Association between ABCC2 Gene Haplotypes and Tenofovir‐Induced Proximal Tubulopathy

Department of Nephrology, La Pitie-Salpetriere Hospital, Assistance Publique-Hopitaux de Paris, Universite Pierre et Marie Curie-Paris IV, 75013 Paris, France.
The Journal of Infectious Diseases (Impact Factor: 6). 12/2006; 194(11):1481-91. DOI: 10.1086/508546
Source: PubMed


Tenofovir disoproxil fumarate (TDF) may induce renal proximal tubulopathy (rPT). There are no data on pharmacogenomic predictors of rPT in the genes encoding the multidrug-resistance protein (MRP) 2 and MRP4 transporters.
Mutational screening of the genes for MRP2 (ABCC2) and MRP4 (ABCC4) was performed using genomic DNA from 13 human immunodeficiency virus type 1 (HIV-1)-infected patients (group 1) presenting with TDF-induced rPT. Concomitantly, 17 unrelated HIV-1-infected patients who had received TDF therapy and who did not have rPT (group 2) were included in a case-control analysis, to assess the influence of single-nucleotide polymorphisms (SNPs) identified in ABCC2 and ABCC4.
Six SNPs were identified in ABCC2. A significant allelic association between the 1249 G-->A SNP and TDF-induced rPT was observed (odds ratio, 6.11 [95% confidence interval, 1.19-31.15]; P<.02). ABCC2 haplotypes were significantly associated with the onset of TDF-induced rPT--CATC appeared to be a predisposing haplotype, as it was found in 40.9% of the group 1 case patients and in 13.7% of the group 2 control subjects (P<.01), whereas CGAC appeared to be a protective haplotype, as it was not observed in the group 1 case patients but was present in 20.2% of the group 2 control subjects (P<.01). No association was observed between ABCC4 polymorphism and TDF-induced rPT in the present study.
ABCC2 haplotypes are associated with rPT induced by TDF in HIV-1-infected patients.

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    • "This substitution leads to impaired ATPase activity which significantly influences cellular drug disposition[24]. Multiple studies have found differences in substrate levels intracellularly, drug activity, or toxicity with these polymorphisms2425262743]. In addition to its effect on the cellular disposition of several drugs, this same polymorphism has been implicated in various disease processes, including post-renal transplantation outcomes[44,45]non-alcoholic fatty liver disease[46], and intrahepatic cholestasis of pregnancy[47]. "
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    • "This discrepancy may reflect the fact that our patients constituted a patient group that had been receiving TDF for a relatively long interval without decreases of eGFR. In contrast, KTD has been reported to occur in numerous cases after 0.6 to 2.5 years of TDF exposure[20,22,25]. It should be noted here that it is a common practice in the hospital to stop TDF administration if patients show renal dysfunction after initiation on TDF-containing drugs. "
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    ABSTRACT: In Thailand, the combined generic anti-retroviral drug stavudine/lamivudine/nevirapine (d4T/3TC/NVP) has been used to treat human immunodeficiency virus (HIV)-infected individuals since 2001. Due to relatively frequent adverse effects, d4T gradually has been replaced with tenofovir disoproxil fumarate (TDF). Although the frequency of adverse drug effects with TDF is lower than that with d4T, TDF is known to induce kidney dysfunction, especially in the proximal tubules. It has been reported that renal tubular transporters, including members of the multi-drug resistant (MDR) protein family, are implicated in tenofovir extrusion and may, therefore, confer susceptibility to TDF-induced kidney tubular dysfunction (KTD). We have explored the association between KTD and polymorphisms in genes that encode adenosine triphosphate-binding cassette (ABC)-type MDRs.
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    • "This contrast with the higher frequency of Fanconi syndrome in HIV patients exposed to TDF where the risk of kidney injury associated to TDF is most likely multifactorial , and exaggerated by older age, lower body weight, pre-existing renal impairment, concomitant use of nephrotoxic medications and such co-morbidities as diabetes or arterial hypertension [4]. However, the association of Fanconi syndrome with HIV may also depend on an interaction with the multidrug-resistance proteins 2 (MRP2) implicated in drug efflux at the apical surface of the proximal tubule whose altered function may lead to drug accumulation within tubular epithelial cells resulting in kidney tubular dysfunction [8] [9] [10]. Indeed, genetic polymorphisms of this protein encoded by the adenosine triphosphate-binding cassette (ABC) gene ABCC2, is strongly associated with development of kidney tubular dysfunction in TDF exposed individuals [9] [10]. "
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