1 study, 20 participants): MD -0.47 mL/min/1.73 m², 95% CI -2.73 to 1.79) or long-term use (12 months) (Analysis 3.3 (1 study, 60 participants): MD 0.18 mL/min/1.73 m², 95% CI -0.04 to 0.40).

All-cause mortality

Mortality was not reported in the studies comparing ACEis with other antihypertensive drugs or studies comparing ARBs with ACEis.

Li 2003 reported no significant difference in mortality between patients treated with ACEis compared with other antihypertensive drugs (Analysis 2.2 (1 study, 60 patients): RR 1.50, 95% CI 0.27 to 8.34).

Cardiovascular events

ARBs versus other antihypertensive drugs

Cardiovascular events were not reported in the studies comparing an ARB with other antihypertensive drugs.

Li 2003 reported no significant differences between ACEis and other antihypertensive drugs for both fatal (Analysis 2.3.1 (1 study, 60 participants): RR 1.00, 95% CI 0.15 to 6.64) and non-fatal (Analysis 2.3.2 (1 study, 60 patients): RR 1.00, 95% CI 0.22 to 4.56) cardiovascular events.

Reyes-Marin 2012 reported no fatal cardiovascular events occurred in either the ARB or ACEi groups, and no significant difference for non-fatal cardiovascular events (Analysis 3.2 (1 study, 60 participants): RR 1.38, 95% CI 0.28 to 6.80).

Urinary protein excretion

There was no significant difference in urinary protein excretion between patients treated with ARBs and those treated with other antihypertensive drugs (Analysis 1.2 (2 studies, 66 patients): MD -0.01 g/d, 95% CI -0.09 to 0.06).

Urinary protein excretion was not reported in the studies comparing an ACEi with other antihypertensive drugs or studies comparing an ARB with an ACEi.

Anuria

Anuria was not reported in the studies comparing an ARB with other antihypertensive drugs.

Li 2003 reported over 12 months ACEis significantly reduced the number progression to complete anuria compared to other antihypertensive drugs (Analysis 2.4 (1 study, 60 participants): RR 0.32, 95% CI 0.11 to 0.94).

Reyes-Marin 2012 reported no significant difference in the progression to complete anuria between the ARB and ACEi groups (Analysis 3.3 (1 study, 42 participants): RR 1.15, 95% CI 0.41 to 3.26).

Dialysis adequacy

Dialysis adequacy was measured in studies comparing ARBs with other antihypertensive drugs. There was no significant difference in Kt/V between patients treated with ARBs and those treated with other antihypertensive drugs (Analysis 1.3 (2 studies, 76 participants): MD 0.10, 95% CI -0.02 to 0.22). There was no significant difference in weekly creatinine clearance between patients treated with ARBs and those treated with other antihypertensive drugs (Analysis 1.4 (3 studies, 110 participants): MD 9.06 mL/wk/1.73 m², 95% CI -2.77 to 20.90; I² = 76%), however significant heterogeneity was identified.

Dialysis adequacy was not reported in studies comparing an ACEi with other antihypertensive drugs or studies comparing an ARB with an ACEi.

Blood pressure

In studies comparing ARBs with other antihypertensive drugs there were no significant differences in either systolic blood pressure (Analysis 1.5 (3 studies, 110 participants): MD -0.67 mm Hg, 95% CI -2.77 to 1.42; I² = 0%) or diastolic blood pressure (Analysis 1.6 (3 studies, 110 participants): MD -0.70 mm Hg, 95% CI -2.14 to 0.74; I² = 0%).

Reyes-Marin 2012 reported no significant differences between the ARB and ACEi groups for either systolic blood pressure (Analysis 3.4 (1 study, 42 participants): MD 0.48 mm Hg, 95% CI -7.76 to 8.72) or diastolic blood pressure (Analysis 3.5 (1 study, 42 participants): MD -0.38 mm Hg, 95% CI -6.76 to 7.52).

Blood pressure was not reported in the studies comparing an ACEi with other antihypertensive drugs.

Peritonitis

Suzuki 2004 reported no significant difference in the number of patients experiencing peritonitis between the ARB and other antihypertensive drug groups (Analysis 1.7 (1 study, 34 participants): RR 0.67, 95% CI 0.18 to 2.54).

Li 2003 reported no significant difference in the number of patients experiencing peritonitis between the ACEi and control groups (Analysis 2.5.1 (1 study, 60 participants): RR 1.13, 95% CI 0.50 to 2.52). There was no significant difference between the groups for those either treated with an aminoglycoside (Analysis 2.5.2: RR 1.20, 95% CI 0.41 to 3.51) or not treated with an aminoglycoside (Analysis 2.5.3: RR 1.00, 95% CI 0.22 to 4.56).

Reyes-Marin 2012 reported no significant difference in the number of patients experiencing peritonitis between the ARB and ACEi groups (Analysis 3.6 (1 study, 60 patients): RR 1.17, 95% CI 0.44 to 3.06).

Cough

Cough was not reported in the studies comparing an ARB or an ACEi with other antihypertensive drugs.

Reyes-Marin 2012 reported no significant difference in the number of patients experiencing cough between the ARB and ACEi groups (Analysis 3.7 (1 study, 60 patients): RR 1.50, 95% CI 0.27 to 8.34).

Serum potassium

Zhong 2007a reported no significant difference in serum potassium level between the ARB and other antihypertensive drug groups (Analysis 1.8 (1 study, 44 participants): MD 0.13 mmol/L, 95% CI -0.12 to 0.38).

Phakdeekitcharoen 2004 reported no statistical difference was observed in serum potassium between the ARB and ACEi groups (Analysis 3.8 (1 study, 42 participants): MD -0.05 mmol/L, 95% CI -0.45 to 0.35).

Serum potassium was not reported in any of the studies comparing an ACEi with other antihypertensive drugs.

Hyperkalaemia

Hyperkalaemia was not reported in studies comparing an ARB or an ACEi with other antihypertensive drugs.

There was no significant difference in the number patients experiencing hyperkalaemia between the ARB and ACEi groups (Analysis 3.9 (2 studies, 84 events): RR 1.20, 95% CI 0.40 to 3.63)

Other outcomes

The following outcomes were not reported by any of the included studies: hypotension; angioedema; the number of patients changing from PD to HD; increasing PD dose due to declining of residual kidney function; or quality of life.

Due to the small number of studies identified we were unable to perform subgroup analyses to investigate heterogeneity, perform sensitivity analyses, assess publication biases, or tabulate adverse events as stated in our protocol.

Discussion

Summary of main results

This review assessed six small RCTs enrolling 257 participants. Three studies compared an ARB with other antihypertensive drugs (Suzuki 2004; Wang 2005d; Zhong 2007a), one study compared an ACEi with other antihypertensive drugs (Li 2003), and two studies compared an ARB with an ACEi (Phakdeekitcharoen 2004; Reyes-Marin 2012). Long-term use (≥ 12 months) of an ARB showed significant benefit in preserving residual kidney function in CAPD patients (MD 1.11 mL/min/1.73 m², 95% CI 0.38 to 1.83), although there was no significant benefit when an ARB were used short-term (≤ 6 months). One study showed that compared with other antihypertensive drugs, long-term use (12 months) of the ACEi ramipril, showed a significant reduction in the decline of residual kidney function in patients on CAPD (MD -0.93 mL/min/1.73 m², 95% CI -1.75 to -0.11), as well as slowing of the progression to complete anuria (RR 0.64, 95% CI 0.41 to 0.99). There was no significant difference in serum potassium levels, urinary protein excretion, Kt/V, weekly creatinine clearance and blood pressure for an ARB versus other antihypertensive drugs. Compared with other antihypertensive drugs, ramipril showed no difference in mortality and cardiovascular events. In two studies, there was no significant difference on residual kidney function preservation between an ARB and an ACEi in short- or long-term use (4 weeks: MD -0.47 mL/min/1.73 m², 95% CI -2.73 to 1.79; 12 months: MD 0.18 mL/min/1.73 m², 95% CI -0.04 to 0.40).

Overall completeness and applicability of evidence

This systematic review presents clinical evidence of the application of an ACEi or an ARB for preserving residual kidney function in PD patients. However, the evidence provided in these six small RCTs is limited in their completeness and applicability.

Firstly, the primary outcome we had planned to investigate were not adequately addressed in the included studies. The long-term effect of an ACEi on residual kidney function was only reported in one study comparing with other antihypertensive drugs (Li 2003). For short-term effects on residual kidney function, only one study reported an ARB compared with other antihypertensive drugs (Zhong 2007a), and the data of short-term effect of an ACEi on residual kidney function was lacking. In the two studies comparing an ARB with an ACEi, Phakdeekitcharoen 2004 was a cross-over study of short-term use (four weeks), and Reyes-Marin 2012 did not provide any information about allocation and blinding.

Secondly, no detailed analysis was provided addressing the divergence in age, sex, aetiologic factors and dosage of ACEis and ARBs. As a result, related subgroup analysis was not performed as planned. Adverse events such as hypotension and angioedema were not reported in any of the included studies.

Thirdly, it was also noteworthy that four studies (Li 2003; Suzuki 2004; Wang 2005d; Zhong 2007a), which compared an ARB or an ACEi with other antihypertensive drugs, all included Asian participants, limiting the applicability of the evidence presented by the review to other ethnic or racial groups.

Quality of the evidence

Of the six included RCTs, two provided detailed random sequence generation methods (computer generated) and applied adequate allocation concealment (Li 2003; Suzuki 2004). In the other four studies, the allocation approach used by Wang 2005d and Zhong 2007a were obtained through corresponding with the original authors. They also used computer software to generate the sequence, but allocation concealment was not used. With the exception of Reyes-Marin 2012 which did not provide any information about blinding, other five included studies were open-label. However, our primary outcome (residual kidney function) were obtained from laboratory tests, and were not likely to be influenced by the blinding of the participants or investigators; BP measurements in four studies (Suzuki 2004; Wang 2005d; Zhong 2007a; Phakdeekitcharoen 2004) might however be influenced. Suzuki 2004 did not report detailed information of patients lost to follow-up. In Zhong 2007a, two patients withdrew from the study, and two patients were lost to follow-up with no reasons reported. In the study by Wang 2005d, two patients withdrew from the study, again with no reasons reported. In Li 2003, five deaths occurred and two patients withdrew due to kidney transplantation; it was noteworthy that five patients in the ACEi group discontinued ramipril due to persistent dizziness or cough, which were common side effects of ACEis. In Phakdeekitcharoen 2004, eight patients (27.6%) withdraw and the reasons were provided. Some parameters listed in the Methods were not further addressed, but all included studies reported the primary outcome. Since study protocols were not available, it was difficult to determine whether there was high risk of selective reporting.

Potential biases in the review process

While we have made efforts to identify clinical studies relevant to our topic in electronic searches and clinical trial registers, we cannot deny the possibility that unpublished studies might exist. Since only four studies were included, we did not construct funnel plots to explore reporting biases. All of these studies did not have protocols available on public clinical trial registers, therefore we couldn't assess selective outcomes reporting.

Agreements and disagreements with other studies or reviews

Akbari 2009 evaluated the effects of ACEis and ARBs in PD, but included only two RCTs (Li 2003; Suzuki 2004) to evaluate the effects of an ACEi and an ARB on residual kidney function. Akbari 2009 reported residual kidney function at 12 months and the weighted MD was 0.91 mL/min/1.73 m² (95% CI 0.14 to 1.68), favouring the use of an ACEi and an ARB, which is similar to our study. However, the result of a recent study by Kolesnyk 2011 is not in line with the results of this review. This study is a large, prospective, multicentre cohort study including 451 Dutch participants, which showed that ACEis and ARBs had no additional benefit in preserving residual kidney function over three years of PD treatment (P = 0.52). However, details of changes of six, 12, 24, 36 months of residual kidney function were lacking. Some bias existed such as non-randomised design, selection bias and attrition bias, which might influence the results of this study. A recent observational study indicated that the absence of an ACEi or an ARB was one of independent risk factors associated with rapidly declining residual kidney function (Herget-Rosenthal 2012).

Authors' conclusions

Implications for practice

Compared with other antihypertensive drugs, long-term use (≥ 12 months) of an ACEi or an ARB showed additional benefits of preserving residual kidney function in CAPD patients. However, limited by the small number of RCTs enrolling small number of participants, there is currently insufficient evidence to support the use of an ACEi or an ARB as first line antihypertensive therapy in PD patients.

Implications for research

More high quality RCTs are needed to evaluate the benefits and harms of ACEis and ARBs for preserving residual kidney function in PD patients. We recommend addressing the following issues in future studies.

  • Register trials before implementation

  • Describe the process of randomised allocation and allocation concealment in detail

  • Apply blinding when appropriate

  • Put restrictions on parameters that might greatly influence the outcomes (i.e. PD schedule and dosage of ACEis or ARBs) when setting up the inclusion and exclusion criteria

  • Report short-term and long-term outcomes of clinical significance, such as mortality, residual kidney function, urine volume and adverse events

  • There are two ongoing studies that are likely to provide useful information to determine which drug (ACEis or ARBs or both) provides better protection of residual kidney function. NCT00721773 will evaluate the effects of effects of benazepril, valsartan or combination of both on residual kidney function in PD patients; and NCT01041963 will study the effect of enalapril and losartan on peritoneal membrane in CAPD patients.

Acknowledgements

We wish to thank:

  • The Cochrane Renal Group for their help with the search strategy and development of this review.

  • The referees for their comments and feedback during the preparation of this review.

Data and analyses

Download statistical data

Comparison 1. ARBs versus other antihypertensive drugs
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Residual kidney function [mL/min/1.73 m²]3 Mean Difference (IV, Random, 95% CI)Subtotals only
1.1 3 months144Mean Difference (IV, Random, 95% CI)-0.44 [-1.53, 0.65]
1.2 6 months144Mean Difference (IV, Random, 95% CI)-0.20 [-1.01, 0.61]
1.3 12 months144Mean Difference (IV, Random, 95% CI)0.64 [0.19, 1.09]
1.4 24 months266Mean Difference (IV, Random, 95% CI)1.49 [1.12, 1.86]
1.5 12 to 24 months3110Mean Difference (IV, Random, 95% CI)1.11 [0.38, 1.83]
2 Urinary protein excretion266Mean Difference (IV, Random, 95% CI)-0.01 [-0.09, 0.06]
3 Kt/V276Mean Difference (IV, Random, 95% CI)0.10 [-0.02, 0.22]
4 Weekly creatinine clearance [mL/wk/1.73 m²]3110Mean Difference (IV, Random, 95% CI)9.06 [-2.77, 20.90]
5 Systolic BP3110Mean Difference (IV, Random, 95% CI)-0.67 [-2.77, 1.42]
6 Diastolic BP3110Mean Difference (IV, Random, 95% CI)-0.70 [-2.14, 0.74]
7 Peritonitis1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
8 Serum potassium1 Mean Difference (IV, Random, 95% CI)Totals not selected
Analysis 1.1.

Comparison 1 ARBs versus other antihypertensive drugs, Outcome 1 Residual kidney function [mL/min/1.73 m²].

Analysis 1.2.

Comparison 1 ARBs versus other antihypertensive drugs, Outcome 2 Urinary protein excretion.

Analysis 1.3.

Comparison 1 ARBs versus other antihypertensive drugs, Outcome 3 Kt/V.

Analysis 1.4.

Comparison 1 ARBs versus other antihypertensive drugs, Outcome 4 Weekly creatinine clearance [mL/wk/1.73 m²].

Analysis 1.5.

Comparison 1 ARBs versus other antihypertensive drugs, Outcome 5 Systolic BP.

Analysis 1.6.

Comparison 1 ARBs versus other antihypertensive drugs, Outcome 6 Diastolic BP.

Analysis 1.7.

Comparison 1 ARBs versus other antihypertensive drugs, Outcome 7 Peritonitis.

Analysis 1.8.

Comparison 1 ARBs versus other antihypertensive drugs, Outcome 8 Serum potassium.

Comparison 2. ACEis versus other antihypertensive drugs
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Change in residual kidney function [mL/min/1.73 m²]1 Mean Difference (IV, Random, 95% CI)Totals not selected
1.1 12 months1 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
2 All-cause mortality1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
3 Cardiovascular events1120Risk Ratio (M-H, Random, 95% CI)1.0 [0.31, 3.27]
3.1 Fatal160Risk Ratio (M-H, Random, 95% CI)1.0 [0.15, 6.64]
3.2 Non-fatal160Risk Ratio (M-H, Random, 95% CI)1.0 [0.22, 4.56]
4 Anuria1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
5 Peritonitis1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
5.1 All patients1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5.2 Treated with an aminoglycoside1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5.3 Not treated with an aminoglycoside1 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 ACEis versus other antihypertensive drugs, Outcome 1 Change in residual kidney function [mL/min/1.73 m²].

Analysis 2.2.

Comparison 2 ACEis versus other antihypertensive drugs, Outcome 2 All-cause mortality.

Analysis 2.3.

Comparison 2 ACEis versus other antihypertensive drugs, Outcome 3 Cardiovascular events.

Analysis 2.4.

Comparison 2 ACEis versus other antihypertensive drugs, Outcome 4 Anuria.

Analysis 2.5.

Comparison 2 ACEis versus other antihypertensive drugs, Outcome 5 Peritonitis.

Comparison 3. ARBs versus ACEis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Residual kidney function [mL/min/1.73 m²]2 Mean Difference (IV, Random, 95% CI)Totals not selected
1.1 1 month1 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
1.2 12 months1 Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]
2 Cardiovascular events (nonfatal)1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
3 Anuria1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
4 Systolic BP1 Mean Difference (IV, Random, 95% CI)Totals not selected
5 Diastolic BP1 Mean Difference (IV, Random, 95% CI)Totals not selected
6 Peritonitis1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
7 Cough1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
8 Serum potassium1 Mean Difference (IV, Random, 95% CI)Totals not selected
9 Hyperkalaemia2144Risk Ratio (M-H, Random, 95% CI)1.2 [0.40, 3.63]
Analysis 3.1.

Comparison 3 ARBs versus ACEis, Outcome 1 Residual kidney function [mL/min/1.73 m²].

Analysis 3.2.

Comparison 3 ARBs versus ACEis, Outcome 2 Cardiovascular events (nonfatal).

Analysis 3.3.

Comparison 3 ARBs versus ACEis, Outcome 3 Anuria.

Analysis 3.4.

Comparison 3 ARBs versus ACEis, Outcome 4 Systolic BP.

Analysis 3.5.

Comparison 3 ARBs versus ACEis, Outcome 5 Diastolic BP.

Analysis 3.6.

Comparison 3 ARBs versus ACEis, Outcome 6 Peritonitis.

Analysis 3.7.

Comparison 3 ARBs versus ACEis, Outcome 7 Cough.

Analysis 3.8.

Comparison 3 ARBs versus ACEis, Outcome 8 Serum potassium.

Analysis 3.9.

Comparison 3 ARBs versus ACEis, Outcome 9 Hyperkalaemia.

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. (ace near/2 inhibitor*):ti,ab,kw

  2. (angiotensin next converting next enzyme next inhibitor*):ti,ab,kw

  3. ("ACE" or "ACE1" or "ACEI" or "ACEs"):ti,ab

  4. (angiotensin near/3 receptor next block*):ti,ab,kw

  5. (angiotensin near/3 receptor next antagonist*):ti,ab,kw

  6. (AT next 2 next receptor next block*):ti,ab,kw

  7. (AT next 2 next receptor next antagon*):ti,ab,kw

  8. ("ARB" or "ARBs"):ti,ab

  9. captopril:ti,ab,kw

  10. enalapril:ti,ab,kw

  11. fosinopril:ti,ab,kw

  12. lisinopril:ti,ab,kw

  13. perindopril:ti,ab,kw

  14. ramipril:ti,ab,kw

  15. quinapril:ti,ab,kw

  16. benazepril:ti,ab,kw

  17. cilazapril:ti,ab,kw

  18. trandolapril:ti,ab,kw

  19. spirapril:ti,ab,kw

  20. delapril:ti,ab,kw

  21. moexipril:ti,ab,kw

  22. zofenopril:ti,ab,kw

  23. candesartan:ti,ab,kw

  24. eprosartan:ti,ab,kw

  25. irbesartan:ti,ab,kw

  26. losartan:ti,ab,kw

  27. olmesartan:ti,ab,kw

  28. telmisartan:ti,ab,kw

  29. valsartan:ti,ab,kw

  30. (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29)

  31. (peritoneal next dialysis):ti,ab,kw

  32. ("PD" or "CAPD" or "CCPD" or "APD"):ti,ab,kw

  33. (#31 OR #32)

  34. (#30 AND #33)

MEDLINE
  1. exp Peritoneal Dialysis/

  2. peritoneal dialysis.tw.

  3. (CAPD or CCPD or APD or TPD or PD).tw.

  4. or/1-3

  5. exp Angiotensin-Converting Enzyme Inhibitors/

  6. angiotensin converting enzyme inhibitor$.tw.

  7. (ace adj2 inhibitor$).tw.

  8. ("ACE" or "ACE1" or "ACEI" or "ACE-I" or "ACEs").tw.

  9. captopril.tw.

  10. enalapril.tw.

  11. fosinopril.tw.

  12. lisinopril.tw.

  13. perindopril.tw.

  14. ramipril.tw.

  15. quinapril.tw.

  16. benazepril.tw.

  17. cilazapril.tw.

  18. trandolapril.tw.

  19. spirapril.tw.

  20. delapril.tw.

  21. moexipril.tw.

  22. zofenopril.tw.

  23. or/5-22

  24. exp Angiotensin II Type 1 Receptor Blockers/

  25. Receptors, Angiotensin/ai [Antagonists & Inhibitors]

  26. angiotensin II receptor blocker$.tw.

  27. angiotensin 2 receptor blocker$.tw.

  28. angiotensin II receptor antagonist$.tw.

  29. angiotensin 2 receptor antagonists$.tw.

  30. AT 2 receptor block$.tw.

  31. AT 2 receptor antagon$.tw.

  32. angiotensin receptor antagonist$.tw.

  33. ("ARB" or "ARBs").tw.

  34. candesartan.tw.

  35. eprosartan.tw.

  36. irbesartan.tw.

  37. losartan.tw.

  38. olmesartan.tw.

  39. telmisartan.tw.

  40. valsartan.tw.

  41. or/24-40

  42. 23 or 41

  43. 4 and 42

EMBASE
  1. Peritoneal Dialysis/

  2. Continuous Ambulatory Peritoneal Dialysis/

  3. peritoneal dialysis.tw.

  4. (CAPD or CCPD or APD or PD).tw.

  5. or/1-4

  6. exp Dipeptidyl Carboxypeptidase Inhibitor/

  7. angiotensin converting enzyme inhibit$.tw.

  8. (ace adj2 inhibit$).tw.

  9. (ACE or ACE1 or ACEI or ACE-I or ACEs).tw.

  10. captopril.tw.

  11. enalapril.tw.

  12. fosinopril.tw.

  13. lisinopril.tw.

  14. perindopril.tw.

  15. ramipril.tw.

  16. quinapril.tw.

  17. benazepril.tw.

  18. cilazapril.tw.

  19. trandolapril.tw.

  20. spirapril.tw.

  21. delapril.tw.

  22. moexipril.tw.

  23. zofenopril.tw.

  24. or/6-23

  25. exp Angiotensin Receptor Antagonist/

  26. (angiotensin adj3 receptor blocker$).tw.

  27. (angiotensin adj3 receptor antagonist$).tw.

  28. AT 2 receptor block$.tw.

  29. AT 2 receptor antagon$.tw.

  30. (ARB or ARBs).tw.

  31. candesartan.tw.

  32. eprosartan.tw.

  33. irbesartan.tw.

  34. losartan.tw.

  35. olmesartan.tw.

  36. telmisartan.tw.

  37. valsartan.tw.

  38. or/25-37

  39. 24 or 38

  40. 5 and 39

Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence

Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
Unclear: Insufficient information about the sequence generation process to permit judgement.

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
Unclear: Randomisation stated but no information on method used is available.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.

Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.

Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting

Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).
High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table

Low risk of bias: The study appears to be free of other sources of bias.
High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Feedback

Comment: D Daley, S Hsieh, A Tejani, 9 October 2014

Summary

Comment: While there is emerging evidence that residual renal function (RRF) may be correlated with better survival outcomes in the peritoneal dialysis (PD) population, we question the clinical utility of measuring RRF as the primary outcome of this review. We acknowledge the reviewers attempts to elucidate the appropriateness of RRF as a surrogate marker, by citing a previous systematic review as well as studies by Szeto and Maiorca. However, closer inspection of the literature reveal that evidence supporting an association between RRF and mortality is primarily derived from observational studies with a specific purpose not necessarily related to preserving RRF with drugs and the impact on mortality. For example, both articles that were cited as the source for the following statement, “each 1 mL/min of residual GFR is associated with a nearly 50% reduction in mortality rate”, were prospective observational studies assessing the relationship between dialysis adequacy on mortality, rather than directly assessing the effects of RRF on mortality (1, 2) . Maiorca et al. provided no effect estimate on mortality with RRF and simply states that “mean residual renal function significantly improved survival” (2). Whereas, Szeto et al. reported only a relative mortality risk of 0.65 (95% CI: 0.45-0.94) with a GFR preservation of 1 mL/min when assessed independently from dialysis adequacy, which is a relative mortality risk that is significantly less than what the review authors have stated (1). Both the aforementioned studies assess the risk of mortality with RRF. In other words, these papers have assessed whether mortality increases with worsening RRF. They have not assessed whether improving RRF with a therapy or intervention is predictably correlated with an reduction in mortality. Therefore, RRF remains an unproven surrogate marker for mortality and it is not clear that improvements in RRF lead to a lower risk of mortality. Given the weak association between RRF and mortality from these two studies, and the issues surrounding the utility of RRF as a surrogate, this Cochrane Review may have overemphasized the clinical utility of measuring RRF as their primary outcome, in its attempt to remedy the paucity of clinical guidance on the maintenance of RRF in PD. Additionally, RRF may also be affected by various patient specific factors such as co-morbidites (e.g. diabetes mellitus) and frequency of use of aminoglycosides (3). The inclusion of studies that do not control for these variables within a review will undoubtedly impact the utility of the findings. Consequently, we believe that applying RRF as a surrogate marker, given its margin of error and questionable clinical utility, may be unwise, and may not merit a comprehensive review. This is further supported by the Cochrane Handbook, which advises against the use of surrogate markers (4). It states that surrogate markers may not accurately predict clinically important outcomes and may potentially mislead readers. Given that one of the primary goals of therapy for dialysis patients with end-stage renal disease is to prolong survival, we suggest redirecting the approach of this review to address the impact of ACEi and ARB on these more clinically relevant outcomes.

The authors’ conclusion states that “[c]ompared with other antihypertensive drugs, long-term use (>= 12 months) of ACEi or ARBs showed additional benefits of preserving residual kidney function in CAPD patients”. At best, we believe that the types of interventions included in this review only allow for the comparison of ACEi/ARB to “routine treatment” (i.e. PD and supportive treatment), as other antihypertensive drugs were not included for comparison. Furthermore, in order for the claim that ACEi or ARB are superior to other antihypertensive drugs in preserving RRF to be meaningful, the benefits of ACEi/ARB and other antihypertensive agents over placebo on RRF must first be established. In order to address this concern, we propose the following hierarchical approach to address the revised review objective:

ACEi + placebo + routine treatment vs placebo + routine treatment ARB + placebo + routine treatment vs placebo + routine treatment Other antihypertensive medication + placebo + routine treatment vs placebo + routine treatment

Only when the above effects have been established, will it be appropriate to compare ACEi/ARB (and routine treatment) with other interventions or with each other. The use of this approach in assessing the literature will prevent misleading the reader and/or prevent authors from falsely implying that the treatment effect is clinically relevant before its effect compared to placebo and routine treatment has been established.

In addition to adopting a more hierarchical approach to the assessment of literature, we also noted a deviation from the review authors’ protocol that was not acknowledged in their final review. These include the addition of the comparison between “ACEi + routine treatment versus ARB + routine treatment”. The Cochrane Handbook acknowledges that “changes in a review protocol are sometimes necessary” under unforeseen circumstances, and states that “[c]hanges in the protocol should be documented and reported in the ‘Difference between protocol and review’ section of the completed review, and sensitivity analyses … exploring the impact of deviations from the protocol should be undertaken when possible” (4).

The review authors’ expressed that the objective was to evaluate the benefits and harms of ACEis and ARBs for preserving RRF in PD patients. We feel that the review authors can be more comprehensive in the assessment of potential harms of these medications observed in the included studies and present this data in a more organized manner. A closer look at the 6 included trials, revealed that the proportion of subjects experiencing cough in Phakdeekitcharoen 2004 was not mentioned in the review. Although the 7 out of 21 subjects who developed mild cough in this study did not discontinue treatment, we feel that this observation was still important to include within the review to better enable the reader to properly weigh the risks of treatment, especially given that the benefit of preserving RRF is still relatively unclear (5). Another observation of cough and dizziness associated with the use of ramipril in Li et al’s study was noted by the review authors in the “Incomplete outcome data” section but not in the “Cough” section of the review. This could easily be missed by readers who scan relevant sections of the article to read. Cough is a well-known and frequent adverse effect of ACEis. A meta-analysis of the pooled incidences of ACEi-induced cough and its associated withdrawal rates revealed rates of 10.60% and 2.54%, respectively (6). Therefore, exclusion of observations from this section of the review article may cause readers to generate a misleading assessment of the actual incidences of cough induced by ACEi and its associated withdrawal rates.

As illustrated above, we question the clinical significance of using RRF to assess the benefits of ACEi or ARB in PD patients. To ensure clinical utility of the review data, we propose revising the objective to assess the benefits and harms of using ACEis and ARBs for reducing mortality in PD patients, and to assess the relevant literature via a hierarchical approach as we described above. In addition, we strongly suggest that a more comprehensive report on cough associated with the use of ACEi/ ARB be included in the review and that these observations be summarized under the “Cough” section, such that it is easier for readers to refer to. We hope that our suggestions will improve the clinical utility of this review in an area where there is little data and allow clinicians to more appropriately assess the risks and benefits of using ACEi/ ARB in PD patients.

References
1. Szeto, C C, Wong, T Y, Leung, C B, et al. (2000). Importance of dialysis adequacy in mortality and morbidity of chinese capd patients. Kidney international, 58(1), 400-407

2. Maiorca, R, Brunori, G, Zubani, R, et al. (1995). Predictive value of dialysis adequacy and nutritional indices for mortality and morbidity in capd and hd patients. a longitudinal study. Nephrology, Dialysis, Transplantation, 10(12), 2295-2305.chinese capd patients. Kidney international, 58(1), 400-407.2.

3. Singhal MK, Bhaskaran S, Vidgen E, Bargman JM, Vas SI, Oreopoulos DG. Rate of decline of residual renal function in patients on continuous peritoneal dialysis and factors affecting it. Perit Dial Int. 2000 Jul-Aug;20(4):429-38.

4. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
5. Phakdeekitcharoen B, Leelasa-nguan P. Effects of an ACE inhibitor or angiotensin receptor blocker on potassium in CAPD patients. Am J Kidney Dis. 2004 Oct;44(4):738-46.

6. Bangalore S1, Kumar S, Messerli FH. Angiotensin-converting enzyme inhibitor associated cough: deceptive information from the Physicians' Desk Reference. Am J Med. 2010 Nov;123(11):1016-30.

We certify that we have no affiliations with or involvement in any organisation or entity with a financial interest in the subject matter of our feedback.

Danika Daley, Stephanie Hsieh, Dr Aaron M Tejani

Reply

We would like to thank Danika and her co-authors for their interest in our review.

We agree that our review had limitations. We found only six small RCTs (all with fewer than 70 subjects) that were eligible for inclusion. Overall, study quality was modest. Although we found some evidence indicating a benefit in residual kidney function resulting associated with long-term use of ACEi or ARB, we do not believe that these results constitute a reason to change clinical practice, but rather support the need for further research.

We agree that mortality is a more powerful outcome than residual kidney function to evaluate ACEi or ARB efficacy for people receiving peritoneal dialysis. However, we found only one small RCT that reported mortality with only one year follow-up between ACEi and control group. Therefore, in the absence of robust data, it was not meaningful to evaluate survival benefits of ACEi or ARB for people undergoing peritoneal dialysis.

Preserving residual kidney function is the primary clinical goal for nephrologists who care for people with chronic kidney disease and dialysis patients. Better residual kidney function is associated with enhanced volume balance, phosphorus control and removal of middle molecular uraemic toxins among people on dialysis. There is no doubt that loss of residual kidney function is an independent mortality risk factor among both peritoneal dialysis and haemodialysis patients (Bargman 2001; Shafi 2010). Residual kidney function is a very valuable asset for people on dialysis, and more attention should be focused on how this can be preserved.

Whether residual kidney function is protective or merely a marker for better health remains uncertain. The mechanisms affecting decline of residual kidney function are poorly understood and few studies have examined its preservation using with medical therapy. The best documented factors that play a role in preserving residual kidney function are related to the RAAS (renin-angiotensin-aldosterone system) blockade (Patel 2014). Our review showed that ACEi or ARB is associated with better residual kidney function protection than control. Among the studies included in our review all control group participants received antihypertensive drugs other than ACEi or ARB for blood pressure control. Because of widespread need for antihypertensive drugs among people on peritoneal dialysis, it is difficult to observe effects of ACEi or ARB on residual kidney function using a placebo-control design.

We also agree that residual kidney function could be affected by patient-specific factors, making it difficult to balance the baseline between ACEi/ARB and control groups in such small sample-size RCTs, and pointing to the desirability for large sample-size RCTs. Although an observational cohort study showed survival benefit of ACEi or ARB for people on peritoneal dialysis (Fang 2008), we found insufficient evidence to enable definitive conclusions about benefits.

We excluded Phakdeekitcharoen 2004 from our analysis of cough as an adverse event because no data were reported for the study's ARB group. However, we agree that cough is a significant problem for people receiving ACEi or ARB therapy.

We believe that further large scale, high-quality RCTs focusing on residual kidney function and mortality relating to long-term ACEi or ARB therapy are necessary to fully understand their effects on people undergoing peritoneal dialysis.

Contributors

Comments: Danika Daley, Stephanie Hsieh, Dr Aaron M Tejani

Authors: Ling Zhang, Xiaoxi Zeng, Ping Fu

What's new

DateEventDescription
1 November 2014Feedback has been incorporatedResponse

Contributions of authors

  • Draft the protocol: Ling Zhang, Xiaoxi Zeng, Ping Fu, Hong Mei Wu

  • Study selection: Xiaoxi Zeng, Ling Zhang

  • Extract data from studies: Xiaoxi Zeng, Ling Zhang

  • Enter data into RevMan: Xiaoxi Zeng, Ling Zhang

  • Carry out the analysis: Xiaoxi Zeng, Ling Zhang, Ping Fu

  • Interpret the analysis: Xiaoxi Zeng, Ling Zhang, Hong Mei Wu

  • Draft the final review: Xiaoxi Zeng, Ling Zhang, Ping Fu

  • Disagreement resolution: Ping Fu, Hong Mei Wu

  • Update the review: Xiaoxi Zeng, Ling Zhang

Declarations of interest

  • Ling Zhang: none known

  • Xiaoxi Zeng: none known

  • Ping Fu: none known

  • Hong Mei Wu: none known

Differences between protocol and review

The following outcomes have been added to the review: anuria, potassium levels; peritonitis

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Li 2003

Methods
  • Study design: open-label RCT

  • Total study duration: NS

  • Duration of follow-up: 12 months

Participants
  • Country: China

  • Setting: single medical centre

  • Patients received CAPD for at least 3 months; residual GFR ≥ 2 mL/min/1.73 m²; BP at least 120/70 mm Hg; no history of taking an ACEi or ARB for at least 6 months

  • Number: treatment group (30); control group (30)

  • Mean age ± SD (years): treatment group (58.0 ± 14.0); control group (59.1 ± 9.8)

  • Sex (M/F): 38/22

  • Exclusion criteria: treatment history of ACEi or ARB; myocardial infarction; valvular disease; malignant hypertension or Keith-Wagener grade III or IV hypertensive retinopathy; hypertensive encephalopathy or cerebrovascular accident; alcohol or drug abuse; chronic liver disease; malignant disease; psychiatric disorder; bilateral renal artery stenosis; allergy or intolerance to an ACEi

Interventions

Treatment group

  • ACEi: ramipril 5 mg/d

  • Antihypertensive drugs other than ACEi were allowed

Control group

  • Clinical management except that ramipril was not prescribed

Outcomes
  • Residual kidney function

  • Anuria rate

  • Mortality

  • Cardiovascular events

  • Proteinuria

  • Duration of hospitalisation

  • Time points for follow-up: 12 months

Notes
  • Target blood pressure was 135/85 mm Hg

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "A computer-generated list that was maintained by a third party not involved in the conduct of the study was used for randomization"
Allocation concealment (selection bias)Low riskQuote: "Investigators were unaware of the randomization schedule when recruiting patients, and both investigators and patients were not blinded during the follow-up period"
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "open-label" but the primary outcome (residual kidney function) was not likely to be influenced by the status of blinding
Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "Analyses were done on an intention-to-treat basis". In study group and control group, 4 (death: 3, kidney transplantation: 1) and 3 patients (death: 2, kidney transplantation: 1) withdrew from study respectively. But 5 patients in the ramipril group discontinued drugs due to persistent dizziness or cough
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement
Other biasUnclear riskCAPD schedules were not provided

Phakdeekitcharoen 2004

Methods
  • Study design: open-label cross-over RCT

  • Total study duration: NS

  • Duration of follow-up: 4 weeks

Participants
  • Country: Thailand

  • Setting: single medical centre

  • Patients received CAPD for at least 3 months; age between 15 and 65 years; normokalaemia; a history of hypertension; residual kidney function < 10 mL/min

  • Number: 21

  • Mean age ± SD: 44.8 ± 10.1 years

  • Sex (M/F): 14/7

  • Exclusion criteria: patients unwilling to participate; severe comorbid conditions such as symptomatic ischaemic heart disease, recent stroke, or decompensated cirrhosis; known allergy or intolerable adverse reactions to ACEi or ARB; recent peritonitis within 1 month; unable to stop drugs that might interfere with serum potassium level such as-blocking agent, diuretic, insulin, cyclosporine, and nonsteroidal anti-inflammatory drugs except low-dose aspirin; alcoholism; severe anorexia; severe medical or surgical disease within 1 month

Interventions

Treatment group 1

  • ACEi: enalapril 10 mg/d

Treatment group 2

  • ARB: candesartan 8 mg/d

Outcomes
  • Residual kidney function

  • Serum electrolyte

  • BP

  • Adverse reactions

  • Adequacy of CAPD

  • Hyperkalaemia

  • Time points for follow-up: 4 weeks

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information about details of randomisation
Allocation concealment (selection bias)Low riskCross-over study with a 2-week washout period
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "open-label" but the primary outcome (residual kidney function) was not likely to be influenced by the status of blinding
Incomplete outcome data (attrition bias)
All outcomes
High risk8 patients (27.6%) withdrew: unwilling to continue the study (2); symptomatic ischaemic heart disease (2); anorexic (2); severe peptic ulcer and sepsis (2)
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement
Other biasUnclear riskInsufficient information to permit judgement

Reyes-Marin 2012

Methods
  • Study design: parallel RCT

  • Total study duration: NS

  • Duration of follow-up: 12 months

Participants
  • Country: Mexico

  • Setting: single medical centre

  • Patients received APD as the initial RRT for at least 1 year; residual GFR ≥ 2 mL/min/1.73 m²

  • Number: treatment group 1 (30); treatment group 2 (30)

  • Mean ± SD (years): treatment group 1 (42.5 ± 18.5); treatment group 2 (49.2 ± 19.6)

  • Sex (M/F): 36/24

  • Exclusion criteria: infectious systemic disease; recurrent peritonitis; severe malnutrition; intolerance to ACEi or ARB; underlying medical conditions such as congestive heart failure, myocardial infarction, malignant hypertension and stroke within the preceding 6 months

Interventions

Treatment group 1

  • ACEi: enalapril 10 mg/

Treatment group 2

  • ARB: losartan 50 mg/d

Outcomes
  • Residual kidney function

  • Episodes of peritonitis

  • Cardiovascular events

  • Adverse events

  • Time points for follow-up: 12 months

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information about details of randomisation
Allocation concealment (selection bias)Low riskQuote: "The participating patients were recruited from the Hospital General ISSEMYM"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information about blinding
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information about incomplete outcome data
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement
Other biasUnclear riskAPD schedules were not provided

Suzuki 2004

Methods
  • Study design: open-label RCT

  • Total study duration: NS

  • Duration of follow-up" 24 months

Participants
  • Country: Japan

  • Setting: single medical centre

  • Patients received CAPD for at least 3 months

  • Number: treatment group (18); control group (16)

  • Mean age ± SD (years): treatment group (63.5 ± 3.7); control group (63.5 ± 3.3)

  • Sex (M/F): treatment group (11/9); control group (11/7)

  • Exclusion criteria: congestive heart failure or therapy with an ACEi or ARB; myocardial infarction; valvular disease; malignant hypertension; hypertensive encephalopathy or cerebrovascular accident; alcohol or drug abuse, chronic liver disease, malignant disease, or psychiatric disorder; history of allergy or intolerance to an ARB

Interventions

Treatment group

  • ARB: valsartan 40 to 80 mg/d

Control group

  • Antihypertensive drugs except ACEi or ARB or both

Outcomes
  • Residual kidney function

  • BP

  • Kt/V

  • Weekly CrCl

  • Cardiovascular events

  • Proteinuria

  • Time points for follow-up: 24 months

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Randomization was performed by using a computer-generated list maintained by a third party not involved in the conduct of the study"
Allocation concealment (selection bias)Low riskQuote: "Randomization was performed by using a computer-generated list maintained by a third party not involved in the conduct of the study"
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "open-label" but the primary outcome (residual kidney function) was not likely to be influenced by the status of blinding
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe number of patients for analysis was equal to that of participants being allocated. However, no information on patients that withdrew or were lost to follow-up was provided
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement
Other biasLow riskFree of other bias

Wang 2005d

Methods
  • Study design: open-label RCT

  • Total study duration: 2004 to 2007

  • Duration of follow-up: 28 ± 13 months

Participants
  • Country: China

  • Setting: single medical centre

  • Patients received CAPD within 3 months; residual GFR ≥ 2 mL/min/1.73 m²

  • Number: treatment group (19); control group (13)

  • Mean age, range: 42 (17-65) years

  • Sex (M/F): 22/12

  • Exclusion criteria: bilateral renal artery stenosis or unitesticle with renal artery stenosis; malignant hypertension, history of hypertensive encephalopathy or cerebrovascular accident; severe congestive heart failure; peritonitis; chronic liver disease; malignant disease; history of allergy or intolerance to an ARB

Interventions

Treatment group

  • ARB: valsartan 300 mg/d

Control group

  • Antihypertensive drugs except ACEi or ARB or both

Outcomes
  • Residual kidney function

  • Urine volume

  • BP

  • Kt/V

  • Weekly CrCl

  • Electrolytes

  • Time points for follow-up: 28 ± 13 months

Notes
  • Target blood pressure was 135/85 mm Hg

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe method for random sequence generation was not reported in the study; but after contacting the original author, we learnt that the random sequence was generated through computer software
Allocation concealment (selection bias)Unclear riskNS
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "open-label" but the primary outcome (residual kidney function) was not likely to be influenced by the status of blinding
Incomplete outcome data (attrition bias)
All outcomes
High riskIn study group, 2 patients withdrew from study, but the reasons for lost-to-follow-up were not known
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement
Other biasUnclear riskThe detailed antihypertensive protocols (other than ACEi and ARB) and CAPD schedules were not provided

Zhong 2007a

  1. a

    ACEi - angiotensin-converting enzyme inhibitors; ARB - angiotensin receptor blockers; APD - automated peritoneal dialysis; BP - blood pressure; CAPD - continuous ambulatory peritoneal dialysis; GFR - glomerular filtration rate; NS - not stated; RCT - randomised controlled trial; RRT - renal replacement therapy

Methods
  • Study design: open-label RCT

  • Total study duration: 2004 to 2007

  • Duration of follow-up: 12 months

Participants
  • Country: China

  • Setting: single medical centre

  • Patients received CAPD for at least 1 months

  • Number: treatment group (24); control group (20)

  • Mean age ± SD: 44.0 ± 14.6 years

  • Sex (M/F): 31/17

  • Exclusion criteria: renal artery stenosis; unitesticle; malignant hypertension, history of hypertensive encephalopathy or cerebrovascular accident; severe congestive heart failure; peritonitis; chronic liver disease; malignant disease; history of allergy or intolerance to an ARB

Interventions

Treatment group

  • ARB: irbesartan 300 mg/d

Control group

  • Antihypertensive drugs except ACEi or ARB or both

Outcomes
  • Residual kidney function

  • Mortality

  • Urine volume

  • BP

  • Kt/V

  • Weekly CrCl

  • Electrolytes

  • Time points for follow-up: 12 months

Notes
  • Target blood pressure was 135/85 mm Hg

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe method for random sequence generation was not reported in the study; but after contacting the original author, we learnt that the random sequence was generated through computer software
Allocation concealment (selection bias)High riskAllocation concealment was not applied
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "open-label" but the primary outcome (residual kidney function) was not likely to be influenced by the status of blinding
Incomplete outcome data (attrition bias)
All outcomes
High riskIn study group and control group, 2 (lost to follow-up: 1, kidney transplantation: 1) and 2 patients (lost to follow-up: 1, changing to HD due to ultrafiltration failure: 1) withdrew from study respectively. But the reasons for lost-to-follow-up were not known
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement
Other biasUnclear riskThe detailed antihypertensive protocols (other than ACEi and ARBs) and CAPD schedules were not provided

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    RCT - randomised controlled trial

Cioni 2010No information about residual kidney function
Favazza 1992No information about residual kidney function
Huang 2002No information about residual kidney function
Kolesnyk 2011Not RCT
Nakamoto 2004No information about residual kidney function
PERFECT Study 1997Includes haemodialysis patients
Rojas-Campos 2005No information about residual kidney function
Shigenaga 2009No information about residual kidney function
Suzuki 2003No information about residual kidney function

Characteristics of studies awaiting assessment [ordered by study ID]

Medcalf 2000

MethodsNot known
ParticipantsNot known
InterventionsNot known
OutcomesNot known
NotesOnly abstract published in congress

Characteristics of ongoing studies [ordered by study ID]

NCT00721773

Trial name or titleEffects of benazepril, valsartan or combination of both on residual renal function in peritoneal dialysis patients
MethodsOpen-label RCT
Participants
  1. CAPD more than 1 month

  2. 20 to 75 years old

  3. Residual kidney function of 3 mL/min or more

  4. hypertension

  5. No history of taking an ACEi or ARB for at least 1 month

Interventions

Benazepril group:10 to 20 mg daily

Valsartan group:80 to 160 mg daily

Benazepril plus valsartan group:10-20 mg benazepril plus 80 to 60 mg valsartan daily

Control group: antihypertensive drugs except ACEi and ARB

Outcomes

Primary outcome: residual kidney function

Secondary outcomes: Kt/V; weekly creatinine clearance; peritoneal membrane function; blood pressure; time to anuria; death

Starting dateSeptember 2008
Contact information

Xueqing Yu, M.D.& Ph.D. Phone:8620-87766335 Email: yuxq@mail.sysu.edu.cn

Haiping Mao, M.D.& Ph.D. Phone:8620-87755766 ext 8143 Email: haipingmao@126.com

NotesTarget blood pressure: 120-140/70-90 mm Hg

NCT01041963

  1. a

    ACEi - angiotensin-converting enzyme; ARB - angiotensin receptor blocker; CAPD - continuous ambulatory peritoneal dialysis

Trial name or titleThe effect of enalapril and losartan on peritoneal membrane in continuous ambulatory peritoneal dialysis patients
MethodsOpen-label RCT
Participants
  1. All patients received CAPD more than 1 months but less than 1 year

  2. Subjects of either sex, more than 20 years old

  3. Hypertension

  4. Provision of written informed consent by subject or guardian

Interventions

Enalapril group: 20 to 40 mg daily

Enalapril plus losartan group: enalapril 20 to 40 mg plus losartan 25 to 50 mg daily

Control group: antihypertensive drugs except ACEi, ARB or spironolactone

Outcomes

Primary outcomes: change in dialysate CA-125; modified peritoneal equilibrium test

Secondary outcomes: dialysis adequacy; residual kidney function; hospitalisation; peritonitis episodes; any adverse drug effects; death from any cause

Starting dateJune 2009
Contact informationTalerngsak Kanjanabuch
NotesTarget blood pressure: 130/80 mm Hg

Ancillary