Skip to main content
SpringerLink
Log in

Incidence, Pathogenesis, and Management of Proton Pump Inhibitor-Induced Nephrotoxicity

  • Review Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Proton pump inhibitors are widely used in the treatment of various acid-related diseases and are among the most commonly used drugs. Studies estimate that 25–70% of proton pump inhibitors are prescribed for inappropriate treatments, doses, and indications, where the benefits of proton pump inhibitor use may be less than the risk of adverse drug reactions for many patients. Acute interstitial nephritis is an immune-mediated atypical kidney injury in the long-term use of proton pump inhibitors that causes problems for clinicians and patients. In this review, we summarize the current knowledge of proton pump inhibitors inducing acute interstitial nephritis, chronic kidney disease, and even end-stage renal disease in terms of incidence, pathogenesis, factors, clinical features, and diagnosis. We discuss how these factors change under conditions of acute interstitial nephritis, chronic kidney disease, and end-stage renal disease. The purpose of this review is to assess the current evidence to help clinicians and patients interpret the potential causal relationship between proton pump inhibitor intake and nephrotoxicity. This prompts clinicians to consider the appropriate dose and duration of proton pump inhibitor therapy to avoid inappropriate use.

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

References

  1. Brewster UC, Perazella MA. Acute kidney injury following proton pump inhibitor therapy. Kidney Int. 2007;71(6):589–93.

    Article  CAS  PubMed  Google Scholar 

  2. Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL. Trends in prescription drug use among adults in the United States from 1999–2012. JAMA. 2015;314(17):1818–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors. BMJ. 2008;336(7634):2–3.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sattayalertyanyong O, Thitilertdecha P, Auesomwang C. The inappropriate use of proton pump inhibitors during admission and after discharge: a prospective cross-sectional study. Int J Clin Pharm. 2020;42(1):174–83.

    Article  PubMed  Google Scholar 

  5. Villamanan E, Ruano M, Lara C, Suarez-de-Parga JM, Armada E, Alvarez-Sala R, et al. Reasons for initiation of proton pump inhibitor therapy for hospitalised patients and its impact on outpatient prescription in primary care. Rev Esp Enferm Dig. 2015;107(11):652–8.

    CAS  PubMed  Google Scholar 

  6. Savarino V, Dulbecco P, de Bortoli N, Ottonello A, Savarino E. The appropriate use of proton pump inhibitors (PPIs): need for a reappraisal. Eur J Intern Med. 2017;37:19–24.

    Article  CAS  PubMed  Google Scholar 

  7. Fossmark R, Martinsen TC, Waldum HL. Adverse effects of proton pump inhibitors: evidence and plausibility. Int J Mol Sci. 2019;20(20):5203.

    Article  CAS  PubMed Central  Google Scholar 

  8. Lazarus B, Chen Y, Wilson FP, Sang Y, Chang AR, Coresh J, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016;176(2):238–46.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Boonpheng B, Thongprayoon C, Bathini T, Sharma K, Mao MA, Cheungpasitporn W. Proton pump inhibitors and adverse effects in kidney transplant recipients: a meta-analysis. World J Transplant. 2019;9(2):35–47.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Antoniou T, Macdonald EM, Hollands S, Gomes T, Mamdani MM, Garg AX, et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open. 2015;3(2):E166–71.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Al-Aly Z, Maddukuri G, Xie Y. Proton pump inhibitors and the kidney: implications of current evidence for clinical practice and when and how to deprescribe. Am J Kidney Dis. 2020;75(4):497–507.

    Article  PubMed  Google Scholar 

  12. Ruffenach SJ, Siskind MS, Lien YH. Acute interstitial nephritis due to omeprazole. Am J Med. 1992;93(4):472–3.

    Article  CAS  PubMed  Google Scholar 

  13. Xie Y, Bowe B, Li T, Xian H, Balasubramanian S, Al-Aly Z. Proton pump inhibitors and risk of incident CKD and progression to ESRD. J Am Soc Nephrol. 2016;27(10):3153–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bruno G, Zaccari P, Rocco G, Scalese G, Panetta C, Porowska B, et al. Proton pump inhibitors and dysbiosis: current knowledge and aspects to be clarified. World J Gastroenterol. 2019;25(22):2706–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Malfertheiner P, Kandulski A, Venerito M. Proton-pump inhibitors: understanding the complications and risks. Nat Rev Gastroenterol Hepatol. 2017;14(12):697–710.

    Article  CAS  PubMed  Google Scholar 

  16. Simpson IJ, Marshall MR, Pilmore H, Manley P, Williams L, Thein H, et al. Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases. Nephrology (Carlton). 2006;11(5):381–5.

    Article  CAS  Google Scholar 

  17. Blank ML, Parkin L, Paul C, Herbison P. A nationwide nested case–control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int. 2014;86(4):837–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Harmark L, van der Wiel HE, de Groot MC, van Grootheest AC. Proton pump inhibitor-induced acute interstitial nephritis. Br J Clin Pharmacol. 2007;64(6):819–23.

    PubMed  PubMed Central  Google Scholar 

  19. Sampathkumar K, Ramalingam R, Prabakar A, Abraham A. Acute interstitial nephritis due to proton pump inhibitors. Indian J Nephrol. 2013;23(4):304–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Muriithi AK, Leung N, Valeri AM, Cornell LD, Sethi S, Fidler ME, et al. Biopsy-proven acute interstitial nephritis, 1993–2011: a case series. Am J Kidney Dis. 2014;64(4):558–66.

    Article  PubMed  Google Scholar 

  21. Moledina DG, Perazella MA. PPIs and kidney disease: from AIN to CKD. J Nephrol. 2016;29(5):611–6.

    Article  CAS  PubMed  Google Scholar 

  22. Rossert J. Drug-induced acute interstitial nephritis. Kidney Int. 2001;60(2):804–17.

    Article  CAS  PubMed  Google Scholar 

  23. Gabbai FB, Hammond TC, Thomson SC, Khang S, Kelly CJ. Effect of acute iNOS inhibition on glomerular function in tubulointerstitial nephritis. Kidney Int. 2002;61(3):851–4.

    Article  CAS  PubMed  Google Scholar 

  24. Myers RP, McLaughlin K, Hollomby DJ. Acute interstitial nephritis due to omeprazole. Am J Gastroenterol. 2001;96(12):3428–31.

    Article  CAS  PubMed  Google Scholar 

  25. Perazella MA. Clinical approach to diagnosing acute and chronic tubulointerstitial disease. Adv Chronic Kidney Dis. 2017;24(2):57–63.

    Article  PubMed  Google Scholar 

  26. Muriithi AK, Leung N, Valeri AM, Cornell LD, Sethi S, Fidler ME, et al. Clinical characteristics, causes and outcomes of acute interstitial nephritis in the elderly. Kidney Int. 2015;87(2):458–64.

    Article  CAS  PubMed  Google Scholar 

  27. Geevasinga N, Coleman PL, Roger SD. Rabeprazole-induced acute interstitial nephritis. Nephrology (Carlton). 2005;10(1):7–9.

    Article  Google Scholar 

  28. Assouad M, Vicks SL, Pokroy MV, Willcourt RJ. Recurrent acute interstitial nephritis on rechallenge with omeprazole. Lancet. 1994;344(8921):549.

    Article  CAS  PubMed  Google Scholar 

  29. Geevasinga N, Coleman PL, Webster AC, Roger SD. Proton pump inhibitors and acute interstitial nephritis. Clin Gastroenterol Hepatol. 2006;4(5):597–604.

    Article  CAS  PubMed  Google Scholar 

  30. Moledina DG, Perazella MA. Drug-induced acute interstitial nephritis. Clin J Am Soc Nephrol. 2017;12(12):2046–9.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Torpey N, Barker T, Ross C. Drug-induced tubulo-interstitial nephritis secondary to proton pump inhibitors: experience from a single UK renal unit. Nephrol Dial Transplant. 2004;19(6):1441–6.

    Article  CAS  PubMed  Google Scholar 

  32. Ray S, Delaney M, Muller AF. Proton pump inhibitors and acute interstitial nephritis. BMJ. 2010;341: c4412.

    Article  CAS  PubMed  Google Scholar 

  33. Cortazar FB, Kibbelaar ZA, Glezerman IG, Abudayyeh A, Mamlouk O, Motwani SS, et al. Clinical features and outcomes of immune checkpoint inhibitor-associated AKI: a multicenter study. J Am Soc Nephrol. 2020;31(2):435–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Seethapathy H, Zhao S, Chute DF, Zubiri L, Oppong Y, Strohbehn I, et al. The incidence, causes, and risk factors of acute kidney injury in patients receiving immune checkpoint inhibitors. Clin J Am Soc Nephrol. 2019;14(12):1692–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ikuta K, Nakagawa S, Momo K, Yonezawa A, Itohara K, Sato Y, et al. Association of proton pump inhibitors and concomitant drugs with risk of acute kidney injury: a nested case–control study. BMJ Open. 2021;11(2): e041543.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sutton SS, Magagnoli J, Cummings TH, Hardin JW. Risk of acute kidney injury in patients with HIV receiving proton pump inhibitors. J Comp Eff Res. 2019;8(10):781–90.

    Article  PubMed  Google Scholar 

  37. Svanstrom H, Lund M, Melbye M, Pasternak B. Use of proton pump inhibitors and the risk of acute kidney injury among patients with rheumatoid arthritis: cohort study. Drug Saf. 2018;41(8):817–26.

    Article  CAS  PubMed  Google Scholar 

  38. Gerstman BB. Proton pump inhibitors and chronic kidney disease: reevaluating the evidence from a randomized controlled trial. Pharmacoepidemiol Drug Saf. 2021;30(1):4–8.

    Article  PubMed  Google Scholar 

  39. Chawla LS, Eggers PW, Star RA, Kimmel PL. Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med. 2014;371(1):58–66.

    Article  PubMed  CAS  Google Scholar 

  40. Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet. 2019;394(10212):1949–64.

    Article  CAS  PubMed  Google Scholar 

  41. Rudler M, Isnard Bagnis C, Rudler H. Proton pump inhibitors and chronic kidney disease: is it related to the accumulation of toxic breakdown products spontaneously formed in the enteric-protected tablets? Gastroenterology. 2018;154(4):1204–5.

    Article  PubMed  Google Scholar 

  42. Kawasaki Y, Umemura T, Saito M, Momma J, Matsushima Y, Sekiguchi H, et al. Toxicity study of a rubber antioxidant, 2-mercaptobenzimidazole, by repeated oral administration to rats. J Toxicol Sci. 1998;23(1):53–68.

    Article  CAS  PubMed  Google Scholar 

  43. Ghebremariam YT, LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH, et al. Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine. Circulation. 2013;128(8):845–53.

    Article  CAS  PubMed  Google Scholar 

  44. Klatte DCF, Gasparini A, Xu H, de Deco P, Trevisan M, Johansson ALV, et al. Association between proton pump inhibitor use and risk of progression of chronic kidney disease. Gastroenterology. 2017;153(3):702–10.

    Article  CAS  PubMed  Google Scholar 

  45. Hart E, Dunn TE, Feuerstein S, Jacobs DM. Proton pump inhibitors and risk of acute and chronic kidney disease: a retrospective cohort study. Pharmacotherapy. 2019;39(4):443–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li T, Xie Y, Al-Aly Z. The association of proton pump inhibitors and chronic kidney disease: cause or confounding? Curr Opin Nephrol Hypertens. 2018;27(3):182–7.

    Article  CAS  PubMed  Google Scholar 

  47. Rodriguez-Poncelas A, Barcelo MA, Saez M, Coll-de-Tuero G. Duration and dosing of proton pump inhibitors associated with high incidence of chronic kidney disease in population-based cohort. PLoS ONE. 2018;13(10): e0204231.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Guedes JVM, Aquino JA, Castro TLB, Augusto de Morais F, Baldoni AO, Belo VS, et al. Omeprazole use and risk of chronic kidney disease evolution. PLoS ONE. 2020;15(3):e0229344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Haring B, Selvin E, Liang M, Coresh J, Grams ME, Petruski-Ivleva N, et al. Dietary protein sources and risk for incident chronic kidney disease: results from the Atherosclerosis Risk in Communities (ARIC) Study. J Ren Nutr. 2017;27(4):233–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mone I, Kraja B, Bregu A, Duraj V, Sadiku E, Hyska J, et al. Adherence to a predominantly Mediterranean diet decreases the risk of gastroesophageal reflux disease: a cross-sectional study in a South Eastern European population. Dis Esophagus. 2016;29(7):794–800.

    Article  CAS  PubMed  Google Scholar 

  51. Mhaskar RS, Ricardo I, Azliyati A, Laxminarayan R, Amol B, Santosh W, et al. Assessment of risk factors of Helicobacter pylori infection and peptic ulcer disease. J Glob Infect Dis. 2013;5(2):60–7.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Fusaro M, Giannini S, Gallieni M. Adverse effects of proton pump inhibitors in chronic kidney disease. JAMA Intern Med. 2016;176(6):866.

    Article  PubMed  Google Scholar 

  53. William JH, Danziger J. Magnesium deficiency and proton-pump inhibitor use: a clinical review. J Clin Pharmacol. 2016;56(6):660–8.

    Article  CAS  PubMed  Google Scholar 

  54. Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case–control study. BMJ. 2013;346: e8525.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Saka Y, Naruse T, Matsumoto J, Takeda Y, Onogi C, Yokoi J, et al. Low serum zinc concentration is associated with infection particularly in patients with stage 5 chronic kidney disease medicated with proton pump inhibitors. J Ren Nutr. 2021;31(6):579–85.

    Article  CAS  PubMed  Google Scholar 

  56. Yang H, Juang SY, Liao KF. Proton pump inhibitors use and risk of chronic kidney disease in diabetic patients. Diabetes Res Clin Pract. 2019;147:67–75.

    Article  CAS  PubMed  Google Scholar 

  57. Halen NV, Cukor D, Constantiner M, Kimmel PL. Depression and mortality in end-stage renal disease. Curr Psychiatry Rep. 2012;14(1):36–44.

    Article  PubMed  Google Scholar 

  58. Ku E, Hsu RK, Johansen KL, McCulloch CE, Mitsnefes M, Grimes BA, et al. Recovery of kidney function after dialysis initiation in children and adults in the US: a retrospective study of United States Renal Data System data. PLoS Med. 2021;18(2): e1003546.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Peng YC, Lin CL, Yeh HZ, Chang CS, Wu YL, Kao CH. Association between the use of proton pump inhibitors and the risk of ESRD in renal diseases: a population-based, case–control study. Medicine (Baltimore). 2016;95(15): e3363.

    Article  CAS  Google Scholar 

  60. Mertz A, Cooney D, Rahman M, Lacey C, Burant CJ, Desai N. Discontinuation of proton pump inhibitors in patients with chronic kidney disease. Hosp Pharm. 2021;56(4):308–13.

    Article  CAS  PubMed  Google Scholar 

  61. Sakaguchi Y, Fujii N, Shoji T, Hayashi T, Rakugi H, Isaka Y. Hypomagnesemia is a significant predictor of cardiovascular and non-cardiovascular mortality in patients undergoing hemodialysis. Kidney Int. 2014;85(1):174–81.

    Article  CAS  PubMed  Google Scholar 

  62. Li L, Streja E, Rhee CM, Mehrotra R, Soohoo M, Brunelli SM, et al. Hypomagnesemia and mortality in incident hemodialysis Patients. Am J Kidney Dis. 2015;66(6):1047–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lacson E Jr, Wang W, Ma L, Passlick-Deetjen J. Serum magnesium and mortality in hemodialysis patients in the United States: a cohort study. Am J Kidney Dis. 2015;66(6):1056–66.

    Article  CAS  PubMed  Google Scholar 

  64. Brewster UC, Perazella MA. Proton pump inhibitors and the kidney: critical review. Clin Nephrol. 2007;68(2):65–72.

    Article  CAS  PubMed  Google Scholar 

  65. Alhosaini M, Walter JS, Singh S, Dieter RS, Hsieh A, Leehey DJ. Hypomagnesemia in hemodialysis patients: role of proton pump inhibitors. Am J Nephrol. 2014;39(3):204–9.

    Article  CAS  PubMed  Google Scholar 

  66. William JH, Nelson R, Hayman N, Mukamal KJ, Danziger J. Proton-pump inhibitor use is associated with lower urinary magnesium excretion. Nephrology (Carlton). 2014;19(12):798–801.

    Article  CAS  Google Scholar 

  67. Sakaguchi Y, Shoji T, Hayashi T, Suzuki A, Shimizu M, Mitsumoto K, et al. Hypomagnesemia in type 2 diabetic nephropathy: a novel predictor of end-stage renal disease. Diabetes Care. 2012;35(7):1591–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chen XX, Zhang L, Wang Y, Zheng JG. Pathological mechanisms of hypomagnesemia aggravating cardiovascular calcification in patients with chronic kidney disease. J Clin Nephrol. 2021;21(07):594–8.

    Google Scholar 

  69. Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-Aly Z. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury. Kidney Int. 2017;91(6):1482–94.

    Article  CAS  PubMed  Google Scholar 

  70. Schiffl H, Al-Nemnem E, Lang SM. Proton-pump inhibitors and chronic kidney disease: hidden consequences of an inappropriate drug use? Saudi J Kidney Dis Transpl. 2020;31(2):312–9.

    Article  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Xiao Wei and Jun Yu contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, 230022, Anhui, China

    Xiao Wei & Yonggui Wu

  2. Blood Purification Center, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

    Xiao Wei

  3. Institute of Clinical Pharmacology, Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui, China

    Jun Yu, Zhengkun Xu & Chun Wang

Authors
  1. Xiao Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhengkun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yonggui Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Chun Wang or Yonggui Wu.

Ethics declarations

Funding

This work was financially supported by the University Synergy Innovation Program of Anhui Province (Grant number: GXXT-2021-064), the Enhancement Programme for Basic and Clinical Cooperative Research of Anhui Medical University (Grant number: 2019xkjT016), the Joint Project of Nephrology and Pharmacology at Anhui Medical University (No. 2021cxk012), the Key Project Foundation of Natural Science Research in Universities of Anhui Province in China (No. KJ2021A0329), and the Foundation of Anhui Medical University (No. 2018xkj065).

Conflict of interest

Xiao Wei, Jun Yu, Zhengkun Xu, Chun Wang, and Yonggui Wu have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Code availability

Not applicable.

Author contributions

XW, JY, and ZKX contributed to the literature review, data collection, and article writing. JY contributed to the language polishing and graphical drawing (partial figure created with BioRender.com). CW and YGW contributed to the project design and article modification. All authors read and approved the final manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wei, X., Yu, J., Xu, Z. et al. Incidence, Pathogenesis, and Management of Proton Pump Inhibitor-Induced Nephrotoxicity. Drug Saf 45, 703–712 (2022). https://doi.org/10.1007/s40264-022-01181-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-022-01181-4

Search

Navigation