title: Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities.
abstract: Tenofovir, a widely prescribed antiretroviral medication for treatment of HIV-1 infection, is infrequently associated with renal dysfunction and biopsy findings of acute tubular necrosis. We examined the clinical and pathological findings in 13 cases of tenofovir nephrotoxicity (7 men and 6 women, mean age of 51.1±9.6 years). Patients received tenofovir therapy for a mean of 19.6 months (range, 3 weeks to 8 years; median 8 months). Nine patients presented with acute kidney injury, and four had mild renal insufficiency with subnephrotic proteinuria. Mean baseline serum creatinine was 1.3±0.3 mg/dl, reaching 5.7±4.0 mg/dl at the time of biopsy, with mean proteinuria of 1.6±0.3 g/day. Glycosuria was documented in seven patients, five of whom were normoglycemic. Renal biopsy revealed toxic acute tubular necrosis, with distinctive proximal tubular eosinophilic inclusions representing giant mitochondria visible by light microscopy. Electron microscopy showed mitochondrial enlargement, depletion, and dysmorphic changes. Clinical follow-up after tenofovir discontinuation was available for 11 of 13 patients (mean duration 13.6 months). Significant recovery of renal function occurred in all patients, including four who required transient hemodialysis. Our study shows that tenofovir nephrotoxicity is a largely reversible form of toxic acute tubular necrosis targeting proximal tubules and manifesting distinctive light microscopic and ultrastructural features of mitochondrial injury.
authors.affiliation: Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. LB684@columbia.edu
authors.forename: Leal C
authors.initials: LC
authors.lastname: Herlitz
authors.forename: Sumit
authors.initials: S
authors.lastname: Mohan
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stokes
authors.forename: Jai
authors.initials: J
authors.lastname: Radhakrishnan
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.forename: Glen S
authors.initials: GS
authors.lastname: Markowitz
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced; D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001706:Biopsy; D004334:Drug Administration Schedule; D005260:Female; D006029:Glycosuria / Q000139:chemically induced; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced* / Q000473:pathology / Q000628:therapy; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D009519:New York City; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D011507:Proteinuria / Q000139:chemically induced; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000139:chemically induced; D012189:Retrospective Studies; D000068698:Tenofovir; D013997:Time Factors
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine