Approximately 30%-40% of patients with type 1 or type 2 diabetes (T1D/T2D) develop diabetic kidney disease (DKD), which can lead to end-stage kidney disease (ESKD). Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been investigated as treatments for DKD. However, these drugs do not prevent overactivation of the mineralocorticoid receptor (MR). Studies have shown a correlation between MR hyperactivation, renal injury, and DKD. Finerenone, a novel and selective nonsteroidal mineralocorticoid receptor antagonist (NS-MRA), was approved for the treatment of patients with DKD, and is associated with lower rates of hyperkalemia. Other NS-MRAs (such as KBP-5074, BR-4628, esaxerenone, and apararenone) may also be effective drugs for the treatment of DKD. This review summarizes the effects of pharmacological MR blockade on diabetes and diabetes-associated CKD, with a particular focus on the therapeutic mechanisms of NS-MRAs in preclinical studies and ongoing clinical studies. Further investigation of combined treatment with renoprotective drugs and NS-MRAs to improve the treatment of DKD is needed.

01 Feb 2016·Journal of the American Society of NephrologyQ1 · MEDICINE

A New Hope?

Q1 · MEDICINE

Communications

Author: Juncos, Luis A ; Juncos, Luis I

A review discussing that BR-4628, a third generation mineralocorticoid receptor (MR) antagonist, is highly protective against exptl. I/R-AKI.

01 Feb 2016·Journal of the American Society of NephrologyQ1 · MEDICINE

Sulfenic Acid Modification of Endothelin B Receptor is Responsible for the Benefit of a Nonsteroidal Mineralocorticoid Receptor Antagonist in Renal Ischemia

Q1 · MEDICINE

Article

Author: Warnock, David G ; Jaisser, Frédéric ; El Moghrabi, Soumaya ; Fadel, Fouad ; Barrera-Chimal, Jonatan ; Kolkhof, Peter ; Prince, Sonia

AKI is associated with high mortality rates and the development of CKD. Ischemia/reperfusion (IR) is an important cause of AKI. Unfortunately, there is no available pharmacologic approach to prevent or limit renal IR injury in common clinical practice. Renal IR is characterized by diminished nitric oxide bioavailability and reduced renal blood flow; however, the mechanisms leading to these alterations are poorly understood. In a rat model of renal IR, we investigated whether the administration of the novel nonsteroidal mineralocorticoid receptor (MR) antagonist BR-4628 can prevent or treat the renal dysfunction and tubular injury induced by IR. Renal injury induced by ischemia was associated with increased oxidant damage, which led to a cysteine sulfenic acid modification in endothelin B receptor and consequently decreased endothelial nitric oxide synthase activation. These modifications were efficiently prevented by nonsteroidal MR antagonism. Furthermore, we demonstrated that the protective effect of BR-4628 against IR was lost when a selective endothelin B receptor antagonist was coadministered. These data describe a new mechanism for reduced endothelial nitric oxide synthase activation during renal IR that can be blocked by MR antagonism with BR-4628.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	Phase 2	-	Bayer AG	-
Heart Failure	Phase 2	DE	Bayer HealthCare Pharmaceuticals, Inc.	-

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