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


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


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


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


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


RESULTS
We identified 27 studies (1549 participants) that were eligible for inclusion. These studies provided no data relating to aldosterone antagonists in addition to ACEi or ARB (or both) on patient-level outcomes including major cardiovascular events and mortality and progression to end-stage kidney disease (ESKD) requiring dialysis or transplantation.Compared with ACEi or ARB (or both), non-selective aldosterone antagonists (spironolactone) combined with ACEi or ARB (or both) significantly reduced 24-hour protein excretion (11 studies, 596 participants): SMD -0.61, 95% CI -1.08 to -0.13). There was a significant reduction in both systolic and diastolic blood pressure (BP) at the end of treatment with additional non-selective aldosterone antagonist therapy (systolic BP (10 studies, 556 participants): MD -3.44 mm Hg, 95% CI -5.05 to -1.83) (diastolic BP (9 studies, 520 participants): MD -1.73 mm Hg, 95% CI -2.83 to -0.62).However, we found that aldosterone antagonist treatment had imprecise effects at the end of treatment on GFR (9 studies, 528 participants; MD -2.55 mL/min/1.73 m², 95% CI -5.67 to 0.51), doubled the risk of hyperkalaemia (11 studies, 632 patients): RR 2.00, 95% CI 1.25 to 3.20; number needed to treat for an additional harmful outcome (NNTH): 7.2, 95% CI 3.4 to ∞) and increased the risk of gynaecomastia compared to ACEi or ARB (or both) (4 studies, 281 patients): RR 5.14, 95% CI 1.14 to 23.23; NNTH: 14.1, 95% CI 8.7 to 37.3).Most studies enrolled few patients (range 12 to 268) and were powered to observe differences in surrogate end points rather than patient-focused outcomes. Nine studies had a cross-over design and the majority of studies did not adequately report study methods to assess methods and study quality.


CONCLUSIONS
Aldosterone antagonists reduced proteinuria and blood pressure in adults who had mild to moderate CKD and were treated with ACEi or ARB (or both), but increase hyperkalaemia and gynaecomastia. Whether adding aldosterone antagonists to ACEi or ARB (or both) reduced the risk of major cardiovascular events or ESKD in this population is unknown.
Institute of Clinical Physiology, CNR - Italian National Council of Research, CNR-IFC Via Vallone Petrara c/o Ospedali Riuniti, Reggio Calabria, Italy, 89100.
Davide
D
Bolignano
Suetonia C
SC
Palmer
Sankar D
SD
Navaneethan
Giovanni F M
GF
Strippoli
D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D018450:Disease Progression; D000077545:Eplerenone; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced / Q000517:prevention & control; D007676:Kidney Failure, Chronic / Q000188:drug therapy*; D000451:Mineralocorticoid Receptor Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D013148:Spironolactone / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000077545:Eplerenone