Causes of Hematuria

First: Pseudo-hematuria (Red Urine Without RBCs)

A. Renal (Intrarenal) Causes

1. Glomerular

• IgA nephropathy - the most common glomerular cause of hematuria worldwide; classically episodic gross hematuria coinciding with mucosal infections
• Thin basement membrane nephropathy (TBMN) - most important differential for isolated microscopic hematuria in young adults
• Alport syndrome - X-linked hereditary nephritis with hematuria, proteinuria, sensorineural deafness, and ocular anomalies
• Postinfectious / post-streptococcal glomerulonephritis - follows throat or skin infection; low complement, ASO elevated
• Lupus nephritis (SLE) - immune complex deposition; ANA/anti-dsDNA positive
• Goodpasture syndrome - anti-GBM antibodies; pulmonary-renal syndrome
• IgA vasculitis (Henoch-Schonlein purpura) - palpable purpura, arthritis, abdominal pain + hematuria/proteinuria
• ANCA-associated vasculitides (GPA, MPA, EGPA) - pauci-immune crescentic GN
• Hemolytic uremic syndrome (HUS) - microangiopathic hemolytic anemia + thrombocytopenia + AKI
• Membranoproliferative GN - recurrent hematuria especially in children/young adults
• Crescentic (rapidly progressive) GN - any of the above progressing to nephritic emergency

2. Tubulointerstitial

• Nephrolithiasis (urolithiasis) - colicky flank pain radiating to groin; very common cause of gross hematuria; calcium oxalate most frequent
• Pyelonephritis - upper UTI with fever, costovertebral angle tenderness; WBC casts on UA
• Acute interstitial nephritis (AIN) - drug-induced (NSAIDs, penicillins, PPIs) or immune; eosinophiluria
• Acute tubular necrosis (ATN)
• Papillary necrosis - associated with sickle cell disease, analgesic nephropathy, diabetes, obstruction
• Polycystic kidney disease (PKD) - autosomal dominant; bilateral cystic kidneys
• Medullary sponge kidney - dilated collecting tubules; associated with nephrocalcinosis and recurrent stones

3. Neoplastic (Renal)

• Renal cell carcinoma - classic triad: hematuria, flank pain, palpable mass (only ~10% present with all three)
• Transitional cell carcinoma (urothelial carcinoma) of the renal pelvis
• Wilms tumor (nephroblastoma) - most common renal malignancy in children
• Benign renal masses - angiomyolipoma, oncocytoma

4. Vascular

• Renal artery embolism or thrombosis - sudden flank pain, hematuria, hypertension
• Renal vein thrombosis - associated with nephrotic syndrome, dehydration in infants
• Arteriovenous malformation (AVM) / arteriovenous fistula
• Nutcracker syndrome - compression of the left renal vein between the aorta and SMA; causes left-sided hematuria and flank pain
• Malignant hypertension

5. Metabolic

• Hypercalciuria - a common cause of hematuria, especially in children; check urine calcium
• Hyperuricosuria

6. Miscellaneous Renal

• Trauma - renal contusion or laceration
• Recurrent familial (benign) hematuria
• Exercise-induced hematuria - resolves within 72 hours of stopping exercise

B. Extrarenal Causes

1. Ureteral

• Mass: benign polyp or urothelial malignancy
• Ureteral stone / calculus
• Stricture

2. Bladder

• Transitional cell (urothelial) carcinoma of the bladder - most common cause of gross hematuria in adults >50; painless hematuria
• Squamous cell carcinoma - associated with chronic schistosomiasis, chronic catheterization
• Infectious cystitis (UTI) - most common cause of hematuria overall; dysuria, frequency, urgency
• Noninfectious cystitis:
  • Hemorrhagic cystitis - from cyclophosphamide or ifosfamide (acrolein metabolite)
  • Radiation cystitis - after pelvic radiation
• Bladder trauma or foreign body

3. Prostate / Urethra

• Benign prostatic hyperplasia (BPH) - common in older men; can cause gross hematuria
• Prostate carcinoma
• Prostatitis
• Urethritis - gonorrheal, chlamydial, or non-specific
• Meatal stenosis / posterior urethral valves - in children
• Urethral stricture
• Urethral caruncle - in postmenopausal women

4. Systemic / Other

• Bleeding diatheses - thrombocytopenia, hemophilia, anticoagulant therapy (warfarin, heparin, DOACs)
• Sickle cell disease / hemoglobinopathy - papillary necrosis, sickling in renal medulla
• Endocarditis - embolic or immune complex nephritis
• Mononucleosis (EBV)
• Schistosomiasis - S. haematobium infects bladder wall; classic cause in endemic areas
• Tuberculosis - sterile pyuria + hematuria; "putty kidney" calcifications

5. Spurious / Contamination

• Menstrual blood contamination
• Rectal bleeding (especially in children)
• Sexual intercourse (transient)

Key Distinguishing Points

Investigation Algorithm: Painless Hematuria in a 55-Year-Old Man

Why This Presentation Demands Urgent Attention

• 20-25% have bladder cancer
• 1.3-10% have prostate cancer
• 0.6-2% have renal cell carcinoma
• ~21% have stones
• 12-13% have BPH

Step 1 - Confirm True Hematuria

• Microscopic urinalysis (UA with microscopy): the gold standard. Confirms hematuria as ≥3 RBCs/hpf. A single positive microscopic UA is sufficient to prompt full evaluation.
• If dipstick is positive but no RBCs on microscopy, consider myoglobinuria (rhabdomyolysis) or hemoglobinuria (hemolysis).
• If urine is red/brown but UA is normal, consider pigmenturia: beets, rifampin, phenazopyridine, porphyrins.

Step 2 - Initial Assessment (History, Exam, Basic Labs)

• Abdominal mass / renal ballottement (RCC, PKD)
• Digital rectal exam (DRE) - prostate size, nodularity, tenderness
• Bimanual exam if bladder tumor suspected
• Blood pressure (hypertension - glomerular disease, RCC)
• Signs of systemic disease (rash, arthritis, edema)

• Full blood count
• Renal function (creatinine, eGFR, electrolytes)
• Coagulation screen (PT/INR, APTT)
• PSA - discuss with patient; ~10% of men with recurrent gross hematuria have prostate cancer - Campbell Walsh Wein Urology

Step 3 - Urine Studies

Key decision point on UA microscopy:

• Dysmorphic RBCs + RBC casts + proteinuria → glomerular hematuria pathway → nephrology referral (± renal biopsy)
• Normal RBC morphology, no casts, no significant proteinuria → non-glomerular / lower urinary tract pathway → urological workup

Step 4 - Imaging

CT Urogram (CTU) - First-Line Imaging

• Multi-phase CT scan: non-contrast phase + nephrographic phase + excretory/delayed phase (opacifies the pelvicalyceal system, ureters, and bladder)
• Sensitivity 92-100% and specificity 94-97% for renal masses, urinary tract stones, and urothelial carcinomas
• Has largely replaced IVP (intravenous pyelogram), plain renal ultrasound alone, and conventional CT for hematuria workup
• Radiation dose is significant - justified in high-risk patients
• If CTU is done first, it may improve the sensitivity of subsequent cystoscopy

Note: Renal/bladder ultrasound alone may suffice for asymptomatic microhematuria in lower-risk patients, but for gross hematuria in a 55-year-old man, CTU is the standard.

Step 5 - Cystoscopy

• Direct visualisation of the entire bladder urothelium and urethra
• Random cold-cup biopsies taken to detect carcinoma in situ (CIS), which is flat and not visible to the naked eye
• Hexaminolevulinate (HAL) fluorescence cystoscopy ("blue light" cystoscopy): photosensitiser instilled intravesically; cancer cells fluoresce red under blue light - improves CIS detection
• If bladder tumour found, transurethral resection of bladder tumour (TURBT) is performed for diagnosis and staging
• Bimanual examination under anaesthesia at time of TURBT assesses for muscle invasion

Diagnostic Algorithm Summary

Painless gross hematuria
        │
        ▼
Confirm with UA microscopy (≥3 RBCs/hpf)
        │
        ├─── Dipstick+ but no RBCs → Myoglobinuria / Hemoglobinuria
        │
        ▼
Urine culture (MSU)
        │
        ├─── Positive → Treat UTI → Repeat UA → if resolved, stop
        │                                         if persistent → full workup
        │
        ▼
Check UA for proteinuria / RBC casts / dysmorphic RBCs
        │
        ├─── Yes (glomerular features) → Nephrology referral
        │                                ± Renal biopsy
        │
        ▼ (No glomerular features)
UROLOGY WORKUP (Simultaneous)
   ┌─────────────────────────┐
   │  CT Urogram              │  ← Upper tract + bladder imaging
   │  Flexible Cystoscopy     │  ← Lower tract, gold standard
   │  Urine Cytology          │  ← Adjunct for urothelial cancer
   │  PSA                     │  ← Prostate cancer
   │  DRE                     │  ← Prostate assessment
   └─────────────────────────┘
        │
        ├─── Bladder tumour → TURBT (diagnostic + therapeutic)
        ├─── Renal mass → Staging CT chest/abdomen/pelvis → Urology/Oncology
        ├─── Calculus → Urology (stone management)
        ├─── BPH → Urology management
        ├─── Prostate cancer → Urology/Oncology staging
        └─── No cause found → Repeat evaluation at 3-5 years

Differential Diagnosis Table (55-Year-Old Male, Painless Hematuria)

Key Principles

1. Never attribute gross hematuria to anticoagulation alone - the underlying cause still requires exclusion
2. Any single episode of gross hematuria in a man >40 requires full urological workup, even if the next UA is clear
3. Urothelial cancer is a must-not-miss diagnosis in gross hematuria not due to infection - Symptom to Diagnosis, 4th ed.
4. Glomerular features (dysmorphic RBCs, casts, heavy proteinuria) divert the workup toward nephrology
5. If a full workup is negative, the risk of malignancy within 6 years is near zero; repeat evaluation can be deferred 3-5 years - Campbell Walsh Wein Urology