Tenofovir disoproxil fumarate-associated renal tubular dysfunction: noninvasive assessment of mitochondrial injury.
To determine whether tenofovir disoproxil fumarate (TDF)-associated renal tubular dysfunction is associated with evidence of mitochondrial injury in urine.



Single-centre cross-sectional observational study of HIV-positive outpatients.



Biochemistry was performed on paired serum and urine samples. Mitochondrial DNA (mtDNA) was studied by real-time PCR and long-range PCR on cellular fractions of urine.



In total, 48 study participants were enrolled of whom half were TDF treated. Mean age was 43 years. 58% had estimated glomerular filtration rate at least 90, with no differences between ART treatment groups. Urinary phosphate wasting was common and independently associated with TDF exposure (P = 0.02). No study participants had low molecular weight proteinuria. Cellular mtDNA content in urine was heavily influenced by the cellularity of the sample. The mtDNA 'common deletion' mutation was detectable significantly more commonly in the urine of TDF exposed study participants compared with unexposed (13/22 TDF study participants (59%), 4/21 TDF (19%), P = 0.01). Common deletion levels were not associated with age, estimated glomerular filtration rate, or urinary phosphate wasting. No mtDNA measures were associated with current or nadir CD4 lymphocyte counts, duration of disease or antiretroviral therapy, or historical exposure to nucleoside analogue reverse transcriptase inhibitors with systemic mitochondrial toxicity.



The presence of mtDNA mutations in the context of TDF exposure adds weight to the hypothesis that TDF-associated renal damage is at least in part mitochondrially mediated. The assessment of mtDNA markers in urine may be a feasible noninvasive investigation for TDF-treated patients.
aWellcome Trust Centre for Mitochondrial Research bInstitute of Genetic Medicine, Newcastle University cDepartment of Infection and Tropical Medicine, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Ryan
R
Samuels
Carla Roca
CR
Bayerri
John A
JA
Sayer
D Ashley
DA
Price
Brendan A I
BAI
Payne
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D003430:Cross-Sectional Studies; D004272:DNA, Mitochondrial / Q000652:urine; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced* / Q000175:diagnosis*; D007684:Kidney Tubules / Q000187:drug effects* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics; D009154:Mutation; D016133:Polymerase Chain Reaction; D000068698:Tenofovir / Q000008:administration & dosage / Q000009:adverse effects*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D000068698:Tenofovir