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Drug induced nephrotoxicity- A mechanistic approach

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Abstract

The main goal of the treatment of patients is its effectiveness and safety. However, all currently prescribed drugs being used also have certain adverse effects, which might be seen as an unavoidable but necessary cost of pharmacotherapy. The kidney is the primary organ for xenobiotics elimination, making it particularly susceptible to the harmful effects of drugs and their metabolites during their excretion from the body. Moreover, certain medications have a preferential nephrotoxicity potential, which means that using them increases the risk of kidney injury. Drug nephrotoxicity is, therefore, both a significant problem and a complication of pharmacotherapy. It should be noted that, there is presently no accepted definition of drug-induced nephrotoxicity and no established diagnostic criteria. The current review briefly describes the pathogenic mechanism of drug-induced nephrotoxicity, the various basic drugs with nephrotoxicity potential and the renal biomarkers for the treatment of the drug-related kidney damage.

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Abbreviations

BUN:

Blood urea nitrogen

PCT:

Proximal convoluted tubule

NSAIDs:

Non-steroidal anti-inflammatory drugs

ATN:

Acute tubular necrosis

GFR:

Glomerular filtration rate

FSGS:

Focal segmental glomerulosclerosis

RTA:

Renal tubular acidosis

CIN:

Contrast induced nephropathy

References

  1. Ferguson MA, Vaidya VS, Bonventre JV (2008) Biomarkers of nephrotoxic acute kidney injury. Toxicology 245(3):182–193. https://doi.org/10.1016/j.tox.2007.12.024

    Article  CAS  PubMed  Google Scholar 

  2. Finn WF, Porter GA (2003) Urinary biomarkers and nephrotoxicity. Clinical nephrotoxins. Springer, Dordrecht, pp 621–655. https://doi.org/10.1007/1-4020-2586-6_33

    Chapter  Google Scholar 

  3. Galley HF (2000) Can acute renal failure be prevented?. J R Coll Surg Edinb, 45(1)

  4. Kohli HS, Bhaskaran MC, Muthukumar T, Thennarasu K, Sud K, Jha V, Gupta KL, Sakhuja V (2000) Treatment-related acute renal failure in the elderly: a hospital-based prospective study. Nephrol dialysis transplantation 15(2):212–217. https://doi.org/10.1093/ndt/15.2.212

    Article  CAS  Google Scholar 

  5. Moisi MI, Bungau SG, Vesa CM, Diaconu CC, Behl T, Stoicescu M, Toma MM, Bustea C, Sava C, Popescu MI (2021) Framing cause-effect relationship of acute coronary syndrome in patients with chronic kidney disease. Diagnostics 11(8):1518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Naughton CA (2008) Drug-induced nephrotoxicity. Am Family Phys 78(6):743–750

    Google Scholar 

  7. Pazhayattil GS, Shirali AC (2014) Drug-induced impairment of renal function. Int J Nephrol renovascular disease 7:457

    Google Scholar 

  8. Rached E, Hoffmann D, Blumbach K, Weber K, Dekant W, Mally A (2008) Evaluation of putative biomarkers of nephrotoxicity after exposure to ochratoxin a in vivo and in vitro. Toxicol Sci 103(2):371–381. https://doi.org/10.1093/toxsci/kfn040

    Article  CAS  PubMed  Google Scholar 

  9. Kirtane AJ, Leder DM, Waikar SS, Chertow GM, Ray KK, Pinto DS, Karmpaliotis D, Burger AJ, Murphy SA, Cannon CP, Braunwald E (2005) Serum blood urea nitrogen as an independent marker of subsequent mortality among patients with acute coronary syndromes and normal to mildly reduced glomerular filtration rates. J Am Coll Cardiol 45(11):1781–1786

    Article  CAS  PubMed  Google Scholar 

  10. BAIDOG A, BUNGAU S, BEHL T, RATIU I, URSU ARONRAC, F., LAZAR, L. and, VESA CM (2020) INTERRELATIONSHIPS BETWEEN HYPERURICEMIA, METABOLIC SYNDROME AND CHRONIC KIDNEY DISEASE IN PATIENTS WITH DIABETES MELLITUS

  11. Kumar A Fausto, Pathological basis of disease 2007;9: 417

  12. Choudhury D, Ahmed Z (2006) Drug-associated renal dysfunction and injury. Nat Clin Pract Nephrol 2(2):80–91. https://doi.org/10.1038/ncpneph0076

    Article  CAS  PubMed  Google Scholar 

  13. Schneider V, Lévesque LE, Zhang B, Hutchinson T, Brophy JM (2006) Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: a population-based, nested case-control analysis. Am J Epidemiol 164(9):881–889. https://doi.org/10.1093/aje/kwj331

    Article  PubMed  Google Scholar 

  14. Markowitz GS, Perazella MA (2005) Drug-induced renal failure: a focus on tubulointerstitial disease. Clin Chim Acta 351(1–2):31–47. https://doi.org/10.1016/j.cccn.2004.09.005

    Article  CAS  PubMed  Google Scholar 

  15. Schnellmann RG, Kelly KJ (1999) Pathophysiology of nephrotoxic acute renal failure. Acute Ren Fail Phila Pa : Blackwell Sci, pp.1–14

  16. Perazella MA (2005) Drug-induced nephropathy: an update. Exp Opin Drug Saf 4(4):689–706

    Article  CAS  Google Scholar 

  17. Pisoni R, Ruggenenti P, Remuzzi G (2001) Drug-induced thrombotic microangiopathy. Drug Saf 24(7):491–501. https://doi.org/10.2165/00002018-200124070-00002

    Article  CAS  PubMed  Google Scholar 

  18. Rossert J (2001) Drug-induced acute interstitial nephritis. Kidney Int 60(2):804–817

    Article  CAS  PubMed  Google Scholar 

  19. Fored CM, Ejerblad E, Lindblad P, Fryzek JP, Dickman PW, Signorello LB, Lipworth L, Elinder CG, Blot WJ, McLaughlin JK, Zack MM (2001) Acetaminophen, aspirin, and chronic renal failure. N Engl J Med 345(25):1801–1808

    Article  CAS  PubMed  Google Scholar 

  20. Rodríguez-Iturbe B, García GG (2010) The role of tubulointerstitial inflammation in the progression of chronic renal failure. Nephron Clin Pract 116(2):c81–c88

    Article  PubMed  Google Scholar 

  21. Coco TJ, Klasner AE (2004) Drug-induced rhabdomyolysis. Curr Opin Pediatr 16(2):206–210

    Article  PubMed  Google Scholar 

  22. Huerta-Alardín AL, Varon J, Marik PE (2004) Bench-to-bedside review: rhabdomyolysis–an overview for clinicians. Crit Care 9(2):1–12. https://doi.org/10.1186/cc2978

    Article  Google Scholar 

  23. Vanholder R, Sever MS, Erek E, Lameire N, Rhabdomyolysis (2000) J Am Soc Nephrol, 11(8), 1553–1561. https://doi.org/10.1681/ASN.V1181553

    Article  PubMed  Google Scholar 

  24. Schoolwerth AC, Sica DA, Ballermann BJ, Wilcox CS (2001) Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the kidney in Cardiovascular Disease and the Council for high blood pressure research of the American Heart Association. Circulation 104(16):1985–1991. https://doi.org/10.1161/hc4101.096153

    Article  CAS  PubMed  Google Scholar 

  25. Palmer BF (2002) Renal dysfunction complicating the treatment of hypertension. N Engl J Med 347(16):1256–1261

    Article  PubMed  Google Scholar 

  26. D’Agati V (2003) March. Pathologic classification of focal segmental glomerulosclerosis. Seminars in nephrology, vol 23. WB Saunders, pp 117–134. 2

  27. Jaffe JA, Kimmel PL (2006) Chronic nephropathies of cocaine and heroin abuse: a critical review. Clin J Am Soc Nephrol 1(4):655–667. https://doi.org/10.2215/CJN.00300106

    Article  CAS  PubMed  Google Scholar 

  28. Markowitz GS, Radhakrishnan JAI, Kambham N, Valeri AM, Hines WH, D’AGATI VD (2000) Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol 11(8):1439–1448. https://doi.org/10.1681/ASN.V1181439

    Article  CAS  PubMed  Google Scholar 

  29. Amoghimath S, Majagi SI (2017) Drug induced kidney disease. Hypertension 347(16):1256–1261

    Google Scholar 

  30. Roderick P, Roth M, Mindell J (2011) Prevalence of chronic kidney disease in England: findings from the 2009 health survey for England. J Epidemiol Community Health 65(Suppl 2):A12–A12

    Article  Google Scholar 

  31. Rosner MH, Okusa MD (2006) Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 1(1):19–32. https://doi.org/10.2215/CJN.00240605

    Article  PubMed  Google Scholar 

  32. Bonventre JV, Vaidya VS, Schmouder R, Feig P, Dieterle F (2010) Next-generation biomarkers for detecting kidney toxicity. Nat Biotechnol 28(5):436–440. https://doi.org/10.1038/nbt0510-436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shao C, Li M, Li X, Wei L, Zhu L, Yang F, Jia L, Mu Y, Wang J, Guo Z, Zhang D (2011) A tool for biomarker discovery in the urinary proteome: a manually curated human and animal urine protein biomarker database. Mol Cell Proteom, 10(11)

  34. Guder WG, Hofmann W (1992) Markers for the diagnosis and monitoring of renal tubular lesions. Clin Nephrol 38:3–7

    Google Scholar 

  35. Prinsen BH, der Velden MG, Kaysen GA, Straver HW, van Rijn HJ, Stellaard F, Berger R, Rabelink TJ (2001) Transferrin synthesis is increased in nephrotic patients insufficiently to replace urinary losses. J Am Soc Nephrol, 12, 1017–1025

    Article  CAS  PubMed  Google Scholar 

  36. Tencer J, Bakoush O, Torffvit O (2000) Diagnostic and prognostic significance of proteinuria selectivity index in glomerular diseases. Clin Chim Acta 297(1–2):73–83

    Article  CAS  PubMed  Google Scholar 

  37. Herget-Rosenthal S, Poppen D, Husing J, Marggraf G, Pietruck F, Jakob HG, Philipp T, Kribben A (2004) Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis. Clin Chem 50(3):552–558. https://doi.org/10.1373/clinchem.2003.027763

    Article  CAS  PubMed  Google Scholar 

  38. Emeigh Hart SG, Lavin A, Bounous DI, Macgregor JT, Harpur E (2005) Assessment of renal injury in vivo: traditional and novel biomarkers. Toxicol Sci 84:2–3

    Google Scholar 

  39. Trof RJ, Di Maggio F, Leemreis J, Groeneveld AJ (2006) Biomarkers of acute renal injury and renal failure. Shock 26(3):245–253

    Article  CAS  PubMed  Google Scholar 

  40. Gorriz JL, Martinez-Castelao A (2012) Proteinuria: detection and role in native renal disease progression. Transplantation reviews 26(1):3–13. https://doi.org/10.1016/j.trre.2011.10.002

    Article  PubMed  Google Scholar 

  41. Alchi B, Nishi S, Kondo D, Kaneko Y, Matsuki A, Imai N, Ueno M, Iguchi S, Sakatsume M, Narita I, Yamamoto T (2005) Osteopontin expression in acute renal allograft rejection. Kidney Int 67(3):886–896. https://doi.org/10.1111/j.1523-1755.2005.00153.x

    Article  CAS  PubMed  Google Scholar 

  42. Vaidya VS, Ferguson MA, Bonventre JV (2008) Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol 48:463–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bailly V, Zhang Z, Meier W, Cate R, Sanicola M, Bonventre JV (2002) Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration. J Biol Chem 277(42):39739–39748

    Article  CAS  PubMed  Google Scholar 

  44. Sales GTM, Foresto RD (2020) Drug-induced nephrotoxicity. Revista da Associação Médica Brasileira 66:s82–s90

    Article  Google Scholar 

  45. Htike NL, Santoro J, Gilbert B, Elfenbein IB, Teehan G (2012) Biopsy-proven vancomycin-associated interstitial nephritis and acute tubular necrosis. Clin Exp Nephrol 16(2):320–324. https://doi.org/10.1007/s10157-011-0559-1

    Article  CAS  PubMed  Google Scholar 

  46. van Hal SJ, Paterson DL, Lodise TP (2013) Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother 57(2):734–744. https://doi.org/10.1128/AAC.01568-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Öktem F, Arslan MK, Ozguner F, Candir Ö, Yilmaz HR, Ciris M, Uz E (2005) In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine. Toxicology 215(3):227–233. https://doi.org/10.1016/j.tox.2005.07.009

    Article  CAS  PubMed  Google Scholar 

  48. Bird ST, Etminan M, Brophy JM, Hartzema AG, Delaney JA (2013) Risk of acute kidney injury associated with the use of fluoroquinolones. CMAJ 185(10):E475–E482. https://doi.org/10.1503/cmaj.121730

    Article  PubMed  PubMed Central  Google Scholar 

  49. Stratta P, Lazzarich E, Canavese C, Bozzola C, Monga G (2007) Ciprofloxacin crystal nephropathy. Am J Kidney Dis 50(2):330–335. https://doi.org/10.1053/j.ajkd.2007.05.014

    Article  PubMed  Google Scholar 

  50. Justo JA, Bosso JA (2015) Adverse reactions associated with systemic polymyxin therapy. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 35(1):28–33. https://doi.org/10.1002/phar.1493

    Article  CAS  Google Scholar 

  51. Mistro S, Maciel IDM, de Menezes RG, Maia ZP, Schooley RT, Badaró R (2012) Does lipid emulsion reduce amphotericin B nephrotoxicity? A systematic review and meta-analysis. Clin Infect Dis 54(12):1774–1777. https://doi.org/10.1093/cid/cis290

    Article  CAS  PubMed  Google Scholar 

  52. Singh HP, Singh TG, Singh R (2021) Evaluation of the renoprotective effect of syringic acid against nephrotoxicity induced by cisplatin in rats. J Appl Pharm Sci 11(1):080–085

    CAS  Google Scholar 

  53. Miller RP, Tadagavadi RK, Ramesh G, Reeves WB (2010) Mechanisms of cisplatin nephrotoxicity. Toxins 2(11):2490–2518. https://doi.org/10.3390/toxins2112490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Pabla N, Murphy RF, Liu K, Dong Z (2009) The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity. Am J Physiology-Renal Physiol 296(3):F505–F511. https://doi.org/10.1152/ajprenal.90545.2008

    Article  CAS  Google Scholar 

  55. Launay-Vacher V, Rey JB, Isnard-Bagnis C, Deray G, Daouphars M (2008) Prevention of cisplatin nephrotoxicity: state of the art and recommendations from the European Society of Clinical Pharmacy Special Interest Group on Cancer Care. Cancer Chemother Pharmacol 61(6):903–909. https://doi.org/10.1007/s00280-008-0711-0

    Article  CAS  PubMed  Google Scholar 

  56. Ciarimboli G, Holle SK, Vollenbröcker B, Hagos Y, Reuter S, Burckhardt G, Bierer S, Herrmann E, Pavenstädt H, Rossi R, Kleta R (2011) New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2. Mol Pharm 8(1):270–279. https://doi.org/10.1021/mp100329u

    Article  CAS  PubMed  Google Scholar 

  57. Widemann BC, Adamson PC (2006) Understanding and managing methotrexate nephrotoxicity. Oncologist 11(6):694–703. https://doi.org/10.1634/theoncologist.11-6-694

    Article  CAS  PubMed  Google Scholar 

  58. Saland J, Leavey PJ, Bash RO, Hansch E, Arbus GS, Quigley R (2002) Effective removal of methotrexate by high-flux hemodialysis. Pediatr Nephrol 17(10):825–829. https://doi.org/10.1007/s00467-002-0946-7

    Article  PubMed  Google Scholar 

  59. Buchen S, Ngampolo D, Melton RG, Hasan C, Zoubek A, Henze G, Bode U, Fleischhack G (2005) Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure. Br J Cancer 92(3):480–487. https://doi.org/10.1038/sj.bjc.6602337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Murphy SW, Barrett BJ, Parfrey PS (2000) Contrast nephropathy. J Am Soc Nephrol 11(1):177–182. https://doi.org/10.1681/ASN.V111177

    Article  PubMed  Google Scholar 

  61. Naesens M, Kuypers DR, Sarwal M (2009) Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4(2):481–508. https://doi.org/10.2215/CJN.04800908

    Article  CAS  PubMed  Google Scholar 

  62. Brewster U, Perazella M (2007) Proton pump inhibitors and the kidney: critical. Clin Nephrol 68:65–72

    Article  CAS  PubMed  Google Scholar 

  63. Simpson IJ, Marshall MR, Pilmore H, Manley P, Williams L, Thein H, Voss D (2006) Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases. Nephrology 11(5):381–385. https://doi.org/10.1111/j.1440-1797.2006.00651.x

    Article  CAS  PubMed  Google Scholar 

  64. Chapman MJ, Carrie A (2005) Mechanisms of Statin-Induced Myopathy. Arteriosclerosis, thrombosis, and vascular biology. https://doi.org/10.1161/10.1161/01.ATV.0000194548.11901.a4

  65. van Zyl-Smit R, Firth JC, Duffield M, Marais AD (2004) Renal tubular toxicity of HMG-CoA reductase inhibitors. Nephrol Dialysis Transplantation 19(12):3176–3179. https://doi.org/10.1093/ndt/gfh474

    Article  CAS  Google Scholar 

  66. Dickenmann M, Oettl T, Mihatsch MJ (2008) Osmotic nephrosis: acute kidney injury with accumulation of proximal tubular lysosomes due to administration of exogenous solutes. Am J Kidney Dis 51(3):491–503. https://doi.org/10.1053/j.ajkd.2007.10.044

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to the Chitkara College of Pharmacy, Chitkara University, Rajpura, Patiala, Punjab, India for providing the necessary facilities to carry out the research work.

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  1. Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India, 140401

    Veerta Sharma & Thakur Gurjeet Singh

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Conceptualization: Thakur Gurjeet Singh. Analyzed the data: Thakur Gurjeet Singh Wrote the manuscript: Veerta Sharma. Visualization: Thakur Gurjeet Singh Editing of the Manuscript: Veerta Sharma, Thakur Gurjeet Singh Critically reviewed the article: Thakur Gurjeet Singh. Supervision: Thakur Gurjeet Singh. All authors read and approved the final manuscript.

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Sharma, V., Singh, T.G. Drug induced nephrotoxicity- A mechanistic approach. Mol Biol Rep 50, 6975–6986 (2023). https://doi.org/10.1007/s11033-023-08573-4

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