What are the guidelines for using Proton Pump Inhibitors (PPIs) in patients with Chronic Kidney Disease (CKD)?

PPI Use in Chronic Kidney Disease

Proton pump inhibitors should be used cautiously in CKD patients, prescribed only for clear indications at the lowest effective dose and shortest duration necessary, with particular attention to gastroprotection when antiplatelet therapy is required.

Key Guideline Recommendations

When PPIs Are Indicated in CKD

PPIs are recommended for gastroprotection in CKD patients on dual antiplatelet therapy (DAPT). 1 This is particularly important given that CKD patients requiring antiplatelet therapy for cardiovascular disease have elevated bleeding risk. 1

• For liver transplant candidates with CKD on DAPT, PPIs are specifically recommended to reduce gastrointestinal bleeding 1
• In patients ≥75 years with increased GI bleeding risk (including those on anticoagulants, antiplatelets, SSRIs, or glucocorticoids), concomitant PPI or misoprostol should be used 1
• The 2024 KDIGO guidelines note PPIs should be used when managing bleeding risk in atrial fibrillation patients on anticoagulation 1

General Principles for PPI Prescribing

All patients without a definitive ongoing indication for chronic PPI should be considered for de-prescribing. 1 The primary care physician should be responsible for reviewing ongoing indications and identifying de-prescribing candidates. 1

Most patients on twice-daily PPI dosing should be stepped down to once-daily dosing. 1 Higher-than-standard doses increase costs and have been more strongly associated with complications including community-acquired pneumonia, hip fracture, and C. difficile infection. 1

FDA-Labeled Warnings Relevant to CKD

Acute tubulointerstitial nephritis (TIN) can occur at any point during PPI therapy. 2, 3 Patients may present with non-specific symptoms of decreased renal function (malaise, nausea, anorexia) or may be diagnosed on biopsy without extra-renal manifestations. 2, 3 Discontinue PPIs and evaluate patients with suspected acute TIN. 2, 3

Additional FDA warnings include:

• Risk of Clostridium difficile-associated diarrhea—use lowest dose and shortest duration 2, 3
• Increased risk of osteoporosis-related fractures with high-dose, long-term therapy 2, 3
• Hypomagnesemia after at least 3 months of therapy, requiring monitoring in patients on prolonged treatment or taking digoxin/diuretics 2, 3
• Cyanocobalamin (vitamin B-12) deficiency with treatment >3 years 2, 3

Evidence on PPI-Associated Kidney Outcomes

Observational research suggests associations between PPI use and CKD development, though causality is not established. The highest quality recent study using propensity score weighting found regular PPI users had 37% higher risk of incident CKD (HR 1.37,95% CI 1.28-1.47) over 8.1 years of follow-up. 4

• High-dose PPIs showed increased CKD risk (HR 1.92,95% CI 1.00-6.19) 5
• Risk became apparent after 3 months of exposure (HR 1.78,95% CI 1.39-2.25) 5
• CKD patients are prescribed PPIs for longer durations than non-CKD patients (median 120 vs 90 days) 6

However, PPI discontinuation in established CKD did not significantly improve renal function. A retrospective study found no statistically significant difference in eGFR change between continuation and discontinuation groups after 1 year (95% CI -5.48 to 2.03, P=0.37). 7

Clinical Algorithm for PPI Use in CKD

Step 1: Assess Indication

• Definite long-term indications: Barrett's esophagus, severe erosive esophagitis (LA grade C/D), gastroprotection in high-risk patients on aspirin/NSAIDs, secondary prevention of peptic ulcers 1
• Conditional indications: PPI-responsive endoscopy-negative reflux disease with recurrence on cessation, esophageal strictures from GERD 1
• Not indicated long-term: Nonerosive reflux disease without sustained response, functional dyspepsia without response 1

Step 2: Risk Stratification

• Monitor for acute TIN symptoms (malaise, nausea, decreased renal function) 2, 3
• Consider baseline and periodic magnesium monitoring if prolonged therapy expected, especially with concurrent diuretics 2, 3
• Assess bleeding risk if on antiplatelet/anticoagulant therapy 1

Step 3: Dose Optimization

• Use lowest effective dose 1, 2, 3
• Step down from twice-daily to once-daily dosing when possible 1
• Avoid double-dose PPIs (not FDA-approved) 1

Step 4: Duration Management

• Use shortest duration appropriate to condition 1, 2, 3
• Reassess indication regularly, particularly after 3 months 5
• Consider de-prescribing trial if no definitive ongoing indication 1

Common Pitfalls

Avoid continuing PPIs indefinitely without documented indication. Up to 15% of PPI users are on higher-than-standard doses without clear justification. 1 The number needed to harm for CKD development is 147.9 at 5 years and 78.6 at 10 years. 4

Do not withhold indicated PPIs due to CKD concerns alone. When gastroprotection is needed for DAPT or high bleeding risk scenarios, the benefits outweigh theoretical CKD progression risks. 1 The observational evidence linking PPIs to CKD does not establish causality and may reflect confounding by indication. 8

Monitor for drug interactions. Omeprazole inhibits CYP2C19 and reduces clopidogrel efficacy—avoid concomitant use or consider alternative PPIs. 3