A 58-year-old man with a 10-year history of osteoarthritis of the knees presents to the outpatient clinic. He has been taking ibuprofen 400 mg three times daily for the past 6 months for pain relief. On examination, his blood pressure is 148/92 mmHg (previously 130/80 mmHg 6 months ago). Serum creatinine has risen from 0.9 mg/dL to 1.4 mg/dL. Urinalysis shows mild proteinuria (1+). He denies any history of diabetes or primary renal disease. Which of the following mechanisms best explains the renal dysfunction observed in this patient?

Explanation

## Mechanism of NSAID-Induced Renal Dysfunction **Key Point:** NSAIDs impair renal function primarily through inhibition of prostaglandin synthesis, particularly COX-2-derived prostaglandins that maintain renal hemodynamics. ### Pathophysiology NSAIDs inhibit both COX-1 and COX-2 enzymes, reducing prostaglandin (PGE₂ and PGI₂) production in the kidney. These prostaglandins normally: 1. Cause vasodilation of the afferent arteriole 2. Maintain renal blood flow and glomerular filtration rate (GFR) 3. Promote sodium excretion When prostaglandin synthesis is blocked: - Afferent arteriolar vasoconstriction occurs - Glomerular capillary hydrostatic pressure decreases - GFR falls, leading to rising serum creatinine - Sodium retention occurs, contributing to hypertension **High-Yield:** This mechanism is particularly important in patients with: - Advanced age (>65 years) - Pre-existing chronic kidney disease - Dehydration or volume depletion - Concomitant ACE inhibitor or ARB use (triple whammy) - Congestive heart failure ### Clinical Presentation in This Case The patient demonstrates: - **Functional renal impairment** (reversible if NSAID is stopped early) - **Hypertension** (from sodium and water retention) - **Mild proteinuria** (from hemodynamic changes) - **No systemic features** (ruling out vasculitis) **Clinical Pearl:** NSAID-induced renal dysfunction is typically **reversible** if caught early and the drug is discontinued. Serum creatinine usually normalizes within days to weeks after cessation. ### Differential Consideration | Feature | NSAID-Induced (Hemodynamic) | Acute Tubular Necrosis | NSAID Hypersensitivity | Crystalline Nephritis | |---------|---------------------------|------------------------|------------------------|----------------------| | **Onset** | Gradual (days to weeks) | Acute (hours to days) | 2–8 weeks after start | Acute (hours to days) | | **Proteinuria** | Mild (<1 g/day) | Variable | Often >1 g/day | Minimal | | **Eosinophiluria** | Absent | May be present | Present (pathognomonic) | Absent | | **Rash/Fever** | No | No | Yes (systemic) | No | | **Urine crystals** | Absent | Muddy brown casts | Absent | Present (uric acid, etc.) | | **Reversibility** | Yes (if stopped early) | Yes (with supportive care) | Yes (with corticosteroids) | Depends on severity | **Warning:** Do not confuse NSAID-induced hemodynamic renal dysfunction with acute interstitial nephritis (AIN), which presents with fever, rash, eosinophiluria, and eosinophilia — a true hypersensitivity reaction requiring corticosteroids.