Tenofovir nephrotoxicity: 2011 update

Abstract

Tenofovir is an acyclic nucleotide analogue reverse-transcriptase inhibitor structurally similar to the nephrotoxic drugs adefovir and cidofovir. Tenofovir is widely used to treat HIV infection and approved for treatment of hepatitis B virus. Despite initial cell culture and clinical trials results supporting the renal safety of tenofovir, its clinical use is associated with a low, albeit significant, risk of kidney injury. Proximal tubular cell secretion of tenofovir explains the accumulation of the drug in these mitochondria-rich cells. Tenofovir nephrotoxicity is characterized by proximal tubular cell dysfunction that may be associated with acute kidney injury or chronic kidney disease. Withdrawal of the drug leads to improvement of analytical parameters that may be partial. Understanding the risk factors for nephrotoxicity and regular monitoring of proximal tubular dysfunction and serum creatinine in high-risk patients is required to minimize nephrotoxicity. Newer, structurally similar molecular derivatives that do not accumulate in proximal tubules are under study.

Figure 1

Chemical structure of the three main nephrotoxic acyclic nucleotide analogs, adefovir, cidofovir and tenofovir, as well as less nephrotoxic tenofovir derivatives under development. A lesser uptake by proximal tubular cells can be achieved by either esterifying the compounds with an alkoxyalkyl group, in effect disguising them as lysophospholipids (hexadeciloxypropyl-tenofovir, CMX157) or by ribose-modification (GS-9148 and its oral prodrug GS-9131).

Figure 2

Tenofovir handling by proximal tubular cells and potential molecular mechanisms and clinical consequences of tenofovir nephrotoxicity. (a) Tenofovir secretion by proximal tubular cells: 20 to 30% of tenofovir is excreted unchanged in the urine through active secretion by proximal tubular cells. OAT1 is the main transporter taking tenofovir into the proximal tubular cell, although OAT3 also collaborates. Once inside this mitochondria-rich cell type, tenofovir must be extruded into the tubular lumen by MRP-2 and MRP-4. Blocking tenofovir uptake by OAT1 may protect tubular cells by keeping intracellular tenofovir level low. Thus, probenecid is routinely used to prevent cidofovir nephrotoxicity since cidofovir is also transported into tubular cells by OAT1. There is less experience preventing tenofovir nephrotoxicity. A decreased GFR will increase plasma tenofovir levels and proximal tubular cell uptake through OAT1. Blocking tenofovir extrusion by MRP-2 and MRP-4 by pharmacological interference may also boost tenofovir nephrotoxicity. OAT: organic acid transporter; MRP: multidrug resistance protein. (b) Potential molecular mechanisms of tenofovir toxicity towards proximal tubular cells. Proximal tubular cells are uniquely susceptible to tenofovir toxicity because they gave a complement of transporters that increase intracellular concentrations of the drug, and they are rich in mitochondria. Tenofovir and other acyclic nucleotides decrease mtDNA content by inhibiting mitochondrial DNA polymerase γ (POLG). This has been related to structural mitochondrial abnormalities, some of them visible even by optical microscopy in cases of tenofovir nephrotoxicity, that include mitochondrial depletion, and wide changes in mitochondria size and shape, with clumping, loss, and disorientation of cristae. In addition, mitochondrial injury may lead to apoptosis. Although tenofovir has not been studied, cidofovir is known to induce proximal tubular cell apoptosis by leading to caspase activation [11]. The mitochondrial pathway of apoptosis includes the release of mitochondrial proteins to the cytosol including cytochrome c (CytC), which is required for caspase 9 activation in the apoptosome Smac/Diablo, inhibitor of apoptosis proteins (IAPs), and apoptosis-inducing factor (AIF) that, among other actions, causes DNA injury. These are potential mediators of tenofovir-induced tubular cell injury that deserve further study. (c) Analytical and clinical consequences of tenofovir proximal tubular cell toxicity. Injured proximal tubular cells fail to perform their functions. These include reabsorbing low-molecular-weight proteins (such as vitamin D-binding protein (DBP) and β2-microglobulin) through the megalin-cubilin system (MCS), glucose through the sodium/glucose cotransporter 2 (SGLT2), aminoacids, phosphate and uric acid, secreting H+ and synthesizing calcitriol by the action of mitochondrial 1α-hydroxylase on 25(OH) vitamin D reabsorbed from the tubular lumenAs more immediate consequences we may observe a variable mixture of low-molecular weight proteinuria, glycosuria, aminoaciduria, hypophosphatemia, hypouricemia, renal tubular acidosis, and vitamin D insufficiency and even osteomalacia as a consequence both of insufficient calcitriol synthesis and urinary losses of 25(OH) vitamin D. Persistent tubular injury may promote tubular cell loss and eventual decreased glomerular filtration and renal failure.