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Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on

Hélène C F Côté1, Alex B Magil, Marianne Harris

  • 1British Columbia Centre for Excellence in HIV/AIDS, Providence Health Care, Vancouver, BC, Canada. helene.cote@ubc.ca

Antiviral Therapy
|March 8, 2006
PubMed
Abstract

Insights

Concurrent use of tenofovir (TDF) and didanosine (ddl) in HIV patients is linked to kidney mitochondrial DNA depletion. TDF use alone showed mitochondrial abnormalities, suggesting complex drug interactions contribute to renal dysfunction.

Area of Science:

  • Nephrology
  • Virology
  • Pharmacology

Background:

  • Tenofovir (TDF) use is associated with renal dysfunction.
  • Mitochondrial nephrotoxicity is a potential mechanism underlying TDF-induced kidney injury.
  • The interaction between TDF and didanosine (ddl) warrants investigation regarding concurrent use and renal effects.

Purpose of the Study:

  • To investigate mitochondrial nephrotoxicity as a mechanism for renal dysfunction in HIV+ individuals exposed to TDF.
  • To compare kidney mitochondrial DNA (mtDNA) to nuclear DNA (nDNA) ratios in HIV+ individuals on TDF, HIV+ individuals not on TDF, and HIV- uninfected controls.
  • To examine the impact of concurrent TDF and ddl use on kidney mtDNA levels and mitochondrial morphology.

Main Methods:

  • Retrospective analysis of kidney biopsy samples.
  • Measurement of relative mtDNA to nDNA ratios.
  • Comparison of three groups: HIV+/TDF+ (n=21), HIV+/TDF- (n=10), and HIV- (n=22).
  • Examination of tubular mitochondria morphology via electron microscopy.
  • Statistical analysis using non-parametric tests on log-transformed mtDNA/nDNA ratios.

Main Results:

  • Kidney mtDNA levels differed significantly among the groups (P=0.046).
  • HIV+/TDF+ subjects had lower mtDNA ratios compared to HIV- controls (P=0.014), but not HIV+/TDF- controls (P=0.82).
  • Concurrent TDF/ddl use was associated with significantly lower mtDNA levels (P=0.003) compared to TDF use without ddl.
  • Abnormal tubular mitochondria were more prevalent in HIV+/TDF+ biopsies (P<0.001).
  • Regression analysis identified HIV infection and concurrent TDF/ddl use as associated with lower mtDNA.

Conclusions:

  • Renal dysfunction in this population may involve mitochondrial nephrotoxicity, potentially involving multiple drugs.
  • Kidney mtDNA depletion is linked to HIV infection and concurrent TDF/ddl therapy, not TDF alone.
  • Ultrastructural mitochondrial abnormalities in the kidney are associated with TDF use.
  • The interaction between TDF and ddl is clinically relevant for kidney function, especially given current dosing recommendations.

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