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. 1. Tenofovir Tenofovir disoproxil fumarate is an orally bioavailable prodrug of tenofovir, an acyclic nucleotide analogue reverse-transcriptase inhibitor (NtRTI) structurally similar to adefovir and cidofovir  (Figure 1). Acyclic nucleotides differ in their side chains: hydroxy phosphonomethoxypropyl (HPMP) for cidofovir, phosphonomethoxyethyl (PME) for adefovir and phosphonomethoxypropyl (PMP) for tenofovir . Tenofovir diphosphate is a structural analog of deoxyadenosine-5′-triphosphate, the usual substrate for viral RNA-directed DNA polymerase, and is a weak inhibitor of mammalian DNA α- and β-polymerases and mitochondrial DNA γ-polymerase . 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). Tenofovir was the first (2001), and remains the only, NtRTI approved by the US Food and Drug Administration (FDA) for the treatment of HIV infection . Tenofovir was also approved for treatment of chronic hepatitis B in adults in 2008 . Tenofovir is now a widely used component of antiretroviral regimens for both treatment-naive and experienced patients on the basis of its
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