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.
Rodríguez-Nóvoa
Sonia
S
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. sonia_r_novoa@hotmail.com
Labarga
Pablo
P
Soriano
Vincent
V
Egan
Deirdre
D
Albalater
Marta
M
Morello
Judit
J
Cuenca
Lorena
L
González-Pardo
Gema
G
Khoo
Saye
S
Back
David
D
Owen
Andrew
A
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D015658:HIV Infections / Q000188:drug therapy*; D006720:Homozygote; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects*; D008297:Male; D008969:Molecular Sequence Data; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D063065:Organophosphonates / Q000009:adverse effects* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D051437:Renal Insufficiency / Q000139:chemically induced*; D000068698:Tenofovir
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000225:Adenine; D019380:Anti-HIV Agents; D002352:Carrier Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D063065:Organophosphonates; D000068698:Tenofovir; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C073492:ABCC4 protein, human; C427207:SLC22A11 protein, human