PII-039

M. T. Eadon, H. Zhang, T. C. Skaar, S. Gupta, Z. Desta; Indiana University, Indianapolis, IN

BACKGROUND: The integrase inhibitors, raltegravir and dolutegravir, are potential first line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion, elevating serum creatinine without affecting filtration. Interestingly, studies with integrase inhibitors reveal a concomitant rise in serum cystatin C, a filtration marker unaffected by secretion. Thus, it is unknown whether a true decrement in filtration exists. We sought to determine if the integrase inhibitors had a direct nephrotoxic effect in mice.
METHODS: C57BL/6 mice were fed standard water (CTRL), or water containing raltegravir (RAL) 40 mg/kg/day or dolutegravir (DTG) 2.7 mg/kg/day for 2 weeks and sacrificed. Doses were 4-fold above the standard human doses. Endpoints were assessed including urine microalbumin by ELISA, Kidney Injury Molecule-1 (KIM-1) renal tissue gene expression, renal histopathology, serum creatinine, and BUN.
RESULTS: The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was non-significantly elevated in RAL and DTG mice compared to control (RAL = 0.25 mg/dL, DTG = 0.30 mg/dL v. CTRL = 0.20 mg/dL). Blood urea Nitrogen, urine microalbumin to creatinine ratios, KIM-1 tissue expression, and renal histopathology were unchanged compared to CTRL mice.
CONCLUSION: These studies are consistent with integrase inhibitors competitively inhibiting creatinine secretion. Highly sensitive injury markers including urine microalbumin, tissue KIM-1 expression, and renal histopathology do not reveal evidence of direct nephrotoxicity after 2 weeks of high dose drug administration in mice.