Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease Under Renal Replacement Therapies: Bridging the Gap Between Cardiovascular and Systemic Benefit, From Heart Failure to Myocardial Infarction

Chronic kidney disease (CKD), increased globally over the past 20 years, with an estimated prevalence of 10% in adults and with an increased number of people undergoing renal replacement therapies (RRT) such as hemodialysis or peritoneal dialysis.1 The leading cause of death in CKD is cardiovascular (CV) death because of both an increased rate of atherosclerosis and the development and progression of heart failure (HF).1–4 There is a strict cross-talk and interplay between the heart and the kidney that has been well-described by the term “cardio–renal syndrome” (CRS). Typically, cardiac diseases (acute and chronic) can cause renal diseases (CRS types 1 and 2), and vice-versa renal diseases (acute and chronic, as CKD) can cause CV diseases (CRS types 3 and 4), but the most common is CRS type 5, in which a systemic condition causes heart and kidney disease.3 Patients with end-stage renal disease (ESRD) have a high CV mortality mainly driven by HF events and by sudden cardiac death (SCD); nearly 20% of hemodialysis and 10%–20% of patients with peritoneal dialysis have HF with reduced ejection fraction (HFrEF), but epidemiological data about HF with mildly reduced ejection fraction and HF with preserved ejection fraction in this population are lacking, suggesting a significantly higher prevalence of HF in ESRD.4,5 Mineralocorticoid receptor antagonists (MRA) are an established pillar of HF treatment that proved to improve CV outcome across the full spectrum of left ventricular ejection fraction (LVEF). In particular, a recently published meta-analysis, which included the main international RCTs on MRA in HF (namely RALES, EMPHASIS-HF, TOPCAT, and FINEARTS-HF) for a total of 13,846 patients, showed that MRAs significantly reduce CV death and HF hospitalizations (HHF), HF hospitalizations (first and recurrent) alone, CV death alone, and all-cause death alone across the full spectrum of LVEF (ie, both in HFrEF and HF with mildly reduced ejection fraction + HF with preserved ejection fraction).6 However, all these RCTs excluded patients with ESRD and on dialysis, having as lower threshold an estimated Glomerular Filtration Rate of 30 or 25 mL/min/1.73 m2; therefore, the evidence of the use of MRAs in these populations comes mainly from large retrospective cohort studies and 2 very little trials.6,7 Added to this, historical concerns about the risk of worsening renal function and hyperkalemia make MRAs the most underused of the 4 pillars.8 The study of Dawadi et al9 is a meta-analysis of the effect of the MRA in patients with ESRD on dialysis. The authors included 15 studies and more than 1000 patients with and without HF, and they confirmed that the MRAs in these populations were associated with a significant reduction in all-cause death, mainly driven by a significant reduction of CV death and cerebrovascular death. Noteworthy—as highlighted by the authors—the reduction of CV death was not driven by a reduction of myocardial infarction (MI) as well as the reduction of cerebrovascular death has not been driven by a reduction of stroke/transient ischemic attack. These results are the same as what previously showed by RCTs as RALES, EMPHASIS-HF (effects of steroidal MRA in HFrEF), EPHESUS (effects of eplerenone post-acute myocardal infarction complicated by LV dysfunction and HF), and by the most recent FIDELIO-DKD and FIGARO-DKD (effects of finerenone on renal and CV outcome in CKD and type 2 diabetes mellitus). All the evidence on MRAs shows that the major drivers of CV death benefits come mainly from the reduction of SCD and HF death, with minor or no effect on MI. Furthermore, another recent meta-analysis on MRA in ESRD on dialysis and a recent very large retrospective cohort from Taiwan (more than 50,000 patients) dedicated to HF with ESRD on dialysis confirmed the same findings.4,10 The reduction of CV death through SCD and HF-death (Fig. 1) reduction is strictly related to the MRAs antiremodeling effects, in particular to the reduction of myocardial fibrosis (MF), hypertrophy, and LV stiffness improving myocardial diastolic and systolic function. These effects have been recently demonstrated in the HOMAGE trial that proved the efficacy of spironolactone in reducing serum PICP (procollagen type I C-terminal propeptide, a marker of systemic and myocardial fibrosis generated during the extracellular conversion of procollagen to mature fibril-forming collagen type 1) concentrations and improving cardiac remodeling over 9 months in a population at risk of developing HF.11 The recent large CLEAR trial on spironolactone in a pure model of uncomplicated ST-segment elevation myocardial infarction (STEMI) showed that in this setting, MRAs do not reduce CV death and all-cause death.12 This provides further confirmation of MRA benefits that are clear in the context of acute MI (including non ST-segment elevation myocardial infarction, who have more prevalent multivessel and complex coronary artery diseases, compared with more prevalent mono or bivessel disease in STEMI) complicated by HF with severe reduction of LVEF (all patients in EPHESUS, but excluded in CLEAR), especially when primary PCI is suboptimal (EPHESUS percentage of PCI was 45.0% vs. 99.0% of CLEAR). In brief, MRAs exert their effects on CV and all-cause death when the myocardial damage and subsequent fibrosis and remodeling are quantitatively important, but with the current optimal timing of primary PCI in STEMI and potent double antiaggregation, the damage and the consequent MF are minimized. Similar effects and results have been shown by angiotensin receptor neprilysin inhibitor and sodium-glucose cotransporter-2 inhibitors, and also glucagon-like peptide 1 receptor agonists proved to reduce MF in CKD and type 2 diabetes.13–17 The antiremodeling effects in patients with ESRD in dialysis have been proven in 2 little dedicated trials.7FIGURE 1.: The multiple benefits of mineralocorticoid receptor antagonists.As highlighted by Dawadi et al9 another important benefit of MRAs is their “smart” effect on blood pressure (BP). Indeed, they reduce BP only in hypertensive patients, have no effect on normotensive patients, and over time they contribute (by antiremodeling effects and increase of LVEF) to increase BP in hypotensive patients (systolic BP < 115 mm Hg). This smart effect is mediated also by SGLT2i and is a major plus, especially in patients with ESRD who very often experience hypotension during hemodialysis.18 The interplay between the heart and the kidney is complex and includes hemodynamic alterations, due to cardiac output and arterial function alterations and increased venous congestion impairing renal perfusion19 and bringing to renal interstitial hypertension, tubular hypertrophy, damage, and fibrosis leading to decreased GFR. Therefore, patients with HFrEF and ESRD on RRT are those who receive more benefit by MRAs and by SGLT2i (studies in patients with RRT are ongoing); indeed, in the population enrolled by Dawadi et al, the magnitude of benefit in all-cause death reduction was higher in the population that included patients with HF when compared with patients without HF (odds ratio: 0.36 vs. 0.44).9,20 Finally, hyperkalemia historically constituted an obstacle to the use of MRAs in CKD. The study of Dawadi et al did not show any increase in the rate of hyperkalemia, as in several previous studies. Indeed, ESRD on RRT patients are meticulously monitored on this side, especially that on hemodialysis. The recent advent of new potent potassium binders as sodium zirconium cyclosilicate and patiromer keep the patients safe also in the nondialysis days minimizing this risk.4 Finally, conflicting evidence exists about the reduction of HHF in this population. Indeed, although preliminary published results of the ALCHEMIST trial (https://www.hcplive.com/view/spironolactone-misses-mark-in-hemodialysis-trial) showed a significant reduction of HHF, large retrospective analyses failed to show this effect. This could be linked to the loss of spontaneous diuresis; therefore, the natriuretic effect mediated by MRAs could be minimized because patients are fully dependent on RRT regarding fluid removal. Furthermore, research in this field, especially on the new nonsteroidal MRA such as finerenone and balcinrenone, which have greater selectivity, lower rate of hyperkalemia, and minimal or no sexual effects, will clarify the benefits of these drugs in both patients with ESRD and HF.