Clinical and genetic factors associated with kidney tubular dysfunction in a real-life single centre cohort of HIV-positive patients

Tenofovir (TDF) is one of the most widely used antiretroviral drug. Despite the high degree of tolerability a small percentage of patients experienced alteration in tubular function during TDF use. Intracellular TDF disposition is regulated by ATP-binding cassette (ABC) drug efflux transporters and,...

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Published in:	BMC infectious diseases Vol. 17; no. 1; p. 396
Main Authors:	Salvaggio, S E, Giacomelli, A, Falvella, F S, Oreni, M L, Meraviglia, P, Atzori, C, Clementi, E G I, Galli, M, Rusconi, S
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 05-06-2017 BioMed Central BMC
Subjects:	Acquired immune deficiency syndrome Adenosine triphosphatase Adenosine triphosphate Adult Age AIDS Alleles Anti-HIV Agents - adverse effects Antiretroviral agents Antiretroviral drugs ATP Bivariate analysis Bone density Bone diseases Clinical medicine Cohort Studies Complications and side effects Deoxyribonucleic acid Diabetes Diabetes mellitus DNA Drug therapy Efflux Female Gene mapping Genetic aspects Genetic factors Health aspects HIV HIV Infections - drug therapy HIV-1 Human immunodeficiency virus Humans Hypertension Infections Infectious diseases Kidney diseases Kidney Diseases - chemically induced Kidney Diseases - genetics Kidney Diseases - physiopathology Kidneys Male Mapping Middle Aged Minority & ethnic groups Multidrug Resistance-Associated Proteins - genetics Multivariate analysis Osteoporosis Patients Pharmacogenetics Phosphate Phosphates Polymorphism, Single Nucleotide Proteinuria Proteinuria - chemically induced Risk factors Single nucleotide polymorphisms Single-nucleotide polymorphism Statistical analysis Tenofovir Tenofovir - adverse effects Tenofovir DF Therapy Tubular dysfunction Urine HIV-1 Tubular dysfunction Pharmacogenetics Tenofovir DF
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Summary:	Tenofovir (TDF) is one of the most widely used antiretroviral drug. Despite the high degree of tolerability a small percentage of patients experienced alteration in tubular function during TDF use. Intracellular TDF disposition is regulated by ATP-binding cassette (ABC) drug efflux transporters and, a reduced transport activity may be implicated in accumulation of TDF into the cells. The aim of our study was to assess the major determinants of TDF associated tubular dysfunction (KTD) in a real-life setting including the usefulness of single-nucleotide polymorphisms (SNPs) mapping into ABCC2, ABCC4 and ABCC10 genes. We retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from April 2013 to June 2016. All patients treated with TDF who underwent a genotypization for the functional variants mapping in ABCC2 rs717620 (-24 C > T), ABCC4 rs1751034 (3463 A > G) and ABCC10 rs2125739 (T > C) were evaluated. KTD was defined as the presence of urine phosphate wasting and/or proteinuria at 24 h urine analysis. One hundred fifty-eight patients were genotyped, of which 42 (26.6%) experienced signs of KTD. No statistical significant differences were observed among patients with or without KTD regarding age, gender, ethnicity and comorbidities (hypertension and diabetes). The percentage of patients with KTD was higher among those with "GG" genotype at rs1751034 of ABCC4 compared to patients without KTD [6 (14.3%) vs 4 (3.5%), p = 0.01]. No statistical significant differences were observed regarding the distribution of ABCC2 and ABCC10 SNPs. Carriers of "G" allele in homozygous status at rs1751034 of ABCC4 showed a significant association with KTD (Odds Ratio 4.67, 95% CI 1.25-17.46, p = 0.02) in bivariate analysis, but this association was lost in multivariable analysis. A significant association between bone diseases and KTD was observed (Odds Ratio 3.178, 95%CI 1.529-6.603, p = 0.002). According to our results ABCC4 rs1751034 could be a genetic determinant of KTD; however validation studies are needed for therapy personalization. Noteworthy, a strong association between bone disease and KTD was also observed.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Undefined-1 ObjectType-Feature-3 content type line 23
ISSN:	1471-2334 1471-2334
DOI:	10.1186/s12879-017-2497-3