What causes Chronic Kidney Disease (CKD) in a non-diabetic patient with a history of long-term omeprazole (proton pump inhibitor) use?

Causes of CKD in Non-Diabetic Patients with Long-Term Omeprazole Use

In a non-diabetic patient with prolonged omeprazole exposure, the most likely causes of CKD are hypertension, omeprazole-induced tubulointerstitial nephritis, or glomerulonephritis—with hypertension being the single most common etiology in developed countries. 1

Primary Non-Diabetic Causes of CKD

Hypertension

• Hypertension is one of the most frequent causes of CKD in developed countries and can both cause kidney damage and result from kidney disease, creating a dangerous cycle that accelerates kidney function decline 1
• Approximately 70% of individuals with elevated serum creatinine have hypertension, making it the dominant risk factor in this population 1
• Uncontrolled systolic blood pressure can accelerate the rate of GFR deterioration to 4-8 mL/min per year, particularly in patients with coexistent renal disease 1

Glomerulonephritis

• Glomerulonephritis is another significant cause of CKD, particularly in certain regions, with chronic glomerulonephritis accounting for a substantial proportion of CKD cases 1
• This diagnosis should be considered when there is hematuria, red cell casts, or dysmorphic RBCs on urinalysis 1

Other Contributing Factors

• Autosomal dominant tubulointerstitial kidney diseases can lead to progressive tubulointerstitial fibrosis and progression to end-stage renal disease 1
• Nephrotoxin exposure, including nonsteroidal anti-inflammatory drugs, heavy metals, agrochemicals, and contaminated drinking water, can cause CKD 1
• Older age and family history of kidney disease are significant risk factors 1

Omeprazole-Specific Kidney Injury

Acute Tubulointerstitial Nephritis (TIN)

The FDA drug label explicitly warns that proton pump inhibitors, including omeprazole, can cause acute tubulointerstitial nephritis that may occur at any point during PPI therapy. 2

• Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia) 2
• In reported case series, some patients were diagnosed on biopsy in the absence of extra-renal manifestations (e.g., fever, rash, or arthralgia) 2
• A case report documented omeprazole-induced acute granulomatous interstitial nephritis requiring hemodialysis, with the patient remaining dialysis-free but with CKD stage IV (eGFR 23 mL/min/1.73 m²) at 5-year follow-up after omeprazole discontinuation 3

Chronic Progression Risk

• A retrospective cohort study found that 70.6% of omeprazole users experienced CKD progression compared to only 10.5% of non-users 4
• The hazard ratio was 7.34 (CI: 3.94-13.71), indicating a significantly higher risk of progression to worse stages of CKD in omeprazole users 4
• This suggests that even past omeprazole use may have contributed to ongoing kidney damage that persists after discontinuation 4

Diagnostic Approach for This Patient

Essential Initial Testing

• Measure both estimated GFR (eGFR) and urinary albumin-to-creatinine ratio (UACR) immediately, as CKD can be diagnosed by either abnormality 1
• CKD is defined as eGFR <60 mL/min/1.73 m² OR presence of albuminuria (UACR ≥30 mg/g) persisting for at least 3 months 1
• Review historical eGFR measurements to determine if kidney dysfunction has persisted >3 months, which is required to confirm CKD diagnosis rather than acute kidney injury 1

Determining the Underlying Cause

• Evaluate for hypertension history and current blood pressure control, as this is the most common non-diabetic cause 1
• Perform urinalysis with microscopy to detect red blood cells, white blood cells, and casts that might suggest glomerulonephritis or other primary kidney diseases 1, 5
• Identify any other nephrotoxic exposures including NSAIDs, lithium, calcineurin inhibitors, and aminoglycosides 1
• Assess for family history of kidney disease, which is a significant risk factor 1

When to Consider Kidney Biopsy

• Kidney biopsy may be necessary to definitively diagnose the cause of CKD when kidneys appear normal on imaging, with up to 30% of patients with presumed diabetic kidney disease having other causes of CKD on kidney biopsy 1
• Immediate nephrology referral is warranted if proteinuria >1,000 mg/24 hours, red cell casts or >80% dysmorphic RBCs, eGFR <30 mL/min/1.73 m², or rapidly declining eGFR 6

Common Pitfalls to Avoid

• Do not assume that discontinuing omeprazole years ago eliminates it as a contributing cause—the drug may have caused irreversible tubulointerstitial damage that continues to progress 3, 4
• Do not rely on serum creatinine alone; always calculate eGFR using validated equations (CKD-EPI 2021) 1
• Do not skip albuminuria testing, as eGFR and UACR provide independent prognostic information for cardiovascular events, CKD progression, and mortality 1
• Do not assume normal kidney size on imaging excludes significant CKD—diabetic kidney disease, minimal change disease, and focal segmental glomerulosclerosis can all present with normal-sized kidneys 1