Skip to main content

Advertisement

SpringerLink
Log in

Pathophysiological and Genetic Basis of Tenofovir-Induced Acute Renal Dysfunction: Strategies and Recent Developments for Better Clinical Outcomes

  • Clinical Pharmacology (L Brunetti, Section Editor)
  • Published:
Current Pharmacology Reports Aims and scope Submit manuscript

Abstract

Purpose of the Review

Several clinical studies have suggested that higher doses of tenofovir disoproxil fumarate (TDF), at dose of 300 mg or higher, are associated with an increased risk of acute renal failure (ARF) by decreasing outflow through the human organic anion transporter (hOAT). TDF can potentially be associated with more renal and bone toxicities with increased low-density lipoprotein (LDL) and total cholesterol levels in HIV patients. In this review, we have critically appraised the pathophysiology, molecular mechanisms, and the genetic variability associated with TDF-induced ARF (TDF-I-ARF). This article also highlights the strategies and recent developments to overcome the TDF-induced ARF.

Recent Findings

TDF-I-ARF has a complex pathophysiological map, which has been associated with cellular accumulation and efflux, mitochondrial dysfunctions, oxidative and endoplasmic reticulum (ER) stress, and inflammation.

Summary

Despite many pharmaceutical interventions, and clinical trials, a concordant pharmacological treatment option to reduce ARF in HIV patients receiving TDF remains far from known. This has been predominantly linked to the incomplete understanding of TDF-I-ARF molecular mechanisms and pathophysiology involved. The altered activity of human renal organic anion transporter 1 (hOAT1)-expressing proximal tubule epithelial cells cause renal toxicity which actively uptake this drug.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

MRP:

Multidrug-resistance protein

OAT:

Organic anion transporter

P-gp:

P-glycoprotein

SNP:

Single-nucleotide polymorphism

TFV-DP:

Tenofovir diphosphate

TFV-MP:

Tenofovir monophosphate

NaDC:

Sodium dicarboxylate symporter

OCT:

Organic cation transporter

FEP:

Fractional excretion of phosphate

P/C ratio:

Protein/creatinine ratio

TP:

Tubular proteinuria

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bhosale PV, Avinash K. Preventable drug harms in renal injuries: a prospective observational study in OPD and IPD patients in medicine department of civil hospital, Nashik. MIMER Med J. 2020;4(1):7–10.

    Google Scholar 

  2. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. NEJM. 2006;354:251–60. https://doi.org/10.1056/NEJMoa05187.

    Article  CAS  PubMed  Google Scholar 

  3. Slusarczyk M, Serpi M, Pertusati F. Phosphoramidates and phosphonamidates (ProTides) with antiviral activity. Antivir Chem Chemother. 2018;26:2040206618775243. https://doi.org/10.1177/2040206618775243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. De Clercq E. Fifty years in search of selective antiviral drugs: miniperspective. J Med Chem. 2019;62(16):7322–39. https://doi.org/10.1021/acs.jmedchem.9b00175.

    Article  CAS  PubMed  Google Scholar 

  5. Ramamoorthy H, Abraham P, Isaac B. Mitochondrial dysfunction and electron transport chain complex defect in a rat model of tenofovir disoproxil fumarate nephrotoxicity. J Biochem Mol Toxicol. 2014;28:246–55. https://doi.org/10.1002/jbt.21560.

    Article  CAS  PubMed  Google Scholar 

  6. Hall AM, Edwards SG, Lapsley M, et al. Subclinical tubular injury in HIV-infected individuals on antiretroviral therapy: a cross-sectional analysis. Am J Kidney Dis. 2009;54:1034–42. https://doi.org/10.1053/j.ajkd.2009.07.012.

    Article  PubMed  Google Scholar 

  7. Jimenez-Nacher I, Garcia B, Barreiro P, et al. Trends in the prescription of antiretroviral drugs and impact on plasma HIV-RNA measurements. J Antimicrob Chemother. 2008;62:816–22. https://doi.org/10.1093/jac/dkn252.

    Article  CAS  PubMed  Google Scholar 

  8. • Nieskens TT, Peters JG, Schreurs MJ, et al. A human renal proximal tubule cell line with stable organic anion transporter 1 and 3 expression predictive for antiviral-induced toxicity. AAPS J. 2016;18(2):465–75.https://doi.org/10.1208/s12248-016-9871-8. (This article summarizes the expression of OAT 1 and 3 transporters in human renal proximal tubule cells for antiretroviral-induced toxicity.)

  9. Barreiro P, Fernández-Montero JV, De Mendoza C, et al. Pharmacogenetics of antiretroviral therapy. Expert Opin Drug Metab Toxicol. 2014;10:1119–30. https://doi.org/10.1517/14740338.2015.1073258.

    Article  CAS  PubMed  Google Scholar 

  10. Atta MG, De Seigneux S, Lucas GM. Clinical pharmacology in HIV therapy. Clin J Am Soc Nephrol. 2019;14(3):435–44. https://doi.org/10.2215/CJN.02240218.

    Article  CAS  PubMed  Google Scholar 

  11. Hall AM, Hendry BM, Nitsch D, et al. Tenofovirassociated kidney toxicity in HIV-infected patients: a review of the evidence. Am J Kidney Dis. 2011;57:773–80. https://doi.org/10.1053/j.ajkd.2011.01.022.

    Article  CAS  PubMed  Google Scholar 

  12. • Kohler JJ, Hosseini SH, Hoying-Brandt A, et al. Tenofovir renal toxicity targets mitochondria of renal proximal tubules. Lab Invest. 2009;89:513–9. https://doi.org/10.1038/labinvest.2009.14. (This article highlights the mitochondrial damage of renal proximal tubules due to tenofovir-induced renal toxicity.)

  13. Soto K, Campos P, Manso R, et al. Severe acute kidney injury and double tubulopathy due to dual toxicity caused by combination antiretroviral therapy. Kidney Int Rep. 2019;4(3):494–9. https://doi.org/10.1016/j.ekir.2018.11.014.

    Article  PubMed  Google Scholar 

  14. •• Izzedine H, Hulot JS, Villard E, et al. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J Infect Dis. 2006;194:1481–91. https://doi.org/10.1086/508546. (This article summarizes the association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy.)

  15. Kiser JJ, Aquilante CL, Anderson PL, et al. Clinical and genetic determinants of intracellular tenofovir diphosphate concentrations in HIV-infected patients. J Acquir Immune Defic Syndr. 2008;47:298–303. https://doi.org/10.1097/QAI.0b013e31815e7478.

  16. •• Rodríguez-Nóvoa S, Labarga P, Soriano V, et al. Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a pharmacogenetic study. Clin Infect Dis. 2009;48:e108–16. https://doi.org/10.1086/598507. (This article summarizes the pharmacogenetic analysis of predictors with renal tubular failure in HIV-positive individuals using tenofovir.)

  17. Taniguchi K, Wada M, Kohno K, Nakamura T, Kawabe T, Kawakami M, et al. A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation. Cancer Res. 1996;56:4124–9.

    CAS  PubMed  Google Scholar 

  18. Tsujii H, Konig J, Rost D, et al. Exonintron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome. Gastroenterology. 1999;117:653–60. https://doi.org/10.1016/S0016-5085(99)70459-2.

    Article  CAS  PubMed  Google Scholar 

  19. Toh S, Wada M, Uchiumi T, et al. Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome. Am J Hum Genet. 1999;64:739–46. https://doi.org/10.1086/302292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Aceti A, Gianserra L, Lambiase L, et al. Pharmacogenetics as a tool to tailor antiretroviral therapy: a review. World J Virol. 2015;4:198. https://doi.org/10.5501/wjv.v4.i3.198.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Fux CA, Simcock M, Wolbers M, et al. Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study. Antivir Ther. 2007;12:1165–74. https://doi.org/10.1177/135965350701200812.

    Article  CAS  PubMed  Google Scholar 

  22. Labarga P, Barreiro P, Martin-Carbonero L, et al. Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. Aids. 2009;23:689–96. https://doi.org/10.1097/QAD.0b013e3283262a64.

    Article  CAS  PubMed  Google Scholar 

  23. Jones R, Stebbing J, Nelson M, et al. Renal dysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently. J Acquir Immune Defic Syndr. 2004;37:1489–95. https://doi.org/10.1097/01.qai.0000138983.45235.02.

    Article  CAS  PubMed  Google Scholar 

  24. Burgess MJ, Zeuli JD, Kasten MJ. Management of HIV/AIDS in older patients–drug/drug interactions and adherence to antiretroviral therapy. HIV/AIDS (Auckland, NZ). 2015;7:251. https://doi.org/10.2147/HIV.S39655.

    Article  CAS  Google Scholar 

  25. zu Schwabedissen HE, Jedlitschky G, Gratz M, et al. Variable expression of MRP2 (ABCC2) in human placenta: influence of gestational age and cellular differentiation. Drug Metab Dispos. 2005;33:896–904. https://doi.org/10.1124/dmd.104.003335.

  26. Meier Y, Pauli-Magnus C, Zanger UM, et al. Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology. 2006;44:62–74. https://doi.org/10.1002/hep.21214.

    Article  CAS  PubMed  Google Scholar 

  27. Gradhand U, Kim RB. Pharmacogenomics of MRP transporters (ABCC1–5) and BCRP (ABCG2). Drug Metab Rev. 2008;40:317–54. https://doi.org/10.1080/03602530801952617.

    Article  CAS  PubMed  Google Scholar 

  28. Hu M, Patel SK, Zhou T, et al. Drug transporters in tissues and cells relevant to sexual transmission of HIV: implications for drug delivery. J Control Release. 2015;219:681–96. https://doi.org/10.1016/j.jconrel.2015.08.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ray A, Cihlar T, Robinson KL, et al. Mechanism of active renal tubular efflux of tenofovir. Antimicrob Agents Chemother. 2006;50(10):3297–304. https://doi.org/10.1128/AAC.00251-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mallants R, Van Oosterwyck K, Van Vaeck L, et al. 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. https://doi.org/10.1080/00498250500354493.

    Article  CAS  PubMed  Google Scholar 

  31. •• Imaoka T, Kusuhara H, Adachi M, et al. 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(2):619–27.https://doi.org/10.1124/mol.106.028233. (This article highlights the use of antiviral medications adefovir and tenofovir eliminated in the kidney by the multidrug resistance-associated protein 4 (MRP4/ ABCC4).)

  32. Li X, Tan XY, Cui XJ, et al. Pharmacokinetics of tenofovir alafenamide fumarate and tenofovir in the chinese people: effects of non-genetic factors and genetic variations. Pharmacogenomics Pers Med. 2021;14:1315. https://doi.org/10.2147/PGPM.S329690.

    Article  CAS  Google Scholar 

  33. van Aubel R, Smeets P, van den Heuvel J, et al. 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:F327-33. https://doi.org/10.1152/ajprenal.00133.2004.

    Article  CAS  PubMed  Google Scholar 

  34. Gorriz JL, Gutierrez F, Trullas JC, et al. Consensus document on the management of renal disease in HIV-infected patients. Nefrología (English Edition). 2014;34:1–81. https://doi.org/10.3265/Nefrologia.pre2014.Jul.12674.

    Article  Google Scholar 

  35. Welsh MM, Mangravite L, Medina MW, et al. Pharmacogenomic discovery using cell-based models. Pharmacol Rev. 2009;61:413–29. https://doi.org/10.1124/pr.109.001461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sodani K, Patel A, Kathawala RJ, et al. Multidrug resistance associated proteins in multidrugresistance. Chin J Cancer. 2012;31:58. https://doi.org/10.5732/cjc.011.10329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Keppler D. Multidrug resistance proteins (MRPs, ABCCs): importance for pathophysiology and drug therapy. Handb Exp Pharmacol. 2011;201:299–323. https://doi.org/10.1007/978-3-642-14541-4_8.

    Article  CAS  Google Scholar 

  38. Hollenstein K, Dawson RJ, Locher KP. Structure and mechanism of ABC transporter proteins. Curr Opin Struct Biol. 2007;17:412–8. https://doi.org/10.1016/j.sbi.2007.07.003.

    Article  CAS  PubMed  Google Scholar 

  39. Liu X. ABC family transporters. Drug transporters in drug disposition, effects and toxicity. 2019;1141:13–100. https://doi.org/10.1007/978-981-13-7647-4_2.

  40. Xu G, Bhatnagar V, Wen GE, et al. Analyses of coding region polymorphisms in apical and basolateral human organic anion transporter (OAT) genes [OAT1 (NKT), OAT2, OAT3, OAT4, URAT (RST)]. Kidney Int. 2005;68:1491–9. https://doi.org/10.1111/j.1523-1755.2005.00612.x.

    Article  CAS  PubMed  Google Scholar 

  41. Bhatnagar V, Xu G, Hamilton BA, et al. Analyses of 5’ regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3). J Hum Genet. 2006;51:575–80. https://doi.org/10.1007/s10038-006-0398-1.

    Article  CAS  PubMed  Google Scholar 

  42. Uwai Y, Ida H, Tsuji Y, et al. Renal transport of adefovir, cidofovir, and tenofovir by SLC22A family members (hOAT1, hOAT3, and hOCT2). Pharm Res. 2007;224:811–5. https://doi.org/10.1007/s11095-006-9196-x.

    Article  CAS  Google Scholar 

  43. •• Mandikova J, Volkova M, Pavek P, et al. Interactions with selected drug renal transporters and transporter-mediated cytotoxicity in antiviral agents from the group of acyclic nucleoside phosphonates. Toxicology. 2013;311(3):135–46.https://doi.org/10.1016/j.tox.2013.07.004. (This article summarizes the interactions of antiviral drug with specific drug renal transporters and transporter-mediated cytotoxicity.)

  44. Harty L, Johnson K, Power A. Race and ethnicity in the era of emerging pharmacogenomics. J Clin Pharmacol. 2006;46:405–7. https://doi.org/10.1177/0091270005286028.

    Article  PubMed  Google Scholar 

  45. Ciarimboli G, Koepsell H, Iordanova M, et al. Individual PKC-phosphorylation sites in organic cation transporter 1 determine substrate selectivity and transport regulation. J Am Soc Neph. 2005;16:1562–70. https://doi.org/10.1681/ASN.2004040256.

    Article  CAS  Google Scholar 

  46. Ulrich CM, Bigler J, Potter JD. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nature Reviews Cancer. 2006;6:130–40. https://doi.org/10.1038/nrc1801.

    Article  CAS  PubMed  Google Scholar 

  47. Perazella MA. Renal vulnerability to drug toxicity. Clin J Am Soc Nephrol. 2009;4:1275–83. https://doi.org/10.2215/CJN.02050309.

    Article  CAS  PubMed  Google Scholar 

  48. Goetz MP, Kamal A, Ames MM. Tamoxifen pharmacogenomics: the role of CYP2D6 as a predictor of drug response. Clin Pharmacol Ther. 2008;83:160–6. https://doi.org/10.1038/sj.clpt.6100367.

    Article  CAS  PubMed  Google Scholar 

  49. Hoskins JM, Goldberg RM, Qu P, et al. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst. 2007;99:1290–5. https://doi.org/10.1093/jnci/djm115.

    Article  CAS  PubMed  Google Scholar 

  50. •• Baxi SM, Greenblatt RM, Bacchetti P, et al. Evaluating the association of single-nucleotide polymorphisms with tenofovir exposure in a diverse prospective cohort of women living with HIV. Pharmacogenomics J. 2018;18(2):245–50.https://doi.org/10.1038/tpj.2017.3. (This article examines the relationship between single-nucleotide polymorphisms and tenofovir exposure in a heterogeneous prospective cohort of HIV-positive women.)

  51. Heyn P, Kalinka AT, Tomancak P, et al. Introns and gene expression: cellular constraints, transcriptional regulation, and evolutionary consequences. Bioessays. 2015;37:148–54. https://doi.org/10.1002/bies.201400138.

    Article  CAS  PubMed  Google Scholar 

  52. Elgar G, Vavouri T. Tuning in to the signals: noncoding sequence conservation in vertebrate genomes. Trends Genet. 2008;24:344–52. https://doi.org/10.1016/j.tig.2008.04.005.

    Article  CAS  PubMed  Google Scholar 

  53. Zimmermann AE, Pizzoferrato T, Bedford J, et al. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis. 2006;42:283–90. https://doi.org/10.1086/499048.

    Article  CAS  PubMed  Google Scholar 

  54. Gutierrez S, Guillemi S, Jahnke N, et al. Tenofovir-based rescue therapy for advanced liver disease in 6 patients coinfected with HIV and hepatitis B virus and receiving lamivudine. Clin Infect Dis. 2008;46:e28–30. https://doi.org/10.1086/525857.

    Article  CAS  PubMed  Google Scholar 

  55. Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 2002;46:716–23. https://doi.org/10.1128/AAC.46.3.716-723.2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Biesecker G, Karimi S, Desjardins J, et al. Evaluation of mitochondrial DNA content and enzyme levels in tenofovir DF-treated rats, rhesus monkeys and woodchucks. Antiviral Res. 2003;58:217–25. https://doi.org/10.1016/S0166-3542(03)00005-6.

  57. Cote HC, Magil AB, Harris M, et al. Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy. Antivir Ther. 2006;11:79–86. https://doi.org/10.1177/135965350601100108.

  58. Abraham P, Ramamoorthy H, Isaac B. Depletion of the cellular antioxidant system contributes to tenofovir disoproxil fumarate-induced mitochondrial damage and increased oxido-nitrosative stress in the kidney. J Biomed Sci. 2013;20:1–5. https://doi.org/10.1186/1423-0127-20-61.

    Article  CAS  Google Scholar 

  59. Menezes AM, Torelly J Jr, Real L, et al. Prevalence and risk factors associated to chronic kidney disease in HIV infected patients on HAART and undetectable viral load in Brazil. PLoS One. 2011;6:e26042. https://doi.org/10.1371/journal.pone.0026042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cooper RD, Wiebe N, Smith N, et al. Systematic review and meta-analysis: renal safety of tenofovir dis_oproxil fumarate in HIV-infected patients. Clin Infect Dis. 2010;51:496–505. https://doi.org/10.1086/655681.

    Article  CAS  PubMed  Google Scholar 

  61. Aberg JA, Gallant JE, Ghanem KG, et al. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58:e1-34. https://doi.org/10.1093/cid/cit665.

    Article  PubMed  Google Scholar 

  62. Neary M, Olagunju A, Sarfo F, et al. Do genetic variations in proximal tubule transporters influence tenofovir-induced renal dysfunction? An exploratory study in a Ghanaian population. J Antimicrob Chemother. 2020;75(5):1267–71. https://doi.org/10.1093/jac/dkaa008.

    Article  CAS  PubMed  Google Scholar 

  63. Gwaza L, Gordon J, Welink J, et al. Interchangeability between first-line generic antiretroviral products prequalified by WHO using adjusted indirect comparisons. AntivirTher. 2017;22(2):135–44. https://doi.org/10.3851/IMP3089.

    Article  CAS  Google Scholar 

  64. Gupta A, Bugeja A, Kirpalani D. Tenofovir-induced nephrotoxicity: myths and facts. Saudi J Kidney Dis Transpl. 2012;23:148.

    PubMed  Google Scholar 

  65. Cheli S, Baldelli S, De Silvestri A, et al. ABCC4 single-nucleotide polymorphisms as markers of tenofovir disoproxil fumarate-induced kidney impairment. Pharmacogenomics J. 2021;21(5):586–93. https://doi.org/10.1038/s41397-021-00235-7.

    Article  CAS  PubMed  Google Scholar 

  66. Günthard HF, Saag MS, Benson CA, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the International Antiviral Society–USA panel. Jama. 2016;316(2):191–210. https://doi.org/10.1001/jama.2016.8900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. • Rodriguez-Nóvoa S, Alvarez E, Labarga P, et al. Renal toxicity associated with tenofovir use. Expert Opin Drug Saf. 2010;9(4):545–59. https://doi.org/10.1517/14740331003627458. (This article summarizes the contributing factors related to renal toxicity associated with tenofovir use.)

  68. Salgado JV, Neves FA, Bastos MG, et al. Monitoring renal function: measured and estimated glomerular filtration rates-a review. Braz J Med Biol Res. 2010;43:528–36. https://doi.org/10.1590/S0100-879X2010007500040.

    Article  CAS  PubMed  Google Scholar 

  69. Liborio AB, Andrade L, Pereira LV, et al. Rosiglitazone reverses tenofovir-induced nephrotoxicity. Kidney Int. 2008;74:910–8. https://doi.org/10.1038/ki.2008.252.

    Article  CAS  PubMed  Google Scholar 

  70. Hara M, Yoshida M, Nishijima H, et al. Melatonin, a pineal secretory product with antioxidant properties, protects against cisplatin-induced nephrotoxicity in rats. J Pineal Res. 2001;30(3):129–38. https://doi.org/10.1034/j.1600-079X.2001.300301.x.

    Article  CAS  PubMed  Google Scholar 

  71. Sener G, Sehirli AO, Altunbas HZ, et al. Melatonin protects against gentamicin-induced nephrotoxicity in rats. J Pineal Res. 2002;32:231–6. https://doi.org/10.1034/j.1600-079X.2002.01858.x.

    Article  CAS  PubMed  Google Scholar 

  72. Ramamoorthy H, Abraham P, Isaac B. Preclinical efficacy of melatonin in the amelioration of tenofovir nephrotoxicity by the attenuation of oxidative stress, nitrosative stress, and inflammation in rats. J Basic Clin Physiol Pharmacol. 2014;27:1–13. https://doi.org/10.1515/jbcpp-2013-0135.

    Article  CAS  Google Scholar 

  73. Izzedine H, Thibault V, Valantin MA, et al. Tenofovir/probenecid combination in HIV/ HBV-coinfected patients: how to escape Fanconi syndrome recurrence? AIDS. 2010;24:1078–9. https://doi.org/10.1097/QAD.0b013e3283313f54.

    Article  PubMed  Google Scholar 

  74. Cundy KC. Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. Clin Pharmacokinet. 1999;36:127–43. https://doi.org/10.2165/00003088-199936020-00004.

    Article  CAS  PubMed  Google Scholar 

  75. Wong CC, Botting NP, Orfila C, et al. Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1/SLC22A6). Biochem Pharmacol. 2011;81:9. https://doi.org/10.1016/j.bcp.2011.01.004.

    Article  CAS  Google Scholar 

  76. Sung MJ, Kim DH, Jung YJ, et al. Genistein protects the kidney from cisplatin-induced injury. Kidney Int. 2008;74(12):1538–47. https://doi.org/10.1038/ki.2008.409.

    Article  CAS  PubMed  Google Scholar 

  77. Trnka J, Blaikie FH, Smith RA, et al. A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondria. Free Radic Biol Med. 2008;44:1406–19. https://doi.org/10.1016/j.freeradbiomed.2007.12.036.

    Article  CAS  PubMed  Google Scholar 

  78. Shahbazi F, Dashti-Khavidaki S, Khalili H, et al. Potential renoprotective effects of silymarin against nephrotoxic drugs: a review of literature. J Pharm Pharm Sci. 2012;15:112–23. https://doi.org/10.18433/J3F88S.

    Article  CAS  PubMed  Google Scholar 

  79. Jafari A, Dashti-Khavidaki S, Khalili H, et al. Potential nephroprotective effects of l-carnitine against drug-induced nephropathy: a review of literature. Expert Opin Drug Saf. 2013;12:523–43. https://doi.org/10.1517/14740338.2013.794217.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are thankful to the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India for their constant support to the Institution.

Author information

Authors and Affiliations

  1. Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research (NIPER), Export Promotions Industrial Park (EPIP), Industrial Area Hajipur, Dist. Vaishali, 844102, Hajipur, Bihar, India

    Ayush Sharma, Krishna Murti, V. Ravichandiran & Sameer Dhingra

  2. Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Hajipur, Bihar, India

    Prakash Kumar & Murali Kumarasamy

  3. Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India

    Siddhartha Dutta

  4. Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India

    Rimple Jeet Kaur & Jaykaran Charan

  5. Department of Pharmacology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

    Gaurav Chikara

  6. Department of Pharmacy Practice, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India

    M. Ramesh

  7. Department of Clinical Medicine, Rajendra Memorial Research Institute of Medical Sciences, Indian Council of Medical Research, Patna, Bihar, India

    Krishna Pandey

  8. Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Kolkata, West Bengal, India

    V. Ravichandiran

Authors
  1. Ayush Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prakash Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Siddhartha Dutta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rimple Jeet Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jaykaran Charan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gaurav Chikara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Krishna Murti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Murali Kumarasamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Ramesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Krishna Pandey
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. V. Ravichandiran
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sameer Dhingra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sameer Dhingra.

Ethics declarations

Conflict of Interest

The authors report no conflicts of interest in this work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

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

This article is part of the Topical Collection on Clinical Pharmacology

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sharma, A., Kumar, P., Dutta, S. et al. Pathophysiological and Genetic Basis of Tenofovir-Induced Acute Renal Dysfunction: Strategies and Recent Developments for Better Clinical Outcomes. Curr Pharmacol Rep 8, 427–438 (2022). https://doi.org/10.1007/s40495-022-00304-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40495-022-00304-w

Keywords

Search

Navigation