Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction.

BACKGROUND: Tenofovir (TFV) causes kidney tubular dysfunction (KTD) in some patients, but the mechanism is poorly understood. Genetic variants in TFV transporters are implicated; we explored whether ABCC10 transports TFV and whether ABCC10 single-nucleotide polymorphisms (SNPs) are associated with KTD. METHODS: TFV accumulation was assessed in parental and ABCC10-transfected HEK293 cells (HEK293-ABCC10), CD4(+) cells and monocyte-derived macrophages (MDMs). Substrate specificity was confirmed by cepharanthine (ABCC10 inhibitor) and small interfering RNA (siRNA) studies. Fourteen SNPs in ABCC10 were genotyped in human immunodeficiency virus-positive patients with KTD (n = 19) or without KTD (controls; n = 96). SNP and haplotype analysis was performed using Haploview. RESULTS: TFV accumulation was significantly lower in HEK293-ABCC10 cell lines than in parental HEK293 cells (35% lower; P = .02); this was reversed by cepharanthine. siRNA knockdown of ABCC10 resulted in increased accumulation of TFV in CD4(+) cells (18%; P = .04) and MDMs (25%; P = .04). Two ABCC10 SNPs (rs9349256: odds ratio [OR], 2.3; P = .02; rs2125739, OR, 2.0; P = .05) and their haplotype (OR, 2.1; P = .05) were significantly associated with KTD. rs9349256 was associated with urine phosphorus wasting (P = .02) and ß2 microglobulinuria (P = .04). CONCLUSIONS: TFV is a substrate for ABCC10, and genetic variability within the ABCC10 gene may influence TFV renal tubular transport and contribute to the development of KTD. These results need to be replicated in other cohorts.

Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a pharmacogenetic study.

BACKGROUND: Tenofovir is one of the most widely used antiretroviral drugs. Tenofovir undergoes renal clearance by a combination of glomerular filtration and active tubular secretion. Although rare, the mechanism by which tenofovir causes renal damage is not well characterized. We have explored the association between kidney tubular dysfunction (KTD) and polymorphisms in genes encoding drug transporters. METHODS: All consecutive, human immunodeficiency virus (HIV)-infected patients receiving tenofovir-containing antiretroviral regimens who were seen at a single institution during the first trimester of 2008 were enrolled in the study. KTD was defined by the presence of at least 2 of the following abnormalities: nondiabetic glucosuria, urine phosphate wasting, hyperaminoaciduria, beta2-microglobulinuria, and increased fractional excretion of uric acid. Twelve single-nucleotide polymorphisms in the ABCC2, ABCC4, SCL22A6, SLC22A11, and ABCB1 genes were analyzed using TaqMan 5'-nuclease assays. RESULTS: A total of 115 HIV-infected patients were examined, of whom 19 (16.5%) had KTD. The percentage of patients with KTD was higher among those with genotype CC at position -24 of ABCC2 than among those with genotypes CT and TT (24% [16 of 68 patients] vs. 6% [3 of 47 patients]; P = .020). In a multivariate analysis, older age (odds ratio [OR], 1.1; 95% confidence interval [CI], 1.0-1.2; P = .024), lower body weight (OR, 0.9; 95% CI, 0.8-0.9; P = .048), and genotype CC at ABCC2 position -24 (OR, 5; 95% CI, 1.2-21; P = .027) were independently associated with KTD. CONCLUSIONS: Approximately 17% of HIV-infected patients treated with tenofovir had KTD. Homozygosity for the C allele at position -24 of the ABCC2 gene was strongly associated with KTD in this population. This polymorphism may help to identify patients at greater risk for developing tenofovir-associated tubulopathy, and close monitoring of renal function is warranted for these patients.

Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir.

BACKGROUND: Tenofovir (TDF) is the most widely prescribed antiretroviral drug. Kidney abnormalities are the main concern using the drug. As glomerular function is infrequently affected in patients treated with TDF, herein, we report the results of an extensive examination of tubular function. METHODS: Cross-sectional study of plasma and 24 h urine markers of kidney tubulopathy (glucosuria, hyperaminoaciduria, hyperphosphaturia, hyperuricosuria and beta2-microglobulinuria) could be allocated in three groups: patients under a TDF-containing HAART; patients on HAART never exposed to TDF; and antiretroviral-naive individuals. Significant tubular damage was defined when at least two of these parameters were repeatedly present, being at least one part of the Fanconi syndrome criteria (glucosuria, hyperaminoaciduria and hyperphosphaturia). Glomerular function was assessed using creatinine clearance. RESULTS: A total of 284 consecutive HIV patients were examined, 154 on TDF, 49 on other HAART regimens and 81 drug-naive. No significant differences in creatinine clearance were observed when comparing distinct groups. The proportion of patients with tubular damage in groups 1, 2 and 3 were 22, 6 and 12%, respectively. In a multivariate analysis [odds ratio (OR) {95% confidence interval (CI)} P], the only independent predictors of tubular dysfunction were TDF use (21.6, 4.1-113, <0.001) and older age (1.1 per year, 1.0-1.1, 0.01). CONCLUSION: Exposure to TDF is associated with an increased risk over time of kidney tubular abnormalities in the absence of significant impaired glomerular function. Although long-term consequences of this tubulopathy are unknown, close monitoring of accelerated bone mineral loss and renal insufficiency are warranted. Periodic screening of tubular function parameters should be recommended to patients receiving TDF.