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

Edmund YM Chung; Marinella Ruospo; Patrizia Natale; Davide Bolignano; Sankar D Navaneethan; Suetonia C Palmer; Giovanni FM Strippoli

doi:10.1002/14651858.CD007004.pub4

. 2020 Oct 27;2020(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,^✉

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC8094274 PMID: 33107592

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.

Plain language summary

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

What is the issue?

People who have chronic kidney disease (CKD) have a higher risk of heart disease and declining kidney function. Increased amounts of protein in the urine is a sign of kidney stress and is linked to declining kidney function. Medications used to lower blood pressure and reduce protein levels in the urine ‐ in particular, angiotensin‐converting enzyme Inhibitors (ACEi) and angiotensin receptor blockers (ARBs) ‐remain the core treatment to prevent the declining of kidney function in CKD.

Protecting kidney function with these medications may however be incomplete and adding an aldosterone antagonist (blocker) (for example, spironolactone, canrenone, eplerenone, or finerenone) may better protect kidney function in the long‐term. By blocking the production of aldosterone, the kidneys excrete more water which can lead to a lowering of blood pressure. However, they can cause side effects including enlargement of male breast tissue, and when used with ACEi or ARBs may cause high levels of potassium in the blood or a decline in kidney function.

What did we do? We reviewed the available studies looking at the addition of aldosterone blockers to standard treatment in people with CKD to see if they slowed the decline of kidney function and the subsequent need for dialysis or a kidney transplant. We looked at whether they reduced heart disease, the amount of protein in urine, or improved blood pressure. We also looked at whether aldosterone blockers were safe in terms of risks of male breast enlargement, potassium levels in the blood, and short‐term effects on kidney function.

What did we find? We found that adding aldosterone blockers to a patient's current medications (ACEi or ARBs), lowered both protein in the urine and systolic blood pressure. Kidney function declined, however the effects on survival were uncertain. The addition of aldosterone blockers increased the amount of potassium in the blood. This may require medication changes, extra blood tests, and may be potentially harmful. Treatment with aldosterone blockers also increased the chance of short‐term decline in kidney function and enlargement of male breast tissue.

Conclusions It is unclear as to whether aldosterone blockers protect kidney function or prevent heart disease in people who have CKD.

Summary of findings

Background

Description of the condition

Chronic kidney disease (CKD) has a global prevalence of 10% to 12% and progression to kidney failure (previously known as end‐stage kidney disease (ESKD)) is rising due to the global diabetes and hypertension pandemics (Mills 2015; Nugent 2011). There is a significant associated economic burden to patients, caregivers, and society, which increases throughout disease progression (Wang 2016). Angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) are the standard of care to slow progression of CKD and reduce incidence of kidney failure in patients with proteinuria irrespective of primary kidney disease (Jafar 2001; Strippoli 2006) because they lower proteinuria and blood pressure, which are both independent predictors of death in adults with CKD (Brenner 2001; GISEN 1997; Mathiesen 1999). However, ACEi or ARB 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 exacerbates glomerulosclerosis resulting in severe proteinuria (Bomback 2007), which is reduced with aldosterone blockade (Aldigier 2005; Green 1996; Rocha 1998; Silvestre 1998). Renin‐angiotensin‐aldosterone system blockade with ACEi or ARB result in incomplete suppression of serum aldosterone levels and is known as the '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 antagonists reduces proteinuria (Fritsch Neves 2003). However, aldosterone antagonism may increase risks of hyperkalaemia and gynaecomastia (Nappi 2011). Novel non‐steroidal mineralocorticoid receptor antagonists such as finerenone are more selective for the mineralocorticoid receptor than other steroid receptors including the glucocorticoid receptor, androgen receptor and progesterone receptor (Bramlage 2016) and may provide similar efficacy as non‐selective aldosterone antagonist but improved safety profile.

Mechanisms of cardiac and kidney damage induced by aldosterone excess

How the intervention might work

Multiple aldosterone‐mediated mechanisms have been shown to contribute to renal vascular injury and fibrosis in animal studies. These include aldosterone‐mediated increases in plasminogen activator inhibitor‐1 (PAI‐1) which inhibits the fibrinolytic system and activates latent growth factors; up‐regulation of transforming growth factor‐b and associated fibroblast differentiation, up‐regulation of collagen synthesis and down regulation of matrix metalloproteinase collagenase; generation of oxygen‐free radicals and hydrogen peroxide; and up regulation of endothelin‐1 with resultant vasoconstriction (Hollenberg 2004). However, a common pathway is yet to be clearly defined. In a rat model, renal radiation injury resulted in an eight‐fold increase in the expression of PAI‐1 messenger RNA (mRNA) and non‐selective aldosterone blockade (spironolactone) significantly decreased PAI‐1 mRNA expression, development of glomerulosclerosis and proteinuria (Brown 2000). In human studies, beneficial effects of aldosterone blockade (non‐selective and selective) have been established in congestive cardiac failure (Hostetter 2003; Pitt 1999; Pitt 2003) and proteinuric CKD (Bianchi 2006; Chrysostomou 2006; Epstein 2006; Rossing 2005; Schjoedt 2005). In animal studies, finerenone had a more potent natriuretic response than eplerenone but no impact on urinary potassium levels (Kolkhof 2014). Therefore, it is hypothesised that non‐steroidal mineralocorticoid receptor antagonists will exhibit the benefits of aldosterone blockade without the risk of hyperkalaemia.

Why it is important to do this review

Aldosterone blockade in combination with ACEi or ARB may reduce proteinuria but their effects on patient‐level outcomes such as kidney failure requiring dialysis or kidney transplantation or major cardiovascular events and their safety in regards to risk of hyperkalaemia and acute kidney injury, particularly in adults who have coexisting CKD, remain uncertain. Thus, we analysed the benefits and harms of aldosterone antagonists in adults who had CKD and who were or who were not already treated with ACEi or ARB (or in combination). We specifically focused on treatment effects for patient‐level outcomes including kidney failure and major cardiovascular events, proteinuria, and kidney function. New relevant studies on CKD patients receiving aldosterone antagonists, including non‐steroidal mineralocorticoid antagonists, have recently been completed and their inclusion to update the previous published versions of this review (Bolignano 2014; Navaneethan 2009) would be valuable.

Objectives

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

Patient‐centred endpoints including kidney failure, major cardiovascular events, and death (any cause)
Kidney function (proteinuria, estimated glomerular filtration rate (eGFR), and doubling of serum creatinine (SCr)
Adverse events (including hyperkalaemia, acute kidney injury, and gynaecomastia).

Methods

Criteria for considering studies for this review

Types of studies

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

Types of participants

Inclusion criteria

Studies enrolling participants 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. The K/DOQI categories for kidney disease are as follows.

CKD stage 1: eGFR > 90 mL/min/1.73 m² and evidence of clinically relevant structural or urinary abnormalities including haematuria or proteinuria (or both)
CKD stage 2: eGFR 60 to 89 mL/min/1.73 m²
CKD stage 3: eGFR 30 to 59 mL/1.73 m²
CKD stage 4: eGFR 15 to 29 mL/min/1.73 m².

Exclusion criteria

We excluded studies in adults on dialysis, recipients of a kidney transplant, participants without evidence of CKD or proteinuria, studies less than 4 weeks of duration, and studies not evaluating any outcome of interest.

Types of interventions

We included studies evaluating aldosterone antagonist treatment given in combination with an ACEi or ARB (or both). We considered studies in which treatment duration was 4 weeks or longer. If any studies compared aldosterone antagonists alone (i.e. no additional RAS antagonists), these studies were also included,

We considered the following treatment comparisons.

Aldosterone antagonists with RAS antagonists versus placebo or standard care
Aldosterone antagonist with RAS antagonists versus diuretic plus ACEi or ARB
Non‐selective aldosterone antagonist with RAS antagonists versus calcium channel blocker
Selective aldosterone antagonist with RAS antagonists versus ACEi or ARB (or both)
Selective aldosterone antagonist with RAS antagonists versus ACEi or ARB (or both) versus ACEi or ARB (or both) plus nitrate
Selective aldosterone antagonist with RAS antagonists versus non‐steroidal mineralocorticoid antagonist.

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

Kidney failure (defined as permanent worsening in eGFR requiring kidney replacement therapy)
Hyperkalaemia (defined as serum potassium > 5.0 mEq/L or mmol/L)

Secondary outcomes

Death (any cause)
Major cardiovascular events as defined by the investigators (including but not limited to myocardial infarction, stroke, congestive heart failure)
Urinary protein excretion rate (24‐hour proteinuria, 24‐hour albuminuria in mg/dL, urine protein:creatinine ratio, or urine albumin:creatinine ratio)
Kidney function: estimated GFR (mL/min or mL/min/1.73 m²); doubling of SCr; progression from micro‐ to macroalbuminuria; regression from macro‐ to microalbuminuria and regression from micro‐ to normoalbuminuria
Blood pressure: systolic and diastolic blood pressure (mmHg)
Serum potassium
Acute kidney injury
Gynaecomastia
Fatigue
Falls

Search methods for identification of studies

Electronic searches

Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
Weekly searches of MEDLINE OVID SP
Searches of kidney and transplant journals, and the proceedings and abstracts from major kidney and transplant conferences
Searching of the current year of EMBASE OVID SP
Weekly current awareness alerts for selected kidney and transplant journals
Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website.

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

Searching other resources

Reference lists of clinical practice guidelines, review articles and relevant studies.
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?
- Participants and personnel (performance bias)
- Outcome assessors (detection bias)
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 (kidney failure, death (any cause), cardiovascular events, doubling of SCr, hyperkalaemia, acute kidney injury, and 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, eGFR or creatinine clearance, blood pressure, and serum potassium), 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

We first assessed the heterogeneity by visual inspection of the forest plot. We then quantified statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values was as follows.

0% to 40%: might not be important
30% to 60%: may represent moderate heterogeneity
50% to 90%: may represent substantial heterogeneity
75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P‐value from the Chi² test, or a confidence interval for I²) (Higgins 2011).

Assessment of reporting biases

We planned to assess for the potential existence of small study bias (Higgins 2011) for outcomes in which sufficient data observations were available (10 or more studies) and in which there was low or no statistical heterogeneity between 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. 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 (selective or non‐selective aldosterone antagonist), dose, duration of aldosterone antagonists and the concomitant use of ACEi or ARB (or both).

'Summary of findings' tables

We presented the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2011a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008; GRADE 2011). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b). We presented the following outcomes in the 'Summary of findings' tables. The absolute treatment effects for dichotomous outcomes was estimated using the risk estimate and 95% CI obtained from the corresponding meta‐analysis.

Primary efficacy outcome

Kidney failure

Primary safety outcome

Hyperkalaemia

Secondary outcomes

Death (any cause)
Cardiovascular events
Doubling SCr
Acute kidney injury
Proteinuria
eGFR

Results

Description of studies

Results of the search

For this 2020 update a search of The Cochrane Kidney and Transplant Register of Studies identified 83 reports. We identified 18 new included studies (32 reports), and four reports of two existing included studies; three new ongoing studies (four reports); 13 new excluded studies (40 reports), and two reports of two existing excluded studies. One study (one report) has been recently completed but no results have been published and is awaiting assessment.

In addition to the new reports, one previously included study has been move to excluded (Schjoedt 2006) as a proportion of the patients have been reported in two other included studies (Schjoedt 2005; Rossing 2005). Two previous ongoing studies have now been included (Abolghasmi 2011; EVALUATE 2010) and one study, while complete, is yet to publish any results and is awaiting assessment (NCT00315016). Four non‐RCTs have been removed from this update.

See Figure 2.

Included studies

For this 2020 update we included 18 new studies (4248 participants) (ARTS 2012; ARTS‐DN 2015; ARTS‐HF 2015; Bianchi 2010; Boesby 2013; Chen 2018b; Esteghamati 2013; EVALUATE 2010; Fogari 2014; Hamid 2017a; Hase 2013; Horestani 2012; Ito 2019a; Kato 2015; Morales 2015; Tylicki 2012; Wang 2013g; Ziaee 2013). This brings the total number of included studies to 44 (85 reports, 5745 participants).

Ten studies were cross‐over studies (Boesby 2011; Morales 2009; Morales 2015; Nielsen 2012; Saklayen 2008; Smolen 2006; Rossing 2005; Schjoedt 2005; Tylicki 2008; Tylicki 2012).

Twenty‐three studies included participants who had kidney disease secondary to diabetes mellitus (ARTS‐DN 2015; Chen 2018b; Chrysostomou 2006; Epstein 2002; Epstein 2006; Esteghamati 2013; Fogari 2014; Hamid 2017a; Hase 2013; Horestani 2012; Ito 2019a; Kato 2015; Koroshi 2010; Mehdi 2009; Nielsen 2012; Ogawa 2006a; Rossing 2005; Saklayen 2008; Schjoedt 2005; Takebayashi 2006; van den Meiracker 2006; Zheng 2011; Ziaee 2013). Two studies included participants with heart failure with associated proteinuric CKD (ARTS 2012; ARTS‐HF 2015). The remaining studies included participants with non‐diabetic kidney disease encompassing IgA nephropathy, benign nephrosclerosis, membranous nephropathy, or idiopathic chronic glomerulonephritis (Abolghasmi 2011; Bianchi 2006; Bianchi 2010; Boesby 2011; Boesby 2013; Cohen 2010; CRIBS II 2009; Furumatsu 2008; Guney 2009; Haykal 2007; Lv 2009a; Morales 2009; Morales 2015; Smolen 2006; Tokunaga 2008a; Tylicki 2008; Tylicki 2012; Wang 2013g). All studies excluded participants with an eGFR below 15 mL/min/1.73 m². For studies measuring 24‐hour urine protein or albumin, the baseline albuminuria/proteinuria excretion rates ranged from 0.15 to 3.6 g/day. Study duration varied from one to 36 months with a median duration of 3 months. Sample size of all studies was variable (range 16 to 1055) and none were powered to detect hard primary outcomes including kidney failure, death, or major cardiovascular events.

Among studies using non‐selective aldosterone antagonists, 22 studies (1441 participants) compared spironolactone plus ACEi or ARB (or both) to ACEi or ARB (or both) (Abolghasmi 2011; Bianchi 2006; Chen 2018b; Chrysostomou 2006; CRIBS II 2009; Furumatsu 2008; Guney 2009; Kato 2015; Koroshi 2010; Lv 2009a; Mehdi 2009; Nielsen 2012; Ogawa 2006a; Rossing 2005; Saklayen 2008; Schjoedt 2005; Tokunaga 2008a; Tylicki 2008; van den Meiracker 2006; Wang 2013g; Zheng 2011; Ziaee 2013). Five studies (220 participants) compared spironolactone plus ACEi or ARB to diuretics plus ACEi or ARB (Hamid 2017a; Hase 2013, Horestani 2012; Morales 2015; Smolen 2006); one study (37 participants) compared spironolactone to calcium channel blockers (Takebayashi 2006); one study (136 participants) compared spironolactone plus ARB to ACEi plus ARB (Esteghamati 2013); one study (120 participants) compared canrenone plus ARB and calcium channel blockers to hydrochlorothiazide plus ARB and calcium channel blockers (Fogari 2014); and one study (128 participants) compared spironolactone plus ACEi and ARB to ACEi (Bianchi 2010). In the studies that analysed the efficacy of non‐selective aldosterone antagonists, 25 mg/day 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/day. Chen 2018b, Lv 2009a, Wang 2013g and Zheng 2011 used 20 mg/day; Horestani 2012, Koroshi 2010and Takebayashi 2006 used 50 mg/day; Mehdi 2009 used 12.5 to 25 mg/day of spironolactone; and Bianchi 2010 used 25 mg three times/week to 50 mg/day of spironolactone. Fogari 2014 used 25 mg/day of canrenone. In Hamid 2017a, the dose of spironolactone was not defined.

Six studies (925 participants) 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; EVALUATE 2010; Tylicki 2012). One study (34 participants) compared eplerenone plus ACEi or ARB (or both) to ACEi or ARB (or both) and to ACEi or ARB (or both) plus nitrate (Cohen 2010), and one study (54 participants) compared the selective aldosterone antagonist eplerenone to placebo (Boesby 2013). Studies that analysed the efficacy of selective aldosterone antagonists used eplerenone at the dose of 200 mg/day (Epstein 2002), 50 to 100 mg/day (Epstein 2006), 25 to 50 mg/day (Boesby 2011; Boesby 2013; Haykal 2007), and 50 mg/day (EVALUATE 2010; Tylicki 2012). In Cohen 2010 the dose of eplerenone administered was not defined.

One cross‐over study (12 participants) compared eplerenone alone (25 mg/day) to ACEi alone (20 mg/day) or ACEi (10 mg/day) plus ARB (16 mg/day) (Morales 2009).

Among studies using non‐steroidal mineralocorticoid antagonists, one study (821 participants) compared finerenone to placebo (ARTS‐DN 2015), one study (392 participants) compared finerenone to placebo or spironolactone (ARTS 2012), one study (1055 participants) compared finerenone to eplerenone (ARTS‐HF 2015), and one study (358 participants) compared esaxerenone to placebo (Ito 2019a). Studies that analysed the efficacy of non‐steroidal mineralocorticoid antagonists used finerenone at the dose of 2.5 to 10 mg/day (ARTS 2012), 1.25 to 25 mg/day (ARTS‐DN 2015), 5 to 20 mg/day (ARTS‐HF 2015), and esaxerenone 0.625 to 5 mg/day (Ito 2019a). Other characteristics of the participants and the interventions of the included studies are detailed in the Characteristics of included studies.

Excluded studies

Twenty‐seven studies (61 reports) were excluded because; they did not include adults with CKD (17 studies); were not studies comparing aldosterone antagonists with or without ACEi or ARB (3); were of short duration (1); included participants already reported in other included studies (1); were terminated early with no reported outcomes (1); or they did not examine outcomes of interest (e.g. pharmacokinetic studies) (1). One study was retracted (1).

For this 2020 update, non‐RCTs have been deleted.

See Characteristics of excluded studies

Risk of bias in included studies

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

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

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

Allocation

Random sequence generation was judged to be at low risk of bias in 12 studies (ARTS‐DN 2015; ARTS‐HF 2015; Bianchi 2006; Chen 2018b; EVALUATE 2010; Mehdi 2009; Morales 2015; Nielsen 2012; Schjoedt 2005; Tylicki 2008; Tylicki 2012; van den Meiracker 2006) and unclear in the remaining 32 studies.

Allocation concealment was judged to be at low risk in five studies (ARTS‐DN 2015; ARTS‐HF 2015; Boesby 2011; Chrysostomou 2006; EVALUATE 2010), one study was judged to be a high risk of bias (Bianchi 2010), and unclear in the remaining 38 studies.

Blinding

Participants and investigators were blinded in 18 studies (Abolghasmi 2011; ARTS 2012; ARTS‐DN 2015; ARTS‐HF 2015; Chrysostomou 2006; CRIBS II 2009; Epstein 2002; Epstein 2006; EVALUATE 2010; Kato 2015; Lv 2009a; Mehdi 2009; Nielsen 2012; Rossing 2005; Saklayen 2008; Schjoedt 2005; Tylicki 2012; van den Meiracker 2006) and not blinded in 13 studies (Bianchi 2006; Bianchi 2010; Boesby 2011; Boesby 2013; Chen 2018b; Esteghamati 2013; Fogari 2014; Furumatsu 2008; Hase 2013; Morales 2009; Tokunaga 2008a; Tylicki 2008; Wang 2013g); blinding was unclear in the remaining 13 studies.

Outcome assessors were not aware of treatment allocation or outcomes were unlikely influenced by treatment allocation in 15 studies (ARTS‐DN 2015; Boesby 2013; CRIBS II 2009; Epstein 2006; Esteghamati 2013; EVALUATE 2010; Fogari 2014; Furumatsu 2008; Guney 2009; Morales 2009; Morales 2015; Nielsen 2012; Saklayen 2008; Smolen 2006; Zheng 2011). Blinding of outcome assessors was unclear in the remaining 29 studies.

Incomplete outcome data

Twenty‐four studies were judged to be at low risk of bias (Abolghasmi 2011; ARTS‐DN 2015; ARTS‐HF 2015; Bianchi 2006; Boesby 2011; Chrysostomou 2006; Cohen 2010; CRIBS II 2009; Epstein 2006; EVALUATE 2010; Fogari 2014; Furumatsu 2008; Hase 2013; Haykal 2007; Kato 2015; Morales 2009; Nielsen 2012; Rossing 2005; Saklayen 2008; Schjoedt 2005; Takebayashi 2006; Tylicki 2008; Tylicki 2012; Zheng 2011). Seven studies where there was some loss to follow‐up (ARTS‐DN 2015; Bianchi 2006; Boesby 2011; Chen 2018b; Epstein 2006; Cohen 2010; CRIBS II 2009) were analysed on an intention‐to‐treat basis. Ten studies were judged to be at high risk of bias (ARTS 2012; Bianchi 2010; Boesby 2013; Chen 2018b; Esteghamati 2013; Guney 2009; Ito 2019a; Mehdi 2009; Morales 2015; van den Meiracker 2006). 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 and all relevant outcomes were reported in 18 studies (ARTS‐DN 2015; ARTS‐HF 2015; Bianchi 2006; Chen 2018b; Chrysostomou 2006; Epstein 2006; Esteghamati 2013; EVALUATE 2010; Fogari 2014; Furumatsu 2008; Guney 2009; Hase 2013; Kato 2015; Lv 2009a; Mehdi 2009; Tokunaga 2008a; Tylicki 2008; Tylicki 2012). Selective reporting was judged to be at high risk of bias in 23 studies (Abolghasmi 2011; Bianchi 2006; Bianchi 2010; Boesby 2011; CRIBS II 2009; Epstein 2002; Hamid 2017a; Haykal 2007; Ito 2019a; Koroshi 2010; Morales 2009; Morales 2015; Nielsen 2012; Ogawa 2006a; Rossing 2005; Saklayen 2008; Schjoedt 2005; Smolen 2006; Takebayashi 2006; van den Meiracker 2006; Wang 2013g; Zheng 2011; Ziaee 2013), and unclear in the remaining three studies.

Other potential sources of bias

Eighteen studies were judged to be at low risk of bias due to funding (Bianchi 2006; Bianchi 2010; Boesby 2011; Boesby 2013; Chrysostomou 2006; CRIBS II 2009; Fogari 2014; Furumatsu 2008; Guney 2009; Hase 2013; Mehdi 2009; Morales 2015; Nielsen 2012; Rossing 2005; Schjoedt 2005; Tylicki 2008; van den Meiracker 2006; Ziaee 2013); six studies were funded by a pharmaceutical company (ARTS 2012; ARTS‐DN 2015; ARTS‐HF 2015; Epstein 2006; EVALUATE 2010; Ito 2019a;); one study excluded participants after randomisation due change in treatment (Horestani 2012) and the risk of bias was unclear in the remaining 19 studies.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6

Summary of findings 1. Aldosterone antagonists versus placebo or standard care for proteinuric chronic kidney disease.

Aldosterone antagonist versus placebo or standard care for proteinuric CKD
Patient or population: proteinuric CKD Intervention: aldosterone antagonist Comparison: placebo or standard care
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with placebo or standard care	Risk with aldosterone antagonist	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Kidney failure	0 per 1,000	0 per 1,000 (0 to 0)	RR 3.00 (0.33 to 27.65)	84 (2)	⊕⊝⊝⊝ VERY LOW ^{1, 2}
Hyperkalaemia	25 per 1,000	55 per 1,000 (37 to 81)	RR 2.17 (1.47 to 3.22)	3001 (17)	⊕⊕⊕⊝ MODERATE ³
Death	14 per 1,000	8 per 1,000 (1 to 50)	RR 0.58 (0.10 to 3.50)	421 (3)	⊕⊕⊝⊝ LOW ^{2, 4}
Cardiovascular events	32 per 1,000	31 per 1,000 (8 to 115)	RR 0.95 (0.26 to 3.56)	1067 (3)	⊕⊕⊝⊝ LOW ^{2, 5}
Doubling serum creatinine	83 per 1,000	107 per 1,000 (57 to 202)	RR 1.30 (0.69 to 2.44)	875 (2)	⊕⊕⊝⊝ LOW ^{2, 5}
AKI	30 per 1,000	61 per 1,000 (31 to 119)	RR 2.04 (1.05 to 3.97)	1446 (5)	⊕⊕⊕⊝ MODERATE ⁶
Proteinuria	The SMD was 0.51 lower with aldosterone antagonists (0.82 lower to 0.20 lower) than placebo or standard care		‐	1193 (14)	⊕⊝⊝⊝ VERY LOW ^{7, 8, 9, 10}
eGFR (mL/min/1.73 m²)	The mean eGFR was 3.00 mL/min/1.73 m² lower with aldosterone antagonists (5.51 lower to 0.49 lower) than placebo or standard care		‐	1144 (12)	⊕⊕⊝⊝ LOW ^{2, 11}
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CKD: chronic kidney disease; CI: confidence interval; RR: risk ratio; AKI: acute kidney injury; eGFR: estimated glomerular filtration rate
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Aldosterone antagonist versus diuretics for proteinuric CKD
Patient or population: proteinuric CKD Intervention: aldosterone antagonist Comparison: diuretics
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with diuretics	Risk with aldosterone antagonist	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Kidney failure	not reported	not reported	‐‐	‐‐	‐‐
Hyperkalaemia	not reported	not reported	‐‐	‐‐	‐‐
Death	not reported	not reported	‐‐	‐‐	‐‐
Cardiovascular events	not reported	not reported	‐‐	‐‐	‐‐
Doubling serum creatinine	not reported	not reported	‐‐	‐‐	‐‐
AKI	not reported	not reported	‐‐	‐‐	‐‐
Proteinuria	The SMD was 1.59 lower (3.8 lower to 0.62 higher) with aldosterone antagonists than diuretics		‐	139 (2)	⊕⊝⊝⊝ VERY LOW ^{1, 2, 3, 4}
eGFR (mL/min/1.73 m²)	The mean eGFR was 2 mL/min/1.73 m² higher with aldosterone antagonists (26.31 lower to 30.31 higher) than diuretics		‐	12 (1)	⊕⊕⊝⊝ LOW ^{4, 5}
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CKD: chronic kidney disease; CI: confidence interval; RR: risk ratio; AKI: acute kidney injury; eGFR: estimated glomerular filtration rate
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Aldosterone antagonists versus calcium channel blocker for proteinuric CKD
Patient or population: proteinuric CKD Intervention: aldosterone antagonist Comparison: calcium channel blocker
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with calcium channel blocker	Risk with aldosterone antagonist	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Kidney failure	not reported	not reported	‐‐	‐‐	‐‐
Hyperkalaemia	not reported	not reported	‐‐	‐‐	‐‐
Death	not reported	not reported	‐‐	‐‐	‐‐
Cardiovascular events	not reported	not reported	‐‐	‐‐	‐‐
Doubling serum creatinine	not reported	not reported	‐‐	‐‐	‐‐
AKI	not reported	not reported	‐‐	‐‐	‐‐
Proteinuria	Data could not to be meta‐analysed		‐	37 (1)	⊕⊕⊝⊝ LOW ^{1, 2}
eGFR (mL/min/1.73 m²)	not reported		‐‐	‐‐	‐‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CKD: chronic kidney disease; CI: Confidence interval; RR: Risk ratio; AKI: acute kidney injury; eGFR: estimated glomerular filtration rate
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Aldosterone antagonists versus ACEi or ACEi plus ARB for proteinuric chronic kidney disease
Patient or population: proteinuric chronic kidney disease Intervention: aldosterone antagonist Comparison: ACEi or ACEi plus ARB
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with ACEi or ACEi plus ARB	Risk with aldosterone antagonist	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Kidney failure	not reported	not reported	‐‐	‐‐	‐‐
Hyperkalaemia	37 per 1,000	60 per 1,000 (24 to 146)	RR 1.62 (0.66 to 3.95)	500 (2)	⊕⊕⊝⊝ LOW ^{1, 2}
Death	not reported	not reported	‐‐	‐‐	‐‐
Cardiovascular events	not reported	not reported	‐‐	‐‐	‐‐
Doubling serum creatinine	not reported	not reported	‐‐	‐‐	‐‐
AKI	not reported	not reported	‐‐	‐‐	‐‐
Proteinuria	Data could not be meta‐analysed		‐	465 (4)	⊕⊝⊝⊝ VERY LOW ^{3, 4, 5}
GFR (mL/min/1.73 m²)	Data could not be meta‐analysed		‐	18 (1)	⊕⊕⊝⊝ LOW ^{6, 7}
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  ACEi: angiotensin‐converting enzyme inhibitors; ARB: angiotensin receptor blocker; CI: confidence interval; RR: risk ratio; AKI: acute kidney injury; eGFR: estimated glomerular filtration rate
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Aldosterone antagonist versus nitrate for proteinuric chronic kidney disease
Patient or population: proteinuric chronic kidney disease Intervention: aldosterone antagonist Comparison: nitrate
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with nitrate	Risk with aldosterone antagonist	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Kidney failure	not reported	not reported	‐‐	‐‐	‐‐
Hyperkalaemia	not reported	not reported	‐‐	‐‐	‐‐
Death	not reported	not reported	‐‐	‐‐	‐‐
Cardiovascular events	not reported	not reported	‐‐	‐‐	‐‐
Doubling serum creatinine	not reported	not reported	‐‐	‐‐	‐‐
AKI	not reported	not reported	‐‐	‐‐	‐‐
Proteinuria	Data could not be meta‐analysed		‐	29 (1)	⊕⊕⊝⊝ LOW ^{1, 2}
eGFR	not reported		‐‐	‐‐	‐‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio; AKI: acute kidney injury; eGFR: estimated glomerular filtration rate
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Non‐steroidal mineralocorticoid receptor antagonist versus selective aldosterone antagonist for proteinuric chronic kidney disease
Patient or population: proteinuric chronic kidney disease Intervention: non‐steroidal mineralocorticoid receptor antagonist Comparison: selective aldosterone antagonist
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with selective aldosterone antagonist	Risk with non‐steroidal mineralocorticoid receptor antagonist	Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Kidney failure	not reported	not reported	‐‐	‐‐	‐‐
Hyperkalaemia	47 per 1,000	42 per 1,000 (21 to 83)	RR 0.89 (0.45 to 1.77)	1023 (1)	⊕⊕⊝⊝ LOW ^{1, 2}
Death	36 per 1,000	25 per 1,000 (11 to 56)	RR 0.70 (0.31 to 1.55)	1055 (1)	⊕⊕⊝⊝ LOW ^{1, 2}
Cardiovascular events	not reported	not reported	‐‐	‐‐	‐‐
Doubling serum creatinine	1/834	0/221**	RR 0.80 (0.03 to 19.51)	1055 (1)	⊕⊕⊝⊝ LOW ^{1, 2}
AKI	not reported	not reported	‐‐	‐‐	‐‐
Proteinuria	not reported		‐‐	‐‐	‐‐
eGFR	not reported		‐‐	‐‐	‐‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Event rate derived from the raw data. A 'per thousand' rate is non‐informative in view of the scarcity of evidence and zero events in the non‐steroidal mineralocorticoid receptor antagonist group  CI: confidence interval; RR: risk ratio; AKI: acute kidney injury; eGFR:** estimated glomerular filtration rate
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Date	Event	Description
15 September 2020	New citation required but conclusions have not changed	New studies added; no change to conclusions
13 January 2020	New search has been performed	New search update

Date	Event	Description
28 April 2014	New citation required and conclusions have changed	10 new studies added, new comparisons added
30 January 2013	New search has been performed	New update search completed, new studies identified
22 February 2012	Amended	Update search completed
20 February 2012	Amended	Search methods & search strategies updated
2 September 2008	Amended	Converted to new review format.

Database	Search terms
CENTRAL	MeSH descriptor Aldosterone Antagonists explode all trees (Canrenoate Potassium):ti,ab,kw in Clinical Trials (Canrenone):ti,ab,kw in Clinical Trials (spironolactone):ti,ab,kw in Clinical Trials (aldosterone antagonist):ti,ab,kw in Clinical Trials (aldactone):ti,ab,kw in Clinical Trials (practon):ti,ab,kw in Clinical Trials (sc‐9420):ti,ab,kw in Clinical Trials (spiractin):ti,ab,kw in Clinical Trials (sc‐14266):ti,ab,kw in Clinical Trials (soldactone):ti,ab,kw in Clinical Trials (soludactone):ti,ab,kw in Clinical Trials (aldadiene):ti,ab,kw in Clinical Trials (phanurane):ti,ab,kw in Clinical Trials (sc‐9376):ti,ab,kw in Clinical Trials (eplerenone):ti,ab,kw in Clinical Trials (finerenone):ti,ab,kw in Clinical Trials {and #1‐#17} MeSH descriptor Renal Insufficiency, Chronic explode all trees (chronic kidney disease* or chronic renal disease):ti,ab,kw in Clinical Trials (chronic kidney failure or chronic renal failure):ti,ab,kw in Clinical Trials (chronic kidney insufficiency or chronic renal insufficiency):ti,ab,kw in Clinical Trials MeSH descriptor Renal Insufficiency, this term only MeSH descriptor Kidney Diseases, this term only (CKF or CKD or CRF or CRD):ti,ab,kw in Trials (predialysis or pre‐dialysis):ti,ab,kw in Trials MeSH descriptor Uremia, this term only uremia or uraemia or uremic or uraemic:ti,ab,kw in Trials MeSH descriptor Diabetic Nephropathies, this term only (diabetic nephropath):ti,ab,kw in Trials "diabetic kidney disease":ti,ab,kw in Trials {and #19‐#31} (#18 AND #32)
MEDLINE	exp Aldosterone Antagonists/ Canrenoate Potassium.tw. Canrenone$.tw. spironolactone$.tw. aldosterone antagonist$.tw. aldactone$.tw. practon$.tw. sc‐9420$.tw. spiractin$.tw. sc‐14266$.tw. soldactone$.tw. soludactone$.tw. aldadiene$.tw. phanurane$.tw. sc‐9376.tw. eplerenone$.tw. Finerenone.tw or/1‐17 Renal Insufficiency/ exp Renal Insufficiency, Chronic/ Kidney Diseases/ (chronic kidney or chronic renal).tw. (CKF or CKD or CRF or CRD).tw. (predialysis or pre‐dialysis).tw. exp Uremia/ ur$emi$.tw. (pre‐dialy$ or predialy$).tw. Diabetic Nephropathies/ diabetic nephropath$.tw. "diabetic kidney disease".tw. or/18‐29 and/18,31
EMBASE	exp Aldosterone Antagonist/ aldosterone antagonist$.tw. spironolactone$.tw. eplerenone$.tw. soludactone$.tw. canrenoate potassium.tw. canrenone$.tw. Finerenone or/1‐8 Kidney Disease/ Chronic Kidney Disease/ Kidney Failure/ Chronic Kidney Failure/ Kidney dysfunction/ (chronic kidney or chronic renal).tw. (CKF or CKD or CRF or CRD).tw. (pre‐dialy$ or predialy$).tw. diabetic nephropathy/ "diabetic kidney disease".tw. or/9‐18 and/9,20

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.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Kidney failure	2	84	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.33, 27.65]
1.1.1 Diabetes	1	54	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 70.53]
1.1.2 No diabetes	1	30	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 68.26]
1.2 Hyperkalaemia	17	3001	Risk Ratio (M‐H, Random, 95% CI)	2.17 [1.47, 3.22]
1.2.1 Diabetes	10	2122	Risk Ratio (M‐H, Random, 95% CI)	1.86 [1.20, 2.91]
1.2.2 No diabetes	6	687	Risk Ratio (M‐H, Random, 95% CI)	3.43 [1.35, 8.72]
1.2.3 Diabetes not reported	1	192	Risk Ratio (M‐H, Random, 95% CI)	6.14 [0.82, 46.20]
1.3 Subgroup analysis: hyperkalaemia ‐ number of RAS inhibitors used	13	1977	Risk Ratio (M‐H, Random, 95% CI)	2.22 [1.42, 3.46]
1.3.1 Aldosterone antagonist plus 1 RAS inhibitor	11	1828	Risk Ratio (M‐H, Random, 95% CI)	2.05 [1.28, 3.28]
1.3.2 Aldosterone antagonist plus 2 RAS inhibitors	4	149	Risk Ratio (M‐H, Random, 95% CI)	4.30 [1.12, 16.51]
1.4 Hyperkalaemia data from cross‐over studies	1		Other data	No numeric data
1.5 Death	3	421	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.10, 3.50]
1.5.1 Diabetes	2	107	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.03, 2.46]
1.5.2 No diabetes	1	314	Risk Ratio (M‐H, Random, 95% CI)	2.82 [0.12, 68.60]
1.6 Cardiovascular events	3	1067	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.33, 3.99]
1.6.1 Diabetes	2	875	Risk Ratio (M‐H, Random, 95% CI)	2.22 [0.57, 8.55]
1.6.2 No diabetes	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
1.6.3 Diabetes not reported	1	192	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.11, 2.47]
1.7 Myocardial infarction	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.7.1 Diabetes	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.7.2 No diabetes	0		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.8 Stroke	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.8.1 Diabetes	3	1233	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.12, 3.44]
1.8.2 No diabetes	0	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
1.9 Proteinuria	14	1193	Std. Mean Difference (IV, Random, 95% CI)	‐0.51 [‐0.82, ‐0.20]
1.9.1 Diabetes	7	572	Std. Mean Difference (IV, Random, 95% CI)	‐0.46 [‐0.64, ‐0.27]
1.9.2 No diabetes	5	367	Std. Mean Difference (IV, Random, 95% CI)	‐0.68 [‐1.57, 0.21]
1.9.3 Diabetes not reported	2	254	Std. Mean Difference (IV, Random, 95% CI)	‐0.24 [‐0.49, 0.01]
1.10 Proteinuria: descriptive outcome data	13		Other data	No numeric data
1.11 Proteinuria data from cross‐over studies	2		Other data	No numeric data
1.12 eGFR [mL/min/1.73 m²]	13	1165	Mean Difference (IV, Random, 95% CI)	‐3.00 [‐5.51, ‐0.49]
1.12.1 Diabetes	8	610	Mean Difference (IV, Random, 95% CI)	‐4.43 [‐8.35, ‐0.51]
1.12.2 No diabetes	3	301	Mean Difference (IV, Random, 95% CI)	‐2.26 [‐8.69, 4.18]
1.12.3 Diabetes not reported	2	254	Mean Difference (IV, Random, 95% CI)	‐0.45 [‐5.85, 4.95]
1.13 eGFR: descriptive outcome data	6		Other data	No numeric data
1.14 eGFR data from cross‐over studies	1		Other data	No numeric data
1.15 Doubling serum creatinine	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.15.1 Diabetes	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.15.2 No diabetes	0		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.16 Systolic BP	14	911	Mean Difference (IV, Random, 95% CI)	‐4.98 [‐8.22, ‐1.75]
1.16.1 Diabetes	6	249	Mean Difference (IV, Random, 95% CI)	‐1.06 [‐1.80, ‐0.31]
1.16.2 No diabetes	5	367	Mean Difference (IV, Random, 95% CI)	‐3.35 [‐5.06, ‐1.65]
1.16.3 Diabetes not reported	3	295	Mean Difference (IV, Random, 95% CI)	‐12.07 [‐29.27, 5.12]
1.17 Diastolic BP	13	875	Mean Difference (IV, Random, 95% CI)	‐1.04 [‐2.82, 0.73]
1.17.1 Diabetes	6	249	Mean Difference (IV, Random, 95% CI)	‐0.26 [‐1.95, 1.44]
1.17.2 No diabetes	4	331	Mean Difference (IV, Random, 95% CI)	‐1.62 [‐2.86, ‐0.38]
1.17.3 Diabetes not reported	3	295	Mean Difference (IV, Random, 95% CI)	‐1.52 [‐10.75, 7.71]
1.18 Blood pressure: descriptive outcome data	9		Other data	No numeric data
1.19 Blood pressure data from cross‐over studies	2		Other data	No numeric data
1.20 Serum potassium	17	1326	Mean Difference (IV, Random, 95% CI)	0.19 [0.10, 0.29]
1.20.1 Diabetes	9	664	Mean Difference (IV, Random, 95% CI)	0.21 [0.14, 0.28]
1.20.2 No diabetes	5	367	Mean Difference (IV, Random, 95% CI)	0.30 [0.10, 0.50]
1.20.3 Diabetes not reported	3	295	Mean Difference (IV, Random, 95% CI)	‐0.03 [‐0.21, 0.15]
1.21 Potassium: descriptive outcome data	6		Other data	No numeric data
1.22 Acute kidney injury	5	1446	Risk Ratio (M‐H, Random, 95% CI)	1.94 [0.99, 3.79]
1.22.1 Diabetes	2	1179	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.26, 3.69]
1.22.2 No diabetes	1	24	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 67.06]
1.22.3 Diabetes not reported	2	243	Risk Ratio (M‐H, Random, 95% CI)	2.42 [1.08, 5.39]
1.23 Gynaecomastia	4	281	Risk Ratio (M‐H, Random, 95% CI)	5.14 [1.14, 23.23]
1.23.1 Diabetes	1	54	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.13, 70.53]
1.23.2 No diabetes	3	227	Risk Ratio (M‐H, Random, 95% CI)	6.02 [1.08, 33.57]
1.24 Subgroup analysis: proteinuria ‐ duration of follow‐up	13	1153	Std. Mean Difference (IV, Random, 95% CI)	‐0.50 [‐0.83, ‐0.17]
1.24.1 Less than 6 months	9	822	Std. Mean Difference (IV, Random, 95% CI)	‐0.39 [‐0.54, ‐0.24]
1.24.2 At least 6 months	4	331	Std. Mean Difference (IV, Random, 95% CI)	‐0.59 [‐1.68, 0.50]
1.25 Subgroup analysis: systolic BP ‐ duration of follow‐up	14	911	Mean Difference (IV, Random, 95% CI)	‐4.98 [‐8.22, ‐1.75]
1.25.1 Less than 6 months	10	580	Mean Difference (IV, Random, 95% CI)	‐5.65 [‐10.96, ‐0.33]
1.25.2 At least 6 months	4	331	Mean Difference (IV, Random, 95% CI)	‐3.62 [‐6.09, ‐1.15]
1.26 Subgroup analysis: diastolic BP ‐ duration of follow‐up	13	884	Mean Difference (IV, Random, 95% CI)	‐1.04 [‐2.81, 0.73]
1.26.1 Less than 6 months	9	553	Mean Difference (IV, Random, 95% CI)	‐0.98 [‐3.71, 1.75]
1.26.2 At least 6 months	4	331	Mean Difference (IV, Random, 95% CI)	‐1.62 [‐2.86, ‐0.38]
1.27 Subgroup analysis: serum potassium ‐ duration of follow‐up	16	1285	Mean Difference (IV, Random, 95% CI)	0.22 [0.13, 0.31]
1.27.1 Less than 6 months	12	954	Mean Difference (IV, Random, 95% CI)	0.16 [0.10, 0.22]
1.27.2 At least 6 months	4	331	Mean Difference (IV, Random, 95% CI)	0.35 [0.04, 0.65]

Proteinuria data from cross‐over studies
Study	Comparison	Descriptive outcome data
Smolen 2006	Spironolactone verus hydrochlorothiazide	At 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)

Potassium data from cross‐over studies
Study	Comparison	Descriptive outcome data
Smolen 2006	Spironolactone verus hydrochlorothiazide	Serum 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)

Proteinuria: descriptive outcome data
Study	Comparison	Description of outcome
Takebayashi 2006	Spironolactone versus amlodipine	Spironolactone reduced UAE from 543.7 mg/g Cr (170 to 1146) to 376.7 mg/g Cr (135 to 794) (P = 0.003). UAE did not change in amlodipine group (P = 0.38)

eGFR: data from cross‐over studies
Study	Comparison	Description of outcome
Tylicki 2012	Eplerenone plus telmisartan 80 mg daily versus telmisartan 160 mg daily	During the 24 week study period, there was no difference between eplerenone plus telmisartan 80 mg daily group versus telmisartan 160 mg daily in creatinine clearance (97.3 ± 8.1 mL/min versus 97.9 ± 8.3 mL/min)

Hyperkalaemia data from cross‐over studies
Study	Comparison	Description of outcome
Nielsen 2012	Spironolactone versus placebo	Two 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

eGFR: descriptive outcome data
Study	Comparison	Description of outcome
ARTS 2012	Finerenone or spironolactone versus placebo	There was a decrease in eGFR in all finerenone groups (mean change from baseline eGFR ranging ‐0.85 to ‐2.69 mL/min/1.73 m²) and the spironolactone group (‐6.70 mL/min/1.73 m²), compared with a small increase in the placebo group (0.87 mL/min/1.73 m²). However, the decrease in the spironolactone group was significantly greater than in all finerenone groups (P = 0.0002 to 0.0133)
ARTS‐DN 2015	Finerenone plus ACEi or ARB versus ACEi or ARB alone	There was absolute decrease in eGFR in all finerenone groups (mean change from baseline eGFR ranging ‐1.9 to ‐3.9 mL/min/1.73 m²) as well as placebo (‐1.5 mL/min/1.73 m²). No P value was reported
Chen 2018b	Spironolactone plus irbesartan (low or high dose) versus irbesartan (low or high dose)	At 72 weeks, eGFR was lower in the spironolactone + high dose irbesartan group (‐3.8 mL/min/1.73 m²) compared to low dose irbesartan (‐0.3 mL/min/1.73 m²) and high dose irbesartan group (‐1.5 mL/min/1.73 m²) (P < 0.05), but not significantly different in the spironolactone + low dose irbesartan group (‐0.6 mL/min/1.73 m²)
EVALUATE 2010	Eplerenone plus ACEi and/or ARB versus ACEi and/or ARB	eGFR was significantly lower with eplerenone (‐4.6 mL/min/1.73 m²) than placebo (+0.47 mL/min/1.73 m²) (P = 0.0041)
Kato 2015	Spironolactone plus ACEi or ARB versus ACEi or ARB	At week 8, there was no difference in eGFR between spironolactone and control (‐3.2 ± 9.7 mL/min/1.73 m²) (P = 0.052)
Lv 2009a	Spironolactone + ACEi or ARB versus ACEi or ARB alone	By the end of the 9th month, the monthly rate of decrease of eGFR was similar in the two groups (‐0.66 mL/min/1.73 m² in spironolactone group versus ‐0.94 mL/min/1.73 m² in control group, P = 0.28)

eGFR data from cross‐over studies
Study	Comparison	Description of outcome
Nielsen 2012	Spironolactone versus placebo	Significant decline in GFR from 78 mL/min/1.73 m² to 72 mL/min/1.73 m² (P = 0.003) during spironolactone treatment

Blood pressure: descriptive outcome data
Study	Comparison	Description of outcome
ARTS 2012	Finerenone or spironolactone versus placebo	Spironolactone significantly decreased systolic BP (‐10.1 mmHg) at day 29 ± 2 compared with either placebo (‐3.1 mmHg, P = 0.0104) or all doses of finerenone (range ‐1.9 to ‐4.2 mmHg, P = 0.0023 to 0.0255)
ARTS‐DN 2015	Finerenone plus ACEi or ARB versus ACEi or ARB alone	Systolic BP from baseline to day 90 decreased in all finerenone groups (placebo corrected least squares mean differences range from −2.8 to −5.1 mmHg). Decreases only significant in 15 mg daily and 20 mg daily groups
Chen 2018b	Spironolactone plus irbesartan (low or high dose) versus irbesartan (low or high dose)	At 72 weeks, there was no difference between systolic of diastolic BP between the spironolactone + high dose irbesartan group (change in systolic BP ‐24 mmHg, diastolic BP ‐14 mmHg) or spironolactone + low dose irbesartan (change in systolic BP ‐24 mmHg, diastolic BP ‐13 mmHg), compared to low dose irbesartan (change in systolic BP ‐23 mmHg, diastolic BP ‐13 mmHg) and high dose irbesartan group (change in systolic BP ‐24 mmHg, diastolic BP ‐14 mmHg)
Cohen 2010	Eplerenone plus ACEi or ARB versus ACEi plus ARB	Systolic BP was reduced by 9.7 ± 6.4 mmHg in the eplerenone group and by 13.4 ± 14.9 mmHg in the ACEi plus ARB group
Epstein 2002	Eplerenone plus ACEi versus ACEi	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
Epstein 2006	Eplerenone plus ACEi versus ACEi	Both systolic and diastolic BP decreased at weeks 4, 8, and 12 in eplerenone and control groups. There were no significant differences in BP reduction between groups
EVALUATE 2010	Eplerenone plus ACEi and/or ARB versus ACEi and/or ARB	Systolic BP was lower with eplerenone (128.8 mmHg) than placebo (132.2 mmHg) (P = 0.0035). Diastolic BP was also lower with eplerenone (76.7 mmHg) than placebo (78.4 mmHg) (P < 0.0370)
Haykal 2007	Eplerenone plus ACEi versus ACEi	Both 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
Kato 2015	Spironolactone plus ACEi or ARB versus ACEi or ARB	At week 8, there was no difference in blood pressure between spironolactone (systolic BP ‐2.68 ± 25.3 mmHg, diastolic BP ‐3.44 ± 14.3 mmHg) and control (no change but exact values not reported) (P value not reported)

Blood pressure data from cross‐over studies
Study	Comparison	Description of outcome
Boesby 2011	Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both) alone	Systolic 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
Nielsen 2012	Spironolactone versus placebo	No significant changes in diastolic and systolic BP after the placebo or spironolactone period

Potassium: descriptive outcome data
Study	Comparison	Description of outcome
ARTS 2012	Finerenone or spironolactone versus placebo	By day 29 ± 2, finerenone 10 mg/day and 5 mg twice/day showed significantly greater mean increases in serum potassium concentration from baseline than placebo (P = 0.02 and P = 0.0003, respectively) Finerenone: 5mg/day and 2.5 mg/day groups were not significantly different from placebo
ARTS‐DN 2015	Finerenone plus ACEi or ARB versus ACEi or ARB alone	Potassium non‐significantly increased in all finerenone groups (absolute mean change from baseline to day 90 range 0.07 to 0.23) and non‐significantly decreased with placebo (‐0.004)
Chen 2018b	Spironolactone plus irbesartan (low or high dose) versus irbesartan (low or high dose)	At 72 weeks, potassium was higher in the spironolactone + high dose irbesartan group (+ 0.5 mmol/L) compared to low dose irbesartan (+ 0.11 mmol/L) and high dose irbesartan group (+ 0.29 mmol/L) (P < 0.05). Potassium was higher in the spironolactone + low dose irbesartan group (+ 0.27 mmol/L) compared to low dose irbesartan group (+ 0.11 mmol/L) (P < 0.05)
EVALUATE 2010	Eplerenone plus ACEi and/or ARB versus ACEi and/or ARB	Potassium increased from baseline more with eplerenone (+0.17 mmol/L) than placebo (+0.02 mmol/L) (P = 0.0043)
Lv 2009a	Spironolactone + ACEi or ARB versus ACEi or ARB alone	Spironolactone caused an increase in serum potassium after 9 months of treatment (from 3.8 ± 0.4 mEq/L to 4.1 ± 0.3 mEq/L, P = 0.029)
Tokunaga 2008a	Spironolactone + ARB versus ARB alone	Spironolactone produced a significant increase in serum potassium levels (from 4.31 ± 0.53 mmol/L to 4.67 ± 0.68 mmol/L, P < 0.05)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Proteinuria	2	139	Std. Mean Difference (IV, Random, 95% CI)	‐1.59 [‐3.80, 0.62]
2.2 Proteinuria: descriptive outcome data	2		Other data	No numeric data
2.3 Proteinuria data from cross‐over studies	1		Other data	No numeric data
2.4 eGFR [mL/min/1.73 m²]	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.5 GFR: descriptive outcome data	1		Other data	No numeric data
2.6 eGFR data from cross‐over studies	1		Other data	No numeric data
2.7 Diastolic BP	3	151	Mean Difference (IV, Random, 95% CI)	‐1.56 [‐3.52, 0.41]
2.8 Systolic BP	3	151	Mean Difference (IV, Random, 95% CI)	‐3.79 [‐14.36, 6.79]
2.9 Blood pressure: descriptive outcome data	1		Other data	No numeric data
2.10 Blood pressure data from cross‐over studies	1		Other data	No numeric data
2.11 Serum potassium	2	121	Mean Difference (IV, Random, 95% CI)	0.31 [0.17, 0.45]
2.12 Potassium: descriptive outcome data	1		Other data	No numeric data
2.13 Potassium data from cross‐over studies	1		Other data	No numeric data
2.14 Fatigue	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

GFR: descriptive outcome data
Study	Comparison	Description of outcome
Hase 2013	Spironolactone plus ACEi or ARB versus trichlormethiazide plus ACEi or ARB	At week 24, eGFR decreased in both spironolactone group (‐9.3 mL/min/1.73 m² from baseline) and trichlormethiazide group (‐9.4 mL/min/1.73 m² from baseline) but there was no between group difference

Outcome or subgroup title	No. of studies	Statistical method	Effect size
3.1 Proteinuria: descriptive outcome data	1	Other data	No numeric data
3.2 Systolic BP	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
3.3 Diastolic BP	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
3.4 Serum potassium	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Hyperkalaemia data from cross‐over studies	1		Other data	No numeric data
4.2 Proteinuria data from cross‐over studies	1		Other data	No numeric data

PERMALINK

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

Edmund YM Chung

Marinella Ruospo

Patrizia Natale

Davide Bolignano

Sankar D Navaneethan

Suetonia C Palmer

Giovanni FM Strippoli

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

1.

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

'Summary of findings' tables

Primary efficacy outcome

Primary safety outcome

Secondary outcomes

Results

Description of studies

Results of the search

2.

Included studies

Excluded studies

Risk of bias in included studies

3.

4.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings 1. Aldosterone antagonists versus placebo or standard care for proteinuric chronic kidney disease.

Summary of findings 2. Aldosterone antagonists versus diuretics for proteinuric chronic kidney disease.

Summary of findings 3. Aldosterone antagonists versus calcium channel blockers for proteinuric chronic kidney disease.

Summary of findings 4. Aldosterone antagonists versus ACEi or ACEi plus ARB for proteinuric chronic kidney disease.

Summary of findings 5. Aldosterone antagonist versus nitrate for proteinuric chronic kidney disease.

Summary of findings 6. Non‐steroidal mineralocorticoid receptor antagonist versus selective aldosterone antagonist for proteinuric chronic kidney disease.

Aldosterone antagonists (selective or non‐selective) versus placebo or standard care

Kidney failure

1.1. Analysis.

5.

Hyperkalaemia

1.2. Analysis.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Hyperkalaemia data from cross‐over studies	1		Other data	No numeric data
5.2 Proteinuria data from cross‐over studies	1		Other data	No numeric data

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Hyperkalaemia	2	500	Risk Ratio (M‐H, Random, 95% CI)	1.62 [0.66, 3.95]
6.2 Proteinuria: descriptive outcome data	4		Other data	No numeric data
6.3 Proteinuria data from cross‐over studies	2		Other data	No numeric data
6.4 eGFR: data from cross‐over studies	1		Other data	No numeric data
6.5 Blood pressure: descriptive outcome data	4		Other data	No numeric data
6.6 Blood pressure data from cross‐over studies	2		Other data	No numeric data
6.7 Serum potassium: data from cross‐over studies	1		Other data	No numeric data

Serum potassium: data from cross‐over studies
Study	Comparison	Description of outcome
Tylicki 2012	Eplerenone plus telmisartan 80 mg daily versus telmisartan 160 mg daily	During the 24 week study period, there was no difference between eplerenone plus telmisartan 80 mg/day group versus telmisartan 160 mg/day in serum potassium (4.28 ± 0.08 mmol/L versus 4.45 ± 0.01 mmol/L)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Proteinuria: descriptive outcome data	1		Other data	No numeric data
7.2 Systolic BP: descriptive outcome data	1		Other data	No numeric data

Systolic BP: descriptive outcome data
Study	Comparison	Description of outcome
Cohen 2010	Eplerenone plus ACEi or ARB (or both) versus ACEi or ARB (or both) plus isosorbide	Systolic 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

Outcome or subgroup title	No. of studies	Statistical method	Effect size
8.1 Hyperkalaemia	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
8.2 Death	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
8.3 eGFR: descriptive outcome data	1	Other data	No numeric data
8.4 Doubling serum creatinine	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
8.5 Blood pressure: descriptive outcome data	1	Other data	No numeric data

Outcome or subgroup title	No. of studies	Statistical method	Effect size
9.1 Hyperkalaemia	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
9.2 Proteinuria	1	Other data	No numeric data
9.3 eGFR [mL/min/1.73 m²]	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
9.4 Systolic BP	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
9.5 Diastolic BP	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
9.6 Serum potassium	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
9.7 Gynaecomastia	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

*Study characteristics*
Methods	Study design: parallel RCT Study duration: not reported Study follow‐up: 12 weeks
Participants	Country: Iran Setting: not reported 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 Spironolactone: 25 to 50 mg/day for 12 weeks Control group Placebo for 12 weeks Co‐interventions Limited salt intake to < 6 g/day ACEi/diuretic/CCB
Outcomes	BP Hyperkalaemia Serum sodium and potassium SCr Urinary sodium
Notes	Funding: not reported Trial registration: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomly divided. No further details provided
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Randomly divided into two groups in a double‐blind fashion".
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported, however outcome measurement unlikely to be affected by awareness of treatment allocation
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants completed the study
Selective reporting (reporting bias)	High risk	The study fails to include results for key outcomes that would be expected to have been reported for such a study
Other bias	Unclear risk	Funding and other sources of bias were unclear

*Study characteristics*
Methods	Study design: double‐blind, placebo‐controlled, parallel‐group RCT divided into two parts. Study duration: not reported Study follow‐up: 6 weeks
Participants	Country: 10 countries Setting: multicentre (55 sites) inclusion criteria Part A: patients with HFrEF with LVEF ≤ 40%) and mild CKD (GFR 60 to 90 mL/min/1.73 m²) Part B: patients with HFrEF with LVEF ≤ 40% and moderate CKD (GFR 30 to 60 mL/min/1.73 m²) Number Part A: treatment group 1 (16); treatment group 2 (16); treatment group 3 (16); control group (16) Part B: treatment group 1 (66); treatment group 2 (67); treatment group 3 (67); treatment group 4 (65); control group 1 (63); control group 2 (65) Mean age, range: Part A (66.3 years, 42 to 85); Part B (72.1 years, 40 to 89) Sex (M/F): Part A (52/13); Part B (312/80) Exclusion criteria: women of child‐bearing potential; known hypersensitivity to the study drug (active substance or excipients) or spironolactone and respective excipients (part B only); anuria; acute kidney failure; Addison’s disease; worsening heart failure requiring hospitalisation and treatment with IV diuretics in the 30 days before the screening visit for patients (NYHA class II–III) naive to aldosterone antagonist therapy or in the 6 months before the screening visit for patients (NYHA class II) who, immediately before study entry, are receiving aldosterone antagonist therapy; acute coronary syndrome or unstable coronary artery disease in the 30 days before randomisation; valvular heart disease requiring surgical intervention during the course of the study; evidence of increased ventricular vulnerability (e.g. survived ventricular fibrillation, sustained ventricular tachycardia, or firing of implantable; cardioverter‐defibrillator in the 30 days before randomisation) requiring any intervention during the course of the study; history of hospitalisation for hyperkalaemia or acute kidney failure induced by previous aldosterone antagonist treatment; history of or clinically significant evidence of any severe disease other than chronic heart failure that would preclude participation in the study; clinically relevant hepatic dysfunction at screening visit indicated by one of the following: total bilirubin concentration more than twice the ULN and alanine aminotransferase levels more than three times the ULN or hepatic insufficiency classified as Child–Pugh B or C; use of any renin inhibitor or aldosterone antagonist in the 30 days before randomisation; concomitant therapy with potassium‐sparing agents, high‐dose acetylsalicylic acid (> 500 mg/day), or continuous treatment with non‐steroidal anti‐inflammatory agents; concomitant therapy with potent CYP isoenzyme 3A4 inhibitors or inducers (to be stopped ≥ 7 days before randomisation) or strong CYP2C8 inhibitors (to be stopped ≥ 48 hours before randomisation) such as gemfibrozil (investigators will be provided with a list of concomitant medications considered potent CYP3A4 inhibitors or inducers or strong CYP2C8 inhibitors); ongoing drug or alcohol abuse; concomitant regular liquorice consumption; uncontrolled hypertension at the screening visit requiring additional antihypertensive treatment during the course of the study; clinically relevant findings from the physical examination that may influence absorption, distribution, metabolism, elimination, or effects of the study drugs, or jeopardize the patient’s safety during the study; poorly controlled DM with HbA1c > 8.5% at screening visit; participation in another clinical study or treatment with another investigational product in the 30 days before randomisation; any other condition or therapy that will make the patient unsuitable for this study and will not allow participation for the full planned study period; previous assignment to treatment during this study
Interventions	Part A treatment groups (1, 2, 3) Finerenone: 2.5, 5, or 10 mg once/day for uncertain duration Part A: control group Placebo for uncertain duration Part B: treatment groups (1, 2, 3, 4) Finerenone (2.5, 5, or 10 mg/day, or 5 mg twice/day) for uncertain duration Part B: control group Open‐label spironolactone (25 to 50 mg) or placebo for uncertain duration Co‐interventions Not reported
Outcomes	Part A Serum potassium concentration Biomarkers of kidney injury eGFR 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
Notes	Funding: Bayer Pharma AG. Editorial work by Oxford PharmaGenesis was funded by Bayer Pharma AG. Trial registration: NCT01345656
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised; method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blinded
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported in sufficient detail to perform adjudication. Some outcomes might have been influenced by knowledge of treatment allocation
Incomplete outcome data (attrition bias) All outcomes	High risk	34/265 participants assigned to BAY 94‐8862 did not complete study follow‐up; 20/128 participants assigned to spironolactone and placebo did not complete
Selective reporting (reporting bias)	Unclear risk	The study fails to include results for key outcomes that would be expected to have been reported for such a study. Outcomes were reported according to the published protocol
Other bias	High risk	Funded by pharmaceutical company.

*Study characteristics*
Methods	Study design: double‐blind, active‐comparator‐controlled, parallel‐group, phase 2b, dose‐finding RCT Study duration: June 2013 to August 2014 Study follow‐up: 90 days
Participants	Country: 25 countries Setting: multicentre (173 sites) Participants at least 18 years and had worsening chronic HFrEF requiring hospitalisation and treatment with intravenous diuretics; type 2 DM and/or CKD (i.e. an estimated GFR of.30 mL/min/1.73 m² in patients with type 2 DM and 30 to 60 mL/min/1.73 m² in patients without type 2 DM), have been receiving treatment with evidence‐based therapy for heart failure for at least the previous 3 months, and have a medical history of a LVEF ≤ 40% within the previous 12 months; patients receiving treatment with spironolactone, eplerenone, renin inhibitors, or potassium‐sparing diuretics at presentation had to be able to discontinue those treatments for 24 hours before randomisation (48 h for spironolactone) and for the duration of the study treatment period Number: finerenone 2.5 to 5 mg (173); finerenone 5 to 10 mg (165); finerenone 7.5 to 15 mg (169); finerenone 10 to 20 mg (170); finerenone 15 to 20 mg (165); eplerenone (224) Age ± SD (years): eplerenone (72.4 ± 9.9); finerenone 2.5 to 5 mg 72.5 ± 9.7; finerenone 5‐10 mg 71.8 ± 10.6; finerenone 7.5‐15 mg 69.3 ± 9.8; finerenone 10‐20 mg 71.3 ± 10.23; finerenone 15‐20 mg 69.2 ± 10.2 Sex (M/F): eplerenone (170/51); finerenone 2.5‐5 mg (135/37); finerenone 5‐10 mg (126/37); finerenone 7.5 to 15 mg (124/43); finerenone 10 to 20 mg (128/41); finerenone 15 to 20 mg (163/31) Exclusion criteria: Patients with acute de novo heart failure or acute inflammatory heart disease, acute coronary syndromes in the last 30 days before the screening visit, cardiogenic shock or valvular heart disease requiring surgical intervention, those with a left ventricular assist device or awaiting heart transplantation, and patients who have experienced a stroke or transient ischaemic attack within 3months before screening.
Interventions	Treatment group (5 groups) Finerenone: 2.5 to 5 mg/day; 5 to 10 mg/day; 7.5 to 15 mg/day; 10 to 20 mg/day; 15 to 20 mg/day for 90 days Control group Eplerenone: 25 mg alternate daily to 50 mg daily for 90 days Co‐interventions Standard therapy for heart failure
Outcomes	NT‐proBNP Cardiovascular hospitalisation Emergency presentation for worsening chronic heart failure Death (any cause) Cardiovascular death Composite of above events Hyperkalaemia (> 5.6 mmol/L) HRQoL Pharmacokinetic data
Notes	Funder: Bayer HealthCare AG Trial registration: NCT01807221
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Interactive voice/web response system
Allocation concealment (selection bias)	Low risk	Interactive voice/web response system
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, investigators, and the sponsor’s clinical team was blinded to treatment allocation
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Clinical endpoints have been adjudicated by the event committee. Blinding of outcome assessment was not reported in sufficient detail to perform adjudication
Incomplete outcome data (attrition bias) All outcomes	Low risk	45/842 allocated to finerenone were not included in full analysis; 17/224 allocated to eplerenone were not included in full analysis
Selective reporting (reporting bias)	Low risk	This study reported outcomes according to published protocol and as expected for a study of this type
Other bias	High risk	Funded by pharmaceutical company