A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice

Abstract

Background: The integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration. We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of highdose integrase inhibitors. Methods: C57BL/6 mice were fed standard water (CTRL, n ¼ 6), raltegravir-containing water (40 mg/kg/day, n ¼ 6), or dolutegravir-containing water (2.7 mg/kg/day, n ¼ 6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen. Results: The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p < 0.05) compared to control (raltegravir ¼ 0.25 mg/dl, dolutegravir ¼ 0.30 mg/dl versus CTRL ¼ 0.17 mg/dl). Blood urea nitrogen, cystatin C, and urine microalbumin were unchanged. Kidney injury molecule-1 tissue expression in raltegravir and dolutegravir groups was nonsignificantly elevated compared to control (1.2-fold compared to control). Renal histopathology by periodic acid-Schiff staining failed to reveal glomerular or tubular renal injury in any group. Conclusion: These studies are consistent with integrase inhibitors competitively inhibiting creatinine secretion. While no evidence of direct nephrotoxicity was observed after two weeks of high-dose drug administration, additional studies may be performed to understand whether these drugs lead to chronic nephropathy.

Dolutegravir induced neural tube defects in mice are folate responsive

“…Females were then separated from males and housed in groups of up to four in individually ventilated cages (GM500, Tecniplast, Italy) in environmentally controlled rooms with a twelve-hour light-dark cycle. At E6.5, female mice received new drinking water mixed with dolutegravir (GSK-1349572A; AmBeed, Arlington Heights, Illinois, USA) in 0, 3.5 mg/l, 17.5 mg/l, or 35 mg/l concentrations to achieve 1×, 5×, or 10× clinical concentrations of DTG in serum [14]. Water and DTG-water consumption did not vary between groups and was approximately 5.45 ml/mouse per day.…”

“…To test our hypothesis, we administered DTG to CD-1 outbred mice provided with normal (3 mg/kg) or low (0.3 mg/kg) folic acid diet. Pregnant dams were treated with water, human equivalent dose (HED) (1×, 3.5 mg/l) [14] or supratherapeutic (5×, 17.5 mg/l; 10 ×, 35 mg/l) levels of DTG from mouse embryonic day E6.5 to E12.5, which encompasses the entirety of neural tube closure in mice. Dams ( n = 20 per treatment group) were sacrificed at term (E18.5).…”

Renal effects of non-tenofovir antiretroviral therapy in patients living with HIV

“…The study authors reported that DTG inhibits renal transporter OCT2, resulting in a mild increase in SCr that is reversible [ 27 ]. Eadon et al subsequently reported that other specific biomarkers showed no evidence of renal injury [ 28 ]. Dolutegravir is eliminated (approximately 64%) in feces [ 29 ].…”

“…Results confirmed that RAL significantly increases the SCr levels (0.25 mg/dL) compared to control (0.17 mg/dL). The study authors concluded that there were no direct signs of nephrotoxicity and attributed the increase in the SCr level to the direct inhibition of renal OCT2 transporters [ 28 ]. The second trial was a single center, retrospective chart review that assessed SCr and CrCl in newly diagnosed PLWH.…”