New insights on the renal protective effects of mineralocorticoid receptor antagonists

The prevalence of chronic kidney diseases (CKD) raises progressively, affecting more than 10% of the general population [1], and leads to three to five times increase in cardiovascular morbidity and mortality, the prevailing cause of death in these patients [2]. However, most therapies with proved efficacy in cardiovascular diseases, for example, statins, β-blockers, angiotensin-converting enzyme inhibitors (ACEI), or angiotensin-receptor blockers (ARB), demonstrated in CKD patients disputable effectiveness in the prevention of cardiovascular diseases [2]. These medications in the setting of hypertension are a noticeable exception that provided consistent improvements of cardiovascular outcomes in end-stage renal disease (ESRD) patients undergoing hemodialysis, as shown by a meta-analysis constituting 1202 patients [3]. The scarcity of efficacious therapies preventing cardiovascular events in the setting of renal failure emphasizes the need of preventive measures, particularly in patients at high-risk of progression toward CKD, aiming at preventing/delaying the progression of renal damage. Acute kidney injury (AKI), especially when it requires dialysis [4], is among the most relevant risk factors for CKD and ESRD [5], complicating the hospital stay of 5% of admitted patients and of 40–70% of ICU patients [6]. The study published by Lin et al.[7] in the current issue of the Journal of Hypertension entailed a cohort of 7252 hypertensive patients who required hemodialysis for AKI during the index hospitalization. Among the patients enrolled, 31% were started on MRAs between 30 and 90 days after discharge and were compared after propensity-score matching with patients treated with other antihypertensive medications. Among these patients, who are at risk of developing CKD and its complications including, in particular, hyperkalemia, those on MRAs had at follow-up, a lower incidence of dialysis dependence than nonusers, whereas the risks for all-cause mortality and major adverse cardiac events were similar. This study suggests that the treatment with MRAs is well tolerated in this setting, allowing their use as antihypertensive drugs in these patients, who may take advantage from the antiproliferative effects of aldosterone inhibition to prevent CKD development. CKD is characterized by increased aldosterone level [8] and sodium overload [9] and, in view of the detrimental effects of the former on the progression of kidney damage (reviewed in [10,11]), the MRAs’ benefits are not surprising. The study of Lin and co-workers might lead to extend this hypothesis to the earlier phases of kidney diseases, where aldosterone may play a crucial pathogenic role toward the progression to CKD. In fact, aldosterone induces podocyte and glomerular remodeling [12,13] and increases albuminuria, a known risk factor for renal disease progression, as confirmed in a cohort of patients with primary aldosteronism [14]. Moreover, aldosterone induces reactive oxygen species and activation of oxidative stress as shown in monocytes [15] as well as in glomeruli via the activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, the serum-glucocorticoid-inducible kinase-1 (SGK-1), with ensuing production of proinflammatory cytokines [interleukin (IL)-1, IL-6, TNF-α], leading to tubulointerstitial and glomerular inflammation and fibrosis [10]. Multiple studies suggested an overall beneficial effect of MRAs in patients with CKD at different stages of the disease. In a randomized controlled clinical trial including 112 patients with stage 2 or 3 CKD, the addition of a MRA for 36 weeks (spironolactone 25 mg per day) on top of ACEI or ARB decreased left ventricular mass and improved arterial stiffness, both predictors of cardiovascular events in these patients [16]. Recent meta-analyses demonstrated a decrease of albuminuria, a known risk factor for CKD progression [17], upon MRA treatment [18,19], although renoprotection has not been confirmed [18] or has been disputed in diabetic nephropathy [19]. More consistent beneficial results of MRA treatment have been obtained in advanced stages of CKD. In fact, a randomized controlled clinical trial including 309 patients with ESRD patients on hemodialysis, who were randomized to MRA or placebo, showed, after 3 years of follow-up, a decrease in cardiovascular events and in cardiovascular and total mortality, with a striking risk reduction higher than 50% [20]. Similar results were obtained in another randomized trial testing the effects of 2 years treatment with low-dose spironolactone in ESRD patients on dialysis who exhibited a lower cardiovascular mortality (4.0 vs. 11.7%) and all-cause mortality (9.6 vs. 19.5%) [21], as recently confirmed in a meta-analysis [22]. The documented advantages of MRAs on cardiovascular outcomes and total mortality in ESRD patients on dialysis should open the way for specifically designed clinical trials aimed to assess the effect of extending MRA treatment, with its known antiproliferative features, to patients in the earlier stages of CKD or at high risk of CKD as those included in the study of Lin et al.[7], which, if unequivocally proved, might effectively contribute to the delay of renal damage progression. All this, naturally, should also take in the due consideration the risk of hyperkalemia, in particular in these type of patients, which mandates extreme caution to the widespread use of MRAs. Nowadays, the availability of the new and really effective drugs such as patiromer and sodium zirconium cyclosilicate [10] for hyperkalemia correction, might further decrease the proportion of patients with CKD exposed to this MRA treatment complication. The results obtained in the patients of Lin et al.'s’ study [7] may be considered a good piece of evidence for the MRAs’ renal protective effect in patients at high risk for renal disease progression. ACKNOWLEDGEMENTS Conflict of interest There are no conflicts of interest.