Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy.
BACKGROUND
Tenofovir (TDF) exposure has been associated with renal dysfunction. Mitochondrial nephrotoxicity was investigated as an underlying mechanism. Given the interaction between TDF and didanosine (ddl), their concurrent use was also investigated.


METHODS
Relative kidney biopsy mitochondrial DNA (mtDNA) to nuclear DNA ratios were measured retrospectively. HIV+ individuals on TDF within 6 months preceeding the biopsy (HIV+/TDF+, n=21) were compared to HIV+ individuals who never received TDF (HIV+/TDF-, n=10) and to HIV uninfected controls (HIV-,n=22). Twelve of the HIV+/TDF+ individuals received concurrent ddl, 10 of those once at unadjusted ddl dosage. Tubular mitochondria morphology was also examined by electron microscopy. Statistical analyses were done on log-transformed mtDNA/nDNA, using non-parametric tests.


RESULTS
Kidney mtDNA levels were different among the three groups (P=0.046). mtDNA ratios were lower in HIV+/TDF+ subjects (7.5 [2.0-12.1]) than in HIV- ones (14.3 [6.0-16.5], P=0.014), but not lower than HIV+/TDF- controls (6.4 [2.8-11.9], P=0.82). Among HIV+ subjects, there was a difference between TDF-, TDF+/ddl- and TDF+/ddl+ (P=0.005), with concurrent TDF/ddl use associated with lower mtDNA (2.1 [1.9-5.5], n=12) than TDF+/ddl- (13.8 [7.5-16.4], n=9, P=0.003). No TDF-/ddl+ biopsies were available. In regression analyses, only HIV infection (P=0.03), and TDF/ddl use (P=0.003) were associated with lower mtDNA. At the ultrastructural level, abnormal tubular mitochondria was more prevalent in HIV+/TDF+ biopsies than HIV+/TDF- and HIV- ones together (P<0.001) but not more so in TDF+/ddl+ biopsies than TDF+/ddl- ones (P=0.67).


CONCLUSIONS
Renal dysfunction in this population may be mediated through mitochondrial nephrotoxicity that involves more than one drug and/or pathogenesis. Kidney mtDNA depletion was associated with HIV infection and concurrent TDF/ddl therapy but not TDF use alone, while kidney ultrastructural mitochondrial abnormalities were seen with TDF use. The interaction between TDF and ddl may be relevant in the kidney where both drugs are cleared. The clinical relevance of our findings needs to be evaluated given the current recommendation for reduced doses of ddl when used in conjunction with TDF.
Côté
Hélène C F
HC
British Columbia Centre for Excellence in HIV/AIDS, Providence Health Care, Vancouver, BC, Canada. helene.cote@ubc.ca
Magil
Alex B
AB
Harris
Marianne
M
Scarth
Brian J
BJ
Gadawski
Izabelle
I
Wang
Nancy
N
Yu
Eugenia
E
Yip
Benita
B
Zalunardo
Nadia
N
Werb
Ron
R
Hogg
Robert
R
Harrigan
P Richard
PR
Montaner
Julio S
JS
D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D001706:Biopsy; D004272:DNA, Mitochondrial / Q000378:metabolism / Q000648:ultrastructure; D016049:Didanosine / Q000008:administration & dosage / Q000009:adverse effects; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D000068698:Tenofovir; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine; D016049:Didanosine