#604 Oral administration of UNI-494 ameliorates acute kidney injury in a rat model of delayed graft function

Abstract

Abstract Background and Aims There are no FDA approved drugs for the treatment of acute kidney injury (AKI), which affects 10-15% of hospitalized patients and often results in renal transplantation or lifelong dialysis. UNI-494 is a novel nicotinamide ester derivative and selective mitochondrial ATP-sensitive potassium channel activator that may be beneficial for several disease states, including AKI. We present results from a study evaluating the in vivo efficacy of oral (PO) UNI-494 in the unilateral renal ischemia-reperfusion (I/R) rat model of AKI, which is a well-established model of delayed graft function (DGF) (Cavaille-Coll, 2013). Method Rats were anesthetized, the right kidney was removed, and I/R was induced in three groups of rats by clamping the renal vessels in the left kidney for 30 minutes; a fourth group had no surgery (sham group) without clamping the renal vessels. 50 mg/kg or 100 mg/kg UNI-494 were administered PO 30 minutes prior to I/R. One I/R group and the sham group were not treated. After 24 hours of reperfusion in metabolic cages, blood samples were collected for serum creatinine (sCr), and urinary samples were collected for albumin-creatinine ratio (ACR) and the tubular injury marker neutrophil gelatinase-associated lipocalin (NGAL). The clamped left kidney was collected and processed for histology for tubular injury scores. Results In this study, I/R induced significant increases of sCr, ACR, NGAL, and proximal convoluted tubular injury scores in the vehicle treated I/R group vs No I/R sham group. A single PO dose of UNI-494 at 50 mg/kg/PO or 100 mg/kg/PO reduced the kidney functional markers sCr and ACR, the tubular injury marker (NGAL), and proximal tubular injury scores (all p < 0.001, Fig. 1). Conclusion The results indicate that UNI-494 dose dependently prevented AKI markers and proximal tubular injury in a rat model of AKI and therefore is a potential candidate for the prevention of DGF and other AKI clinical conditions.