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Meta-Analysis
. 2020 Oct 27;10(10):CD007004.
doi: 10.1002/14651858.CD007004.pub4.

Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease

Edmund Ym Chung  1 , Marinella Ruospo  2   3 , Patrizia Natale  2   3 , Davide Bolignano  4 , Sankar D Navaneethan  5 , Suetonia C Palmer  6 , Giovanni Fm Strippoli  2   3   7
Affiliations
Meta-Analysis

Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease

Edmund Ym Chung et al. Cochrane Database Syst Rev. .

Abstract

Background: Treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is 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 Cochrane review first published in 2009 and updated in 2014.

Objectives: To evaluate the effects of aldosterone antagonists (selective (eplerenone), non-selective (spironolactone or canrenone), or non-steroidal mineralocorticoid antagonists (finerenone)) in adults who have CKD with proteinuria (nephrotic and non-nephrotic range) on: patient-centred endpoints including kidney failure (previously know as end-stage kidney disease (ESKD)), major cardiovascular events, and death (any cause); kidney function (proteinuria, estimated glomerular filtration rate (eGFR), and doubling of serum creatinine); blood pressure; and adverse events (including hyperkalaemia, acute kidney injury, and gynaecomastia).

Search methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 13 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov.

Selection criteria: We included randomised controlled trials (RCTs) and quasi-RCTs that compared aldosterone antagonists in combination with ACEi or ARB (or both) to other anti-hypertensive strategies or placebo in participants with proteinuric CKD.

Data collection and analysis: Two authors independently assessed study quality and extracted data. Data were summarised using random effects meta-analysis. We expressed summary treatment estimates as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) when different scales were used together with their 95% confidence interval (CI). Risk of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE.

Main results: Forty-four studies (5745 participants) were included. Risk of bias in the evaluated methodological domains were unclear or high risk in most studies. Adequate random sequence generation was present in 12 studies, allocation concealment in five studies, blinding of participant and investigators in 18 studies, blinding of outcome assessment in 15 studies, and complete outcome reporting in 24 studies. All studies comparing aldosterone antagonists to placebo or standard care were used in addition to an ACEi or ARB (or both). None of the studies were powered to detect differences in patient-level outcomes including kidney failure, major cardiovascular events or death. Aldosterone antagonists had uncertain effects on kidney failure (2 studies, 84 participants: RR 3.00, 95% CI 0.33 to 27.65, I² = 0%; very low certainty evidence), death (3 studies, 421 participants: RR 0.58, 95% CI 0.10 to 3.50, I² = 0%; low certainty evidence), and cardiovascular events (3 studies, 1067 participants: RR 0.95, 95% CI 0.26 to 3.56; I² = 42%; low certainty evidence) compared to placebo or standard care. Aldosterone antagonists may reduce protein excretion (14 studies, 1193 participants: SMD -0.51, 95% CI -0.82 to -0.20, I² = 82%; very low certainty evidence), eGFR (13 studies, 1165 participants, MD -3.00 mL/min/1.73 m², 95% CI -5.51 to -0.49, I² = 0%, low certainty evidence) and systolic blood pressure (14 studies, 911 participants: MD -4.98 mmHg, 95% CI -8.22 to -1.75, I² = 87%; very low certainty evidence) compared to placebo or standard care. Aldosterone antagonists probably increase the risk of hyperkalaemia (17 studies, 3001 participants: RR 2.17, 95% CI 1.47 to 3.22, I² = 0%; moderate certainty evidence), acute kidney injury (5 studies, 1446 participants: RR 2.04, 95% CI 1.05 to 3.97, I² = 0%; moderate certainty evidence), and gynaecomastia (4 studies, 281 participants: RR 5.14, 95% CI 1.14 to 23.23, I² = 0%; moderate certainty evidence) compared to placebo or standard care. Non-selective aldosterone antagonists plus ACEi or ARB had uncertain effects on protein excretion (2 studies, 139 participants: SMD -1.59, 95% CI -3.80 to 0.62, I² = 93%; very low certainty evidence) but may increase serum potassium (2 studies, 121 participants: MD 0.31 mEq/L, 95% CI 0.17 to 0.45, I² = 0%; low certainty evidence) compared to diuretics plus ACEi or ARB. Selective aldosterone antagonists may increase the risk of hyperkalaemia (2 studies, 500 participants: RR 1.62, 95% CI 0.66 to 3.95, I² = 0%; low certainty evidence) compared ACEi or ARB (or both). There were insufficient studies to perform meta-analyses for the comparison between non-selective aldosterone antagonists and calcium channel blockers, selective aldosterone antagonists plus ACEi or ARB (or both) and nitrate plus ACEi or ARB (or both), and non-steroidal mineralocorticoid antagonists and selective aldosterone antagonists.

Authors' conclusions: The effects of aldosterone antagonists when added to ACEi or ARB (or both) on the risks of death, major cardiovascular events, and kidney failure in people with proteinuric CKD are uncertain. Aldosterone antagonists may reduce proteinuria, eGFR, and systolic blood pressure in adults who have mild to moderate CKD but may increase the risk of hyperkalaemia, acute kidney injury and gynaecomastia when added to ACEi and/or ARB.

Trial registration: ClinicalTrials.gov NCT01345656 NCT01874431 NCT01807221 NCT00430924 NCT01100203 NCT00106561 NCT00291720 NCT01667614 NCT02345057 NCT00381134 NCT00498537 NCT00528385 NCT02235077 NCT01146197 NCT00232180 NCT01062763 NCT02040441 NCT00335413 NCT00094302 NCT00315016 NCT02540993 NCT00870402.

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Conflict of interest statement

  1. Edmund YM Chung: none known

  2. Marinella Ruospo: none known

  3. Patrizia Natale: none known

  4. Davide Bolignano: none known

  5. Sankar D Navaneethan: none known

  6. Suetonia C Palmer: none known

  7. Giovanni FM Strippoli: none known

Figures

1
1
Mechanisms of cardiac and kidney damage induced by aldosterone excess
2
2
Study flow diagram.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
5
5
Effect of aldosterone antagonists versus placebo or standard care on kidney failure
6
6
Effect of aldosterone antagonists versus placebo or standard care on hyperkalaemia
7
7
Effect of aldosterone antagonists versus placebo or standard care on proteinuria.
8
8
Effect of aldosterone antagonists versus placebo or standard care on GFR [mL/min/1.73 m²].
9
9
Funnel plot of comparison studies comparing aldosterone antagonist versus control for the study endpoint of GFR [mL/min/1.73 m²].
10
10
Funnel plot of comparison studies comparing aldosterone antagonist versus control for the study endpoint of hyperkalaemia.
1.1
1.1. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 1: Kidney failure
1.2
1.2. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 2: Hyperkalaemia
1.3
1.3. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 3: Subgroup analysis: hyperkalaemia ‐ number of RAS inhibitors used
1.5
1.5. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 5: Death
1.6
1.6. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 6: Cardiovascular events
1.7
1.7. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 7: Myocardial infarction
1.8
1.8. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 8: Stroke
1.9
1.9. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 9: Proteinuria
1.12
1.12. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 12: eGFR [mL/min/1.73 m²]
1.15
1.15. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 15: Doubling serum creatinine
1.16
1.16. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 16: Systolic BP
1.17
1.17. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 17: Diastolic BP
1.20
1.20. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 20: Serum potassium
1.22
1.22. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 22: Acute kidney injury
1.23
1.23. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 23: Gynaecomastia
1.24
1.24. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 24: Subgroup analysis: proteinuria ‐ duration of follow‐up
1.25
1.25. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 25: Subgroup analysis: systolic BP ‐ duration of follow‐up
1.26
1.26. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 26: Subgroup analysis: diastolic BP ‐ duration of follow‐up
1.27
1.27. Analysis
Comparison 1: Aldosterone antagonist versus placebo/standard care (all studies), Outcome 27: Subgroup analysis: serum potassium ‐ duration of follow‐up
2.1
2.1. Analysis
Comparison 2: Aldosterone antagonist plus RAS inhibitor versus other diuretic plus RAS inhibitor, Outcome 1: Proteinuria
2.4
2.4. Analysis
Comparison 2: Aldosterone antagonist plus RAS inhibitor versus other diuretic plus RAS inhibitor, Outcome 4: eGFR [mL/min/1.73 m²]
2.7
2.7. Analysis
Comparison 2: Aldosterone antagonist plus RAS inhibitor versus other diuretic plus RAS inhibitor, Outcome 7: Diastolic BP
2.8
2.8. Analysis
Comparison 2: Aldosterone antagonist plus RAS inhibitor versus other diuretic plus RAS inhibitor, Outcome 8: Systolic BP
2.11
2.11. Analysis
Comparison 2: Aldosterone antagonist plus RAS inhibitor versus other diuretic plus RAS inhibitor, Outcome 11: Serum potassium
2.14
2.14. Analysis
Comparison 2: Aldosterone antagonist plus RAS inhibitor versus other diuretic plus RAS inhibitor, Outcome 14: Fatigue
3.2
3.2. Analysis
Comparison 3: Spironolactone versus calcium channel blockers, Outcome 2: Systolic BP
3.3
3.3. Analysis
Comparison 3: Spironolactone versus calcium channel blockers, Outcome 3: Diastolic BP
3.4
3.4. Analysis
Comparison 3: Spironolactone versus calcium channel blockers, Outcome 4: Serum potassium
6.1
6.1. Analysis
Comparison 6: Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both), Outcome 1: Hyperkalaemia
8.1
8.1. Analysis
Comparison 8: Finerenone versus eplerenone, Outcome 1: Hyperkalaemia
8.2
8.2. Analysis
Comparison 8: Finerenone versus eplerenone, Outcome 2: Death
8.4
8.4. Analysis
Comparison 8: Finerenone versus eplerenone, Outcome 4: Doubling serum creatinine
9.1
9.1. Analysis
Comparison 9: Spironolactone plus ACEi and ARB versus ACEi, Outcome 1: Hyperkalaemia
9.3
9.3. Analysis
Comparison 9: Spironolactone plus ACEi and ARB versus ACEi, Outcome 3: eGFR [mL/min/1.73 m²]
9.4
9.4. Analysis
Comparison 9: Spironolactone plus ACEi and ARB versus ACEi, Outcome 4: Systolic BP
9.5
9.5. Analysis
Comparison 9: Spironolactone plus ACEi and ARB versus ACEi, Outcome 5: Diastolic BP
9.6
9.6. Analysis
Comparison 9: Spironolactone plus ACEi and ARB versus ACEi, Outcome 6: Serum potassium
9.7
9.7. Analysis
Comparison 9: Spironolactone plus ACEi and ARB versus ACEi, Outcome 7: Gynaecomastia
See this image and copyright information in PMC

Update of

Comment in

References

References to studies included in this review

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CRIBS II 2009 {published data only}
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Epstein 2002 {published data only}
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Epstein 2006 {published data only}
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Fogari 2014 {published data only}
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Furumatsu 2008 {published data only}
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Horestani 2012 {published data only}
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Kato 2015 {published data only}
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    1. Koroshi A, Idrizi A, Gjergji Z, Hoxha B, Emrullaj E, Spahia E, et al. Combination of angiotensin converting enzyme inhibitors with mineralocorticoid antagonists in diabetic nephropathy [abstract no: SU342]. NDT Plus 2010;3(Suppl 3):iii424. [EMBASE: 70484562]
Lv 2009a {published data only}
    1. Lv J, Qin S, Li Y, Zhang H, Liu L, Shi S, et al. Change of proteinuria after adding spironolactone ACE inhibitor or angiotensin receptor blockers in IGA nephropathy, a pilot study [abstract no: SA309]. NDT Plus 2009;2(Suppl 2):ii1029. [CENTRAL: CN-01657692]
Mehdi 2009 {published data only}
    1. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. Journal of the American Society of Nephrology 2009;20(12):2641-50. [MEDLINE: ] - PMC - PubMed
    1. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Effect of an angiotensin receptor blocker (ARB) or a mineralocorticoid antagonist (MRA) added-on to maximally-dosed angiotensin converting enzyme inhibitor (ACEi) regimen in diabetic nephropathy (DN) [abstract no: TH-FC128]. Journal of the American Society of Nephrology 2008;19(Abstracts Issue):28A. [CENTRAL: CN-00756304]
    1. Srivastava A, Adams-Huet B, Vega GL, Toto RD. Effect of losartan and spironolactone on lipoprotein metabolism in diabetic nephropathy [abstract no: 266]. American Journal of Kidney Diseases 2012;59(4):A81. [EMBASE: 71074879]
    1. Srivastava A, Adams-Huet B, Vega GL, Toto RD. Effect of losartan and spironolactone on triglyceride-rich lipoproteins in diabetic nephropathy. Journal of Investigative Medicine 2016;64(6):1102-8. [MEDLINE: ] - PMC - PubMed
    1. Van Buren PN, Adams-Huet B, Nguyen M, Molina C, Toto RD. Potassium handling with dual renin-angiotensin system inhibition in diabetic nephropathy. Clinical Journal of the American Society of Nephrology: CJASN 2014;9(2):295-301. [MEDLINE: ] - PMC - PubMed
Morales 2009 {published data only}
    1. Morales E, Huerta A, Gutierrez E, Gutierrez SE, Segura J, Praga M. The antiproteinuric effect of the blockage of the renin-angiotensin-aldosterone system (RAAS) in obese patients. Which treatment option is the most effective? [Efecto antiproteinurico del bloqueo del sistema renina-angiotensina-aldosterona (SRAA) en los pacientes obesos. Cual es la opcion terapeutica mas eficaz]. Nefrologia 2009;29(5):421-9. [MEDLINE: ] - PubMed
    1. Morales E, Huerta A, Gutierrez-Millet V, Gutierrez E, Gutierrez-Solis E, Hernandez E, et al. Antiproteinuric effect of renin-angiotensin-aldosterone system (RAAS) in obese patients. Which is the most effective option? [abstract no: SA131]. NDT Plus 2009;2(Suppl 2):ii882. [CENTRAL: CN-01657690]
    1. Morales E, Huerta A, Gutierrez-Solis E, Gutierrez E, Polanco N, Gutierrez-Millet V, et al. Antiproteinuric effect of renin-angiotensin-aldosterone system (RAAS) in obese patients. Which is the most effective option? [abstract no: F-PO1941]. Journal of the American Society of Nephrology 2008;19(Abstracts Issue):549A. [CENTRAL: CN-00790676]
Morales 2015 {published data only}
    1. Morales E, Caro J, Gutierrez E, Sevillano A, Aunon P, Fernandez C, et al. Diverse diuretics regimens differentially enhance the antialbuminuric effect of renin-angiotensin blockers in patients with chronic kidney disease. Kidney International 2015;88(6):1434-41. [MEDLINE: ] - PubMed
    1. Morales E, Caro J, Gutierrez E, Sevillano A, Aunon P, Praga M. Crossover randomized clinical trial to evaluate the albuminuric effect of three different types of diuretics (spironolactone, hydroclorothiazide and hydroclorothiazide+amiloride) on top of RAAS blockade in proteinuric nephropathies [abstract no: SP309]. Nephrology Dialysis Transplantation 2015;30(Suppl 3):iii482. [EMBASE: 72207635]
    1. Morales E, Espada PJ, Gutierrez-Martinez E, Praga M. Crossover randomised clinical trial to evaluate the antialbuminuric effect of three different types of diuretics (spironolactone, hydrochlorothiazide and hydrochlorothiazide + amiloride) on top of RAAS blockade in proteinuric nephropathies [abstract no: TH-PO655]. Journal of the American Society of Nephrology 2014;25(Abstract Suppl):257A.
Nielsen 2012 {published data only}
    1. Nielsen S, Persson F, Frandsen E, Sugaya T, Hess G, Zdunek D, et al. Spironolactone diminishes urinary albumin excretion in type 1 diabetic patients with microalbuminuria: a randomised placebo-controlled crossover study [abstract no: 1099]. Diabetologia 2011;54(Suppl 1):S445. [EMBASE: 70563244] - PubMed
    1. Nielsen S, Persson F, Frandsen E, Sugaya T, Zdunek DW, Pedersen K, et al. Spironolactone diminishes urinary albumin excretion in type 1 diabetic patients with microalbuminuria: a randomized placebo-controlled crossover study [abstract no: TH-PO548]. Journal of the American Society of Nephrology 2011;22(Abstracts):238A. [CENTRAL: CN-01912458]
    1. Nielsen SE, Persson F, Frandsen E, Sugaya T, Hess G, Zdunek D, et al. Spironolactone diminishes urinary albumin excretion in patients with type 1 diabetes and microalbuminuria: a randomized placebo-controlled crossover study. Diabetic Medicine 2012;29(8):e184-90. [MEDLINE: ] - PubMed
Ogawa 2006a {published data only}
    1. Ogawa S, Takeuchi K, Mori T, Nako K, Ito S. Spironolactone further reduces urinary albumin excretion and plasma B-type natriuretic peptide levels in hypertensive type II diabetes treated with angiotensin-converting enzyme inhibitor. Clinical & Experimental Pharmacology & Physiology 2006;33(5-6):477-9. [MEDLINE: ] - PubMed
Rossing 2005 {published data only}
    1. Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care 2005;28(9):2106-12. [MEDLINE: ] - PubMed
Saklayen 2008 {published data only}
    1. Saklayen M, Gyebi L, Tasosa J, Yap J. Spironolactone reduces proteinuria further in diabetic patients who are already on ACE inhibitor or ARB therapy: results of a randomized, placebo-controlled, double-blind cross-over trial [abstract no: TH-PO240]. Journal of the American Society of Nephrology 2006;17(Abstracts):157A. [CENTRAL: CN-00615896]
    1. Saklayen MG, Gyebi LK, Tasosa J, Yap J. Effects of additive therapy with spironolactone on proteinuria in diabetic patients already on ACE inhibitor or ARB therapy: results of a randomized, placebo-controlled, double-blind, crossover trial. Journal of Investigative Medicine 2008;56(4):714-9. [MEDLINE: ] - PubMed
Schjoedt 2005 {published data only}
    1. Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Rossing P, Parving HH. Beneficial impact of spironolactone in diabetic nephropathy. Kidney International 2005;68(6):2829-36. [MEDLINE: ] - PubMed
    1. Schjoedt KJ, Rossing K, Tarnow L, Parving H. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy [abstract no: F-FC090]. Journal of the American Society of Nephrology 2005;16(Abstracts):57A. [CENTRAL: CN-00689347] - PubMed
Smolen 2006 {published data only}
    1. Smolen E, Nowicki M. Contrasting effects of spironolactone and hydrochlorothiazide in patients with persistent glomerular proteinuria [abstract no: MP260]. Nephrology Dialysis Transplantation 2006;21(Suppl 4):iv386. [CENTRAL: CN-00716094]
Takebayashi 2006 {published data only}
    1. Matsumoto S, Takebayashi K, Aso Y. The effect of spironolactone on circulating adipocytokines in patients with type 2 diabetes mellitus complicated by diabetic nephropathy. Metabolism: Clinical & Experimental 2006;55(12):1645-52. [MEDLINE: ] - PubMed
    1. Takebayashi K, Matsumoto S, Aso Y, Inukai T. Aldosterone blockade attenuates urinary monocyte chemoattractant protein-1 and oxidative stress in patients with type 2 diabetes complicated by diabetic nephropathy. Journal of Clinical Endocrinology & Metabolism 2006;91(6):2214-7. [MEDLINE: ] - PubMed
Tokunaga 2008a {published data only}
    1. Tokunaga M, Tamura M, Kabashima N, Serino R, Shibata T, Matsumoto M, et al. Add-on spironolactone in patients with advanced chronic kidney disease treated with angiotensin II receptor blockers [abstract no: F-PO1840]. Journal of the American Society of Nephrology 2008;19(Abstracts Issue):525A. [CENTRAL: CN-01657689]
Tylicki 2008 {published data only}
    1. Larczynski W, Tylicki L, Rutkowski P, Renke M, Rutkowski B. The triple renin-angiotensin-aldosterone system blockade - new promising nephroprotective strategy in patients with proteinuric nondiabetic renal disease [abstract no: SAP081]. Nephrology Dialysis Transplantation 2007;22(Suppl 6):vi259. [CENTRAL: CN-00653742]
    1. Tylicki L, Rutkowski P, Renke M, Larczynski W, Aleksandrowicz E, Lysiak-Szydlowska W, et al. Triple pharmacological blockade of the renin-angiotensin-aldosterone system in nondiabetic CKD: an open-label crossover randomized controlled trial. American Journal of Kidney Diseases 2008;52(3):486-93. [MEDLINE: ] - PubMed
    1. Tylicki L, Rutkowski P, Renke M, Rutkowski B. Addition of aldosterone receptor blocker to dual renin-angiotensin-aldosterone blockade leads to limitation of tubulointerstitial injury of kidney. Kidney International 2007;72(9):1164-5. [MEDLINE: ] - PubMed
Tylicki 2012 {published data only}
    1. Lizakowski S, Rutkowski P, Tylicki L, Renke M, Sulikowska B, Donderski R, et al. The effect of various types of the renin-angiotensin-aldosteron system blockade on proteinuria in chronic non-diabetic kidney disease: a double-blind cross-over randomised controlled trial [abstract no: FP112]. Nephrology Dialysis Transplantation 2012;27(Suppl 2):ii109. [EMBASE: 70765606]
    1. Lizakowski S, Tylicki L, Rutkowski P, Renke M, Sulikowska B, Heleniak Z, et al. Safety of enhanced renin-angiotensin-aldosterone system inhibition with aliskiren in nondiabetic patients with chronic kidney disease. Polskie Archiwum Medycyny Wewnetrznej 2013;123(5):221-7. [MEDLINE: ] - PubMed
    1. Tylicki L, Lizakowski S, Rutkowski P, Renke M, Sulikowska B, Heleniak Z, et al. The enhanced renin-angiotensin-aldosteron system pharmacological blockade--which is the best? Kidney & Blood Pressure Research 2012;36(1):335-43. [MEDLINE: ] - PubMed
van den Meiracker 2006 {published data only}
    1. den Meiracker AH, Baggen RG, Pauli S, Lindemans A, Vulto AG, Poldermans D. Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function. Journal of Hypertension 2006;24(11):2285-92. [MEDLINE: ] - PubMed
Wang 2013g {published data only}
    1. Wang W, Li L, Zhou Z, Gao J, Sun Y. Effect of spironolactone combined with angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers on chronic glomerular disease. Experimental & Therapeutic Medicine 2013;6(6):1527-31. [MEDLINE: ] - PMC - PubMed
Zheng 2011 {published data only}
    1. Zheng H, Qiu H, Liu X, Jiang B. Clinical investigation of combined therapy with benazepril and spironolactone in diabetic nephropathy. Pharmaceutical Care & Research 2011;11(4):266-8. [EMBASE: 2011509942]
Ziaee 2013 {published data only}
    1. Ziaee A, Abbas Vaezi A, Oveisi S, Javadi A, Hashemipour S, Kazemifar AM. Effects of additive therapy with spironolactone on albuminuria in diabetes mellitus: a pilot randomized clinical trial. Caspian Journal of Internal Medicine 2013;4(2):648-53. [EMBASE: 369112192] - PMC - PubMed

References to studies excluded from this review

ATHENA‐HF 2019 {published data only}
    1. Butler J, Anstrom KJ, Felker GM, Givertz MM, Kalogeropoulos AP, Konstam MA, et al. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiology 2017;2(9):950-8. [MEDLINE: ] - PMC - PubMed
    1. Butler J, Hernandez AF, Anstrom KJ, Kalogeropoulos A, Redfield MM, Konstam MA, et al. Rationale and design of the ATHENA-HF Trial: aldosterone targeted neurohormonal combined with natriuresis therapy in heart failure. JACC Heart Failure 2016;4(9):726-35. [MEDLINE: ] - PMC - PubMed
    1. Greene SJ, Felker GM, Giczewska A, Kalogeropoulos AP, Ambrosy AP, Chakraborty H, et al. Spironolactone in acute heart failure patients with renal dysfunction and risk factors for diuretic resistance: from the ATHENA-HF trial. Canadian Journal of Cardiology 2019;35(9):1097-105. [MEDLINE: ] - PMC - PubMed
    1. Greene SJ, Felker GM, Giczewska A, Kalogeropoulos AP, Ambrosy AP, Chakraborty H, et al. Spironolactone in acute heart failure patients with renal dysfunction and risk factors for diuretic resistance: from the ATHENA-HF trial [abstract no: 10456]. Circulation 2018;138(Suppl 1):A10456. [EMBASE: 627102576] - PMC - PubMed
Barr 1995 {published data only}
    1. Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers AD. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. American Journal of Cardiology 1995;76(17):1259-65. [MEDLINE: ] - PubMed
Berry 2007 {published data only}
    1. Berry C, Murphy NF, De Vito G, Galloway S, Seed A, Fisher C, et al. Effects of aldosterone receptor blockade in patients with mild-moderate heart failure taking a beta-blocker.[Erratum in: Eur J Heart Fail. 2007 Oct;9(10):1074 Note: Murphy, Niamh [corrected to Murphy, Niamh F]]. European Journal of Heart Failure 2007;9(4):429-34. [MEDLINE: ] - PubMed
Blanchard 2015 {published data only}
    1. Blanchard A, Vargas-Poussou R, Vallet M, Caumont-Prim A, Allard J, Desport E, et al. Indomethacin, amiloride, or eplerenone for treating hypokalemia in Gitelman syndrome. Journal of the American Society of Nephrology 2015;26(2):468-75. [MEDLINE: ] - PMC - PubMed
EMPHASIS‐HF 2010 {published data only}
    1. Eschalier R, McMurray JJ, Swedberg K, Veldhuisen DJ, Krum H, Pocock SJ, et al. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure). Journal of the American College of Cardiology 2013;62(17):1585-93. [MEDLINE: ] - PubMed
    1. Ferreira JP, Abreu P, McMurray JJ, Veldhuisen DJ, Swedberg K, Pocock SJ, et al. Renal function stratified dose comparisons of eplerenone versus placebo in the EMPHASIS-HF trial. European Journal of Heart Failure 2019;21(3):345-51. [EMBASE: 626398757] - PubMed
    1. Krum H, Shi H, Pitt B, McMurray J, Swedberg K, Veldhuisen DJ, et al. Clinical benefit of eplerenone in patients with mild symptoms of systolic heart failure already receiving optimal best practice background drug therapy: analysis of the EMPHASIS-HF study. Circulation: Heart Failure 2013;6(4):711-8. [MEDLINE: ] - PubMed
    1. Rogers JK, McMurray JJ, Pocock SJ, Zannad F, Krum H, Veldhuisen DJ, et al. Eplerenone in patients with systolic heart failure and mild symptoms: analysis of repeat hospitalizations. Circulation 2012;126(19):2317-23. [MEDLINE: ] - PubMed
    1. Rossignol P, Dobre D, McMurray JJ, Swedberg K, Krum H, Veldhuisen DJ, et al. Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Circulation: Heart Failure 2014;7(1):51-8. [MEDLINE: ] - PubMed
Epstein 1998 {published data only}
    1. Epstein M, Alexander JC, Roniker B. Eplerenone, a new selective aldosterone receptor antagonist (SARA): efficacy in patients with mild to moderate hypertension [abstract no: A1640]. Journal of the American Society of Nephrology 1998;9(Program & Abstracts):322-3A. [CENTRAL: CN-00445239]
Essaian 2007 {published data only}
    1. Essaian A, Kaukov I, Karabayeva A, Kadinskaya M, Katysheva N. The influence of spironolactone on plasma level of plasminogen-activator inhibitor type 1 (PAI-1) in anuric hemodialysis patients [abstract no: SaP266]. Nephrology Dialysis Transplantation 2007;22(Suppl 6):vi322. [CENTRAL: CN-00716089]
Hollenberg 2003a {published data only}
    1. Hollenberg NK, Williams GH, Anderson R, Akhras KS, Bittman RM, Krause SL. Symptoms and the distress they cause: comparison of an aldosterone antagonist and a calcium channel blocking agent in patients with systolic hypertension. Archives of Internal Medicine 2003;163(13):1543-8. [MEDLINE: ] - PubMed
Karalliedde 2006 {published data only}
    1. Karalliedde J, Buckingham R, Starkie M, Lorand D, Stewart M, Viberti G, et al. Effect of various diuretic treatments on rosiglitazone-induced fluid retention. Journal of the American Society of Nephrology 2006;17(12):3482-90. [MEDLINE: ] - PubMed
Makhlough 2014 {published data only}
    1. Makhlough A, Kashi Z, Akha O, Zaboli E, Yazdanicharati J. Effect of spironolactone on diabetic nephropathy compared to the combination of spironolactone and losartan. Nephrourology Monthly 2014;6(1):e12148. [MEDLINE: ] - PMC - PubMed
    1. Makhlough A, Kashi Z, Akha O. Effect of spironolactone-placebo and spironolacton-losartan on microalbuminuria in type II diabetes patients [abstract]. Iranian Journal of Kidney Diseases 2011;5(Suppl 2):46. [EMBASE: 70673884]
Medeiros 2017 {published data only}
    1. Medeiros M, Ramirez S, Velasquez L, Hernandez AM, Valverde S, Vargas A, et al. Aldosterone blockade in children with chronic allograft nephropathy [abstract no: O-10]. Pediatric Nephrology 2010;25(9):1808. [EMBASE: 70438169]
    1. Medeiros M, Sosa J, Velasquez L, Hernandez AM, Ramirez S, Valverde S, et al. Aldosterone blockade in children with chronic allograft nephropathy [abstract no: 1296]. American Journal of Transplantation 2010;10(Suppl 4):411. [EMBASE: 70464672]
    1. Medeiros M, Velasquez-Jones L, Hernandaz AM, Ramirez S, Fuentes Y, Valverdes S, et al. Aldosterone blockade in children with chronic allograft nephropathy [abstract no: 234]. Pediatric Transplantation 2011;15(Suppl 1):98-9. [EMBASE: 70508755]
    1. Medeiros M, Velasquez-Jones L, Hernandez AM, Ramon-Garcia G, Valverde S, Fuentes Y, et al. Randomized controlled trial of mineralocorticoid receptor blockade in children with chronic kidney allograft nephropathy. Clinical Journal of the American Society of Nephrology: CJASN 2017;12(8):1291-300. [MEDLINE: ] - PMC - PubMed
    1. Medeiros M, Velasquez-Jones L, Hernandez AM, Valverde S, Fuentes Y, Barrera-Chimal J, et al. Mineralocorticoid receptor blockade in children with chronic allograft injury [abstract no: 116]. Pediatric Transplantation 2013;17(Suppl 1):71. [EMBASE: 71163526]
Oxlund 2015 {published data only}
    1. Lindhardt M, Oxlund CS, Mischak H, Jacobsen IA, Rossing P, Lambers Heerspink HJ. A urinary peptide classifier predicts albuminuria response to spironolactone in patients with type 2 diabetes and hypertension [abstract no: SA-PO255]. Journal of the American Society of Nephrology 2014;25(Abstract Suppl):694A.
    1. Lindhardt M, Persson F, Oxlund C, Jacobsen IA, Zurbig P, Mischak H, et al. Predicting albuminuria response to spironolactone treatment with urinary proteomics in patients with type 2 diabetes and hypertension. Nephrology Dialysis Transplantation 2018;33(2):296-303. [MEDLINE: ] - PubMed
    1. Oxlund C, Kurt B, Schwarzensteiner I, Hansen MR, Staehr M, Svenningsen P, et al. Albuminuria is associated with an increased prostasin in urine while aldosterone has no direct effect on urine and kidney tissue abundance of prostasin. Pflugers Archiv - European Journal of Physiology 2017;469(5-6):655-67. [MEDLINE: ] - PubMed
    1. Oxlund CS, Cangemi C, Henriksen JE, Jacobsen IA, Gram J, Schousboe K, et al. Low-dose spironolactone reduces plasma fibulin-1 levels in patients with type 2 diabetes and resistant hypertension. Journal of Human Hypertension 2015;29(1):28-32. [MEDLINE: ] - PubMed
Preston 2009 {published data only}
    1. Preston RA, Afshartous D, Garg D, Medrano S, Alonso AB, Rodriguez R. Mechanisms of impaired potassium handling with dual renin-angiotensin-aldosterone blockade in chronic kidney disease. Hypertension 2009;53(5):754-60. [MEDLINE: ] - PubMed
PRIORITY 2014 {published data only}
    1. Lindhardt M, Persson F, Currie G, Pontillo C, Beige J, Delles C, et al. Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy in TYpe 2 diabetic patients with normoalbuminuria (PRIORITY): essential study design and rationale of a randomised clinical multicentre trial. Trials 2016;6(3):e010310. [MEDLINE: ] - PMC - PubMed
    1. Siwy J, Schanstra JP, Argiles A, Bakker SJ, Beige J, Boucek P, et al. Multicentre prospective validation of a urinary peptidome-based classifier for the diagnosis of type 2 diabetic nephropathy. Nephrology Dialysis Transplantation 2014;29(8):1563-70. [MEDLINE: ] - PMC - PubMed
    1. Tofte N, Lindhardt M, Adamova K, Beige J, Beulens JW, Birkenfeld AL, et al. Characteristics of high- and low-risk individuals in the PRIORITY study: urinary proteomics and mineralocorticoid receptor antagonism for prevention of diabetic nephropathy in Type 2 diabetes. Diabetic Medicine 2018;35(10):1375-82. [MEDLINE: ] - PubMed
    1. Tofte N, PRIORITY Study Group. Baseline characteristics in PRIORITY study: proteomics and mineralocorticoid receptor antagonism for prevention of diabetic nephropathy in type 2 diabetes [abstract no: TH-PO718]. Journal of the American Society of Nephrology 2017;28(Abstract Suppl):284.
Rachmani 2004 {published data only}
    1. Anonymous. The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: a randomized controlled study.[Retraction of: Rachmani R, Slavachevsky I, Amit M, Levi Z, Kedar Y, Berla M, Ravid M. Diabet Med. 2004 May;21(5):471-5; PMID: 15089793]. Diabetic Medicine 2006;23(7):818. [MEDLINE: ] - PubMed
    1. Rachmani R, Slavachevsky I, Amit M, Levi Z, Kedar Y, Berla M, et al. The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: A randomized controlled study. Diabetic Medicine 2004;21(5):471-5. [MEDLINE: ] - PubMed
RALES 1995 {published data only}
    1. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). American Journal of Cardiology 1996;78(8):902-7. [MEDLINE: ] - PubMed
    1. Glick HA, Orzol SM, Tooley JF, Remme WJ, Sasayama S, Pitt B. Economic evaluation of the randomized aldactone evaluation study (RALES): treatment of patients with severe heart failure. Cardiovascular Drugs & Therapy 2002;16(1):53-9. [MEDLINE: ] - PubMed
    1. Hauben M, Reich L, Gerrits CM, Madigan D. Detection of spironolactone-associated hyperkalaemia following the Randomized Aldactone Evaluation Study (RALES). Drug Safety 2007;30(12):1143-9. [MEDLINE: ] - PubMed
    1. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. New England Journal of Medicine 1999;341(10):709-17. [MEDLINE: ] - PubMed
    1. Pitt D. ACE inhibitor co-therapy in patients with heart failure: rationale for the Randomized Aldactone Evaluation Study (RALES). European Heart Journal 1995;16 Suppl N:107-10. [MEDLINE: ] - PubMed
Schjoedt 2006 {published data only}
    1. Schjoedt KJ, Rossing K, Juhl TR, Boomsa F, Tarnow L, Rossing P, et al. Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney International 2006;70(3):536-42. [MEDLINE: ] - PubMed
Schjoedt 2009 {published data only}
    1. Schjoedt KJ, Christensen PK, Jorsal A, Boomsma F, Rossing P, Parving HH. Autoregulation of glomerular filtration rate during spironolactone treatment in hypertensive patients with type 1 diabetes: a randomized crossover trial. Nephrology Dialysis Transplantation 2009;24(11):3343-9. [MEDLINE: ] - PubMed
    1. Schjoedt KJ, Rossing K, Christensen PK, Parving HH, Rossing P. Autoregulation of the glomerular filtration rate during spironolactone treatment [abstract no: PUB561]. Journal of the American Society of Nephrology 2007;18(Abstracts Issue):953A. [CENTRAL: CN-00689324]
Schmidt 2005 {published data only}
    1. Schmidt BM, Schneider A, Kalizki T, Rastatter A, Schwarz TK, Schmieder RE. Low dose spironolactone rapidly reduces left ventricular mass [abstract no: F-FC099]. Journal of the American Society of Nephrology 2005;16:60A. [CENTRAL: CN-00716088]
Schmidt 2005a {published data only}
    1. Schmidt B, Sammer U, Schaufele T, Schmieder R. Effects of aldosterone on kidney blood flow. Medizinische Klinik 2005;100(Abstract-Band):68. [CENTRAL: CN-00777290]
Schmidt 2008 {published data only}
    1. Schmidt BM, Raff U, Schwab J, Bar I, Schmieder RE. Eplerenone at low dose induces regression of left ventricular hypertrophy in resistant hypertension [abstract no: SA-PO2251]. Journal of the American Society of Nephrology 2008;19(Abstracts Issue):617A. [CENTRAL: CN-01657688]
STOP‐CKD 2014 {published data only}80658312
    1. Ng KP, Jain P, Gill PS, Heer G, Townend JN, Freemantle N, et al. Results and lessons from the Spironolactone To Prevent Cardiovascular Events in Early Stage Chronic Kidney Disease (STOP-CKD) randomised controlled trial. BMJ Open 2016;6(2):e010519. [MEDLINE: ] - PMC - PubMed
    1. Ng KP, Jain P, Heer G, Redman V, Chagoury OL, Dowswell G, et al. Spironolactone to prevent cardiovascular events in early-stage chronic kidney disease (STOP-CKD): study protocol for a randomized controlled pilot trial. Trials [Electronic Resource] 2014;15(1):158. [MEDLINE: ] - PMC - PubMed
Swift 2006 {published data only}
    1. Swift PA, Markandu ND, Wood M, Sagnella GA, MacGregor GA. A double blind randomized crossover trial of amiloride and spironolactone in black hypertensives with and without the T594M b-subunit epithelial sodium channel polymorphism [abstract no: TH-FC153]. Journal of the American Society of Nephrology 2006;17(Abstracts):33-4A. [CENTRAL: CN-00716092]
Taheri HD 2009 {published data only}
    1. Mortazavi M, Taheri S, Shahidi S, Pourmoghaddas A, Yaraghi MG, Seyrafian S, et al. Spironolactone in chronic hemodialysis patients improves cardiac function [abstract no: FP379]. Nephrology Dialysis Transplantation 2007;22(Suppl 6):vi145. [CENTRAL: CN-00716090] - PubMed
    1. Taheri S, Mortazavi M, Shahidi S, Pourmoghadas A, Garakyaraghi M, Seirafian S, et al. Spironolactone in chronic hemodialysis patients improves cardiac function. Saudi Journal of Kidney Diseases & Transplantation 2009;20(3):392-7. [MEDLINE: ] - PubMed
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TOPCAT 2014 {published data only}
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Viswanathan 2013 {published data only}
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References to studies awaiting assessment

NCT00315016 {published data only}
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SPIRO‐CKD 2017 {published data only}94696478
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BARACK D 2014 {published data only}44522369
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References to other published versions of this review

Bolignano 2014
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