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.
Highlights
Chronic kidney disease (CKD) is major contributor to the global burden of disease, increasing the risks of morbidity and mortality associated with cardiovascular diseases, diabetes, hypertension, human immunodeficiency virus (HIV) infection, and malaria, among others
We compared the novel non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 with the steroidal MRA eplerenone in parallel studies using a rat model of mineralocorticoid-induced renal injury
therapeutic indices (TIs) was calculated as the ratio of the EC50 for increasing serum K+ to the EC50 of decreasing urinary albumin-to-creatinine ratio (UACR) and was found to be greater for KBP-5074 than for eplerenone
Summary
Chronic kidney disease (CKD) is major contributor to the global burden of disease, increasing the risks of morbidity and mortality associated with cardiovascular diseases, diabetes, hypertension, human immunodeficiency virus (HIV) infection, and malaria, among others. An estimated 1.2 million people died from kidney failure in 2015, an increase of 32% from 2005 (Luyckx et al, 2018). Both blood pressure (BP) control and a reduction in proteinuria have been associated with slowing glomerular filtration rate (GFR) decline and, CKD progression (Lea et al, 2005; Anderson et al, 2015). Renin–angiotensin–aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensinII receptor blockers (ARB), have historically been the main tools available to clinicians to slow GFR decline but, do not stop progression, with a large number of patients developing macroalbuminuria and end-stage kidney disease, possibly due to increased levels of angiotensin II and aldosterone or aldosterone alone (Sarafidis and Ruilope, 2012; Vejakama et al, 2017). Expression of the MR has been found in non-classic kidney tissues, such as the vascular endothelium and smooth muscle cells, as well as inflammatory cells, podocytes, and fibroblasts, which may be pathophysiological (Jaisser and Farman, 2016)
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