Is it correct that both cyclooxygenase‑1 (COX‑1) and cyclooxygenase‑2 (COX‑2) generate renal prostaglandins (PGE₂ and PGI₂) that dilate the afferent arteriole to preserve glomerular filtration rate, that NSAIDs inhibit COX causing afferent constriction, decreased GFR, and acute kidney injury in low‑flow states, that loop diuretics stimulate prostaglandin synthesis and NSAIDs blunt their natriuretic effect, and that the BUN/creatinine ratio in NSAID‑induced AKI is not invariably >20 : 1?

Accuracy Assessment of COX/Prostaglandin Renal Physiology for USMLE

Your summary is largely accurate with one critical correction needed regarding COX isoform expression in the kidney and one important clarification about BUN/creatinine ratios in NSAID-induced AKI.

Core Renal Physiology: Accurate

Prostaglandin-Mediated Afferent Arteriolar Dilation

• Both COX-1 and COX-2 are constitutively expressed in renal tissue and generate prostaglandins (PGE₂ and PGI₂) that dilate the afferent arteriole to maintain GFR during low-flow states 1, 2, 3.
• Your statement that "COX-1 is constitutively expressed and is the predominant isoform" requires nuance: both COX-1 and COX-2 are constitutively expressed in the kidney (unlike other tissues where COX-2 is primarily inducible), and both contribute to renal prostaglandin production 2, 3, 4.
• The protective "buffer" mechanism you describe is accurate: when systemic blood pressure drops or vasoconstrictors like angiotensin II are elevated, prostaglandins counterbalance by dilating the afferent arteriole 5, 2.

NSAID Toxicity Mechanism: Accurate

• NSAIDs inhibit both COX-1 and COX-2, leading to afferent arteriole constriction and decreased GFR 1, 2.
• COX-2 selective inhibitors (celecoxib, rofecoxib) produce renal effects qualitatively similar to non-selective NSAIDs, including decreased GFR, sodium retention, and hyperkalemia 2, 3, 6, 4.
• The high-risk populations you identify (heart failure, cirrhosis, dehydration, pre-existing CKD) are correct 1.

Loop Diuretic Interaction: Accurate

• Loop diuretics like furosemide stimulate prostaglandin synthesis to increase renal blood flow, and NSAIDs can blunt this natriuretic effect 1.
• This interaction is clinically significant and frequently tested 7.

BUN/Creatinine Ratio: Requires Clarification

Your statement about BUN/Cr ratio >20:1 is oversimplified and potentially misleading. Here's the nuance:

• NSAID-induced AKI typically causes intrinsic renal injury (acute tubular injury from ischemia due to afferent vasoconstriction) 1, 8.
• The BUN/Cr ratio pattern depends on the clinical context:
  • If the patient has concurrent volume depletion (common in the vignettes you describe), the ratio may be >20:1 (prerenal component superimposed on NSAID effect) 1.
  • If NSAID toxicity occurs in a euvolemic patient, the ratio is typically <20:1 (intrinsic renal injury pattern) 8.
• The key teaching point: NSAID-induced AKI is fundamentally an intrinsic renal injury from afferent arteriolar vasoconstriction, not a prerenal azotemia, even though it may coexist with prerenal factors 1, 2.

ACE Inhibitor vs. NSAID Contrast: Accurate

Your comparison is excellent and clinically important:

• NSAIDs constrict the afferent arteriole by blocking prostaglandin-mediated vasodilation 5, 2.
• ACE inhibitors dilate the efferent arteriole by blocking angiotensin II-mediated vasoconstriction 1, 5.
• Both can cause AKI, but through opposite mechanisms on different arterioles 1, 5.
• The 10-20% creatinine rise with ACE inhibitors is expected and represents reversal of hyperfiltration (a therapeutic effect), not true AKI 1, 5.

Key Takeaway Refinement

Your mnemonic is excellent but add this critical caveat:

"Prostaglandins (via both COX-1 and COX-2) dilate the afferent arteriole (the 'intake'), while angiotensin II constricts the efferent arteriole (the 'exit') to maintain GFR. Both COX isoforms are constitutively expressed in the kidney and contribute to this protective mechanism 2, 3, 4."

Common USMLE Trap: Accurate with Addition

Your trap about COX-2 relevance is correct, but add:

• The exam may suggest COX-2 selective inhibitors are "kidney-safe" because they spare the GI tract—this is false 2, 3, 6, 4.
• Both selective COX-2 inhibitors and non-selective NSAIDs carry similar renal risks and should be avoided in high-risk patients (CKD, heart failure, cirrhosis, volume depletion) 1.

Additional High-Yield Clinical Pearls

Risk Stratification for NSAID Use

• Avoid NSAIDs entirely when eGFR <30 mL/min/1.73 m² 1.
• Monitor renal function when using NSAIDs in patients with eGFR <60 mL/min/1.73 m² 1.
• Avoid NSAIDs in patients taking ACE inhibitors/ARBs plus diuretics ("triple whammy") 1.

Specific Contraindications

• Absolute avoidance: cirrhosis with ascites, heart failure with volume overload, bilateral renal artery stenosis, severe CKD 1.
• Nephrotoxic medications (NSAIDs, aminoglycosides, contrast dye) should be discontinued immediately when AKI develops 1.