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Approach to Azotemia, Proteinuria, and Hematuria

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PART 1: AZOTEMIA

What is Azotemia?

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1A. PRERENAL AZOTEMIA

• True hypovolemia: hemorrhage, burns, diarrhea, diuretics
• Volume sequestration: pancreatitis, peritonitis, rhabdomyolysis
• Decreased effective arterial volume: CHF, liver failure (hepatorenal syndrome), sepsis
• Impaired renal autoregulation: NSAIDs (block afferent prostaglandin dilation), ACE inhibitors / ARBs (block efferent angiotensin II constriction), cyclosporine

• Reduced renal perfusion → activation of sympathetic NS + RAAS + AVP → avid Na/water retention
• GFR is maintained by two counterbalancing mechanisms: prostaglandin-mediated afferent dilation AND angiotensin II-mediated efferent constriction
• Once mean arterial pressure drops below 80 mmHg, GFR falls steeply
• Key point: Prolonged prerenal azotemia → ischemic tubular injury → ATN

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1B. INTRINSIC AKI (Renal Azotemia)

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1C. POSTRENAL AZOTEMIA

• Bladder outlet obstruction (BPH, prostate cancer, neurogenic bladder)
• Bilateral ureteral obstruction (retroperitoneal fibrosis, bilateral calculi, pelvic malignancy)

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1D. DIFFERENTIATING PRERENAL vs. INTRINSIC (ATN) - THE KEY TABLE

FENa (%) = (UNa × PCr) / (PNa × UCr) × 100

• FENa can be falsely low (<1%) with ATN in: contrast nephropathy, rhabdomyolysis, hemolysis, early obstruction, glomerulonephritis
• FENa is unreliable with diuretic use → use FEurea instead (FEurea <35% = prerenal; >50% = intrinsic)

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1E. GFR Measurement

• Gold standard: Inulin or iothalamate clearance (rarely used clinically)
• Creatinine clearance (CrCl): 24-h urine collection; adequate if male excretes 18.5-25 mg/kg/day, female 16.5-22.4 mg/kg/day
• Cockcroft-Gault: CrCl = [(140-age) × LBW (kg)] / [PCr × 72] × 0.85 if female
• MDRD: eGFR = 186.3 × PCr^(-1.154) × age^(-0.203) × 0.742 (female) × 1.21 (Black)
• CKD-EPI: Currently most accurate for population-level use

• Rises acutely after eating cooked meat
• Secreted by proximal tubule (overestimates GFR in advanced CKD)
• Varies with muscle mass (misleadingly normal in elderly, cachectic patients)

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PART 2: PROTEINURIA

What is Normal Protein Excretion?

• Normal: <150 mg/day total protein (<30 mg/day albumin)
• Microalbuminuria: 30-300 mg/day (or ACR 30-300 mg/g)
• Macroalbuminuria (overt): >300 mg/day

How Proteins Are Filtered

1. Size-selective barrier: Functional pores in the GBM restrict molecules >150 kDa
2. Charge-selective barrier: Glycosaminoglycans repel negatively charged albumin

Types / Causes of Proteinuria

Nephrotic vs. Nephritic Proteinuria

Why Proteinuria Matters - Prognostic Power

Quantification Methods

Orthostatic (Postural) Proteinuria

Management Principles

• ACE inhibitors / ARBs: reduce proteinuria and slow CKD progression by reducing intraglomerular pressure (efferent dilation) AND reducing podocyte injury via angiotensin II blockade + decreasing TGF-β expression
• SGLT-2 inhibitors: renoprotective in CKD with or without diabetes
• BP target: <130/80 mmHg in proteinuric CKD
• Specific treatment based on underlying cause (steroids for MCD, immunosuppression for FSGS/MN/lupus nephritis)

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PART 3: HEMATURIA

Definition

• Gross hematuria: Blood visible to naked eye
• Microscopic hematuria: ≥3 RBCs/high-power field (hpf) on microscopy (adults)
  • In children: >5 RBCs/hpf on at least 2 weekly samples
• Important: Dipstick alone is insufficient - myoglobin and hemoglobin also give positive dipstick. Microscopy is required for true confirmation.

Pseudohematuria

• Beetroot, blackberries, rhubarb (foods)
• Rifampin, phenazopyridine, phenytoin (drugs)
• Myoglobinuria, hemoglobinuria (dipstick positive, no RBCs on micro)
• Porphyria

Clinical Approach

• Initial stream hematuria → prostatic or urethral source
• Total stream hematuria → bladder or above
• Terminal hematuria → bladder neck (contracts at end of void)
• Clot shape: Vermiform (worm-like) = upper tract origin; cuboid = bladder

• Age >50 (most common cause of gross hematuria in >50 y/o = bladder cancer)
• Smoking history
• Industrial chemical/dye exposure (aniline, benzidine)
• Alkylating chemotherapy (cyclophosphamide)
• Analgesic abuse
• Chronic indwelling foreign bodies
• Gross hematuria (even single episode) in adults

Hematuria confirmed by microscopy
        │
        ├─── Exclude: UTI, menstruation, trauma, recent urologic procedure
        │
        ├─── Glomerular features (dysmorphic RBCs, RBC casts, proteinuria)?
        │         → Nephrology: serologies, renal biopsy
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        └─── No glomerular features (eumorphic RBCs, no casts)?
                  → Urologic evaluation:
                       1. Imaging (CT urogram - gold standard for upper tract)
                       2. Cystoscopy (for lower tract - mandatory in adults >35)
                       3. Urine cytology
                       4. Urine culture

• All adults with asymptomatic microscopic hematuria should be evaluated
• In young women, exclude UTI first (common benign cause)
• Gross hematuria: aggressive workup regardless of suspected benign cause (e.g. stones) - always rule out concurrent malignancy
• Even after finding a "cause" (e.g. stone), follow-up urinalysis is required as hematuria can be a harbinger of serious pathology

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SYNTHESIS: The Nephrologic Syndrome Framework

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CLINICAL PEARLS

1. BUN:Cr >20:1 with FENa <1% = prerenal until proven otherwise
2. Muddy-brown granular casts = ATN signature
3. RBC casts are pathognomonic of glomerulonephritis - never normal
4. WBC casts = AIN or pyelonephritis
5. Broad waxy casts = severe chronic kidney disease (end-stage tubules)
6. Dipstick misses light chains (myeloma) - always check SSA or UPEP when suspected
7. A single episode of gross hematuria in a patient >50 years needs full urologic workup
8. Orthostatic proteinuria in a young person: split collections, benign if absent when recumbent
9. FENa is unreliable with diuretics - use FEurea (<35% = prerenal)
10. ACE inhibitors/ARBs reduce both proteinuria and progression - they are renoprotective beyond BP control

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