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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
LETTER TO THE EDITOR  
Year : 2012  |  Volume : 23  |  Issue : 1  |  Page : 148-149
Tenofovir-induced nephrotoxicity: Myths and facts


Department of Nephrology, Unit 318, 1833, Riverside Drive, Ottawa, Ontario, K1G 0E8, Canada

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Date of Web Publication3-Jan-2012
 

How to cite this article:
Gupta A, Bugeja A, Kirpalani D. Tenofovir-induced nephrotoxicity: Myths and facts. Saudi J Kidney Dis Transpl 2012;23:148-9

How to cite this URL:
Gupta A, Bugeja A, Kirpalani D. Tenofovir-induced nephrotoxicity: Myths and facts. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2019 Oct 18];23:148-9. Available from: http://www.sjkdt.org/text.asp?2012/23/1/148/91407
To the Editor,

The burden of retroviral infection is on an increase. With a broader armamentarium of antiretroviral drugs, their usage too has increased. We herein highlight the potential nephrotoxicity of one of the more commonly used drug, tenofovir.

Tenofovir Disoproxil Fumarate (TDF) is the first nucleotide analog approved for human immunodeficiency virus 1 (HIV-1) treatment. It is a prodrug of tenofovir. High-fat meals may increase the area under the plasma concentration-time curve (AUC) up to 40%. The half life of elimination is 14-17 h, and 70-80% of the parent drug is excreted renally. The active uptake of tenofovir into proximal tubular cells occurs via human renal organic anion transporter-1 (hOAT-1) and, to a lesser degree, by hO-AT-3. Tenofovir is then secreted into the tubular lumen via a multi-drug-resistant associated protein-4 (MAP-4). An increase in intracellular drug levels may result in proximal tubular injury by inducing a functionally relevant depletion of mitochondrial DNA (mDNA) and dysfunction of mDNA-encoded respiratory chain subunits. [1]

Although prospective controlled clinical trials have not shown excess nephrotoxicity, [2],[3] in practice, the incidence of serious renal adverse events among more than 10,000 patients receiving TDF in the Viread Expanded Access Program was 1.5 per 1000 patient-years. [4] Progressive renal tubular dysfunction usually associated with declining glomerular filtration rate (GFR) is a well-recognized complication. Significant nephrotoxicity develops in 1-2% of HIV-infected adults receiving TDF.

The classic presentation of tenofovir nephrotoxicity is Fanconi's syndrome, resulting in proteinuria, hypokalemia, hypophosphatemia, phosphaturia, aminoaciduria and glycosuria. Other manifestations include nephrogenic diabetes insipidus, acute kidney injury (AKI) - acute tubular necrosis (ATN), rickets and osteomalacia.

It is often stated that concurrent use of ritonavir-boosted protease inhibitors (PI) are a risk factor for TDF nephrotoxicity. Pharmacokinetic interaction studies performed with TDF and ritonavir co-administered with other PI have refuted this interaction. Tubular secretion by MAP-4 is not inhibited by PI. Even in an analysis of patients treated with TDF, lopinavir/ritonavir use was not associated with decrease in GFR after controlling for other clinical variables. [5]

Animal studies suggest that rosiglitazone treatment might be useful in patients presenting with TDF-induced nephrotoxicity, especially in those with hypophosphatemia or reduced GFR. TDF can cause renal failure associated with many tubular anomalies that may be due to down regulation of a variety of ion transporters. Rosiglitazone is shown to reverse TDF-induced tubular nephrotoxicity, normalized urinary biochemical parameters and membrane transporter protein expression. [6]

GS-9148 is a novel ribose-modified nucleotide HIV reverse transcriptase inhibitor, and its oral prodrug, GS-9131, is currently being evaluated as an anti-HIV agent. Compared with acyclic nucleotide analogs, GS-9148 was found to have lower net active tubular secretion in dogs. Collectively, these results suggest that GS-9148 exhibits a low potential for renal accumulation and nephrotoxicity. [7]

Till the use of novel drugs, to abrogate TDF nephrotoxicity, to become readily available, simple measures should be adopted. All HIV-infected patients should have creatinine clearance estimated at initial work up and before instituting any of the renally excreted drugs like TDF. The Infectious Disease Society of America recommends biannual measurements of serum creatinine, phosphate and urinalysis for protein and glucose in TDF-treated patients with eGFR <90 mL/min/1.73 m², patients receiving concomitant nephrotoxic agents or drugs that undergo renal excretion and patients with diabetes and hypertension. [8] It should be stopped in an event of worsening renal functions. Evaluation by the nephrologist is recommended. In non-responsive cases, hemodialysis may be useful as plasma protein binding of TDF is <8%. It can increase the AUC of didanosine, and the drugs probably should not be used together.

A high index of suspicion may help to prevent TDF nephrotoxicity. Internists and renal care physicians need to be aware of this, sometimes, potentially irreversible complication.

 
   References Top

1.Lebrecht D, Venhoff AC, Kirschner J, Wiech T, Venhoff N, Walker UA. Mitochondrial tubulopathy in tenofovir disoproxil fumarate treated rats. J Acquir Immune Defic Syndr 2009;51: 258-63.  Back to cited text no. 1
    
2.Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in anti-retroviral-naïve patients: a 3-year randomized trial. JAMA 2004;292:191-201.  Back to cited text no. 2
    
3.Gallant JE, Dejesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. Zidovudine, lamuvudine, and efavirenz for HIV. N Engl J Med 2006;354:251-60.  Back to cited text no. 3
    
4.Nelson M, Cooper D, Schooley R, et al. The safety of tenofovir DF for treatment of HIV infection: the first 4 years. In: Program and Abstracts of 13 th Conference on Retro-viruses and Opportunistic Infections. Denver, CO, USA: 5-8 February 2006 (Abstract 781).  Back to cited text no. 4
    
5.Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005;40:1194-8.  Back to cited text no. 5
    
6.Liborio AB, Andrade L, Pereira LV, Sanches TR, Shimizu MH, Seguro AC. Rosiglitazone reverses tenofovir-induced nephrotoxicity. Kidney Int 2008;74:910-8.  Back to cited text no. 6
    
7.Cihlar T, Laflamme G, Fisher R, et al. Novel nucleotide human immunodeficiency virus reverse transcriptase inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation. Antimicrob Agents Chemother 2009;53:150-6.  Back to cited text no. 7
    
8.Gupta S, Eustace AC, Winston JA, et al. Guidelines for the management of chronic kidney disease in HIV-infected patients: Recommendations of the HIV Medicine Association of the Infectious Disease Society of America. Cin Infect Dis 2005;40:1559-85.  Back to cited text no. 8
    

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Correspondence Address:
Ankur Gupta
Department of Nephrology, Unit 318, 1833, Riverside Drive, Ottawa, Ontario, K1G 0E8
Canada
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PMID: 22237241

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