ABCC4 single-nucleotide polymorphisms as markers of tenofovir disoproxil fumarate-induced kidney impairment

Pharmacogenomics J. 2021 Oct;21(5):586-593. doi: 10.1038/s41397-021-00235-7. Epub 2021 Apr 13.


Recently, the use of antiretroviral drug tenofovir disoproxil fumarate (TDF) is increased, thanks to the new co-formulation with doravirine, the availability of booster-free regimens, and its advantageous lipid-lowering effect. The aim of our study was to identify genetic markers that contribute to assess the risk of TDF-related renal toxicity. We have retrospectively investigated, in 179 HIV positive patients treated with TDF, the association between the main variants in ABCC2, ABCC4, and ABCC10 genes and four safety endpoints, three clinically relevant as renal outcomes and a higher tenofovir plasma concentration. In patients with an annual eGFR decline >5 mL/min/1.73 m2 a difference in genotype frequencies was observed for ABCC10 c.1875 + 526 G>A (3 subjects AA vs. 44 GG + GA, p = 0.045). In patients with an eGFR decrement >25%, plus a decline in GFR category and TDF discontinuation, a difference was observed for ABCC4 c.*38T>G (35 subjects TG + GG vs. 18 TT, p = 0.052). At univariate analysis OR was 1.39 [(95% CI 1.00-1.96) p = 0.054] and at multivariate analysis OR was 1.49 [(95% CI 1.00-2.22) p = 0.049]. The stronger associations were found between the tenofovir accumulation and ABCC4 c.*38T>G and c.3348G>A: the percentage of these patients was higher in the TG + GG (p = 0.011) and in the AA (p = 0.004) genotype, respectively. The logistic regression analysis confirmed these significant relationships. No significant association was observed in patients with eGFR < 60 mL/min/1.73m2 and with the studied ABCC2 polymorphisms. Our results show a major role for a combined determination of ABCC4/ABCC10 variants as an indicator of tenofovir toxicity in the clinical practice.

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / genetics
  • Adenine / analogs & derivatives*
  • Adenine / blood
  • Adenine / toxicity
  • Adult
  • Anti-HIV Agents / blood
  • Anti-HIV Agents / toxicity*
  • Female
  • Genetic Markers / genetics
  • Genotyping Techniques
  • HIV Infections / drug therapy
  • Humans
  • Male
  • Middle Aged
  • Multidrug Resistance-Associated Protein 2 / genetics
  • Multidrug Resistance-Associated Proteins / genetics*
  • Phosphorous Acids / blood
  • Phosphorous Acids / toxicity*
  • Polymorphism, Single Nucleotide / genetics*
  • Retrospective Studies


  • 9-(2-((bis(pivaloyloxymethoxy)phosphinoyl)methoxy)propyl)adenine
  • ABCC10 protein, human
  • ABCC2 protein, human
  • ABCC4 protein, human
  • Anti-HIV Agents
  • Genetic Markers
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • Phosphorous Acids
  • Adenine