Role of mineralocorticoid receptor antagonists in kidney diseases

Abstract

Mineralocorticoid receptor (MR) antagonists, for example, spironolactone and eplerenone, are in clinical use to treat hypertension. Increasing evidence suggests that mineralocorticoid receptor activation causes the pathogenesis and progression of chronic kidney disease. Aldosterone‐induced MR activation increases inflammation, fibrosis, and oxidative stress in the kidney. MR antagonists (MRAs) have demonstrated therapeutic actions in chronic kidney disease (CKD), diabetic nephropathy (DN), renal fibrosis, and drug‐induced renal injury in preclinical and clinical studies. We have summarized and discussed these studies in this review. The nonsteroidal MRA, esaxerenone, recently received approval for the treatment of hypertension. It has also shown a positive therapeutic effect in phase 3 clinical trials in patients with DN. Other nonsteroidal MRA such as apararenone, finerenone, AZD9977, and LY2623091 are in different clinical trials in patients with hypertension suffering from renal or hepatic fibrotic diseases. Hyperkalemia associated with MRA therapy has frequently led to the discontinuation of the treatment. The new generation nonsteroidal MRAs like esaxerenone are less likely to cause hyperkalemia at therapeutic doses. It appears that the nonsteroidal MRAs can provide optimum therapeutic benefit for patients suffering from kidney diseases.

Efficacy and safety of finerenone in patients with chronic kidney disease: a systematic review with meta-analysis and trial sequential analysis

“…This may be associated with the treatment mechanism of MRAs. MRA use increases sodium excretion and decreases potassium excretion in the kidney, resulting in an increase in serum potassium levels (35). Even though the incidence of hyperkalaemia was increased in comparison with that in the placebo group, finerenone is associated with a lower risk than classic steroidal MRAs (spironolactone or eplerenone) according to recent trials and meta-analyses (30,35,36).…”

“…MRA use increases sodium excretion and decreases potassium excretion in the kidney, resulting in an increase in serum potassium levels (35). Even though the incidence of hyperkalaemia was increased in comparison with that in the placebo group, finerenone is associated with a lower risk than classic steroidal MRAs (spironolactone or eplerenone) according to recent trials and meta-analyses (30,35,36). Current research has reported that compared with eplerenone, finerenone has a much better effect on preventing cardiac fibrosis and improving strain parameters in mice (37).…”

Signaling Pathways Involved in Diabetic Renal Fibrosis

“…It has been well established that overactivation of the mineralocorticoid receptor (MR) results in renal fibrosis and is closely linked to the progression of renal injury in DKD ( Shrestha et al, 2019 ; Patel et al, 2020 ). Therefore, new drugs targeting MR are considered as potential therapies that slow the progression of renal fibrosis.…”

Chronic Kidney Disease as a Systemic Inflammatory Syndrome: Update on Mechanisms Involved and Potential Treatment

“…Mineralocorticoid receptor antagonists (MRAs) have demonstrated beneficial effects on renal inflammation in various animal studies, directly regulating inflammatory cell function and indirectly suppressing proinflammatory cytokines, chemoattractants, and pro-oxidants, increasing anti-inflammatory cytokines in kidneys [ 88 ]. Spironolactone and eplerenone in particular demonstrated beneficial effects, reducing the kidney’s inflammatory markers [ 89 , 90 ].…”