Mineralocorticoid receptor antagonists in diabetic kidney disease - mechanistic and therapeutic effects

Chronic kidney disease (CKD) is the leading complication in type 2 diabetes (T2D) and current therapies that limit CKD progression and the development of cardiovascular disease (CVD) include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and sodium-glucose co-transporter 2 (SGLT2) inhibitors. Despite the introduction of these therapeutics, an important residual risk of CKD progression and cardiovascular death remains in patients with T2D. Mineralocorticoid receptor antagonists (MRAs) are a promising therapeutic option in diabetic kidney disease (DKD) owing to the reported effects of mineralocorticoid receptor activation in inflammatory cells, podocytes, fibroblasts, mesangial cells and vascular cells. In preclinical studies, MRAs consistently reduce albuminuria, CKD progression, and activation of fibrotic and inflammatory pathways. DKD clinical studies have similarly demonstrated that steroidal MRAs lead to albuminuria reduction compared with placebo, although hyperkalaemia is a major secondary effect. Non-steroidal MRAs carry a lower risk of hyperkalaemia than steroidal MRAs, and the large FIDELIO-DKD clinical trial showed that the non-steroidal MRA finerenone also slowed CKD progression and reduced the risk of adverse cardiovascular outcomes compared with placebo in patients with T2D. Encouragingly, other non-steroidal MRAs have anti-albuminuric properties in DKD. Whether or not combining MRAs with other renoprotective drugs such as SGLT2 inhibitors might provide additive protective effects warrants further investigation. Novel non-steroidal mineralocorticoid receptor antagonists have a better safety profile than steroidal formulations. This Review examines the pro-inflammatory and profibrotic activity of mineralocorticoid receptor activation and discusses the therapeutic potential of MRAs in the treatment of diabetic kidney disease to improve kidney and cardiovascular outcomes.