Abstract and Commentary
By Dean L. Winslow, MD, FACP, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center, Clinical Professor of Medicine, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Synopsis: Tenofovir disoproxil fumarate (TDF)-associated acute renal failure (ARF) was diagnosed in 5 HIV-infected patients and an additional 22 patients previously described in the literature are reviewed. ARF resolved in 22 of 27 patients after discontinuation of TDF.
Source: Zimmermann AE, et al. Tenofovir-Associated Acute and Chronic Kidney Disease: A Case of Multiple Drug Interactions. Clin Infect Dis. 2006;42:283-290.
This paper reports on 5 HIV-infected patients receiving TDF-containing antiretroviral (ARV) therapy who developed ARF. One patient had associated Fanconi syndrome/renal tubular acidosis (RTA). One patient who did not have RTA underwent renal biopsy, which revealed acute tubular injury with loss and irregularity of tubular epithelial cells. A literature review performed by Zimmerman and colleagues resulted in 22 additional cases of TDF-associated ARF. Looking at the combined cohort, the majority of patients recovered normal renal function following discontinuation of TDF, however GFR in 5 patients did not return to baseline values after a mean duration of follow-up of 7.5 months. Sixteen patients had RTA. Renal biopsies performed in 8 patients all revealed ATN with nuclear swelling and karyomegaly of proximal tubular nuclei. Development of nephrotoxicity did not appear to correlate with either CD4 count or HIV RNA level. However, nephrotoxicity was associated with concomitant treatment with RTV, LPV/r, ATV, or ddI.
The disastrous experience with nephrotoxicity associated with another Gilead Sciences nucleotide analog reverse transcriptase inhibitor, adefovir dipivoxil (ADV) dosed at either 120 mg or 60 mg daily, clearly sensitized clinicians to the potential for nephrotoxicity associated with this class of antiretroviral agents. Fortunately, despite widespread use of the related drug tenofovir disoproxil fumarate (TDF), nephrotoxicity associated with TDF has fortunately been quite rare in both registrational trials and in clinical practice. In fact, in most of Gilead’s Phase III registrational trials, the incidence of nephrotoxicity in the TDF arms has not significantly exceeded that seen in the control arms of these studies.
Despite the safety, potency, good tolerability, and convenience of TDF (also available in fixed combination with emtricitabine), most clinicians have now had patients in their practices develop TDF-associated renal failure. In contrast to the experience with ADV, where development of decreased GFR was usually preceded by development of RTA manifested by phosphaturia/hypophosphatemia, hyperchloremic metabolic acidosis, glycosuria, and low-level proteinuria, many cases of TDF-associated nephrotoxicity seem to present more acutely with an ATN-like picture.
This review makes a good case for the role of RTV (with or without LPV) as a contributing factor to the development of nephrotoxicity. Preclinical studies with both ADV and TDF consistently show a relative lack of mitochondrial toxicity with these agents as compared to the dideoxynucleoside analogue reverse transcriptase inhibitors (ddI and d4T). However, it is known that TDF is eliminated by active tubular secretion, as well as glomerular filtration. Nucleotides are actively taken up into the proximal renal tubular epithelial cells via hOAT1 located on the basolateral membrane of the proximal tubule.1 Once accumulated, nucleotides are secreted into the urine via multidrug-resistance protein 2 (MRP2), located on the apical side of the proximal tubule. Ritonavir is known to be a potent inhibitor of both MRP2 (as well as another efflux pump for organic cations, P glycoprotein), which provides a most plausible explanation for this toxicity in vivo.2 My suspicion that the apparent weaker relationship with nephrotoxicity to atazanavir may be coincidental or possibly related to ritonavir boosting of ATV in some cases (the data on this are not clear in this paper) since ATV does not display significant inhibition of MRP2, although it is an inhibitor of P-glycoprotein, as well as CYP 3A.3
Tenofovir remains an important part of modern day antiretroviral therapy, but clinicians need to be vigilant for nephrotoxicity in TDF-treated patients, especially those who are receiving ritonavir-boosted protease inhibitor-containing regimens.
- Cihlar T, et al. Human Renal Organic Anion Transporter 1 (hOAT1) and Its Role in the Nephrotoxicity of Antiviral Nucleotide Analogs. Nucleosides Nucleotides Nucleic Acids. 2001;20:641-648.
- Schooley RT, et al. Tenofovir DF in Antiretroviral-Experienced Patients: Results from a 48-Week, Randomized, Double-Blind Study. AIDS. 2002;16:1257-1263.
- Perloff ES, et al. Atazanavir: Effects on P-Glycoprotein Transport and CYP3A Metabolism In Vitro. Drug Metab Dispos. 2005;33:764-770.