Non‐steroidal mineralocorticoid antagonists: Prospects for renoprotection in diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) is the major cause of kidney failure in the world and the combination of DKD and diabetes mellitus contributes to an additive incidence of worsening cardiovascular mortality rates. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) remain the mainstay of therapy and have reduced kidney function decline in DKD from 8 to 10 to~4 mL/min/y. Sodium-glucose co-transporter-2 (SGLT2) inhibitors, in the presence of ACE inhibitors or ARB agents, further slowdown DKD progression by an additional 58% to 1.8 mL/min/y. Moreover, SGLT2 inhibitors reduce heart failure risk. However, the normal rate of kidney function decline in humans is between 0.7 and 0.9 mL/min/y, hence, there is still room for improvement. Mineralocorticoid receptor antagonists (MRAs) already have a track record of benefit in heart failure risk reduction, and efficacy in reducing albuminuria and treating resistant hypertension; however hyperkalaemia and other adverse effects preclude their routine use in DKD. Novel non-steroidal MRAs offer a reduced risk of hyperkalaemia, and yet have many benefits that they share with their steroidal cousins. This paper reviews the data for both steroidal and non-steroidal MRAs in DKD and presents some data from soon-to-becompleted ongoing renal and cardiovascular outcome trials in DKD.

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

“…MR overactivation can lead to inflammation, increased oxidative stress, necrosis, fibrosis and finally, organ damage. It has been linked to arterial hypertension, coronary artery disease, heart failure, metabolic syndrome, DM and chronic kidney disease [15,[49][50][51][52].…”

“…DKD is a form of chronic kidney disease that is mostly driven by renal and vascular inflammation, matrix formation and fibrosis [15]. Inflammation affecting the podocytes leads to albuminuria, which leads to kidney disease progression and is associated with high cardiovascular risk [58].…”

“…Inflammation affecting the podocytes leads to albuminuria, which leads to kidney disease progression and is associated with high cardiovascular risk [58]. The inflammatory and proliferative response in DKD is stimulated by relative aldosterone excess [15]. This persists even after the use of ACE inhibitors or ARB, due to the so-called aldosterone escape phenomenon [15].…”

“…The inflammatory and proliferative response in DKD is stimulated by relative aldosterone excess [15]. This persists even after the use of ACE inhibitors or ARB, due to the so-called aldosterone escape phenomenon [15]. Namely, aldosterone secretion is not only stimulated by angiotensin II, but also by other stimuli like hyperkalemia and atrial natriuretic peptide [15].…”

“…Therefore, treatment of DKD encompasses appropriate lifestyle changes (i.e., weight reduction, physical activity, appropriate diet, smoking cessation), glycemic and blood pressure control [14]. The cornerstone of therapy in patients with albuminuria are angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), which slow down the rate of kidney function decline [15]. However, they do not reduce the number of cardiovascular events [16].…”