Renal Effects of PPIs Among Patients With CKD

Recent research has raised concerns about the renal effects of long-term use of proton pump inhibitors (PPIs) for gastrointestinal problems. However, most evidence focuses on PPI use among individuals with normal renal function.   

Chien-Huei Huang and colleagues, instead, sought to assess whether PPI use accelerated kidney disease progression and increased the risk of acute kidney injury (AKI) among patients with moderate to advanced chronic kidney disease (CKD) before end-stage renal disease (pre-ESRD) compared with the use of an H2 blocker (H2B). Their retrospective, population-based cohort study used data from the National Health Insurance Research Database (NHIRD) in Taiwan. Participants comprised adults aged 20 or older with CKD stages 3b to 5 who began PPI or H2B therapy between 2011 and 2018. The study results appeared in BMC Nephrology.

The cohort included 83,432 pre-ESRD patients, of whom 1,051 were treated with PPIs and 5,138 were treated with H2Bs. The remaining 77,243 (92.6%) did not receive PPI or H2B treatment. The mean (SD) participant age was 71.0 (12.9) years in the PPI group and 69.7 (13.3) years in the H2B group (P=.0042). Of the PPI users, 646 (61.5%) were male; 2,855 (55.6%) H2B users were male (P=.0004).  

The study approach was similar to an intention-to-treat analysis. The primary outcome was progression to ESRD, identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 585 or International Classification of Diseases, Tenth Revision (ICD-10) code N18.6 from the Registry for Catastrophic Illness Patients. The secondary outcome was AKI, identified by ICD-9-CM code 584 or ICD-10 code N17. Subgroup analyses evaluated the risks associated with individual PPIs.  

Categorical variables were analyzed with the χ2 test. Continuous variables were evaluated with the t test. Kaplan-Meier survival curves were created to compare time-to-event outcomes using the log-rank test. The Cox proportional hazard model was used to estimate the adjusted hazard ratios (aHRs) with 95% CIs to assess the risk of renal events. Sensitivity analyses, including propensity score matching, as-treated analysis, and subgroup analysis, were performed. P<.05 was considered statistically significant.   

During one year of follow-up, the primary outcome of progression to ESRD occurred in 9.71% of PPI users versus 7.36% of H2B users (aHR, 1.495; 95% CI, 1.198-1.867). The secondary outcome, AKI, occurred in 6.18% of PPI users compared with 4.81% of H2B users (aHR, 1.395;  95% CI, 1.058-1.840).  

Analysis of specific PPIs revealed that omeprazole and esomeprazole, which are predominantly metabolized by cytochrome P450 2C19 (CYP2C19), were significantly associated with a higher risk of progression to ESRD (aHR, 1.784, 95% CI, 1.079-2.951) and AKI (aHR, 1.847; 95% CI, 1.332-2.561). The PPI rabeprazole, however, was associated with a potentially lower risk of progression to ESRD and AKI.  

For the sensitivity analyses, propensity score matching was used to select 2,102 pre-ESRD patients (1,051 per group), resulting in a better balance of baseline characteristics between groups. After matching, the incidence of ESRD was 9.71% among PPI users and 8.47% among H2B users (aHR, 1.359; 95% CI, 1.023-1.807). Incidence of AKI was 6.18% among PPI users and 3.71% among H2B users (aHR, 1.903; 95% CI, 1.279-2.831).   

With the as-treated design, the incidence of ESRD was 3.43% in PPI users and 1.81% in H2B users (aHR, 2.184; 95% CI, 1.477-3.229). The incidence of AKI was 3.71% in PPI users and 1.93% in H2B users (aHR, 1.909; 95% CI, 1.284-2.837).   

The subgroup analyses uncovered a consistent trend across various subgroups after adjusting for covariates with statistically significant P values.  

The authors acknowledged that their study had some limitations. The primary shortcoming is the inability to evaluate medication adherence and the use of over-the-counter PPIs. To address this gap, the researchers chose H2Bs, which are widely available without a prescription, as an active comparator. Another limitation was the lack of detailed staging information for CKD in the NHIRD. To address this issue, the authors focused on patients in Taiwan’s pre-ESRD program, who were likely in moderate to advanced stages of CKD.  

In summary, this study found that the use of PPIs is associated with an increased and accelerated risk of progression to ESRD and AKI compared with H2B use among a pre-ESRD population. Furthermore, subgroup analyses revealed that omeprazole and esomeprazole, which exhibit autoinhibition effects on CYP2C19, are associated with higher hazard ratios for developing ESRD than other PPIs. Considering the findings, the authors suggest that a more personalized approach to PPI use by pre-ESRD patients is needed. 

Source: BMC Nephrology