title: 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 high-dose integrase inhibitors.
  
  
  METHODS
  C57BL/6 mice were fed standard water (CTRL, n = 6), raltegravir-containing water (40 mg/kg/day, n = 6), or dolutegravir-containing water (2.7 mg/kg/day, n = 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 = 0.25 mg/dl, dolutegravir = 0.30 mg/dl versus CTRL = 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Nephrology, Indiana University School of Medicine, Indianapolis, USA Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, USA meadon@iupui.edu.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Eadon
authors.affiliation: Division of Nephrology, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: Hongji
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
authors.affiliation: Division of Nephrology, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hato
authors.affiliation: Division of Nephrology, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: Pierre C
authors.initials: PC
authors.lastname: Dagher
authors.affiliation: Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: Samir K
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003404:Creatinine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000068898:Raltegravir Potassium / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000099226:Dolutegravir
chemical_list: D003404:Creatinine; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir
keywords: HIV; Highly active antiretroviral therapy; drug interactions; integrase inhibitor; nephrotoxicity