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Proton pump inhibitors use and risk of chronic kidney disease: Evidence-based meta-analysis of observational studies

Published:January 08, 2018DOI:https://doi.org/10.1016/j.cegh.2017.12.008

      Abstract

      Introduction

      Proton pump inhibitors (PPIs) are one of the widely used drugs available as over the counter for treatment of acid-related gastrointestinal disorders. Concerns have been raised about the risk of developing chronic kidney disease (CKD) with the prolonged use of PPIs. This meta-analysis aims to determine the association between PPI use and risk of developing CKD.

      Methods

      The methodology complies with our registered protocol at PROSPERO (CRD42016040073). PubMed and Embase were searched from inception to 27th September 2017. Two reviewers independently screened and selected the observational studies comparing CKD outcome in patients on PPI. The quality of selected studies was assessed using Newcastle-Ottawa Scale. Subgroup and sensitivity analysis were also performed. All the analysis was performed by using RevMan v5.3.

      Results

      The 6 included studies comprised of 4 cohorts and 2 case-control studies with 720758 patients from cohort and 84078 patients from the case-control study. All the studies were of highest quality. Overall pooled relative risk (RR) of developing CKD was 1.32(95% CI 1.19 to 1.46), (p-value = <0.00001) and for end-stage renal disease (ESRD) RR was 1.88 (95% CI: 1.71 to 2.07), (p = <0.00001) in patients receiving PPI. The higher incidence of CKD was seen in diabetic patients taking PPI with RR of 1.82 (95% CI 1.22 to 1.72), (p-value = 0.004).

      Conclusion

      An association between proton pump inhibitor use and risk of developing chronic kidney disease and ESRD was found in the study.

      Keywords

      1. Introduction

      Chronic Kidney Disease (CKD) or Chronic Renal Failure (CRF) is a long-term condition characterized by steady loss of kidney function over a period of time.
      About chronic kidney disease.
      CKD is a major global public health problem with prevalence 11–13%.
      • Hill N.R.
      • Fatoba S.T.
      • Oke J.L.
      • Hirst J.A.
      • O’Callaghan C.A.
      • Lasserson D.S.
      • et al.
      Global prevalence of chronic kidney disease?a systematic review and meta-analysis.
      It is more prevalent in the elderly population and is relatively more common in females.
      National chronic kidney disease fact sheet.
      The high prevalence of CKD and increasing cost of long-term dialysis imparts a substantial economic burden on the healthcare systems across the globe.
      • Couser W.G.
      • Remuzzi G.
      • Mendis S.
      • Tonelli M.
      The contribution of chronic kidney disease to the global burden of major noncommunicable diseases.
      Furthermore, the poor health-related quality of life (HRQOL) due to declined physical functioning and comorbid conditions such as hypertension, anemia, ischemic heart disease, diabetes, and stroke results in increasing the societal burden associated with CKD.
      • Mujais S.K.
      • Story K.
      • Brouillette J.
      • Takano T.
      • Soroka S.
      • Franek C.
      • et al.
      Health-related quality of life in CKD patients: correlates and evolution over time.
      As per the Global Burden of Disease study for the global cause of mortality in the year 2010, CKD jumped to the 18th rank from the original 27th rank in the year 1990.
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • Lim S.
      • Shibuya K.
      • Aboyans V.
      • et al.
      Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
      Proton pump inhibitors (PPIs) introduced in the late 80 s are the class of drugs comprising omeprazole, esomeprazole, lansoprazole, pantoprazole, and others.
      • Mullin J.M.
      • Gabello M.
      • Murray L.J.
      • Farrell C.P.
      • Bellows J.
      • Wolov K.R.
      • et al.
      Proton pump inhibitors: actions and reactions.
      Being one of the most widely used drugs worldwide, PPIs are the mainstay of gastroesophageal reflux disease (GERD) treatment.
      • Forgacs I.
      • Loganayagam A.
      Overprescribing proton pump inhibitors.
      Considering the acceptable safety profile, PPIs with over 113 million prescriptions and over-the-counter (OTC) sale, account for a market of $13 billion globally.
      • Savarino V.
      • Dulbecco P.
      • de Bortoli N.
      • Ottonello A.
      • Savarino E.
      The appropriate use of proton pump inhibitors (PPIs): need for a reappraisal.
      Additionally, the perceived favorable safety profile has contributed to significant over prescription with a reported 25–70% of PPIs prescribed without an appropriate indication.
      • Forgacs I.
      • Loganayagam A.
      Overprescribing proton pump inhibitors.
      • Savarino V.
      • Dulbecco P.
      • de Bortoli N.
      • Ottonello A.
      • Savarino E.
      The appropriate use of proton pump inhibitors (PPIs): need for a reappraisal.
      Despite an acceptable safety profile of PPIs, studies have linked them to adverse health outcomes including hip fracture,
      • Hussain S.
      • Najmi A.K.
      • Anil D.
      Proton pump inhibitors use and risk of hip fracture: a meta-analysis of observational studies.
      clostridium difficile infection,
      • Pohl J.F.
      Clostridium difficile infection and proton pump inhibitors.
      community-acquired pneumonia,
      • Lambert A.A.
      • Lam J.O.
      • Paik J.J.
      • Ugarte-Gil C.
      • Drummond M.B.
      • Crowell T.A.
      Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis.
      acute kidney injury (AKI),
      • Antoniou T.
      • Macdonald E.M.
      • Hollands S.
      • Gomes T.
      • Mamdani M.M.
      • Garg A.X.
      • et al.
      Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study.
      and acute interstitial nephritis (AIN).
      • Sierra F.
      • Suarez M.
      • Rey M.
      • Vela M.
      Systematic review: proton pump inhibitor-associated acute interstitial nephritis.
      Various studies have suggested the association between PPI use and the risk of developing renal complications; explicitly acute kidney disorders.
      • 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.
      • Klepser D.G.
      • Collier D.S.
      • Cochran G.L.
      Proton pump inhibitors and acute kidney injury: a nested case–control study.
      • Lazarus B.
      • Chen Y.
      • Wilson F.P.
      • Sang Y.
      • Chang A.R.
      • Coresh J.
      • et al.
      Proton pump inhibitor use and the risk of chronic kidney disease.
      Though the association between PPI exposure and acute kidney disease has been well studied, it is still unclear whether prolonged use of PPI is associated with the risk of developing CKD. Hence, this meta-analysis aimed to assess the association between PPI use and the risk of developing CKD.

      2. Methodology

      2.1 Protocol

      This systematic review was conducted in accordance with the review protocol registered at the PROSPERO (Registration number: CRD42016040073).
      • Hussain S.
      • Singh A.
      • Najmi A.K.
      Proton pump inhibitors use and the risk of chronic kidney disease: a systematic review.
      The meta-analysis was conducted in compliance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines
      • Moher D.
      • Shamseer L.
      • Clarke M.
      • Ghersi D.
      • Liberati A.
      • Petticrew M.
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
      (Refer supplementary Table 1).

      2.2 Search Strategy

      PubMed and Embase electronic search engine were searched from inception to 27th September 2017 for studies assessing the risk of CKD in PPIs users. Keywords such as: proton pump inhibitors OR proton pump inhibitor* OR PPI* OR omeprazole OR lansoprazole OR dexlansoprazole OR esmoperazole OR pantoprazole OR rabeprazole OR ilaprazole AND chronic renal failure OR chronic kidney disease* OR chronic kidney failure OR chronic renal disease* OR chronic renal insufficienc* OR end-stage renal disease OR ESRD OR end-stage kidney disease OR ESKD were used to develop the search string. Hands-searching of the reference list of relevant articles was also done to find any additional appropriate article.

      2.3 Study Selection

      Two reviewers (SH and AS) independently screened the articles retrieved for potential inclusion using the title and abstract. Excel spreadsheet was used for screening of articles. Studies were included as per the pre-specified inclusion criteria detailed in the study protocol.
      • Hussain S.
      • Singh A.
      • Najmi A.K.
      Proton pump inhibitors use and the risk of chronic kidney disease: a systematic review.
      Full-text articles selected on the basis of abstract and title were retrieved for further assessment and inclusion. The reviewers (SH and AS) independently screened the retrieved full-text studies for final inclusion. In the case of disagreement over inclusion, the third reviewer (AKN) was consulted.

      2.4 Data extraction

      Full-text article of the included studies was examined and data were abstracted by two reviewers (SH and AS) independently using a standardized excel sheet. The information such as: (i) name of first author, publication year, and country; (ii) study design; (iii) number of subjects and CKD cases and size of the cohort; (iv) effect estimates and 95% confidence intervals; (v) assessment of PPI exposure and assessment of CKD; (vi) control of confounding factors, if any; and other relevant information were abstracted.

      2.5 Quality assessment

      Quality assessment of all the included studies was performed by two reviewers (SH, AH) independently. Newcastle-Ottawa Scale (NOS) is the most commonly used scale to judge the quality of observational studies specific to case-control and cohort studies. Thus, all the included studies were evaluated for quality using the NOS. NOS scale is divided into three major headings: selection, comparability, and exposure. Each study can obtain a maximum of one point for each numbered item within the selection and exposure categories. A maximum of two points can be given for comparability. Thus, each study can receive points between 0–9. Based on the score on NOS scale, studies can be classified as: high quality (8–9 points), medium quality (6–7 points), and low quality (<6 points).

      2.6 Statistical analysis

      The primary outcome was to calculate the pooled risk ratio of all the included studies with 95% confidence interval. The heterogeneity among the pooled studies was analyzed using Cochrane Q and I square statistics. Cochrane Q (p < 0.10) or I square statistics value lie between 0 to 100%, I square value 0–25% represents low heterogeneity, 25–50% indicates moderate heterogeneity and values >50% was considered as the presence of statistically significant heterogeneity.
      • Higgins J.P.
      • Green S.
      Cochrane Handbook for Systematic Reviews of Interventions.
      If significant heterogeneity noticed then random effect model applied over fixed effect model with an inverse variance method to calculate the pooled relative risk. Publication bias was assessed initially by visual inspection of the funnel plot and further confirmed by Egger’s test. Duval and Tweedie nonparametric trim and fill method was applied if significant publication bias exists. Subgroup analysis was performed according to co-morbidity, follow-up period, study design, and gender to assess the factors responsible for heterogeneity among the studies in reporting risk ratios. We also performed the sensitivity analysis to ensure the robustness of results by excluding each study sequentially. All the analysis were performed using Review Manager (RevMan v5.3).
      Review Manager (RevMan) [Computer program]. Version5.3.

      3. Result

      3.1 Search result and study characteristics

      We identified 1508 records from the database search. After removing the duplicates and primary screening of title and abstract 1355 articles were retrieved, of which only six articles
      • Arora P.
      • Gupta A.
      • Golzy M.
      • Patel N.
      • Carter R.L.
      • Jalal K.
      • et al.
      Proton pump inhibitors are associated with increased risk of development of chronic kidney disease.
      ,
      • Lazarus B.
      • Chen Y.
      • Wilson F.P.
      • Sang Y.
      • Chang A.R.
      • Coresh J.
      • et al.
      Proton pump inhibitor use and the risk of chronic kidney disease.
      ,
      • Peng Y.C.
      • Lin C.L.
      • Yeh H.Z.
      • Chang C.S.
      • Wu Y.L.
      • Kao C.H.
      Association between the use of proton pump inhibitors and the risk of ESRD in renal diseases: a population-based, case-control study.
      ,
      • 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.
      ,
      • Klatte D.C.F.
      • Gasparini A.
      • Xu H.
      • de Deco P.
      • Trevisan M.
      • Johansson A.L.V.
      Association between proton pump inhibitor use and risk of progression of chronic kidney disease.
      were found appropriate for inclusion after the secondary screening with full text. Bibliographic hand searching of the retrieved literature did not yield any additional article for inclusion. (Fig. 1).
      Fig. 1
      Fig. 1PRISMA flow diagram showing study selection process.
      Among the included articles
      • Arora P.
      • Gupta A.
      • Golzy M.
      • Patel N.
      • Carter R.L.
      • Jalal K.
      • et al.
      Proton pump inhibitors are associated with increased risk of development of chronic kidney disease.
      • Lazarus B.
      • Chen Y.
      • Wilson F.P.
      • Sang Y.
      • Chang A.R.
      • Coresh J.
      • et al.
      Proton pump inhibitor use and the risk of chronic kidney disease.
      • Peng Y.C.
      • Lin C.L.
      • Yeh H.Z.
      • Chang C.S.
      • Wu Y.L.
      • Kao C.H.
      Association between the use of proton pump inhibitors and the risk of ESRD in renal diseases: a population-based, case-control study.
      • 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.
      • Klatte D.C.F.
      • Gasparini A.
      • Xu H.
      • de Deco P.
      • Trevisan M.
      • Johansson A.L.V.
      Association between proton pump inhibitor use and risk of progression of chronic kidney disease.
      Lazarus et al.
      • Lazarus B.
      • Chen Y.
      • Wilson F.P.
      • Sang Y.
      • Chang A.R.
      • Coresh J.
      • et al.
      Proton pump inhibitor use and the risk of chronic kidney disease.
      has included two cohorts in his article namely Atherosclerosis Risk in Communities (ARIC) study and Geisinger Health System Replication Cohort (GHSRC) study. Hence, we considered four cohort studies and two case-control studies for inclusion with 720758 patients from cohort and 84078 patients from the case-control study. Studies were from the USA,
      • Arora P.
      • Gupta A.
      • Golzy M.
      • Patel N.
      • Carter R.L.
      • Jalal K.
      • et al.
      Proton pump inhibitors are associated with increased risk of development of chronic kidney disease.
      • Lazarus B.
      • Chen Y.
      • Wilson F.P.
      • Sang Y.
      • Chang A.R.
      • Coresh J.
      • et al.
      Proton pump inhibitor use and the risk of chronic kidney disease.
      • 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.
      Taiwan,
      • Peng Y.C.
      • Lin C.L.
      • Yeh H.Z.
      • Chang C.S.
      • Wu Y.L.
      • Kao C.H.
      Association between the use of proton pump inhibitors and the risk of ESRD in renal diseases: a population-based, case-control study.
      and Sweden
      • Klatte D.C.F.
      • Gasparini A.
      • Xu H.
      • de Deco P.
      • Trevisan M.
      • Johansson A.L.V.
      Association between proton pump inhibitor use and risk of progression of chronic kidney disease.
      . All the studies published in the year 2016 except by Klatte et al.
      • Klatte D.C.F.
      • Gasparini A.
      • Xu H.
      • de Deco P.
      • Trevisan M.
      • Johansson A.L.V.
      Association between proton pump inhibitor use and risk of progression of chronic kidney disease.
      The follow-up period among studies ranged from 5–13.9 years. Table 1, Table 2 and present a detailed description of the characteristics of the included studies.
      Table 1Characteristics of included cohort studies.
      Author,YearStudy typeCountryData sourceStudy PeriodStudy Follow-upIncident chronic kidney disease (CKD) definition% MenMean Age (Years)Total sampleNo. of PPI usersNo of CKD cases in PPINo. of PPI non-usersCKD cases in non-PPIHazard RatioAdjustment
      Klatte et al. 2017
      • Klatte D.C.F.
      • Gasparini A.
      • Xu H.
      • de Deco P.
      • Trevisan M.
      • Johansson A.L.V.
      Association between proton pump inhibitor use and risk of progression of chronic kidney disease.
      CohortSwedenStockholm CREAtinine Measurements (SCREAM)

      healthcare-utilization cohort study
      2006–20115 yearsDoubling of serum creatinine or as >30% decline in eGFR39.7%62.4 (48.8–73.8)* (Interquartile Range) years1148831053051104595787151.26 (1.16–1.36)Adjusted for age, sex, eGFR at baseline, indications for acid-suppression therapy, diabetes mellitus, hypertension, peripheral vascular disease, acute myocardial infarction, cerebrovascular disease, congestive heart

      failure, chronic obstructive pulmonary disease, NSAIDs, RAAS-inhibitors, beta blockers, calcium channel blockers, antithrombotics,

      statins, and diuretics.
      Larazus et al. 2016
      • Lazarus B.
      • Chen Y.
      • Wilson F.P.
      • Sang Y.
      • Chang A.R.
      • Coresh J.
      • et al.
      Proton pump inhibitor use and the risk of chronic kidney disease.
      CohortUSAtherosclerosis Risk in Communities (ARIC) study1996–201113.9 yearsIncident CKD was defined by diagnostic codes that indicated CKD at hospital discharge, or death, or by incident ESRD. (estimated glomerular filtration rate of at least 60 mL/min/1.73m
      • Hill N.R.
      • Fatoba S.T.
      • Oke J.L.
      • Hirst J.A.
      • O’Callaghan C.A.
      • Lasserson D.S.
      • et al.
      Global prevalence of chronic kidney disease?a systematic review and meta-analysis.
      )
      43.90%63 years10482322561016013821.35 (1.17–1.55)Adjusted for the age, sex, race, study center, education, health insurance status, baseline eGFR, ratio of urinary albumin to creatinine, smoking status, BMI, systolic blood pressure, diabetes mellitus, cardiovascular disease, antihypertensive medication use, and anticoagulant medication use.
      Larazus et al. 2016
      • Lazarus B.
      • Chen Y.
      • Wilson F.P.
      • Sang Y.
      • Chang A.R.
      • Coresh J.
      • et al.
      Proton pump inhibitor use and the risk of chronic kidney disease.
      CohortUSGeisinger Health System Replication Cohort (GHSRC) study1997–20146.9 yearsIncident CKD was defined as the first outpatient eGFR of less than 60 mL/min/1.73m
      • Hill N.R.
      • Fatoba S.T.
      • Oke J.L.
      • Hirst J.A.
      • O’Callaghan C.A.
      • Lasserson D.S.
      • et al.
      Global prevalence of chronic kidney disease?a systematic review and meta-analysis.
      43.44%NR248751169001921231861282261.22 (1.19–1.25)Adjusted for the age, sex, race, baseline eGFR, smoking status, body mass index, systolic blood pressure, diabetes mellitus, cardiovascular disease, antihypertensive medication use, anticoagulant medication use, and statin, aspirin use.
      Xie et al. 2016
      • 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.
      CohortUSUnited States Department of Veterans Affairs (VA) databasesOctober 2006- September 20085 yearsCKD defined as two eGFRs,60 ml/min per 1.73 m
      • Hill N.R.
      • Fatoba S.T.
      • Oke J.L.
      • Hirst J.A.
      • O’Callaghan C.A.
      • Lasserson D.S.
      • et al.
      Global prevalence of chronic kidney disease?a systematic review and meta-analysis.
      at least 90 days apart. The first measurement date considered as date of CKD occurrence
      93.04%56.85 years34664217332126193173321174261.28 (1.22–1.34)Adjusted for baseline eGFR, age, race, sex, diabetes mellitus, hypertension, cardiovascular disease, peripheral artery disease, cerebrovascular disease, chronic lung disease, hepatitis C, HIV, dementia, gastroesophageal reflux disease, upper gastrointestinal tract bleeding, ulcer disease, H. pylori infection.
      BMI: Body Mass Index; CKD: Chronic Kidney Disease; eGFR: Estimated Glomerular Filtration Rate; HIV: Human Immunodeficiency Virus; H. pylori: Helicobacter pylori; NSAIDs: Nonsteroidal Anti-inflammatory Drugs; RAAS: Renin-Angiotensin-Aldosterone System.
      Table 2Characteristics of included case-control studies.
      Author, YearStudy typeCountryData sourceStudy PeriodStudy Follow-upPatient setting% MenTotal no of PPI userNo. of cases (CKD)No. of controls (Non-CKD)Hazard RatioAdjustment
      Peng et al. 2016
      • Peng Y.C.
      • Lin C.L.
      • Yeh H.Z.
      • Chang C.S.
      • Wu Y.L.
      • Kao C.H.
      Association between the use of proton pump inhibitors and the risk of ESRD in renal diseases: a population-based, case-control study.
      Case-controlTaiwanTaiwan National Health Insurance Research Database, (LHID 2000) and RCIPD2006–2011Case group (ESRD) 3.99 ± 3.46 years Control group 4.02 ± 3.04 yearsRenal disease patients (age ≥ 20 years)52.20%7616Total: 3808Total: 38081.88 (1.71–2.06)Adjusted for gender, age, calcium channel blocker, diabetes, and hypertension.
      PPINon-PPIPPINon-PPI
      2647116121021706
      Arora et al. 2016
      • Arora P.
      • Gupta A.
      • Golzy M.
      • Patel N.
      • Carter R.L.
      • Jalal K.
      • et al.
      Proton pump inhibitors are associated with increased risk of development of chronic kidney disease.
      Case-controlUSVeterans Affairs Health Care Upstate New York (VISN2) database2001–20087 yearsCases are the patient with eGFR >60 ml/min/1.73m2Not reported22734No. of cases (CKD)No. of controls (Non-CKD)1.10 (1.04–1.16)Controlling for age, sex, race, GI and pre-PPI comorbidities
      1931157151
      PPINon-PPIPPINon-PPI
      4711146001802339128
      ESRD: End Stage Renal Disease; CKD: Chronic Kidney Disease; eGFR: Estimated Glomerular Filtration Rate; US: United States.

      3.2 Quality assessment

      All cohort
      • Lazarus B.
      • Chen Y.
      • Wilson F.P.
      • Sang Y.
      • Chang A.R.
      • Coresh J.
      • et al.
      Proton pump inhibitor use and the risk of chronic kidney disease.
      • 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.
      • Klatte D.C.F.
      • Gasparini A.
      • Xu H.
      • de Deco P.
      • Trevisan M.
      • Johansson A.L.V.
      Association between proton pump inhibitor use and risk of progression of chronic kidney disease.
      and case-control study
      • Arora P.
      • Gupta A.
      • Golzy M.
      • Patel N.
      • Carter R.L.
      • Jalal K.
      • et al.
      Proton pump inhibitors are associated with increased risk of development of chronic kidney disease.
      • Peng Y.C.
      • Lin C.L.
      • Yeh H.Z.
      • Chang C.S.
      • Wu Y.L.
      • Kao C.H.
      Association between the use of proton pump inhibitors and the risk of ESRD in renal diseases: a population-based, case-control study.
      assessed for methodological quality on the NOS were found to be of high-quality, based on the scores attainment in: selection, comparability, and outcome parameters of NOS scale (Table 3).
      Table 3Quality assessment of the study by using NewCastle-Ottawa scale.
      StudySelectionComparabilityOutcomeTotal scoreQuality of the study
      Klatte et al. 2017
      • Klatte D.C.F.
      • Gasparini A.
      • Xu H.
      • de Deco P.
      • Trevisan M.
      • Johansson A.L.V.
      Association between proton pump inhibitor use and risk of progression of chronic kidney disease.
      *********9High quality
      Lazarus et al. 2016 (ARIC)
      • Lazarus B.
      • Chen Y.
      • Wilson F.P.
      • Sang Y.
      • Chang A.R.
      • Coresh J.
      • et al.
      Proton pump inhibitor use and the risk of chronic kidney disease.
      *********9High quality
      Lazarus et al. 2016 (GHSRC)
      • Lazarus B.
      • Chen Y.
      • Wilson F.P.
      • Sang Y.
      • Chang A.R.
      • Coresh J.
      • et al.
      Proton pump inhibitor use and the risk of chronic kidney disease.
      ********8High quality
      Xie et al. 2016
      • 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.
      *********9High quality
      Arora et al. 2016
      • Arora P.
      • Gupta A.
      • Golzy M.
      • Patel N.
      • Carter R.L.
      • Jalal K.
      • et al.
      Proton pump inhibitors are associated with increased risk of development of chronic kidney disease.
      *********9High quality
      Peng et al. 2016
      • Peng Y.C.
      • Lin C.L.
      • Yeh H.Z.
      • Chang C.S.
      • Wu Y.L.
      • Kao C.H.
      Association between the use of proton pump inhibitors and the risk of ESRD in renal diseases: a population-based, case-control study.
      *********9High quality

      3.3 PPI use and risk of CKD

      Study conducted in Taiwan by Peng et al.
      • Peng Y.C.
      • Lin C.L.
      • Yeh H.Z.
      • Chang C.S.
      • Wu Y.L.
      • Kao C.H.
      Association between the use of proton pump inhibitors and the risk of ESRD in renal diseases: a population-based, case-control study.
      has not reported the number of events, so the author was contacted to get the data for inclusion in the pooled analysis. Random effect model was applied over fixed effect model since significant heterogeneity was observed in the included studies (p = <0.00001, I square = 95%). Our study findings showed that the pooled RR of developing CKD was 1.32 (95% CI 1.19 to 1.46), (p-value = <0.0001) in PPI users as compared to non-PPI users (Fig. 2a).
      Fig. 2
      Fig. 2a Forest plot showing association between proton-pump inhibitors use and risk of chronic kidney disease. b Forest plot showing association between proton-pump inhibitors use and risk of ESRD.

      3.4 PPI use and risk of progression of kidney dysfunction and end-stage renal disease (ESRD)

      Three studies
      • Peng Y.C.
      • Lin C.L.
      • Yeh H.Z.
      • Chang C.S.
      • Wu Y.L.
      • Kao C.H.
      Association between the use of proton pump inhibitors and the risk of ESRD in renal diseases: a population-based, case-control study.
      • 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.
      • Klatte D.C.F.
      • Gasparini A.
      • Xu H.
      • de Deco P.
      • Trevisan M.
      • Johansson A.L.V.
      Association between proton pump inhibitor use and risk of progression of chronic kidney disease.
      reported data for ESRD and two studies reported the data for >30% decline in estimated glomerular filtration rate (eGFR) from the baseline.
      • 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.
      • Klatte D.C.F.
      • Gasparini A.
      • Xu H.
      • de Deco P.
      • Trevisan M.
      • Johansson A.L.V.
      Association between proton pump inhibitor use and risk of progression of chronic kidney disease.
      PPI use was significantly associated with the risk of developing ESRD with a pooled RR of 1.88 (95% CI: 1.71–2.07), (p = <0.00001, I square = 0%) (Fig. 2b). PPI use was also significantly associated for risk of progression of kidney dysfunction as determined by declining in eGFR by >30% [RR 1.30 (95% CI 1.25–1.36), (p-value = <0.0001, I square = 0%).

      3.5 Subgroup analysis

      In subgroup analysis based on the gender, no significant association was observed for the PPI use and risk of CKD among male and female. Studies reporting the follow-up period >5 years were categorized under long-term follow-up study. Based on the duration of exposure, the RR of developing the CKD was found to be highly significant for long-term exposure 1.20 (95% CI 1.10 to 1.31), (p-value = 0.92). Based on study design the, pooled data from cohort studies showed the RR of CKD in PPI user to be 1.24 (95% CI = 1.21 to 1.26), (p-value = < 0.00001), whereas for the case-control study it was 1.44 (95% CI 1.16 to 1.80), (p-value = 0.18). A detailed description is presented in Table 4. Subgroup analysis was also performed based on the disease status. We found the statistically significant deteriorative effect of PPI use in a diabetic population with a pooled RR of 1.82 (95% CI 1.22–2.72), (p-value = 0.004) (Fig. 3). We also assessed the effect of concomitant drug use. The pooled estimate of PPI user with ACE-I/ARB compared to only PPI user did not show any significant association for the development of CKD. Pooled estimate showed significant association for the CKD in PPI diuretic users as compared to only PPI users [RR 2.29 (95% CI 2.09–2.50)], (p-value = < 0.00001) [two studies- ARIC & GHSRC cohort
      • Lazarus B.
      • Chen Y.
      • Wilson F.P.
      • Sang Y.
      • Chang A.R.
      • Coresh J.
      • et al.
      Proton pump inhibitor use and the risk of chronic kidney disease.
      ].
      Table 4Overall effect estimates for chronic kidney disease and proton pump inhibitors use according to subgroups.
      CharacteristicsNumber of studiesRR (95% CI)p-valueCochrane QI
      • Hill N.R.
      • Fatoba S.T.
      • Oke J.L.
      • Hirst J.A.
      • O’Callaghan C.A.
      • Lasserson D.S.
      • et al.
      Global prevalence of chronic kidney disease?a systematic review and meta-analysis.
      Gender
      Male31.03(0.84–1.28)0.7758.4095%
      Female31.03 (0.98–1.09)0.244.4533%
      Study Design
      Cohort41.24 (1.21–1.26) < 0.000014.9640%
      Case-control21.44 (0.85–2.43)0.1894.8199%
      Follow-up
      Long term31.20 (1.10–1.31) < 0.000114.2086%
      Short term31.44 (1.16–1.80)0.00156.4296%
      Fig. 3
      Fig. 3Pooled risk ratio of CKD in diabetic PPI user as compared to non-diabetic PPI user.

      3.6 Sensitivity analysis

      Each study was sequentially excluded to assess the robustness of the pooled risk ratio. Exclusion of any of the specific studies did not demonstrate any alteration in the results as evident from the sensitivity analysis.

      3.7 Publication bias

      Visual inspection of funnel plot did not suggest the presence of publication bias, which was further confirmed by Egger’s test (p = 0.59).

      4. Discussion

      In this systematic review and meta-analysis, we set out to examine the risk of CKD with the use of PPI. The studies identified by this systematic review and analysed by the meta-analysis demonstrate that PPI use appears to be associated with significant elevated risk of developing CKD in PPI users compared to the non-PPI users (pooled RR = 1.32 (95% CI 1.19–1.46), (p-value = <0.0001). The associations are independent of gender; however diabetic PPI user population are at higher risk of developing CKD compared to non-PPI users as seen in the subgroup analysis.
      PPIs are one of the most common causes of drug-induced acute interstitial nephritis (AIN) worldwide.
      • Brewster U.
      • Perazella M.
      Proton pump inhibitors and the kidney: critical review.
      • Moledina D.G.
      • Perazella M.A.
      PPIs and kidney disease: from AIN to CKD.
      Though the exact mechanism by which PPIs induce AIN is still to be explained, it is postulated that the metabolites of PPIs may deposit inside the tubulointerstitium of the kidney to directly stimulate T-cells or act as either a hapten to mediate AIN.
      • Ruffenach S.J.
      • Siskind M.S.
      • Lien Y.-H.H.
      Acute interstitial nephritis due to omeprazole.
      PPIs were first identified to have a causal relationship with AIN and acute renal injury in the year 1992.
      • Ruffenach S.J.
      • Siskind M.S.
      • Lien Y.-H.H.
      Acute interstitial nephritis due to omeprazole.
      In 2006 Simpson et al.
      • Simpson I.J.
      • Marshall M.R.
      • Pilmore H.
      • Manley P.
      • Williams L.
      • Thein H.
      • et al.
      Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases.
      in a case series reported the incidence of AIN to be 8.0 per 100,000 person-years (95% CI 2.6–18.7); similar results were reported by Blank et al.
      • 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.
      in a case-control study. While Simpson et al.
      • Simpson I.J.
      • Marshall M.R.
      • Pilmore H.
      • Manley P.
      • Williams L.
      • Thein H.
      • et al.
      Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases.
      reported a partial recovery of renal function after PPI-induced AIN, Geevasinga et al.
      • Geevasinga N.
      • Coleman P.L.
      • Webster A.C.
      • Roger S.D.
      Proton pump inhibitors and acute interstitial nephritis.
      in a separate case series in the same year reported that in 18 PPI-induced AIN cases patients recovered the renal function, however, the mean calculated creatinine clearance was lower than baseline at 3 and 6 months. The impairing effect of PPIs on the renal function is also one of the possible explanation for its ill effect on kidney and hence CKD.
      • Lodato F.
      • Azzaroli F.
      • Turco L.
      • Mazzella N.
      • Buonfiglioli F.
      • Zoli M.
      • et al.
      Adverse effects of proton pump inhibitors.
      Furthermore, in patients with PPI-induced AIN, early diagnosis and withdrawal of PPI are often jeopardised by that fact that, roughly 10% of the patients manifest classic triad of hypersensitivity reactions (i.e. fever, rash, and eosinophilia).
      • Klatte D.C.F.
      • Gasparini A.
      • Xu H.
      • de Deco P.
      • Trevisan M.
      • Johansson A.L.V.
      Association between proton pump inhibitor use and risk of progression of chronic kidney disease.
      Furthermore, in a recent systematic review and meta-analysis by Xie et al.
      • 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.
      the patient on PPI therapy were found to be at increased risk of chronic renal outcomes even in the absence of intervening AKI.
      This systematic review found that the PPI user with pre-existing diabetes was more likely to develop CKD compared to the similar non-PPI users diabetic population. Diabetes is a well-established risk factor for the kidney disease with ∼30% of the patients with type 1 diabetes and 10–40% of those with type 2 diabetes predisposed kidney failure.
      • Harjutsalo V.
      • Groop P.H.
      Epidemiology and risk factors for diabetic kidney disease.
      In diabetic population hyperfiltration injury, advanced glycosylation end products, and reactive oxygen species are found to be a responsible mechanism for kidney disease.
      • Lea J.P.
      • Nicholas S.B.
      Diabetes mellitus and hypertension: key risk factors for kidney disease.
      In the process of study selection, we observed that the study conducted by Lazarus et al.
      • Lazarus B.
      • Chen Y.
      • Wilson F.P.
      • Sang Y.
      • Chang A.R.
      • Coresh J.
      • et al.
      Proton pump inhibitor use and the risk of chronic kidney disease.
      had included cohort from two different databases namely, ARIC and GHSRC. Hence, we considered them as an independent cohort and analysed accordingly. The strength of this review includes: protocol oriented approach,
      • Hussain S.
      • Singh A.
      • Najmi A.K.
      Proton pump inhibitors use and the risk of chronic kidney disease: a systematic review.
      an exhaustive search of two major bibliographic databases, and hand searching of the relevant articles. Although most of the included studies were of high quality as reflected by the quality assessment scores, this meta-analysis had some limitations. Hence, the results should be interpreted with caution. The notable limitations of this review are: the heterogeneity among selected studies, in terms of the follow-up duration, dose of PPI therapy, and study quality assessed on NOS. The heterogeneity assessment, the pooled effects estimate, and the publication bias of the studies may be imprecise since the number of included studies reporting on PPI exposure and risk of CKD was small.
      • Higgins J.P.
      • Green S.
      Cochrane Handbook for Systematic Reviews of Interventions.
      Furthermore, to be noted, funnel plot is thought to be unreliable methods of investigating publication bias, particularly if the number of included studies is small.
      • Sedgwick P.
      • Marston L.
      How to read a funnel plot in a meta-analysis.
      Also as a meta-analysis of observational studies with significant heterogeneity, this systematic review could only demonstrate an association and has its own limitation in establishing the causality.

      5. Conclusion

      This meta-analysis demonstrated an increased risk of CKD and ESRD among the PPIs users. However, pertaining to the inherent limitations in methodology and heterogeneity of the included studies, the results should be interpreted accordingly.

      Funding

      None.

      Conflict of interest

      Authors declare that they have no conflict of interest.

      Meeting Presentation

      This paper (abstract) was accepted for poster presentation at the 54th ERA-EDTA Congress, Madrid, Spain, June 3rd–6th 2017.

      Acknowledgements

      First author (SH) thankful to Sun Pharmaceuticals, India, for providing assistantship for this project under the joint collaboration for the Ph.D. programme with Jamia Hamdard, Hamdard University, New Delhi, India.

      Appendix A. Supplementary data

      The following is Supplementary data to this article:

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