Key points are not available for this paper at this time.
The magnitude of the suspected increase in risk of acute interstitial nephritis among proton pump inhibitor users is uncertain. Here, we conducted a nested case-control study using routinely collected national health and drug dispensing data in New Zealand to estimate the relative and absolute risks of acute interstitial nephritis resulting in hospitalization or death in users of proton pump inhibitors. The cohort included 572,661 patients without a history of interstitial nephritis or other renal diseases who started a new episode of proton pump inhibitor use between 2005 and 2009. Cases had a first diagnosis after cohort entry of acute interstitial nephritis confirmed by hospital discharge letter or death record, and renal histology (definite, 46 patients), or discharge letter or death record only (probable, 26 patients). Ten controls, matched by birth year and sex, were randomly selected for each case. In the case-control analysis based on definite cases and their controls, the unadjusted matched odds ratio (95% confidence interval) for current versus past use of proton pump inhibitors was 5.16 (2.21–12.05). The estimate was similar when all cases (definite and probable) and their corresponding controls were analyzed, and when potential confounders were added to the models. The crude incidence rates and confidence intervals per 100,000 person-years were 11.98 (9.11–15.47) and 1.68 (0.91–2.86) for current and past use, respectively. Thus, current use of a proton pump inhibitor was associated with a significantly increased risk of acute interstitial nephritis, relative to past use. The magnitude of the suspected increase in risk of acute interstitial nephritis among proton pump inhibitor users is uncertain. Here, we conducted a nested case-control study using routinely collected national health and drug dispensing data in New Zealand to estimate the relative and absolute risks of acute interstitial nephritis resulting in hospitalization or death in users of proton pump inhibitors. The cohort included 572,661 patients without a history of interstitial nephritis or other renal diseases who started a new episode of proton pump inhibitor use between 2005 and 2009. Cases had a first diagnosis after cohort entry of acute interstitial nephritis confirmed by hospital discharge letter or death record, and renal histology (definite, 46 patients), or discharge letter or death record only (probable, 26 patients). Ten controls, matched by birth year and sex, were randomly selected for each case. In the case-control analysis based on definite cases and their controls, the unadjusted matched odds ratio (95% confidence interval) for current versus past use of proton pump inhibitors was 5.16 (2.21–12.05). The estimate was similar when all cases (definite and probable) and their corresponding controls were analyzed, and when potential confounders were added to the models. The crude incidence rates and confidence intervals per 100,000 person-years were 11.98 (9.11–15.47) and 1.68 (0.91–2.86) for current and past use, respectively. Thus, current use of a proton pump inhibitor was associated with a significantly increased risk of acute interstitial nephritis, relative to past use. Concern about a possible increased risk of acute interstitial nephritis among omeprazole users was first raised in 1992.1.Ruffenach S.J. Siskind M.S. Lien Y.H.H. Acute interstitial nephritis due to omeprazole.Am J Med. 1992; 93: 472-473Abstract Full Text PDF PubMed Scopus (97) Google Scholar Subsequently, several published case reports and case series suggested a class effect of proton pump inhibitors (PPIs) (including omeprazole, pantoprazole, lansoprazole, rabeprazole, and esomeprazole) on the occurrence of acute interstitial nephritis.2.Baudeau C. Dard S. Zylberberg H. et al.Rabeprazole induced acute interstitial nephritis.Rev Med Interne. 2008; 29: 834-836Crossref PubMed Scopus (4) Google Scholar, 3.Chan M.R. Yevzlin A.S. Zhong W. et al.A 78-year-old woman with proton pump inhibitor-induced acute interstitial nephritis.Hosp Phys. 2009; 2: 43-47Google Scholar, 4.Eken J. Phadke G. Ahmed S. et al.Lansoprazole-induced acute interstitial nephritis.South Med J. 2009; 102: 335-336Crossref PubMed Scopus (6) Google Scholar, 5.Geevasinga N. Coleman P.L. Webster A.C. et al.Proton pump inhibitors and acute interstitial nephritis.Clin Gastroenterol Hepatol. 2006; 4: 597-604Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 6.Klassen S. Krepinsky J.C. Prebtani A.P.H. Pantoprazole-induced acute interstitial nephritis.CMAJ. 2013; 185: 56-59Crossref PubMed Scopus (10) Google Scholar Anecdotal case reports received by national drug safety authorities prompted regulators in several countries to urge caution when prescribing PPIs7.Ministry of Health Labour and Welfare Pharmaceuticals and Medical Devices Safety Information No.215. Ministry of Health, Labour and Welfare, Tokyo2005Google Scholar, 8.Ministry of Health Labour and Welfare Pharmaceuticals and Medical Devices Safety Information No. 234. Ministry of Health, Labour and Welfare, Tokyo2007Google Scholar, 9.Medsafe Omeprazole-induced interstitial nephritis.Prescriber Update. 2000; 20: 11-13Google Scholar, 10.Medsafe Watching Briefs-Proton pump inhibitors and interstitial nephritis.Prescriber Update. 2006; 27: 2-3Google Scholar, 11.Medsafe Proton pump inhibitors and interstitial nephritis.Prescriber Update. 2011; 32: 25Google Scholar, 12.Therapeutic Goods Administration Proton pump inhibitors and acute interstitial nephritis Australian Prescriber. 2011; 34: 190Google Scholar; however, despite these warnings, several studies have shown concerning and continuing levels of inappropriate prescribing of PPIs in both hospital and primary care settings.13.Batuwitage B.T. Kingham J.G.C. Morgan N.E. et al.Inappropriate prescribing of proton pump inhibitors in primary care.Postgrad Med J. 2007; 83: 66-68Crossref PubMed Scopus (155) Google Scholar, 14.Eid S.M. Boueiz A. Paranji S. et al.Patterns and predictors of proton pump inhibitor overuse among academic and non-academic hospitalists.Intern Med. 2010; 49: 2561-2568Crossref PubMed Scopus (67) Google Scholar, 15.Grant K. Al-Adhami N. Tordoff J. et al.Continuation of proton pump inhibitors from hospital to community.Pharm World Sci. 2006; 28: 189-193Crossref PubMed Scopus (61) Google Scholar, 16.Reid M. Keniston A. Heller J.C. et al.Inappropriate prescribing of proton pump inhibitors in hospitalized patients.J Hosp Med. 2012; 7: 421-425Crossref PubMed Scopus (51) Google Scholar Surprisingly, however, only one study has formally explored the risk of acute interstitial nephritis in PPI users. This study comparing the use of omeprazole on the index date with nonuse reported an odds ratio of 3.20; however, the diagnoses were not histologically validated and chance could not be ruled out as a possible explanation (95% confidence interval (95% CI) 0.80–12.79).17.Leonard C.E. Freeman C.P. Newcomb C.W. et al.Proton pump inhibitors and traditional nonsteroidal anti-inflammatory drugs and the risk of acute interstitial nephritis and acute kidney injury.Pharmacoepidemiol Drug Saf. 2012; 21: 1155-1172Crossref PubMed Scopus (70) Google Scholar Other research has suggested that the absolute risk is very low, but has relied on unsystematic case identification methods and imprecise estimates of PPI exposure.9.Medsafe Omeprazole-induced interstitial nephritis.Prescriber Update. 2000; 20: 11-13Google Scholar,18.Simpson I.J. Marshall M.R. Pilmore H. et al.Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases.Nephrology. 2006; 11: 381-385Crossref PubMed Scopus (106) Google Scholar We did a population-based case-control study nested in a cohort of New Zealand users of omeprazole, pantoprazole, or lansoprazole (the PPIs available in New Zealand) to estimate the relative and absolute risks of acute interstitial nephritis resulting in hospitalization or death in current and recent users of these drugs compared with past users. From 1 January 2005 to 31 August 2009, the Ministry of Health identified 794,230 patients from the Pharmaceutical Collection who had been dispensed at least one course of PPI treatment (Figure 1). The study cohort comprised 572,661 patients who had correctly linked health and dispensing data, begun an episode of PPI use between 1 May 2005 and 31 August 2009, and did not have a history of renal disease (including interstitial nephritis) before cohort entry. From the study cohort, we identified 1164 patients as potential cases. We excluded 529 patients whose additional diagnoses indicated an infection of the kidney or urinary tract, and requested hospital discharge letters, postmortem reports, and renal histology reports for the remaining 635 potentially eligible cases, receiving information for 617 patients (97.2%). On the basis of this information, an additional 545 patients were excluded (most had pyelonephritis). The case-control study therefore included 72 validated cases who presented acutely with interstitial nephritis (46 definite, histologically confirmed; 26 probable, discharge letter confirmed) and 719 matched controls (460 definite and 259 probable). There were no fatal cases. Owing to a data management oversight, only nine controls were selected for one case. Table 1 shows the characteristics of the cases and controls. Cases (definite and all) were more likely than controls to be of European ethnicity, to be current users of drugs other than PPIs associated with increased risk of acute interstitial nephritis, to have been hospitalized in the previous year for any reason, and to live in the most deprived socioeconomic areas (Supplementary Table S1 online). Omeprazole was the most commonly dispensed PPI at the last dispensing before the index date, and almost two-thirds of cases and controls who were current users were dispensed a ‘standard’ daily dose at the last dispensing before the index date (Supplementary Table S2 online).Table 1Characteristics of cases and matched controls at index dateDefiniteAllCasesControlsCasesControls(n=46)(n=460)(n=72)(n=719)Age (years) (mean (s.d.))65.4 (11.3)65.4 (11.2)64.7 (13.9)64.7 (13.8)Female (n (%))26 (56.5)260 (56.5)44 (61.1)440 (61.2)EthnicityaMultiple recorded ethnicities were categorized according to a prioritization algorithm developed by Statistics New Zealand: Māori, Pacific Island, Asian, Other, European.(n(%)) European43 (93.5)370 (80.4)63 (87.5)582 (81.0) Māori2 (4.4)19 (4.1)4 (5.6)35 (4.9) Pacific Island1 (2.2)9 (2.0)2 (2.8)18 (2.5) Asian—25 (5.4)1 (1.4)36 (5.0) Other—4 (0.9)—4 (0.6) Missing—33 (7.2)2 (2.8)44 (6.1)PPI type at last dispensing before the index date (n (%)) OmeprazolebIncludes patients dispensed Helicobacter pylori triple therapy, which consists of omeprazole and two antibiotics.41 (89.1)419 (91.1)65 (90.3)652 (90.7) Pantoprazole4 (8.7)39 (8.5)6 (8.3)62 (8.6) Lansoprazole1 (2.2)2 (0.4)1 (1.4)5 (0.7)Use of other drugs associated with increased interstitial nephritis risk in the 30 days before index datec10 cases (13.9%) and 40 controls (5.6%) had incomplete dispensing information because their index dates occurred <30 days after cohort entry.,dNonsteroidal anti-inflammatory drugs, other analgesics, aspirin and other anticoagulants, antibiotics and other antimicrobials, anxiolytics, anti-epileptics, diuretics, ACE inhibitors, angiotensin II antagonists, beta-blockers, calcium channel blockers, H2 receptor antagonists, immune modulators and miscellaneous other drugs (see Supplementary Table S9 online for a complete listing).(n(%)) Yes26 (56.5)190 (41.3)42 (58.3)289 (40.2)Hospitalization in the year before the index date for any diagnosis (n (%)) Yes23 (50.0)136 (29.6)36 (50.0)214 proton pump recorded ethnicities were categorized according to a prioritization algorithm developed by Statistics New Zealand: Māori, Pacific Island, Asian, Other, patients dispensed Helicobacter pylori triple therapy, which consists of omeprazole and two cases (13.9%) and 40 controls (5.6%) had incomplete dispensing information because their index dates occurred <30 days after cohort anti-inflammatory drugs, other analgesics, aspirin and other anticoagulants, antibiotics and other antimicrobials, anxiolytics, anti-epileptics, diuretics, ACE inhibitors, angiotensin II antagonists, beta-blockers, calcium channel blockers, H2 receptor antagonists, immune modulators and miscellaneous other drugs (see Supplementary Table S9 online for a complete in a new proton pump inhibitors. The of the analysis shown in Table In the matched analysis to definite cases and controls, the unadjusted odds ratio was 5.16 (95% for current use of any study PPI compared with past use cases and controls odds ratio use was associated with however, the were not In we no of a or effect (Supplementary and online). patients who were only dispensed omeprazole the study the unadjusted matched odds ratio for definite cases and controls was (95% for current use compared with past use cases and controls odds ratio use was associated with a increase in of acute interstitial nephritis in users of the proton pump inhibitors omeprazole, pantoprazole, or odds ratio (95% by discharge letter and renal and by discharge letter confidence by discharge letter and renal and by discharge letter cases. in a new with Supplementary confidence for ethnicity, socioeconomic use of other drugs associated with increased risk of interstitial nephritis in the 30 days before the index date (including nonsteroidal anti-inflammatory drugs and and hospital in the year before the index date for any reason, for associated with renal disease in had a effect on the of the primary and Table shows that the crude absolute risk of acute interstitial nephritis per 100,000 person-years was for current users compared with past users and was in recent users The absolute risk for current users who were and was than for current for for 100,000 PPI users in the about per year developed acute interstitial nephritis as compared with per year in rates for acute interstitial nephritis in users of the proton pump inhibitors omeprazole, pantoprazole, or (95% CI) per 100,000 study (9.11–15.47) users by (years) at cohort case was confidence The case was in a new confidence We that the current use of the PPIs omeprazole, pantoprazole, or lansoprazole was associated with a significantly increased risk of acute interstitial nephritis resulting in hospitalization compared with past use. The absolute risks were very low, but in users. these rates be with caution to and the effect has the and the use of PPIs in patients data from the New Zealand Statistics New Scholar we that about of the New Zealand or more was dispensed a PPI at least between 1 January 2005 and 31 August 2009, as compared with in PPIs were by of New Zealand per We to to studies that PPIs and the risk of interstitial case-control study using data from the on only an odds ratio of (95% when comparing the use of omeprazole on the index date with C.E. Freeman C.P. Newcomb C.W. et al.Proton pump inhibitors and traditional nonsteroidal anti-inflammatory drugs and the risk of acute interstitial nephritis and acute kidney injury.Pharmacoepidemiol Drug Saf. 2012; 21: 1155-1172Crossref PubMed Scopus (70) Google Scholar the of the have been because the cohort included a of new and users we no of a and the included both past and users. recent study based on information from a reported a between PPI use and acute kidney ratio however, was potential for of the cases were not and only of the cases had an interstitial nephritis Proton pump inhibitors and acute kidney a nested case-control 2013; PubMed Scopus Google Scholar We only one published of absolute which cases reported to the and dispensing information from PPI in the of New The an incidence similar to of per 100,000 person-years (95% based on 15 cases and an dispensed I.J. Marshall M.R. Pilmore H. et al.Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases.Nephrology. 2006; 11: 381-385Crossref PubMed Scopus (106) Google Scholar In two cases of interstitial nephritis from a cohort of omeprazole users were reported in the as of a in New Omeprazole-induced interstitial nephritis.Prescriber Update. 2000; 20: 11-13Google Scholar both studies for cases, the identification of cases in the research likely in more complete case the use of dispensing information for more estimates of person-years at risk for each study more information by the incidence of acute interstitial nephritis in past users to with the incidence in current and recent users. study has a of additional compared with previous We by using routinely collected health and dispensing data for an is to the This information is likely to be and to national for hospital discharge and information, and a that only dispensing case only included patients whose interstitial nephritis was to hospitalization or death no fatal cases were the that current users of PPIs were more likely to be and because were of a possible between PPI use and acute interstitial nephritis and In to using a in the identification of potential cases, we diagnoses with renal histology is the only to acute interstitial nephritis, we collected information on patients without as by or The were similar when histologically confirmed cases and all cases. We likely identified all users of the study drugs were available only by the study and a very of PPI dispensing included Health which to dispensing and health data in to in In we compared the risk of acute interstitial nephritis in similar of users by cohort to patients who a new episode of PPI use the study of the incomplete Health in the of the is possible that users have been included in the study cohort, a very We on the basis of dispensing data, and not on is to patients their as any likely be similar between cases and controls and in an of by sex, drug use (including nonsteroidal anti-inflammatory drugs and or other is to the Cases and controls were matched by birth year and sex, and we excluded patients with a recorded history of kidney disease before cohort entry. by have been as all study were a PPI at the study by other associated with interstitial nephritis, or associated with increased risk of renal disease in was explored in the analysis with effect on the we did not have information about or drugs not recorded in the Pharmaceutical diagnoses in primary or as and aspirin and several nonsteroidal anti-inflammatory drugs were available the study we that most users of these drugs be by to We were to for diagnoses in primary care the dispensing data, and that for a of for as or did not the we information, the of the for current users was that a have to a effect to study had several a of identified cases, which the of the as shown by the cases the series to be published to date, and the dispensing data available for the study cohort more estimates of absolute risk than previous We were by the of before which that we did not have hospitalization data for most in the study care was to patients with previous interstitial nephritis or other renal disease from the study cohort, the of any cases have to a of the the episode of interstitial nephritis occurred the was the In this study to a of that current users of PPIs at an increased risk of acute interstitial nephritis, and is the first study to a to absolute PPIs have the care of patients with these drugs not without caution is the of patients using these drugs, of inappropriate use, and of these in the and the We routinely collected information from New from of Health Ministry of Health, Scholar and Collection hospital and of Health Collection Ministry of Health, Scholar in these data were recorded using the of and Australian We information on dispensed drugs in the Pharmaceutical of Health Pharmaceutical Ministry of Health, Scholar which dispensing for all in New information in these data was linked using Health to of the New Zealand of Health Health Ministry of Health, Scholar The study was by the New Zealand patients who were dispensed a study PPI (including users of Helicobacter pylori triple at least between 1 January 2005 and 31 August were identified from the Pharmaceutical Collection by the Ministry of The Ministry the Health of these patients to their dispensing and health information, with the data, of all of the study PPIs and all other from 2005 to 2009, hospital from death were in of Health for all patients identified by the Ministry as potential cases (see entry was the date of the first dispensing of a study PPI between 1 January 2005 and 31 August 2009. We excluded linked in which the dispensing and health information could not have to the patients who received before their recorded birth that the study cohort included only patients who a new episode of PPI use the study users and after a we excluded all patients who were dispensed a study PPI between 1 January 2005 and 30 2005 Zealand a dispensed of a PPI at one We excluded patients with a recorded history of interstitial nephritis or other renal diseases before their cohort entry date (Supplementary and online). We the Ministry to all patients who were potentially with acute interstitial nephritis after cohort entry by the hospital discharge and data using the in with a which interstitial nephritis be and information for patients who in had not been we the of death for these patients for we an algorithm to patients whose additional diagnoses indicated an infection of the kidney or urinary (Supplementary and online). to the diagnoses of the remaining potential cases, hospital discharge letters, postmortem reports, and any renal histology reports were requested and by and who were to the PPI In cases was about a diagnosis a renal was and patients in interstitial nephritis was to a or who were were cases were patients who presented acutely with interstitial nephritis that was by discharge letter or death record, and renal cases were patients with only discharge letter or death record The diagnosis date was as the index date for each case and their matched controls. We risk S. S. Google Scholar from the study cohort to randomly controls to PPI for each matched by birth year and controls were of the study cohort who were at risk of acute interstitial nephritis on the index Cases and controls were as current users of PPIs their dispensed the before the index date, recent users their to days before the index date, and past users their days before the index the index date, the PPI of each case and their matched controls was therefore at the at risk for current of PPI type or daily were by the dispensing data by the Ministry of use as a series of in which was no more than a between the of one dispensed and the of the of current use were the the of the study or a case was with acute interstitial The of all were to the person-years of current use for the study patients who a we person-years of in recent users by the of days after the of each episode days person-years of in past users were by the of or more days after the of each in recent and past users was a new episode was the or the of the study or a case was with acute interstitial The of in recent and past users added to the recent and past person-years for the study to patients only current current and recent and and past person-years (Figure In to birth year and sex, we information on the potential socioeconomic use of other drugs in the 30 days before the index date, which associated with increased risk of interstitial nephritis (including nonsteroidal anti-inflammatory drugs and antibiotics Supplementary Table S9 and hospital in the year before the index date for any reason, and for associated with increased risk of renal disease in and II and was to estimate odds and We the risk of acute interstitial nephritis resulting in hospitalization or death in definite cases and their controls, and in all (definite and probable) cases and controls. The primary analysis explored the risk of acute interstitial nephritis in current and recent of the study with past users as the In we explored the risk of acute interstitial nephritis according to of use in the of users who had PPIs between cohort entry and the index date who PPI use the study were excluded from this the of daily dose and by current users of any and the risk in the of cases and controls who were only dispensed was by the potential confounders one at a the and the in estimate S. S. Scholar was to incidence rates in and past users and rates in current users were using the cohort data by the of cases in a by that person-years of The was to was for all We and for for selected for on the and for on an of this was by the Health of New Zealand and was to a of The had no in the of the or in the or of the Table of cases and matched controls. Table daily dose in current users of the proton pump inhibitors omeprazole, pantoprazole, and lansoprazole at the last dispensing before the index Table of acute interstitial nephritis in current users of the proton pump inhibitors omeprazole, pantoprazole, or lansoprazole daily compared to past users. Table of acute interstitial nephritis in current users of the proton pump inhibitors omeprazole, pantoprazole, or lansoprazole, by of current use. Table of Australian to study cohort with kidney disease diagnoses before cohort entry. Table of Australian to study cohort with kidney disease diagnoses before cohort entry. Table of Australian that were to and potential cases who had a kidney or urinary infection with or and any of the in the were of other were Table of Australian that were to and potential cases who had a kidney or urinary infection and had not been excluded according to Table with or and any of the in the were were no other Table drugs in the New Zealand or suspected of the risk of interstitial nephritis, by Supplementary is linked to the online of the at with Supplementary
Blank et al. (Wed,) studied this question.