Aldosterone antagonists for preventing the progression of chronic kidney disease

  • Conclusions changed
  • Review
  • Intervention

Authors

  • Davide Bolignano,

    1. CNR - Italian National Council of Research, Institute of Clinical Physiology, Reggio Calabria, Italy
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  • Suetonia C Palmer,

    1. University of Otago Christchurch, Department of Medicine, Christchurch, New Zealand
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  • Sankar D Navaneethan,

    1. Glickman Urological and Kidney Institute, Cleveland Clinic, Department of Nephrology and Hypertension, Cleveland, OH, USA
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  • Giovanni FM Strippoli

    Corresponding author
    1. The Children's Hospital at Westmead, Cochrane Renal Group, Centre for Kidney Research, Westmead, NSW, Australia
    2. University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy
    3. Mario Negri Sud Consortium, Department of Clinical Pharmacology and Epidemiology, Santa Maria Imbaro, Italy
    4. The University of Sydney, Sydney School of Public Health, Sydney, Australia
    5. Diaverum, Medical-Scientific Office, Lund, Sweden
    6. Amedeo Avogadro University of Eastern Piedmont, Division of Nephrology and Transplantation, Department of Translational Medicine, Novara, Italy
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Abstract

Background

Treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is increasingly used to reduce proteinuria and retard the progression of chronic kidney disease (CKD). However, resolution of proteinuria may be incomplete with these therapies and the addition of an aldosterone antagonist may be added to further prevent progression of CKD. This is an update of a review first published in 2009.

Objectives

To evaluate the effect of aldosterone antagonists (both selective (eplerenone) and non-selective (spironolactone)) alone or in combination with ACEi or ARB in adults who have CKD with proteinuria (nephrotic and non-nephrotic range) on: patient-centred endpoints including major cardiovascular events, hospitalisation and all-cause mortality; kidney function (proteinuria, glomerular filtration rate (GFR), serum creatinine, and need for renal replacement therapy; and adverse events (including gynaecomastia and hyperkalaemia).

Search methods

For this update, we searched the Cochrane Renal Group's Specialised Register to 30 January 2013 using search terms relevant to this review.

Selection criteria

We included randomised controlled trials (RCTs) and quasi-RCTs that compared aldosterone antagonists alone or in combination with ACEi or ARB (or both) with other anti-hypertensive strategies or placebo.

Data collection and analysis

Two authors independently assessed study quality and extracted data. Data were summarised using random effects meta-analysis. We tested for heterogeneity in estimated treatment effects using the Cochran Q test and I² statistic. We expressed summary treatment estimates as a risk ratio (RR) for dichotomous outcomes together with their 95% confidence intervals (CI) and mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) when different scales were used.

Main results

We identified 27 studies (1549 participants) that were eligible for inclusion. These studies provided no data relating to aldosterone antagonists in addition to ACEi or ARB (or both) on patient-level outcomes including major cardiovascular events and mortality and progression to end-stage kidney disease (ESKD) requiring dialysis or transplantation.

Compared with ACEi or ARB (or both), non-selective aldosterone antagonists (spironolactone) combined with ACEi or ARB (or both) significantly reduced 24-hour protein excretion (11 studies, 596 participants): SMD -0.61, 95% CI -1.08 to -0.13). There was a significant reduction in both systolic and diastolic blood pressure (BP) at the end of treatment with additional non-selective aldosterone antagonist therapy (systolic BP (10 studies, 556 participants): MD -3.44 mm Hg, 95% CI -5.05 to -1.83) (diastolic BP (9 studies, 520 participants): MD -1.73 mm Hg, 95% CI -2.83 to -0.62).

However, we found that aldosterone antagonist treatment had imprecise effects at the end of treatment on GFR (9 studies, 528 participants; MD -2.55 mL/min/1.73 m², 95% CI -5.67 to 0.51), doubled the risk of hyperkalaemia (11 studies, 632 patients): RR 2.00, 95% CI 1.25 to 3.20; number needed to treat for an additional harmful outcome (NNTH): 7.2, 95% CI 3.4 to ∞) and increased the risk of gynaecomastia compared to ACEi or ARB (or both) (4 studies, 281 patients): RR 5.14, 95% CI 1.14 to 23.23; NNTH: 14.1, 95% CI 8.7 to 37.3).

Most studies enrolled few patients (range 12 to 268) and were powered to observe differences in surrogate end points rather than patient-focused outcomes. Nine studies had a cross-over design and the majority of studies did not adequately report study methods to assess methods and study quality.

Authors' conclusions

Aldosterone antagonists reduced proteinuria and blood pressure in adults who had mild to moderate CKD and were treated with ACEi or ARB (or both), but increase hyperkalaemia and gynaecomastia. Whether adding aldosterone antagonists to ACEi or ARB (or both) reduced the risk of major cardiovascular events or ESKD in this population is unknown.

Résumé scientifique

Antagonistes de l'aldostérone pour prévenir l'évolution de la maladie rénale chronique

Contexte

Le traitement par les inhibiteurs de l'enzyme de conversion de l'angiotensine (IECA) et les antagonistes des récepteurs de l'angiotensine (ARA) est de plus en plus utilisé pour réduire la protéinurie et retarder la progression de la maladie rénale chronique (MRC). Cependant, la résolution de la protéinurie peut être incomplète avec ces traitements et un antagoniste de l'aldostérone peut être ajouté pour mieux prévenir la progression de la MRC. Ceci est une mise à jour d'une revue publiée pour la première fois en 2009.

Objectifs

Évaluer l'effet des antagonistes de l'aldostérone (sélectifs (éplérénone) et non sélectifs (spironolactone)), seuls ou en association avec des IECA ou des ARA chez les adultes souffrant de MRC avec protéinurie (éventail néphrotique et non néphrotique) sur : les critères de jugement centrés sur le patient, y compris les événements cardio-vasculaires majeurs, l'hospitalisation et la mortalité toutes causes confondues ; la fonction rénale (protéinurie, taux de filtration glomérulaire (TFG), la créatinine sérique et la nécessité d'une thérapie de remplacement rénal ; et les événements indésirables (y compris la gynécomastie et l'hyperkaliémie).

Stratégie de recherche documentaire

Pour cette mise à jour, nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur le rein jusqu'au 30 janvier 2013 en utilisant des termes de recherche pertinents pour cette revue.

Critères de sélection

Nous avons inclus les essais contrôlés randomisés (ECR) et quasi-ECR qui comparaient les antagonistes de l'aldostérone seuls ou en association avec des IECA ou des ARA (ou les deux) avec d'autres stratégies antihypertenseurs ou un placebo.

Recueil et analyse des données

Deux auteurs ont évalué indépendamment la qualité des études et extrait les données. Les données ont été résumées à l'aide d'une méta-analyse à effets aléatoires. Nous avons testé l'hétérogénéité des effets thérapeutiques estimés à l'aide du test Q de Cochran et de la statistique I². Nous avons exprimé les estimations résumées des traitements sous forme de risques relatifs (RR) pour les résultats dichotomiques avec des intervalles de confiance (IC) à 95 % et de différences moyennes (DM) pour les résultats continus, ou de différences moyennes standardisées (DMS) lorsque différentes échelles étaient utilisées.

Résultats principaux

Nous avons identifié 27 études (1 549 participants) qui étaient éligibles pour l'inclusion. Ces études ne fournissaient pas de données concernant les antagonistes de l'aldostérone en plus des IECA ou des ARA (ou les deux) sur les résultats au niveau du patient, y compris les événements cardio-vasculaires majeurs, la mortalité et la progression jusqu'à la maladie rénale terminale (MRT) requérant la dialyse ou une greffe.

Par rapport aux IECA ou aux ARA (ou les deux), les antagonistes de l'aldostérone non sélectifs (la spironolactone) associés à des IECA ou des ARA (ou les deux) entraînaient une réduction significative de l'excrétion de protéines dans les urines sur 24 heures (11 études, 596 participants) : DMS de -0,61, IC à 95 % de -1,08 à -0,13). Une réduction significative de la pression artérielle (PA) systolique et diastolique était constatée à la fin du traitement avec le traitement complémentaire par les agonistes de l'aldostérone non sélectifs (PA systolique (10 études, 556 participants) : DM de -3,44 mmHg, IC à 95 % de -5,05 à -1,83) (PA diastolique (9 études, 520 participants) : DM de -1,73 mmHg, IC à 95 % de -2,83 à -0,62).

Cependant, nous avons trouvé que le traitement par des antagonistes de l'aldostérone avait des effets imprécis à la fin du traitement sur le TFG (9 études, 528 participants ; DM de -2,55 mL/min/1,73 m², IC à 95 % de -5,67 à 0,51), avait doublé le risque d'hyperkaliémie (11 études, 632 patients) : RR 2,00, IC à 95 % de 1,25 à 3,20 ; nombre nécessaire pour nuire (NNN) : 7,2, IC à 95 % de 3,4 à ∞) et avait augmenté le risque de gynécomastie par rapport aux IECA ou aux ARA (ou les deux) (4 études, 281 patients) : RR 5,14, IC à 95 % de 1,14 à 23,23 ; NNN : 14,1, IC à 95 % de 8,7 à 37,3).

La plupart des études avaient recruté peu de patients (fourchette de 12 à 268) et étaient de puissance suffisante pour observer des différences au niveau des critères de jugement de substitution plutôt que des critères de jugement axés sur le patient. Neuf études avaient un plan d'étude croisé et la majorité des études n'avaient pas correctement rendu compte des méthodes d'étude pour pouvoir évaluer les méthodes et la qualité des études.

Conclusions des auteurs

Les antagonistes de l'aldostérone ont réduit la protéinurie et la pression artérielle chez les adultes atteints de MRC légère à modérée traités par des IECA ou des ARA (ou les deux), mais ont augmenté l'hyperkaliémie et la gynécomastie. Nous ne savons pas si l'ajout d'antagonistes de l'aldostérone aux IECA ou aux ARA (ou les deux) a réduit le risque d'événements cardio-vasculaires majeurs ou de MRT dans cette population.

Zusammenfassung

Aldosteron-Antagonisten zur Vorbeugung des Fortschreitens chronischer Nierenerkrankung

Hintergrund

Eine Behandlung mit Angiotensin-konvertierenden Enzymhemmern (ACE-Hemmern) und Angiotensin-Rezeptor Blockern (AT-1-Blocker) wird zunehmend zur Reduktion der Proteinurie und des Fortschreitens der chronischen Niereninsuffizienz (NI) eingesetzt. Allerdings kann die Eindämmung der Proteinurie mit diesen Therapien unvollständig und somit der Zusatz eines Aldosteron-Antagonisten sinnvoll sein. Dies ist eine Aktualisierung eines bereits 2009 erstmals veröffentlichen Reviews. Dies ist ein Update eines Reviews, welches erstmals im Jahr 2009 publiziert wurde.

Ziele

Ziel dieses Reviews ist die Beurteilung der Wirkung von Aldosteron-Antagonisten (beide selektiv (Eplerenon) wie nicht-selektiv (Spironolakton)) allein oder in Kombination mit ACE-Hemmern oder AT-1-Blockern bei Erwachsenen mit chronischer NI und Proteinurie (im nephrotischen und nicht nephrotischen Bereich). Folgende Endpunkte wurden untersucht: schwere kardiovaskuläre Ereignisse, Krankenhauseinweisung sowie Gesamtmortalität (alle Patienten-relevant); Nierenfunktion (Proteinurie, glomeruläre Filtrationsrate (GFR), Serum-Kreatinin und die Notwendigkeit einer Nierenersatztherapie) und unerwünschte Ereignisse (Gynäkomastie und Hyperkaliämie mit eingeschlossen).

Literatursuche

Für diese Aktualisierung wurde eine Suche im Cochrane Renal Group’s Specialised Register mit den für dieses Review relevanten Suchbegriffen zum 30. Januar 2013 durchgeführt.

Auswahlkriterien

Es wurden alle randomisierten und quasi-randomisierten, kontrollierten Studien eingeschlossen, welche eine Therapie mit Aldosteron-Antagonisten allein oder in Kombination mit ACE-Hemmern oder AT1-Blockern (oder beiden) mit anderen anti-hypertensiven Strategien oder Placebo vergleichen.

Datenerhebung und -analyse

Zwei Autoren bewerteten unabhängig voneinander die methodische Qualität der Studien und extrahierten Daten. Die Daten wurden mittels Random Effects Model in einer Meta-Analyse zusammengefasst. Die Heterogenität wurde mit Hilfe des Cochrane Q Tests und der I2- Statistik berechnet. Der geschätzte Behandlungseffekt wurde als Risikoverhältnis (RR) für dichotome Endpunkte mit 95% Konfidenzintervallen (KI) berechnet, der Mittelwertdifferenz (MD) für kontinuierliche Endpunkte oder der standardisierten Mittelwertdifferenz (SDM), wenn unterschiedliche Skalen benutzt wurden.

Wesentliche Ergebnisse

Es wurden 27 Studien mit 1549 Teilnehmern identifiziert und eingeschlossen. Diese Studien lieferten keine Daten zu den hier untersuchten Patienten-relevanten Endpunkten (schwere kardiovaskuläre Ereignisse, Mortalität und Progression in ein Endstadium einer Nierenerkrankung, das eine Dialyse oder eine Transplantation erforderlich macht) bezüglich einer Therapie mit Aldosteron-Antagonisten kombiniert mit ACE-Hemmern oder AT1-Blockern (oder beiden).

Verglichen mit ACE-Hemmern oder AT1-Blockern (oder beiden) reduzierten nicht-selektive Aldosteron-Antagonisten (Spironolacton) kombiniert mit ACE-Hemmern oder AT1-Hemmern (oder beiden) die 24-Stunden Proteinurie (11 Studien mit insgesamt 596 Teilnehmern) signifikant: SMD -0,61, 95% KI -1,08 bis -0,13. Es konnte außerdem eine signifikante Senkung des systolischen sowie des diastolischen Blutdrucks erreicht werden: systolischer Blutdruck (10 Studien, 556 Teilnehmer): MD -3,44 mmHg, 95% KI -5,05 bis -1,83; diastolischer Blutdruck (9 Studien, 520 Teilnehmer): MD -1,73 mmHg, 95% KI -2,83 bis -0,62).

Allerdings konnte gezeigt werden, dass die Behandlung mit Aldosteron-Antagonisten eine unpräzise Wirkung auf die GFR am Ende der Behandlung hat (9 Studien, 528 Patienten; MD -2,55 mL/min/1,73 m², 95% KI -5,67 bis 0,51), das Risiko einer Hyperkaliämie verdoppelt (11 Studien, 632 Patienten): RR 2,00, 95% KI 1,25 bis 3,20; number needed to treat for an additional harmful outcome (NNTH): 7,2) und das Risiko einer Gynäkomastie verglichen mit ACE-Hemmern oder AT1-Blockern (oder beiden) erhöht (4 Studien mit 281 Patienten): RR 5,14, 95% KI 1,14 - 23,23; NNTH: 14,1, 95% KI 8,7 - 37,3).

Die meisten Studien konnten nur wenige Patienten einschließen (zwischen 12 und 268 Teilnehmern) und wurden dahingehend gepowert, Unterschiede in Surrogatparametern statt in Patienten-bezogenen Endpunkten festzustellen. Neun Studien hatten ein Cross-over Design und bei der Mehrheit der Studien fehlte eine adäquate Beschreibung die Studienmethodik, um diese sowie die Studienqualität zu bewerten.

Schlussfolgerungen der Autoren

Aldosteron-Antagonisten reduzieren die Proteinurie und den Blutdruck bei Erwachsenen, die eine milde bis mittlere chronischen NI haben und mit ACE-Hemmern oder AT1-Blockern (oder beiden) behandelt werden. Allerdings erhöhen sie das Risiko einer Gynäkomastie und Hyperkaliämie. Ob unter dieser Behandlung das Risiko von schweren kardiovaskulären Ereignissen oder einer chronischen NI im Endstadium in dieser Population verringert wird, ist unklar.

Anmerkungen zur Übersetzung

S. Schmidt, C. Bollig und I. Töws, freigegeben durch Cochrane Deutschland.

Plain language summary

Aldosterone antagonists for preventing the progression of chronic kidney disease

People who have chronic kidney disease (CKD) are at increased risk of heart disease and worsening kidney disease needing treatment with dialysis or a kidney transplant. Increased amounts of protein in the urine are a sign of kidney stress and are linked to a greater chance of worsening kidney function. Treatments that lower urine protein levels and protect kidney function are available and include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. However, protection of kidney function with these two drugs may be incomplete and adding aldosterone blockers (for example, spironolactone or eplerenone) may better protect kidney function. The use of numerous drugs may also increase side-effects. This review of available trials showed that adding aldosterone antagonist treatment to standard therapy reduced protein release into the urine and lowered blood pressure but had uncertain effects on kidney function and survival. Treatment also increases the amount of potassium in the blood which may require treatment changes, extra blood tests and is potentially harmful. Whether aldosterone blockers protect kidney function to lower the chances needing dialysis or kidney transplantation or prevent heart disease in people who have CKD is unclear and not answered by existing research.

Résumé simplifié

Antagonistes de l'aldostérone pour prévenir l'évolution de la maladie rénale chronique

Les personnes qui ont une maladie rénale chronique (MRC) sont à risque accru de maladie cardiaque et d'une aggravation de la maladie rénale nécessitant un traitement par la dialyse ou une greffe de rein. Une augmentation de la quantité de protéines dans l'urine est un signe de stress du rein et elle est liée à un plus grand risque d'aggravation de la fonction rénale. Des traitements qui font baisser les taux de protéines dans les urines et protègent la fonction rénale sont disponibles et comprennent des inhibiteurs de l'enzyme de conversion de l'angiotensine et des bloqueurs des récepteurs de l'angiotensine. Cependant, la protection de la fonction rénale avec ces deux médicaments peut être incomplète et l'ajout d'antagonistes de l'aldostérone (par exemple, la spironolactone ou l'éplérénone) pourrait permettre de mieux protéger la fonction rénale. L'utilisation de nombreux médicaments peut toutefois entraîner également une augmentation des effets secondaires. Cette revue des essais disponibles a montré que l'ajout d'un traitement par un antagoniste de l'aldostérone au traitement standard réduisait la libération de protéines dans l'urine et diminuait la pression artérielle, mais ses effets sur la fonction rénale et la survie étaient incertains. Le traitement augmente également la quantité de potassium dans le sang, ce qui peut nécessiter des changements dans le traitement ainsi que des tests sanguins supplémentaires et est potentiellement dangereux. Les recherches existantes ne permettent pas d'affirmer si les antagonistes de l'aldostérone protègent la fonction rénale pour réduire les risques de recours à la dialyse ou à la greffe de rein ou s'ils peuvent prévenir la maladie cardiaque chez les personnes souffrant de MRC, et ces questions restent ouvertes.

Notes de traduction

Traduit par: French Cochrane Centre 22nd July, 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

Laienverständliche Zusammenfassung

Aldosteron-Antagonisten zur Vorbeugung des Fortschreitens chronischer Nierenerkrankung

Menschen mit einer chronischen Nierenerkrankung (CKD) haben ein erhöhtes Risiko für Herzerkrankungen und für eine Verschlechterung der Nierenerkrankung, die dann eine Behandlung durch Dialyse oder eine Nierentransplantation notwendig macht. Erhöhte Mengen von Protein im Urin sind ein Zeichen von Nierenbelastung und sind mit einer größeren Wahrscheinlichkeit für eine Verschlechterung der Nierenfunktion verbunden. Behandlungen, die Proteinspiegel im Urin senken und die Nierenfunktion erhalten sind verfügbar und beinhalten Angiotensin-converting-Enzym-Hemmer (ACE-Hemmer) und Angiotensin-Rezeptorblocker (ARB). Jedoch könnte der Schutz der Nierenfunktion bei diesen beiden Arzneimittelgruppen unvollständig sein und durch Zugabe von Aldosteron-Antagonisten (z.B. Spironolacton oder Eplerenon) verbessert werden. Die Verwendung von mehreren Medikamenten könnte aber auch das Auftreten von Nebenwirkungen steigern. Dieser Review der verfügbaren Studien zeigt, dass die Zugabe von Aldosteron-Antagonisten zur Standardtherapie die Ausscheidung von Proteinen über den Urin vermindert und den Blutdruck senkt, aber ungewisse Auswirkungen auf die Nierenfunktion und das Überleben hat. Die Behandlung erhöht auch die Menge an Kalium im Blut, die wiederum Veränderung der Behandlung und zusätzliche Blutuntersuchungen erforderlich macht, und potenziell schädlich ist. Ob Aldosteron-Antagonisten bei Menschen mit CKD die Nierenfunktion soweit schützen, dass die Wahrscheinlichkeit der Notwendigkeit einer Dialyse oder Nierentransplantation gesenkt wird oder Herzerkrankungen verhindert werden ist unklar und nicht von bestehenden Studien beantwortet.

Anmerkungen zur Übersetzung

S. Schmidt, C. Bollig und I. Töws, freigegeben durch Cochrane Deutschland.

Ringkasan bahasa mudah

Antagonis aldosterone untuk mencegah progressi penyakit buah pinggang kronik

Penghidap penyakit buah pinggang kronik (CKD) adalah berisiko tinggi untuk penyakit jantung dan penyakit buah pinggang semakin teruk yang memerlukan rawatan dialisis atau pemindahan buah pinggang. Pertambahan jumlah protin dalam urin merupakan tanda stres buah pinggang dan dikaitkan dengan kebarangkalian kemerosotan fungsi buah pinggang yang lebih. Rawatan yang merendahkan paras protein urin dan melindungi fungsi buah pinggang boleh didapati dan ini termasuk perencat enzim pengubah angiotensin dan penghalang reseptor angiotensin. Walau bagaimanapun, perlindungan fungsi buah pinggang oleh kedua-dua ubat ini mungkin tidak lengkap dan penambahan penghalang aldosterone (misalnya spironolactone atau eplerenone) mungkin melindungi fungsi buah pinggang dengan lebih baik. Penggunaan pelbagai ubat juga mungkin menambah kesan sampingan. Ulasan kajian-kajian sedia ada menunjukkan rawatan penambahan antagonis aldosterone kepada rawatan standard mengurangkan pelepasan protein ke dalam urin dan merendahkan tekanan darah tetapi mempunyai kesan yang tidak pasti ke atas fungsi buah pinggang dan survival. Rawatan juga menambahkan amaun kalium dalam darah yang mungkin memerlukan perubahan rawatan, lebih banyak ujian darah dan berpotensi berbahaya. Sama ada penghalang aldosterone melindungi fungsi buah pinggang dengan merendahkan kebarangkalian keperluan dialisis atau pemindahan buah pinggang atau mencegah penyakit jantung dalam kalangan pesakit yang mempunyai CKD adalah tidak jelas dan belum terjawab oleh kajian sedia ada.

Catatan terjemahan

Diterjemahkan oleh Noor Salwah S Omar (Universiti Sains Malaysia). Disunting oleh Noorliza Mastura Ismail (Kolej Perubatan Melaka-Manipal). Untuk sebarang pertanyaan berkaitan terjemahan ini sila hubungi salwah@usm.my.

Background

Description of the condition

Chronic kidney disease (CKD) affects approximately one in eight adults globally and is increasing in part due to epidemics of diabetes, hypertension and obesity (Coresh 2007; Grassmann 2005). In the past few decades, several treatment options have become available to slow progression of progression of kidney damage (Brenner 2003; Klahr 1994). To date, the major impact on the progression of CKD and the incidence of end-stage kidney disease (ESKD) has been through the treatment of proteinuria and reduction in blood pressure (BP), which are both independent predictors of mortality in adults who have CKD (Brenner 2001; GISEN 1997; Mathiesen 1999). Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blocker agents (ARB) are standard of care to slow progression of CKD in patients with proteinuria (irrespective of cause) (Jafar 2001; Strippoli 2006). However, ACEi and ARB agents slow, but may not completely retard, the progression of CKD (Schieppati 2003).

Description of the intervention

Animal studies have shown that aldosterone has an independent role in the development of hypertensive kidney disease and vascular injury resulting in myocardial and renal fibrosis (Figure 1) and its blockade reduces proteinuria (Aldigier 2005; Green 1996; Rocha 1998; Silvestre 1998). Renin-angiotensin system (RAS) blockade with ACEi and ARB result in incomplete suppression of serum aldosterone levels and is known as 'aldosterone escape phenomenon' (Staessen 1981). Further experimental studies have established this theory and in humans, the treatment of adults with CKD exhibiting aldosterone escape phenomenon with aldosterone blockers reduces proteinuria and improves kidney outcomes such as proteinuria (Fritsch Neves 2003). However, aldosterone antagonism may increase risks of hyperkalaemia and gynaecomastia (Nappi 2011).

Figure 1.

Mechanisms of cardiac and renal damage induced by aldosterone excess

How the intervention might work

Beneficial effects of aldosterone blockade in congestive heart failure have been established (Hostetter 2003; Pitt 1999). The selective aldosterone blocker, eplerenone, was introduced and its cardiovascular benefit has also been established (Pitt 2003). Both spironolactone and eplerenone have been evaluated in randomised controlled trials (RCTs) to analyse their role in reducing albuminuria or proteinuria and slowing progression of CKD (Bianchi 2006; Chrysostomou 2006; Epstein 2006; Rossing 2005; Schjoedt 2005).

Why it is important to do this review

Aldosterone blockade alone or in combination with ACEi and ARB has the potential to cause hyperkalaemia and may impair kidney function due to reduced renal blood flow, particularly in adults who have coexisting CKD. In addition, while aldosterone antagonism may reduce proteinuria, the effects of treatment on clinical outcomes including need for treatment with dialysis or kidney transplantation and prevention of major cardiovascular events remain uncertain. Thus, we analysed the benefits and harms of selective and non-selective aldosterone antagonists treatment in adults who had CKD and who were or who were not already treated with ACEi or ARB (alone or in combination). We specifically focused on treatment effects for proteinuria, kidney function and patient-level outcomes including ESKD and major cardiovascular events. New relevant studies on CKD patients receiving aldosterone antagonists have recently been completed and results made available in current literature. We therefore felt as necessary to update the previous published version of this review (Navaneethan 2009), incorporating results from the most recent studies published on this topic.

Objectives

To evaluate the effect of aldosterone antagonists (both selective (eplerenone) and non-selective (spironolactone)) alone or in combination with ACEi or ARB in adults who have CKD with proteinuria (nephrotic and non-nephrotic range) on:

  • patient-centred endpoints including major cardiovascular events, hospitalisation and all-cause mortality

  • kidney function (proteinuria, glomerular filtration rate (GFR), serum creatinine (SCr), and need for renal replacement therapy (RRT)

  • adverse events (including gynaecomastia and hyperkalaemia)

Methods

Criteria for considering studies for this review

Types of studies

All RCTs and quasi-RCTs of aldosterone antagonists (both selective and non-selective antagonists) used alone and also in combination with ACEi alone, ARB alone (or both) were included. Data from the first period of randomised cross-over studies was also included.

Types of participants

Inclusion criteria

Studies enrolling patients with CKD stages 1 to 4, as defined by the by Kidney Disease Outcomes Quality Initiative (K-DOQI) guidelines (Levey 2003) and who had albuminuria or proteinuria were considered for inclusion. We included studies in adults who had CKD regardless of aetiology including individuals with diabetes complicated by kidney disease. The K/DOQI categories for kidney disease are:·        

  • CKD stage 1: GFR > 90 mL/min/1.73 m² and evidence of clinically relevant structural or urinary abnormalities including haematuria or proteinuria (or both)

  • CKD stage 2: GFR 60 to 89 mL/min/1.73 m²

  • CKD stage 3: GFR 30 to 59 mL/1.73 m²

  • CKD stage 4: GFR 15 to 29 mL/min/1.73 m²

Exclusion criteria

We excluded studies in adults with CKD stage 5 (GFR < 15 mL/min/1.73 m²) including those treated with dialysis and recipients of a kidney transplant.

Types of interventions

We included studies evaluating aldosterone antagonist treatment (both selective and non-selective antagonists) given alone or in combination with an ACEi or ARB (or both). We considered studies in which treatment duration was 4 weeks or longer. We considered the following treatment comparisons:

  • Non-selective aldosterone antagonists versus placebo or standard care

  • Non-selective aldosterone antagonists with ACEi versus ACEi plus placebo

  • Non-selective aldosterone antagonists with ARB versus ARB plus placebo

  • Non-selective aldosterone antagonists with ACEi plus ARB versus ACEi plus ARB plus placebo or other antihypertensive drugs

  • Selective aldosterone antagonists with versus placebo or other antihypertensive drugs

  • Selective aldosterone antagonists with ACEi versus ACEi plus placebo

  • Selective aldosterone antagonists with ARB versus ARB plus placebo

  • Selective aldosterone antagonists with ACEi plus ARB versus ACEi plus ARB plus placebo or other antihypertensive drugs

If disaggregated outcome data were not available for the three groups (ACEi alone, ARB alone or the combination separately), we used combined data when available.

Types of outcome measures

Primary outcomes
  • Major cardiovascular events as defined by the investigators (including but not limited to myocardial infarction, stroke, congestive heart failure)

  • All-cause mortality

  • Hospitalisation.

Secondary outcomes
  • Urinary protein excretion rate (24 hour proteinuria, 24 hour albuminuria in mg/dL, urine protein:creatinine ratio, or urine albumin:creatinine ratio)

  • Kidney function: SCr (mg/dL), GFR, estimated (e) GFR (mL/min or mL/min/1.73 m²); need for RRT; doubling of SCr; progression from micro- to macroalbuminuria; regression from macro- to microalbuminuria and regression from micro- to normoalbuminuria

  • BP: systolic BP and diastolic BP (mm Hg)

  • Hyperkalaemia (defined as serum potassium > 5.0 mEq/L or mmol/L)

  • Gynaecomastia

  • Withdrawal rates due to secondary

  • Study-related adverse events

Search methods for identification of studies

There were no differences in search methods between the original review and this update.

Electronic searches

We searched the Cochrane Renal Group's Specialised Register to 30 January 2013 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. Quarterly 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 update.

Searching other resources

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

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

Data collection and analysis

Disagreements were resolved in consultation with two authors who also provided methodological assistance throughout the review process.

Selection of studies

The search strategy described was used to obtain titles and abstracts of studies relevant to the review. For this update, titles and abstracts were screened independently by two authors, who discarded studies that were not applicable; however, studies and reviews that may have included relevant data or information on studies were retained initially. Two authors independently assessed retrieved abstracts, and if necessary the full text, of these studies 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 language journals were translated before assessment. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data were used in the analyses. Where relevant outcomes were only published in earlier versions these data were used. Any discrepancies between published versions were highlighted.

Assessment of risk of bias in included studies

The following items were independently assessed by two authors 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)?

  • Were 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?

Discrepancies were resolved by discussion with a third author.

Measures of treatment effect

For dichotomous outcomes (all-cause mortality, cardiovascular events, one or more hospitalisations, one or more episodes of hyperkalaemia, gynaecomastia) results were expressed as a risk ratio (RR) with 95% confidence intervals (CI). When continuous scales of measurement were used to assess the effects of treatment (end of treatment protein excretion rate or albumin excretion rate, SCr, serum potassium, or eGFR or creatinine clearance), we used the mean difference (MD) or the standardised mean difference (SMD) when different measurement scales were used

Dealing with missing data

We contacted study authors to seek additional information. We were successful in obtaining additional data from Drs KJ Schjoedt, K Rossing, A Chrysostomou, S Bianchi, S Nielsen and K Takebayashi These data were included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat (ITT), as-treated and per-protocol (PP) population were performed. Attrition rates, such as drop-outs, losses to follow-up and withdrawals were investigated. Issues of missing data and imputation methods were critically appraised (Higgins 2011).

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 planned to assess for the potential existence of small study bias (Higgins 2011), there was an insufficient number of studies.

Data synthesis

Data were pooled using random effects meta-analysis, but the fixed effects model was also analysed to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was used to explore possible sources of heterogeneity (e.g. participants, treatments and study quality). Heterogeneity among participants could be related to age, stage of kidney disease, aetiology of kidney disease and amount of proteinuria. Heterogeneity in treatments could be related to prior agent(s) used and the agent, dose and duration of aldosterone antagonists and the concomitant use of ACEi or ARB (or both). We also conducted a separate analysis for development of hyperkalaemia using different definitions of serum potassium (5.0 to 5.5 mEq/L, 5.5 to 6.0 mEq/L, and > 6.0 mEq/L). Studies of at least four weeks duration were selected for the purposes of this systematic review. If possible, the effect of short and long term follow-up as a source of significant heterogeneity between studies was analysed. Formal test of interaction to detect differences between the subgroups (based on type of kidney disease and use of triple versus double agents) was conducted.

Results

Description of studies

Seventeen new studies (811 participants) (Abolghasmi 2011; Boesby 2011; Cohen 2010; CRIBS II Study 2009; Guney 2009; Haykal 2007; Koroshi 2010; Lv 2009a; Mehdi 2009; Morales 2009; Nielsen 2012; Ogawa 2006a; Saklayen 2008; Smolen 2006; Takebayashi 2006; Tokunaga 2008a; Zheng 2011) and four ongoing studies (ARTS Study 2012; EVALUATE Study 2010; NCT00315016; NCT00870402) were included in this update.

Results of the search

The combined search of MEDLINE, EMBASE, CENTRAL and the Cochrane Renal Group's Specialised Register identified 195 citations of which 112 were excluded (non-RCTs and studies that evaluated other interventions not relevant to this review). Full-text assessment of 83 potentially relevant articles resulted in the identification of 27 eligible studies (49 reports) enrolling a total of 1549 patients (Abolghasmi 2011; Bianchi 2006; Boesby 2011; Chrysostomou 2006; Cohen 2010; CRIBS II Study 2009; Epstein 2002; Epstein 2006; Furumatsu 2008; Guney 2009; Haykal 2007; Koroshi 2010; Lv 2009a; Mehdi 2009; Morales 2009; Nielsen 2012; Ogawa 2006a; Rossing 2005; Saklayen 2008; Schjoedt 2005; Schjoedt 2006; Smolen 2006; Takebayashi 2006; Tokunaga 2008a; Tylicki 2008; van den Meiracker 2006; Zheng 2011) and four ongoing studies (ARTS Study 2012; EVALUATE Study 2010; NCT00315016; NCT00870402). Authors of all included studies were contacted for additional information and clarification relating to study methods and any unreported data, with six responding to our queries (Bianchi 2006; Chrysostomou 2006; Rossing 2005; Schjoedt 2006; Nielsen 2012; Takebayashi 2006). See Figure 2.

Figure 2.

Study flow diagram.

Included studies

Nine studies were cross-over studies (Boesby 2011; Morales 2009; Nielsen 2012; Saklayen 2008; Smolen 2006; Rossing 2005; Schjoedt 2005; Schjoedt 2006; Tylicki 2008).

Thirteen studies included participants who had kidney disease secondary to diabetes mellitus (Chrysostomou 2006; Epstein 2002; Epstein 2006; van den Meiracker 2006; Rossing 2005; Schjoedt 2005; Schjoedt 2006; Mehdi 2009; Nielsen 2012; Ogawa 2006a; Saklayen 2008; Takebayashi 2006; Zheng 2011). The large study of Bianchi 2006 included patients with various forms of glomerulonephritis while the remaining studies included patients with non-diabetic kidney disease encompassing IgA nephropathy, benign nephrosclerosis and membranous nephropathy (Abolghasmi 2011; Furumatsu 2008; Tylicki 2008; Boesby 2011; Cohen 2010; CRIBS II Study 2009; Guney 2009; Haykal 2007; Koroshi 2010; Lv 2009a; Morales 2009; Smolen 2006; Tokunaga 2008a). All studies excluded patients with an eGFR below 30 mL/min/1.73 m². Baseline albuminuria/proteinuria excretion rates ranged from 0.5 to 3.6 g/d.

Among studies using non-selective aldosterone antagonists, 17 studies (785 patients) compared spironolactone plus ACEi or ARB (or both) to ACEi or ARB (or both) ( Bianchi 2006; Chrysostomou 2006; CRIBS II Study 2009; Furumatsu 2008; Rossing 2005; Mehdi 2009; Schjoedt 2005; Schjoedt 2006; Tylicki 2008; Guney 2009; Koroshi 2010; Ogawa 2006a;Saklayen 2008; Tokunaga 2008a; van den Meiracker 2006; Zheng 2011). Two studies (92 patients) compared spironolactone to placebo (Abolghasmi 2011; Nielsen 2012;); in these studies, co-treatment with ACEi or ARB (or both) was not specified. Smolen 2006 (16 patients) compared spironolactone plus ACEi to ACEi plus diuretics and Takebayashi 2006 (37 patients) compared spironolactone to calcium channel blockers. In the studies that analysed the efficacy of non-selective aldosterone antagonists, 25 mg/d of spironolactone was used throughout the study period except for Abolghasmi 2011, Saklayen 2008 and van den Meiracker 2006, who used 25 to 50 mg/d; Lv 2009a and Zheng 2011, used 20 mg/d; Koroshi 2010 and Takebayashi 2006, used 50 mg/d, and Mehdi 2009 used 12.5 to 25 mg/d of spironolactone.

Study duration varied from two to 20 months. Sample size of all studies was small (range 12 to 268) and none were powered to detect hard primary outcomes including mortality or long-term renal outcomes. Four studies (571 patients) compared the selective aldosterone antagonist eplerenone plus ACEi or ARB (or both) to ACEi or ARB (or both) (Boesby 2011; Haykal 2007; Epstein 2002; Epstein 2006). Morales 2009 (12 patients) compared eplerenone to ACEi or ACEi and ARB and Cohen 2010 (34 patients) compared eplerenone plus ACEi or ARB (or both) to ACEi or ARB (or both) and to ACEi or ARB (or both) plus nitrate. Studies that analysed the efficacy of selective aldosterone antagonists used eplerenone at the dose of 200 mg/d (Epstein 2002), 50 to 100 mg/d (Epstein 2006), 25 to 50 mg/d (Boesby 2011; Haykal 2007), and 25 mg/d (Morales 2009). In Cohen 2010 the dose of eplerenone administered was not defined. Other characteristics of the participants and the interventions of the included studies are detailed in the Characteristics of included studies.

Excluded studies

Sixteen reports (24 studies) were excluded because they were not RCTs; they did not include adults with CKD; were not studies comparing aldosterone antagonists with or without ACEi or ARB; or they did not examine outcomes of interest (e.g. pharmacokinetic studies). One study was retracted.

Risk of bias in included studies

Risks of bias in the available studies are shown in Figure 3 and Figure 4.

Figure 3.

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

Figure 4.

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

Allocation

Random sequence generation was adequate in nine studies (Bianchi 2006; Chrysostomou 2006; Mehdi 2009; Nielsen 2012; Rossing 2005; Schjoedt 2005; Schjoedt 2006; Tylicki 2008; van den Meiracker 2006) and unclear in the remaining 18 studies.

Allocation concealment was adequate in four studies (Boesby 2011; Morales 2009; Nielsen 2012; van den Meiracker 2006), and unclear in the remaining 23 studies.

Blinding

Participants and investigators were blinded in 11 studies (Chrysostomou 2006; CRIBS II Study 2009; Epstein 2002; Epstein 2006; Mehdi 2009; Nielsen 2012; Rossing 2005; Saklayen 2008; Schjoedt 2005; Schjoedt 2006; van den Meiracker 2006) and not blinded in four studies (Bianchi 2006; Boesby 2011; Furumatsu 2008; Tylicki 2008); blinding was unclear in the remaining 12 studies.

Outcome assessors were not aware of treatment allocation in a single study (Saklayen 2008), while in four studies patients and or investigators were aware of treatment assignment (Bianchi 2006; Boesby 2011; Furumatsu 2008; Tylicki 2008). Blinding of outcome assessors was unclear in the remaining 22 studies.

Incomplete outcome data

Eighteen studies were judged to be at low risk of bias (Abolghasmi 2011; Bianchi 2006; Boesby 2011; Chrysostomou 2006; Cohen 2010; CRIBS II Study 2009; Epstein 2006; Furumatsu 2008; Haykal 2007; Morales 2009; Rossing 2005; Saklayen 2008; Schjoedt 2005; Schjoedt 2006; Takebayashi 2006; Tylicki 2008; van den Meiracker 2006; Zheng 2011). Five studies where there was some loss to follow-up (Bianchi 2006; Boesby 2011; Epstein 2006; Cohen 2010; CRIBS II Study 2009) were analysed on an intention-to-treat basis. One study was judged to be at high risk of bias (Mehdi 2009). The dropout rate from study follow-up ranged from 0% to 37% and did not differ between the treatment and control groups.

Selective reporting

All the pre-specified outcomes were reported in thirteen studies (Abolghasmi 2011; Cohen 2010; CRIBS II Study 2009; Furumatsu 2008; Guney 2009; Mehdi 2009; Morales 2009; Ogawa 2006a; Rossing 2005; Schjoedt 2005; Schjoedt 2006; Tylicki 2008; van den Meiracker 2006). Selective reporting was unclear in the remaining 14 studies.

Other potential sources of bias

Eight studies were judged to be at low risk of bias due to funding (Bianchi 2006; Chrysostomou 2006; CRIBS II Study 2009; Mehdi 2009; Rossing 2005; Schjoedt 2005; Schjoedt 2006; Tylicki 2008); one study was funded by a pharmaceutical company (Epstein 2006); and the risk of bias was unclear in the remaining 18 studies.

Effects of interventions

Non-selective aldosterone antagonists (spironolactone) plus ACEi or ARB (or both) versus ACEi or ARB (or both)

Death

Mehdi 2009 reported one patient in the control group died (Analysis 1.1).

Cardiovascular events

Mehdi 2009 reported no significant differences in cardiovascular events between the two groups (Analysis 1.2 (54 patients): RR 3.00, 95% CI 0.66 to 13.56).

End-stage kidney disease

There were no significant differences in developing ESKD (permanent worsening in GFR requiring RRT) between the two groups (Analysis 1.3 (2 studies, 42 patients): RR 3.00, 95% CI 0.33 to 27.65; I² = 0%).

End of treatment protein excretion rate

Spironolactone in addition to an ACEi or ARB (or both) reduced protein excretion rate (Analysis 1.4 (11 studies, 596 patients): SMD -0.61, 95% CI -1.08 to -0.13). There was a moderate to high heterogeneity between treatment effects identified by studies included in this analysis (Chi² = 20.56, P = 0.001, I² = 85%).

End of treatment glomerular filtration rate

Spironolactone plus ACEi or ARB (or both) had uncertain effects on eGFR (Analysis 1.5 (9 studies, 528 patient)s; MD -2.55 mL/min/1.73 m², 95% CI -5.67 to 0.51; I² = 0%) compared to ACEi or ARB (or both) alone.

End of treatment blood pressure

Spironolactone in combination with ACEi or ARB (or both) reduced systolic BP compared with ACEi or ARB (or both) alone (Analysis 1.6 (10 studies, 556 patients): MD -3.44 mm Hg, 95% CI -5.05 to -1.83; I² = 0%).

Spironolactone in combination with ACEi or ARB (or both) reduced diastolic BP compared with ACEi or ARB (or both) alone (Analysis 1.7 (9 studies, 520 patients): MD -1.73 mm Hg, 95% CI -2.83 to -0.62; I² = 0%).

Adverse effects
Hyperkalaemia

Spironolactone in combination with ACEi or ARB (or both) increased hyperkalaemia (Analysis 1.8 (11 studies, 632 patients): RR 2.00, 95% CI 1.25 to 3.20; I² = 0%) (number needed to treat for an additional harmful outcome (NNTH) 7.2, 95% CI 3.4 to ∞) compared to ACEi or ARB (or both) alone.

In subgroup analyses, treatment with spironolactone in combination with both ACEi and ARB treatment increased hyperkalaemia compared with ACEi and ARB alone (Analysis 1.9.1 (4 studies, 149 patients): RR 4.30, 95% CI 1.12 to 16.51; I² = 0%) (NNTH 8.9, 95% CI 5.2 to 31.7). Hyperkalaemia also increased when spironolactone was used in addition to either an ACEi or ARB  compared to ACEi or ARB alone (Analysis 1.9.2 (9 studies, 483 patients): RR 1.80, 95% CI 1.09 to 2.96; I² = 0%) (NNTH 13.3, 95% CI 7.8 to 45.9). A formal test of interaction found no differences across the estimates for these subgroups (P = 0.23).

Serum potassium

Spironolactone combined with ACEi or ARB (or both) increased serum potassium compared with ACEi or ARB (or both) alone (Analysis 1.10 (11 studies, 596 patients): MD 0.26 mEq/L, 0.13 to 0.39). There was a significant heterogeneity between treatment estimated in the studies included in this analysis (Chi² = 55.21, P < 0.00001, I² = 82%)

Gynaecomastia

Spironolactone plus ACEi or ARB (or both) markedly increased gynaecomastia compared to ACEi or ARB (or both) alone (Analysis 1.11 (4 studies, 281 patients): RR 5.14, 95% CI 1.14 to 23.23; I² = 0%) (NNTH 14.1, 95% CI 8.7 to 37.3). Bianchi 2006 reported that 6/83 patients developed gynaecomastia (only one patient warranting discontinuation of medication and five patients with mild gynaecomastia) in the spironolactone group but none (out of 82 patients) in the placebo arm. Furumatsu 2008 reported 1/15 patient who developed gynaecomastia in the spironolactone group.

Analysis of heterogeneity

Heterogeneity in the effects of spironolactone on proteinuria was explored through sub-group analyses (based on the type of CKD and study duration). We could not explore the influence of baseline kidney function on the heterogeneity as sufficient data were not extractable from included studies.

Type of baseline kidney disease

Spironolactone had statistically similar effects on 24-hour proteinuria levels in patients who had non-diabetic CKD (Analysis 1.12.1 (5 studies, 367 patients): SMD -0.68, 95% CI -1. 57 to 0.21; I² = 93%) and those who had CKD secondary to diabetes (Analysis 1.12.2 (6 studies, 229 patients): SMD -0.52, 95% CI -0.82 to -0.23; I² = 0%) (P = 0.75 for difference between subgroups).

Study duration

Spironolactone therapy reduced 24-hour proteinuria to a greater extent in studies reporting follow up of fewer than six months (Analysis 1.13 (7 studies, 265 patients): SMD -0.60, 95% CI -0.87 to -0.33; I² = 0%) than in studies with a follow up duration longer than six months (Analysis 1.13 (4 studies, 331 patients): SMD -0.59, 95% CI -1.68 to -0.50; I² = 95%) (P = 0.99 for difference between subgroups).

Other outcomes

Data for the following outcomes were not extractable in a format required for inclusion in analyses or not reported in the available studies.     

  • Doubling of SCr     

  • Progression from micro to macroalbuminuria      

  • Regression from macro to microalbuminuria      

  • Regression from micro to normoalbuminuria

Non-selective aldosterone antagonists (spironolactone) versus placebo

End of treatment proteinuria

In one cross-over study (Nielsen 2012), spironolactone treatment reduced albuminuria by 60% when compared to placebo (P = 0.01).We could not conduct a meta-analysis as additional data could not be obtained from the investigators.

End of treatment glomerular filtration rate

In one cross-over study (Nielsen 2012), spironolactone reduced eGFR. We could not conduct a meta-analysis as additional data could not be obtained from the investigators.

End of treatment blood pressure

After 12 weeks treatment, spironolactone significantly reduced systolic BP (Abolghasmi 2011). In a cross-over study (Nielsen 2012), no significant changes were noticed in systolic BP after the placebo or spironolactone period. We could not conduct a meta-analysis as only descriptive data were available from Nielsen 2012 and actual data could not be obtained from the investigators.

After 12 weeks treatment, spironolactone significantly reduced diastolic BP as compared to placebo (Abolghasmi 2011). In one cross-over study (Nielsen 2012), no significant changes were noticed in diastolic BP after the placebo or spironolactone period. We could not conduct a meta-analysis as only descriptive data were available from Nielsen 2012 and actual data could not be obtained from the investigators.

Adverse effects
Serum potassium

In Abolghasmi 2011, serum potassium remained stable at the end of treatment in both spironolactone and control groups.

Hyperkalaemia

In Abolghasmi 2011, hyperkalaemia occurred in one patient in the spironolactone group. In one cross-over study (Nielsen 2012), two patients experienced severe hyperkalaemia (plasma potassium > 5.7 mmol ⁄ L). Four patients experienced mild to moderate hyperkalaemia (plasma potassium = 5.0 to 5.4 mmol/L). Hyperkalaemia was mainly observed two weeks after the start of spironolactone treatment.

Other outcomes

These outcomes were not analysed or reported in the published studies.

  • All-cause mortality

  • Hospitalisation

  • Doubling of SCr

  • Progression from micro- to macroalbuminuria

  • Regression from macro- to microalbuminuria

  • Regression from micro- to normoalbuminuria.

Non-selective aldosterone antagonists (spironolactone) plus ACEi versus ACEi plus diuretics

End of treatment protein excretion rate

In Ogawa 2006a after 12 months, spironolactone plus ACEi significantly reduced proteinuria while the addition of furosemide to ACEi did not induce any change. In one cross-over study (Smolen 2006) after 8 weeks of treatment with spironolactone proteinuria was significantly reduced while it remained unchanged after hydrochlorothiazide. We could not conduct a meta-analysis as only descriptive data were available and actual data could not be obtained from the investigators.

End of treatment glomerular filtration rate

In one cross-over study (Smolen 2006), eGFR was unchanged after the spironolactone and the hydrochlorothiazide treatment period. Only descriptive data were available and actual data could not be obtained from the investigators.

End of treatment blood pressure

Ogawa 2006a reported a more significant reduction in systolic and diastolic BP after 12 months of spironolactone plus ACEi as compared to ACEi plus furosemide. In one cross-over study (Smolen 2006) mean 24h BP was unchanged by spironolactone or hydrochlorothiazide. We could not conduct a meta-analysis as only descriptive data were available and actual data could not be obtained from the investigators.

End of treatment potassium

In one cross-over study (Smolen 2006) potassium significantly increased after the spironolactone period while it remained stable after hydrochlorothiazide treatment. Only descriptive data were available and actual data could not be obtained from the investigators.

Other outcomes

Data for the following outcomes were not extractable in a format required for inclusion in analyses or not reported in the available studies.

  • All-cause mortality

  • Hospitalisation

  • ESKD

  • Adverse events (hyperkalaemia, gynaecomastia)

  • Doubling of SCr

  • Progression from micro- to macroalbuminuria

  • Regression from macro- to microalbuminuria

  • Regression from micro- to normoalbuminuria.

Non-selective aldosterone antagonists (spironolactone) versus calcium channel blockers

End of treatment blood pressure

After 12 weeks, systolic BP was significantly reduced in both the spironolactone and control group with no differences reported between the two groups (129 ± 9 mm Hg versus 128 ± 11 mm Hg). Diastolic BP remained stable in the spironolactone group (70 ± 4 mm Hg) and decreased significantly in the control group (69 ± 8 mm Hg). We could not conduct a meta-analysis as only one study (Takebayashi 2006) was included.

End of treatment potassium

After 12 weeks, potassium was significantly increased by spironolactone treatment (4.51 ± 0.45 mmol/L) while remained unchanged in the control group (4.03 ± 0.24 mmol/L). We could not conduct a meta-analysis as only one study (Takebayashi 2006) was included.

End of treatment protein excretion rate

After 12 weeks, spironolactone significantly reduced urinary albumin excretion (UAE). UAE was unchanged in amlodipine group. We could not conduct a meta-analysis as only one study (Takebayashi 2006) was included. Only descriptive data were available and actual data could not be obtained from the investigators.

Other outcomes

Data for the following outcomes were not extractable in a format required for inclusion in analyses or not reported in the available studies.

  • All-cause mortality

  • Hospitalisation

  • ESKD

  • Adverse events (hyperkalaemia, gynaecomastia)

  • Doubling of SCr

  • eGFR

  • Progression from micro- to macroalbuminuria

  • regression from macro- to microalbuminuria

  • regression from micro- to normoalbuminuria.

Selective aldosterone antagonists (eplerenone) plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone

End of treatment protein excretion rate

In Epstein 2002 proteinuria was reduced by 74% in the eplerenone and by 45% in the control group after 24 weeks. In Epstein 2006 eplerenone treatment significantly reduced albuminuria at 12 weeks compared with ACEi alone. In both cases additional data could not be obtained from the investigators. In a cross-over study (Boesby 2011), eplerenone reduced albuminuria compared with no treatment. In Cohen 2010 proteinuria was reduced by 1.04 ± 0.4 g/24 h in the eplerenone and by 0.32 ± 0.2 g/24 h in the control group. In another abstract study (Haykal 2007) eplerenone plus ACEi reduced proteinuria after four weeks and the effect was maintained up to 12 weeks. Only descriptive data were available in this study and actual data could not be obtained from the investigators.

End of treatment blood pressure

In Epstein 2002, systolic BP was reduced by 21.8% and 20.4% in the eplerenone and control group respectively. Diastolic BP was reduced by 16.2% and 15% in the eplerenone and control group respectively. In Epstein 2006 both systolic and diastolic BP decreased at 12 weeks in eplerenone and control groups but there were no significant differences in BP reduction between groups. In both studies additional data could not be obtained from the investigators. In Haykal 2007, both systolic and diastolic BP decreased at weeks four, eight and 12 and BP reduction was slightly higher in eplerenone plus ACEi than in ACEi alone group. Only descriptive data were available in this study and actual data could not be obtained from the investigators. In Cohen 2010, Systolic BP was reduced by 9.7 ± 6.4 mm Hg in the eplerenone group and by 13.4 ± 14.9 mm Hg in the ACEi/ARB group. In the cross-over study by Boesby 2011 systolic and diastolic BP were significantly lower during add-on eplerenone treatment when compared to the control period. Systolic and diastolic BP were significantly reduced after two and four weeks of eplerenone treatment, respectively. Significant differences in diastolic BP were reported between the treatment period and control period at the same time point, while there were no significant differences between diastolic BP at the end of the two periods. No significant carry-over, or time effects for systolic or diastolic BP were observed. In all these studies only descriptive data were available in this study and actual data could not be obtained from the investigators.

End of treatment glomerular filtration rate

There was no significant difference in end of treatment eGFR with eplerenone plus ACEi compared to ACEi plus placebo (Epstein 2006). Only descriptive data were available in this study and actual data could not be obtained from the investigators.

Adverse events
Hyperkalaemia

There was a significant increase in the risk of hyperkalaemia with eplerenone plus ACEi compared to ACEi plus placebo (Analysis 5.1 (2 studies, 509 patients): RR 1.62, 95% CI 0.66 to 3.95; I² = 0%) (NNTH 45.2, 95% CI 16.5 to ∞).

Gynaecomastia

In one study, there was no incidence of gynaecomastia or female breast pain reported in the eplerenone arm in comparison to ACEi (Epstein 2006).

Other outcomes

Data for the following outcomes were not extractable in a format required for inclusion in analyses or not reported in the available studies.

  • All-cause mortality

  • Hospitalisation

  • ESKD

  • Adverse events (gynaecomastia)

  • Doubling of SCr

  • eGFR

  • Progression from micro- to macroalbuminuria

  • Regression from macro- to microalbuminuria

  • Regression from micro- to normoalbuminuria

Selective aldosterone antagonists (eplerenone) alone versus ACEi alone

End of treatment protein excretion rate

In one cross-over study (Morales 2009) the reduction in proteinuria achieved with eplerenone was more significant than that achieved with ACEi. Only descriptive data were available in this study and actual data could not be obtained from the investigators.

Adverse events
Hyperkalaemia

In one cross-over study (Morales 2009), 2/12 patients (16%) had serum potassium above 5.5 mEq/L at the end of the ACEi period while none of the patients experienced this complication after the eplerenone period.

Other outcomes

Data for the following outcomes were not extractable in a format required for inclusion in analyses or not reported in the available studies.

  • All-cause mortality

  • Hospitalisation

  • ESKD

  • Adverse events (hyperkalaemia, gynaecomastia)

  • Doubling SCr

  • eGFR

  • Progression from micro- to macroalbuminuria

  • Regression from macro- to microalbuminuria

  • Regression from micro- to normoalbuminuria

Selective aldosterone antagonists (eplerenone) alone versus ACEi plus ARB

End of treatment protein excretion rate

In the cross-over study by Morales 2009 proteinuria was significantly reduced from baseline after both the eplerenone and the ACEi plus ARB period (P = 0.045 and P =0.034 respectively).

Adverse events
Hyperkalaemia

In the cross-over study by Morales 2009, 2/12 patients (16%) had serum potassium above 5.5 mEq/L at the end of the ACEi plus ARB period versus none of the patients after the eplerenone period.

Other outcomes

Data for the following outcomes were not extractable in a format required for inclusion in analyses or not reported in the available studies.

  • All-cause mortality

  • Hospitalisation

  • ESKD

  • Adverse events (hyperkalaemia, gynaecomastia)

  • Doubling SCr

  • eGFR

  • Progression from micro- to macroalbuminuria

  • Regression from macro- to microalbuminuria

  • Regression from micro- to normoalbuminuria

Selective aldosterone antagonists (eplerenone) plus ACEi or ARB (or both) versus ACEi or ARB (or both) plus nitrate

End of treatment protein excretion rate

Urine protein excretion was significantly reduced after four weeks of eplerenone while it increased in the comparator group. We could not conduct a meta-analysis as additional data could not be obtained from the investigators (Cohen 2010).

End of treatment blood pressure

Systolic BP was reduced by 9.7 ± 6.4 mm Hg in the eplerenone group and by 1.0 ± 5.4 mm Hg in the ACEi/ARB plus isosorbide group at 4 weeks. No data were available about diastolic BP. We could not conduct a meta-analysis as additional data could not be obtained from the investigators (Cohen 2010).

Other outcomes

Data for the following outcomes were not extractable in a format required for inclusion in analyses or not reported in the available studies.

  • All-cause mortality

  • Hospitalisation

  • ESKD

  • Adverse events (hyperkalaemia, gynaecomastia)

  • Doubling SCr

  • eGFR

  • Progression from micro- to macroalbuminuria

  • Regression from macro- to microalbuminuria

  • Regression from micro- to normoalbuminuria

Discussion

Summary of main results

Non-selective (spironolactone) aldosterone blockade treatment has uncertain effects on progression of kidney disease, major cardiovascular events, while doubling the risk of hyperkalaemia and markedly increasing gynaecomastia in adults who have CKD stages 1 to 3 (GFR > 60 mL/min/1.73 m²) when given in addition to ACEi or ARB (or both). Aldosterone blockade reduced proteinuria by 0.6 g/d on average during 12 weeks of treatment and lowered BP but has little or no effect on kidney function. Data for treatment effects in more severe CKD (stages 4 and 5) are unavailable, and treatment effects of selective aldosterone blockade (eplerenone) are sparse. Treatment effects for spironolactone appear similar in diabetic and non-diabetic kidney disease.

Overall completeness and applicability of evidence

Although this updated review has provided additional evidence that aldosterone antagonists reduce proteinuria and BP, data on treatment effects on patient-relevant outcomes including progression to ESKD and major cardiovascular events remain inconclusive. Furthermore, caution should be advised since treatment using spironolactone in combination with ACEi or ARB (or both) might increase risks of hyperkalaemia and gynaecomastia.

Quality of the evidence

Most studies enrolled few patients and were powered to observe differences in surrogate end points rather than patient-focused outcomes. Nine studies had a cross-over design (Boesby 2011; Morales 2009; Nielsen 2012; Saklayen 2008; Smolen 2006; Rossing 2005; Schjoedt 2005; Schjoedt 2006; Tylicki 2008) and the majority of studies did not adequately report study methods to assess methods and study quality. Evidence for selective aldosterone blockers (eplerenone) in adults who have CKD are sparse and evidence for all aldosterone antagonists in severe forms of CKD (stages 4 and 5) are lacking.

Potential biases in the review process

Our review has a number of strengths and limitations. The review is based on a peer-reviewed protocol, a systematic search of electronic databases including the Cochrane Renal Group’s Specialised Register of studies, and data extraction and analysis and study quality assessment by two independent authors. The key limitation of the review is the data provided by available studies. First, long-term data for the effects of spironolactone therapy or eplerenone on major patient-centred endpoints including mortality, ESKD, and major cardiovascular events are absent or sparse. Second, data for patients who had severe CKD (stages 4 and 5) were not available in the included studies. Finally, there was a significant heterogeneity between studies in treatment effects on proteinuria. Although we explored causes of heterogeneity by type of kidney disease and study duration, yet insufficient data were available for testing the effect of baseline kidney function. Treatment duration and other factors may therefore modify the treatment effects we observed.

Agreements and disagreements with other studies or reviews

Widespread adoption of treatment using ACEi with or without ARB for adults who have diabetic or non-diabetic CKD proportionately reduces progression of CKD to ESKD requiring dialysis or transplantation by approximately 20% (RENAAL 2004; Strippoli 2005; Strippoli 2006). In addition, these agents have cardioprotective effects (RENAAL 2004; Strippoli 2005; Strippoli 2006). However, some patients treated with ACEi with or without ARB exhibit aldosterone escape, a phenomenon resulting in blunting of the effect of ACEi or ARB treatment (Staessen 1981). Addition of selective and non-selective aldosterone antagonists has been purported to avoid this phenomenon to provide additional protection against adverse kidney and cardiovascular events in adults who have CKD. The beneficial effects noted with this add-on therapy are attributed to the anti-fibrotic and antihypertensive effects of aldosterone antagonists observed both in animal and human studies (Nakhoul 2008; Tylicki 2008).

Meta-analysis of all available study data now confirm that non-selective aldosterone treatment in addition to standard RAS blockade lowers proteinuria, however the effects of treatment on clinical kidney and cardiovascular outcomes are uncertain and treatment is associated with important potential harms including hyperkalaemia and gynaecomastia. In a subgroup analysis, the risks of hyperkalaemia using spironolactone combined with both an ACEi and an ARB (triple therapy) resulted in a four-fold increase in hyperkalaemia when compared to dual blockade alone (spironolactone with either an ACEi or an ARB alone). Most patients who developed hyperkalaemia in these studies had GFR between 30 to 60 mL/min/1.73 m² (stage 3 CKD) and a separate analysis based on the severity of kidney disease could not be conducted as data stratified by GFR were unavailable from all the studies.

After publication of the Randomised Aldactone Study (RALES Study), a higher incidence of hyperkalaemia was reported as spironolactone use increased in patients with congestive heart failure (Juurlink 2004). Phillips 2007 showed that combination therapy for spironolactone with ACEi and ARB in individuals who had symptomatic left ventricular dysfunction was accompanied by a fourfold increase in the risk of hyperkalaemia (RR 4.87, 95% CI, 2.39 to 9.94). The recently published Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET 2008) found a higher incidence of hyperkalaemia in patients who were on ACEi and ARB in comparison to ACEi or ARB alone. Thus, clinicians need to be aware of this risk of hyperkalaemia whenever RAS blockade is being used in individuals with kidney or cardiac dysfunction (or both) and the addition of aldosterone antagonist may further increase this risk. Close monitoring of potassium levels is warranted when spironolactone is added to ARB or ACEi (or both) in all patients and especially in for those who have an eGFR < 30 mL/min/1.73 m².

Authors' conclusions

Implications for practice

In adults with CKD who have an eGFR between 30 and 90 mL/min/1.73 m² and who have persistent proteinuria despite being on maximal doses of ACEi or ARB (or both), aldosterone antagonists reduce proteinuria and BP but treatment effects on patient-relevant outcomes including progression to ESKD and major cardiovascular events are unknown. Treatment using spironolactone in combination with ACEi or ARB (or both) increases risks of hyperkalaemia and gynaecomastia. Evidence for selective aldosterone blockers (eplerenone) in adults who have CKD are sparse and evidence for all aldosterone antagonists in severe forms of CKD (stages 4 and 5) are absent.

Implications for research

Currently data supporting the use of aldosterone antagonists to improve survival, cardiovascular events and progression of CKD are absent and further studies would be informative, particularly for a safe use of these agents. Data for the use of aldosterone blockade in adults who have severe CKD (stages 4 and 5) are needed.

Acknowledgements

We would like to thank Sagar Nigwekar and Ashwini Sehgal who contributed to the design, quality assessment, data collection, entry, analysis and interpretation, and writing of the first version (Navaneethan 2009) of this review.

We would like to thank the referees for their editorial advice during the preparation of this review. We thank Narelle Willis of Cochrane Renal Group, for her help in co-ordinating and editing this review and Ruth Mitchell and Gail Higgins of Cochrane Renal Group for assistance in the development of search strategies. We also thank Drs KJ Schjoedt, K Rossing, A Chrysostomou, S Bianchi, S Nielsen and K Takebayashi for providing additional details about their studies which were included in this review.

Data and analyses

Download statistical data

Comparison 1. Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
2 Cardiovascular events1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
3 ESKD284Risk Ratio (M-H, Random, 95% CI)3.0 [0.33, 27.65]
4 Proteinuria11596Std. Mean Difference (IV, Random, 95% CI)-0.61 [-1.08, -0.13]
5 GFR [mL/min/1.73 m²]9528Mean Difference (IV, Random, 95% CI)-2.55 [-5.61, 0.51]
6 Systolic BP10556Mean Difference (IV, Random, 95% CI)-3.44 [-5.05, -1.83]
7 Diastolic BP9520Mean Difference (IV, Random, 95% CI)-1.73 [-2.83, -0.62]
8 Hyperkalaemia11632Risk Ratio (M-H, Random, 95% CI)2.00 [1.25, 3.20]
9 Hyperkalaemia: number of RAS inhibitors used11632Risk Ratio (M-H, Random, 95% CI)2.00 [1.25, 3.19]
9.1 Spironolactone plus 2 RAS inhibitors4149Risk Ratio (M-H, Random, 95% CI)4.30 [1.12, 16.51]
9.2 Spironolactone plus 1 RAS inhibitor9483Risk Ratio (M-H, Random, 95% CI)1.80 [1.09, 2.96]
10 Serum potassium11596Mean Difference (IV, Random, 95% CI)0.26 [0.13, 0.39]
11 Gynaecomastia4281Risk Ratio (M-H, Random, 95% CI)5.14 [1.14, 23.23]
12 Proteinuria: type of kidney disease11596Std. Mean Difference (IV, Random, 95% CI)-0.61 [-1.08, -0.13]
12.1 Non-diabetic kidney disease5367Std. Mean Difference (IV, Random, 95% CI)-0.68 [-1.57, 0.21]
12.2 Diabetic kidney disease6229Std. Mean Difference (IV, Random, 95% CI)-0.52 [-0.82, -0.23]
13 Proteinuria: study duration11596Std. Mean Difference (IV, Random, 95% CI)-0.61 [-1.08, -0.13]
13.1 Less than 6 months7265Std. Mean Difference (IV, Random, 95% CI)-0.60 [-0.87, -0.33]
13.2 More than 6 months4331Std. Mean Difference (IV, Random, 95% CI)-0.59 [-1.68, 0.50]
14 Proteinuria: descriptive outcome data  Other dataNo numeric data
15 GFR: descriptive outcome data  Other dataNo numeric data
16 Potassium: descriptive outcome data  Other dataNo numeric data
Analysis 1.1.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 1 Death.

Analysis 1.2.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 2 Cardiovascular events.

Analysis 1.3.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 3 ESKD.

Analysis 1.4.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 4 Proteinuria.

Analysis 1.5.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 5 GFR [mL/min/1.73 m²].

Analysis 1.6.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 6 Systolic BP.

Analysis 1.7.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 7 Diastolic BP.

Analysis 1.8.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 8 Hyperkalaemia.

Analysis 1.9.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 9 Hyperkalaemia: number of RAS inhibitors used.

Analysis 1.10.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 10 Serum potassium.

Analysis 1.11.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 11 Gynaecomastia.

Analysis 1.12.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 12 Proteinuria: type of kidney disease.

Analysis 1.13.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 13 Proteinuria: study duration.

Analysis 1.14.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 14 Proteinuria: descriptive outcome data.

Proteinuria: descriptive outcome data
StudyComparisonDescription of outcome
Koroshi 2010Spironolactone + ACEi versus ACEiIn comparison with placebo group, proteinuria decreased by 42.3% (95% CI, P = 0.004) in the group assigned to spironolactone
Lv 2009aSpironolactone + ACEi or ARB versus ACEi or ARB aloneAfter 9 month therapy, proteinuria decreased significantly (1.25 ± 0.61 g/d at baseline, 0.85 ± 0.56 g/d at 3rd month, 0.81 ± 0.61 g/d at 6th month, and 0.64 ± 0.42 g/d, at 9th month, P < 0.05) in patients treated with spironolactone, while it didn't change in control group
Mehdi 2009Spironolactone + ACEi versus ARBDuring the 48 week of treatment, albuminuria (UACR) decreased significantly from baseline in the ARB (P = 0.001) and spironolactone (P < 0.0001) groups but not in the placebo group (P = 0.08). At 48 weeks, the percentage change from the baseline was 24.6% (95% CI 54.8% to 25.9%) in those assigned to placebo, 38.2% (95% CI 59.3% to 5.9%) in those assigned to ARB, and 51.6% (95% CI 70.2% to 21.4%) in those assigned to spironolactone
Tokunaga 2008aSpironolactone + ARB versus ARB aloneSpironolactone reduced proteinuria from 1.70 ± 1.12 to 1.11 ± 1.13 g/g Cr (P < 0.05)

Analysis 1.15.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 15 GFR: descriptive outcome data.

GFR: descriptive outcome data
StudyComparisonDescription of outcome
Lv 2009aSpironolactone + ACEi or ARB versus ACEi or ARB aloneBy the end of 9th month, the monthly rate of decrease of eGFR was similar in the two groups (-0.66 in spironolactone group vs -0.94 mL/min/1.73 m² in control group, P = 0.28)

Analysis 1.16.

Comparison 1 Spironolactone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone, Outcome 16 Potassium: descriptive outcome data.

Potassium: descriptive outcome data
StudyComparisonDescription of outcome
Lv 2009aSpironolactone + ACEi or ARB versus ACEi or ARB aloneSpironolactone caused an increase in serum potassium after 9 months of treatment (from 3.8 ± 0.4 to 4.1 ± 0.3 mEq/L, P = 0.029)
Tokunaga 2008aSpironolactone + ARB versus ARB aloneSpironolactone produced a significant increase in serum potassium levels (from 4.31 ± 0.53 to 4.67 ± 0.68 mmol/L, P < 0.05)
Comparison 2. Spironolactone versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Systolic BP1 Mean Difference (IV, Random, 95% CI)Totals not selected
2 Diastolic BP1 Mean Difference (IV, Random, 95% CI)Totals not selected
3 Serum potassium1 Mean Difference (IV, Random, 95% CI)Totals not selected
4 Hyperkalaemia1 Risk Ratio (IV, Random, 95% CI)Totals not selected
5 Proteinuria data from cross-over studies  Other dataNo numeric data
6 GFR data from cross-over studies  Other dataNo numeric data
7 Blood pressure data from cross-over studies  Other dataNo numeric data
8 Hyperkalaemia data from cross-over studies  Other dataNo numeric data
Analysis 2.1.

Comparison 2 Spironolactone versus placebo, Outcome 1 Systolic BP.

Analysis 2.2.

Comparison 2 Spironolactone versus placebo, Outcome 2 Diastolic BP.

Analysis 2.3.

Comparison 2 Spironolactone versus placebo, Outcome 3 Serum potassium.

Analysis 2.4.

Comparison 2 Spironolactone versus placebo, Outcome 4 Hyperkalaemia.

Analysis 2.5.

Comparison 2 Spironolactone versus placebo, Outcome 5 Proteinuria data from cross-over studies.

Proteinuria data from cross-over studies
StudyComparisonDescriptive outcome data
Nielsen 2012Spironolactone versus placeboDuring spironolactone treatment, urinary albumin excretion was reduced by 60% (21% to 80%) from 90 mg/24 h to 35 mg/24 h when compared with placebo (P = 0.01)

Analysis 2.6.

Comparison 2 Spironolactone versus placebo, Outcome 6 GFR data from cross-over studies.

GFR data from cross-over studies
StudyComparisonDescriptive outcome data
Nielsen 2012spironolactone versus placeboSignificant decline in GFR from 78 mL/min/1.73 m² to 72 mL/min/1.73 m² (P = 0.003) during spironolactone treatment

Analysis 2.7.

Comparison 2 Spironolactone versus placebo, Outcome 7 Blood pressure data from cross-over studies.

Blood pressure data from cross-over studies
StudyComparisonDescription of outcomes
Nielsen 2012Spironolactone versus placeboNo significant changes in diastolic and systolic BP after the placebo or spironolactone period

Analysis 2.8.

Comparison 2 Spironolactone versus placebo, Outcome 8 Hyperkalaemia data from cross-over studies.

Hyperkalaemia data from cross-over studies
StudyComparisonDescription of outcomes
Nielsen 2012Spironolactone versus placeboTwo patients had severe hyperkalaemia (plasma potassium = 5.7 mmol/L). Four patients experienced light to moderate hyperkalaemia (plasma potassium = 5.0 to 5.4 mmol/L). Hyperkalaemia was mainly observed 2 weeks after the start of spironolactone treatment
Comparison 3. Spironolactone plus ACEi versus ACEi plus diuretics
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Proteinuria1 Mean Difference (IV, Random, 95% CI)Totals not selected
2 Systolic BP1 Mean Difference (IV, Random, 95% CI)Totals not selected
3 Diastolic BP1 Mean Difference (IV, Random, 95% CI)Totals not selected
4 Proteinuria data from cross-over studies  Other dataNo numeric data
5 Blood pressure data from cross-over studies  Other dataNo numeric data
6 GFR data from cross-over studies  Other dataNo numeric data
7 Potassium data from cross-over studies  Other dataNo numeric data
Analysis 3.1.

Comparison 3 Spironolactone plus ACEi versus ACEi plus diuretics, Outcome 1 Proteinuria.

Analysis 3.2.

Comparison 3 Spironolactone plus ACEi versus ACEi plus diuretics, Outcome 2 Systolic BP.

Analysis 3.3.

Comparison 3 Spironolactone plus ACEi versus ACEi plus diuretics, Outcome 3 Diastolic BP.

Analysis 3.4.

Comparison 3 Spironolactone plus ACEi versus ACEi plus diuretics, Outcome 4 Proteinuria data from cross-over studies.

Proteinuria data from cross-over studies
StudyComparisonDescriptive outcome data
Smolen 2006Spironolactone verus hydrochlorothiazideAt the start of treatment with spironolactone or hydrochlorothiazide, PCR was 1.65 ± 1.39 and 1.46 ± 1.28 g/g, respectively. After 8 weeks of treatment with spironolactone proteinuria was significantly reduced to 0.99 ± 1.03 g/g (P = 0.03; a decrease of 0.66 ± 0.64 g/g) but not after hydrochlorothiazide (1.28 ± 1.18 g/g; P = 0.35, a decrease of 0.18 ± 0.83 g/g)

Analysis 3.5.

Comparison 3 Spironolactone plus ACEi versus ACEi plus diuretics, Outcome 5 Blood pressure data from cross-over studies.

Blood pressure data from cross-over studies
StudyComparisonDescriptive outcome data
Smolen 2006Spironolactone verus hydrochlorothiazideMean 24 h BP was similar at the start of treatment with spironolactone or hydrochlorothiazide (95.7 ± 10.2 and 95.6 ± 9.1 mm Hg, respectively). Both drugs did not significantly influence the 24 h BP (post-treatment values were 95.6 ± 10.4 and 96.4 ± 12.1 mm Hg, respectively)

Analysis 3.6.

Comparison 3 Spironolactone plus ACEi versus ACEi plus diuretics, Outcome 6 GFR data from cross-over studies.

GFR data from cross-over studies
StudyComparisonDescriptive outcome data
Smolen 2006Spironolactone versus hydrochlorothiazideMean baseline GFR was 94 ± 25 in the spironolactone and 95 ± 28 mL/min in the hydrochlorothiazide group. After treatment the GFR remained similar in the two groups (91 ± 28 versus 93 ± 29 mL/min respectively)

Analysis 3.7.

Comparison 3 Spironolactone plus ACEi versus ACEi plus diuretics, Outcome 7 Potassium data from cross-over studies.

Potassium data from cross-over studies
StudyComparisonDescriptive outcome data
Smolen 2006Spironolactone verus hydrochlorothiazideSerum potassium concentration was 4.23 ± 0.39 and 4.29 ± 0.37 mmol/L, in the spironolactone and hydrochlorothiazide group, respectively. It tended to increase in the spironolactone group after treatment (0.29 ± 0.39 mmol/L, P = 0.01) while it remained stable in the hydrochlorothiazide group (-0.13 ± 0.4 mmol/L, P = 0.18)
Comparison 4. Spironolactone versus calcium channel blockers
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Systolic BP1 Mean Difference (IV, Random, 95% CI)Totals not selected
2 Diastolic BP1 Mean Difference (IV, Random, 95% CI)Totals not selected
3 Potassium1 Mean Difference (IV, Random, 95% CI)Totals not selected
4 Proteinuria: descriptive outcome data  Other dataNo numeric data
Analysis 4.1.

Comparison 4 Spironolactone versus calcium channel blockers, Outcome 1 Systolic BP.

Analysis 4.2.

Comparison 4 Spironolactone versus calcium channel blockers, Outcome 2 Diastolic BP.

Analysis 4.3.

Comparison 4 Spironolactone versus calcium channel blockers, Outcome 3 Potassium.

Analysis 4.4.

Comparison 4 Spironolactone versus calcium channel blockers, Outcome 4 Proteinuria: descriptive outcome data.

Proteinuria: descriptive outcome data
StudyComparisonDescription of outcome
Takebayashi 2006Spironolactone versus amlodipineSpironolactone reduced UAE from 543.7 (170 to 1146) to 376.7 (135 to 794) mg/g Cr (P = 0.003). UAE did not change in amlodipine group (P = 0.38)
Comparison 5. Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Hyperkalaemia2500Risk Ratio (M-H, Random, 95% CI)1.62 [0.66, 3.95]
2 Proteinuria data from cross-over studies  Other dataNo numeric data
3 Proteinuria: descriptive outcome data  Other dataNo numeric data
4 Blood pressure data from cross-over studies  Other dataNo numeric data
5 Blood pressure: descriptive outcome data  Other dataNo numeric data
6 Systolic BP: descriptive outcome data  Other dataNo numeric data
Analysis 5.1.

Comparison 5 Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both), Outcome 1 Hyperkalaemia.

Analysis 5.2.

Comparison 5 Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both), Outcome 2 Proteinuria data from cross-over studies.

Proteinuria data from cross-over studies
StudyComparisonDescription of outcome
Boesby 2011Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both)Albuminuria was significantly lower during the add-on eplerenone period as compared with the control period with a 22% (95% CI 14 to 28, P < 0.001), lower excretion. The mean 24 h excretion was 1481 mg (95% CI 1192 to 1840) during the control period and 1163 mg (95% CI 921 to 1468) during add-on eplerenone. No significant carry-over, P = 0.3 or time effect, P = 0.3, was detected for the UAE

Analysis 5.3.

Comparison 5 Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both), Outcome 3 Proteinuria: descriptive outcome data.

Proteinuria: descriptive outcome data
StudyComparisonDescription of outcome
Cohen 2010Eplerenone plus ACEi or ARB versus ACEi plus ARBUrine protein excretion (g/24 h) was reduced by 1.04 ± 0.4 in the eplerenone and by 0.32 ± 0.2 in the ACEi plus ARB group
Epstein 2002Eplerenone plus ACEi versus ACEiUAE was reduced by 74% in the eplerenone and by 45% in the control group
Epstein 2006Eplerenone plus ACEi versus ACEiEplerenone treatment significantly reduced albuminuria from baseline as early as week 4
and continued throughout weeks 8 and 12. ACEi treatment did not result in any significant decrease from baseline in albuminuria
Haykal 2007Eplerenone plus ACEi versus ACEiEplerenone treatment reduced proteinuria after 4 weeks. The effect continued throughout weeks 8 and 12 (P < 0.001)

Analysis 5.4.

Comparison 5 Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both), Outcome 4 Blood pressure data from cross-over studies.

Blood pressure data from cross-over studies
StudyComparisonDescription of outcome
Boesby 2011Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both) aloneSystolic and diastolic BP was significantly lower during add-on eplerenone treatment when compared to the control period. There was a significant reduction of systolic BP after 2 weeks of eplerenone treatment (P = 0.003). The diastolic BP was significantly reduced after 4 weeks of eplerenone treatment (P = 0.002), and there was a significant difference in diastolic BP between the treatment period and control period at the same time point (P = 0.004).There were no significant differences between diastolic BP at the end of the 2 periods. There were no significant carry-over, P = 0.4 and P = 0.9, or time effects, P = 0.5 and P = 0.2 for systolic BP or diastolic BP

Analysis 5.5.

Comparison 5 Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both), Outcome 5 Blood pressure: descriptive outcome data.

Blood pressure: descriptive outcome data
StudyComparisonDescription of outcome
Epstein 2002Eplerenone plus ACEi versus ACEiSystolic BP was reduced by 21.8% and 20.4% in the eplerenone and control group respectively. Diastolic BP was reduced by 16.2% and 15% in the eplerenone and control group respectively
Epstein 2006Eplerenone plus ACEi versus ACEiBoth systolic and diastolic BP decreased in at weeks 4, 8, and 12 in eplerenone and control groups. There were no significant differences in BP reduction between groups
Haykal 2007Eplerenone plus ACEi versus ACEiBoth systolic and diastolic BP decreased in the two groups at weeks 4, 8 and 12 (P < 0.001). BP reduction was slightly higher in eplerenone group

Analysis 5.6.

Comparison 5 Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both), Outcome 6 Systolic BP: descriptive outcome data.

Systolic BP: descriptive outcome data
StudyComparisonDescription of outcome
Cohen 2010Eplerenone plus ACEi or ARB versus ACEi plus ARBSystolicBP was reduced by 9.7 ± 6.4 mm Hg in the eplerenone group and by 13.4 ± 14.9 mm Hg in the ACEi plus ARB group
Comparison 6. Eplerenone versus ACEi
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Proteinuria data from cross-over studies  Other dataNo numeric data
2 Hyperkalaemia data from cross-over studies  Other dataNo numeric data

Analysis 6.1.

Comparison 6 Eplerenone versus ACEi, Outcome 1 Proteinuria data from cross-over studies.

Proteinuria data from cross-over studies
StudyComparisonDescriptive outcome data
Morales 2009Eplerenone versus ACEiACEi (lisinopril) induced a reduction in proteinuria (11.3 ± 34.8%) which was not statistically significant with respect to baseline values (P = 0.158), while that induced by eplerenone (28.4 ± 31.6%) was significant with respect to baseline values (comparison P = 0.034) and to the lisinopril group (P = 0.034)

Analysis 6.2.

Comparison 6 Eplerenone versus ACEi, Outcome 2 Hyperkalaemia data from cross-over studies.

Hyperkalaemia data from cross-over studies
StudyComparisonDescription of outcome
Morales 2009Eplerenone versus ACEiThe number of patients in which serum potassium was above 5.5 mEq/L after treatment was 2/12
(16%) with ACEi (lisinopril) while none of the patients treated with eplerenone reached this level of potassium
Comparison 7. Eplerenone versus ACEi plus ARB
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Proteinuria data from cross-over studies  Other dataNo numeric data
2 Hyperkalaemia data from cross-over studies  Other dataNo numeric data

Analysis 7.1.

Comparison 7 Eplerenone versus ACEi plus ARB, Outcome 1 Proteinuria data from cross-over studies.

Proteinuria data from cross-over studies
StudyComparisonDescription of outcome
Morales 2009Eplerenone versus ACEi plus ARBBoth eplerenone and the combination of ACEi plus ARB (lisinopril and candesartan) obtained a significant reduction of proteinuria from baseline (26.9 ± 30.6% and 28.4 ± 31.6%, P = 0.045 and P = 0.034 respectively)

Analysis 7.2.

Comparison 7 Eplerenone versus ACEi plus ARB, Outcome 2 Hyperkalaemia data from cross-over studies.

Hyperkalaemia data from cross-over studies
StudyComparisonDescription of outcome
Morales 2009Eplerenone versus ACEi plus ARBThe number of patients in which serum potassium was above 5.5 mEq/L after treatment was 2/12 (16%) with ACEi plus ARBs (lisinopril plus candesartan) while none of the patients treated with eplerenone reached this level of potassium
Comparison 8. Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both) plus nitrate
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Proteinuria: descriptive outcome data  Other dataNo numeric data
2 Systolic BP: descriptive outcome data  Other dataNo numeric data

Analysis 8.1.

Comparison 8 Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both) plus nitrate, Outcome 1 Proteinuria: descriptive outcome data.

Proteinuria: descriptive outcome data
StudyComparisonDescription of outcome
Cohen 2010Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both) plus isosorbideUrine protein excretion (g/24 h) was reduced by 1.04 ± 0.4 in the eplerenone group but increased in the ACEi/ARB plus isosorbide group by 0.2 ± 0.3

Analysis 8.2.

Comparison 8 Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both) plus nitrate, Outcome 2 Systolic BP: descriptive outcome data.

Systolic BP: descriptive outcome data
StudyComparisonDescription of outcome
Cohen 2010Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both) plus isosorbideSystolic blood pressure was reduced by 9.7 ± 6.4 mm Hg in the eplerenone group and by 1.0 ± 5.4 mm Hg in the ACEi/ARB plus isosorbide group

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. MeSH descriptor Aldosterone Antagonists explode all trees

  2. (Canrenoate Potassium*):ti,ab,kw in Clinical Trials

  3. (Canrenone*):ti,ab,kw in Clinical Trials

  4. (spironolactone*):ti,ab,kw in Clinical Trials

  5. (aldosterone antagonist*):ti,ab,kw in Clinical Trials

  6. (aldactone*):ti,ab,kw in Clinical Trials

  7. (practon*):ti,ab,kw in Clinical Trials

  8. (sc-9420*):ti,ab,kw in Clinical Trials

  9. (spiractin*):ti,ab,kw in Clinical Trials

  10. (sc-14266*):ti,ab,kw in Clinical Trials

  11. (soldactone*):ti,ab,kw in Clinical Trials

  12. (soludactone*):ti,ab,kw in Clinical Trials

  13. (aldadiene*):ti,ab,kw in Clinical Trials

  14. (phanurane*):ti,ab,kw in Clinical Trials

  15. (sc-9376*):ti,ab,kw in Clinical Trials

  16. (eplerenone*):ti,ab,kw in Clinical Trials

  17. (#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)

  18. MeSH descriptor Renal Insufficiency, Chronic explode all trees

  19. (chronic kidney disease* or chronic renal disease*):ti,ab,kw in Clinical Trials

  20. (chronic kidney failure* or chronic renal failure*):ti,ab,kw in Clinical Trials

  21. (chronic kidney insufficiency or chronic renal insufficiency):ti,ab,kw in Clinical Trials

  22. MeSH descriptor Renal Insufficiency, this term only

  23. MeSH descriptor Kidney Diseases, this term only

  24. (CKF or CKD or CRF or CRD):ti,ab,kw in Trials

  25. (predialysis or pre-dialysis):ti,ab,kw in Trials

  26. MeSH descriptor Uremia, this term only

  27. uremia or uraemia or uremic or uraemic:ti,ab,kw in Trials

  28. MeSH descriptor Diabetic Nephropathies, this term only

  29. (diabetic nephropath*):ti,ab,kw in Trials

  30. "diabetic kidney disease":ti,ab,kw in Trials

  31. (#18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30)

  32. (#17 AND #31)

MEDLINE
  1. exp Aldosterone Antagonists/

  2. Canrenoate Potassium.tw.

  3. Canrenone$.tw.

  4. spironolactone$.tw.

  5. aldosterone antagonist$.tw.

  6. aldactone$.tw.

  7. practon$.tw.

  8. sc-9420$.tw.

  9. spiractin$.tw.

  10. sc-14266$.tw.

  11. soldactone$.tw.

  12. soludactone$.tw.

  13. aldadiene$.tw.

  14. phanurane$.tw.

  15. sc-9376.tw.

  16. eplerenone$.tw.

  17. or/1-16

  18. Renal Insufficiency/

  19. exp Renal Insufficiency, Chronic/

  20. Kidney Diseases/

  21. (chronic kidney or chronic renal).tw.

  22. (CKF or CKD or CRF or CRD).tw.

  23. (predialysis or pre-dialysis).tw.

  24. exp Uremia/

  25. ur$emi$.tw.

  26. (pre-dialy$ or predialy$).tw.

  27. Diabetic Nephropathies/

  28. diabetic nephropath$.tw.

  29. "diabetic kidney disease".tw.

  30. or/18-29

  31. and/17,30

EMBASE
  1. exp Aldosterone Antagonist/

  2. aldosterone antagonist$.tw.

  3. spironolactone$.tw.

  4. eplerenone$.tw.

  5. soludactone$.tw.

  6. canrenoate potassium.tw.

  7. canrenone$.tw.

  8. or/1-7

  9. Kidney Disease/

  10. Chronic Kidney Disease/

  11. Kidney Failure/

  12. Chronic Kidney Failure/

  13. Kidney dysfunction/

  14. (chronic kidney or chronic renal).tw.

  15. (CKF or CKD or CRF or CRD).tw.

  16. (pre-dialy$ or predialy$).tw.

  17. diabetic nephropathy/

  18. "diabetic kidney disease".tw.

  19. or/9-18

  20. and/8,19

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.

What's new

DateEventDescription
28 April 2014New citation required and conclusions have changed10 new studies added, new comparisons added
30 January 2013New search has been performedNew update search completed, new studies identified

History

DateEventDescription
22 February 2012AmendedUpdate search completed
20 February 2012AmendedSearch methods & search strategies updated
2 September 2008AmendedConverted to new review format.

Contributions of authors

  • Writing of protocol and review: SP, DB, SDN, SUN, AS, GS

  • Screening of titles and abstracts: DB, SDN, SUN

  • Assessment for inclusion: DB, SDN, SUN

  • Quality assessment: DB, SDN, SUN

  • Data extraction: DB, SDN, SUN

  • Data entry into RevMan: DB, SDN

  • Data analysis and interpretation: DB, SP, SDN, SUN, GS

  • Disagreement resolution: SP, GS

Declarations of interest

SP receives a Fellowship from the Consorzio Mario Negri Sud from an unrestricted educational grant from Amgen Dompé and is a recipient of the 2012 L’Oreal For Women in Science Fellowship in Australia and New Zealand. DB received an Honorary Fellowship from the Cochrane Renal Group as fellow of the European Renal Best Practice (ERBP) group.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Abolghasmi 2011

Methods
  • Study design: parallel RCT

  • Study duration: NS

  • Study follow-up: 12 weeks

Participants
  • Country: Iran

  • Setting: NS

  • Patients with CKD and resistant hypertension

  • Number: treatment group (19); control group (22)

  • Mean age ± SD (years): treatment group (49 ± 13.2); control group (50 ± 10.1)

  • Sex (M/F): treatment group (10/9); control group (12/10)

  • Exclusion criteria: secondary hypertension (renovascular, primary hyperaldosteronism, pheochromocytoma, cushing)

Interventions

Treatment group

  • SPL: 25 to 50 mg/d for 12 weeks

Control group

  • Placebo for 12 weeks

Outcomes
  • BP

  • Hyperkalaemia

Notes
  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"randomly divided into two groups" unsure how this was done
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk"randomly divided into two groups in a double-blind fashion". unsure who was blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk"randomly divided into two groups in a double-blind fashion". unsure who was blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients completed the study
Selective reporting (reporting bias)Low riskAll defined outcomes have been reported
Other biasUnclear riskFunding: NS

Bianchi 2006

Methods
  • Study design: open-label RCT

  • Study duration: NS

  • Follow-up: 12 months

Participants
  • Country: Italy

  • Setting: NS

  • CKD from idiopathic glomerulonephritis (proteinuria >1 g/g Cr with no evidence of systemic disease)

  • Number: treatment group (83); control group (82)

  • Mean age ± SEM (years): treatment group (55 ± 1.2); control group (54.4 ± 1.2)

  • Sex (M/F): treatment group (50/32); control group (56/27)

  • Exclusion criteria: DM; renovascular and malignant hypertension; secondary glomerular diseases; malignancy; CHF; hyperkalaemia (serum potassium > 5 mEq/L); eGFR < 30 mL/min

Interventions

Treatment group

  • SPL: 25 mg/d

  • Conventional treatment: ACEi or ARB (or both)

Control group

  • Conventional treatment: ACEi or ARB (or both)

Duration of intervention: one year

Outcomes
  • Proteinuria

  • BP

  • Serum potassium

  • eGFR

  • Need for RRT

  • Gynaecomastia

Notes
  • Funding: "This study was supported with private funding. No support was received by pharmaceutical companies."

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskquote: "The randomisation was performed using a computed generated system"
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label study
Incomplete outcome data (attrition bias)
All outcomes
Low risk5/83 patients in the SPL group and 4/82 in the control group withdrew. They were included in the analysis as ITT
Selective reporting (reporting bias)Unclear riskAll defined outcomes have been reported
Other biasLow riskPrivately funded

Boesby 2011

Methods
  • Study design: cross-over RCT

  • Study duration: April 2007 to August 2009

  • Follow-up: 8 weeks

Participants
  • Country: Denmark

  • Setting: NS

  • Age > 18 years; 24 h proteinuria > 500 mg; 24 h albuminuria > 300 mg; BP > 130/80 mm Hg

  • Number: 40

  • Age (range): 45 years (21–71)

  • Sex (M/F): 27/13

  • Exclusion criteria: DKD; eGFR < 20 mL/min; potassium > 5.0 mEq/L; allergy to AA; pregnancy; liver insufficiency; lithium; steroids

Interventions

Treatment group

  • EPL: 25 to 50 mg/d

  • Standard therapy (including ACEi or ARB)

Control group

  • Standard therapy (including ACEi or ARB)

Duration of intervention: 8 weeks

Outcomes
  • 24 h albuminuria

  • BP changes

  • Serum potassium

  • eGFR

Notes
  • Cross-over study, no washout period

  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Low riskRandomization was done through drawing sealed opaque envelopes
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label study
Incomplete outcome data (attrition bias)
All outcomes
Low riskUse of ITT analysis. Two patients dropped out
Selective reporting (reporting bias)Unclear riskAll defined outcomes have been reported
Other biasUnclear riskFunding: NS

Chrysostomou 2006

Methods
  • Study design: parallel RCT

  • Study duration: January 2002 to September 2004

  • Follow-up: 3 months

Participants
  • Country: Australia

  • Setting: university

  • 24 h proteinuria > 1.5 g/24 h; SCr < 200 µmol/L; treatment with ACEi for at least 6 months

  • Number: treatment group (11); control group (10)

  • Mean age ± SD (years): treatment group (55.9 ± 15.4); control group (56.3 ± 8.8)

  • Sex (M/F): treatment group (6/5); control group (8/2)

  • Exclusion criteria: severe hypertension; hyperkalaemia (> 5 mEq/L); renovascular disease; serum bicarbonate < 20 mEq/L

Interventions

Treatment group

  • SPL: 25 mg/d

  • ACEi and ARB

Control group

  • Placebo

  • ACEi and ARB

Duration of intervention: 3 months

Outcomes
  • Proteinuria

  • BP

  • Serum potassium

  • Need for RRT

  • Gynaecomastia

  • CrCl

Notes
  • Funding: investigator initiated and entirely internally funded

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote "Treatment assignment was by simple randomisation"
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up
Selective reporting (reporting bias)Low riskAll defined outcomes have been reported
Other biasLow riskInternally funded

Cohen 2010

Methods
  • Study design: RCT

  • Study duration: NS

  • Follow-up: 4 months

Participants
  • Country: USA

  • Setting: NS

  • CKD stages 1-3; proteinuria > 500 mg/d

  • Number: treatment group (14); control group 1 (7); control group 2 (13)

  • Mean age ± SD (years): 53.9 ± 13.6

  • Sex (M/F): 82% males

  • Exclusion criteria: NS

Interventions

Treatment group

  • EPL

  • ACEi or ARB

Control group 1

  • ACEi and ARB

Control group 2

  • ACEi and ARB

  • Isosorbide

Duration of intervention: 4 months

Outcomes
  • Proteinuria

Notes
  • Abstract only

  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNS
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Low risk2/7 patients in one comparator group withdrew. They were analysed as ITT
Selective reporting (reporting bias)Unclear riskUnclear
Other biasUnclear riskFunding: NS

CRIBS II Study 2009

Methods
  • Study design: parallel RCT

  • Study duration: 2005 to 2007

  • Follow-up: 36 weeks

Participants
  • Country: UK

  • Setting: university teaching hospital

  • Age 18 to 80 years; stage 2 (GFR 60 to 89 mL/min/1.73 m² and evidence of kidney damage for 3 months) or stage 3 (GFR 30 to 59 mL/min/1.73 m²) CKD (15); treatment with an ACEi or ARB (or both) for at least 6 months; controlled BP (mean daytime BP on ambulatory monitoring 130/85 mm Hg)

  • Number: treatment group (56); control group (56)

  • Mean age ± SD (years): treatment group (54 ± 12); control group (53 ± 12)

  • Sex (males): treatment group (57%); control group (59%)

  • Exclusion criteria: a history or other evidence of angina, myocardial infarction, heart failure, cerebral or peripheral vascular disease; DM; previous hyperkalaemia; valvular heart disease; atrial fibrillation; renovascular disease; anaemia (Hb < 12 g/dL)

Interventions

Treatment group

  • SPL: 25 mg/d

  • ACEi or ARB

Control group

  • Placebo

  • ACEi or ARB

Duration of intervention:36 weeks (plus 4 weeks run in)

Outcomes
  • LV mass/arterial stiffness

  • Aortic distensibility

  • BP

  • Albuminuria

NotesFunding: British Heart Foundation project grant
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Low risk4/112 patients withdrew from the study. These patients were included in the final analysis as ITT.
Selective reporting (reporting bias)Low riskAll defined outcomes have been reported
Other biasLow riskGrant from British Heart Foundation

Epstein 2002

Methods
  • Study design: parallel RCT

  • Study duration: NS

  • Follow-up: 6 months

Participants
  • Country: USA

  • Setting: university

  • Type 2 diabetes with mild to moderate hypertension (diastolic BP > 95 mm Hg and < 110 mm Hg; systolic BP < 180 mm Hg); microalbuminuria (urinary albumin:Cr ratio < 50 mg/g)

  • Number: treatment group (67); control group (74)

  • Mean age ± SD (years): NS

  • Sex (M/F): NS

  • Exclusion criteria: NS

Interventions

Treatment group

  • EPL: 200 mg/d

  • ACEi

Control group

  • ACEi

Duration of intervention: 6 months

Outcomes
  • Serum potassium

  • Need for RRT

Notes
  • Abstract

  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNS
Selective reporting (reporting bias)Unclear riskNS
Other biasUnclear riskFunding: NS

Epstein 2006

Methods
  • Study design: parallel RCT

  • Study duration: NS

  • Follow-up: 3 months

Participants
  • Country: USA

  • Setting: university; multicentre

  • Type 2 diabetes with albuminuria (urinary albumin:Cr ratio > 50 mg/g)

  • Number: treatment group (177); control group (91)

  • Median age (years): treatment group (58); control group (60)

  • Sex (M/F): treatment group (116/61); control group (50/41)

  • Exclusion criteria: severe hypertension; CrCl < 70 mL/min; orthostatic hypotension 

Interventions

Treatment group

  • EPL: 50 to 100 mg/d

  • ACEi

Control group

  • Placebo

  • ACEi

Duration of intervention: 3 months

Co-interventions: amlodipine if BP uncontrolled at 4 weeks

Outcomes
  • Serum potassium

  • Need for RRT

Notes
  • Funding: financial support for this study was provided by Pharmacia, Inc. (currently Pfizer Inc.), Skokie, IL. Editorial support was provided by Jennifer L. Alexander, MSc, at Medesta Publication Group and was funded by Pfizer Inc.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Low risk11/91 patients in the control group, 8/91 and 9/86 in the EPL 50 and 100 mg groups respectively, withdrew. The overall percentage of withdrawal was 13%. These patients were analysed on a ITT basis
Selective reporting (reporting bias)Unclear riskNS
Other biasHigh riskFunded by Pharmacia, Inc

Furumatsu 2008

Methods
  • Study design: parallel RCT

  • Study duration: 2002 to 2004

  • Follow-up: 12 months

Participants
  • Country: Japan

  • Setting: university; multicentre (2)

  • CKD (SCr < 3.0 mg/dL or calculated CrCl > 30 mL/min/1.73 m²); controlled BP < 130/80 mm Hg; persistent proteinuria (urinary protein excretion > 0.5 g/d)

  • Number: treatment group (15); control group (15)

  • Mean age ± SD (years): treatment group (49.8 ± 2.7); control group (53.9 ± 2.7)

  • Sex (M/F): treatment group (10/5); control group (9/6)

  • Exclusion criteria:

  • DM (> HbA1c 5.8%); severe kidney failure (SCr > 3.0 mg/dL); uncontrolled hyperkalaemia (serum potassium concentration > 5.0 mEq/L); proteinuria > 5.0 g/g Cr; renovascular hypertension or malignant hypertension

Interventions

Treatment group

  • SPL: 25 mg/d

  • ACEi and ARB

Control group

  • ACEi and ARB

  • Furosemide if Cr ≥1.8 mg/dL or trichlormethiazide if Cr < 1.8 mg/dL

Duration of intervention: one year

Outcomes
  • Proteinuria

  • BP

  • Serum potassium

  • SCr

  • eGFR

  • Gynaecomastia

Notes
  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label study
Incomplete outcome data (attrition bias)
All outcomes
Low riskOne patient in the SPL and one in the control group were lost to follow-up 
Selective reporting (reporting bias)Low riskall defined outcomes have been reported
Other biasUnclear riskFunding: NS

Guney 2009

Methods
  • Study design: parallel RCT

  • Study duration: NS

  • Follow-up: 6 months

Participants
  • Country: Turkey

  • Setting: NS

  • Age of 20–70 years; controlled BP < 130/80 mm Hg; CKD (SCr < 3.0 mg/dL or eGFR > 30 mL/min/1.73 m², and persistent proteinuria as defined by urinary protein excretion exceeding 0.5 mg/mg Cr and daily treatment with ACEI or ARB (or both) for 6 months or more

  • Number: treatment group (15); control group (15)

  • Mean age ± SD (years): treatment group (45.9 ± 11.2); control group (39.1 ± 13.0)

  • Sex (M/F): treatment group (9/3); control group (8/4)

  • Exclusion criteria: DM; UTI; need for treatment with corticosteroids, non-steroidal anti-inflammatory drugs, or immunosuppressive drugs; hyperkalaemia (serum potassium concentration > 5.5 mEq/L); proteinuria > 10 g/d; hypoalbuminaemia < 2.8 mg/dL; pregnancy

Interventions

Treatment group

  • SPL: 25 mg/d

  • Standard therapy including ACEi or ARB

Control group

  • Standard therapy including ACEi or ARB

Duration of intervention:6 months

Outcomes
  • Proteinuria

  • eGFR

  • BP

  • Plasma aldosterone

  • Hyperkalaemia

Notes
  • Funding: this study was supported by Ali Raif Drug Industry A.C. for providing TGF-b1 and aldosterone kits

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNS
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNS
Selective reporting (reporting bias)Low riskAll defined outcomes data have been reported
Other biasUnclear riskUnsure if the company only supplied kits or if they also funded the study

Haykal 2007

Methods
  • Study design: parallel RCT

  • Study duration: NS

  • Follow-up: 12 weeks

Participants
  • Country: Ukraine

  • Setting: NS

  • CKD stage 1-3; non nephrotic proteinuria

  • Number: treatment group (12); control group (10)

  • Mean age ± SD (years): 23.4 ± 2.1

  • Sex (M/F): 14/8

  • Exclusion criteria: NS

Interventions

Treatment group

  • EPL: 25 to 50 mg/d

  • ACEi

Control group

  • ACEi

Duration of intervention:28 weeks

Outcomes
  • Proteinuria

  • GFR

  • BP

Notes
  • Abstract

  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNS
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Low risk3/15 patients in both treatment and control groups withdrew. However, these patients were not included in the final analysis (no ITT)
Selective reporting (reporting bias)Unclear riskNS
Other biasUnclear riskFunding: NS

Koroshi 2010

Methods
  • Study design: parallel RCT

  • Study duration: NS

  • Follow-up: 72 weeks

Participants
  • Country: Albania

  • Setting: NS

  • DKD; arterial hypertension; proteinuria (> 300 mg/d)

  • Number: 62

  • Mean age ± SD (years): NS

  • Sex (M/F): NS

  • Exclusion criteria: NS

Interventions

Treatment group

  • SPL: 50 mg/d

  • ACEi

Control group 1

  • Placebo

  • ACEi

Control group 2

  • ACEi and ARB

Duration of intervention: 72 weeks

Outcomes
  • Proteinuria

  • BP

Notes
  • Abstract

  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNS
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNS
Selective reporting (reporting bias)Unclear riskNS
Other biasUnclear riskFunding: NS

Lv 2009a

Methods
  • Study design: parallel RCT

  • Study duration: NS

  • Follow-up: 9 months

Participants
  • Country: China

  • Setting: NS

  • eGFR > 30 mL/min; proteinuria > 0.5 g/d

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

  • Mean age ± SD (years): NS

  • Sex (M/F): NS

  • Exclusion criteria: NS

Interventions

Treatment group

  • SPL: 20 mg/d

  • ACEi or ARB

Control group

  • ACEi or ARB

Duration of intervention: 9 months

Outcomes
  • Proteinuria

  • eGFR

  • BP

Notes
  • Abstract

  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNS
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNS
Selective reporting (reporting bias)Unclear riskNS
Other biasUnclear riskFunding: NS

Mehdi 2009

Methods
  • Study design: parallel RCT

  • Study duration: August 2003 to March 2007

  • Follow-up: 52 weeks

Participants
  • Country: USA

  • Setting: university

  • Systolic BP > 130 mm Hg, UACR > 300 mg/g

  • Number: treatment group (27); control group 1 (27); control group 2 (26)

  • Mean age ± SD (years): treatment group (52 ± 9); control group 1 (49 ± 9); control group 2 (52 ± 9)

  • Sex (M/F): treatment group (13/14); control group 1 (12/15); control group 2 (13/13)

  • Exclusion criteria: BMI > 45; SCr > 3.0; potassium > 5.5 mEq/L; HbA1c > 11; recent IMA or stroke, heart failure

Interventions

Treatment group

  • SPL: 12.5-25 mg/d

  • ACEi: lisinopril 80 mg/d

Control group 1

  • Placebo

  • ACEi: lisinopril 80 mg/d

Control group 2

  • ARB: losartan 50 to 100 mg/d

  • ACEi: lisinopril 80 mg/d

Duration of intervention:48 weeks plus 4 weeks run-in

Co-interventions: add-on antihypertensive medications, including diuretics, and blockers, central acting agonists, and vasodilators, were used to achieve and maintain a goal systolic BP < 130 mm Hg

Outcomes
  • Albuminuria

  • BP

  • GFR

  • ESRD

  • Potassium

  • Mortality

Notes
  • Funding: this study was supported by the National Institute of Diabetes Digestive and Kidney Diseases (2-R01 DK6301001) and the National Center for Research Resources General Clinical Research Center (M01-RR-00633 and CTSA UL1-RR-024982).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlocked randomisation stratified by diabetes type was programmed to determine treatment assignment
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind study
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
High risk10/27 patients assigned to SPL, 6/27 assigned to placebo and 9/27 assigned to losartan withdrew
Selective reporting (reporting bias)Low riskAll defined outcomes have been reported
Other biasLow riskFunded by National Institute of Diabetes Digestive and Kidney Diseases (2-R01 DK6301001) and the National Center for Research Resources General Clinical Research Center (M01-RR-00633 and CTSA UL1-RR-024982)

Morales 2009

Methods
  • Study design: parallel RCT

  • Study duration: NS

  • Follow-up: 6 weeks

Participants
  • Country: Spain

  • Setting: university

  • Proteinuria > 0.5 g/d; BMI > 30; eGFR > 15 mL/min

  • Number: treatment group (12); control group 1 (12); control group 2 (12)

  • Mean age ± SD (years): 57 ± 14.13

  • Sex (M/F): 7/5

  • Exclusion criteria: NS

Interventions

Treatment group

  • EPL: 25 mg/d

Control group 1

  • ACEi: lisinopril 20 mg/d

Control group 2

  • ACEi: lisinopril 10 mg/d

  • Candesartan: 16 mg/d

Duration of intervention: 6 weeks

Outcomes
  • 24 h proteinuria

  • BP

  • GFR

  • Plasma aldosterone

  • Plasma renin activity

Notes
  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Low riskRandomisation was carried out by means of envelopes containing the order of treatment which the patients was to receive
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNS
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll the patients completed the study
Selective reporting (reporting bias)Low riskAll defined outcomes have been reported
Other biasUnclear riskFunding: NS

Nielsen 2012

Methods
  • Study design: cross-over RCT

  • Study duration: NS

  • Follow-up: 2 months

Participants
  • Country: Denmark

  • Setting: single centre

  • Type I DM with albuminuria

  • Number: 21

  • Mean age ± SD (years): 58.3 ± 10.1

  • Sex (M/F): 14/7

  • Exclusion criteria: macroalbuminuria (> 300 mg/24 h) at any time before inclusion or at randomisation; plasma potassium > 4.7 mmol/L; pregnancy; breastfeeding; lack of safe contraception in women; abuse of alcohol or medicine; allergy to ACEi, ARB, or SPL; BP > 160/100 mm Hg; HbA1c > 86 mmol/mol (HbA1c > 10%); treatment with aldosterone antagonists

Interventions

Treatment group

  • SPL: 25 mg/d

  • Standard therapy (including ACEi or ARB)

Control group

  • Placebo

  • Standard therapy (including ACEi or ARB)

Duration of intervention: 2 months

Outcomes
  • Albuminuria

  • BP

  • GFR

  • Hyperkalaemia

  • Markers of tubular damage

Notes
  • No washout period

  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote "randomisation was ensured with computer-generated envelopes with an unknown block size and frequency"
Allocation concealment (selection bias)Low riskQuote "placebo tablets and active drugs were identical"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blinded study
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll patients completed the study
Selective reporting (reporting bias)Unclear riskNS
Other biasUnclear riskFunding: NS

Ogawa 2006a

Methods
  • Study design: parallel RCT

  • Study duration: NS

  • Follow-up: 12 months

Participants
  • Country: Japan

  • Setting: university

  • ACR > 3 0 mg/g; DM

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

  • Mean age ± SD (years): treatment group (63.5 ± 5.5); control group (61.2 ± 6.4)

  • Sex (M/F): NS

  • Exclusion criteria: NS

Interventions

Treatment group

  • SPL: 25 mg/d

  • ACEi: imidapril 5 mg/d

Control group

  • ACEi: imidapril 5 mg/d

  • Furosemide: 20 mg/d

Duration of intervention: 12 months

Outcomes
  • Albuminuria

  • B-type natriuretic peptide

  • Plasma aldosterone

  • Plasma renin activity

Notes
  • 12 months run-in phase (without assuming SPL) to stabilize albuminuria before randomisation

  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNS
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNS
Selective reporting (reporting bias)Low riskAll defined outcomes have been reported
Other biasUnclear riskFunding: NS

Rossing 2005

Methods
  • Study design: cross-over RCT

  • Study duration:

  • Follow-up: 8 weeks

Participants
  • Country: Denmark

  • Setting: university

  • Type 2 diabetic patients with kidney disease defined as albuminuria > 300 mg/d on maximally recommended dose of ACEi or ARB (or both)

  • Number: 20

  • Mean age ± SD (years): 58 ± 10

  • Sex (M/F): 17/3

  • Exclusion criteria: non-diabetic kidney disease; eGFR < 30 mL/min; serum potassium > 4.5 mEq/L

Interventions

Treatment group

  • SPL: 25 mg/d

  • ACEi or ARB (or both)

Control group

  • Matching placebo

  • ACEi or ARB (or both)

Duration of intervention: 8 weeks

Co-interventions: diuretic treatment

Outcomes
  • CrCl

  • BP

  • Serum potassium

  • Need for RRT

Notes
  • Washout period: NS

  • Funding: supported by Danish Diabetes Association

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote "randomisation was concealed with computer-generated envelopes"
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly 1 patient withdrew
Selective reporting (reporting bias)Low riskAll defined outcomes have been reported
Other biasLow riskFunding: supported by Danish Diabetes Association

Saklayen 2008

Methods
  • Study design: cross-over RCT

  • Study duration: NS

  • Follow-up: 3 months

Participants
  • Country: USA

  • Setting: university

  • DKD

  • Number: 34

  • Mean age: 64 years

  • Sex (M/F): 34/0

  • Exclusion criteria: SCr > 2.0 mg/dL; potassium > 5.0 mEq/L

Interventions

Treatment group

  • SPL: 25 to 50 mg/d

  • ACEi or ARBs

Control group

  • Placebo

  • ACEi or ARBs

Duration of intervention: 3 months

Outcomes
  • BP

  • proteinuria

  • GFR

Notes
  • Washout period: 1 month between the 2 phases

  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe investigators and the study nurse remained blind regarding the assignment until the code was broken at the end of the study
Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe investigators and the study nurse remained blind regarding the assignment until the code was broken at the end of the study
Incomplete outcome data (attrition bias)
All outcomes
Low risk6/30 randomised patients withdrew. However these patients were not included in the final analysis (no ITT)
Selective reporting (reporting bias)Unclear riskAll defined outcomes have been reported
Other biasUnclear riskFunding: NS

Schjoedt 2005

Methods
  • Study design: cross-over RCT

  • Study duration: NS

  • Follow-up: 8 weeks

Participants
  • Country: Denmark

  • Setting: university

  • Type 1 diabetes with albuminuria (> 300 mg/d) despite ACEi or ARB (or both) treatment

  • Number: 20

  • Mean age ± SD: 45 ± 7 years

  • Sex (M/F): 15/5

  • Exclusion criteria: eGFR < 30 mL/min; serum potassium > 4.5 mEq/L; known renal artery stenosis

Interventions

Treatment group

  • SPL: 25 mg/d

  • ACEi or ARB (or both)

Control group

  • Matching placebo

  • ACEi or ARB (or both)

Duration of intervention: 8 weeks

Co-interventions: diuretic treatment

Outcomes
  • Proteinuria

  • CrCl

  • BP

  • Serum potassium

  • Need for RRT

Notes
  • No washout period between treatments

  • Funding: supported by The Danish Diabetes Association

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote "Randomization was concealed with computer generated envelopes"
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Low risk20/22 patients completing the study were included in the final analysis
Selective reporting (reporting bias)Low riskAll defined outcomes have been reported
Other biasLow riskFunding: supported by The Danish Diabetes Association

Schjoedt 2006

Methods
  • Study design: cross-over RCT

  • Study duration: NS

  • Follow-up: 8 weeks

Participants
  • Country: Denmark

  • Setting: university

  • Diabetes (type 1 and 2) and hypertension with kidney disease (albuminuria > 2500 mg/d on maximally recommended dose of ACEi or ARB (or both))

  • Number: type 1 DM (9); type 2 DM (11)

  • Mean age ± SD (years): type 1 DM (45.7 ± 8); type 2 DM (52.7 ± 9)

  • Sex (M/F): type 1 DM (8/1); type 2 DM (9/2)

  • Exclusion criteria: eGFR < 30 mL/min; serum potassium > 4.5 mEq/L; known renal artery stenosis

Interventions

Treatment group

  • SPL: 25 mg/d

  • ACEi or ARB (or both)

Control group

  • Matching placebo

  • ACEi or ARB (or both)

Duration of intervention: 8 weeks

Co-interventions: diuretic treatment

Outcomes
  • Proteinuria

  • CrCl

  • BP

  • Serum potassium

  • Need for RRT

Notes
  • No washout period between treatments

  • Funding: supported by The Danish Diabetes Association

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote "Randomization was concealed with computer generated envelopes"
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo patients were excluded from the study
Selective reporting (reporting bias)Low riskAll defined outcomes have been reported
Other biasLow riskFunding: supported by The Danish Diabetes Association

Smolen 2006

Methods
  • Study design: cross-over RCT

  • Study duration: NS

  • Follow-up: 8 weeks

Participants
  • Country: Poland

  • Setting: NS

  • Glomerulonephritis; persistent non-nephrotic proteinuria; hypertension

  • Number: 16

  • Mean age ± SD (years): NS

  • Sex (M/F): NS

  • Exclusion criteria: NS

Interventions

Treatment group

  • SPL: 25 mg/d

Control group

  • Hydrochlorothiazide: 25 mg/d

Duration of intervention: 8 weeks

Outcomes
  • Proteinuria

  • BP

  • GFR

  • Potassium

  • Plasma renin activity

Notes
  • Abstract

  • Washout period: 1 week

  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNS
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNS
Selective reporting (reporting bias)Unclear riskNS
Other biasUnclear riskFunding: NS

Takebayashi 2006

Methods
  • Study design: parallel RCT

  • Study duration: June 2004 to June 2005

  • Follow-up: 12 weeks

Participants
  • Country: Japan

  • Setting: university

  • ACR > 30 mg/g; DM

  • Number: treatment group (23); control group (14)

  • Mean age ± SD (years): treatment group (60.1 ± 8.0); control group (56.5 ± 13.4)

  • Sex (M/F): NS

  • Exclusion criteria: NS

Interventions

Treatment group

  • SPL: 50 mg/d

Control group

  • Amlodipine: 2.5 mg/d

Duration of intervention: 12 weeks

Outcomes
  • Albuminuria

  • BP

  • Plasma aldosterone

  • Plasma renin activity

Notes
  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNS
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Low risk2/25 patients in the SPL group were excluded from the analysis due to symptoms of common cold. 1/15 patient in the control group was excluded due to poor compliance
Selective reporting (reporting bias)Unclear riskAll defined outcomes have been reported
Other biasUnclear riskFunding: NS

Tokunaga 2008a

Methods
  • Study design: parallel RCT

  • Study duration: NS

  • Follow-up: 17.1 ± 11.5 months

Participants
  • Country: Japan

  • Setting: NS

  • Patients receiving ARB with CKD stages 3-4

  • Number: treatment group (32); control group (32)

  • Mean age ± SD (years): NS

  • Sex (M/F): NS

  • Exclusion criteria: NS

Interventions

Treatment group

  • SPL

  • ARB

Control group

  • ARB

Duration of intervention: NS

Outcomes
  • Doubling SCr

  • Proteinuria

  • Potassium

  • ESKD

Notes
  • Abstract

  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNS
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNS
Selective reporting (reporting bias)Unclear riskNS
Other biasUnclear riskFunding: NS

Tylicki 2008

Methods
  • Study design: cross-over RCT

  • Study duration: March 2005 to February 2006

  • Follow-up: 24 weeks

Participants
  • Country: Poland

  • Setting: university

  • Non-diabetic proteinuric CKD; normal or slightly impaired stable kidney function (SCr < 1.7 mg/dL (< 150 µmol/L; eGFR < 45 mL/min (< 0.75 mL/s)); stable proteinuria > 0.3 g/24 h; hypertension

  • Number: 18

  • Mean age ± SD: 42 ± 1.9 years

  • Sex (M/F): 11/7

  • Exclusion criteria: nephrotic syndrome

Interventions

Treatment group

  • SPL: 25 mg/d

  • Conventional treatment: ACEi and ARB

Control group

  • Conventional treatment: ACEi and ARB

Duration of intervention: 8 weeks

Outcomes
  • Proteinuria

  • BP

  • Serum potassium

  • SCr

  • eGFR

  • Gynaecomastia

Notes
  • Washout period: none

  • Funding: The study was supported by a grant from the Polish Committee for Scientific Research (KBN) through the Medical University of Gdansk (ST-4)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote "Allocation was performed independent of the research team person according to a computer-generated randomisation list"
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label study
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll the patients completed the study
Selective reporting (reporting bias)Low riskAll defined outcomes have been reported
Other biasLow riskFunding: The study was supported by a grant from the Polish Committee for Scientific Research (KBN) through the Medical University of Gdansk (ST-4)

van den Meiracker 2006

Methods
  • Study design: parallel RCT

  • Study duration: NS

  • Follow-up: 12 months

Participants
  • Country: Netherlands

  • Setting: university

  • Type 2 diabetes with macroalbuminuria (24 h urinary albumin excretion > 300 mg or an UACR > 20 mg/mmol) despite use of an ACEi or ARB

  • Number: treatment group (24); control group (29)

  • Mean age, range (years): treatment group (55.2, 38-78); control group (55.2, 29-75)

  • Sex (M/F): treatment group (16/7); control group (17/12)

  • Exclusion criteria: SCr > 265 mmol/L; serum potassium > 5.0 mmol/L; kidney disease other than DKD; nephrotic syndrome

Interventions

Treatment group

  • SPL: 25 to 50 mg/d

  • ACEi and ARB

Control group

  • Placebo

  • ACEi and ARB

Duration of intervention: 12 months

Outcomes
  • Serum potassium

  • Need for RRT

  • Gynaecomastia

Notes
  • Funding: NS

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote "Eligible participants were randomised for spironolactone or placebo using a computerized randomisation list"
Allocation concealment (selection bias)Low riskQuote "Appearance and taste of active and placebo tablets were similar"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Low risk5/29 patients in the SPL group and 2/30 in the control group withdrew. Apparently, they were not included in the final analysis.
Selective reporting (reporting bias)Low riskAll defined outcomes have been reported
Other biasUnclear riskFunding: NS

Zheng 2011

  1. a

    ACR - albumin creatinine ratio; BMI - body mass index; BP - blood pressure; ACEi - angiotensin converting enzyme inhibitors; ARB - angiotensin receptor blockers; CHF - chronic heart failure; Cr - creatinine; DKD - diabetic kidney disease; DM - diabetes mellitus; eGFR - estimated glomerular filtration rate; EPL - eplerenone; NS - not stated; RRT - renal replacement therapy; SCr - serum creatinine; SPL - spironolactone; UACR - urinary albumin creatinine ratio

Methods
  • Study design: parallel RCT

  • Study duration: NS

  • Follow-up: 3 months

Participants
  • Country: China

  • Setting: NS

  • Patients with DKD (duration of diabetes 8 to 18 years); urinary protein excretion > 300 mg/24 h; SCr < 150 L mol/L; fasting plasma glucose < 10 mmol/L

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

  • Mean age ± SD: 58 ± 5.7 years

  • Sex (M/F): 22/18

  • Exclusion criteria: NS

Interventions

Treatment group

  • SPL: 20 mg/d

  • ACEi: benazepril, 10 mg/d

Control group

  • ACEi: benazepril, 10 mg/d

Duration of intervention: 3 months

Outcomes
  • Proteinuria

  • Creatinine

  • Potassium

NotesFunding: NS
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNS
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNS
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients apparently completed the study
Selective reporting (reporting bias)Unclear riskNS
Other biasUnclear riskFunding: NS

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Epstein 1998Wrong population (hypertensive patients; not stated whether CKD was present)
Essaian 2007Wrong population (haemodialysis patients)
Horita 2004Not RCT
Medeiros 2010Wrong population (children with chronic allograft nephropathy)
Preston 2009Experimental study; wrong intervention (potassium was administered to patients)
Rachmani 2004

Diabetic Medicine has been advised by the Chief Executive Officer of the Mair Medical Center that the above study, done in collaboration with the Sackler University of Tel Aviv, has raised concerns over ethical conduct and security of findings. Specifically, a local investigatory committee found that ethical permission was only given approximately 3 months after Diabetic Medicine accepted the paper for publication. In addition, whilst the investigatory committee believed that the research had been undertaken, they were unable to access research records and thus confirm the results, even though the study was conducted as recently as 2001.

In these circumstances, Diabetic Medicine regrets publication of the article, and suggests that its readers treat its findings with caution. The senior author has been advised of our wish to have the article retracted and has made a statement of confidence in the findings.

Renke 2008Comment paper
Rosado Rubio 2010Not RCT
Schjoedt 2009Experimental study; no outcomes of interest
Schmidt 2005Wrong population (healthy subjects and hypertensive patients without a clear diagnosis of CKD)
Schmidt 2005aNo outcomes of interest
Schmidt 2008Wrong population (CKD not present)
Shahbazian 2010Not RCT
Swift 2006Wrong population (only patients with Liddle syndrome)
Taheri 2009Wrong population (haemodialysis patients)
Toto 2005Wrong intervention; no aldosterone antagonists has been used

Characteristics of ongoing studies [ordered by study ID]

ARTS Study 2012

Trial name or titleMinerAlocorticoid Receptor Antagonist Tolerability Study
MethodsMulticentre, randomised, double-blind, placebo-controlled, parallel-group study divided into two parts
Participants

Part A: patients with heart failure and reduced ejection fraction (HFREF) and mild CKD (eGFR 60 to 90 mL/min/1.73 m²)

Part B: patients with HFREF and moderate CKD (eGFR 30 to 60 mL/min/1.73 m²)

Interventions

Part A: oral BAY 94-8862 (2.5, 5, or 10 mg once daily) compared with placebo

Part B: oral BAY 94-8862 (2.5, 5, or 10 mg once daily) compared with placebo and open-label spironolactone (25 to 50 mg)

Outcomes

Part A: serum potassium concentration, biomarkers of renal injury, eGFR, and albuminuria

Part B: changes in serum potassium concentration, safety and tolerability, biomarkers of cardiac and kidney function or injury, eGFR, albuminuria; BAY 94-8862 pharmacokinetics

Starting dateMay 2011
Contact informationBertram Pitt; bpitt@med.umich.edu; University of Michigan School of Medicine, Ann Arbor, MI 48109-0366, USA
NotesThe study has been completed but, so far, no published data.

EVALUATE Study 2010

Trial name or titleRationale and design of the Eplerenone combination Versus conventional Agents to Lower blood pressure on Urinary Antialbuminuric Treatment Effect
MethodsDouble-blinded, randomised, placebo-controlled
Participants340 hypertensive patients (BP: 130 to 180/80 to 100 mm Hg) with albuminuria (UACR: 30 to 600 mg/g-1 in the first morning void urine), who are treated with an inhibitor of the RAS
InterventionsEplerenone: 50 mg/d
OutcomesChange in the UACR
Starting date2010
Contact informationKatsuyuki Ando; Department of Nephrology and Endocrinology, Faculty of Medicine, University of Tokyo Hospital, Tokyo, Japan.
NotesNo published data available

NCT00315016

Trial name or titleEplerenone, ACE inhibition and albuminuria
MethodsInterventional randomised phase II study
Participants

Inclusion criteria

  • Documented DKD with albuminuria > 0.020 g/L, stable kidney function (i.e. increase of SCr < 25%/6 months); CrCl > 40 mL/min/1.73 m², in spite of maximal ACE inhibition (40 mg fosinopril/d)

  • BP < 140/90 mm Hg ( at baseline)

  • Serum potassium < 5.0 mmol/L (at baseline).

Exclusion criteria

  • Use of NSAIDs or immunosuppressive drugs

  • Use of ARB, intolerance for ACE inhibition

  • Use of diuretics that increase potassium such as triamterene, spironolactone or eplerenone

  • Pregnancy

  • Rash or cough on one on the drugs

  • Severe heart disease or instable angina

Interventions
  • Eplerenone

  • Fosinopril

  • Placebo

Outcomes
  • Proteinuria

  • BP

  • Differential protein excretion in 2 h urine (B2 microglobulin, GST)

  • GFR and RPF

Starting dateJanuary 2007
Contact informationJacob Deinum, University Medical Center Nijmegen St Radboud, The Netherlands
NotesThe study has been completed but, so far, no published data

NCT00870402

  1. a

    BP - blood pressure; CKD - chronic kidney disease; CrCl - creatinine clearance; DKD - diabetic kidney disease; eGFR - estimated glomerular filtration rate; RAS - renin-angiotensin system; SCr - serum creatinine; UACR - urinary albumin creatinine ratio

Trial name or titleAldosterone in Diabetic Nephropathy (ALDODN)
MethodsInterventional, randomised, double blind phase IV trial
Participants

Inclusion criteria

  • Diabetic subjects with maximum ten years after diagnosis

  • Diabetic nephropathy with albuminuria

  • Normal kidney function

  • Diastolic dysfunction

  • Taking a IECA or ARA drug family previously

Exclusion criteria

  • Diabetics subjects with macroangiopathy

  • Acute coronary syndrome in the 3 months before

  • Hyperkalaemia > 5.5 mEq/L

  • Pregnancy

Interventions
  • Spironolactone: 25 mg/d

  • Placebo

  • Duration: nine months

Outcomes
  • Reduction of albuminuria

  • Reduction of diastolic dysfunction

Starting dateMarch 2009
Contact informationFrancisco G Espinoza, fespinoz@mi.cl, Universidad Los Andes
NotesEstimated primary completion date: December 2009. No recent updates on the trial status

Ancillary