Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Pharmacogenetic determinants of kidney-associated urinary and serum abnormalities in antiretroviral-treated HIV-positive patients

Abstract

Tenofovir disoproxyl fumarate (TDF) has been associated with renal tubular abnormalities, phosphaturia and proteinuria (retinol binding protein, RBP, loss): vitamin D (VD) and PTH affect these markers. Aim was to understand if some single nucleotide polymorphisms (SNPs) were predictors of renal abnormalities in an Italian cohort of HIV-affected patients. DNA was analyzed through real-time PCR, urinary RBP corrected by creatinine (uRBP/Cr). The majority of patients received TDF. Abnormal uRBP/Cr was more frequent in TDF recipients: eGFR <90 mL/min and TDF were predictors in the whole cohort, whereas eGFR <90 mL/min, TDF concentrations and CYP24A1-3999TT in TDF-treated patients. Phosphate levels were higher low VD level patients: age <50 years, CYP27B1 + 2838CC genotype and non-European ancestry were predictors. PTH levels were border-line higher in TDF patients: non-European ancestry, females, TDF, VD levels < 30 ng/mL and SLC28A2-124CT/TT and ABCC2-24CC were predictors. For the first time, SNPs were associated with PTH, phosphate, calcium and tubular dysfunction in HIV-infected patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hogg RS, Eyawo O, Collins AB, Zhang W, Jabbari S, Hull MW, et al. Health-adjusted life expectancy in HIV-positive and HIV-negative men and women in British Columbia, Canada: a population-based observational cohort study. Lancet HIV. 2017;4:e270–6.

  2. Gallant JE, Pham PA. Tenofovir disoproxil fumarate (Viread) for the treatment of HIV infection. Expert Rev Anti Infect Ther. 2003;1:415–22.

    Article  CAS  PubMed  Google Scholar 

  3. Calcagno A, Di Perri G, Bonora S. What do we know about tailoring treatment with tenofovir? Pharmacogenomics. 2016;17:531–4.

    Article  CAS  PubMed  Google Scholar 

  4. Dahlin A, Wittwer M, de la Cruz M, Woo JM, Bam R, Scharen-Guivel V, et al. A pharmacogenetic candidate gene study of tenofovir-associated Fanconi syndrome. Pharmacogenet Genomics. 2015;25:82–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hemkens LG, Ewald H, Santini-Oliveira M, Buhler JE, Vuichard D, Schandelmaier S, et al. Comparative effectiveness of tenofovir in treatment-naive HIV-infected patients: systematic review and meta-analysis. HIV Clin Trials. 2015;16:178–89.

    Article  CAS  PubMed  Google Scholar 

  6. Rodriguez-Novoa S, Labarga P, Soriano V. Pharmacogenetics of tenofovir treatment. Pharmacogenomics. 2009;10:1675–85.

    Article  CAS  PubMed  Google Scholar 

  7. Gallant JE, Deresinski S. Tenofovir disoproxil fumarate. Clin Infect Dis. 2003;37:944–50.

    Article  CAS  PubMed  Google Scholar 

  8. Maggi P, Bartolozzi D, Bonfanti P, Calza L, Cherubini C, Di Biagio A, et al. Renal complications in HIV disease: between present and future. AIDS Rev. 2012;14:37–53.

    PubMed  Google Scholar 

  9. Casado JL, Banon S, Santiuste C, Serna J, Guzman P, Tenorio M, et al. Prevalence and significance of proximal renal tubular abnormalities in HIV-infected patients receiving tenofovir. AIDS. 2016;30:231–9.

    Article  CAS  PubMed  Google Scholar 

  10. Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis. 2010;51:496–505.

    Article  CAS  PubMed  Google Scholar 

  11. Gallant JE, Winston JA, DeJesus E, Pozniak AL, Chen SS, Cheng AK, et al. The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients. AIDS. 2008;22:2155–63.

    Article  CAS  PubMed  Google Scholar 

  12. Vrouenraets SM, Fux CA, Wit FW, Garcia EF, Furrer H, Brinkman K, et al. Persistent decline in estimated but not measured glomerular filtration rate on tenofovir may reflect tubular rather than glomerular toxicity. AIDS. 2011;25:2149–55.

    Article  PubMed  Google Scholar 

  13. Calcagno A, Cusato J, Marinaro L, Simiele M, Lucchiari M, Alcantarini C, et al. Tenofovir clearance is reduced in HIV-positive patients with subclinical tubular impairment. AIDS. 2015;30:915–20.

    Article  CAS  Google Scholar 

  14. Scherzer R, Estrella M, Li Y, Choi AI, Deeks SG, Grunfeld C, et al. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS. 2012;26:867–75.

    Article  CAS  PubMed  Google Scholar 

  15. Mocroft A, Lundgren JD, Ross M, Law M, Reiss P, Kirk O, et al. Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study. PLoS Med. 2015;12:e1001809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Poizot-Martin I, Solas C, Allemand J, Obry-Roguet V, Pradel V, Bregigeon S, et al. Renal impairment in patients receiving a tenofovir-cART regimen: impact of tenofovir trough concentration. J Acquir Immune Defic Syndr. 2012;62:375–80.

    Article  CAS  Google Scholar 

  17. Scarpino M, Santoro MM, Pellicano’ G. HIV infection and kidney disease: literature review. Infect Dis Trop Med. 2015;1:1–8.

  18. Salvaggio SE, Giacomelli A, Falvella FS, Oreni ML, Meraviglia P, Atzori C, et al. Clinical and genetic factors associated with kidney tubular dysfunction in a real-life single centre cohort of HIV-positive patients. BMC Infect Dis. 2017;17:396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Izzedine H, Hulot JS, Villard E, Goyenvalle C, Dominguez S, Ghosn J, et al. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J Infect Dis. 2006;194:1481–91.

    Article  CAS  PubMed  Google Scholar 

  20. Pushpakom SP, Liptrott NJ, Rodriguez-Novoa S, Labarga P, Soriano V, Albalater M, et al. Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction. J Infect Dis. 2011;204:145–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kiser JJ, Aquilante CL, Anderson PL, King TM, Carten ML, Fletcher CV. Clinical and genetic determinants of intracellular tenofovir diphosphate concentrations in HIV-infected patients. J Acquir Immune Defic Syndr. 2008;47:298–303.

    Article  CAS  PubMed  Google Scholar 

  22. Nishijima T, Komatsu H, Higasa K, Takano M, Tsuchiya K, Hayashida T, et al. Single nucleotide polymorphisms in ABCC2 associate with tenofovir-induced kidney tubular dysfunction in Japanese patients with HIV-1 infection: a pharmacogenetic study. Clin Infect Dis. 2012;55:1558–67.

    Article  CAS  PubMed  Google Scholar 

  23. Likanonsakul S, Suntisuklappon B, Nitiyanontakij R, Prasithsirikul W, Nakayama EE, Shioda T, et al. A single-nucleotide polymorphism in ABCC4 is associated with tenofovir-related beta2-microglobulinuria in thai patients with HIV-1 infection. PLoS ONE. 2016;11:e0147724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Achhra AC, Nugent M, Mocroft A, Ryom L, Wyatt CM. Chronic kidney disease and antiretroviral therapy in HIV-positive individuals: recent developments. Curr HIV/AIDS Rep. 2016;13:149–57.

    Article  PubMed  Google Scholar 

  25. Kiser JJ, Carten ML, Aquilante CL, Anderson PL, Wolfe P, King TM, et al. The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharm Ther. 2008;83:265–72.

    Article  CAS  Google Scholar 

  26. Rungtivasuwan K, Avihingsanon A, Thammajaruk N, Mitruk S, Burger DM, Ruxrungtham K, et al. Influence of ABCC2 and ABCC4 polymorphisms on tenofovir plasma concentrations in Thai HIV-infected patients. Antimicrob Agents Chemother. 2015;59:3240–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rodriguez-Novoa S, Labarga P, Soriano V, Egan D, Albalater M, Morello J, et al. Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a pharmacogenetic study. Clin Infect Dis. 2009;48:e108–16.

    Article  CAS  PubMed  Google Scholar 

  28. Neumanova Z, Cerveny L, Ceckova M, Staud F. Interactions of tenofovir and tenofovir disoproxil fumarate with drug efflux transporters ABCB1, ABCG2, and ABCC2; role in transport across the placenta. AIDS. 2014;28:9–17.

    Article  CAS  PubMed  Google Scholar 

  29. Kohler JJ, Hosseini SH, Green E, Abuin A, Ludaway T, Russ R, et al. Tenofovir renal proximal tubular toxicity is regulated by OAT1 and MRP4 transporters. Lab Invest. 2011;91:852–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lu H. Crosstalk of HNF4alpha with extracellular and intracellular signaling pathways in the regulation of hepatic metabolism of drugs and lipids. Acta Pharm Sin B. 2016;6:393–408.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Calcagno A, Cusato J, Marinaro L, Trentini L, Alcantarini C, Mussa M, et al. Clinical pharmacology of tenofovir clearance: a pharmacokinetic/pharmacogenetic study on plasma and urines. Pharmacogenomics J. 2015;16:514–8.

    Article  CAS  PubMed  Google Scholar 

  32. Seifert SM, Chen X, Meditz AL, Castillo-Mancilla JR, Gardner EM, Predhomme JA, et al. Intracellular tenofovir and emtricitabine anabolites in genital, rectal, and blood compartments from first dose to steady state. AIDS Res Hum Retroviruses. 2016;32:981–91.

  33. Cusato J, Calcagno A, De Nicolo A, Mogyorosi K, D’Avolio A, Di Perri G, et al. Tenofovir alafenamide and tenofovir disoproxil fumarate are not transported by concentrative nucleoside transporter 2. Diagn Microbiol Infect Dis. 2019;94:202–4.

    Article  CAS  PubMed  Google Scholar 

  34. Lerma-Chippirraz E, Guerri-Fernandez R, Villar Garcia J, Gonzalez Mena A, Guelar Grinberg A, Montero MM, et al. Validation protocol of vitamin D supplementation in patients with HIV-infection. AIDS Res Treat. 2016;2016:5120831.

    PubMed  PubMed Central  Google Scholar 

  35. Havens PL, Kiser JJ, Stephensen CB, Hazra R, Flynn PM, Wilson CM, et al. Association of higher plasma vitamin D binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and intracellular tenofovir pharmacokinetics: cause of a functional vitamin D deficiency? Antimicrob Agents Chemother. 2013;57:5619–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Woodward CL, Hall AM, Williams IG, Madge S, Copas A, Nair D, et al. Tenofovir-associated renal and bone toxicity. HIV Med. 2009;10:482–7.

    Article  CAS  PubMed  Google Scholar 

  37. Rosenvinge MM, Gedela K, Copas AJ, Wilkinson A, Sheehy CA, Bano G, et al. Tenofovir-linked hyperparathyroidism is independently associated with the presence of vitamin D deficiency. J Acquir Immune Defic Syndr. 2010;54:496–9.

    Article  CAS  PubMed  Google Scholar 

  38. Masia M, Padilla S, Robledano C, Lopez N, Ramos JM, Gutierrez F. Early changes in parathyroid hormone concentrations in HIV-infected patients initiating antiretroviral therapy with tenofovir. AIDS Res Hum Retroviruses. 2012;28:242–6.

    Article  CAS  PubMed  Google Scholar 

  39. Childs KE, Fishman SL, Constable C, Gutierrez JA, Wyatt CM, Dieterich DT, et al. Short communication: Inadequate vitamin D exacerbates parathyroid hormone elevations in tenofovir users. AIDS Res Hum Retroviruses. 2010;26:855–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Havens PL, Stephensen CB, Hazra R, Flynn PM, Wilson CM, Rutledge B, et al. Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial. Clin Infect Dis. 2012;54:1013–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bech A, Van Bentum P, Telting D, Gisolf J, Richter C, De Boer H. Treatment of calcium and vitamin D deficiency in HIV-positive men on tenofovir-containing antiretroviral therapy. HIV Clin Trials. 2012;13:350–6.

    Article  CAS  PubMed  Google Scholar 

  42. Canale D, de Braganca AC, Goncalves JG, Shimizu MH, Sanches TR, Andrade L, et al. Vitamin D deficiency aggravates nephrotoxicity, hypertension and dyslipidemia caused by tenofovir: role of oxidative stress and renin-angiotensin system. PLoS ONE. 2014;9:e103055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tarcin O, Yavuz DG, Ozben B, Telli A, Ogunc AV, Yuksel M, et al. Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects. J Clin Endocrinol Metab. 2009;94:4023–30.

    Article  CAS  PubMed  Google Scholar 

  44. Borges-Santos MD, Moreto F, Pereira PC, Ming-Yu Y, Burini RC. Plasma glutathione of HIV(+) patients responded positively and differently to dietary supplementation with cysteine or glutamine. Nutrition. 2012;28:753–6.

    Article  CAS  PubMed  Google Scholar 

  45. Van Den Bout-Van Den Beukel CJ, Fievez L, Michels M, Sweep FC, Hermus AR, Bosch ME, et al. Vitamin D deficiency among HIV type 1-infected individuals in the Netherlands: effects of antiretroviral therapy. AIDS Res Hum Retroviruses. 2008;24:1375–82.

    Article  CAS  Google Scholar 

  46. Kuhlmann H. [Therapy of diabetic glomerulosclerosis (Kimmelstiel-Wilson syndrome)]. Dtsch Med Wochenschr. 1976;101:1769–72.

    Article  CAS  PubMed  Google Scholar 

  47. Michigami T. Update on recent progress in vitamin D research. Vitamin D Metabolism and Its Regulation. Clin Calcium. 2017;27:1517–23.

    CAS  PubMed  Google Scholar 

  48. Begley R, Martin H, Lawson EB, Wei X, Vimal M, Marbury TC, et al. (2014). Pharmacokinetics and safety of tenofovir alafenamide in subjects with mild or moderate hepatic impairment In: Proceedings of the 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. Washington, DC.

  49. Hill A, Hughes SL, Gotham D, Pozniak AL. Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety? J Virus Erad. 2018;4:72–9.

    PubMed  PubMed Central  Google Scholar 

  50. Walensky RP, Horn TH, Paltiel AD. The Epi-TAF for tenofovir disoproxil fumarate? Clin Infect Dis. 2015;62:915–8.

    PubMed  Google Scholar 

  51. Lazio GR (2017). Aggiornamento del Decreto “Razionalizzazione dell’uso dei farmaci per la terapia antiretroviraIe HIV”: Rome. http://www.regione.lazio.it/binary/rl_sanita/tbl_normativa/SAN_DCA_U00244_28_06_2017.pdf.

Download references

Acknowledgements

We thank CoQua Lab (www.coqualab.it) for its methodological support and assistance in the preparation and execution of the study and analysis. This research was supported by research grant from Gilead (Gilead Fellowship Program 2012, c2b35f7351) and received funding specifically dedicated to the Department of Medical Sciences from Italian Ministry for Education, University and Research (Ministero dell’Istruzione, dell’Università e della Ricerca—MIUR) under the programme “Dipartimenti di Eccellenza 2018–2022”. Project no° D15D18000410001.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jessica Cusato.

Ethics declarations

Conflict of interest

AC has received grants from Gilead and Bristol-Myers Squibb (BMS), travel grants and speaker’s honoraria from Abbvie, BMS, Merck Sharp & Dohme (MSD), Gilead, Janssen-Cilag, and Viiv. GDP and SB have received grants, travel grants and consultancy fees from Abbvie, Boehringer-Inghelheim, BMS, MSD, Gilead, Janssen-Cilag, and Viiv. The other authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cusato, J., Calcagno, A., Marinaro, L. et al. Pharmacogenetic determinants of kidney-associated urinary and serum abnormalities in antiretroviral-treated HIV-positive patients. Pharmacogenomics J 20, 202–212 (2020). https://doi.org/10.1038/s41397-019-0109-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41397-019-0109-x

This article is cited by

Search

Quick links