The association between use of proton-pump inhibitors and excess mortality after kidney transplantation: A cohort study


Autoři: Rianne M. Douwes aff001;  António W. Gomes-Neto aff001;  Michele F. Eisenga aff001;  Elisabet Van Loon aff002;  Joëlle C. Schutten aff001;  Rijk O. B. Gans aff001;  Maarten Naesens aff002;  Else van den Berg aff001;  Ben Sprangers aff002;  Stefan P. Berger aff001;  Gerjan Navis aff001;  Hans Blokzijl aff003;  Björn Meijers aff002;  Stephan J. L. Bakker aff001;  Dirk Kuypers aff002
Působiště autorů: Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands aff001;  Department of Nephrology and Renal Transplantation, University Hospitals Leuven and Nephrology & Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium aff002;  Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands aff003
Vyšlo v časopise: The association between use of proton-pump inhibitors and excess mortality after kidney transplantation: A cohort study. PLoS Med 17(6): e32767. doi:10.1371/journal.pmed.1003140
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003140

Souhrn

Background

Chronic use of proton-pump inhibitors (PPIs) is common in kidney transplant recipients (KTRs). However, concerns are emerging about the potential long-term complications of PPI therapy. We aimed to investigate whether PPI use is associated with excess mortality risk in KTRs.

Methods and findings

We investigated the association of PPI use with mortality risk using multivariable Cox proportional hazard regression analyses in a single-center prospective cohort of 703 stable outpatient KTRs, who visited the outpatient clinic of the University Medical Center Groningen (UMCG) between November 2008 and March 2011 (ClinicalTrials.gov Identifier NCT02811835). Independent replication of the results was performed in a prospective cohort of 656 KTRs from the University Hospitals Leuven (NCT01331668). Mean age was 53 ± 13 years, 57% were male, and 56.6% used PPIs. During median follow-up of 8.2 (4.7–9.0) years, 194 KTRs died. In univariable Cox regression analyses, PPI use was associated with an almost 2 times higher mortality risk (hazard ratio [HR] 1.86, 95% CI 1.38–2.52, P < 0.001) compared with no use. After adjustment for potential confounders, PPI use remained independently associated with mortality (HR 1.68, 95% CI 1.21–2.33, P = 0.002). Moreover, the HR for mortality risk in KTRs taking a high PPI dose (>20 mg omeprazole equivalents/day) compared with patients taking no PPIs (HR 2.14, 95% CI 1.48–3.09, P < 0.001) was higher than in KTRs taking a low PPI dose (HR 1.72, 95% CI 1.23–2.39, P = 0.001). These findings were replicated in the Leuven Renal Transplant Cohort. The main limitation of this study is its observational design, which precludes conclusions about causation.

Conclusions

We demonstrated that PPI use is associated with an increased mortality risk in KTRs, independent of potential confounders. Moreover, our data suggest that this risk is highest among KTRs taking high PPI dosages. Because of the observational nature of our data, our results require further corroboration before it can be recommended to avoid the long-term use of PPIs in KTRs.

Trial registration

ClinicalTrials.gov Identifier: NCT02811835, NCT01331668.

Klíčová slova:

Cardiovascular diseases – Death rates – Diabetes mellitus – Magnesium – Platelets – Renal diseases – Renal transplantation – Vitamin K


Zdroje

1. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999 Dec;341(23):1725–30. doi: 10.1056/NEJM199912023412303 10580071

2. Jofre R, Lopez-Gomez JM, Moreno F, Sanz-Guajardo D, Valderrabano F. Changes in quality of life after renal transplantation. Am J Kidney Dis. 1998 Jul;32(1):93–100. doi: 10.1053/ajkd.1998.v32.pm9669429 9669429

3. Schippers HM, Kalff MW. Cost comparison haemodialysis and renal transplantation. Tissue Antigens. 1976 Feb;7(2):86–90. doi: 10.1111/j.1399-0039.1976.tb01036.x 775684

4. Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant. 2011;11(3):450–62. doi: 10.1111/j.1600-6143.2010.03283.x 20973913

5. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant. 2004;4(3):378–83. doi: 10.1111/j.1600-6143.2004.00332.x 14961990

6. Coemans M, Süsal C, Döhler B, Anglicheau D, Giral M, Bestard O, et al. Analyses of the short- and long-term graft survival after kidney transplantation in Europe between 1986 and 2015. Kidney Int. 2018;94(5):964–73. doi: 10.1016/j.kint.2018.05.018 30049474

7. Oterdoom LH, de Vries AP, van Ree RM, Gansevoort RT, van Son WJ, van der Heide JJ, et al. N-terminal pro-B-type natriuretic peptide and mortality in renal transplant recipients versus the general population. Transplantation. 2009;87(10):1562–70. doi: 10.1097/TP.0b013e3181a4bb80 19461495

8. Epstein M, McGrath S, Law F. Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N Engl J Med. 2006;355(17):1834–6. doi: 10.1056/NEJMc066308 17065651

9. Park CH, Kim EH, Roh YH, Kim HY, Lee SK. The association between the use of proton pump inhibitors and the risk of hypomagnesemia: a systematic review and meta-analysis. PLoS ONE. 2014 Nov;9(11):e112558. doi: 10.1371/journal.pone.0112558 25394217

10. Kieboom BC, Jong JCK, Eijgelsheim M, Franco OH, Kuipers EJ, Hofman A, et al. Proton pump inhibitors and hypomagnesemia in the general population: a population-based cohort study. Am J Kidney Dis. 2015 Nov;66(5):775–82. doi: 10.1053/j.ajkd.2015.05.012 26123862

11. Regolisti G, Cabassi A, Parenti E, Maggiore U, Fiaccadori E. Severe hypomagnesemia during long-term treatment with a proton pump inhibitor. Am J Kidney Dis. 2010 Jul;56(1):168–74. doi: 10.1053/j.ajkd.2010.03.013 20493607

12. William JH, Nelson R, Hayman N, Mukamal KJ, Danziger J. Proton-pump inhibitor use is associated with lower urinary magnesium excretion. Nephrology. 2014 Dec;19(12):798–801. doi: 10.1111/nep.12330 25142949

13. Hashimoto R, Matsuda T, Chonan A. Iron-deficiency anemia caused by a proton pump inhibitor. Intern Med. 2014;53(20):2297–9. doi: 10.2169/internalmedicine.53.2743 25318791

14. Lam JR, Schneider JL, Quesenberry CP, Corley DA. Proton Pump Inhibitor and Histamine-2 Receptor Antagonist Use and Iron Deficiency. Gastroenterology. 2017 Mar;152(4):821–829.e1. doi: 10.1053/j.gastro.2016.11.023 27890768

15. 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 Dec;12(6):448–57. doi: 10.1007/s11894-010-0141-0 20882439

16. Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol. 2012 Jul;107(7):1001–10. doi: 10.1038/ajg.2012.179 22710578

17. Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. 2012 Jul;107(7):1011–9. doi: 10.1038/ajg.2012.108 22525304

18. Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA. Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. PLoS ONE. 2015 Jun;10(6):e0128004. doi: 10.1371/journal.pone.0128004 26042842

19. 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 Feb;176(2):238–46. doi: 10.1001/jamainternmed.2015.7193 26752337

20. 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 Jun;91(6):1482–94. doi: 10.1016/j.kint.2016.12.021 28237709

21. Blank M-L, 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 Oct;86(4):837–44. doi: 10.1038/ki.2014.74 24646856

22. 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. doi: 10.1681/ASN.2015121377 27080976

23. Maggio M, Corsonello A, Ceda GP, Cattabiani C, Lauretani F, Butto V, et al. Proton pump inhibitors and risk of 1-year mortality and rehospitalization in older patients discharged from acute care hospitals. JAMA Intern Med. 2013 Apr;173(7):518–23. doi: 10.1001/jamainternmed.2013.2851 23460307

24. Bell JS, Strandberg TE, Teramura-Gronblad M, Laurila J V, Tilvis RS, Pitkala KH. Use of proton pump inhibitors and mortality among institutionalized older people. Arch Intern Med. 2010 Sep;170(17):1604–5. doi: 10.1001/archinternmed.2010.304 20876414

25. Teramura-Gronblad M, Hosia-Randell H, Muurinen S, Pitkala K. Use of proton-pump inhibitors and their associated risks among frail elderly nursing home residents. Scand J Prim Health Care. 2010 Sep;28(3):154–9. doi: 10.3109/02813432.2010.493315 20586539

26. Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-Aly Z. Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans. BMJ Open. 2017 Jul;7(6):e015735-2016–015735.

27. de Francisco ALM, Varas J, Ramos R, Merello JI, Canaud B, Stuard S, et al. Proton Pump Inhibitor Usage and the Risk of Mortality in Hemodialysis Patients. Kidney Int Reports. 2018 Mar;3(2):374–84.

28. Vanhove T, Annaert P, Lambrechts D, Kuypers DRJ. Effect of ABCB1 diplotype on tacrolimus disposition in renal recipients depends on CYP3A5 and CYP3A4 genotype. Pharmacogenomics J. 2017;17(6):556–62. doi: 10.1038/tpj.2016.49 27378609

29. van den Berg E, Engberink MF, Brink EJ, van Baak MA, Joosten MM, Gans RO, et al. Dietary acid load and metabolic acidosis in renal transplant recipients. Clin J Am Soc Nephrol. 2012 Nov;7(11):1811–8. doi: 10.2215/CJN.04590512 22935845

30. Weiner MG, Livshits A, Carozzoni C, McMenamin E, Gibson G, Loren AW, et al. Derivation of malignancy status from ICD-9 codes. AMIA Annu Symp Proc. 2003;1050. 14728553

31. van den Berg E, Geleijnse JM, Brink EJ, van Baak MA, van der Heide JJH, Gans RO, et al. Sodium intake and blood pressure in renal transplant recipients. Nephrol Dial Transplant. 2012 Aug;27(8):3352–9. doi: 10.1093/ndt/gfs069 22499024

32. Levey AS, Stevens LA, Schmid CH, Zhang YL, AFC 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12. doi: 10.7326/0003-4819-150-9-200905050-00006 19414839

33. Concato J, Peduzzi P, Holford TR, Feinstein AR. Importance of events per independent variable in proportional hazards analysis I. Background, goals, and general strategy. J Clin Epidemiol. 1995;48(12):1495–501. doi: 10.1016/0895-4356(95)00510-2 8543963

34. Peduzzi P, Concato J, Feinstein AR, Holford TR. Importance of events per independent variable in proportional hazards regression analysis II. Accuracy and precision of regression estimates. J Clin Epidemiol. 1995;48(12):1503–10. doi: 10.1016/0895-4356(95)00048-8 8543964

35. Schisterman EF, Cole SR, Platf RW. Overadjustment bias and unnecessary adjustment in epidemiologic studies. Epidemiology. 2009 Jul;20(4):488–95. doi: 10.1097/EDE.0b013e3181a819a1 19525685

36. Patorno E, Garry EM, Patrick AR, Schneeweiss S, Gillet VG, Zorina O, et al. Addressing limitations in observational studies of the association between glucose-lowering medications and all-cause mortality: a review. Drug Saf. 2015 Mar 1;38(3):295–310. doi: 10.1007/s40264-015-0280-1 25761856

37. Douwes RM, Gomes-Neto AW, Eisenga MF, Vinke JSJ, de Borst MH, van den Berg E, et al. Chronic Use of Proton-Pump Inhibitors and Iron Status in Renal Transplant Recipients. J Clin Med. 2019 Sep 3;8(9):1382.

38. Schafer JL, Graham JW. Missing data: our view of the state of the art. Psychol Methods. 2002 Jun;7(2):147–77. 12090408

39. Douwes RM, Gomes-Neto AW, Schutten JC, van den Berg E, de Borst MH, Berger SP, et al. Proton-Pump Inhibitors and Hypomagnesaemia in Kidney Transplant Recipients. J Clin Med. 2019 Dec 6;8(12):2162.

40. Eisenga MF, Minovic I, Berger SP, Kootstra-Ros JE, van den Berg E, Riphagen IJ, et al. Iron deficiency, anemia, and mortality in renal transplant recipients. Transpl Int. 2016 Nov;29(11):1176–83. doi: 10.1111/tri.12821 27516242

41. Imoagene-Oyedeji AE, Rosas SE, Doyle AM, Goral S, Bloom RD. Posttransplantation anemia at 12 months in kidney recipients treated with mycophenolate mofetil: risk factors and implications for mortality. J Am Soc Nephrol. 2006 Nov;17(11):3240–7. doi: 10.1681/ASN.2006010027 17035616

42. Chhabra D, Grafals M, Skaro AI, Parker M, Gallon L. Impact of anemia after renal transplantation on patient and graft survival and on rate of acute rejection. Clin J Am Soc Nephrol. 2008 Jul;3(4):1168–74. doi: 10.2215/CJN.04641007 18463170

43. Joosten MM, Gansevoort RT, Mukamal KJ, Kootstra-Ros JE, Feskens EJM, Geleijnse JM, et al. Urinary Magnesium Excretion and Risk of Hypertension. Hypertension. 2013 Jun;61(6):1161–7. doi: 10.1161/HYPERTENSIONAHA.113.01333 23608650

44. Joosten MM, Gansevoort RT, Mukamal KJ, van der Harst P, Geleijnse JM, Feskens EJ, et al. Urinary and plasma magnesium and risk of ischemic heart disease. Am J Clin Nutr. 2013 Jun;97(6):1299–306. doi: 10.3945/ajcn.112.054114 23485414

45. Kieboom BCT, Niemeijer MN, Leening MJG, van den Berg ME, Franco OH, Deckers JW, et al. Serum Magnesium and the Risk of Death From Coronary Heart Disease and Sudden Cardiac Death. J Am Heart Assoc. 2016 Jan 13;5(1):pii: e002707. doi: 10.1161/JAHA.115.002707 26802105

46. Ferrè S, Li X, Adams-Huet B, Maalouf NM, Sakhaee K, Toto RD, et al. Association of serum magnesium with all-cause mortality in patients with and without chronic kidney disease in the Dallas Heart Study. Nephrol Dial Transplant. 2018 Aug 1;33(8):1389–96. doi: 10.1093/ndt/gfx275 29077944

47. Shah NH, LePendu P, Bauer-Mehren A, Ghebremariam YT, Iyer S V, Marcus J, et al. Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population. PLoS ONE. 2015 Jun;10(6):e0124653. doi: 10.1371/journal.pone.0124653 26061035

48. Schoenfeld AJ, Grady D. Adverse Effects Associated With Proton Pump Inhibitors. JAMA Intern Med. 2016 Feb;176(2):172–4. doi: 10.1001/jamainternmed.2015.7927 26751904

49. Leonard J, Marshall JK, Moayyedi P. Systematic Review of the Risk of Enteric Infection in Patients Taking Acid Suppression. Am J Gastroenterol. 2007 Sep;102(9):2047–56. doi: 10.1111/j.1572-0241.2007.01275.x 17509031

50. Imhann F, Bonder MJ, Vila AV, Fu J, Mujagic Z, Vork L, et al. Proton pump inhibitors affect the gut microbiome. Gut. 2016;65(5):740–8. doi: 10.1136/gutjnl-2015-310376 26657899

51. Imhann F, Vich Vila A, Bonder MJ, Lopez Manosalva AG, Koonen DPY, Fu J, et al. The influence of proton pump inhibitors and other commonly used medication on the gut microbiota. Gut Microbes. 2017 Jul 4;8(4):351–8. doi: 10.1080/19490976.2017.1284732 28118083

52. Lee JR, Muthukumar T, Dadhania D, Toussaint NC, Ling L, Pamer E, et al. Gut microbial community structure and complications after kidney transplantation: a pilot study. Transplantation. 2014;98(7):697–705. doi: 10.1097/TP.0000000000000370 25289916

53. Fricke WF, Maddox C, Song Y, Bromberg JS. Human microbiota characterization in the course of renal transplantation. Am J Transplant. 2014 Feb;14(2):416–27. doi: 10.1111/ajt.12588 24373208

54. Holler E, Butzhammer P, Schmid K, Hundsrucker C, Koestler J, Peter K, et al. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20(5):640–5. doi: 10.1016/j.bbmt.2014.01.030 24492144

55. Evenepoel P, Claus D, Geypens B, Maes B, Hiele M, Rutgeerts P, et al. Evidence for impaired assimilation and increased colonic fermentation of protein, related to gastric acid suppression therapy. Aliment Pharmacol Ther. 1998 Oct;12(10):1011–9. doi: 10.1046/j.1365-2036.1998.00377.x 9798807

56. Knorr JP, Sjeime M, Braitman LE, Jawa P, Zaki R, Ortiz J. Concomitant proton pump inhibitors with mycophenolate mofetil and the risk of rejection in kidney transplant recipients. Transplantation. 2014 Mar 15;97(5):518–24. doi: 10.1097/01.tp.0000436100.65983.10 24162246

57. George CJ, Korc B, Ross JS. Appropriate proton pump inhibitor use among older adults: a retrospective chart review. Am J Geriatr Pharmacother. 2008 Dec;6(5):249–54. doi: 10.1016/j.amjopharm.2008.12.001 19161927

58. Zink DA, Pohlman M, Barnes M, Cannon ME. Long-term use of acid suppression started inappropriately during hospitalization. Aliment Pharmacol Ther. 2005;21(10):1203–9. doi: 10.1111/j.1365-2036.2005.02454.x 15882240

59. Batuwitage BT, Kingham JG, Morgan NE, Bartlett RL. Inappropriate prescribing of proton pump inhibitors in primary care. Postgrad Med J. 2007 Jan;83(975):66–8. doi: 10.1136/pgmj.2006.051151 17267683

60. Nardino RJ, Vender RJ, Herbert PN. Overuse of acid-suppressive therapy in hospitalized patients. Am J Gastroenterol. 2000 Nov;95(11):3118–22. doi: 10.1111/j.1572-0241.2000.03259.x 11095327

61. van Vliet EP, Otten HJ, Rudolphus A, Knoester PD, Hoogsteden HC, Kuipers EJ, et al. Inappropriate prescription of proton pump inhibitors on two pulmonary medicine wards. Eur J Gastroenterol Hepatol. 2008 Jul;20(7):608–12. doi: 10.1097/MEG.0b013e3282f52f95 18679061

62. Strid H, Simren M, Bjornsson ES. Overuse of acid suppressant drugs in patients with chronic renal failure. Nephrol Dial Transplant. 2003;18(3):570–5. doi: 10.1093/ndt/18.3.570 12584281

63. Courson AY, Lee JR, Aull MJ, Lee JH, Kapur S, McDermott JK. Routine prophylaxis with proton pump inhibitors and post-transplant complications in kidney transplant recipients undergoing early corticosteroid withdrawal. Clin Transplant. 2016 Jun;30(6):694–702. doi: 10.1111/ctr.12736 27004722

64. Scarpignato C, Gatta L, Zullo A, Blandizzi C, SIF-AIGO-FIMMG Group for the S-A-F, Italian Society of Pharmacology, the Italian Association of Hospital Gastroenterologists, and the Italian Federation of General Practitioners on behalf of the IS of, et al. Effective and safe proton pump inhibitor therapy in acid-related diseases—A position paper addressing benefits and potential harms of acid suppression. BMC Med. 2016;14(1):179. doi: 10.1186/s12916-016-0718-z 27825371

65. Yadlapati R, Kahrilas PJ. When is proton pump inhibitor use appropriate? BMC Med. 2017;15(1):36. doi: 10.1186/s12916-017-0804-x 28219434

66. Niklasson A, Lindström L, Simrén M, Lindberg G, Björnsson E. Dyspeptic Symptom Development After Discontinuation of a Proton Pump Inhibitor: A Double-Blind Placebo-Controlled Trial. Am J Gastroenterol. 2010 Jul;105(7):1531–7. doi: 10.1038/ajg.2010.81 20332770

67. Reimer C, Sondergaard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology. 2009 Jul;137(1):80–7, 87.e1. doi: 10.1053/j.gastro.2009.03.058 19362552

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