Skip Navigation

Predictors of Kidney Tubular Dysfunction in HIV-Infected Patients Treated with Tenofovir: A Pharmacogenetic Study

  1. Sonia Rodríguez-Nóvoa1,
  2. Pablo Labarga1,
  3. Vincent Soriano1,
  4. Deirdre Egan3,
  5. Marta Albalater2,
  6. Judit Morello1,
  7. Lorena Cuenca1,
  8. Gema González-Pardo1,
  9. Saye Khoo3,
  10. David Back3, and
  11. Andrew Owen3
  1. 1Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain
  2. 2Nephrology Department, Fundación Jiménez-Díaz, Madrid, Spain
  3. 3Department of Pharmacology and Therapeutics, Liverpool University, Liverpool, United Kingdom
  1. Reprints or correspondence: Dr. Sonia Rodríguez-Nóvoa, Dept. of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain (sonia_r_novoa{at}hotmail.com).
 
Next Section

Abstract

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, β2-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.

Tenofovir is a nucleotide reverse-transcriptase inhibitor widely used for the treatment of human immunodeficiency virus (HIV) infection. Tenofovir undergoes renal clearance by a combination of glomerular filtration and active tubular secretion. Although large prospective trials have shown that tenofovir is relatively safe for the kidney, with a very low rate of renal insufficiency [1], cases of tubular dysfunction, including development of Fanconi syndrome, have been reported [2–8], and concern exists about the long-term use of tenofovir.

The mechanism by which tenofovir may cause renal damage is not well understood, although interference with transporter proteins in the renal tubule may play a role. Tenofovir entry into the epithelial cells of the kidney tubule through the basolateral membrane involves organic anion transporters (OATs), mainly OAT1 and, to lesser extent, OAT3 [9, 10]. These influx transporters are encoded by the solute carrier genes SLC22A6 and SLC22A8, respectively. Known substrates for OAT1 include cyclic adenosine monophosphate, cyclic guanosine monophosphate, antiviral agents (acyclovir, cidofovir, and zidovudine), antibiotics, and diuretics [11]. OAT1 and OAT3 are expressed in the basolateral membrane, whereas other members of the OAT family, such as OAT4 (encoded by SLC22A11), are expressed in the luminal membrane [12]. A polymorphism in this gene (rs11231809) has previously been shown to interfere with excretion of the diuretic torsemide [13] and could play a role in the renal clearance of other compounds.

Once tenofovir enters tubular cells, its secretion is an active process that depends on efflux by transporters on the luminal membrane. Although tenofovir uptake from blood into the proximal tubule has been studied, the efflux transport through the apical surface is less well characterized. Proteins implicated in tenofovir efflux at the luminal surface include multidrug-resistance protein 2 (MRP2) [14, 15] and MRP4 [16, 17]. These proteins are encoded by the adenosine triphosphate-binding cassette (ABC) genes ABCC2 and ABCC4, respectively. Both MRP2 and MRP4 are energy-dependent pumps that efflux their substrates into the glomerular filtrate [12]. For many antiviral drugs, the efflux at the luminal membrane is rate limiting, occasionally resulting in intracellular accumulation. Therefore, drugs such as cidofovir and adefovir may produce concentration-dependent renal toxicity [18]. Because tenofovir has structural similarity to these compounds (all are nucleotide analogues), its accumulation within tubular epithelial cells may interfere with renal function. Moreover, transporter expression may modulate the extent of tubular damage. The objective of this study was to explore the association between polymorphisms in ABCC2, ABCC4, ABCB1, SLC22A6, and SLC22A11 and the development of tubular dysfunction in HIV-infected patients treated with tenofovir.

Previous SectionNext Section

Patients and Methods

Study population. All HIV-infected patients receiving tenofovir-containing therapy who were seen at a single clinic in Madrid during the first trimester of 2008 were invited to participate in this cross-sectional study of markers of tubulopathy in 24-h urine samples. The study protocol was approved by the hospital ethics committee. Proximal tubular renal dysfunction was determined on the basis of the following abnormalities: nondiabetic glucosuria (urine glucose level, >300 mg daily), total excretion of phosphorus (urine phosphorus × urine volume) >1200 mg daily, fractional tubular resorption of phosphorus (1 − [(urine phosphorus × plasma creatinine)/(plasma phosphorus × urine creatinine)]) <0.82, hyperaminoaciduria (any amino acid in urine, with the exception of hystidine, glycine, and serine), β2-microglobulinuria (β2-microglobulin level, >1 mg daily), and fractional excretion of uric acid ([(urine uric acid × plasma creatinine)/(urine creatinine × plasma uric acid)] × 100) >15%. Kidney tubular dysfunction (KTD) was defined by the presence of at least 2 of these abnormalities, with at least 1 being a Fanconi syndrome criterion (glucosuria in nondiabetic patients, hyperaminoaciduria, or hyperphosphaturia).

Genetic polymorphisms. Single-nucleotide polymorphisms (SNPs) in genes encoding tubular transporters were selected on the basis of functional significance and/or reported minor-allele frequencies >5%. The 12 SNPs selected were as follows: (i) ABCC2 −24C→T, which has been associated with higher excretion of tenofovir [19]; (ii) ABCC2 1249G→A (exon 10), 3563T→A (exon 25), and 3972C→T (exon 28), which along with −24C→T, define a haplotype that predisposes to tenofovir-associated nephrotoxicity [20]; (iii) ABCC2 4544G→A (exon 32), which has been reported to be underrepresented in patients with tenofovir-associated renal toxicity [20]; (iv) ABCC4 3463A→G, which has been associated with decreased renal tenofovir clearance [19], ABCC4 4131T→G, found at high frequency in Caucasians, and ABCC4 669C→T, which has been found at higher frequency among patients with tenofovir-associated renal toxicity [20]; (v) SCL22A6 453G→A, which has been shown to influence protein expression [21]; (vi) SLC22A11 rs11231809, which has been associated with abnormal torsemide clearance; and (vii) ABCB1 3435C→T and 1236C→T, which have been associated with altered P-glycoprotein expression. P-glycoprotein is capable of transporting tenofovir disoproxil fumarate, the prodrug of tenofovir, so the altered expression of P-glycoprotein in enterocytes could influence tenofovir exposure [22–24]. Figure 1 summarizes the transporter proteins, genes, and polymorphisms analyzed in the study.

Figure 1
View larger version:
Figure 1

Protein transporters involved in tenofovir (TFV) elimination at basolateral and luminal surface of the proximal renal tubule. MRP2, multidrug-resistance protein 2; MRP4, multidrug-resistance protein 4; OAT1, organic anion transporter 1; OAT3, organic anion transporter 3; OAT4, organic anion transporter 4; P-gp, P-glycoprotein; SNP, single-nucleotide polymorphism; TFV-DP, tenofovir diphosphate; TFV-MP, tenofovir monophosphate. *Mitochondrial toxicity could be one of the mechanisms by which tenofovir causes tubular damage. **The role of MRP2 in tenofovir transport is not clear.

Pharmacogenetic analyses. DNA was extracted from peripheral blood mononuclear cells by using a QIAamp DNA Mini Kit (QIAGEN). ABCB1 3435C→T and 1236C→T were identified by direct sequencing, and all other genotyping was performed by allelic discrimination using TaqMan 5′-nuclease assays with standard protocols (TaqMan SNP Genotyping Assays; Applied Biosystems). All primer and probe sequences are available on request.

Statistical analyses. Descriptive results of continuous variables were expressed as medians and interquartile ranges. Continuous variables were compared using a parametric test (Student's t test) or nonparametric test (Wilcoxon test), as required. For the comparison of proportions, the χ 2 test was used, with Yates or Fisher's corrections applied when needed. Bivariate and multivariate logistic regression analyses were performed for the identification of factors associated with kidney tubular toxicity. Parameters with P values <.2 in the bivariate analysis were entered into a stepwise multivariate analysis. All statistics were conducted using SPSS, version 11.0 (SPSS), and differences with P values <.05 were considered to be statistically significant. ABCC2 and ABCC4 haplotypes for individual samples were constructed using PHASE, version 2.1 (University of Washington, Seattle) [25, 26].

Previous SectionNext Section

Results

Study population. A total of 124 HIV-infected patients receiving stable antiretroviral regimens containing tenofovir were originally identified. Informed consent and DNA samples for genotypic analyses were obtainable from 115 of these patients. A total of 19 (16.5%) of the 115 patients fulfilled criteria for KTD. The main characteristics of the study population are given in table 1. The median follow-up time was 35 months (interquartile range, 11–47 months). There were no statistically significant differences in age, sex, body weight, race, hepatitis C virus coinfection, use of protease inhibitors, and the duration of tenofovir therapy (in months) between patients with and patients without KTD. Similarly, baseline biochemical parameters, such are urea, glucose, creatinine, phosphorus, and uric acid levels, did not differ significantly between the 2 groups.

Table 1
View larger version:
Table 1

Characteristics of the study population.

Association of ABCC2, ABCC4, SLC22A6, SLC22A11, and ABCB1 with KTD. The distribution of genotypes at the ABCC2, ABCC4, SLC22A6, ABCB1, and SLC22A11 genes is given in table 2. All polymorphisms were in Hardy-Weinberg equilibrium. The single SNP analysis showed a higher percentage of patients with KTD among C homozygotes at position −24 of ABCC2, compared with the patients with other genotypes (24% [16 of 68 patients] vs. 6% [3 of 47 patients]; P=.020). No other statistically significant differences were observed.

Table 2
View larger version:
Table 2

Genotypes and allelic frequencies at ABCC2, ABCC4, ABCB1, SLC22A6, and SLC22A11 in human immunodeficiency virus-infected patients with and without kidney tubular dysfunction (KTD).

The analysis of the association of a single renal parameter with the different SNPs showed the relevance of 5 SNPs. ABCC2 −24 genotype CC was associated with phosphorus wasting and with β2-microglobulin excretion; ABCC2 1249 genotype GA/AA was associated with the altered excretion of amino acids; ABCC2 3972 genotype CC was associated with β2-microglobulin excretion; ABCC4 669 genotype CC was associated with phosphorus wasting; and ABCC4 4131 genotype TG/GG and OAT4 rs11231809 genotype TT were associated with uric acid excretion altered.

Association of haplotypes atABCC2 and ABCC4 with KTD. The distribution of ABCC2 and ABCC4 haplotypes is given in table 3. The TGTT haplotype of ABCC2 was less prevalent among patients with KTD than among the remaining patients (11% vs. 26%; P=.037). No statistically significant differences were found for ABCC4 haplotypes.

Table 3
View larger version:
Table 3

Distribution of ABCC2 and ABCC4 haplotypes among human immunodeficiency virus-infected patients with and without kidney tubular dysfunction (KTD).

Predictors of KTD in patients treated with tenofovir. Regression analysis was used to determine the predictors of KTD in the study population. In the multivariate analysis that included sex, age, body weight, hepatitis C virus coinfection, number of months of treatment with tenofovir, plasma HIV RNA level, use of protease inhibitors, concomitant exposure to nephrotoxic drugs, diabetes, hypertension, creatinine clearance, and relevant genotypes, the following parameters were independently associated with KTD: older age (OR, 1.1; 95% CI, 1.0–1.2; P=.024), lower body weight (OR, 0.9; 95% CI, 0.8–0.9; P=.048), and homozygosity for the C allele at position −24 of ABCC2 (OR, 5; 95% CI, 1.2–21; P=.027) (table 4).

Table 4
View larger version:
Table 4

Predictors of kidney tubular dysfunction in human immunodeficiency virus (HIV)-infected patients treated with tenofovir.

Previous SectionNext Section

Discussion

Prospective clinical trials have consistently reported a relatively low rate of renal insufficiency in patients exposed to tenofovir [1, 27]. However, the renal safety profile of tenofovir is still being debated, and reports of Fanconi syndrome are emerging in the literature, often involving HIV-infected patients with prior underlying renal abnormalities and/or concomitant exposure to nephrotoxic agents [2–8]. We report the results of an investigation of the pharmacogenetic determinants of KTD in HIV-infected patients receiving stable tenofovir therapy. The most important finding was the association between KTD and genotype CC at position −24 of ABCC2.

The mechanism by which MRP2 influences the risk of KTD in these patients is not well understood. Three hypotheses may be considered. First, tenofovir could be excreted less efficiently by tubular cells in ABCC2 −24C homozygotes, as suggested elsewhere [19]. Increased intracellular concentrations of tenofovir within epithelial tubular cells could be deleterious. However, tenofovir metabolites have not been found to be increased in peripheral blood mononuclear cells of carriers of genotype CC at ABCC2 [28], although this may be accounted for by differences in the nucleotide pool equilibrium and metabolism between blood cells and epithelial tubular cells. Second, MRP2 may transport an as-yet-unidentified endogenous chemical or protein that influences tenofovir toxicity to the kidney, and this genotype is associated with alteration in this factor. This explanation is supported by the observation that, although tenofovir appears to affect hepatobiliary elimination in rats [14], it is not a substrate for human MRP2 in vitro [9, 16]. It should also be noted that in vitro studies with hugely exaggerated expression systems may overestimate the contribution of a transporter in vivo but that false-negative results are very unlikely when appropriate controls are used. Finally, the ABCC2 −24C allele may be in linkage disequilibrium with other SNPs in genes coding for as-yet-unidentified proteins that influence tubular function.

The CATC haplotype of ABCC2, defined by SNPs at positions −24, 1249, 3563, and 3972, has already been associated with a higher risk of tenofovir-associated KTD [20]. However, we did not find an association with the same haplotype in our study. It must be noted, however, that these studies are not directly comparable, because of differences in study design and, most importantly, in the criteria used to define renal toxicity. Izzedine et al. [20] defined renal toxicity on the basis of metabolic acidosis, urine potassium loss, hypophosphoremia, low uric acid levels, and aminoaciduria within 1 month after initiation of tenofovir therapy. It is possible that longer exposure could increase the proportion of patients with tubular abnormalities. In contrast, our cross-sectional study examined HIV-infected patients with a median duration of exposure to tenofovir of 34 months. Because patients who developed early renal toxicity would have been excluded, our results may have underestimated the real incidence of KTD associated with tenofovir therapy. This issue also underscores the importance of a consensus on an accurately defined phenotype for clinical diagnosis of KTD and the need for pharmacogenetic association studies in this area.

Kidney tubular damage is often multifactorial, and tenofovir-associated KTD is unlikely to be an exception. In addition to the impact of genetic polymorphisms, other factors could influence the risk for developing KTD. Indeed, age and body weight were statistically significant risk factors for KTD in our study. Interestingly, both factors tend to result in a reduced tenofovir clearance, and pharmacokinetic studies show that tenofovir elimination is dependent on the ratio of body weight to serum creatinine level [29]. With lower body weight, the ratio diminishes, and tenofovir exposure increases. Following this rationale, studies examining a potential association between tenofovir plasma concentrations and KTD are warranted.

Several limitations of our study must be acknowledged. First, only a limited number of polymorphisms in candidate transporters were examined in a limited number of patients, and other unexplored genotypes may have a greater impact on susceptibility to KTD. Second, other transporters that were not considered could be involved in the elimination of tenofovir throughout the renal tubule. Finally, the cross-sectional design of our study involving patients receiving long-term tenofovir therapy could have missed individuals with more serious renal toxicity manifested at early time points. Prospective studies, with follow-up for sufficient duration and involving patients initiating treatment with tenofovir, are warranted to confirm our findings.

In summary, these results suggest the existence of a genetic predisposition to developing tenofovir-associated renal toxicity, primarily recognizable as tubular dysfunction. Other factors, such as older age and lower body weight, may also contribute. Collectively, a high accumulation of tenofovir within tubular epithelial cells may account for an increased risk of tubular damage in patients treated with tenofovir. This concentration-dependent effect is important because tenofovir may be used for treatment of conditions other than HIV infection (e.g., chronic hepatitis B virus infection), in which dose reduction might be an option. Moreover, if tubular damage persists for long periods in the absence of renal insufficiency, laboratory and clinical manifestations other than those associated with kidney failure may develop. This is the case in premature osteoporosis due to bone mineral loss. If these preliminary data are confirmed in prospective studies, then close monitoring of tubular function is warranted for patients receiving treatment with tenofovir, particularly for ABCC2 −24C homozygotes.

Previous SectionNext Section

Acknowledgments

Financial support. Fundación Ramón Areces, Fondo de Investigaciones Sanitarias (FIS-CP07/00016), Fundación para la Investigación y Educación en SIDA, Agencia Lain Entralgo, Red de Investigacion en SIDA (project ISCIII-RETIC RD06/006), and the European AIDS Treatment Network. A.O. is supported by the UK Medical Research Council and the European Commission.

Potential conflicts of interest. S.K. has received research funding from Boehringer Ingelheim, GlaxoSmithKline, Abbott Laboratories, Pfizer, Astra Zeneca, Tibotec, Merck, and Roche Pharmaceuticals; has consulted for Boehringer Ingelheim, Bristol-Myers Squibb, Delphic Diagnostics, and Tibotec; and has served on the speakers' bureau for Tibotec. D.B. has received research funding from Boehringer Ingelheim, GlaxoSmithKline, Abbott Laboratories, Pfizer, AstraZeneca, Tibotec, Merck, and Roche Pharmaceuticals; has consulted for Boehringer Ingelheim, Bristol-Myers Squibb, Delphic Diagnostics, and Tibotec; and has served on the speakers' bureau for Merck and Tibotec. A.O. has received research funding from Boehringer Ingelheim, GlaxoSmithKline, Abbott Laboratories, Pfizer, AstraZeneca, Tibotec, Merck, and Roche Pharmaceuticals and has served on the speakers' bureau for Bristol-Myers Squibb. All other authors: no conflicts.

  • Received November 19, 2008.
  • Accepted January 22, 2009.
Previous Section
 

References

  1. ↵
    1. Nelson M,
    2. Katlama C,
    3. Montaner J,
    4. et al
    . The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS 2007;21:1273-81.
    CrossRefMedlineWeb of Science
  2. ↵
    1. Coca S,
    2. Perazella M
    . Acute renal failure associated with tenofovir: evidence of drug-induced nephrotoxicity. Am J Med Sci 2002;324:342-4.
    CrossRefMedlineWeb of Science
    1. Rifkin B,
    2. Perazella M
    . Tenofovir-associated nephrotoxicity: Fanconi syndrome and renal failure. Am J Med 2004;117:282-4.
    CrossRefMedlineWeb of Science
    1. Mauss S,
    2. Berger F,
    3. Schmutz G
    . Antiretroviral therapy with tenofovir is associated with mild renal dysfunction. AIDS 2005;19:93-5.
    MedlineWeb of Science
    1. Karras A,
    2. Lafaurie M,
    3. Furco A,
    4. et al
    . Tenofovir-related nephrotoxicity in HIV-infected patients: three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis 2003;36:1070-3.
    Abstract/FREE Full Text
    1. Barrios A,
    2. Garcia-Benayas T,
    3. Gonzalez-Lahoz J,
    4. Soriano V
    . Tenofovir-related nephrotoxicity in HIV-infected patients. AIDS 2004;18:960-3.
    CrossRefMedlineWeb of Science
    1. Peyriere H,
    2. Reynes J,
    3. Rouanet I,
    4. et al
    . Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. J Acquir Immune Defic Syndr 2004;35:269-73.
    CrossRefMedlineWeb of Science
  8. ↵
    1. Verhelst D,
    2. Monge M,
    3. Meynard JL,
    4. et al
    . Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis 2002;40:1331-3.
    CrossRefMedlineWeb of Science
  9. ↵
    1. Ray AS,
    2. Cihlar T,
    3. Robinson KL,
    4. et al
    . Mechanism of active renal tubular efflux of tenofovir. Antimicrob Agents Chemother 2006;50:3297-304.
    Abstract/FREE Full Text
  10. ↵
    1. Cihlar T,
    2. Ho E,
    3. Lin D,
    4. Mulato A
    . Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids 2001;20:641-8.
    CrossRefMedlineWeb of Science
  11. ↵
    1. Robertson E,
    2. Rankin G
    . Human renal organic anion transporters: characteristics and contributions to drug and drug metabolite excretion. Pharmacol Ther 2006;109:399-412.
    CrossRefMedlineWeb of Science
  12. ↵
    1. van Aubel R,
    2. Smeets P,
    3. van den Heuvel P,
    4. Russel F
    . Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites. Am J Physiol Renal Physiol 2005;288:327-33.
    CrossRef
  13. ↵
    1. Vormfelde S,
    2. Schirmer M,
    3. Hagos Y,
    4. et al
    . Torsemide renal clearance and genetic variation in luminal and basolateral organic anion transporters. Br J Clin Pharmacol 2006;62:323-35.
    CrossRefMedlineWeb of Science
  14. ↵
    1. Mallants R,
    2. Van Oosterwyck K,
    3. Van Vaeck L,
    4. Mols R,
    5. De Clercq E,
    6. Augustijins P
    . Multidrug resistance-associated protein 2 (MRP2) affects hepatobiliary elimination but not the intestinal disposition of tenofovir disoproxil fumarate and its metabolites. Xenobiotica 2005;35:1055-66.
    CrossRefMedlineWeb of Science
  15. ↵
    1. Miller D
    . Nucleoside phosphonate interactions with multiple organic anion transporters in renal proximal tubule. J Pharmacol Exp Ther 2001;299:567-74.
    Abstract/FREE Full Text
  16. ↵
    1. Imaoka T,
    2. Kusuhara H,
    3. Adachi M,
    4. Schuetz J,
    5. Takeuchi K,
    6. Sugiyama Y
    . Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir. Mol Pharmacol 2007;71:619-27.
    Abstract/FREE Full Text
  17. ↵
    1. van Aubel R,
    2. Smeets P,
    3. Peters J,
    4. Bindels R,
    5. Russel F
    . The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J Am Soc Nephrol 2002;13:595-603.
    Abstract/FREE Full Text
  18. ↵
    1. Izzedine H,
    2. Launay-Vacher V,
    3. Deray G
    . Antiviral drug-induced nephrotoxicity. Am J Kidney Dis 2005;45:804-17.
    CrossRefMedlineWeb of Science
  19. ↵
    1. Kiser J,
    2. Carten M,
    3. Aquilante C,
    4. et al
    . The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharmacol Ther 2008;83:265-72.
    CrossRefMedlineWeb of Science
  20. ↵
    1. Izzedine H,
    2. Hulot J,
    3. Villard E,
    4. et al
    . Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J Infect Dis 2006;194:1481-91.
    Abstract/FREE Full Text
  21. ↵
    1. Bleasby K,
    2. Hall L,
    3. Perry J,
    4. Mohrenweiser H,
    5. Pritchard J
    . Functional consequences of single nucleotide polymorphisms in the human organic anion transporter hOAT1 (SLC22A6). J Pharmacol Exp Ther 2005;314:923-31.
    Abstract/FREE Full Text
  22. ↵
    1. Hoffmeyer S,
    2. Burk O,
    3. von Richter O,
    4. et al
    . Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000;97:3473-8.
    Abstract/FREE Full Text
    1. Horinouchi M,
    2. Sakaeda T,
    3. Nakamura T,
    4. et al
    . Significant genetic linkage of MDR1 polymorphisms at positions 3435 and 2677: functional relevance to pharmacokinetics of digoxin. Pharm Res 2002;19:1581-5.
    CrossRefMedlineWeb of Science
  24. ↵
    1. Kurata Y,
    2. Leiri I,
    3. Kimura M,
    4. et al
    . Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther 2002;72:209-19.
    CrossRefMedlineWeb of Science
  25. ↵
    1. Stephens M,
    2. Smith N,
    3. Donnelly P
    . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001;68:978-89.
    CrossRefMedlineWeb of Science
  26. ↵
    1. Stephens M,
    2. Donnelly P
    . A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003;73:1162-9.
    CrossRefMedlineWeb of Science
  27. ↵
    1. Izzedine H,
    2. Hulot JS,
    3. Vittecoq D,
    4. et al
    . Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral-naïve HIV-1-infected patients: data from a double-blind randomized active-controlled multicentre study. Nephrol Dial Transplant 2005;20:743-6.
    Abstract/FREE Full Text
  28. ↵
    1. Kiser J,
    2. Aquilante C,
    3. Anderson P,
    4. King T,
    5. Carten M,
    6. Fletcher C
    . Clinical and genetic determinants of intracellular tenofovir diphosphate concentrations in HIV-infected patients. J Acquir Immune Defic Syndr 2008;47:298-303.
    CrossRefMedlineWeb of Science
  29. ↵
    1. Jullien V,
    2. Treluyer JM,
    3. Rey E,
    4. et al
    . Population pharmacokinetics of tenofovir in HIV-infected patients taking highly active antiretroviral therapy. Antimicrob Agents Chemother 2005;49:3361-6.
    Abstract/FREE Full Text
| Table of Contents

This Article

  1. Clin Infect Dis. (2009) 48 (11): e108-e116. doi: 10.1086/598507
  1. AbstractFree
  2. » Full Text (HTML)Free
  3. Full Text (PDF)Free

Classifications

Share

  1. Email this article

Navigate This Article

Current Issue

  1. March 1, 2012 54 (5)
  1. Clinical Infectious Diseases
  1. Alert me to new issues

Most