The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury

Abstract

The therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27 days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26 days of treatment. Serum K+ was evaluated after 14 and 27 days of treatment. Urinary Na+, urinary K+, and urinary Na+/K+ ratio were evaluated after 7, 14, and 26 days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC50) for increasing serum K+ to the EC50 for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K+, and decreased urinary Na+ relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5 mg/kg BID while eplerenone did so only at the two highest doses of 50 and 450 mg/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K+ seen in the aldosterone treatment group, with significant increases in serum K+ at the high doses only (5 mg/kg and 450 mg/kg BID, respectively). Additionally, the urinary Na+ and Na+/K+ ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window.

The mineralocorticoid receptor in chronic kidney disease

“…The non-steroidal MRAs SM-368229 (N-4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-ylthiophene-2-sulfonamide), CS-3150 (esaxerenone) and AZD9977 have also shown promising effects on renal pathology in this context (Arai et al, 2016;Bamberg et al, 2018;Nariai et al, 2012). Similarly, the non-steroidal MRA KBP-5074 showed a better therapeutic index than eplerenone in a rat model of kidney injury induced by aldosterone, salt and unilateral nephrectomy (Jaisser et al, 2021). Of note, AZ9977 showed a reduced effect on renal sodium excretion relative to that of eplerenone, while retaining its renal protection benefit (Bamberg et al, 2018).…”

Novel non‐steroidal mineralocorticoid receptor antagonists in cardiorenal disease

“…These beneficial actions were confirmed in stroke‐prone spontaneously hypertensive rats, in which KBP‐5074 also inhibited the increase in BP, reduced urinary albumin excretion and decreased kidney‐to‐body and heart‐to‐body weight ratios (Chow et al, 2017). Recently, a comparative study with eplerenone in high‐salt diet‐fed rats with aldosterone infusion showed an improved efficacy and therapeutic index, calculated as the ratio of the EC 50 for increasing K + to the EC 50 of decreasing UACR, with KBP‐5074 (Jaisser et al, 2021). Preclinical analyses were completed by toxicity and safety studies in rats and dogs, in which no toxicity and good tolerability were demonstrated (Chow et al, 2018).…”

Aldosterone, Mineralocorticoid Receptor Activation, and CKD: A Review of Evolving Treatment Paradigms

“…In response to concerns about the benefit-safety profile of steroidal MRAs, several new selective nonsteroidal MRAs were developed with the dual goal of improving efficacy and reducing unwanted side effects, primarily hyperkalemia. 3,32 Figure 2 provides a direct comparison between the steroidal MRAs (spironolactone and eplerenone) and the recently approved and most widely investigated Representative examples compiled from Jaisser et al, 2 Kintscher et al, 3 Buonafine et al, 8 Fuller et al, 9 and Barrera-Chimal et al 15 Abbreviations: CKD, chronic kidney disease; eNOS, endothelial nitric oxide synthase; ICAM-1, intercellular adhesion molecule 1; MCP-1, monocyte chemoattractant protein 1; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist; NADPH, reduced nicotinamide adenine dinucleotide phosphate; Nox2, NADPH oxidase 2; Rac1, Rac family small guanosine triphosphatase 1; VCAM-1, vascular cell adhesion molecule 1.…”

“…Strong evidence has now accumulated to show that MR activation leads to many "off-target" effects on the heart, the vasculature, and the kidney. [1][2][3] In this review, we summarize our growing understanding of role of MR activation in propagating kidney injury, inflammation, and fibrosis and the consequent progression of CKD. We review the recent clinical studies that investigated and defined the efficacy of MR antagonism in attenuating progressive kidney disease 4,5 and that culminated in an MR antagonist (MRA) becoming an approved treatment for retarding CKD progression.…”