Mineralocorticoid Receptor Antagonism for Cardiovascular Protection in End‐Stage Renal Disease: New Data But the Controversy Continues

Patients with end-stage renal disease (ESRD) have one of the highest rates of cardiovascular morbidity and mortality. Unlike in the general population where ischemic atherosclerotic events are the most common causes of cardiovascular death, among people with ESRD, serious arrhythmias and cardiac arrests make up the bulk of cardiovascular mortality. The huge burden of sudden cardiac deaths in these individuals is attributable to a number of pathophysiological alterations related to ESRD, including left ventricular (LV) hypertrophy, intermyocardiocytic fibrosis, and disturbances in electrolyte balance. Notably, prospective observational studies have demonstrated that among ESRD patients, LV hypertrophy represents a strong and independent predictor of future cardiovascular events, particularly sudden cardiac death. In the setting of ESRD, overactivity of the reninangiotensin-aldosterone axis is proposed to be a prominent player in the complex mechanistic background of LV hypertrophy. Experimental studies have shown that excessive aldosterone is directly involved in the process of intermyocardiocytic fibrosis. Initially, aldosterone triggers an inflammatory response mediated through monocyte and macrophage infiltration and increased expression of proinflammatory cytokines. This inflammatory reaction is followed by fibroblast proliferation and increased collagen deposition, resulting in perivascular and, lastly, interstitial fibrosis. In most experimental models, mineralocorticoid receptor antagonists (MRAs) were shown to downregulate the proinflammatory and profibrotic actions of aldosterone, reversing in this way the adverse myocardial remodeling. On the basis of the aforementioned background data, clinical studies have provided evidence that small doses of MRAs alone or in combination with angiotensinconverting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) caused regression of LV mass in patients with essential hypertension and LV hypertrophy or in patients with primary hyperaldosteronism. An evolution around the potential cardioprotective properties of MRAs began with the publication of the Randomized Aldactone Evaluation Study (RALES). This trial and the subsequent Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) clearly demonstrated that among patients with heart failure and reduced LV ejection fraction, add-on MRA therapy on top of background treatment with ACE inhibitors or ARBs and/or b-blockers effectively and safely reduced cardiovascular morbidity and mortality. However, patients with severely impaired renal function (ie, estimated glomerular filtration rate <30 mL/min/ 1.73 m) were excluded from these studies; thus, it remains unclear whether MRAs carry the ability to offer cardiovascular risk reduction in patients with advanced kidney disease, including those receiving maintenance dialysis. This question is further complicated by the fact that the increased use of MRAs in heart failure patients after the publication of the RALES trial was associated with a 4.5-fold increase in incidence of hospitalizations caused by hyperkalemia and a 6.6-fold increase in hyperkalemia-associated mortality, along with the propensity of patients with advanced chronic kidney disease towards hyperkalemia. Among ESRD patients, the efficacy of MRAs is largely understudied. This is because of the concerns that any advantages of these agents in causing regression of LV hypertrophy may be compensated by excess risk of life-threatening hyperkalemia, since MRAs could theoretically decrease potassium removal through the intestine, which comprises an important route for ESRD patients. However, a systematic review of 10 small studies evaluating the safety profile of the MRA spironolactone in dialysis patients suggested that administration of this compound at low doses (up to 50 mg daily) is accompanied by relevant small increases in serum potassium levels (on average 0.3–0.5 mmol/L); thus, it appears that the overall risk of incident hyperkalemia with MRA therapy may be lower than originally thought. A recent randomized study compared the safety profile of eplerenone relative to placebo in 146 hemodialysis patients. Administration of eplerenone up to a maximal dose of 50 mg/d for 13 weeks was, indeed, associated with significantly higher incidence of hyperkalemia, defined as serum Address for correspondence: Panagiotis I. Georgianos, MD, PhD, Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, St. Kyriakidi 1, Thessaloniki, Greece E-mail: pangeorgi@yahoo.gr