Tenofovir-Associated Kidney Toxicity in HIV-Infected Patients: A Review of the Evidence  Andrew M. Hall, MD, PhD, Bruce M. Hendry, MD, PhD, Dorothea Nitsch, MD, MSc, John O. Connolly, MD, PhD  American Journal of Kidney Diseases  Volume 57, Issue 5, Pages 773-780 (May 2011) DOI: 10.1053/j.ajkd.2011.01.022 Copyright © 2011 National Kidney Foundation, Inc. Terms and Conditions

Figure 1 Electron micrographs of proximal tubule cells in a kidney biopsy specimen from a patient with Fanconi syndrome secondary to tenofovir toxicity. (A) Mitochondrial size and morphologic characteristics are highly irregular, with (B) disruption of the normal cristae (arrows) and (C) occasional giant mitochondria. (Scale bars = 500 nm.) American Journal of Kidney Diseases 2011 57, 773-780DOI: (10.1053/j.ajkd.2011.01.022) Copyright © 2011 National Kidney Foundation, Inc. Terms and Conditions

Figure 2 Tenofovir (TDF) transport in the renal proximal tubule. TDF enters proximal tubular cells across the basolateral membrane through organic anion transporters (OAT), where it competes for binding with didanosine, and exits the tubule across the apical membrane through the multidrug resistance transporter MRP4. Ritonavir is a substrate for MRP2 and may interact with TDF excretion through mechanisms that presently are unclear. The proximal tubule contains a high density of mitochondria, which lie in a basolateral striated distribution, and evidence suggests that these organelles are the target of TDF toxicity. A variety of solutes (X) are reabsorbed across the apical membrane through sodium (Na+)-mediated cotransport, which is driven by the Na+ gradients generated by the activity of the basolateral adenosine triphosphatase sodium-potassium pump (Na+-K+-ATPase). The proximal tubule also is responsible for the uptake of low-molecular-weight proteins (such as retinol-binding protein [RBP]) from the renal filtrate through receptor-mediated endocytosis. Mitochondrial toxicity in the proximal tubule leads to impaired reabsorption of low-molecular-weight proteins and other solutes, with urinary wasting and the clinical features of renal Fanconi syndrome. American Journal of Kidney Diseases 2011 57, 773-780DOI: (10.1053/j.ajkd.2011.01.022) Copyright © 2011 National Kidney Foundation, Inc. Terms and Conditions

Figure 3 Suggested algorithm for monitoring patients using tenofovir for kidney toxicity. Based on guidelines from the HIV Medicine Association of the Infectious Diseases Society of America, with modifications (see text). The 90-mL/min threshold for estimated glomerular filtration rate (eGFR) in determining risk is based on the existing guidelines of this organization (Gupta et al62); an update is expected in 2012. It should be noted that interpretation of eGFR may be complicated in human immunodeficiency virus (HIV)-infected patients; current creatinine-based estimating equations are imprecise and systematically underestimate measured GFR at higher ranges in non–HIV-infected patients. In HIV-infected patients, muscle wasting may lead to overestimation of measured GFR. Confirmatory tests should be considered. Abbreviation: RBP, retinol-binding protein. American Journal of Kidney Diseases 2011 57, 773-780DOI: (10.1053/j.ajkd.2011.01.022) Copyright © 2011 National Kidney Foundation, Inc. Terms and Conditions