Proton pump inhibitor (PPI) use is associated with an increased risk of acute kidney injury (AKI), incident chronic kidney disease (CKD), and progression to end-stage renal disease (ESRD). PPI-associated CKD is presumed to be mediated by intervening AKI. However, whether PPI use is associated with an increased risk of chronic renal outcomes in the absence of intervening AKI is unknown. To evaluate this we used the Department of Veterans Affairs national databases to build a cohort of 144,032 incident users of acid suppression therapy that included 125,596 PPI and 18,436 Histamine H2 receptor antagonist (H2 blockers) consumers. Over 5 years of follow-up in survival models, cohort participants were censored at the time of AKI occurrence. Compared with incident users of H2 blockers, incident users of PPIs had an increased risk of an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73m 2 (hazard ratio 1.19; 95% confidence interval 1.15-1.24), incident CKD (1.26; 1.20-1.33), eGFR decline over 30% (1.22; 1.16-1.28), and ESRD or eGFR decline over 50% (1.30; 1.15-1.48). Results were consistent in models that excluded participants with AKI either before chronic renal outcomes, during the time in the cohort, or before cohort entry. The proportion of PPI effect mediated by AKI was 44.7%, 45.47%, 46.00%, and 46.72% for incident eGFR under 60 ml/min/1.73m 2 , incident CKD, eGFR decline over 30%, and ESRD or over 50% decline in eGFR, respectively. Thus, PPI use is associated with increased risk of chronic renal outcomes in the absence of intervening AKI. Hence, reliance on antecedent AKI as warning sign to guard against the risk of CKD among PPI users is not sufficient as a sole mitigation strategy.

Proton pump inhibitors (PPI) are widely used for acid suppression therapy. Results of the National Health and Nutrition Examination Survey estimate that 7.8% of US adults had used prescription PPIs in the previous 30 days.These figures likely underestimate the real prevalence of PPI use as several PPIs are also widely available for sale over the counter without prescription in the United States.Several observational studies suggest that PPI use is associated with an increased risk of a number of adverse health outcomes.PPI use is also associated with an increased risk of acute kidney injury (AKI), incident chronic kidney disease (CKD), CKD progression, and end-stage renal disease (ESRD).

AKI is a significant risk factor for the development of CKD, CKD progression, and ESRD.CKD increases the propensity for the development of AKI where a bidirectional nexus exists between AKI and CKD and progression to ESRD.The association between PPI exposure and risk of AKI and acute interstitial nephritis is well documented.Studies that established the relationship of PPI use and CKD have postulated that the association is likely mediated by the occurrence of intervening AKI, from which some patients recover, but others do not or experience incomplete recovery and CKD might develop and progress to ESRD.It has also been suggested that PPI use may lead to subclinical AKI, AKI that is not clinically diagnosed, or chronic indolent renal damage.Previous studies have not addressed whether PPI-associated CKD is mediated by the occurrence of intervening AKI or via other pathways. Whether the use of PPI is associated with untoward long-term kidney outcomes including the development of CKD and progression to ESRD in the absence of intervening AKI is not known.

In this work, we aimed to examine the association of PPI use and the risk of long-term renal outcomes in those without intervening AKI. We therefore used the US Department of Veterans Affairs (VA) databases to build a national cohort of new users of acid suppression therapy (either PPI or histamine H2 receptor antagonists [H2 blockers]) without kidney disease at baseline (baseline estimated glomerular filtration rate [eGFR] >60 ml/min per 1.73 m2) and followed them for 5 years to characterize the association of PPI use with the risk of incident CKD, the risk of CKD progression, and the risk of ESRD in the absence of intervening AKI.

In order to optimize control of confounding, we additionally built high-dimensional propensity score–adjusted survival models following the multistep algorithm described by Schneeweiss et al.Among new users of acid suppression therapy, in high-dimensional propensity score–adjusted models (in which score was considered as continuous), new PPI users had an increased risk of incident eGFR <60 ml/min per 1.73 m(HR 1.15, 95% CI 1.10–1.19), incident CKD (HR 1.20, 95% CI 1.13–1.27), an eGFR decrease >30% (HR 1.19, 95% CI 1.14–1.25), and an ESRD or eGFR decrease >50% (HR 1.30, 95% CI 1.15–1.48) ( Supplementary Table S8 ). Similar results were obtained where the high-dimensional propensity score was considered in deciles ( Supplementary Table S8 ). We evaluated the association in participants without gastrointestinal conditions; the intent of this analysis was to examine the association in a lower risk cohort. Results suggest a significant relationship between PPI use and the risk of chronic renal outcomes ( Supplementary Table S9 ). In separate analyses, we additionally controlled for glycated hemoglobin (HbA1c) and microalbumin/creatinine ratio and considered those with a microalbumin/creatinine ratio <30 mg/g; results remained consistent ( Supplementary Tables S10, S11, and S12 ).

An instrumental variable approach was used to account for the lack of random assignment of PPI and H2 blockers, and results suggest that PPI users had an increased risk of an incident eGFR <60 ml/min per 1.73 m(HR 1.36, 95% CI 1.25–1.48), incident CKD (HR 1.68, 95% CI 1.48–1.91), an eGFR decrease >30% (HR 1.40, 95% CI 1.25–1.57), and an ESRD or eGFR decrease >50% (HR 1.50, 95% CI 1.13–2.00) ( Supplementary Table S7 ).

In models that included incident H2 blocker users who switched to PPI use and where exposure was modeled as time dependent, compared with H2 blocker use, PPI use was associated with an increased risk of chronic renal outcomes ( Supplementary Table S4 ). Analyses in which covariates were treated as time-dependent variables produced consistent results ( Supplementary Table S5 ). Examination of the association in Fine and Gray models in which death and AKI were considered competing risks yielded consistent results ( Supplementary Table S6 ).

Additional sensitivity analyses were conducted in models that censored participants at the time of AKI occurrence ( Figure 2 , analytic approach A). In analyses using the modified NHS England AKI algorithm, as reported by Sawhney et al.,which has a very high sensitivity (>90%) for the detection of biochemical AKI (AKI based on actual laboratory values, not International Classification of Diseases, Ninth Revision [ICD-9] codes),PPI use was associated with an increased risk of chronic renal outcomes, and the results were consistent with those shown in the primary analysis ( Supplementary Table S3A ). Analyses in which AKI was defined by KDIGO criteria and separately where AKI was defined by ICD-9 codes occurring during a hospital stay yielded consistent results ( Supplementary Tables 3B and 3C ).

We evaluated the robustness of study results in a number of sensitivity analyses. As a test of calibration, we examined the relationship of PPI use and the risk of AKI and, separately, the relationship of PPI use and risk of chronic renal outcomes (without taking into account the possible occurrence of intervening AKI). The intent of this analysis was to verify the presence of an association where a priori knowledge suggests that an association is expected.Results show that PPI users have an increased risk of AKI (HR 1.47, 95% CI 1.41–1.54). PPI use was associated with an increased risk of an eGFR <60 ml/min per 1.73 m(HR 1.25, 95% CI 1.21–1.29), incident CKD (HR 1.33, 95% CI 1.27–1.40), an eGFR decrease >30% (HR 1.31, 95% CI 1.26–1.37), and an ESRD or eGFR decrease >50% (HR 1.43, 95% CI 1.33–1.1.54).

In analyses evaluating the cumulative duration of exposure and risk of renal outcomes, there was a graded association between duration of use and risk in that a more prolonged duration of PPI exposure was associated with a greater risk of chronic renal outcomes ( Figure 4 and Supplementary Table S2 ).

Mediation analyses showed the proportion of PPI effect mediated by AKI was 44.7% for an incident eGFR <60 ml/min per 1.73 m, 45.47% for incident CKD, 46.00% for an eGFR decrease >30%, and 46.72% for an ESRD or >50% decrease in eGFR ( Figure 3 and Supplementary Table S1 ).

Mediation analyses of the association between proton pump inhibitor (PPI) use and chronic renal outcomes where acute kidney injury (AKI) was considered a mediator. Pathway a = a1 + a2 represents the pathway mediated by AKI. Pathway b represents the pathway not mediated by AKI. ( a ) Incident estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m 2 . ( b ) Incident chronic kidney disease (CKD). ( c ) eGFR decrease >30%. ( d ) End-stage renal disease (ESRD) or eGFR decrease >50%.

Figure 3 Mediation analyses of the association between proton pump inhibitor (PPI) use and chronic renal outcomes where acute kidney injury (AKI) was considered a mediator. Pathway a = a1 + a2 represents the pathway mediated by AKI. Pathway b represents the pathway not mediated by AKI. ( a ) Incident estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m 2 . ( b ) Incident chronic kidney disease (CKD). ( c ) eGFR decrease >30%. ( d ) End-stage renal disease (ESRD) or eGFR decrease >50%.

Because a history of AKI increases the risk of both AKI recurrence and CKD,we evaluated the research question among cohort participants without a history of AKI within 5 years before cohort entry (N = 132,699) ( Figure 2 , analytic approach D), in which cohort participants were censored at the time of AKI occurrence; compared with new users of H2 blockers, new users of PPIs had an increased risk of chronic renal outcomes including an eGFR <60 ml/min per 1.73 m(HR 1.19, 95% CI 1.15–1.25), incident CKD (HR 1.27, 95% CI 1.20–1.34), an eGFR decrease >30% (HR 1.22, 95% CI 1.16–1.29), and an ESRD or eGFR decrease >50% (HR 1.32, 95% CI 115–1.52) ( Table 6 ).

Survival models of the association between PPI use and risk of chronic renal outcomes in new users of acid suppression therapy (H2 blockers [referent] and PPIs) in a cohort participants with no history of AKI (no AKI before cohort entry) and in which cohort participants were censored at the time of AKI occurrence (N=132,699)

Table 6 Survival models of the association between PPI use and risk of chronic renal outcomes in new users of acid suppression therapy (H2 blockers [referent] and PPIs) in a cohort participants with no history of AKI (no AKI before cohort entry) and in which cohort participants were censored at the time of AKI occurrence (N=132,699)

To evaluate the relationship of PPI use and the risk of chronic renal outcomes in participants who do not experience AKI before the onset of chronic renal outcome, we excluded cohort participants who experienced AKI before chronic renal outcomes (any AKI between the time of cohort entry (T0) and before chronic renal outcome) ( Figure 2 , analytic approach B); compared with new users of H2 blockers, incident users of PPIs had an increased risk of an eGFR <60 ml/min per 1.73 m(HR 1.22, 95% CI 1.17–1.27), incident CKD (HR 1.29, 95% CI 1.22–1.36), an eGFR decrease >30% (HR 1.26, 95% CI 1.19–1.32), and an ESRD or eGFR decrease >50% (HR 1.35, 95% CI 1.19–1.53) ( Table 4 ). In order to evaluate the association of PPI use and the risk of chronic renal outcomes in those who do not experience AKI after exposure to acid suppression, we excluded cohort participants in whom AKI developed during the time in the cohort (from T0 until the end of follow-up, either before or after the occurrence of chronic renal outcomes) ( Figure 2 , analytic approach C). The analyses yielded consistent results in that PPI users had an increased risk of an eGFR <60 ml/min per 1.73 m(HR 1.17, 95% CI 1.12–1.22), incident CKD (HR 1.23; 95% CI 1.16–1.30), an eGFR decrease >30% (HR 1.19; 95% CI 1.13–1.26), and an ESRD or eGFR decrease >50% (HR 1.21, 95% CI 1.04–1.40) ( Table 5 ).

Survival models of the association between PPI use and risk of chronic renal outcomes in new users of acid suppression therapy (H2 blockers [referent] and PPIs) in which cohort participants included those with no AKI between time of cohort entry (T0) and end of follow-up (N = 118,793)

Table 5 Survival models of the association between PPI use and risk of chronic renal outcomes in new users of acid suppression therapy (H2 blockers [referent] and PPIs) in which cohort participants included those with no AKI between time of cohort entry (T0) and end of follow-up (N = 118,793)

Survival models of the association of PPI use and risk of chronic renal outcomes in new users of acid suppression therapy (H2 blockers [referent] and PPIs) in which cohort participants included those with no AKI before onset of chronic renal outcome (excluded from cohort entry those participants with AKI between the time of cohort entry time 0 and before chronic renal outcome)

Table 4 Survival models of the association of PPI use and risk of chronic renal outcomes in new users of acid suppression therapy (H2 blockers [referent] and PPIs) in which cohort participants included those with no AKI before onset of chronic renal outcome (excluded from cohort entry those participants with AKI between the time of cohort entry time 0 and before chronic renal outcome)

We examined the association of PPI use and the risk of chronic renal outcomes in the absence of intervening AKI using the analytic strategies outlined in Figure 2 . In order to evaluate the association between PPI use and the risk of chronic renal outcomes in the absence of intervening AKI, we built survival models in which cohort participants were censored at the time of AKI occurrence ( Figure 2 , analytic approach A). In a cohort of 144,032 incident users of acid suppression therapy and over a median follow-up period of 5 years (interquartile range, 5–5), compared with new users of H2 blockers, new users of PPIs had a significantly increased risk of an eGFR <60 ml/min per 1.73 m(hazard ratio [HR]1.19, 95% confidence interval [CI] 1.15–1.24), incident CKD (HR 1.26, 95% CI 1.20–1.33), an eGFR decrease >30% (HR 1.22, 95% CI 1.16–1.28), and an ESRD or eGFR decrease >50% (HR 1.30, 95% CI 1.15–1.48) ( Table 2 ). To ascertain that associations observed in the previous models were not reversible and remained until end of cohort follow-up, we built multivariate analyses in which we used the last eGFR before censorship (time of first occurrence of AKI, ESRD, death, or end of follow-up) to define chronic renal outcomes; new users of PPIs had an increased odds of an eGFR <60 ml/min per 1.73 m(odds ratio 1.26, 95% CI 1.19–1.32); an eGFR decrease >30% (odds ratio 1.24, 95% CI 1.17–1.31), and an eGFR decrease >50% (odds ratio 1.34, 95% CI 1.19–1.52) (ESRD is, by definition, a terminal event and was not included as an outcome in this analysis) ( Table 3 ).

Based on a comparison of the first and last eGFRs, in which the last eGFR was the eGFR before and closest to first occurrence of AKI, ESRD, death, or end of follow-up.

a Based on a comparison of the first and last eGFRs, in which the last eGFR was the eGFR before and closest to first occurrence of AKI, ESRD, death, or end of follow-up.

Multivariate logistic regression models of the association between PPI use and the odds of chronic renal outcomes in new users of acid suppression therapy (H2 blockers [referent] and PPIs) where the last eGFR before the first occurrence of AKI, ESRD, death, or end of follow-up was used to define outcomes (N = 144,032)

Table 3 Multivariate logistic regression models of the association between PPI use and the odds of chronic renal outcomes in new users of acid suppression therapy (H2 blockers [referent] and PPIs) where the last eGFR before the first occurrence of AKI, ESRD, death, or end of follow-up was used to define outcomes (N = 144,032)

Survival models of the association between PPI use and risk of chronic renal outcomes among new users of acid suppression therapy (H2 blockers [referent] and PPIs) in which cohort participants were censored at the time of AKI occurrence (N = 144,032)

Table 2 Survival models of the association between PPI use and risk of chronic renal outcomes among new users of acid suppression therapy (H2 blockers [referent] and PPIs) in which cohort participants were censored at the time of AKI occurrence (N = 144,032)

There were 144,032 new users of acid suppression therapy; 18,436 and 125,596 were new users of H2 blockers and PPIs, respectively. There were 118,793 cohort participants with no AKI during the time in the cohort (from time 0 [T0] at cohort entry until the end of follow-up or ESRD or death); 16,101 and 102,692 were incident users of H2 blockers and PPIs, respectively. The demographic and health characteristics are given in Table 1 . Overall, new users of PPIs and H2 blockers had comparable demographic characteristics, but PPI users were more likely to have diabetes, chronic lung disease, hyperlipidemia, and cardiovascular disease ( Table 1 ). New users of PPIs were more likely to have gastrointestinal conditions ( Table 1 ). Survival probability for chronic kidney outcomes including an incident eGFR <60 ml/min per 1.73 m, incident CKD, an eGFR decrease >30%, and ESRD or eGFR decrease >50% by type of acid suppressant is shown in Figure 1 a–d .

Discussion

In this work, we show that among new users of acid suppression therapy, incident PPI users have an increased risk of chronic renal outcomes including incident CKD, CKD progression, and ESRD in the absence of intervening AKI. We built numerous models in which we censored cohort participants at the time of AKI occurrence (an analytic approach designed to ensure that events captured in the models precede the occurrence of AKI), and in alternative analytic strategies, we excluded participants in whom AKI developed before chronic renal outcomes, excluded participants in whom AKI developed during the time in the cohort, and excluded participants with AKI before cohort entry. Mediation analyses showed the proportion of PPI effect mediated by AKI was ∼50% for each of the chronic renal outcomes examined in this study, endorsing the possibility of a direct effect of PPI on chronic renal outcomes. The results were consistent using various definitions of AKI (NHS England AKI algorithm definition, KDIGO definition, and a definition based on inpatient ICD-9 codes). The findings were robust to changes in other multiple sensitivity analyses including time-dependent analyses (for exposure and covariates), analyses that accounted for the competing risk of death and AKI, and analyses using an instrumental variable approach and high-dimensional propensity score–adjusted models. In all analyses, the results showed a significant association between PPI use and chronic renal outcomes including incident CKD, CKD progression, and ESRD in the absence of intervening AKI.

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et al. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. , 13 Praga M.

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et al. The nexus of acute kidney injury, chronic kidney disease, and World Kidney Day 2009. , 9 Coca S.G.

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et al. Proton pump inhibitors and risk of incident CKD and progression to ESRD. , 7 Lazarus B.

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et al. Proton pump inhibitor use and the risk of chronic kidney disease. , 23 Wyatt C.M. Proton pump inhibitors and chronic kidney disease: is it time to sound the alarm?. 18 Moledina D.G.

Perazella M.A. Proton pump inhibitors and CKD. The relationship between PPI exposure and the risk of AKI and acute interstitial nephritis is well established,and AKI is associated with an increased risk of CKD.The newly reported association of PPI and the risk of the development and progression of CKD was postulated to be mediated by the occurrence of intervening AKI.It was suggested that PPI-induced AKI serves as an antecedent event that may (i) offer a warning sign and induce avoidance of PPIs as acid suppressants and (ii) identify those at risk and who are susceptible to (or with a predilection for) chronic renal outcomes associated with PPI use.However, whether PPI-related CKD and other chronic renal outcomes are mediated solely by the occurrence of AKI is clinically relevant but not known. Our study was designed to address this knowledge gap and answer this clinically relevant question; the results suggest that a significant association exists between PPI use and CKD outcomes without an intervening AKI. The finding that PPI use is associated with adverse chronic renal outcomes independent of the occurrence of AKI suggests that monitoring for AKI or acute interstitial nephritis among PPI users is not sufficient to guard against the development of CKD and ESRD. Although we examined the research question using 4 definitions of AKI, our design will not detect (or capture) subclinical AKI (AKI that does not meet the definition threshold), and unrecognized AKI (i.e., AKI that occurs in the outpatient setting between clinical encounters and that may have resolved by the time the laboratory parameters are obtained). In our studies, we used AKI as a surrogate measure of AKI and acute interstitial nephritis, and our analyses do not differentiate on the basis of AKI etiology. However, we designed an analytic strategy in which we examined the relationship using a number of approaches that all yielded consistent results; the constellation of findings strongly suggests a relationship between PPI use and the risk of CKD and progression to ESRD in the absence of intervening AKI.

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Evenepoel P. Adverse effects of proton pump inhibitors in chronic kidney disease. 25 Kucuk H.F.

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et al. Effect of proton pump inhibitors on hepatic regeneration. 26 Becker J.C.

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et al. Beyond gastric acid reduction: proton pump inhibitors induce heme oxygenase-1 in gastric and endothelial cells. 27 Nath K.A. Heme oxygenase-1 and acute kidney injury. 27 Nath K.A. Heme oxygenase-1 and acute kidney injury. 28 Yepuri G.

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et al. Proton pump inhibitors accelerate endothelial senescence. , 29 Wu D.

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et al. Systematic toxicity mechanism analysis of proton pump inhibitors: an in silico study. 30 Mullin J.M.

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et al. Systematic toxicity mechanism analysis of proton pump inhibitors: an in silico study. The biological mechanisms supporting the observed association of PPI with chronic renal outcomes are unclear. Poesen et al.proposed a hypothesis that in addition to AKI, altered gut microbial composition and metabolism may be in the causal pathway between PPIs and CKD. Experimental evidence in rats suggests that PPI administration limits the regenerative capacity of the liver after partial hepatectomy.It is unclear whether PPI exposure also limits the regenerative capacity of renal tubular cells, for example. Such a mechanism, if verified, may at least partially explain the increased risk of renal outcomes in PPI users. It has also been noted that administration of PPIs upregulates the expression of mRNA and protein level and subsequent increased activity of the heme oxygenase-1 enzyme in gastric and endothelial cells.Heme oxygenase-1 is generally seen as salutatory in the setting of AKI as it may decrease the sensitivity of the kidney to AKI and may reduce the propensity of AKI to CKD transition.However, the salutary properties of heme oxygenase-1 are evident at lower doses and are vitiated at higher doses or in cases of sustained duration of expression.It is unclear whether and to what extent PPIs upregulate heme oxygenase-1 in renal tissue and whether prolonged duration of PPI exposure leads to a high level of sustained heme oxygenase-1 where its beneficial effect is abrogated or reversed. PPIs are enriched in acidic organelles where they are activated and inhibit vacuolar H+-ATPases and acid hydrolases. A significant body of evidence suggests that PPIs impair lysosomal acidification and proteostasis, which may lead to increased oxidative stress, dysfunction, telomere shortening, and accelerated senescence in human endothelial cells.PPIs have also been reported to induce a transepithelial leak.In a high-throughput in silico analysis of microarray data, PPI upregulated genes in the cellular retinol metabolism pathway and downregulated genes in the complement and coagulation cascades pathway.How the changes in gene expression contribute to renal manifestations is not clear as there is a substantial lack of published experimental and mechanistic evidence to facilitate a better understanding the putative off-target effects of PPIs.

We conducted a systematic PubMed search using a comprehensive list of search terms to identify animal studies of PPI-induced acute or chronic renal injury. The search results yielded no published animal studies. The conspicuous absence of published literature evaluating possible mechanisms of PPI-related renal injury suggests a significant knowledge gap and highlights the pressing need for experimental work to further enhance our understanding of the effect of PPIs on the kidney.

Our study has a number of limitations. The analytic cohort included mostly older white male US veterans, which may limit the generalizability of study results. Our datasets did not include information on the volume of daily urine output. We cannot account for AKI that is not clinically detected, and although we used a sensitive definition to capture the occurrence of AKI, subclinical AKI (i.e., an increase in creatinine that does not meet the threshold of the AKI definition) cannot be captured but may gradually over time contribute the development of CKD and its progression to ESRD. Although we considered known covariates in the analyses, it remains possible that there may be residual confounders, either unknown or unmeasured, that may explain the observed associations. In our analyses, we defined drug exposure as having a prescription for it; because PPIs (and H2 blockers) are also available without prescription in the United States, it is possible that some participants in this cohort may have acquired PPIs without prescription. However, due to financial considerations, this possibility is not highly likely, and if it occurred in some cohort participants, it would have biased the results against the primary hypothesis and resulted in an underestimation of risk. Duration of wash out (time from VA enrollment until T0 without exposure to acid suppressants) varied among cohort participants, and it is likely that a small number of participants had a brief wash-out period (where we could ascertain the lack of exposure to acid suppressants); however, this bias would have reduced risk estimates (and biased the results toward the null hypothesis). The study has a number of strengths including the use of national large-scale data from a network of integrated health systems that were captured during routine medical care, which minimizes selection bias. We utilized a new user (incident user) design and evaluated the association between PPI use and the risk of chronic renal outcomes using a number of analytical approaches in sensitivity analyses. In sum, our results show a significant association of PPI use and the risk of CKD and progression to ESRD in the absence of intervening AKI. Reliance on antecedent AKI as warning sign to guard against the risk of the development of CKD and progression to ESRD among PPI users is not sufficient as a sole risk mitigation strategy. Exercising vigilance in PPI use, even in the absence of AKI, and careful attention to kidney function in PPI users may be a reasonable approach.