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Effects of mineralocorticoid receptor antagonists in proteinuric kidney disease

a systematic review and meta-analysis of randomized controlled trials

Alexandrou, Maria-Elenia,b; Papagianni, Aikaterinib; Tsapas, Apostolosc; Loutradis, Charalamposb; Boutou, Afroditid; Piperidou, Alexiae; Papadopoulou, Dorotheaa; Ruilope, Luisf; Bakris, Georgeg; Sarafidis, Pantelisb

doi: 10.1097/HJH.0000000000002187
REVIEWS AND META-ANALYSES
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Background: Reductions in albuminuria of more than 30% are considered a strong marker of delay of chronic kidney disease (CKD) progression. Single renin–angiotensin system (RAS) blockade represents the cornerstone of CKD treatment. However, as CKD progression still occurs, other nephroprotective options were explored; mineralocorticoid receptor antagonists (MRA) were tested with generally positive results.

Methods: We conducted a systematic review and meta-analysis on the effects of MRAs on albuminuria/proteinuria, and adverse events, such as change in renal function and hyperkalemia incidence. A detailed search in electronic databases, clinical trial registries and grey literature was performed to retrieve randomized controlled trials (RCTs) in which administration of an MRA alone or on-top of ACEi/ARB was compared with placebo or active treatment.

Results: Of the 45 initially identified reports, 31, with 2767 participants, were included in analysis of the primary outcome. The use of MRAs (alone or on top of RAS blockade) compared with placebo decreased urine albumin-to-creatinine ratio (UACR) by −24.55% (95% CI −29.57 to −19.53%), urine protein-to-creatinine ratio (UPCR) by −53.93% (95% CI −79% to −28.86%) and 24 h albumin excretion by −32.47% (95% CI −41.1 to −23.85%). MRAs also reduced UACR by −22.48% (95% CI −24.51 to −20.44%) compared with calcium-channel-blockers (CCBs), whereas no differences were found compared with a second ACEi/ARB or nonpotassium-sparing diuretics. Addition of an MRA was associated with change in estimated glomerular filtration rate (eGFR) of −2.38 ml/min per 1.73 m2 (95% CI −3.51 to −1.25), rise in potassium by 0.22 mEq/l (95% CI 0.16–0.28 mEq/l) and a 2.6-fold increase in hyperkalemia risk (RR 2.63, 95% CI 1.69–4.08) compared with placebo/active control.

Conclusion: Use of MRAs alone or on top of RAS blockade confers important antiproteinuric effects in patients with CKD, with a slight increase in mean potassium levels.

aDepartment of Nephrology, Papageorgiou Hospital

bDepartment of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital

cClinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki

dDepartment of Respiratory Medicine, Papanikolaou Hospital

e2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki Hospital General Hippokration, Thessaloniki, Greece

fInstitute of Research i+12, Hospital Universitario 12 de Octubre, and School of Doctoral Studies and Research, Universidad Europea de Madrid, Madrid, Spain

gDepartment of Medicine, American Society of Hypertension Comprehensive Hypertension Center, The University of Chicago Medicine, Chicago, Illinois, USA

Correspondence to Pantelis Sarafidis, MD, MSc, PhD, Department of Nephrology, Aristotle University of Thessaloniki, Hippokration Hospital, Konstantinoupoleos 49, GR54642, Thessaloniki, Greece. Tel/fax: +30 2313 312930; e-mail: psarafidis11@yahoo.gr

Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blockers; BP, blood pressure; CCBs, calcium channel blockers; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ERA/EDTA, European Renal Association/European Dialysis and Transplant Association; HFrEF, heart failure with reduced ejection fraction; K-DOQI, Kidney Disease Outcomes Quality Initiative; LVH, left ventricular hypertrophy; MRAs, mineralocorticoid receptor antagonists; RAS, renin–angiotensin system; RR, risk ratio; SMD, standardized mean difference; UACR, urine albumin-to-creatinine ratio; UAE, urine albumin excretion; UPCR, urine protein-to-creatinine ratio; UPE, urine protein excretion; WMD, weighted mean difference

Received 23 March, 2019

Revised 4 June, 2019

Accepted 9 June, 2019

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