Mitochondrial Tubulopathy in Tenofovir Disoproxil Fumarate-Treated Rats

Objectives: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·kg−1·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.

[1]  V. Soriano,et al.  Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir , 2009, AIDS.

[2]  J. Gallant,et al.  The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients , 2008, AIDS.

[3]  Samir K. Gupta.  Tenofovir-associated Fanconi syndrome: review of the FDA adverse event reporting system. , 2008, AIDS patient care and STDs.

[4]  P. Harrigan,et al.  Tenofovir-based rescue therapy for advanced liver disease in 6 patients coinfected with HIV and hepatitis B virus and receiving lamivudine. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[5]  Nihal Ahmad,et al.  Dose translation from animal to human studies revisited , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  U. Walker,et al.  Mitochondrial Toxicity of Tenofovir, Emtricitabine and Abacavir Alone and in Combination with Additional Nucleoside Reverse Transcriptase Inhibitors , 2007, Antiviral therapy.

[7]  I. Hidalgo,et al.  Effects of Human Immunodeficiency Virus Protease Inhibitors on the Intestinal Absorption of Tenofovir Disoproxil Fumarate In Vitro , 2007, Antimicrobial Agents and Chemotherapy.

[8]  A. Geist,et al.  Dexrazoxane prevents doxorubicin‐induced long‐term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats , 2007, British journal of pharmacology.

[9]  T. Cihlar,et al.  Molecular Assessment of the Potential for Renal Drug Interactions between Tenofovir and HIV Protease Inhibitors , 2007, Antiviral therapy.

[10]  R. Ebrahimi,et al.  Pharmacokinetics and Safety of Tenofovir Disoproxil Fumarate on Coadministration With Lopinavir/Ritonavir , 2006, Journal of acquired immune deficiency syndromes.

[11]  Francesc Villarroya,et al.  In Vitro Cytotoxicity and Mitochondrial Toxicity of Tenofovir Alone and in Combination with Other Antiretrovirals in Human Renal Proximal Tubule Cells , 2006, Antimicrobial Agents and Chemotherapy.

[12]  V. Kan,et al.  Hypokalemia in HIV patients on tenofovir , 2006, AIDS.

[13]  D. Sanz,et al.  Utilidad de la gammagrafía ósea en el diagnóstico de osteomalacia secundaria en un paciente en tratamiento con tenofovir , 2006 .

[14]  Joel E Gallant,et al.  Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. , 2006, The New England journal of medicine.

[15]  P. Harrigan,et al.  Exploring Mitochondrial Nephrotoxicity as a Potential Mechanism of Kidney Dysfunction among HIV-Infected Patients on Highly Active Antiretroviral Therapy , 2006, Antiviral therapy.

[16]  Michael S Saag,et al.  Treatment for Adult HIV Infection 2006 Recommendations of the International AIDS Society–USA Panel , 2006 .

[17]  J. González-lahoz,et al.  [Role of bone gammagraphy in the diagnosis of secondary osteomalacia in a patient treated with tenofovir]. , 2006, Revista espanola de medicina nuclear.

[18]  E. Kinai,et al.  Renal tubular toxicity associated with tenofovir assessed using urine-beta 2 microglobulin, percentage of tubular reabsorption of phosphate and alkaline phosphatase levels , 2005, AIDS.

[19]  E. De Clercq,et al.  Multidrug resistance-associated protein 2 (MRP2) affects hepatobiliary elimination but not the intestinal disposition of tenofovir disoproxil fumarate and its metabolites , 2005, Xenobiotica; the fate of foreign compounds in biological systems.

[20]  N. Snowden,et al.  The development of hypophosphataemic osteomalacia with myopathy in two patients with HIV infection receiving tenofovir therapy , 2005, HIV medicine.

[21]  V. Soriano,et al.  Hepatic and Renal Safety Profile of Tenofovir in HIV-Infected Patients with Hepatitis C, Including Patients on Interferon Plus Ribavirin , 2005, HIV clinical trials.

[22]  H. Mohrenweiser,et al.  Functional Consequences of Single Nucleotide Polymorphisms in the Human Organic Anion Transporter hOAT1 (SLC22A6) , 2005, Journal of Pharmacology and Experimental Therapeutics.

[23]  H. Izzedine,et al.  Renal tubular transporters and antiviral drugs: an update , 2005, AIDS.

[24]  Joel E Gallant,et al.  Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. , 2004, JAMA.

[25]  J. Hulot,et al.  Renal safety of tenofovir in HIV treatment-experienced patients , 2004, AIDS.

[26]  U. Walker,et al.  Mitochondrial DNA and its respiratory chain products are defective in doxorubicin nephrosis. , 2004, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[27]  M. Wientjes,et al.  Pharmacokinetics of Oral 2′,3′-Dideoxyinosine in Rats , 1992, Pharmaceutical Research.

[28]  Jörg Haberstroh,et al.  Time-Dependent and Tissue-Specific Accumulation of mtDNA and Respiratory Chain Defects in Chronic Doxorubicin Cardiomyopathy , 2003, Circulation.

[29]  G. Biesecker,et al.  Evaluation of mitochondrial DNA content and enzyme levels in tenofovir DF-treated rats, rhesus monkeys and woodchucks. , 2003, Antiviral research.

[30]  D. Droz,et al.  Tenofovir-related nephrotoxicity in human immunodeficiency virus-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[31]  A. Rötig.  Renal disease and mitochondrial genetics. , 2003, Journal of nephrology.

[32]  U. Walker,et al.  Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors , 2002, AIDS.

[33]  T. Cihlar,et al.  Assessment of Mitochondrial Toxicity in Human Cells Treated with Tenofovir: Comparison with Other Nucleoside Reverse Transcriptase Inhibitors , 2002, Antimicrobial Agents and Chemotherapy.

[34]  V. D’Agati,et al.  Adefovir nephrotoxicity: possible role of mitochondrial DNA depletion. , 2001, Human pathology.

[35]  T. Cihlar,et al.  NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 641–648 (2001) HUMAN RENAL ORGANIC ANION TRANSPORTER 1 (hOAT1) AND ITS ROLE IN THE NEPHROTOXICITY OF ANTIVIRAL NUCLEOTIDE ANALOGS , 2003 .

[36]  P. Reiss,et al.  Comparison of the plasma pharmacokinetics and renal clearance of didanosine during once and twice daily dosing in HIV‐1 infected individuals , 1998, AIDS.