Mineralocorticoid Receptor Antagonists and Cardiovascular Health with Kidney Failure

In patients receiving hemodialysis in 2018, the reported prevalence of cardiovascular disease was 77%, with heart failure being one of the most common diagnoses (¹). Nevertheless, the management of cardiovascular disease in the setting of kidney failure presents an ongoing challenge. Despite certain advances, effective therapeutic options remain scarce. In particular, the distinct pathophysiology and milieu of uremia as well as the altered pharmacodynamics, pharmacokinetics, and bioavailability of drugs in kidney failure require studying the effects of standard therapies under these unique circumstances rather than simply extrapolating from trials conducted in the general population. The dialysis (hemodialysis or peritoneal dialysis) treatment likely adds another element of complexity with regard to dosing and pharmacology.

Mineralocorticoid receptor antagonists (MRAs) are particularly interesting in this respect. Aldosterone plays an important role in cardiovascular health and contributes to cardiovascular remodeling, inflammation, and fibrosis in animals on a high-salt diet (²). The most widely understood functions of aldosterone are sodium and potassium regulation via direct actions on the distal convoluted tubule and collecting duct with concomitant increases in BP due to volume retention. However, there are also critical mechanistic pathways that appear to be independent of the angiotensin II, volume, and BP effects. In vitro, aldosterone causes oxidative stress in vascular smooth muscle cells, endothelial cells, and cardiomyocytes (²). In animal models of hypertension, aldosterone promotes vascular inflammation, but the effect is attenuated by MRAs, which also have been shown to prevent myocardial fibrosis in a BP-independent fashion (³). Similarly, both spironolactone and eplerenone prevent angiotensin II– and L-N^G-nitro arginine methyl ester–induced myocardial necrosis, inflammation, and fibrosis via sodium- and potassium-independent mechanisms (⁴).

Several of these effects have been studied and confirmed in clinical studies. In a clinical study of patients with diastolic heart failure, low-dose MRA prevented and treated myocardial fibrosis at least partly independent of BP effects (⁵). A randomized, double-blind placebo-controlled study involving patients with CKD stages 2 and 3 demonstrated significant improvement in left ventricular mass and aortic stiffness irrespective of the BP effect in the spironolactone group, suggesting a beneficial cardiovascular effect in early stages of CKD (⁶). Furthermore, several lines of evidence suggest a correlation between aldosterone levels and left ventricular hypertrophy in patients with kidney failure on hemodialysis that appears to be independent of BP (⁷).

Although similar considerations have sparked interest and trials of MRA in other populations (⁸,⁹), use of spironolactone and the more selective agent eplerenone in patients with kidney failure does not match this enthusiasm, perhaps due, in part, to the lack of experience and questions on dosing in patients on maintenance dialysis.

Optimal MRA dosing in kidney failure remains uncertain. After absorption, spironolactone undergoes extensive first-pass metabolism. It has two main active metabolites, canrenone (80%) and 7α-methyl spironolactone, with a long half-life (15–20 hours) and 95% plasma protein binding. These metabolites are mainly excreted by the kidney. Use of a lower dose in advanced CKD is recommended, but because of the high molecular weight and extensive protein binding, existing evidence suggests that levels are unchanged with hemodialysis. Although no definitive pharmacokinetic or dialyzer clearance studies of spironolactone have been performed in humans, limited data come from a study of 14 individuals on maintenance hemodialysis who received spironolactone 25 mg postdialysis three times a week. At 48 hours, the main active metabolite, canrenone, had a concentration of approximately 50% of the 24-hour concentration in healthy volunteers receiving a daily dose of 50 mg—the daily dose targeted in the landmark RALES heart failure study. Eplerenone has no active metabolites, and thus, no dosage adjustment has been deemed necessary. After a 4-hour hemodialysis session, only 10% of eplerenone was removed (¹⁰).

Although questions about pharmacology have been partly addressed by the above studies, concerns regarding the optimal dose in terms of the perceived risk of hyperkalemia and a paucity of evidence regarding the effect on hard cardiovascular end points in patients with kidney failure are likely the primary factors limiting more widespread use at this time, but the study by Chen et al. (¹¹) in this issue of CJASN provides important data. The authors report the findings of a meta-analysis, the largest to date, with data from 14 randomized controlled trials published between 2005 and 2020, including 1309 patients enrolled in studies comparing the effect of MRAs with either placebo or no treatment in patients with kidney failure requiring dialysis.

The primary outcomes of interest were cardiovascular mortality and all-cause mortality. Secondary outcomes included nonfatal cardiovascular events, stroke, BP changes, left ventricular mass index, left ventricular ejection fraction, and hyperkalemia. Chen et al. (¹¹) reported reductions of 59% in cardiovascular mortality and 56% in all-cause mortality. Using the Grading of Recommendations Assessment, Development and Evaluation method, the authors considered the level of evidence to be high. There were no significant effects on BP, left ventricular ejection fraction, left ventricular mass index, or hyperkalemia—the definitions of which varied across studies.

Although the mortality results are impressive, they mandate careful consideration. This effect size is much higher than what was observed in the landmark heart failure trials (relative risk reduction of 30% in RALES [⁸] and 15% in EPHESUS [⁹]), in which the reduction in death was mainly attributed to decreased cardiovascular death. Results in this meta-analysis are also mainly driven by two trials. Interestingly, neither of these studies included patients with heart failure. One of the studies was also an open-label trial, raising questions of potential ascertainment bias.

Furthermore, the explanation for the reduction in all-cause mortality is uncertain.

There was no significant improvement in left ventricular ejection fraction or left ventricular mass index, which was attributed to insufficient data due to dissimilar outcomes reporting in several studies. Although the authors allude to the fact that left ventricular hypertrophy in kidney failure is multifactorial and that this likely speaks to heterogeneity of the dialysis population, it is unclear how MRAs would improve cardiovascular mortality to this extent without a discernible effect on measures of myocardial structure and function. The follow-up period in the underlying trials, however, varied from 7 to 156 weeks, and the spironolactone dosage ranged from 12.5 mg daily to 50 mg twice a day (with some studies choosing three times a week dosing). It is quite possible that the lack of significant difference in secondary outcomes could be due to inadequate follow-up. Furthermore, the effect of spironolactone is dose dependent, and the varying doses utilized could create variance in the clinical effect despite very low statistical heterogeneity.

Similarly, no significant improvement in BP was noted. Hypertension in patients on dialysis has long been argued to indicate volume overload and be best addressed by increasing ultrafiltration and adjusting the estimated dry weight rather than increasing the pill burden by adding yet another medication. Given the report of Chen et al. (¹¹), the evidence for spironolactone to be used solely for BP management in patients on dialysis is not yet convincing.

Finally, with regard to hyperkalemia, overall risks were nonsignificant. The pooled analysis revealed a nonsignificant increment in hyperkalemia risk (RR, 1.12; 95% confidence interval, 0.91 to 1.36; P=0.29). Furthermore, of three trials reporting on hyperkalemia risk defined as potassium >6.5 mEq/L, two used spironolactone doses of 50 mg daily, whereas the third used eplerenone dose 50 mg daily. The authors advise caution and monitoring when using spironolactone in kidney failure given the findings from meta-analysis, although their data suggest that risks of serious hyperkalemia are primarily observed with higher doses of MRA. Prior evidence has demonstrated U-shaped associations between mortality and potassium in kidney failure. Whether the potential for increased benefits of MRAs on cardiovascular structure and function at these higher doses will outweigh the potential risk of hyperkalemic arrhythmia in kidney failure is unanswered by this meta-analysis because the underlying trials were underpowered or failed to explore hard outcomes.

The meta-analysis by Chen et al. (¹¹) convincingly highlights the potential role for MRAs to lower cardiovascular mortality in patients requiring maintenance dialysis as well as the need for caution to be exercised with higher doses with regard to the risk of hyperkalemia. However, despite the authors’ conclusion that the level of evidence for a mortality benefit is high, their meta-analysis in fact shines light on important limitations of completed trials and available data. For nephrologists taking care of patients on dialysis, several steps are desired prior to adopting evidence from these studies to practice. At the forefront is the appropriate patient selection. The ongoing multicenter, randomized controlled trial—Aldosterone Blockade for Health Improvement Evaluation in End Stage Renal Disease (ClinicalTrials.gov Identifier: NCT03020303)—is evaluating whether spironolactone will yield similar cardiovascular mortality benefits in patients with kidney failure as it did in heart failure. The results of this study are eagerly awaited and anticipated to answer some of the above questions.

Disclosures

D.M. Charytan reports employment with the New York University School of Medicine; consultancy agreements with Allena Pharmaceuticals (DSMB), Amgen, AstraZeneca, Eli Lilly/Boehringer Ingelheim, Fresenius, Gilead, GSK, Janssen (steering committee), Medtronic, Merck, Novo Nordisk, and PLC Medical (clinical events committee); receiving research funding from Amgen, Bioporto (clinical trial support), Gilead, Medtronic (clinical trial support), and NovoNordisk; serving as an associate editor of CJASN; and receiving expert witness fees related to proton pump inhibitors. Q.H. Soomro reports employment with New York University Langone Health.

Funding

None.