https://doi.org/10.4081/aiua.2022.4.507
Risk of urinary stone formation associated to proton pump inhibitors: A systematic review and metanalysis
Published: December 28, 2022
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Supplementary Material: 84
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
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Objective: Proton pump inhibitors are widely used as treatment of acid-related disorders. They are considered safe although their long-term use has been associated with some adverse effects including an increased propensity for urinary calculi formation. The aim of this study was to systematically review available data from studies evaluating the association of PPIs and nephrolithiasis.
Materials and methods: We searched two electronic databases (PubMed and EMBASE) for cohort studies or case-control studies evaluating the relationship between treatment with proton pump inhibitors and the risk of stone formation published up to 31 October 2022. The overall association of PPIs and urinary calculi was analyzed using a random effects model (RevMan5). The quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale.
Results: A total of 550 studies were retrieved; 7 were selected by title and abstract screening; after removal of duplicates, 4 records were evaluated by full-text examination. An additional study was retrieved by handsearching the references included in screened studies. In the unadjusted analysis, the odds of urinary calculi were greater in subjects taking PPIs compared to controls (unadjusted OR = 2.10, 95% CI 1.74-2.52, p < 0.00001). The pooled odds ratio of two case-control studies confirmed that use of PPIs increased the odds of urinary calculi compared with non-use (OR 2.44, 95% CI 2.29 to 2.61). Pooled analysis of three cohort studies evaluating incident nephrolithiasis showed an overall hazard ratio estimate of 1.34 (95% CI = 1.28-1.40). One study found lower urinary citrate and urinary magnesium levels in subjects exposed to PPIs. The Newcastle-Ottawa Quality Assessment Scale scores ranged between 6 and 8.
Conclusions: PPIs showed an association with urinary calculi in patients included in the studies included in this review. If these data will be confirmed in adequately powered randomized trials, clinicians may consider limiting the long-term use of PPIs, to avoid unnecessary prolongation of treatment. Urinary magnesium and citrate should be evaluated in renal stone forming patients taking PPIs to supplement their intake when requested.
Zamburak RD, Schubert ML. Control of gastric acid secretion.Histamine H2-receptor antagonists and H+K(+)-ATPase inhibitors.
Gastroenterol Clin North Am. 1992; 21:527-50.
DOI: https://doi.org/10.1016/S0889-8553(21)00047-9
Laheij RJ, Sturkenboom MC, Hassing RJ, et al. Risk of community- acquired pneumonia and use of gastric acid suppressive drugs. JAMA 2004; 292:1955-1960.
DOI: https://doi.org/10.1001/jama.292.16.1955
Yang YX, Lewis JD, Epstein S, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006; 296:2947-2953.
DOI: https://doi.org/10.1001/jama.296.24.2947
Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep. 2010; 12:448-57.
DOI: https://doi.org/10.1007/s11894-010-0141-0
Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol. 2007; 102:2047-2056.
DOI: https://doi.org/10.1111/j.1572-0241.2007.01275.x
Dial S, Delaney JAC, Barkun AN, et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile- associated disease. JAMA. 2005; 294:2989-2995.
DOI: https://doi.org/10.1001/jama.294.23.2989
Trifan A, Stanciu C, Girleanu I, et al. Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis. World J Gastroenterol. 2017; 23:6500-15.
DOI: https://doi.org/10.3748/wjg.v23.i35.6500
Charlot M, Grove EL, Hansen PR, et al. Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patient with first time myocardial infarction: a nationwide propensity score matched analysis. BMJ. 2011; 342:d2690.
DOI: https://doi.org/10.1136/bmj.d2690
Lazarus B, Chen Y, Wilson FP, et al. Proton pump inhibitor use and risk of chronic kidney disease. JAMA Intern Med. 2016;176:238-246.
DOI: https://doi.org/10.1001/jamainternmed.2015.7193
Gomm W, von Holt K, Thome F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016; 73:410-416.
DOI: https://doi.org/10.1001/jamaneurol.2015.4791
Makunts T, Cohen IV, Awdishu L, Abagyan R. Analysis of postmarketing safety data for proton-pump inhibitors reveals increased propensity for renal injury, electrolyte abnormalities, and nephrolithiasis. Sci Rep. 2019; 9:2282.
DOI: https://doi.org/10.1038/s41598-019-39335-7
Ferraro PCG, Gambaro G, Taylor E. Proton Pump Inhibitors, Histamine Receptor-2 Blockers and the Risk of Incident Kidney Stones. American Society of Nephrology Kidney Week; Chicago, IL 2016; p.467A.
Kwak YE, Buller G, Masoud A. Increased risk of nephrolithiasis in patients using chronic proton pump inhibitor and antacid agents. Gastroenterology. 2017; 152:5(Suppl 1)(S273-).
DOI: https://doi.org/10.1016/S0016-5085(17)31210-6
Kim SY, Yoo DM, Bang WJ, Choi HG. Association between Urolithiasis and History Proton Pump Inhibitor Medication: A Nested Case-Control Study. J Clin Med. 2022; 11:5693.
DOI: https://doi.org/10.3390/jcm11195693
Simonov M, Abel EA, Skanderson M, et al. Use of Proton Pump Inhibitors Increases Risk of Incident Kidney Stones. Clin Gastroenterol Hepatol. 2021; 19:72-79.e21.
DOI: https://doi.org/10.1016/j.cgh.2020.02.053
Sui W, Miller NL, Gould ER, et al. Proton pump inhibitors use and risk of incident nephrolithiasis. Urolithiasis. 2022; 50:401-409.
DOI: https://doi.org/10.1007/s00240-022-01326-1
Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-analyses: The PRISMA Statement. PLoS Med. 2009; 6:e1000097.
DOI: https://doi.org/10.1371/journal.pmed.1000097
Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses; 2013. https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
Daudon M, Frochot V, Bazin D, Jungers P. Drug-Induced Kidney Stones and Crystalline Nephropathy: Pathophysiology, Prevention and Treatment. Drugs. 2018; 78:163-201.
DOI: https://doi.org/10.1007/s40265-017-0853-7
Shkembi B, Huppertz T. Calcium Absorption from Food Products: Food Matrix Effects. Nutrients. 2021; 14:180.
DOI: https://doi.org/10.3390/nu14010180
Voets T, Nilius B, Hoefs S, et al. TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem. 2004;279:19-25
DOI: https://doi.org/10.1074/jbc.M311201200
Li M, Du J, Jiang J, Ratzan W, et al. Molecular determinants of Mg2+ and Ca2+ permeability and pH sensitivity in TRPM6 and TRPM7. J Biol Chem. 2007; 282:25817-25830.
DOI: https://doi.org/10.1074/jbc.M608972200
Thongon N, Krishnamra N. Apical acidity decreases inhibitory effect of omeprazole on Magnesium(2+) absorption and claudin-7 and -12 expression in Caco-2 monolayers. Exp Mol Med. 2012; 44:684-93.
DOI: https://doi.org/10.3858/emm.2012.44.11.077
Kieboom BC, Kiefte-de Jong JC, Eijgelsheim M, et al. Proton pump inhibitors and hypomagnesemia in the general population: a population based cohort study. Am J Kidney Dis. 2015; 66:775-82.
DOI: https://doi.org/10.1053/j.ajkd.2015.05.012
Atkinson NS, Reynolds DJ, Travis SP. 'Lemonade Legs': Why do Some Patients Get Profound Hypomagnesaemia on Proton-Pump Inhibitors? Intest Res. 2015; 13:227-32.
DOI: https://doi.org/10.5217/ir.2015.13.3.227
Fatuzzo P, Portale G, Scollo V, et al. Proton pump inhibitors and symptomatic hypomagnesemic hypoparathyroidism. J Nephrol. 2017; 30:297-301.
DOI: https://doi.org/10.1007/s40620-016-0319-0
Negri AL, Valle EE. Hypomagnesaemia/hypokalemia associated with the use of esomeprazole. Curr Drug Saf. 2011; 6:204-6.
DOI: https://doi.org/10.2174/157488611797579320
Patel PM, Kandabarow AM, Aiwerioghene E, et al. Proton-pump inhibitors associated with decreased urinary citrate excretion. Int Urol Nephrol. 2021; 53:679-683.
DOI: https://doi.org/10.1007/s11255-020-02719-0
William JH, Nelson R, Hayman N, et al. Proton-pump inhibitor use is associated with lower urinary magnesium excretion. Nephrology 2014; 19:798-801.
DOI: https://doi.org/10.1111/nep.12330
William JH, Danziger J. Proton-Pump inhibitor-induced hypomagnesemia: current research and proposed mechanisms. World J Nephrol. 2016; 5:152.
DOI: https://doi.org/10.5527/wjn.v5.i2.152
Simpson DP. Citrate excretion: a window on renal metabolism. Am J Physiol. 1983; 244:F223-34.
DOI: https://doi.org/10.1152/ajprenal.1983.244.3.F223
Howden CW, Reid JL. Omeprazole, a gastric 'proton pump inhibitor': lack of effect on renal handling of electrolytes and urinary acidification. Eur J Clin Pharmacol. 1984; 26:639-40.
DOI: https://doi.org/10.1007/BF00543501
Isse N, Hashimoto M. Omeprazole-induced hypomagnesaemia, causing renal tubular acidosis with hypokalaemia, hypocalcaemia, hyperlactacidaemia and hyperammonaemia. BMJ Case Rep. 2020;13:e235385.
DOI: https://doi.org/10.1136/bcr-2020-235385
Penniston KL, Li S, Nakada SY, Jhagroo RA. Omeprazole lowers 24-hour urinary magnesium excretion in patients with a history of urolithiasis: Single center experience. J Urol. 2021; 206(Suppl 3):e143.
DOI: https://doi.org/10.1097/JU.0000000000001980.11
Hautmann RE. The stomach: a new and powerful oxalate absorption site in man. J Urol. 1993; 149:1401-4.
DOI: https://doi.org/10.1016/S0022-5347(17)36400-5
Sonnenberg A, Turner KO, Genta RM. Decreased risk for microscopic colitis and inflammatory bowel disease among patients with reflux disease. Colorectal Dis. 2018; 20:813-820.
DOI: https://doi.org/10.1111/codi.14114
Lovell RM, Ford AC. Prevalence of gastro-esophageal reflux-type symptoms in individuals with irritable bowel syndrome in the community: a meta-analysis. Am J Gastroenterol. 2012; 107:1793-801.
DOI: https://doi.org/10.1038/ajg.2012.336
Jacobson BC, Somers SC, Fuchs CS, et al. Body-mass index and symptoms of gastroesophageal reflux in women. N Engl J Med. 2006; 354:2340-8.
DOI: https://doi.org/10.1056/NEJMoa054391
Locke GR 3rd, Talley NJ, Fett SL, et al. Risk factors associated with symptoms of gastroesophageal reflux. Am J Med. 1999;106:642-9.
DOI: https://doi.org/10.1016/S0002-9343(99)00121-7
Aune D, Mahamat-Saleh Y, Norat T, Riboli E. Body fatness, diabetes,physical activity and risk of kidney stones: a systematic review and meta-analysis of cohort studies. Eur J Epidemiol. 2018; 33:1033-1047.
DOI: https://doi.org/10.1007/s10654-018-0426-4
Zhang M, Hou ZK, Huang ZB, et al. Dietary and Lifestyle Factors Related to Gastroesophageal Reflux Disease: A Systematic Review. Ther Clin Risk Manag. 2021; 17:305-323.
DOI: https://doi.org/10.2147/TCRM.S296680
Taylor EN, Fung TT, Curhan GC. DASH-style diet associates with reduced risk for kidney stones. J Am Soc Nephrol. 2009; 20:2253-9.
DOI: https://doi.org/10.1681/ASN.2009030276
Moayyedi P. Leaving No Stone Unturned in the Search for Adverse Events Associated With Use of Proton Pump Inhibitors. Clin Gastroenterol Hepatol. 2021; 19:41-42.
DOI: https://doi.org/10.1016/j.cgh.2020.04.053
Moayyedi P, Eikelboom JW, Bosch J, et al.; COMPASS Investigators. Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin. Gastroenterology. 2019; 157:682-691.e2.
Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med. 2000; 342:1887-92.
DOI: https://doi.org/10.1056/NEJM200006223422507
How to Cite
Bapir, R., Bhatti, K. H., Eliwa, A., García-Perdomo, H. A., Gherabi, N., Hennessey, D., Magri, V., Mourmouris, P., Ouattara, A., Perletti, G., Philipraj, J., Stamatiou, K., Adetola Tolani, M., Tzelves, L., Trinchieri, A., & Buchholz, N. (2022). Risk of urinary stone formation associated to proton pump inhibitors: A systematic review and metanalysis. Archivio Italiano Di Urologia E Andrologia, 94(4), 507–514. https://doi.org/10.4081/aiua.2022.4.507
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