Table 1. Characteristics of studies.

proton pump inhibitors (PPIs), chronic kidney disease (CKD), gastroesophageal reflux disease (GERD), acute kidney injury (AKI), acute interstitial nephritis (AIN), nonsteroidal anti-inflammatory drugs (NSAIDs), Atherosclerosis Risk in Communities (ARIC), hospital-acquired acute kidney injury (HA-AKI), major adverse renal events (MARE), estimated glomerular filtration rate (eGFR), hazard ratio (HR), health maintenance organization (HMO), odd ratio (OR), adjusted odd ratio (aOR), confidence interval (CI).

Citation and Year of Publication	WHO region	Country of the study	The focus of the study	Findings	Key  observation
Hart, et al. 2019 [14]	Region of the Americas	United States of America	In a sizable population-based health maintenance organization (HMO) cohort, this retrospective cohort study investigated the relationship between PPI usage and the incident risk of AKI and CKD.	A significantly higher risk of AKI was linked to PPI exposure (adjusted odds ratio [aOR] 4.35, 95% confidence interval [CI] 3.14-6.04, p<0.0001). When compared to controls, PPIs were linked to a greater risk of chronic kidney disease (CKD) (aOR 1.20, 95% CI 1.12-1.28, p<0.0001).	An elevated incidence of incident AKI and CKD is linked to PPI use. Propensity score-matched analyses revealed that there were still relationships between PPI use and AKI and CKD.
Guedes, et al. 2020 [15]	Region of the Americas	Brazil	The objective of this retrospective cohort study was to examine the relationship between omeprazole use over time and the development of chronic kidney disease (CKD) in adults and older people.	Compared to non-users (10.5%), those taking omeprazole had a greater percentage of CKD development (70.6%). The hazard ratio of 7.34 (CI: 3.94-13.71) showed that omeprazole users had a higher chance of progressing to worse stages of CKD than non-users. Regarding the remaining characteristics, there was no discernible variation between the groups (p > 0.05).	Omeprazole use on a regular basis was significantly associated with worsening stages of chronic kidney disease (CKD) in adult and elderly patients.
Aurora, et al. 2016 [16]	Region of the Americas	United States of America	A prospective logistic regression analysis of the data was combined with two different retrospective case-control research designs to look at the link between taking PPIs and getting chronic kidney disease (CKD) or dying.	PPI-using patients had greater risks of developing CKD (OR 1.10, 95% CI 1.05–1.16) and dying (OR 1.76, 95% CI 1.67–1.84) than non-PPI-using patients, according to a prospective logistic analysis of case-control data.	Proton pump inhibitor use is linked to a higher chance of developing CKD and passing away. According to the study, using PPIs raised the likelihood of developing CKD by 10% and was linked to a 75% higher risk of death.
Lu, et al. 2022 [17]	Western Pacific Region	China	The purpose of the study was to determine if PPIs influence the metabolism of gut-derived uremic toxins, such as trimethylamine-N-oxide, p-cresyl sulfate, and indoxyl sulfate (IS), as a potential cause of chronic kidney disease (CKD).	The study found that when mice were given PPIs (omeprazole, lansoprazole, and pantoprazole at 30 mg/kg) for three weeks, only the IS plasma levels of the three gut-derived uremic toxins went up. PPIs increase the levels of CYP2E1 protein in the liver, which is an important enzyme in the creation of IS. This is because PPIs prevent this enzyme from being broken down, which raises the exposure to IS. It is noteworthy that kidney impairment with mild glomerular structural alterations and fibrosis symptoms only happened after three weeks of high-dose PPI treatment (30 mg/kg).	PPI use has been linked to an increased risk of chronic kidney disease (CKD). This association may be explained by the biological mechanism of PPI-induced IS production via increased hepatic CYP2E1 protein levels and increased IS exposure.
Shih-Chang, et al. 2018 [18]	East Asia	Republic of China (Taiwan)	This population-based case-control study aims to identify 16,704 cases of newly diagnosed CKD in individuals 20 years of age or older between 2000 and 2013.	Those who used PPIs had an OR for CKD of 1.41 (95% confidence interval (CI) 1.34, 1.48) when compared to those who had never used PPIs. Cumulative duration and dosage regression analysis shows a weak relationship between higher risks of CKD and almost all main forms of PPIs. The odds ratio (OR) for the total amount of time (month) spent using PPIs was 1.02 (95% CI 1.01, 1.02) and the OR for the total amount of time (microgram) spent using PPIs was 1.23 (95% CI 1.18, 1.28).	Taiwan health insurance claims data analysis using PPIs revealed 1.4-fold greater risks of CKD.
Rodríguez-Poncelas, et al. 2018 [19]	European region	Portugal (Southwest Europe)	People who were 15 years of age or older between January 1, 2005, and December 31, 2012, are included in this retrospective cohort. Prescriptions were tracked during a follow-up session to gauge PPI use.	In the analysis that controlled for several clinical factors, the use of proton pump inhibitors was linked to incident CKD (hazard ratio (HR) 1.18; 95% CI 1.04–1.51) in both those who started using PPI during the follow-up and those who took it during the initial visit (HR 1.37; 95% CI 1.25–1.50). High PPI dosages raised the incidence of incident CKD (HR 1.92; 95%CI 1.00–6.19) for both people who used high doses for the duration of the follow-up and for any kind of PPI exposure (HR 2.40; 95%CI 1.65–3.46). Following three months of PPI use, there was an increase in the incidence of incident CKD (HR 1.78; 95% CI 1.39–2.25) between the third and sixth months and (HR 1.30; 95% CI 1.07–1.72) following the sixth month.	PPI use has been linked to an increased incidence of CKD incidents. After three months of exposure, this relationship becomes noticeable and is stronger for high dosages.
Laville, et al. 2018 [20]	Western Europe	Europe (France)	Thirty-three outpatients with CKD (eGFR between 15 and 60 ml min-1.73 m-2) are part of the CKD-REIN cohort. At study enrollment, we looked at the daily dosages of pharmacological medicines administered. In relation to kidney function, we evaluated the frequency and contributing factors of incorrect drug prescriptions (i.e., contraindications or excessive dosages) in patients with CKD receiving nephrology care. We also evaluated the effect of the GFR estimation equation on the prevalence estimations.	At least one incorrect medicine prescription had been given to half of the patients. Medications for cardiovascular disease, gout, and diabetes made up the majority of prescriptions that were improperly written. Different GFR equations produced different percentages of improper prescriptions: 52% with the CKD-EPI equation, 47% with the de-indexed CKD-EPI equation, and 41% with the CG equation. The results of a multiple logistic regression analysis indicated that patients who were male (1.28 [1.07; 1.53]), had diabetes (1.34 [1.06; 1.70]), had a high BMI (1.58 [1.25; 1.99]), and had a low GFR (10.2 [6.02; 17.3]) had significantly higher odds ratios [95% confidence intervals] for inappropriate prescriptions. The number of pharmaceuticals per patient increased the chance of receiving at least one incorrect prescription (P for trend < 0.0001). Consequently, the odds ratio for patients who received at least 11 prescribed prescriptions was 5.88 [4.17; 8.28] compared to those who received fewer than 5.	Our findings highlight the difficulty in managing medications for individuals with chronic kidney disease (CKD), for whom improper prescriptions seem to be widespread.
Giusti, et al. 2021 [21]	West-South Central Region of the US	United States	This study examines the relationship between the rate of decrease in renal function and chronic PPI use among veterans with CKD (G3a–G4).	Dialysis, all-cause death, and the progression of CKD were all markedly more likely to occur in the PPI group (aHR, 1.83; 95% CI, 1.53 to 2.19; aHR, 1.84; 95% CI, 1.26 to 2.67; and aHR, 1.34; 95% CI, 1.08 to 1.65, respectively). Although the difference was not statistically significant, the PPI cohort also showed a trend toward the development of metabolic acidosis (aHR, 1.34; 95% CI, 0.998 to 1.80).	According to the research, long-term PPI use increases the risk of renal disease development and is linked to a higher death rate in CKD patients.
Lazarus, et al. 2016 [22]	North America	United States of America	The purpose of this prospective community-based cohort study is to measure the incidence of CKD and PPI use.	The use of proton pump inhibitors was linked to incident chronic kidney disease (CKD) in three different analyses: unadjusted (hazard ratio [HR], 1.45; 95% CI, 1.11-1.90); adjusted (HR, 1.50; 95% CI, 1.14-1.96); and adjusted (adjusted HR, 1.35; 95% CI, 1.17-1.55) with PPI ever use modeled as a time-varying variable.	The use of PPIs increases the risk of AKI and CKD independently.
Antoniou, et al. 2015 [23]	Region of the Americas	Ontario, Canada	This population-based cohort study aims to evaluate older patients' risk of acute kidney injury and acute interstitial nephritis.	Acute interstitial nephritis (0.32 vs. 0.11 per 1000 person-years; HR 3.00, 95% CI 1.47 to 6.14) and acute kidney damage (13.49 vs. 5.46 per 1000 person-years; HR 2.52, 95% CI 2.27 to 2.79) were more common in people who were given PPI than in people who were not.	When older patients began PPI medication, they were more likely to develop interstitial nephritis and acute renal injury.
Pannoi, et al. 2022 [24]	Southeast Asia	Thailand	This is a retrospective cohort to evaluate the hypomagnesemia and chronic kidney disease (CKD) hazards related to PPI usage.	There was a statistically significant correlation between PPIs and CKD (adjusted hazard ratio [HR] = 3.753, 95% CI = 2.385–5.905).	In this hospital-based population, PPIs linked to CKD had a statistically significant effect.
Zhang, et al. 2023 [25]	North America	United States of America	The purpose of this multicenter prospective matched cohort study is to evaluate the relationship between the use of PPIs and the risk of acute renal injury during hospitalization.	PPI use and the risk of post-hospitalization AKI were not statistically significantly associated after adjusting for baseline co-morbidities, drug use histories, and demographic characteristics (rate ratio [RR], 0.91; 95% CI, 0.38 to 1.45). According to baseline AKI status, there were no significant associations between the use of PPIs and the incidence or risk of recurrent AKI (RR, 1.01; 95% CI, 0.27 to 1.76) at all.	Regardless of the individuals' baseline AKI status, PPI usage following the index hospitalization was not a significant risk factor for post-hospitalization AKI and the advancement of renal disorders.
Svanström, et al. 2018 [26]	European Region	Denmark	This prospective cohort study uses proton pump inhibitor-treated rheumatoid arthritis patients to evaluate their risk of acute kidney injury.	Acute kidney damage risk was considerably higher in patients who used proton pump inhibitors (hazard ratio 2.30, 95% confidence interval 1.26–4.20). A significantly higher risk of the secondary outcome of any major renal incident was also linked to the use of proton pump inhibitors (hazard ratio 2.61, 95% confidence interval 1.80–3.80).	In this group study of rheumatoid arthritis patients, using a proton pump inhibitor was linked to a much higher rate of acute renal injury.
Scott, et al. 2019 [27]	Region of the Americas	United States of America	To assess the risk of acute kidney damage (AKI) in HIV patients taking proton pump inhibitors (PPI), a cohort study was carried out.	21,643 patients in all—6,000 PPI and 15,643 non-PPI—met all research requirements. When compared to controls, the PPI cohort had a twice as high incidence of AKI (2.12, hazard ratio: 1.46-3.1).	A nationwide cohort study confirmed an elevated incidence of AKI in patients taking PPIs.
Grant, et al. 2019 [28]	European Region	United Kingdom	To find out if PPI use is linked to major adverse renal events (MARE) in patients with CKD, retrospective observational cohort research including patients with the disease is being conducted.	In addition to having a lower estimated glomerular filtration rate (eGFR) and greater proteinuria, the PPI group was younger. After multiple factors were taken into account, the use of PPI was linked to the worsening of MARE (hazard ratio 1.13 [95% confidence interval 1.02–1.25], P = 0.021). Significantly higher proteinuria, comorbidities, and decreased eGFR were also linked to the progression to MARE.	In individuals with CKD, PPI usage was linked to the progression to MARE but not death after controlling for variables such as reduced eGFR, proteinuria, and comorbidities that are known to predict worsening renal function.
Xie, et al. 2016 [10]	Region of the Americas	United States of America	To determine the relationship between the use of proton pump inhibitors and the risk of incident CKD and progression to ESRD, a cohort study was carried out.	CKD and eGFR<60 ml/min per 1.73 m2 were more likely to happen in the PPI group compared to the H2 blockers group (HR, 1.22; 95% CI, 1.18 to 1.26; and HR, 1.28; 95% CI, 1.23 to 1.34, respectively). Patients taking PPI also had a higher chance of having their serum creatinine level double (HR, 1.53; 95% CI, 1.42 to 1.65), their eGFR drop by more than 30% (HR, 1.32; 95% CI, 1.28 to 1.37), and they developing end-stage renal disease (HR, 1.96; 95% CI, 1.21 to 3.18). Additionally, compared to individuals exposed for ≤30 days, we found a graded connection between the length of PPI exposure and the risk of renal outcomes for those exposed for 31–90, 91–180, 181–360, and 361–720 days.	PPI exposure raises the risk of incident CKD, CKD progression, and end-stage renal disease (ESRD).
Pakkir, et al. 2023 [29]	Eastern Mediterranean Region	UAE	The negative effects of using proton pump inhibitors over an extended period of time are the main topic of this review article.	The Atherosclerosis Risk in Communities (ARIC) study, a population-based cohort study, found that PPI users were more likely to get incident CKD.	PPIs have been linked in several studies to the development of renal illnesses, including end-stage renal disease (ESRD), acute kidney injury (AKI), chronic kidney disease (CKD), and acute interstitial nephritis (AIN).
Ikuta, et al., 2022 [30]	Western Pacific Region	Japan	The purpose of this case series study was to examine the relationship between PPI use and the incidence of AKI, as well as the relationship between exposure to macrolide antibiotics and the IRR of AKI in PPI users. The investigation was carried out utilizing computerized medical data at Kyoto University Hospital.	When comparing the period with PPIs to the one without, the estimated IRR and aIRR were 2.46 and 2.01, respectively. The predicted IRR and aIRR for the period including PPIs and macrolide antibiotics in comparison to those involving PPIs alone were 1.26 and 0.82, respectively.	The use of PPIs was linked in the study to an elevated risk of AKI at any stage. On the other hand, no correlation was found between the concurrent use of PPIs and macrolide antibiotics.
Zhang, et al. 2021 [31]	European Region	United Kingdom	462,421 people in the United Kingdom Biobank were part of the prospective cohort study. Self-reported PPI use was documented using an electronic questionnaire and verified by staff members with training. The medical history was used to identify the incident of CKD.	Over a median follow-up of 8.1 years, 7,031 instances of CKD were reported. According to overlap propensity score weighting analysis, regular PPI users were 37% more likely than non-users to experience a CKD episode.	The regular use of PPIs was linked to an increased risk of chronic kidney disease (CKD), according to this large cohort study.
Wu, et al. 2023 [32]	Western Pacific Region	Taiwan	observational studies assessing the relationship between PPI usage and the risk of chronic kidney disease (CKD)	Ten observational studies totaling 6,829,905 people were included. PPI usage was substantially linked to a higher risk of chronic kidney disease (CKD) compared to non-PPI use (RR 1.72, 95% CI: 1.02–2.87, p = 0.03).	PPI use is associated with a higher risk of chronic kidney disease (CKD).
Chen, et al. 2022 [33]	Western Pacific Region	Taiwan	A retrospective cohort study looked at patients with chronic kidney disease (CKD) who were followed up on after starting acid-suppressant drugs (H2RA and PPI). The goal was to find out how these drugs affected renal and survival outcomes.	For the cohort study, individuals who were new to using PPI, H2RA, or neither (as controls) were taken into account. Users of H2RA and PPI showed adjusted hazard ratios of 1.15 (0.91–1.45) for ESRD and 1.83 (1.65–2.03) for death, and 0.40 (95% confidence interval, 0.30–0.53) for ESRD and 0.64 (0.57–0.72) for death, respectively.	While PPI usage was linked to an increased risk of overall mortality in patients with CKD but not ESRD, dose-dependent H2RA use was linked to a decreased risk of both ESRD and overall mortality in CKD patients.
Wakabayashi, et al. 2021 [34]	Western Pacific Region	Japan	A retrospective observational study was conducted to evaluate the relationship between senior hypertension patients' declining kidney function and a modest dose of proton pump inhibitors.	The 152 patients in the study had a mean age of 74.5 years and were 57.9% male. PPI users made up 35.5% of the group (low dose: 17.1%; high dose: 18.4%). In the high-dose PPI group, the eGFR was considerably lower (P = 0.009) than in the low-dose PPI or non-user groups. Similarly, in the low-dose PPI and non-user groups, there were no significant changes in Scr between baseline and three years prior to treatment; but, in the high-dose PPI group, there was a significant rise in Scr (P = 0.0009).	Low PPI dosages may be secure in therapeutic situations.
Ikuta, et al. 2021 [35]	Western Pacific Region	Japan	In this nested case-control study, the researchers wanted to find out if taking proton pump inhibitors (PPIs) along with antibiotics (penicillins, macrolides, cephalosporins, or fluoroquinolones) or non-steroidal anti-inflammatory drugs (NSAIDs) raised the risk of acute kidney injury (AKI).	317 cases of AKI were found over a mean follow-up of 2.4 (SD, 1.7) years (incidence rate: 6.1/10 000 person-years). Compared to prior PPI usage, the use of PPIs is currently linked to a greater risk of AKI (unadjusted OR, 4.09; 95% CI, 3.09 to 5.44). In comparison to the present use of PPIs alone, the unadjusted ORs of AKI for the combination of PPIs and NSAIDs, cephalosporins, and fluoroquinolones were 3.92 (95% CI, 2.40 to 6.52), 2.57 (1.43 to 4.62), and 3.08 (1.50 to 6.38), respectively.	In the modified model, the effects of co-using PPIs with NSAIDs, cephalosporins, or fluoroquinolones are still considerable. The studies on the absolute risk of AKI validated the results from the nested case-control research.
Peng, et al. 2016 [36]	Western Pacific Region	Taiwan	Proton pump inhibitor (PPI) use may be linked to acute renal damage and nephritis, according to a case-control study. Research is required to determine whether PPI use increases the risk of renal function decline in patients with renal disorders.	In individuals with renal illness, the use of PPIs was linked to a notably increased risk of ESRD (adjusted OR = 1.88, 95% CI = 1.71–2.06). The adjusted OR of all PPI types together was 1.92 (95% CI = 1.74–2.13) for individuals with cumulative DDD <100, and 1.74-fold (95% CI = 1.52–2.00) for those with cumulative DDD ≥ 100.	The use of PPIs raises a patient's risk of end-stage renal disease (ESRD). Patients diagnosed with renal disease must have their PPI prescriptions appropriately coordinated with continuous monitoring of their renal function.
Nadri, et al. 2014 [37]	Eastern Mediterranean Region	UAE	Omeprazol-induced acute granulomatous interstitial nephritis (GIN)	With stable CKD stage IV, omeprazole-induced GIN led to enough renal recovery, enabling dialysis independence.	With a score of 6, the Naranjo adverse medication response likelihood scale indicated that omeprazole was most likely the cause.
Li, et al. 2020 [38]	Western Pacific Region	China.	a multicenter retrospective cohort study assessing the association between the use of proton pump inhibitors (PPI) and the risk of hospital-acquired acute kidney injury (HA-AKI) in pediatric patients admitted to hospitals	37,296 (27.2%), 1,760 (4.2%), and 3,514 (8.3%) of the 42,232 children analyzed used PPI, histamine 2 receptor antagonists (H2RA), and HA-AKI while in the hospital. Over 85 percent of PPI prescriptions were issued with the intention of preventing gastro-duodenal lesions in children. When compared to people who didn't use PPI (OR = 1.37; 95% CI = 1.23–1.53) or who used H2RA (OR = 1.24; 95% CI = 1.01–1.52), people who did use PPI were much more likely to have HA-AKI. For children of various ages, genders, PPI subtypes, and administration styles, the associations were constant. There was a higher impact on children with chronic kidney illness (OR, 3.37; 95% CI, 2.46–4.62) and those in critical care (OR, 1.54; 95% CI, 1.33–1.78). The risk of HA-AKI increased even when PPI was used within the recommended dosage range.	PPIs were widely used and associated with an increased risk of HA-AKI in hospitalized children in China.
Sampathkumar, et al. 2013 [39]	South-East Asia Region	India	There are four cases total—one male and three female. Two PPIs—pantoprazole and one each of omeprazole and esomeprazole—were implicated. After receiving medication for an average of four weeks, AIN appeared.	PPIs affect kidney function.	In India, PPI-induced AIN is probably not well known or treated. It has non-specific symptoms. If the doctor has strong suspicions about this illness, they should cease the medication, do a renal biopsy if necessary, and begin steroid therapy to stop the kidney disease from getting worse.