Pathophysiological and Genetic Basis of Tenofovir-Induced Acute Renal Dysfunction: Strategies and Recent Developments for Better Clinical Outcomes

Several clinical studies have suggested that higher doses of tenofovir disoproxil fumarate (TDF), at dose of 300 mg or higher, are associated with an increased risk of acute renal failure (ARF) by decreasing outflow through the human organic anion transporter (hOAT). TDF can potentially be associated with more renal and bone toxicities with increased low-density lipoprotein (LDL) and total cholesterol levels in HIV patients. In this review, we have critically appraised the pathophysiology, molecular mechanisms, and the genetic variability associated with TDF-induced ARF (TDF-I-ARF). This article also highlights the strategies and recent developments to overcome the TDF-induced ARF. TDF-I-ARF has a complex pathophysiological map, which has been associated with cellular accumulation and efflux, mitochondrial dysfunctions, oxidative and endoplasmic reticulum (ER) stress, and inflammation. Despite many pharmaceutical interventions, and clinical trials, a concordant pharmacological treatment option to reduce ARF in HIV patients receiving TDF remains far from known. This has been predominantly linked to the incomplete understanding of TDF-I-ARF molecular mechanisms and pathophysiology involved. The altered activity of human renal organic anion transporter 1 (hOAT1)-expressing proximal tubule epithelial cells cause renal toxicity which actively uptake this drug.