Protamine protects against vancomycin-induced kidney injury.

Abstract

Vancomycin causes kidney injury by accumulating in the proximal tubule, likely mediated by megalin uptake. Protamine is a putative megalin inhibitor that shares binding sites with heparin and is approved for the treatment of heparin overdose. We employed a well-characterized Sprague-Dawley rat model to assess kidney injury and function in animals that received vancomycin, protamine alone, or vancomycin plus protamine over 5 days. Urinary KIM-1 was used as the primary measure for kidney injury, while plasma iohexol clearance was calculated to assess kidney function. Animals had samples drawn pre-treatment in order to serve as their own controls. Additionally, since protamine is not a known nephrotoxin, the protamine group also served as a control. Cellular inhibition studies were performed to assess the ability of protamine to inhibit organic anion transporter (OAT1 and OAT3) and organic cation transporter-2 (OCT2). Rats that received vancomycin alone had significantly increased urinary KIM-1 on day 2 (24.9 ng/24 h, 95% CI 1.87-48.0) compared to the protamine alone group. By day 4, animals that received protamine with their vancomycin had KIM-1 amounts that were elevated compared to protamine alone as a base comparison (KIM-1 29.0 ng/24 h, 95% CI 5.0-53.0). No statistically observed differences were identified for iohexol clearance changes between drug groups or when comparing clearance change from baseline (P > 0.05). No substantial inhibition of OAT1, OAT3, or OCT2 was observed with protamine. IC₅₀ values for protamine were 0.1 mM for OAT1 and OAT3 and 0.043 mM for OCT2. Protamine, when added to vancomycin therapy, delays vancomycin-induced kidney injury as defined by urinary KIM-1 in the rat model by 1-3 days. Protamine putatively acts through the blockade of megalin and does not appear to have significant inhibition on OAT1, OAT3, or OCT2. Since protamine is an approved FDA medication, it has clinical potential as a therapeutic to reduce vancomycin-related kidney injury; however, greater utility may be found by pursuing compounds with fewer adverse event liabilities.