title: Renal Toxicity of Concomitant Exposure to Tenofovir and Inhibitors of Tenofovir's Renal Efflux Transporters in Patients Infected With HIV Type 1.
abstract: BACKGROUND
  Exposure to tenofovir disoproxil fumarate (TDF) may cause renal toxicity. Inhibitors of TDF's apical multidrug-resistance-associated protein efflux-transporters (MRPs) in the renal proximal tubule could enhance this unwanted effect.
  
  
  METHODS
  We performed a cohort study involving patients with human immunodeficiency virus type 1 (HIV) infection. All patients had a suppressed viral load and were receiving TDF as a part of combination antiretroviral therapy. Data on mean cumulative defined daily doses (DDDs) of MRP inhibitors (NSAIDs, PDE5-i, salicylates, dipyridamole) were collected. The effects of MRP inhibitors on the estimated glomerular filtration rate (eGFR) and proximal tubular function were evaluated by generalized linear models, with adjustment for renal- and HIV-specific factors.
  
  
  RESULTS
  A total of 721 HIV-infected patients were included (76.3% were male; median age, 45 years; median CD4(+) T-cell count, 600 cells/mm(3)). The median duration of TDF exposure was 54 months, and the total cumulative exposure duration was 3484 patient-years. Three hundred twenty-one patients had MRP inhibitor exposure, ranging from 0.02 to 120 mean DDDs/month. Exposure to MRP inhibitors was associated with an additional mean eGFR change of -1.4 mL/min (95% confidence interval [CI], -2.9 to .1 mL/min) over 12 months in patients with ≥1 year of continuous TDF exposure. Associations were observed between MRP inhibitor exposure and eGFR declines of >10 mL/min (odds ratio [OR], 1.38; 95% CI, .97 to 1.95), or >25% (OR, 2.14; 95% CI, 1.19 to 3.85) since initiation of TDF therapy. Overall, no clinically significant associations were found between MRP inhibitor exposure and abnormal protein, glucose, or phosphate handling in the proximal tubule or with the presence of ≥2 of these markers.
  
  
  CONCLUSIONS
  Concomitant incidental exposure to MRP inhibitors and TDF did not result in major additional TDF-related renal toxicity in HIV-infected patients.
authors.affiliation: Department of Internal Medicine, Section of Infectious Diseases.
authors.forename: Casper
authors.initials: C
authors.lastname: Rokx
authors.affiliation: Department of Internal Medicine, Section of Infectious Diseases.
authors.forename: Hanin
authors.initials: H
authors.lastname: Alshangi
authors.affiliation: Department of Internal Medicine, Section of Infectious Diseases.
authors.forename: Annelies
authors.initials: A
authors.lastname: Verbon
authors.affiliation: Department of Internal Medicine, Section of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Zietse
authors.affiliation: Department of Internal Medicine, Section of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ewout J
authors.initials: EJ
authors.lastname: Hoorn
authors.affiliation: Department of Internal Medicine, Section of Infectious Diseases.
authors.forename: Bart J A
authors.initials: BJ
authors.lastname: Rijnders
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced*; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015331:Cohort Studies; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D000068698:Tenofovir / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D000068698:Tenofovir
keywords: HIV; cART; drug transporters; renal toxicity; tenofovir disoproxil fumarate