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.