45.2 Hematuria Workup & Glomerulonephritis

Definitions, Epidemiology & Clinical Significance of Hematuria

Hematuria is one of the most frequent reasons for referral to nephrology and urology. In the ambulatory setting, clinicians must distinguish macroscopic (gross) hematuria from microscopic hematuria, exclude benign mimics and pseudohematuria, and localize bleeding to either the nephron (glomerular) or the urinary tract (non-glomerular).

Gross (Macroscopic) Hematuria

• Definition: Visible pink, bright red, or tea/brown discoloration of the urine recognized by the naked eye.
• Malignancy Risk: In adult patients presenting with gross hematuria, the risk of harboring an underlying urothelial or renal malignancy is 10% to 20% (most commonly urothelial bladder carcinoma, followed by renal cell carcinoma, ureteral urothelial carcinoma, and prostate cancer).
• Mandatory Clinical Directive: A single episode of gross hematuria mandates a complete, comprehensive urological evaluation in all adults, regardless of whether the bleeding is painless, self-limiting, transient, or occurs in a patient on therapeutic anticoagulation or antiplatelet therapy. Anticoagulants unmask, but do not cause, neoplastic bleeding.

Microscopic Hematuria

• AUA / SUO Guideline Definition: The 2020 American Urological Association (AUA) and Society of Urologic Oncology (SUO) guideline strictly defines microscopic hematuria as >=3 red blood cells per high-power field (RBCs/HPF) on microscopic examination of a single, properly collected, clean-catch unspun midstream urine specimen.
• The Pitfall of Urine Dipstick Testing: The reagent strip detects the pseudoperoxidase activity of the heme moiety. Although dipstick testing boasts a high sensitivity (>90%), its specificity is poor (65% to 90%).

[!IMPORTANT] AUA GUIDELINE MANDATE: DIPSTICK ALONE IS INSUFFICIENT A positive urine dipstick for heme/blood does NOT establish the diagnosis of microscopic hematuria. A positive dipstick must ALWAYS be confirmed with formal microscopic urinalysis demonstrating >=3 RBCs/HPF before initiating an extensive diagnostic evaluation. If microscopy reveals <3 RBCs/HPF, the workup for hematuria should NOT be pursued.

Causes of Pseudohematuria (False Positives on Dipstick or Red Urine)

Clinicians must systematically rule out benign pigments, endogenous molecules, and medications that alter urine color:

                    DIFFERENTIAL DIAGNOSIS OF PSEUDOHEMATURIA

   Condition / Substance       Dipstick Heme   Urine Microscopy   Mechanism / Clinical Features
   ═══════════════════════════════════════════════════════════════════════════════════════════
   Myoglobinuria               POSITIVE (4+)   0 to 1 RBCs/HPF    • Rhabdomyolysis (trauma, statins,
   (Endogenous heme)                                                extreme exertion, heat stroke)
                                                                  • Serum CK markedly elevated (>5000)
                                                                  • Pigmented granular / brown casts

   Hemoglobinuria              POSITIVE (4+)   0 to 1 RBCs/HPF    • Intravascular hemolysis (PNH, G6PD,
   (Free hemoglobin)                                                prosthetic heart valves, DIC)
                                                                  • Low haptoglobin, elevated LDH

   Dietary Pigments            NEGATIVE        0 RBCs/HPF         • Betaturia (beets in non-metabolizers)
   (Anthocyanins, betalain)                                       • Blackberries, rhubarb

   Pharmacologic Agents:                                          
   • Rifampin                  NEGATIVE        0 RBCs/HPF         • Bright orange/red urine, tears, sweat
   • Phenazopyridine           NEGATIVE        0 RBCs/HPF         • Bright orange/red urine; interferes
     (Pyridium)                                                     with dipstick colorimetric readings
   • Sulfasalazine, Senna      NEGATIVE        0 RBCs/HPF         • Orange to red-brown discoloration
   • Metronidazole             NEGATIVE        0 RBCs/HPF         • Dark brown / tea-colored urine
   ═══════════════════════════════════════════════════════════════════════════════════════════

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Glomerular vs. Non-Glomerular (Urological) Hematuria

The fundamental branch point in evaluating confirmed hematuria is determining whether the bleeding originates from the glomerulus (nephron) or from the extraglomerular urinary tract (calyces, renal pelvis, ureters, bladder, prostate, or urethra).

                LOCALIZATION: GLOMERULAR VS. NON-GLOMERULAR BLEEDING

   Clinical Feature            Glomerular Origin                   Non-Glomerular (Urological)
   ═══════════════════════════════════════════════════════════════════════════════════════════
   Urine Color                 • Smoky, brown, cola-, or           • Bright red, pink, or frank
                                 tea-colored                         bloody urine

   Blood Clots                 • ABSENT (clots cannot pass         • PRESENT (pathognomonic for
                                 through glomerular barrier;         lower tract bleeding from bladder,
                                 urokinase degrades fibrin)          prostate, ureter, or pelvis)

   RBC Morphology              • DYSMORPHIC RBCs (>80%)            • ISOMORPHIC RBCs (>80%)
                                 Acanthocytes (ring cells with       Uniform, smooth, biconcave
                                 protruding blebs / Mickey Mouse     disc-shaped red blood cells
                                 ears >5% is pathognomonic)

   Urinary Casts               • RED BLOOD CELL CASTS              • ABSENT (may see normal
                                 (pathognomonic for GN);             hyaline casts)
                                 Pigmented granular casts

   Proteinuria                 • SIGNIFICANT (>500 mg/day;         • ABSENT or TRACE (<500 mg/day;
                                 UPCR >0.5; dipstick >=2+)           protein is proportional to blood)

   Associated Findings         • Hypertension, periorbital /       • Flank colic (stone), dysuria,
                                 pretibial edema, oliguria,          fever, palpable mass, or completely
                                 elevated serum creatinine           asymptomatic (malignancy)
   ═══════════════════════════════════════════════════════════════════════════════════════════

Clinical Implications of Localization

• Glomerular Bleeding Identified: The patient requires a medical nephrology evaluation (serologic immunological testing, quantitation of 24-hour proteinuria or spot protein-to-creatinine ratio, and potential percutaneous renal biopsy). CT urography and cystoscopy are not indicated unless there is concomitant urological disease.
• Non-Glomerular Bleeding Identified: The patient requires a structural urological workup to rule out urothelial carcinomas, renal cell carcinoma, nephrolithiasis, and benign prostatic hyperplasia.

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AUA/SUO 2020 Risk-Stratified Guideline for Microscopic Hematuria

The American Urological Association (AUA) and Society of Urologic Oncology (SUO) revolutionized the evaluation of microscopic hematuria by replacing the historical "one-size-fits-all" aggressive imaging approach with an evidence-based, risk-stratified paradigm for adults >=35 years of age.

               AUA 2020 MICROSCOPIC HEMATURIA RISK STRATIFICATION

   Risk Category   Patient Characteristics & Criteria          Recommended Diagnostic Action
   ═══════════════════════════════════════════════════════════════════════════════════════════
   LOW RISK        Must meet ALL of the following:             • Shared Decision-Making:
                   • Women <50 years; Men <40 years             1) Repeat UA in 6 months, OR
                   • Smoking history: <10 pack-years            2) Renal Ultrasound + Cystoscopy
                   • 3 to 10 RBCs/HPF on microscopy            • Multiphasic CTU is NOT indicated
                   • No additional malignancy risk factors

   INTERMEDIATE    Meets ANY of the following:                 • RENAL ULTRASOUND +
   RISK            • Women 50 to 59 years; Men 40 to 59 years   • CYSTOSCOPY (Rigid or Flexible)
                   • Smoking history: 10 to 30 pack-years      • Avoids ionizing radiation of CT
                   • 11 to 25 RBCs/HPF on microscopy             while maintaining high sensitivity
                   • Low-risk patient with additional risks:
                     - Prior pelvic radiation
                     - Cyclophosphamide exposure
                     - Occupational dyes / aromatic amines
                     - Chronic indwelling Foley catheter

   HIGH RISK       Meets ANY of the following:                 • MULTIPHASIC CT UROGRAPHY (CTU)
                   • All patients >=60 years                     (Non-contrast, nephrographic,
                   • Smoking history: >30 pack-years              and excretory/delayed phases)
                   • >25 RBCs/HPF on microscopy                 • PLUS CYSTOSCOPY
                   • History of GROSS HEMATURIA                 • Gold standard comprehensive workup
   ═══════════════════════════════════════════════════════════════════════════════════════════

Detailed Imaging Protocols

1. Multiphasic CT Urography (CTU): The imaging modality of choice for high-risk patients. CTU utilizes a three-phase acquisition:
   • Non-contrast Phase: Identifies nephrolithiasis and calcifications.
   • Nephrographic Phase (90-100 sec post-IV contrast): Maximally opacifies the renal parenchyma, optimizing detection of renal cell carcinoma and cortical lesions.
   • Excretory / Delayed Phase (10-15 min post-contrast): Iodinated contrast opacifies the urinary collecting system, allowing detailed visualization of filling defects in the renal calyces, renal pelvis, and ureters (urothelial carcinoma).
2. Renal Ultrasound: Preferred in intermediate-risk patients to eliminate radiation exposure. Accurately identifies renal masses, hydronephrosis, and cysts, but cannot reliably detect small urothelial tumors of the ureters or bladder.
3. Cystoscopy: Transurethral endoscopic visualization of the bladder lumen, bladder neck, and urethra. Cystoscopy is the single most sensitive method for diagnosing bladder urothelial carcinoma; cross-sectional imaging (CT or ultrasound) cannot reliably rule out flat, non-muscle-invasive bladder tumors or carcinoma in situ (CIS).
4. Contraindications to Iodinated Contrast: In patients with severe renal impairment (eGFR <30 mL/min) or severe contrast allergy, multiphasic CTU cannot be performed. Alternative protocols combine Renal Ultrasound or Non-Contrast CT with Bilateral Retrograde Pyelography (RPG) performed under fluoroscopy during cystoscopy.

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Glomerulonephritis & Nephritic Syndrome

When urinalysis reveals glomerular bleeding (dysmorphic RBCs, RBC casts, and proteinuria), the clinical syndrome of Acute Glomerulonephritis (Nephritic Syndrome) must be suspected.

The Cardinal Clinical Tetrad

Nephritic syndrome is characterized by an inflammatory destruction of the glomerular filtration barrier, presenting with:

1. Hematuria: Smoky, cola-colored urine with microscopic dysmorphic RBCs and pathognomonic red blood cell casts.
2. Hypertension: Impaired glomerular filtration of sodium and water triggers extracellular volume expansion, suppression of plasma renin activity, and systemic hypertension.
3. Edema: Secondary to sodium and water retention. Classically presents as periorbital puffiness/edema upon awakening in the morning (loose subcutaneous tissues) and dependent pretibial pitting edema in the evening.
4. Oliguria & Acute Kidney Injury: Abrupt decline in GFR leading to oliguria (<400-500 mL urine/24 hr) and rapidly escalating serum BUN and creatinine.

                    NEPHRITIC SYNDROME VS. NEPHROTIC SYNDROME

   Feature             Nephritic Syndrome                   Nephrotic Syndrome
   ═══════════════════════════════════════════════════════════════════════════════════════════
   Pathophysiology     Glomerular INFLAMMATION & necrosis   PODOCYTE EFFACEMENT / charge defect
   Urine Sediment      ACTIVE: Dysmorphic RBCs, RBC CASTS   BLAND: Oval fat bodies, Maltese cross
   Proteinuria         Sub-nephrotic (<3.5 g/24 hr; 0.5-3g) MASSIVE: Nephrotic (>3.5 g/24 hr)
   Serum Albumin       Normal or mildly depressed           SEVERELY DEPRESSED (<3.0 g/dL)
   Edema               Mild to moderate (periorbital)       SEVERE, GENERALIZED (Anasarca, ascites)
   Blood Pressure      HYPERTENSION (volume expansion)      Normal or low (intravascular depletion)
   Lipids              Normal                               HYPERLIPIDEMIA (elevated LDL/chol)
   ═══════════════════════════════════════════════════════════════════════════════════════════

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Major Etiologies, Serologic Profiles & Clinical Pearls

Primary care physicians must master the clinical distinctions, serological profiles, complement patterns, and management strategies for the five major glomerulonephritides.

                  SEROLOGIC & COMPLEMENT PROFILES IN GLOMERULONEPHRITIS

   Etiology            Complement C3 / C4        Diagnostic Serology & Pathology Markers
   ═══════════════════════════════════════════════════════════════════════════════════════════
   Post-Streptococcal  LOW C3 (Normal/Low C4)    • Elevated ASO (post-pharyngitis) & Anti-DNase B
   GN (PSGN)           Normalizes in 6-8 weeks   • Subepithelial humps on EM; "starry sky" IgG/C3

   IgA Nephropathy     NORMAL C3 & C4            • Galactose-deficient IgA1; Normal complement
   (Berger Disease)                              • Mesangial IgA & C3 deposition on IF

   Anti-GBM Disease    NORMAL C3 & C4            • Serum Anti-GBM antibodies (alpha-3 chain Col IV)
   (Goodpasture)                                 • Bright LINEAR IgG along GBM on IF

   ANCA-Associated     NORMAL C3 & C4            • GPA: c-ANCA / PR3-ANCA (sinus/lung cavitary)
   Vasculitis                                    • MPA: p-ANCA / MPO-ANCA (pulmonary-renal)
                                                 • Pauci-immune crescentic GN (NO immune deposits)

   Lupus Nephritis     LOW C3 & LOW C4           • ANA positive (>98%); Anti-dsDNA (mirrors flare)
   (SLE Class III/IV)  (Classical pathway)       • "Full house" immunofluorescence (IgG, A, M, C3, C1q)
   ═══════════════════════════════════════════════════════════════════════════════════════════

1. Post-Streptococcal Glomerulonephritis (PSGN)

• Pathophysiology: Immune complex-mediated glomerulonephritis triggered by nephritogenic strains of Group A Beta-Hemolytic Streptococcus (GAS, Streptococcus pyogenes). Soluble streptococcal antigens (speB) deposit in the glomerular basement membrane, fixing complement and attracting neutrophils.
• Latent Period:
  • 1 to 3 weeks (average 10 to 14 days) following streptococcal pharyngitis.
  • 3 to 6 weeks following streptococcal impetigo / pyoderma.
• Laboratory Findings:
  • Hypocomplementemia: Markedly depressed serum C3, with normal or mildly depressed C4. Serum C3 levels MUST return to normal within 6 to 8 weeks. If hypocomplementemia persists beyond 8 weeks, alternative diagnoses (membranoproliferative GN or lupus nephritis) must be investigated.
  • Serology: Elevated Antistreptolysin O (ASO) titer (positive in >80% following pharyngitis, but unreliable following skin infections) and elevated Anti-DNase B titer (positive in >90% of both pharyngeal and impetigo-associated cases).
• Biopsy: Electron microscopy demonstrates pathognomonic large subepithelial electron-dense "humps"; immunofluorescence shows granular "starry sky" or "garland" deposition of IgG and C3.
• Management & Prognosis: Supportive therapy. Sodium and fluid restriction, loop diuretics (furosemide) for volume overload and hypertension, and blood pressure control. Antibiotic therapy (penicillin) is given to eradicate residual pharyngeal or cutaneous streptococci to prevent transmission, but antibiotics do NOT alter or shorten the course of glomerulonephritis. Prognosis is exceptionally favorable in pediatric patients (>95% complete clinical recovery); adults experience higher rates of persistent microscopic hematuria and hypertension (~20%).

2. IgA Nephropathy (Berger Disease)

• Epidemiology: The most common primary glomerulonephritis worldwide, with marked predilection for young adults (males > females, peak incidence 15 to 35 years; high prevalence in East Asian and Caucasian populations).
• Pathophysiology: Multi-hit hypothesis: Genetically driven overproduction of galactose-deficient IgA1 (Gd-IgA1). Host IgG autoantibodies recognize Gd-IgA1, forming circulating immune complexes that deposit in the glomerular mesangium, stimulating mesangial cell proliferation, matrix expansion, and cytokine release.
• Classic Clinical Presentation: Recurrent episodes of painless, macroscopic, cola-colored hematuria that occur synchronously or within 24 to 48 hours of an acute upper respiratory tract infection or gastrointestinal viral illness ("synpharyngitic hematuria").

[!IMPORTANT] HIGH-YIELD CLINICAL DISTINCTION: PSGN VS. IgA NEPHROPATHY

• IgA Nephropathy: Synpharyngitic hematuria (onset within 1 to 2 days of illness onset). Complement C3 and C4 levels are COMPLETELY NORMAL.
• PSGN: Post-infectious hematuria with a distinct latent period (1 to 3 weeks post-pharyngitis, 3 to 6 weeks post-impetigo). Complement C3 is DEPRESSED.

• Systemic Counterpart: Henoch-Schönlein Purpura (IgA Vasculitis) represents the identical mesangial IgA nephropathy associated with a systemic small-vessel leukocytoclastic vasculitis, presenting with non-thrombocytopenic palpable purpura (buttocks/lower extremities), severe colicky abdominal pain, and arthralgias.
• Management: Blood pressure optimization (<120 mmHg systolic) using maximal tolerated doses of ACE inhibitors or ARBs. SGLT2 inhibitors (dapagliflozin/empagliflozin) reduce chronic kidney disease progression. In patients with high risk of progression (persistent proteinuria >1 g/day despite 3 months of optimized supportive therapy), targeted-release oral budesonide (Tarpeyo) or a 6-month course of systemic corticosteroids is indicated.

3. Anti-Glomerular Basement Membrane (Anti-GBM) Disease / Goodpasture Syndrome

• Pathophysiology: Severe autoimmune disease caused by circulating autoantibodies directed against the non-collagenous (NC1) domain of the alpha-3 chain of Type IV collagen in basement membranes.
• Clinical Presentation: Rapidly progressive glomerulonephritis (RPGN) with acute, catastrophic oliguric renal failure. When accompanied by pulmonary alveolar hemorrhage (hemoptysis, dyspnea, bilateral diffuse alveolar infiltrates on chest imaging, iron-deficiency anemia), it is termed Goodpasture Syndrome.
• Diagnostic Serology: High-titer serum anti-GBM antibodies (sensitivity and specificity >95% to 98%). Complement C3 and C4 levels are normal.
• Renal Biopsy: Pathognomonic bright, smooth, continuous LINEAR deposition of IgG and C3 along the glomerular basement membrane on direct immunofluorescence, with extensive crescent formation (>50% of glomeruli) on light microscopy.
• Emergent Management: Anti-GBM disease is a true medical emergency. Delay leads to irreversible fibrous crescents and dialysis dependence within days. Immediate treatment mandates:
  1. Plasmapheresis (Plasma Exchange): Daily or alternate-day sessions for 14 days to directly remove circulating pathogenic anti-GBM autoantibodies.
  2. High-Dose Immunosuppression: Pulse IV methylprednisolone (1 g daily x 3 days) followed by oral prednisone PLUS oral or IV cyclophosphamide to suppress de novo antibody synthesis.

4. ANCA-Associated Vasculitis (Pauci-Immune Crescentic GN)

• Pathophysiology: Systemic necrotizing small-vessel vasculitis characterized by circulating Anti-Neutrophil Cytoplasmic Antibodies (ANCA) that activate primed neutrophils, causing endothelial damage and necrotizing crescentic glomerulonephritis with an absence or paucity of immune complex deposition ("pauci-immune").
• Granulomatosis with Polyangiitis (GPA, formerly Wegener): Strongly associated with c-ANCA / anti-Proteinase 3 (PR3-ANCA) (>80% to 90%). Characterized by upper respiratory tract destruction (chronic refractory sinusitis, otitis media, nasal crusting, saddle-nose deformity), pulmonary necrotizing granulomas and cavitary lesions, and crescentic GN.
• Microscopic Polyangiitis (MPA): Strongly associated with p-ANCA / anti-Myeloperoxidase (MPO-ANCA) (>70% to 80%). Presents as a pulmonary-renal syndrome (alveolar hemorrhage and rapidly progressive GN) without granulomatous inflammation or upper airway involvement.
• Management: Rapid induction with high-dose corticosteroids combined with Rituximab (anti-CD20 B-cell depleting monoclonal antibody) or cyclophosphamide. Avacopan (oral complement C5a receptor antagonist) is approved as an adjunctive steroid-sparing agent.

5. Lupus Nephritis

• Pathophysiology: Autoimmune immune-complex deposition in systemic lupus erythematosus (SLE), activating the classical complement cascade.
• Diagnostic Markers: Positive ANA (>98%), elevated anti-double-stranded DNA (anti-dsDNA) (antibody titers correlate directly with renal disease activity and impending renal flares), anti-Smith antibodies, and profoundly low C3 and C4 levels (classical pathway consumption).
• Biopsy Classification: Renal biopsy is mandatory to guide therapy. Class III (focal proliferative) and Class IV (diffuse proliferative—most common and most severe) carry high risk of end-stage renal disease. Induction requires high-dose corticosteroids plus either Mycophenolate Mofetil (MMF) or IV cyclophosphamide, alongside universal background hydroxychloroquine.