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Uric Acid-Related Disorders

1. Biochemistry of Uric Acid

• De novo pathway: purine nucleotides built from non-purine precursors
• Salvage pathway: free purine bases from diet or DNA/RNA degradation are recycled

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2. Hyperuricemia: Causes and Classification

Primary Hyperuricemia

• In >99% of cases, the cause is uncertain ("essential" hyperuricemia with polygenic basis)
• ~80% of patients: decreased renal tubular secretion of uric acid
• ~25% of patients: metabolic overproduction (increased PRPP amidotransferase activity)
• Very rarely: inherited enzymatic defects in purine metabolism

Secondary Hyperuricemia

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3. Disorders Associated with Uric Acid

A. GOUT

Epidemiology and Risk Factors

• Affects men far more than women (95% of cases), typically in the 4th-6th decades; women develop gout mainly postmenopause
• Estrogen promotes renal urate clearance, explaining sex-based differences
• Asymptomatic hyperuricemia is common (~19% of individuals in the USA/UK), but only ~1 in 8 patients with urate between 7-8 mg/dL develop clinical gout over 14 years
• Risk factors for progression to gout: serum urate >9 mg/dL, CKD, hypertension, cardiovascular disease, obesity, diabetes - Grainger & Allison's Diagnostic Radiology

Pathogenesis

1. Crystal deposition: Monosodium urate (MSU) crystals precipitate in joints and periarticular tissues
2. Inflammasome activation: Resident macrophages phagocytose MSU crystals → activate the NLRP3 inflammasome → activate caspase-1 → produce active IL-1β
3. Neutrophil influx: IL-1 recruits neutrophils → release cytokines, free radicals, proteases
4. Phagolysosomal damage: Crystals rupture phagolysosomes → lysosomal enzyme leakage → acute inflammation
5. Result: Acute arthritis, typically self-limiting in days-weeks; repeated attacks form tophi - Robbins & Kumar Basic Pathology

Clinical Stages

Imaging

• X-ray: Asymmetric soft-tissue swelling, "punched-out" periarticular erosions (overhanging edge sign)
• Ultrasound: Hyperechoic foci in effusion/synovium/cartilage surface ("double contour sign"); tophus as irregular soft-tissue thickening; cortical irregularity at erosion sites
• Dual Energy CT (DECT): Identifies urate crystal deposits; monitors response to treatment

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B. URIC ACID NEPHROLITHIASIS (Uric Acid Kidney Stones)

1. Low urine pH (most important - most patients have normal uric acid excretion but persistently low pH)
2. Low urine volume (concentrated urine)
3. Hyperuricosuria (excess uric acid excretion)

• Congenital: Defects in renal tubular urate transport or uric acid metabolism
• Acquired: Chronic diarrhea (acidic urine + volume depletion), myeloproliferative disorders, high animal protein intake, uricosuric drugs
• "Gouty diathesis": Decreased fractional excretion of urate; typically absent clinical gout

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C. URATE NEPHROPATHY

1. Acute urate nephropathy: Rapid, massive hyperuricemia (e.g., tumor lysis syndrome) → urate crystals precipitate in renal tubules → acute tubular obstruction → oliguric acute kidney injury. - Harrison's Principles of Internal Medicine 22e
2. Chronic urate nephropathy: Long-standing deposition of urate crystals in renal interstitium → chronic kidney disease. Controversial whether it is a distinct entity vs. comorbid CKD + hypertension.

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D. LESCH-NYHAN SYNDROME

• X-linked recessive disorder
• Complete absence of HGPRT (hypoxanthine-guanine phosphoribosyltransferase)
• Results in: severe hyperuricemia + neurologic manifestations (intellectual disability, self-mutilation, choreoathetosis, spasticity)
• Neurologic features dominate; classified as secondary gout
• Compare: partial HGPRT deficiency = gout/nephrolithiasis only, no neurologic features - Robbins & Kumar Basic Pathology

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4. Treatment

Acute Gout Attack

• NSAIDs (first-line: indomethacin, naproxen) - main focus is pain relief
• Colchicine (most effective when started within 24-36 hrs; inhibits tubulin polymerization → impairs neutrophil migration)
• Corticosteroids (oral, intra-articular, or IV) - when NSAIDs/colchicine contraindicated
• Rest, topical ice

Urate-Lowering Therapy (ULT) - Long-Term

• Frequent acute flares (≥2/year)
• Stage 3+ CKD
• Palpable tophi
• Urolithiasis
• Uric acid overproduction
• Severe/difficult-to-treat acute attacks or chronic tophaceous gout

Drug Options

Lifestyle Modifications

• Avoid high-purine foods: organ meats (liver, kidneys), red meat, sardines, shellfish
• Limit alcohol (especially beer/spirits)
• Avoid drugs that raise urate: thiazide diuretics, salicylates (low-dose aspirin)
• Maintain adequate hydration
• Weight loss in obesity

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5. Uric Acid and Cardiovascular/Renal Disease

• Chronic kidney disease progression (elevated urate may accelerate CKD; CKD also raises urate - bidirectional relationship)
• Hypertension
• Cardiovascular disease (metabolic syndrome, coronary artery disease)
• Recent meta-analysis (PMID 39352584) examined CV outcomes of uric acid-lowering medications; urate-lowering therapy appears to have potential cardioprotective effects
• A 2025 network meta-analysis (PMID 40012480) confirms febuxostat and allopurinol are comparably efficacious in CKD stage 3-5 with asymptomatic hyperuricemia, supporting urate management in renal patients

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Summary Table: Key Uric Acid Disorders

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Uric Acid-Related Disorders: Segregated by Serum Level and System Involved

REFERENCE RANGES

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PART I: HYPERURICEMIA-RELATED DISORDERS

Caused by overproduction of uric acid, reduced renal excretion, or both.

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🦴 MUSCULOSKELETAL SYSTEM

1. Acute Gout (Acute Gouty Arthritis)

• Mechanism: Monosodium urate (MSU) crystals precipitate in supersaturated synovial fluid → phagocytosed by macrophages → NLRP3 inflammasome → caspase-1 → IL-1β → neutrophil recruitment → acute inflammation
• Classic site: 1st metatarsophalangeal joint (podagra) in 50% of cases; also ankle, knee, midfoot
• Features: Sudden onset severe pain, erythema, swelling; typically self-resolves in days-weeks; serum uric acid can be normal during an acute attack
• Diagnosis: Negatively birefringent needle-shaped MSU crystals on joint aspirate (pathognomonic)
• Robbins & Kumar Basic Pathology; Grainger & Allison's Diagnostic Radiology

2. Chronic Tophaceous Gout

• Mechanism: Repeated MSU crystal deposition in joints and periarticular soft tissues when no longer pain-free between attacks
• Features: Tophi (aggregates of urate crystals + inflammatory tissue) in synovial membranes, periarticular tissue, cartilage; progressive joint destruction; affects small joints of hands/feet, ankles, knees
• Imaging: Punched-out periarticular erosions with overhanging edge on X-ray; double contour sign on ultrasound; quantified by dual-energy CT (DECT)
• Grainger & Allison's Diagnostic Radiology; Robbins & Kumar

3. Lesch-Nyhan Syndrome (Secondary Gout - Joint Component)

• Urate deposition in joints contributing to severe gouty arthritis on top of the neurologic syndrome (see Nervous System below)
• Robbins & Kumar Basic Pathology

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🫘 RENAL SYSTEM

4. Acute Urate Nephropathy

• Mechanism: Massive, rapid hyperuricemia (classically tumor lysis syndrome) → urate crystals precipitate in renal tubular lumens → acute tubular obstruction → oliguric acute kidney injury
• Cause: Bulky haematologic cancers undergoing chemotherapy; rarely other causes of rapid cell lysis
• Treatment: Rasburicase (recombinant uricase), allopurinol prophylaxis, aggressive IV hydration, urinary alkalinization
• Harrison's Principles of Internal Medicine 22e; Rheumatology 2-Volume Set (Elsevier)

5. Chronic Urate Nephropathy

• Mechanism: Chronic interstitial deposition of urate crystals → tubulointerstitial nephritis → progressive CKD
• Note: This entity is controversial - many cases represent CKD from hypertension/atherosclerosis co-existing with gout; true isolated urate nephropathy is rare
• Tietz Textbook of Laboratory Medicine 7e

6. Uric Acid Nephrolithiasis (Uric Acid Kidney Stones)

• Three determinants: Low urine pH (most important) + low urine volume + hyperuricosuria
• Mechanism of low pH: Insulin resistance → impaired renal ammoniagenesis → unbuffered H⁺ in urine → pH falls → uric acid precipitates (pKa 5.35; at pH 5 even modest uric acid exceeds solubility)
• Strong association: Type 2 diabetes, metabolic syndrome (insulin resistance, hypertriglyceridemia, obesity, hypertension) - uric acid stones represent 36% of stones in T2DM patients vs 11% in non-diabetics
• Complication: Uric acid also acts as a nidus for calcium oxalate stones via heterogeneous nucleation
• Treatment: Potassium citrate (alkalinize urine to pH 6.0-6.5), high fluid intake, dietary protein restriction, allopurinol if hyperuricosuria
• Campbell Walsh Wein Urology

7. Familial Juvenile Hyperuricemic Nephropathy / ADTKD-UMOD

• Now classified as: Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)
• Mechanism: UMOD gene mutation → defective uromodulin protein in thick ascending limb → decreased salt reabsorption → compensatory increased proximal tubular reabsorption of NaCl and uric acid → hyperuricemia → progressive CKD
• Features: Early-onset hyperuricemia, gout in young patients, progressive CKD with bland urinary sediment
• Comprehensive Clinical Nephrology 7e

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🧠 NERVOUS SYSTEM

8. Lesch-Nyhan Syndrome

• Cause: X-linked recessive; complete absence of HGPRT (hypoxanthine-guanine phosphoribosyltransferase) → no purine salvage → all purines degraded to uric acid → severe hyperuricemia
• Key features:
  • Intellectual disability
  • Choreoathetosis and spasticity
  • Compulsive self-mutilation (pathognomonic - lip and finger biting)
  • Gouty arthritis
  • Uric acid nephrolithiasis
• Treatment: Allopurinol (reduces uric acid, prevents urate nephropathy) - but has no effect on CNS symptoms; behavioral and symptomatic management for neurologic features
• Adams & Victor's Principles of Neurology 12e; Robbins & Kumar

Compare: Partial HGPRT deficiency (Kelley-Seegmiller syndrome) → hyperuricemia + gout/nephrolithiasis only, NO neurologic features

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❤️ CARDIOVASCULAR SYSTEM

9. Hyperuricemia and Cardiovascular Disease

• Elevated urate is associated with hypertension, coronary artery disease, heart failure, and metabolic syndrome
• Proposed mechanisms: oxidative stress via xanthine oxidase, endothelial dysfunction, promotion of vascular inflammation
• Uric acid stone formers share features of metabolic syndrome: hypertriglyceridemia, hyperglycemia, obesity, hypertension
• Urate-lowering therapy has potential CV benefits per recent meta-analysis (PMID 39352584), though causality remains debated
• Brenner & Rector's The Kidney; Campbell Walsh Wein Urology

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🩸 HAEMATOLOGY / ONCOLOGY

10. Tumor Lysis Syndrome (Hyperuricemia Component)

• Cause: Rapid destruction of tumor cells (especially leukemia, lymphoma, myeloma) by chemotherapy → massive nucleic acid release → purine catabolism → acute hyperuricemia
• Consequence: Acute urate nephropathy (tubular obstruction), also hyperkalemia, hyperphosphatemia, hypocalcemia
• Tietz Textbook of Laboratory Medicine 7e

11. Hyperuricemia in Myeloproliferative Disorders

• Increased cell turnover → increased nucleic acid catabolism → secondary hyperuricemia
• Secondary gout and uric acid stones can develop

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🤰 OBSTETRICS

12. Preeclampsia

• Uric acid is elevated in preeclampsia due to reduced renal urate excretion (decreased GFR + increased tubular reabsorption)
• Historically used as a marker, but now recognized to have limited clinical utility in distinguishing preeclampsia from other hypertensive disorders of pregnancy or predicting adverse outcomes
• Diuretic therapy in pregnancy raises serum uric acid further, invalidating its use as a preeclampsia marker
• Brenner & Rector's The Kidney; Creasy & Resnik's Maternal-Fetal Medicine

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🧬 METABOLIC / INHERITED DISORDERS (Causing Hyperuricemia)

13. Glucose-6-Phosphatase Deficiency (Von Gierke Disease, GSD Type I)

• Leads to hyperuricemia via increased purine synthesis and lactic acidosis (which competes with tubular urate secretion)

14. Altered ATP Metabolism / Tissue Hypoxia

• Rapid ATP degradation → AMP → IMP → inosine → hypoxanthine → xanthine → uric acid
• Occurs in strenuous exercise, myocardial infarction, status epilepticus

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🩺 SKIN / DERMATOLOGY

15. Psoriasis-Associated Hyperuricemia

• Rapid keratinocyte turnover → increased nucleic acid catabolism → secondary hyperuricemia
• Gout can occur as a complication of psoriasis
• Tietz Textbook of Laboratory Medicine 7e

16. Gouty Tophi (Cutaneous Manifestations)

• Urate crystal deposits in skin and subcutaneous tissue, especially over ears (helix), olecranon bursae, Achilles tendon, fingers
• Appear as firm, chalky white nodules

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PART II: HYPOURICEMIA-RELATED DISORDERS

Serum urate < 2.0 mg/dL. Caused by reduced uric acid production or excess renal excretion.

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🫘 RENAL SYSTEM

1. Hereditary Renal Hypouricemia (Familial Renal Hypouricemia)

• Inheritance: Autosomal recessive
• Two types:

• Features: Very low serum uric acid (<2.5 mg/dL men, <2.1 mg/dL women); fractional excretion of urate 50-150% (normal ~10%)
• Complications:
  • Exercise-induced AKI: Hyperuricosuria + dehydration + low pH → uric acid "gravel" → acute tubular injury → AKI (paradoxically, despite hypouricemia in blood, massive uricosuria causes renal damage)
  • Nephrolithiasis: ~25% of patients; only 1/3 of those are uric acid stones (others are calcium stones due to associated hypercalciuria)
• Treatment: High fluid intake; urine alkalinization and allopurinol for persistent stone formers
• Brenner & Rector's The Kidney; Comprehensive Clinical Nephrology 7e

2. Fanconi Syndrome

• Generalized proximal tubular dysfunction → loss of urate reabsorption → hypouricemia + uricosuria (alongside glycosuria, aminoaciduria, phosphaturia, bicarbonate wasting)
• Causes: Cystinosis, Wilson disease, galactosemia, heavy metal toxicity, tenofovir, multiple myeloma (light chains)
• Urolithiasis from uricosuria is rare because high urine flow and alkaline pH prevent precipitation
• Comprehensive Clinical Nephrology 7e

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🧬 METABOLIC / INHERITED DISORDERS (Causing Hypouricemia)

3. Hereditary Xanthinuria

• Inheritance: Autosomal recessive
• Type I: Xanthine dehydrogenase (XDH) deficiency
• Type II: Combined XDH + aldehyde oxidase deficiency
• Mechanism: No xanthine oxidase activity → xanthine and hypoxanthine cannot be converted to uric acid → very low serum urate AND very low urine urate (key distinction from renal hypouricemia where urine urate is HIGH)
• Features: Xanthine stones (radiolucent) in ~1/3 of cases; hematuria; occasionally occult renal failure; elevated urinary xanthine + hypoxanthine
• Note: Acquired xanthinuria can occur with allopurinol treatment (xanthine stones may form if allopurinol is overused in Lesch-Nyhan or myeloproliferative disorders)
• Brenner & Rector's The Kidney

4. Molybdenum Cofactor Deficiency

• Combined deficiency of xanthine oxidase + sulfite oxidase (both require molybdenum cofactor)
• Results in hypouricemia + xanthinuria + neurologic damage (from sulfite accumulation)
• Tietz Textbook of Laboratory Medicine 7e

5. Purine Nucleoside Phosphorylase (PNP) Deficiency

• Rare inherited defect → impaired purine catabolism → very low uric acid
• Associated with profound T-cell immunodeficiency (lymphopenia, recurrent infections) - the immunologic features dominate

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🫀 HEPATIC SYSTEM

6. Severe Hepatocellular Disease

• Liver is the primary site of xanthine oxidase activity and purine synthesis
• Severe hepatic failure → reduced xanthine oxidase activity → reduced uric acid synthesis → hypouricemia
• Tietz Textbook of Laboratory Medicine 7e

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💊 DRUG-INDUCED HYPOURICEMIA

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MASTER SUMMARY TABLE

Hyperuricemia Disorders by System

Hypouricemia Disorders by System

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• High urine uric acid → renal leak (Fanconi, renal hypouricemia)
• Low urine uric acid → reduced production (xanthinuria, hepatic disease, drug inhibition)

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Causes of High Urea (BUN) Accumulation

Biochemical Basis

2NH₃ + CO₂ → Urea + H₂O

• > 20:1 = prerenal state (urea reabsorption + sodium)
• 10-20:1 = intrinsic renal disease (ATN)
• < 10:1 = low urea production (malnutrition, liver disease) or rhabdomyolysis
• Morgan & Mikhail's Clinical Anesthesiology 7e; Harrison's Principles of Internal Medicine 22e

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Overview Diagram

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1. Increased urea production (non-renal)
2. Decreased urea excretion (renal - pre/intra/postrenal)

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CATEGORY A: INCREASED UREA PRODUCTION (Non-Renal Causes)

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1. High Dietary Protein Intake

• Excess animal protein → increased hepatic urea synthesis
• BUN rises without kidney disease
• Seen in high-protein diets (bodybuilders, carnivorous diets, hyperalimentation/TPN)

2. Gastrointestinal (GI) Bleeding

• Blood in the GI lumen is digested as protein → massive purine/amino acid load → increased hepatic urea synthesis
• Upper GI bleeding (peptic ulcer, varices, Mallory-Weiss tear) causes more pronounced BUN rise than lower GI bleeding (blood is fully digested in the small intestine)
• BUN:Cr ratio classically > 20:1
• Harrison's Principles of Internal Medicine 22e; Symptom to Diagnosis 4e

3. Increased Tissue Catabolism

4. Glucocorticoid / Corticosteroid Use

• Steroids are antianabolic and promote protein catabolism → increased urea production
• Also cause mild volume depletion → increased tubular urea reabsorption
• Frameworks for Internal Medicine; Harrison's Principles

5. Tetracyclines (Antianabolic Effect)

• Tetracyclines block hepatic protein synthesis → shift amino acids toward catabolism → increased urea generation
• Particularly significant in patients with borderline renal function

6. Large Hematoma Reabsorption

• Blood trapped in tissue (post-trauma, post-surgical) is reabsorbed and metabolized as protein → BUN rises
• Similar mechanism to GI bleeding

7. Hypercatabolic States

• Severe inflammation, cancer treatment (tumor lysis), cytokine storms → accelerated nucleic acid and protein breakdown

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CATEGORY B: DECREASED UREA EXCRETION (Renal Causes)

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PRERENAL (Reduced Renal Perfusion)

A. Hypovolemia (True Volume Depletion)

B. Reduced Cardiac Output (Cardiorenal Syndrome)

• Congestive heart failure, cardiogenic shock, severe valvular disease
• Decreased effective arterial blood volume → renal hypoperfusion despite normal or increased total body fluid
• Smith & Tanagho's General Urology 19e

C. Distributive Shock

• Septic shock, anaphylaxis → vasodilation → effective circulating volume falls → renal underperfusion

D. Hepatorenal Syndrome

• Advanced cirrhosis → splanchnic vasodilation → reduced effective renal perfusion
• Urinary findings mimic prerenal failure; responds to liver transplantation, not fluid resuscitation
• Smith & Tanagho's General Urology 19e

E. Medications Causing Functional Prerenal State

F. Renal Artery Stenosis

• Bilateral (or unilateral in solitary kidney) → chronic prerenal state
• Brenner & Rector's The Kidney

G. Abdominal Compartment Syndrome

• Raised intra-abdominal pressure → compresses renal vasculature → functional prerenal AKI

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INTRINSIC RENAL (Parenchymal Causes)

1. Tubular Causes

Acute Tubular Necrosis (ATN) - Most Common Intrinsic Cause

2. Glomerular Causes (Glomerulonephritis)

• Rapidly progressive GN (RPGN): Anti-GBM disease, ANCA-associated vasculitis, immune complex GN
• Acute post-infectious GN: Post-streptococcal
• Lupus nephritis
• IgA nephropathy (Berger disease)

3. Vascular Causes

4. Interstitial Causes (Acute Interstitial Nephritis - AIN)

• Drug-induced (most common): Penicillins, cephalosporins, NSAIDs, PPIs, sulfonamides, rifampicin
• Infectious: Pyelonephritis, leptospirosis, hantavirus
• Autoimmune: Sarcoidosis, Sjögren syndrome, SLE, TINU syndrome (tubulointerstitial nephritis and uveitis)

5. Chronic Kidney Disease (CKD)

• Any cause leading to progressive nephron loss → sustained reduction in GFR → chronic urea accumulation (uremia)
• Note: 2/3 of renal function must be lost before a significant BUN rise becomes evident
• Common causes: Diabetic nephropathy, hypertensive nephrosclerosis, chronic GN, polycystic kidney disease
• Smith & Tanagho's General Urology 19e

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POSTRENAL (Urinary Tract Obstruction)

Intraluminal Obstruction

Intramural / Wall Infiltration

• Ureteric/bladder malignancy invading the wall

Extrinsic Compression

Functional Obstruction (Neurogenic Bladder)

• Anticholinergic medications (antihistamines, antipsychotics, TCAs)
• Diabetic autonomic neuropathy
• Spinal cord injury
• Harrison's Principles of Internal Medicine 22e; Frameworks for Internal Medicine

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MASTER SUMMARY TABLE

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Clinical Pearl: BUN alone is an unreliable marker of GFR because it is influenced by so many non-renal factors. Serum creatinine (or cystatin C) is more specific for kidney function. However, a rising BUN with a rising BUN:Cr ratio > 20:1 in the absence of GI bleed or catabolic state strongly suggests a prerenal mechanism. - Brenner & Rector's The Kidney; Morgan & Mikhail's Clinical Anesthesiology 7e