Are the statements that COX‑1 and COX‑2 generate prostaglandins (PGE₂, PGI₂) which dilate the afferent arteriole to preserve glomerular filtration rate, that NSAIDs inhibit this dilation causing decreased GFR, and that the BUN‑to‑creatinine ratio is not a reliable discriminator in NSAID‑induced acute kidney injury accurate?

NSAID-Induced Renal Hemodynamics and Acute Kidney Injury

Yes, your summary is accurate: both COX-1 and COX-2 constitutively generate prostaglandins (PGE₂ and PGI₂) that dilate the afferent arteriole to preserve GFR, NSAIDs inhibit this protective mechanism causing afferent arteriolar constriction and decreased GFR, and the BUN-to-creatinine ratio cannot reliably distinguish prerenal from intrinsic AKI in NSAID-induced injury. 1

COX Isoforms and Renal Prostaglandin Synthesis

Both COX-1 and COX-2 are constitutively expressed in the kidney—this is a critical point that distinguishes renal physiology from other organ systems. 2, 3 Unlike the gastrointestinal tract where COX-1 predominates in homeostatic functions, the kidney expresses meaningful amounts of both isoforms under baseline conditions. 4

• Prostaglandins PGE₂ and PGI₂ dilate the afferent arteriole, maintaining renal blood flow and GFR during physiologic stress states such as volume depletion, heart failure, or cirrhosis. 1, 2
• This prostaglandin-mediated vasodilation serves as a compensatory buffer against systemic vasoconstrictors like angiotensin II and norepinephrine. 1
• COX-2 appears particularly important for sodium excretion, renin release, and antagonism of antidiuretic hormone, while COX-1 may play a larger role in renal hemodynamics, though both contribute. 4

NSAID Mechanism of Renal Injury

NSAIDs cause acute kidney injury primarily through hemodynamic mechanisms by blocking prostaglandin synthesis, eliminating the kidney's compensatory vasodilation. 1, 5

• Afferent arteriolar constriction occurs when prostaglandin-mediated dilation is inhibited, reducing glomerular perfusion pressure and GFR. 1, 6
• This represents intrinsic renal injury—specifically ischemic acute tubular injury from sustained afferent vasoconstriction—not simply prerenal azotemia. 1
• The injury mechanism is fundamentally different from prerenal states: NSAIDs cause direct tubular cell ischemia from reduced perfusion, classified as "dysfunction and injury" by KDIGO. 7

COX-2 Selective Inhibitors Offer No Renal Safety Advantage

COX-2 selective inhibitors (celecoxib, rofecoxib) produce qualitatively similar renal effects as nonselective NSAIDs, including decreased GFR, sodium retention, and edema. 2, 3

• Clinical studies demonstrate that COX-2 inhibitors alter urinary prostaglandin excretion and GFR comparably to traditional NSAIDs. 2
• All NSAIDs, regardless of COX selectivity, must be avoided in high-risk patients. 6

BUN-to-Creatinine Ratio in NSAID-Induced AKI

The BUN-to-creatinine ratio cannot reliably distinguish prerenal from intrinsic AKI in NSAID-induced injury because the pathophysiology involves both hemodynamic (prerenal-like) and ischemic tubular injury (intrinsic) components. 1

• A ratio ≥20:1 suggests prerenal physiology (volume depletion, hypoperfusion), while ≤15:1 suggests intrinsic disease with impaired tubular urea reabsorption. 8
• NSAID-induced AKI may present with either pattern depending on whether concurrent volume depletion exists alongside the afferent vasoconstriction. 1
• When NSAIDs are used in volume-depleted states, the BUN:creatinine ratio may exceed 20:1 despite underlying ischemic tubular injury, creating diagnostic confusion. 1

High-Risk Clinical Scenarios

NSAIDs should be avoided entirely when eGFR <30 mL/min/1.73 m² and used with extreme caution when eGFR is 30-59 mL/min/1.73 m². 7, 6

Absolute Contraindications to NSAIDs:

• Heart failure with volume overload 6
• Cirrhosis with ascites 6
• Severe chronic kidney disease (eGFR <30) 7
• Bilateral renal artery stenosis 6
• Current volume depletion or hypotension 6

The "Triple Whammy" Combination

Concurrent use of NSAID + ACE inhibitor/ARB + diuretic markedly increases AKI risk and must be avoided. 6

• ACE inhibitors dilate the efferent arteriole by blocking angiotensin II, while NSAIDs constrict the afferent arteriole—this combination eliminates both compensatory mechanisms maintaining GFR. 1
• Loop diuretics stimulate prostaglandin synthesis to enhance natriuresis; NSAIDs blunt this effect. 1

Common USMLE Testing Pitfalls

Students frequently confuse NSAID effects (afferent constriction) with ACE inhibitor effects (efferent dilation). 1

• NSAIDs → afferent arteriolar constriction → decreased GFR
• ACE inhibitors → efferent arteriolar dilation → decreased GFR (but this represents reduced hyperfiltration, not true injury) 1
• ACE inhibitors typically raise serum creatinine by 10-20% as a reversible hemodynamic effect, not tubular injury. 1

Classic Vignette Pattern

The typical USMLE question presents an elderly patient with heart failure or cirrhosis who begins taking ibuprofen or naproxen for joint pain, then develops:

• Increased serum creatinine (acute kidney injury) 1
• Decreased GFR due to afferent arteriole constriction 1
• Variable BUN:creatinine ratio depending on volume status 1

Management of NSAID-Induced AKI

Upon development of AKI, NSAIDs must be discontinued immediately. 1

• NSAID-induced AKI is usually reversible with favorable prognosis after drug discontinuation. 5
• Serial creatinine monitoring is essential in any patient with risk factors who receives NSAIDs. 6
• Alternative analgesics such as acetaminophen should be used for non-inflammatory pain in patients with kidney dysfunction. 6

Patient Education is Critical

Patients must understand to avoid over-the-counter NSAIDs (ibuprofen, naproxen) and consult before taking new medications, as these are widely available without prescription. 6