PPIs and Your Kidneys: What You Need to Know

As nephrologists, it’s not uncommon to feel a twinge of concern when we spot proton pump inhibitors (PPIs) on a patient’s medication list. These common drugs, often prescribed for acid-related disorders, have been under scrutiny for their potential adverse effects on kidney function. Here’s a quick look at the key points we’ll cover:

• What are PPIs and why are they prescribed?
• Findings from the COMPASS trial on PPIs and kidney function.
• Supporting evidence from other studies.
• Practical advice for patients and doctors.

But how significant are these risks really? A recent post-hoc analysis of the COMPASS trial provides some illuminating insights.

The COMPASS Trial: A Brief Overview

The COMPASS trial was a large, randomized controlled trial (RCT) that aimed to evaluate the effectiveness of aspirin and rivaroxaban in patients with vascular disease. Importantly, the trial included a partial factorial design where over 17,000 patients were randomized to receive either a PPI (pantoprazole) or a placebo. This subset of the trial provided a unique opportunity to assess the impact of PPI use on kidney function over time.

Inclusion Criteria and Outcomes

Participants in the COMPASS trial included individuals with coronary artery disease (CAD) or peripheral artery disease (PAD), aged 65 or older, or those with additional risk factors such as smoking, diabetes, chronic kidney disease (CKD) stage 3 or worse, heart failure, or a recent cerebrovascular accident (CVA).

The primary outcome of interest in this analysis was the decline in estimated glomerular filtration rate (eGFR) from baseline to the start of the open-label extension period. For those unfamiliar, eGFR is a measure of how well your kidneys are filtering waste from your blood—essentially, it reflects the percentage of kidney function you have. Secondary outcomes included the incidence of CKD, acute kidney injury (AKI), and acute interstitial nephritis (AIN).

Key Findings

In this post-hoc analysis, eGFR declined 0.27 ml/min per 1.73 m² per year more quickly in the pantoprazole group compared with the placebo group, representing an approximately 1.2-fold greater rate of decline. This consistent effect on CKD suggests a negative impact of pantoprazole on kidney function.

Our results are broadly consistent with observational studies demonstrating an association between PPI use and adverse kidney outcomes. While pantoprazole is deleterious to kidney function, our findings inform the magnitude of the effect. For example, for patients at low risk of progressive CKD, PPIs may result in only a marginal loss of kidney function while effectively treating gastroesophageal reflux and improving quality of life. Conversely, in patients without a strong indication for acid suppressive therapy and/or at high risk of kidney failure, PPIs may be undesirable due to the risk of accelerating kidney function decline.

Supporting Evidence from Observational Studies

Multiple observational studies and meta-analyses have shown a consistent association between PPI use and an increased risk of CKD progression. For instance:

• Klatte et al. found that PPI users had an increased risk of CKD progression, defined as a doubling of creatinine or a decrease in eGFR of 30% or more, compared to users of histamine H2 receptor antagonists (HR, 1.26; 95% CI, 1.16-1.36).
• Xie et al. reported that PPI use was associated with a higher risk of incident CKD, CKD progression, and end-stage renal disease (ESRD) (HR for CKD progression, 1.32; 95% CI, 1.28-1.37).
• Giusti et al. found that chronic PPI use in veterans with CKD stages G3a to G4 was associated with an increased risk of CKD progression and all-cause mortality (aHR, 1.83; 95% CI, 1.53-2.19).
• Grant et al. demonstrated that PPI use was associated with major adverse renal events (MARE), including doubling of creatinine or ESRD (HR, 1.13; 95% CI, 1.02-1.25).
• A meta-analysis by Wu et al. confirmed that PPI use is significantly associated with an increased risk of CKD (RR 1.72; 95% CI, 1.02-2.87).

Widespread Use of PPIs Among the Elderly

Proton pump inhibitors (PPIs) are frequently found on the medication lists of elderly patients, often used for extended periods beyond their intended duration. Studies indicate that PPI use is particularly prevalent among older populations, with significant percentages—sometimes as high as 40-50%—reported in elderly individuals and those in residential care settings. The increasing dispensation of PPIs over time, especially among the elderly who may be more vulnerable to their adverse effects, underscores the need for careful evaluation and management of these medications.

Building on this understanding of PPI use, the COMPASS trial offers significant insights into the implications of long-term PPI use, particularly with pantoprazole, on kidney function. This post hoc analysis of the trial, which included 17,598 participants, revealed that pantoprazole led to a statistically significant greater rate of eGFR decline compared with placebo. Specifically, the pantoprazole group experienced a 0.27 ml/min per 1.73 m² per year greater decline in eGFR than the placebo group. Additionally, while the odds ratio for the effect of pantoprazole on incident CKD was slightly elevated, it was not statistically significant, suggesting a nuanced impact on kidney health. These findings highlight the necessity of more rigorous monitoring and potentially reevaluating the need for PPI therapy, especially among the elderly who are already at a higher risk for kidney dysfunction.

Clinical Implications and Expert Opinions

The assessment of this risk–benefit profile is complex. We cannot definitively know whether the excess loss of eGFR is absolute or relative to the baseline rate of eGFR loss. If the effect of pantoprazole is relative, it could significantly impact those with faster rates of decline. Subgroup analyses from the COMPASS trial, particularly among patients with peripheral artery disease, suggest a more rapid rate of eGFR decline with pantoprazole, indicating a potentially relative effect.

Addressing Limitations

Our analysis addressed several limitations inherent in observational studies. Issues like residual confounding and biases (indication, selection, information) were minimized in this large RCT with a long follow-up period. However, it’s important to note that these are post-hoc analyses without adjustment for multiple testing, and they should be interpreted with caution. Only 51% of the trial population had follow-up eGFR assessed, which introduces potential bias. However, supportive evidence suggests that this likely minimally impacted our results.

Conclusion and Recommendations

In conclusion, pantoprazole use was associated with a greater rate of decline in eGFR compared with placebo. While the clinical significance of this effect size is unclear, it is important to weigh the potential benefits and risks of PPI use. For patients with clear benefits and low risk of kidney failure, chronic PPI use may be reasonable. However, for those at high risk of kidney failure, chronic use of PPIs may not be advisable.

These findings should inform shared decision-making and monitoring strategies for patients prescribed PPIs. Additional research is needed to clarify the magnitude of PPIs’ effect in populations at higher risk of adverse kidney outcomes. These results should not deter the use of PPIs when clinically indicated, such as in Barrett esophagus or peptic ulcer disease. Serial monitoring of kidney function for patients on PPIs may help prevent more severe kidney function decline.

Common PPIs for Patient Reference

Proton pump inhibitors (PPIs) are a group of drugs used to reduce the production of stomach acid. Here are some of the most commonly prescribed PPIs:

• Omeprazole (often known by brand names like Prilosec)
• Esomeprazole (Nexium)
• Lansoprazole (Prevacid)
• Pantoprazole (Protonix)
• Rabeprazole (Aciphex)
• Dexlansoprazole (Dexilant)

These medications are typically used to treat conditions like gastroesophageal reflux disease (GERD), stomach ulcers, and Zollinger-Ellison syndrome.

Tags: #Nephrology #PPIs #KidneyHealth #COMPASSTrial #NephJC #ClinicalPractice

References:

1. Pyne, Lonnie; Smyth, Andrew; Molnar, Amber O.; Moayyedi, Paul; Muehlhofer, Eva; Yusuf, Salim; Eikelboom, John; Bosch, Jacqueline; Walsh, Michael. The Effects of Pantoprazole on Kidney Outcomes: Post Hoc Observational Analysis from the COMPASS Trial. Journal of the American Society of Nephrology. 2024;35(7):901-909. doi:10.1681/ASN.0000000000000356.
2. Klatte DCF, Gasparini A, Xu H, et al. Association Between Proton Pump Inhibitor Use and Risk of Progression of Chronic Kidney Disease. Gastroenterology. 2017;153(3):702-710. doi:10.1053/j.gastro.2017.05.046.
3. Xie Y, Bowe B, Li T, et al. Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD. Journal of the American Society of Nephrology: JASN. 2016;27(10):3153-3163. doi:10.1681/ASN.2015121377.
4. Giusti S, Lin Y, Sogbetun F, et al. The Effect of Proton Pump Inhibitor Use on the Course of Kidney Function in Patients With Chronic Kidney Disease Stages G3a to G4. The American Journal of the Medical Sciences. 2021;362(5):453-461. doi:10.1016/j.amjms.2021.05.017.
5. Grant CH, Gillis KA, Lees JS, et al. Proton Pump Inhibitor Use and Progression to Major Adverse Renal Events: A Competing Risk Analysis. QJM: Monthly Journal of the Association of Physicians. 2019;112(11):835-840. doi:10.1093/qjmed/hcz166.
6. Wu CC, Liao MH, Kung WM, Wang YC. Proton Pump Inhibitors and Risk of Chronic Kidney Disease: Evidence From Observational Studies. Journal of Clinical Medicine. 2023;12(6):2262. doi:10.3390/jcm12062262.