Skip to main content

Advertisement

SpringerLink
Log in

Proton pump inhibitors use and risk of incident nephrolithiasis

  • Original Article
  • Published:
Urolithiasis Aims and scope Submit manuscript

Abstract

Proton pump inhibitors (PPIs) are widely prescribed medications that have effects on both enteric and urinary solute handling with an unknown effect on risk of nephrolithiasis. Our objectives were to examine the association between PPI exposure and incident nephrolithiasis and to determine its effect on 24H urine chemistry. We performed a single-center retrospective study on patients diagnosed with gastroesophageal reflux disease (GERD) without a history of kidney stones. Exposure to PPIs was abstracted, and then subsequent kidney stone diagnoses were identified. Multivariable Cox models with time-varying covariates were used to estimate the hazard of PPI use on incident nephrolithiasis. We used multivariable linear regression to analyze a subset of patients who went through 24-h urine analysis. We identified n = 55,765 PPI-naïve GERD patients without prior kidney stone diagnoses of whom 40,866 (73.2%) were exposed to PPI over a median of 3 year follow up. On multivariable analysis, PPI use was associated with higher risk of incident kidney stone diagnoses (HR 1.19, 95% CI 1.06–1.34). Among 593 patients with GERD with 24-H urine data, the PPI-exposed group (n = 307) had significantly lower mean urinary citrate (mean 3.0 vs 3.4 mmol, p = 0.029) and urinary magnesium (mean 3.6 vs 4.3 mmol, p < 0.001) on multivariable analyses. Exposure to PPIs is associated with an increased risk of kidney stones among patients with GERD. Hypomagnesemia and hypocitraturia associated with PPI exposure may contribute to kidney stone risk.

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

Similar content being viewed by others

Abbreviations

24H urine:

24-Hour urine

BMI:

Body mass index

CKD:

Chronic kidney disease

EMR:

Electronic medical record

H2RA:

Histamine-2 receptor antagonist

GERD:

Gastroesophageal reflux disease

PPI:

Proton pump inhibitor

SSCaOx:

Supersaturation of calcium oxalate

SSCaP:

Supersaturation of calcium phosphate

SSUA:

Supersaturation of uric acid

References

  1. Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL (2015) Trends in prescription drug use among adults in the United States from 1999–2012. JAMA 314:1818–1831. https://doi.org/10.1001/jama.2015.13766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schoenfeld AJ, Grady D (2016) Adverse effects associated with proton pump inhibitors. JAMA Intern Med 176:172–174. https://doi.org/10.1001/jamainternmed.2015.7927

    Article  PubMed  Google Scholar 

  3. Gomm W, von Holt K, Thome F, Broich K, Maier W, Fink A et al (2016) Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol 73:410–416. https://doi.org/10.1001/jamaneurol.2015.4791

    Article  PubMed  Google Scholar 

  4. Cheung KS, Chan EW, Wong AYS, Chen L, Wong ICK, Leung WK (2018) Long-term proton pump inhibitors and risk of gastric cancer development after treatment for helicobacter pylori: a population-based study. Gut 67:28–35. https://doi.org/10.1136/gutjnl-2017-314605

    Article  CAS  PubMed  Google Scholar 

  5. Wilhelm SM, Rjater RG, Kale-Pradhan PB (2013) Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev Clin Pharmacol 6:443–451. https://doi.org/10.1586/17512433.2013.811206

    Article  CAS  PubMed  Google Scholar 

  6. Wan QY, Wu XT, Li N, Du L, Zhou Y (2019) Long-term proton pump inhibitors use and risk of gastric cancer: a meta-analysis of 926 386 participants. Gut 68:762–764. https://doi.org/10.1136/gutjnl-2018-316416

    Article  CAS  PubMed  Google Scholar 

  7. Xie Y, Bowe B, Li T, Xian H, Balasubramanian S, Al-Aly Z (2016) Proton pump inhibitors and risk of incident CKD and progression to ESRD. J Am Soc Nephrol 27:3153–3163. https://doi.org/10.1681/ASN.2015121377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lazarus B, Chen Y, Wilson FP, Sang Y, Chang AR, Coresh J et al (2016) Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med 176:238–246. https://doi.org/10.1001/jamainternmed.2015.7193

    Article  PubMed  PubMed Central  Google Scholar 

  9. Klatte DCF, Gasparini A, Xu H, de Deco P, Trevisan M, Johansson ALV et al (2017) Association between proton pump inhibitor use and risk of progression of chronic kidney disease. Gastroenterology 153:702–710. https://doi.org/10.1053/j.gastro.2017.05.046

    Article  CAS  PubMed  Google Scholar 

  10. Simonov M, Abel EE, Skanderson M, Masoud A, Hauser RG, Brandt CA et al (2020) Use of proton pump inhibitors increases risk of incident kidney stones. Clin Gastroenterol Hepatol. https://doi.org/10.1016/j.cgh.2020.02.053

    Article  PubMed  PubMed Central  Google Scholar 

  11. Makunts T, Cohen IV, Awdishu L, Abagyan R (2019) Analysis of postmarketing safety data for proton-pump inhibitors reveals increased propensity for renal injury, electrolyte abnormalities, and nephrolithiasis. Sci Rep 9:2282. https://doi.org/10.1038/s41598-019-39335-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Park CH, Kim EH, Roh YH, Kim HY, Lee SK (2014) The association between the use of proton pump inhibitors and the risk of hypomagnesemia: a systematic review and meta-analysis. PLoS ONE 9:e112558. https://doi.org/10.1371/journal.pone.0112558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li MK, Blacklock NJ, Garside J (1985) Effects of magnesium on calcium oxalate crystallization. J Urol 133:123–125

    Article  CAS  Google Scholar 

  14. William JH, Nelson R, Hayman N, Mukamal KJ, Danziger J (2014) Proton-pump inhibitor use is associated with lower urinary magnesium excretion. Nephrology 19:798–801. https://doi.org/10.1111/nep.12330

    Article  CAS  PubMed  Google Scholar 

  15. Pak CY (1994) Citrate and renal calculi: an update. Miner Electrolyte Metab 20:371–377

    CAS  PubMed  Google Scholar 

  16. Patel PM, Kandabarow AM, Aiwerioghene E, Blanco-Martinez E, Hart S, Leehey DJ et al (2020) Proton-pump inhibitors associated with decreased urinary citrate excretion. Int Urol Nephrol. https://doi.org/10.1007/s11255-020-02719-0

    Article  PubMed  PubMed Central  Google Scholar 

  17. Danciu I, Cowan JD, Basford M, Wang X, Saip A, Osgood S et al (2014) Secondary use of clinical data: the vanderbilt approach. J Biomed Inform 52:28–35. https://doi.org/10.1016/j.jbi.2014.02.003

    Article  PubMed  PubMed Central  Google Scholar 

  18. Quamme GA (1997) Renal magnesium handling: new insights in understanding old problems. Kidney Int 52:1180–1195. https://doi.org/10.1038/ki.1997.443

    Article  CAS  PubMed  Google Scholar 

  19. Schwartz BF, Bruce J, Leslie S, Stoller ML (2001) Rethinking the role of urinary magnesium in calcium urolithiasis. J Endourol 15:233–235. https://doi.org/10.1089/089277901750161638

    Article  CAS  PubMed  Google Scholar 

  20. Markovits N, Loebstein R, Halkin H, Bialik M, Landes-Westerman J, Lomnicky J et al (2014) The association of proton pump inhibitors and hypomagnesemia in the community setting. J Clin Pharmacol 54:889–895. https://doi.org/10.1002/jcph.316

    Article  PubMed  Google Scholar 

  21. William JH, Danziger J (2016) Magnesium deficiency and proton-pump inhibitor use: a clinical review. J Clin Pharmacol 56:660–668. https://doi.org/10.1002/jcph.672

    Article  CAS  PubMed  Google Scholar 

  22. Luk CP, Parsons R, Lee YP, Hughes JD (2013) Proton pump inhibitor-associated hypomagnesemia: what do FDA data tell us? Ann Pharmacother 47:773–780. https://doi.org/10.1345/aph.1R556

    Article  CAS  PubMed  Google Scholar 

  23. Hess MW, Hoenderop JG, Bindels RJ, Drenth JP (2012) Systematic review: hypomagnesaemia induced by proton pump inhibition. Aliment Pharmacol Ther 36:405–413. https://doi.org/10.1111/j.1365-2036.2012.05201.x

    Article  CAS  PubMed  Google Scholar 

  24. Zuckerman JM, Assimos DG (2009) Hypocitraturia: pathophysiology and medical management. Rev Urol 11:134–144

    PubMed  PubMed Central  Google Scholar 

  25. Pak CY (2004) Medical management of urinary stone disease. Nephron Clin Pract 98:c49-53. https://doi.org/10.1159/000080252

    Article  PubMed  Google Scholar 

  26. Allie S, Rodgers A (2003) Effects of calcium carbonate, magnesium oxide and sodium citrate bicarbonate health supplements on the urinary risk factors for kidney stone formation. Clin Chem Lab Med 41:39–45. https://doi.org/10.1515/CCLM.2003.008

    Article  CAS  PubMed  Google Scholar 

  27. Rodgers A (1999) Aspects of calcium oxalate crystallization: theory, in vitro studies, and in vivo implementation. J Am Soc Nephrol 10(Suppl 14):S351–S354

    CAS  PubMed  Google Scholar 

  28. Blaine J, Chonchol M, Levi M (2015) Renal control of calcium, phosphate, and magnesium homeostasis. Clin J Am Soc Nephrol 10:1257–1272. https://doi.org/10.2215/CJN.09750913

    Article  CAS  PubMed  Google Scholar 

  29. Mackay JD, Bladon PT (2010) Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series. QJM 103:387–395. https://doi.org/10.1093/qjmed/hcq021

    Article  CAS  PubMed  Google Scholar 

  30. El-Serag HB, Sweet S, Winchester CC, Dent J (2014) Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 63:871–880. https://doi.org/10.1136/gutjnl-2012-304269

    Article  PubMed  Google Scholar 

  31. Vlasschaert ME, Bejaimal SA, Hackam DG, Quinn R, Cuerden MS, Oliver MJ et al (2011) Validity of administrative database coding for kidney disease: a systematic review. Am J Kidney Dis 57:29–43. https://doi.org/10.1053/j.ajkd.2010.08.031

    Article  PubMed  Google Scholar 

  32. Xia B, Yang M, Nguyen LH, He Q, Zhen J, Yu Y et al (2021) Regular use of proton pump inhibitor and the risk of inflammatory bowel disease: pooled analysis of 3 prospective cohorts. Gastroenterology 161:1842-1852.e10. https://doi.org/10.1053/j.gastro.2021.08.005

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge and thank Dr. John Asplin and Dr. Nicholas Kavoussi for their assistance in review of this manuscript.

Funding

The publication described was supported by CTSA award No. UL1 TR002243 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Urology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Wilson Sui, Nicole L. Miller & Ryan S. Hsi

  2. Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Edward R. Gould

  3. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

    Kevin C. Zhang & Tatsuki Koyama

Authors
  1. Wilson Sui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicole L. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edward R. Gould
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kevin C. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tatsuki Koyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ryan S. Hsi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ryan S. Hsi.

Ethics declarations

Conflict of interest

None.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 30 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sui, W., Miller, N.L., Gould, E.R. et al. Proton pump inhibitors use and risk of incident nephrolithiasis. Urolithiasis 50, 401–409 (2022). https://doi.org/10.1007/s00240-022-01326-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00240-022-01326-1

Keywords

Search

Navigation