Mitochondrial tubulopathy in tenofovir disoproxil fumarate-treated rats.
OBJECTIVE
Tenofovir disoproxil fumarate (tenofovir DF) use has been associated with renal dysfunction and Fanconi syndrome. Tenofovir is taken up into renal tubules by anion transporters where high intracellular drug concentration may induce a functionally relevant depletion of mitochondrial DNA (mtDNA). We investigated if tenofovir may induce renal mtDNA depletion and respiratory chain dysfunction.


METHODS
Rats (n = 8) were gavaged daily with 100 mg x kg(-1) x d(-1) of tenofovir DF or didanosine. Kidneys and livers were examined after 8 weeks of treatment.


RESULTS
The tenofovir group had significantly lower body and kidney weights than rats exposed to water or didanosine. Proximal but not distal tubules were of increased diameter and contained small lipid droplets. Tubular mitochondria were enlarged, and their crystal architecture was disrupted. Tenofovir-exposed kidneys contained low mtDNA copy numbers and impaired expression of mtDNA-encoded cytochrome c oxidase (COX) I but not nucleus-encoded COX IV subunits. Histochemistry demonstrated low tubular COX and nicotinamide adenine dinucleotide dehydrogenase (NADH-DH) activities, whereas succinate dehydrogenase activity was preserved. COX activity was preserved in the glomeruli of tenofovir-exposed rats. Didanosine did not elicit renal effects but, unlike tenofovir, depleted mtDNA in liver (by 52%).


CONCLUSIONS
Tenofovir DF induces an organ-specific nephrotoxicity with mtDNA depletion and dysfunction of mtDNA-encoded respiratory chain subunits. The data do not support nephrotoxicity of didanosine.
Lebrecht
Dirk
D
Department of Rheumatology, University Hospital, Freiburg, Germany.
Venhoff
Ana C
AC
Kirschner
Janbernd
J
Wiech
Thorsten
T
Venhoff
Nils
N
Walker
Ulrich A
UA
D000225:Adenine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D004272:DNA, Mitochondrial / Q000187:drug effects*; D016049:Didanosine / Q000633:toxicity; D004579:Electron Transport / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000187:drug effects / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000473:pathology; D009245:NADH Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D063065:Organophosphonates / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*; D000068698:Tenofovir
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV; D000225:Adenine; D016049:Didanosine