Background:  Tenofovir (TDF) is one of the most widely used ARV drugs. TDF undergoes renal clearance by a combination of glomerular filtration and active tubular secretion. The mechanism by which TDF may cause renal damage is not well understood and current studies are focusing on alterations in tubular transporter proteins. We have explored the association between altered kidney tubular function and polymorphisms within genes that code for putative drug transporters.

Methods:  All HIV patients on TDF-containing HAART regimens during the first trimester of year 2008 at our institution were identified. Altered kidney tubular function was defined when at least 2 of the following abnormalities were present:  non-diabetic glucosuria, urine phosphate wasting, hyperaminoaciduria, b₂-microglobulinuria, or increased fractional excretion of uric acid. We analyzed 12 single nucleotide polymorphisms at 5 genes:  ABCC2— -24, 1249, 3563, 3972, 4555; ABCC4—3463, 559, 669, 4131; SCL22A6 (OAT1)—453; SLC22A11 (OAT4)—rs11231809; ABCB1—3435, 1236, 2677. DNA was extracted from peripheral blood mononuclear cells and genotypic analysis was carried out by allelic discrimination using TaqMan 5´-nuclease assays.

Results:  A total of 115 HIV patients (19 with altered kidney tubular function, 96 with normal kidney tubular function), with a median exposure to TDF of 35 months (IQR 11 to 47) were examined. The proportion of patients with abnormal kidney tubular function was higher in ABCC2-24G homozygotes compared to genotypes GT and TT (24% vs 6%; p = 0.015). There were no differences in kidney tubular function frequency for other allelic variants. In the multivariate analysis (OR, 95%CI, p) including gender, age, weight, hepatitis C virus co-infection, months on TDF, HIV RNA, protease inhibitor use, nephrotoxic drugs use, diabetes, hypertension, creatinine clearance, and GG genotype ABCC2-24, the following parameters were independently associated with altered kidney tubular function:  older age (1.1, 1.0 to 1.2, 0.017), weight (0.9, 0.8 to 0.9, 0.016), and genotype GG at ABCC2-24 (5.7, 1.4 to 23.1, 0.016).

Conclusions:  A substantial proportion of HIV patients (16.5%) show kidney tubular function abnormalities. Older age, weight, and genotype GG at ABCC2-24 are independently associated with abnormal tubular function. Genetic analysis of ABCC2-24 could help to identify patients at greater risk (5 times) for renal tubulopathy. Since TDF has been shown not to serve as a substrate for ABCC2, the precise mechanism of this association requires elucidation. Close monitoring of renal function is warranted in this subset of patients.