PPIs and CKD association present after exclusion of AKI

PPIs have been associated with AKI including acute interstitial nephritis; CKD development; and CKD progression to ESRD. That is, in over 10,000 Atherosclerosis Risk in Communities participants followed for at least 10 years, incident CKD developed among PPI users with a hazard ratio of 1.5 compared to non-users in models that adjusted for co-morbidities, demographics, and concomitant medications. In addition, the current researchers have published similar results in their earlier work, showing that new PPI users are at a higher risk for poor renal outcomes even against a 1:1 propensity score-matched cohort of non-users and users of H2 blockers. This was covered in detail by Praveen Malavade on RFN last year and the number 2 story on Top Nephrology Stories of 2016.

It was previously thought that AKI events were largely driving the association seen between PPI use and CKD.

A recent study from Xie et al in Kidney International aimed to examine the relationship between PPI use and renal outcomes over five years in those without AKI.

Methods: The researchers gathered a cohort of 144,032 veterans (125,000+ new to PPIs and 18,000+ new to H2 blockers). They then created survival models with Kaplan Meier curves to show survival probability for their four renal outcomes: incident eGFR < 60 ml/min/m2, incident CKD, eGFR decrease >30%, and ESRD or >50% decrease in eGFR. Participants were censored at the time of AKI. All efforts were made to exclude subjects with AKI, even before cohort entry. Of note, AKI was defined in four different ways, but the researchers were not able to detect unrecognized AKI (i.e., outpatient AKI that occurs and resolves between lab checks). Covariates used in their multivariate logistic regression model included numerous co-morbidities, medication use such as NSAIDs or ACEI/ARBs, and patient characteristics such as age, race, and BMI.

Results:
New PPI users had an increased risk of

• all renal outcomes compared to users of H2 blockers including eGFR < 60 ml/min/m² with a hazard ratio of 1.19 (95% CI 1.15-1.24)
• incident CKD with a HR of 1.26 (95% CI 1.20-1.33)
• eGFR decline >30% with a HR of 1.22 (95% CI 1.16-1.28)
• ESRD or >50% decrease in eGFR with a HR of 1.30 (95% CI 1.15-1.48).

Discussion: The researchers conclude their data suggest a true association between PPI use and CKD even in those patients that do not develop an AKI along the way. Besides AKI, other possible, underdeveloped explanations for the observed relationship between CKD and PPIs include altered gut microbiome; reduced cell regeneration; upregulated heme oxygenase-1; and increased oxidative stress. The researchers conclude that further investigation is needed and that caution should be applied when considering long term PPI use as well as monitoring kidney function in PPI users.

Personal reflection: Observational data from two cohorts (ARIC participants and veterans) analyzed by two research groups (Lazarus et al and Xie et al) show an association between PPIs and CKD. While this work is not based on randomized controlled trial data nor has it been replicated numerous times over by several different investigators, it is noteworthy. Yet, association is not causality. Should clinical practice change? And to what degree should it change given the many other considerations that can influence renal function including diabetes and hypertension? While we wait for more evidence, my practice has been to discuss PPI use with my patients and encourage alternatives when possible if no clear indication for the medication exists. This is stems from the above information as well as an effort to reduce pill burden and improve medication compliance. Specifically, I ask patients to discuss PPI use with their primary care doctors (or whichever provider started the medication) and suggest the following: weaning down and then off of the medication; avoiding known food triggers; and using H2 blockers as needed.

Melissa Makar, Nephrology Fellow, Duke