A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome

Abstract

BACKGROUND Tenofovir disoproxil fumarate (TDF) is a widely used antiretroviral agent with favorable efficacy, safety and tolerability profiles. However, renal adverse events, including rare Fanconi syndrome (FS), may occur in a small subset of HIV-infected treated patients. OBJECTIVES The aim of this study was to identify genetic variants that may associate with TDF-associated FS (TDF-FS). METHODS DNA samples collected from a 19 cases with TDF-FS and 36 matched controls were sequenced and genetic association studies were performed in eight candidate genes: ATP-binding cassette (ABC) transporters ABCC2 (MRP2) and ABCC4 (MRP4), solute carrier family members SLC22A6 (OAT1) and SLC22A8 (OAT3), adenylate kinases 2 (AK2) and 4 (AK4), chloride transporter CIC-5 CLCN5, and Lowe syndrome protein OCRL. Functional effects of a SNP predicted to alter transport of tenofovir were then investigated in cells expressing an identified variant or ABCC4. RESULTS Overall, the case group showed a trend towards a higher proportion of rare alleles. Six SNPs in ABCC2 (3 SNPs), ABCC4 (1 SNP) and OCRL (2 SNPs) were associated with TDF-FS case status, but did not remain significant after correction for multiple testing. Six SNPs, in OCRL (4 SNPs) and ABCC2 (2 SNPs), were significantly associated with increased serum creatinine levels in the cases, and remained significant after multiple test correction (P < 2 × 10−04). One synonymous SNP in ABCC2 (rs8187707; P=2.10 ×10−04; β =−73.3 ml/min/1.73m2)) was also significantly associated with decreased estimated glomerular filtration rate of creatinine in the cases. However, these results were driven by rare SNPs present in a small number of severely affected cases. A previously uncharacterized, non-synonymous SNP, rs11568694, that was predicted to alter MRP4 function, had no significant effect on tenofovir cellular accumulation in vitro. CONCLUSIONS While no single predictive genetic marker for the development of TDF-FS was identified, these findings suggest that multiple rare variants in multiple genes involved in renal handling of tenofovir and/or renal cell homeostasis may be associated with increased susceptibility to TDF-FS.

Pharmacogenetic Analysis of the Model‐Based Pharmacokinetics of Five Anti‐HIV Drugs: How Does This Influence the Effect of Aging?

“…showed that TFV was not substrate of MRP2 using transporter‐overexpressing cell lines. However, some gene association studies showed that ABCC2 variants were associated with TFV‐induced renal side effects in HIV‐infected patients . One patient had very high TFV‐DP CL in in our studied cohort (408% of the median), potentially driving the significance of this relationship; however, the effects of our significant SNPs on this parameter were independent.…”

“…However, some gene association studies showed that ABCC2 variants were associated with TFV-induced renal side effects in HIV-infected patients. 44,45 One patient had very high TFV-DP CL in in our studied cohort (408% of the median), potentially driving the significance of this relationship; however, the effects of our significant SNPs on this parameter were independent. FTC-TP has higher CL out from the cells given an ABCC2_c.1249G>A variant, which increases MRP2 function.…”

“…One patient had very high TFV‐DP CL in in our studied cohort (408% of the median), potentially driving the significance of this relationship; however, the effects of our significant SNPs on this parameter were independent. FTC‐TP has higher CL out from the cells given an ABCC2 _c.1249G>A variant, which increases MRP2 function . The p16 INK4a expression remains a significant predictor, potentially related to effects of cellular aging on the transport of drugs and/or the catabolic and anabolic processes for the metabolites …”

809 Reversal of Proximal Renal Tubular Dysfunction After Nucleotide Analogue Withdrawal in Chronic Hepatitis B

“…It is unclear why PRTD remained protracted in this case despite discontinuation of nucleotide analogues for more than one year. Rare variants in genes involved in the renal handling of nucleotide analogue may be associated with increased susceptibility to Fanconi's syndrome or overt PRTD [35]. Of note, the diagnosis of Fanconi's syndrome with a bicarbonate-loading test was not done to differentiate Fanconi's syndrome from overt RTD in this study.…”

Serum NGAL can act as an early renal safety biomarker during long‐term nucleos(t)ide analogue antiviral therapy in chronic hepatitis B

“…The most serious complication linked with nucleotide analogue therapy is Fanconi syndrome, a drug‐induced form of severe renal tubular damage. Fanconi syndrome is characterized by profound (but reversible) hypophosphatemia, normoglycemic glycosuria, and nonalbumin proteinuria …”