Tenofovir effect on the kidneys of HIV-infected patients: a double-edged sword?

Abstract

Tenofovir disoproxil fumarate (TDF), the first nucleotidic inhibitor of HIV reverse transcription, became available in 2001. It has been extensively used worldwide and is now the most prescribed antiretroviral (ARV) drug. Its high antiviral activity and favorable metabolic profile are responsible for its success. Furthermore, TDF has been associated with other ARVs to form new combined antiretroviral treatments in only one tablet once-a-day, which increases treatment adherence. Fears of potential nephrotoxicity that tenofovir would have in common with two other drugs from the same family (adefovir, used to treat hepatitis B, and cidofovir, used to treat cytomegalovirus infections) were alleviated by the early clinical trials. Yet, in 2001, the first case of TDF-induced acute nephrotoxicity was published. Numerous cases have been published since then, and it is now established that TDF presents a tubular toxicity risk. Some facilitating factors have been identified, such as co-prescription of didanosine or boosted protease inhibitor, preexisting CKD, low body weight, and associated diabetes mellitus. Conversely, whether TDF is nephrotoxic in the long term is a highly debated question. Some studies suggest a decreased GFR when TDF is prescribed for a long period, while others indicate that TDF is safe for the kidneys even after many years of use. Here we review the differences in patient characteristics, study designs, and measured outcomes that can possibly explain these conflicting findings. We conclude with rational recommendation for appropriate TDF prescription.

Figure 1.

TDF-induced epithelial cell dysfunction is due to mitochondrial damage. Enlarged mitochondria (*) are visible adjacent to normal-size mitochondria (+). Large mitochondria appear devoid of cristae, while other mitochondria show normal cristae content. When cristae are visible in dysmorphic mitochondria, they are usually grouped at a pole. (Original magnification ×8000.) Photograph kindly provided by Leal C. Herlitz, MD, Department of Pathology, Columbia University Medical Center in New York, New York.

Figure 2.

Cytoplasmic accumulation of TDF is responsible for mDNA depletion and oxidative respiratory chain dysfunction resulting in epithelial cell apoptosis. TDF enters tubular epithelial cells through hOAT1 and hOAT3 receptor at the basolateral pole. It is excreted in tubular lumen through receptors MRP2 and MRP4. TDF intracellular concentrations can be modified by drugs that specifically inhibit these receptors. Once inside a mitochondrion, TDF inhibits DNA polymerase γ, which results in a progressive depletion of mitochondrial DNA, a decreased synthesis of respiratory chain proteins and morphologic abnormalities of mitochondria (enlargement, loss of cristae). Some respiratory chain protein are released in the cytoplasm which can be detected by the caspase pathway and induce apoptosis of the cell. Polγ, DNA polymerase γ; CytC, cytochrome C; NSAID, nonsteroid anti-inflammatory drug.