Effects of mineralocorticoid receptor antagonists on left ventricular mass in chronic kidney disease patients: a systematic review and meta-analysis.
Topic: Hormone Therapy

Mineralocorticoid receptor antagonists (MRAs) are used widely in treatment of heart failure, but their effects on cardiovascular complications and mortality of chronic kidney disease (CKD) are not well known. Thus, we aim to assess such therapeutic effects of MRAs on CKD.

PICO
Population: Chronic kidney disease patients
Intervention: Mineralocorticoid receptor antagonists
Comparison: Placebo or standard care
Outcomes: Left ventricular mass

Included studies:
title: Spironolactone use and higher hospital readmission for Medicare beneficiaries with heart failure, left ventricular ejection fraction <45%, and estimated glomerular filtration rate <45 ml/min/1.73 m(2.).
abstract: Although randomized controlled trials have demonstrated benefits of aldosterone antagonists for patients with heart failure and reduced ejection fraction (HFrEF), they excluded patients with serum creatinine >2.5 mg/dl, and their use is contraindicated in those with advanced chronic kidney disease (CKD). In the present analysis, we examined the association of spironolactone use with readmission in hospitalized Medicare beneficiaries with HFrEF and advanced CKD. Of the 1,140 patients with HFrEF (EF <45%) and advanced CKD (estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 m(2)), 207 received discharge prescriptions for spironolactone. Using propensity scores (PSs) for the receipt of discharge prescriptions for spironolactone, we estimated PS-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for spironolactone-associated outcomes. Patients (mean age 76 years, 49% women, 25% African-American) had mean EF 28%, mean eGFR 31 ml/min/1.73 m(2), and mean potassium 4.5 mEq/L. Spironolactone use had significant PS-adjusted association with higher risk of 30-day (HR 1.41, 95% CI 1.04 to 1.90) and 1-year (HR 1.36, 95% CI 1.13 to 1.63) all-cause readmissions. The risk of 1-year all-cause readmission was higher among 106 patients with eGFR <15 ml/min/1.73 m(2) (HR 4.75, 95% CI 1.84 to 12.28) than among those with eGFR 15 to 45 ml/min/1.73 m(2) (HR 1.34, 95% CI 1.11 to 1.61, p for interaction 0.003). Spironolactone use had no association with HF readmission and all-cause mortality. In conclusion, among hospitalized patients with HFrEF and advanced CKD, spironolactone use was associated with higher all-cause readmission but had no association with all-cause mortality or HF readmission.
title: Spironolactone improves endothelial and cardiac autonomic function in non heart failure hemodialysis patients.
abstract: Hemodialysis patients have a cardiovascular mortality rate of 20-40 times that of the general population. Aldosterone inhibition by spironolactone has exerted beneficial, prognostically significant cardiovascular effects in patients with heart failure maintained on hemodialysis or peritoneal dialysis. Our aim was to investigate spironolactone's effect in non heart failure hemodialysis patients.
title: Spironolactone in chronic hemodialysis patients improves cardiac function.
abstract: We performed this study to assess whether low dose spironolactone could be administered in hemodialysis (HD) patients with moderate to severe heart failure to improve cardiovascular function and reduce hospitalization without inducing hyperkalemia. We enrolled 16 chronic HD patients with moderate to severe heart failure and left ventricle ejection fraction :5 45%. In a double blinded randomized placebo controlled study, one group of 8 patients received 25 mg of spironolactone after each dialysis session within six months, and the rest received a placebo. Echocardiography was performed on all the patients to assess ejection fraction and left ventricular mass during 12 hours after completion of hemodialysis at the beginning and the end of study. Serum potassium was measured predialysis every 4 weeks. The mean ejection fraction increased significantly more in spironolactone group during the study period than in the placebo group (6.2 +/- 1.64 vs. 0.83 +/- 4.9, P= 0.046). The mean left ventricular mass decreased in the spironolactone group, but increased significantly in the placebo group during the period (-8.4 +/- 4.72 vs. 3 +/- 7.97. 95%, P= 0.021). The incidence of hyperkalemia was not significantly increased in the study or controlled groups. In conclusion, we found in this study that administration of spironolactone in chronic HD patients with moderate to severe heart failure substantially improved their cardiac function and decreases left ventricular mass without development of significant hyperkalemia.
title: Biology of organ transplantation.
title: Long-term effects of spironolactone in peritoneal dialysis patients.
abstract: ESRD treated with dialysis is associated with increased left ventricular hypertrophy, which, in turn, is related to high mortality. Mineralocorticoid receptor antagonists improve survival in patients with chronic heart failure; however, the effects in patients undergoing dialysis remain uncertain. We conducted a multicenter, open-label, prospective, randomized trial with 158 patients receiving angiotensin-converting enzyme inhibitor or angiotensin type 1 receptor antagonist and undergoing peritoneal dialysis with and without (control group) spironolactone for 2 years. As a primary endpoint, rate of change in left ventricular mass index assessed by echocardiography improved significantly at 6 (P=0.03), 18 (P=0.004), and 24 (P=0.01) months in patients taking spironolactone compared with the control group. Rate of change in left ventricular ejection fraction improved significantly at 24 weeks with spironolactone compared with nontreatment (P=0.02). The benefits of spironolactone were clear in patients with reduced residual renal function. As secondary endpoints, renal Kt/V and dialysate-to-plasma creatinine ratio did not differ significantly between groups during the observation period. No serious adverse effects, such as hyperkalemia, occurred. In this trial, spironolactone prevented cardiac hypertrophy and decreases in left ventricular ejection fraction in patients undergoing peritoneal dialysis, without significant adverse effects. Further studies, including those to determine relative effectiveness in women and men and to evaluate additional secondary endpoints, should confirm these data in a larger cohort.
title: [Diabetes mellitus and pregnancy].
title: Influence of baseline and worsening renal function on efficacy of spironolactone in patients With severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study).
abstract: This study investigated the influence of baseline and worsening renal function (WRF) on the efficacy of spironolactone in patients with severe heart failure (HF).
title: A randomized, double-blind, placebo-controlled trial of spironolactone on carotid intima-media thickness in nondiabetic hemodialysis patients.
abstract: Hemodialysis patients (HD) display high rates of cardiac diseases and mortality. In chronic kidney disease, vascular injury leads to coronary artery disease, heart failure, and stroke. Carotid intima-media thickness (CIMT) measurements are currently widely used in randomized controlled trials (RCTs) to study the efficacy of interventions. An RCT was designed for the assessment of the safety and effectiveness of spironolactone to inhibit the progression of CIMT in HD patients as a primary outcome. Secondary outcomes included measurements of plasma potassium.
title: Long-Term Effects of Low-Dose Spironolactone on Chronic Dialysis Patients: A Randomized Placebo-Controlled Study.
abstract: The purpose of this 2-year multicentric, randomized, placebo-controlled study was to evaluate the long-term effects and adverse effects of spironolactone on chronic dialysis patients. A total of 253 non-heart failure dialysis patients with end-stage renal disease were randomly assigned to 2-year treatment with spironolactone (25 mg once daily, n=125) or a matching placebo (n=128) as add-on therapy. The primary outcome was a composite of death from cardiocerebrovascular (CCV) events, aborted cardiac arrest, and sudden cardiac death, and the secondary outcome was death from all causes. Other CCV-related indexes such as left ventricular mass index, left ventricular ejection fraction, heart rate variability, vascular endothelial function, and blood pressure-lowering effect were analyzed for patients who completed the whole 2-year follow-up study. Sociodemographic, clinical, and relevant laboratory data were also collected. During the 2-year follow-up, the primary outcome occurred less frequently in the spironolactone group vs the control group (7.2% vs 18.0%; adjusted hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.26-0.78). Death from CCV events occurred in 4.0% of patients in the spironolactone group and in 11.7% of patients in the control group. Neither aborted cardiac arrest nor sudden cardiac death was significantly reduced by spironolactone treatment. The secondary outcome occurred less frequently in the spironolactone group vs the control group (9.6% vs 19.5%; adjusted HR, 0.52; 95% CI, 0.29-0.94). Other CCV-related indexes except for heart rate variability were significantly improved. This study demonstrates that use of low-dose spironolactone in non-heart failure dialysis patients can effectively reduce the risks of both CCV morbidity and mortality with few side effects. Moreover, the beneficial effect was mediated through improving the endothelial function or reducing left ventricular size independent of blood pressure changes, rather than mediation through changes in salt or potassium handling in the kidney.
title: The Safety of Eplerenone in Hemodialysis Patients: A Noninferiority Randomized Controlled Trial.
abstract: Mineralocorticoid receptor antagonism reduces morbidity and mortality in patients with heart failure, but the safety of these drugs in patients receiving dialysis is unclear. This study evaluated whether hyperkalemia and/or hypotension limited the use of eplerenone, a selective mineralocorticoid receptor antagonist, in hemodialysis patients.
title: Left ventricular hypertrophy in new hemodialysis patients without symptomatic cardiac disease.
abstract: Although left ventricular hypertrophy (LVH) is a characteristic finding in hemodialysis (HD) populations, few risk factors for progressive LVH have been identified.
title: A prospective double-blind randomized placebo-controlled clinical trial to evaluate the safety and efficacy of spironolactone in patients with advanced congestive heart failure on continuous ambulatory peritoneal dialysis.
abstract: Congestive heart failure (CHF) is frequent in patients with chronic renal failure, and may contribute to high cardiovascular morbidity and mortality. There is little data in the literature about the safety and efficacy of use of spironolactone in patients with end-stage renal disease with heart failure. In this study, we evaluated the safety and efficacy of spironolactone in patients on continuous ambulatory peritoneal dialysis (CAPD) with CHF. This randomized prospective double-blind placebo-controlled clinical trial was performed at the St. Al-Zahra peritoneal dialysis center. Eighteen CAPD patients with New York Heart Association (NYHA) class III or IV heart failure, ejection fraction (EF) ≤45%, serum potassium level ≤5.5 mEq/L and who were eligible, were randomly assigned to taking either spironolactone (25 mg every other day) or placebo for six months. The serum potassium was measured monthly and echocardiography was repeated at the end of the study period. The serum potassium levels rose in both groups, and there was no statistically significant difference intragroup and between the groups during the study period. Only in one patient in the spironolactone group did the serum potassium level reach above the critical level (5.70 mEq/L) at the end of the second month of study, necessitating patient exclusion. The EF did not change significantly in the placebo group (33.3 ± 11.7 vs. 34.2 ± 11.6, F = 1, P = 0.363), but in the spironolactone group the EF rose significantly (25.7 ± 7.3 vs. 33.3 ± 7.8, F = 27.45, P = 0.002). Our study suggests that spironolactone could be used in CHF patients on CAPD to improve their cardiac function, but close monitoring of their serum potassium level is required.
title: Spironolactone is associated with reduced risk of new-onset atrial fibrillation in patients receiving renal replacement therapy.
abstract: Whether the spironolactone treatment remains effective for the prevention of atrial fibrillation (AF) in dialysis patients is unclear.
title: Spironolactone is secure and reduces left ventricular hypertrophy in hemodialysis patients.
abstract: There is recent evidence that aldosterone play a role in the pathogenesis of cardiovascular disease in dialysis patients, which leads to the opportunity to block its actions for the benefit of these patients. In nondialytic chronic kidney disease, spironolactone was safe and effective in reducing left ventricular hypertrophy. However, routine use has been precluded in hemodialysis patients due to the risk of hyperkalemia. The aim of this study is to verify the safety and efficacy in regression of left ventricular hypertrophy with spironolactone in hemodialysis patients undergoing pharmacotherapeutic monitoring.
title: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators.
abstract: Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes.
title: Eplerenone in patients with systolic heart failure and mild symptoms.
abstract: Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms.
title: Clinical benefit of spironolactone in patients with acute decompensated heart failure and severe renal dysfunction: Data from the Korean Heart Failure Registry.
abstract: We investigated the relationship between spironolactone use and all-cause mortality in acute decompensated heart failure (ADHF) patients with severe renal dysfunction. The clinical benefit of spironolactone in the treatment of heart failure (HF) has been described in several large randomized clinical trials. However, its clinical benefits have not been studied in hospitalized ADHF patients with severe renal dysfunction (estimated glomerular filtration rate [eGFR] <45 mL/min per 1.73 m(2)).
title: Effect of spironolactone on left ventricular mass and aortic stiffness in early-stage chronic kidney disease: a randomized controlled trial.
abstract: We sought to determine whether the addition of spironolactone to angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) improves left ventricular mass and arterial stiffness in early-stage chronic kidney disease (CKD).
title: Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients.
abstract: This study sought to assess whether spironolactone treatment reduces the high incidence of cardiovascular and cerebrovascular (CCV) morbidity and mortality in hemodialysis (HD) patients.