Endothelin receptor antagonists in kidney protection for diabetic kidney disease and beyond?

Abstract

The burden of chronic kidney disease is increasing worldwide, largely due to the increasing global prevalence of diabetes mellitus and hypertension. While renin angiotensin system inhibitors and sodium-glucose cotransporter two inhibitors are the management cornerstone for reducing kidney and cardiovascular complications in patients with diabetic and non-diabetic kidney disease (DKD), they are partially effective and further treatments are needed to prevent the progression to kidney failure. Endothelin receptor antagonism represent a potential additional therapeutic option due to its beneficial effect on pathophysiological processes involved in progressive kidney disease including proteinuria, which are independently associated with progression of kidney disease. This review discusses the biological mechanisms of endothelin receptor antagonists (ERA) in kidney protection, the efficacy and safety of ERA in randomised controlled trials reporting on kidney outcomes, and its potential future use in both diabetic and non-DKDs.

Keywords: chronic kidney disease; endothelin; fluid retention; kidney failure; proteinuria.

FIGURE 1

The role of endothelin‐1 (ET‐1) in the pathophysiology of chronic kidney disease. ET‐1 is highly expressed in many organs including kidney cells such as podocytes, mesangial cells, endothelial and inflammatory cells. ET‐1 can be triggered by common mediators of chronic kidney disease as well as its complications. Chronic stimulation of ET‐1 leads to unchecked proinflammatory and pro‐fibrotic milieu that promotes progressive CKD. ET_A receptor, endothelin A receptor; IL‐1, interleukin‐1; TNF‐α, tumour‐necrosis factor‐α.

FIGURE 2

Regulation of sodium and water homeostasis by the actions of ET‐1 on the collecting ducts. ET‐1‐mediated ET_B receptor activation causes natriuresis by inhibiting sodium reabsorption at the cortical collecting duct and inhibiting water reabsorption at the medullary collecting duct. Cortical collecting duct (upper figure): ET‐1‐mediated ET_B receptor activation leads to: (1) inhibition of epithelial sodium channel (ENaC) functioning activity (nitric oxide and MAPK dependent pathways), (2) promote ENaC endocytosis. Medullary collecting duct (lower figure): ET‐1‐mediated ET_B receptor activation leads to: (1) inhibition of vasopressin activity, and (2) inhibition of aquaporin‐2 (AQP2)‐mediated water reabsorption. Therefore, non‐selective ERAs (especially inhibition of ET_B antagonism) can lead to sodium retention and water resorption. Created with Biorender.com. AC, adenylyl cyclase; β1Pix, beta 1 Pix; DAG, diacylglycerol; ENaC, epithelial sodium channel; IP3, inositol trisphosphate; MAPK, mitogen‐activated protein kinase; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C.

FIGURE 3

Forest plot of the treatment effect of selective ET_A receptor inhibitors on albuminuria compared with placebo. ERA, endothelin receptor antagonist; SMD, standardized mean difference; CI, confidence interval. The RADAR trial could not be included in the meta‐analysis as standard deviation of change in albuminuria was not reported.

FIGURE 4

wForest plot of the treatment effect of selective ET_A receptor inhibitors or non‐selective ET_A/ET_B receptor inhibitors on patient‐level kidney endpoints compared with placebo. ERA, endothelin receptor antagonist; RR, relative risk; CI, confidence interval. Patient‐level kidney endpoints defined as the composite of the doubling of serum creatinine, end‐stage kidney disease, or kidney failure reported in as a serious adverse event.