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 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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    ABSTRACT: Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor widely used to treat patients with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. Despite the excellent safety records of this regimen, a few cases of acute renal failure and Fanconi syndrome have been reported among HIV patients exposed to TDF. In the HBV monoinfection scenario, only two cases of TDF-associated Fanconi syndrome have been reported thus far. Here, we describe two additional patients with chronic hepatitis B (CHB) who developed a TDF-induced Fanconi syndrome that reverted after TDF withdrawal and had viral replication fully suppressed upon switching to entecavir (ETV). Though the overall risk of TDF associated severe renal toxicity in HBV patients appears to be negligible, both glomerular and tubular function should be monitored in patients exposed to TDF, especially when other renal risk factors or a history of previous exposure to adefovir dipivoxil (ADV) are present.
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    11/2012; 2012(9):473829. DOI:10.6064/2012/473829
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    • "Our results suggest that RBPCR results may need to be interpreted in the context of eGFR and ethnicity. The observed association between ethnicity and tubular biomarkers is of interest and suggests that tubular handling of LMWP may be different in patients of different ethnic backgrounds, or that the prevalence of genetic polymorphisms of the organic anion transporters and/or multi-drug resistant proteins, which have been implicated in the pathogenesis of cART-associated tubular dysfunction [27,40], may vary by ethnicity. Alternatively, a higher muscle mass in black patients may have resulted in higher urinary creatinine concentrations, and thus somewhat lower RBPCR, NGALCR and CCR values. "
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    ABSTRACT: Chronic kidney disease is common in HIV positive patients and renal tubular dysfunction has been reported in those receiving combination antiretroviral therapy (cART). Tenofovir (TFV) in particular has been linked to severe renal tubular disease as well as proximal tubular dysfunction. Markedly elevated urinary concentrations of retinal-binding protein (RBP) have been reported in patients with severe renal tubular disease, and low-molecular-weight proteins (LMWP) such as RBP may be useful in clinical practice to assess renal tubular function in patients receiving TFV. We analysed 3 LMWP as well as protein and albumin in the urine of a sample of HIV positive patients. In a cross-sectional fashion, total protein, albumin, RBP, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) were quantified in random urine samples of 317 HIV positive outpatients and expressed as the ratio-to-creatinine (RBPCR, CCR and NGALCR). Exposure to cART was categorised as none, cART without TFV, and cART containing TFV and a non-nucleoside reverse-transcriptase-inhibitor (TFV/NNRTI) or TFV and a protease-inhibitor (TFV/PI). Proteinuria was present in 10.4 % and microalbuminuria in 16.7 % of patients. Albumin accounted for approximately 10 % of total urinary protein. RBPCR was within the reference range in 95 % of patients while NGALCR was elevated in 67 % of patients. No overall differences in urine protein, albumin, and LMWP levels were observed among patients stratified by cART exposure, although a greater proportion of patients exposed to TFV/PI had RBPCR >38.8 μg/mmol (343 μg/g) (p = 0.003). In multivariate analyses, black ethnicity (OR 0.43, 95 % CI 0.24, 0.77) and eGFR <75 mL/min/1.73 m2 (OR 3.54, 95 % CI 1.61, 7.80) were independently associated with upper quartile (UQ) RBPCR. RBPCR correlated well to CCR (r2 = 0.71), but not to NGALCR, PCR or ACR. In HIV positive patients, proteinuria was predominantly of tubular origin and microalbuminuria was common. RBPCR in patients without overt renal tubular disease was generally within the reference range, including those receiving TFV. RBP therefore appears a promising biomarker for monitoring renal tubular function in patients receiving TFV and for distinguishing patients with normal tubular function or mild tubular dysfunction from those with severe renal tubular disease or Fanconi syndrome.
    BMC Nephrology 08/2012; 13(1):85. DOI:10.1186/1471-2369-13-85 · 1.69 Impact Factor
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