Do PPIs Increase the Risk of Renal Disease?
Yes, proton pump inhibitors are associated with an increased risk of kidney disease, including acute kidney injury, chronic kidney disease, and end-stage renal disease, as documented in FDA labeling and multiple clinical studies.
FDA-Recognized Renal Complications
The FDA drug label for omeprazole explicitly warns that PPIs can cause tubulointerstitial nephritis, a type of kidney problem that can occur at any time during treatment 1. Patients should be monitored for decreased urine output or blood in the urine 1.
Evidence of Chronic Kidney Disease Risk
Population-Based Studies
The strongest evidence comes from a large Taiwanese case-control study demonstrating that PPI use in patients with existing renal disease significantly increases the risk of progression to end-stage renal disease (adjusted OR = 1.88,95% CI = 1.71-2.06). 2 This risk persisted across different cumulative doses:
- Patients on <100 cumulative defined daily doses: adjusted OR = 1.92 (95% CI = 1.74-2.13) 2
- Patients on ≥100 cumulative defined daily doses: adjusted OR = 1.74 (95% CI = 1.52-2.00) 2
Prescription Patterns in CKD Patients
Paradoxically, chronic kidney disease patients receive PPIs more frequently and for longer durations than non-CKD patients 3. The median duration of PPI use was 120 days in stage 3-4 CKD patients compared to 90 days in non-CKD patients 3. This is concerning given that these are the patients at highest risk for PPI-related renal complications.
Spectrum of PPI-Associated Kidney Injury
PPIs are linked to multiple adverse kidney outcomes 4:
- Acute interstitial nephritis 4, 5
- Acute kidney injury 4
- Incident chronic kidney disease 4
- CKD progression 4
- End-stage renal disease 4
- Increased all-cause mortality related to kidney disease 4
Clinical Implications and Monitoring
High-Risk Populations
Particular caution is warranted when prescribing PPIs to patients with:
- Pre-existing chronic kidney disease (creatinine clearance <60 mL/min) 6
- Congestive heart failure 6
- Cirrhosis 6
- Concurrent use of nephrotoxic medications (NSAIDs, ACE inhibitors, angiotensin receptor blockers) 6
Appropriate Long-Term Indications
PPIs should only be continued long-term for definitive indications 7:
- Barrett's esophagus 7
- Severe erosive esophagitis (LA Classification grade C/D) 7
- Gastroprotection in high-risk NSAID/aspirin users 7
- Secondary prevention of gastric/duodenal ulcers 7
- Zollinger-Ellison Syndrome 7
When PPIs Are Recommended Despite Risks
Certain clinical scenarios justify PPI use despite renal concerns:
- Routine use with triple antithrombotic therapy (dual antiplatelet therapy plus oral anticoagulation) to prevent gastrointestinal bleeding 6
- Post-endoscopic variceal ligation in cirrhotic patients to reduce ulcer size and bleeding risk, though use should be cautious and time-limited due to increased risk of spontaneous bacterial peritonitis and hepatic encephalopathy 6
- Prophylaxis during intragastric balloon therapy for obesity 6
Deprescribing Considerations
When to Discontinue
All patients without definitive indications for chronic PPI therapy should be considered for deprescription 7. However, a 2021 study found that PPI discontinuation in CKD patients did not result in significant improvement in renal function after one year (change in eGFR not statistically significant between continuation and discontinuation groups, P = 0.37) 8. This suggests that while PPIs may contribute to CKD development, discontinuation may not reverse established damage.
Who Should NOT Discontinue
Patients with complicated GERD (severe erosive esophagitis, esophageal ulcer, peptic stricture, or Barrett's esophagus) should generally continue PPI therapy 7.
Practical Recommendations
Use the lowest effective dose for the shortest duration necessary 1. All patients on PPIs should have:
- Regular review of ongoing indications 7
- Documentation of the indication 7
- Monitoring of renal function, particularly in high-risk patients 2
- Consideration for step-down from twice-daily to once-daily dosing when appropriate 7
Common Pitfalls
The most significant pitfall is the widespread use of PPIs without clear medical indication and continuation beyond the necessary treatment period 4. PPIs are frequently purchased over-the-counter and rarely deprescribed despite lack of ongoing indication 4. Physicians prescribing to patients with existing renal disease must balance gastrointestinal protection benefits against the documented risk of renal deterioration 2.