The role of drug transporters in the kidney: lessons from tenofovir

Abstract

Tenofovir disoproxil fumarate, the prodrug of nucleotide reverse transcriptase inhibitor tenofovir, shows high efficacy and relatively low toxicity in HIV patients. However, long-term kidney toxicity is now acknowledged as a modest but significant risk for tenofovir-containing regimens, and continuous use of tenofovir in HIV therapy is currently under question by practitioners and researchers. Co-morbidities (hepatitis C, diabetes), low body weight, older age, concomitant administration of potentially nephrotoxic drugs, low CD4 count, and duration of therapy are all risk factors associated with tenofovir-associated tubular dysfunction. Tenofovir is predominantly eliminated via the proximal tubules of the kidney, therefore drug transporters expressed in renal proximal tubule cells are believed to influence tenofovir plasma concentration and toxicity in the kidney. We review here the current evidence that the actions, pharmacogenetics, and drug interactions of drug transporters are relevant factors for tenofovir-associated tubular dysfunction. The use of creatinine and novel biomarkers for kidney damage, and the role that drug transporters play in biomarker disposition, are discussed. The lessons learnt from investigating the role of transporters in tenofovir kidney elimination and toxicity can be utilized for future drug development and clinical management programs.

Determinants of bone diseases in tenofovir-treated HIV patients

“…The latter finding seems to argue against a potential contribution of TDF overexposure on the development of bone diseases, at variance with findings in HIV-infected patients experiencing TDF-related kidney complications [2,3]. This may be eventually related to the fact that, at variance with kidney diseasesin which a direct mechanism linked to the selective accumulation of TDF within renal -4 -tubular cells has been identified [6][7][8] -TDF is only one of the risk factors for bone loss, and its effect may be eventually diluted by the presence of other clinical covariates (such as, patients' sex, age, diet, body mass index, etc) known to play a key pathogenetic role in bone diseases [4,5]. This hypothesis has been indirectly confirmed by the findings that patients with altered OCT levels have significantly higher TDF plasma trough concentrations compared with patients with physiologic OC levels, whereas no association was found with CTX levels.…”

Abundance of Drug Transporters in the Human Kidney Cortex as Quantified by Quantitative Targeted Proteomics

“…Proximal tubule drug transporters have also been associated with the renal toxicity of drugs (Takeda et al, 1999;Enomoto et al, 2002;Ludwig et al, 2004;Iwata et al, 2012;Moss et al, 2014;Mandíková et al, 2016). For example, cisplatin produces renal toxicity due to its accumulation in the tubular epithelial cells mediated by OCT2.…”

Organic Cation Transporter 2 Overexpression May Confer an Increased Risk of Gentamicin-Induced Nephrotoxicity

“…The processes involved in renal excretion include glomerular filtration, tubular reabsorption, and tubular secretion and are governed by several protein-mediated transport systems (8). The disruption of tubular reabsorption or secretion due to altered expression and/or activity of these carriers can alter the disposition of many drugs (9,10). Obesity is associated with several pathophysiological changes (11,12).…”