• Smoking — the single most important modifiable risk factor for urothelial carcinoma (2–6× risk, dose-dependent) ^[1][5]
• Occupational exposure to chemicals — aromatic amines and polycyclic aromatic hydrocarbons used in rubber, dye, plastic, petroleum, and organic solvent industries ^[1][4][5]
  • Classic occupations: hairdressers, painters, rubber workers, chemical plant workers
• Exposure to carcinogenic agents: aristolochic acid in traditional Chinese medicine (TCM) — highly relevant in Hong Kong; cyclophosphamide; pelvic radiation ^[4]
• Age > 35–40 years, male sex ^[1]
• Prior history of gross haematuria, urological disease, irritative urinary symptoms ^[4]
• Chronic UTI, chronic indwelling foreign body (e.g., long-term catheter) — associated with squamous cell carcinoma of bladder
• Family history of renal cell carcinoma (note: FHx of urothelial CA is NOT associated with increased risk) ^[4]
• Analgesic abuse (phenacetin nephropathy → upper tract urothelial carcinoma) ^[4]

• Male predominance (M:F = 3:1), age 40–60s ^[5]
• Anatomical abnormalities: medullary sponge kidneys, horseshoe kidneys ^[5]
• Dietary: high oxalate, high protein, high sodium, low fluid intake ^[2][5]
• Medical: primary hyperparathyroidism (hypercalciuria), gout (hyperuricaemia), inflammatory bowel disease, RTA type I ^[5]
• Family history of stone disease ^[4]
• Occupational dehydration (outdoor workers with heavy sweating) ^[4]

• Recent upper respiratory tract infection (IgA nephropathy — "synpharyngitic haematuria")
• Autoimmune conditions: SLE, ANCA-associated vasculitis, Goodpasture disease
• Family history of kidney disease (e.g., Alport syndrome, polycystic kidney disease) ^[4]
• TB exposure ^[4]

• Antiplatelet/anticoagulant use — does NOT cause haematuria per se but may unmask an underlying lesion; these patients still need full investigation ^[1][2]
• Cyclophosphamide/ifosfamide → haemorrhagic cystitis ^[4]

1. Kidneys

   • Glomeruli: The filtration unit. The glomerular basement membrane (GBM) normally prevents RBCs from crossing into the filtrate. When the GBM is damaged (e.g., glomerulonephritis), RBCs squeeze through and become dysmorphic (distorted as they pass through damaged fenestrations) → dysmorphic RBCs and RBC casts on microscopy = glomerular origin.
   • Renal parenchyma: Tumours (renal cell carcinoma), cysts (polycystic kidney disease), infarction, infection (pyelonephritis), and vascular malformations can all erode into the collecting system.

2. Renal pelvis and ureters (upper urinary tract)

   • Lined by urothelium — subject to urothelial carcinoma (same field cancerization concept as bladder).
   • Three points of anatomical narrowing where stones tend to lodge:
     • Pelviureteric junction (PUJ): where renal pelvis meets ureter
     • Pelvic brim: where ureter crosses the common iliac artery bifurcation
     • Vesicoureteric junction (VUJ): where ureter pierces the bladder wall ^[5]
   • Stones cause mucosal trauma → haematuria; obstruction → hydronephrosis → loin pain.

3. Urinary bladder

   • Largest surface area of urothelium → most common site of urothelial carcinoma.
   • Stores urine — irritation here (stones, infection, tumour) causes irritative LUTS (frequency, urgency, nocturia).
   • Bladder neck pathology (tumour, stone) → terminal haematuria (blood appears at end of voiding when the bladder contracts maximally and squeezes the lesion).

4. Prostate (males)

   • BPH: enlarged prostate has increased vascularity → fragile vessels can bleed.
   • Prostate cancer rarely causes haematuria unless locally advanced.
   • Prostatitis → perineal pain + haematuria.

5. Urethra

   • Anterior urethral pathology → initial haematuria (blood at start of stream before urine washes it away).
   • Urethral trauma, stricture, or tumour.

This is critical to understanding why glomerular haematuria looks different from urological haematuria:

• The barrier consists of three layers: fenestrated endothelium → GBM → podocyte foot processes.
• In glomerulonephritis, inflammatory damage disrupts this barrier → RBCs are forced through under filtration pressure → they become dysmorphic (irregular, fragmented, budding).
• Additionally, urokinase in glomerular filtrate lyses any clots that form → therefore glomerular bleeding typically does NOT produce blood clots ^[2].
• In contrast, urological bleeding (from tumours, stones, infection) releases normal (isomorphic) RBCs directly into the urine, and clotting can occur → blood clots suggest a urological (non-glomerular) cause ^[2].

High Yield: Dysmorphic RBCs / RBC casts = glomerular origin. Isomorphic RBCs ± clots = urological origin. This single microscopic finding is the most important branch point in the approach to haematuria.

Timing (early/whole/end stream) — though the lecture notes caution this is unreliable in predicting location ^[1]:

This is the modern risk-stratification approach that guides the intensity of investigation:

The glomerular filtrate contains urokinase (a plasminogen activator), which is produced by renal tubular cells. This fibrinolytic enzyme lyses any fibrin clots that form in the urinary space. Therefore, glomerular haematuria characteristically lacks clots, whereas urological haematuria (where blood enters the urinary tract below the glomerulus, beyond the reach of urokinase) can form clots ^[2].

In IgA nephropathy, there is overproduction of abnormally glycosylated IgA1. During a mucosal infection (URTI, GI infection), there is a surge in IgA production → overwhelming the clearance mechanisms → more IgA1-containing immune complexes deposit in the mesangium → acute inflammatory flare → haematuria. This is why haematuria occurs during the infection (synpharyngitic) rather than 1–3 weeks after (as in post-infectious GN, where the latency reflects the time needed to mount an adaptive immune response with IgG antibody formation and complement activation).

Tumours, especially urothelial carcinoma, grow insidiously. They develop new blood vessels (angiogenesis) that are fragile and bleed intermittently. Because the tumour itself doesn't acutely stretch or obstruct anything (unlike a stone causing colic or infection causing inflammation), there is no pain. The bleeding is often intermittent — a single episode of painless gross haematuria in a patient > 35 years old demands investigation for malignancy.

The entire urothelium (from renal pelvis to urethra) is exposed to the same carcinogens dissolved in urine. This means:

• Multifocal tumours can arise simultaneously at different sites ^[5]
• A patient with bladder UCC has a 2–4% risk of concurrent or subsequent upper tract UCC ^[5]
• This is why upper tract imaging is essential in patients diagnosed with bladder cancer, and vice versa
• Spreads through urothelium via intraluminal seeding or intraepithelial migration ^[5]

These present with dysmorphic RBCs, RBC casts, proteinuria, cola-coloured urine, and no clots.

Bleeding tendencies seldom cause haematuria on their own — 81% are associated with an underlying urinary cause ^[4][9]. Always investigate further.

When a patient (often young) presents with persistent microscopic haematuria, normal BP, normal renal function, and no systemic disease, the differential classically narrows to three causes:

1. IgA nephropathy — most common; adult onset; synpharyngitic gross haematuria episodes; may have flank pain and AKI
2. Alport syndrome — X-linked; childhood onset; sensorineural hearing loss + ocular abnormalities (anterior lenticonus); FHx of renal failure/deafness in males
3. Thin basement membrane disease (TBMD) — AD; generally benign; persistent microscopic haematuria; 30–50% have FHx of haematuria; gross haematuria unusual (< 10%)

Distinguishing them clinically ^[11]:

• Hx of gross haematuria: common in IgAN and Alport, unusual in TBMD
• FHx of CKD/deafness: Alport
• FHx of benign haematuria: TBMD
• Definitive: renal biopsy (IgA deposits in IgAN; thin/splitting GBM in Alport; uniformly thin GBM in TBMD) or genetic testing for COL4A mutations

This is a medical emergency. The differential includes:

• Anti-GBM disease (Goodpasture): linear IgG on GBM; type IV collagen autoantibodies
• ANCA-associated vasculitis (GPA, MPA): pauci-immune crescentic GN; c-ANCA (GPA) or p-ANCA (MPA)
• SLE: immune complex-mediated; multi-system involvement
• IgA vasculitis (HSP): rare in adults; palpable purpura

Always review the drug chart:

• Cyclophosphamide / ifosfamide → haemorrhagic cystitis (acrolein metabolite)
• Anticoagulants / antiplatelets → unmask underlying lesion (not a cause per se)
• NSAIDs → can cause AIN, papillary necrosis
• Radiation → radiation cystitis (delayed by years)

Urine dipstick is the initial screening test. It detects the peroxidase activity of the haem moiety — which is present in intact RBCs (haematuria), free haemoglobin (haemoglobinuria), AND myoglobin (myoglobinuria). Therefore:

All Hb-positive dipstick results should be accompanied by urine microscopy to differentiate true haematuria from pigmenturia ^[2].

Definitions for confirmed haematuria ^[2][8]:

• Gross haematuria: Red or brown urine visible to the naked eye; confirmed by centrifugation → red sediment with clear supernatant = haematuria; red supernatant → test with dipstick (positive = haemoglobinuria/myoglobinuria; negative = drug/food pigment) ^[8]
• Microscopic haematuria: ≥3 RBC per HPF in 2 out of 3 properly collected midstream urine specimens processed by centrifugation ^[2]

Once true haematuria is confirmed, the single most important diagnostic step is urine microscopy to determine the origin of bleeding:

High Yield: Acanthocytes (> 5% of urinary RBCs) are considered the most specific dysmorphic RBC type for glomerular bleeding ^[8]. RBC casts are diagnostic of glomerulonephritis ^[8][13].

Immunological/Serological Panel (When Glomerular Origin Suspected) [4][9][15]

This panel helps narrow the glomerular differential. The logic is based on the pathogenesis of each GN:

Why this matters: Significant proteinuria (> 500 mg/day) alongside haematuria strongly suggests glomerular origin and is an indication for renal biopsy ^[4][15].

• What it is: "Cysto" = bladder, "scopy" = to look. A scope (flexible or rigid) inserted via the urethra to directly visualise the urethra, prostate, and entire bladder mucosa.

• Types:

  • Flexible cystoscopy (16 Fr): Performed under local anaesthetic in clinic; standard for diagnostic purposes ^[4]
  • Rigid cystoscopy: Performed under general/spinal anaesthesia; allows washout of clots, TURBT, and more complex procedures ^[2]

• Indications: Should be done in ALL patients with gross non-glomerular haematuria (even if a stone is found on KUB — because a concurrent malignancy could coexist) ^[4][9]

• Possible findings ^[4]:

• Allows biopsy for histopathological diagnosis ^[4][8]

• What it is: Percutaneous needle biopsy of renal cortex under ultrasound guidance

• Why we do it: Definitive diagnosis of glomerular disease (light microscopy, immunofluorescence, electron microscopy)

• Indications ^[8][4]:

  • Glomerular haematuria with significant proteinuria (> 1 g/day)
  • Rising serum creatinine not otherwise explained
  • Active urinary sediment (dysmorphic RBCs, RBC casts) with progressive renal impairment
  • Nephritic syndrome (most cases require biopsy ^[15])
  • Suspected lupus nephritis with proteinuria > 500 mg/day ^[4]
  • NOT usually done for isolated microscopic haematuria with normal renal function and minimal proteinuria (usually benign course)

• Key immunofluorescence patterns — this is the most helpful diagnostic feature ^[15]:

• Contraindications to percutaneous renal biopsy ^[8]:
  • Bleeding diathesis (coagulopathy, anticoagulation)
  • Severe hypertension (uncontrolled)
  • Solitary functioning kidney
  • Small kidneys indicative of chronic irreversible disease (biopsy won't change management)
  • Hydronephrosis
  • Renal or perirenal infection

1. Airway and Breathing: Usually not compromised in haematuria (unlike haemoptysis). Ensure patient is monitored.
2. Circulation:
   • Establish large-bore IV access (at least two 16–18G cannulae)
   • Send bloods: CBC, clotting profile, group and crossmatch (T/S), RFT, electrolytes ^[13]
   • IV fluid resuscitation with crystalloids (normal saline or Hartmann's) if hypovolaemic
   • Blood transfusion if Hb < 7 g/dL or haemodynamically unstable despite fluids ^[17]
   • Correct any coagulopathy: If on warfarin → vitamin K ± PCC/FFP; if on DOACs → specific reversal agents (idarucizumab for dabigatran, andexanet alfa for factor Xa inhibitors); if thrombocytopenic → platelet transfusion ^[18]

When haematuria produces clots that obstruct the bladder outlet, the patient develops acute retention of urine (AROU) — they are in pain, unable to void, and the bladder is distended with clot.

Management ^[8][17]:

1. 3-way Foley catheter insertion (large bore, typically 22–24 Fr):

   • 3-way catheter has three lumina: one for balloon inflation, one for drainage, and one for irrigation
   • Indicated in patients with haematuria with clot formation which can lead to AROU or in patients requiring pharmacological therapy ^[8]
   • The large bore is needed because clots can block smaller catheters

2. Manual bladder washout (first step):

   • Using a 50 mL bladder syringe, flush normal saline through the catheter to manually evacuate clots
   • Repeat until irrigant runs clear

3. Continuous bladder irrigation (CBI):

   • Saline is infused through the irrigation port and drained through the catheter ^[8]
   • Purpose: Dilute blood in the bladder to prevent further clot formation, maintain catheter patency
   • Adjust irrigation rate to keep effluent light pink/clear

4. If catheterisation fails or clots cannot be cleared:

   • Cystoscopy under GA → clot evacuation using Ellik evacuator + direct visualisation to identify and cauterise bleeding source (e.g., diathermy of a bleeding bladder tumour)

Catheterisation contraindications and alternatives ^[8][4]:

The haematuria resolves when the infection is treated. Detailed UTI management is covered elsewhere, but in summary:

• Repeat urinalysis after treatment to confirm haematuria has resolved
• If haematuria persists after UTI treatment, investigate for underlying malignancy (the UTI may have been incidental)

BPH rarely causes significant haematuria, but when it does (due to increased prostatic vascularity → fragile vessels), the haematuria usually resolves with treatment of the BPH itself:

Regardless of the specific GN subtype, the following supportive measures apply:

Note: Protein restriction is NOT recommended despite heavy urinary protein loss — patients should have normal protein intake because ↑albumin excretion is associated with poorer outcomes ^[9].

Treat with forced diuresis if not severe ^[7]. Factor replacement is generally NOT indicated for isolated haematuria (risk of clot formation in the urinary tract if factor levels become too high). If severe, factor replacement with concurrent hydration.

• Avoid antifibrinolytics (e.g., tranexamic acid) in haematuria from haemophilia — these prevent clot lysis and can cause obstructive clots in the ureter/urethra ^[7].
• Analgesics as needed: COX-2 inhibitors or paracetamol → avoid NSAIDs (impair platelet function) ^[7]

• What happens: Heavy bleeding into the bladder produces blood clots. These clots accumulate and physically obstruct the bladder outlet (internal urethral orifice) or block the catheter → the patient cannot void → bladder distends painfully → acute retention of urine (AROU) ^[8][9].
• Pathophysiology: Whole blood in sufficient volume within the bladder coagulates (unlike glomerular haematuria where urokinase prevents this). The clot mass acts as a ball-valve at the bladder neck. The detrusor contracts against an obstructed outlet → pain, distension, and further mucosal injury from overdistension.
• Clinical features: Inability to void, severe suprapubic pain, palpable distended bladder, patient in obvious distress
• Why it matters: If not relieved urgently, the back-pressure transmits up the ureters → bilateral hydronephrosis → obstructive nephropathy → acute kidney injury (AKI) ^[13]
• Management: Large-bore 3-way catheter → manual clot evacuation with bladder syringe → continuous bladder irrigation (CBI) → cystoscopy under GA if refractory ^[8]

• What happens: Chronic or recurrent haematuria leads to iron-deficiency anaemia through ongoing urinary blood loss ^[4][9].
• Pathophysiology: Each millilitre of blood contains ~0.5 mg of iron. Chronic blood loss depletes iron stores → ↓haemoglobin synthesis → microcytic hypochromic anaemia. Acute massive haematuria can cause normocytic anaemia (haemodilution after fluid resuscitation).
• Clinical features: Anaemic symptoms: pallor, palpitations, SOB, lightheadedness, malaise ^[4][9]. In severe acute haematuria → tachycardia, hypotension, syncope.
• Why it matters: Especially dangerous in elderly patients with cardiovascular comorbidities — even mild anaemia can precipitate angina or heart failure.
• Management: Treat the underlying cause of bleeding; oral/IV iron supplementation for iron deficiency; transfusion if Hb < 7 g/dL or symptomatic.

• What happens: Rare but life-threatening — massive haematuria (usually from tumour erosion into a large vessel, trauma, or arteriovenous malformation) can cause sufficient blood loss to produce hypovolaemic shock.
• Pathophysiology: Blood volume loss → ↓venous return → ↓cardiac output → ↓tissue perfusion → organ failure
• Clinical features: Tachycardia, hypotension, cold clammy peripheries, oliguria, altered consciousness
• Management: ABC resuscitation, massive transfusion protocol if necessary, urgent surgical/interventional radiology control of bleeding (embolisation, cystoscopy with cauterisation, or surgical exploration)

• What happens: Blood clots can obstruct not only the bladder outlet but also the ureters — vermiform (worm-shaped) clots can cast the ureteric lumen and obstruct it, especially in upper tract bleeding sources.
• Pathophysiology: Ureteric obstruction by clot → proximal hydronephrosis → ↑intratubular pressure → ↓GFR → AKI. If bilateral (or unilateral in a single functioning kidney), this progresses to renal failure.
• Renal impairment: ↓urine output, S/S of fluid overload (ankle oedema…) ^[4][9]
• Management: Urgent decompression — JJ stent or percutaneous nephrostomy (PCN) ^[13]

• What happens: The sight of blood in urine is extremely distressing to patients. Many immediately fear cancer.
• Why it matters: Even when the cause is benign (e.g., UTI, exercise-induced), the psychological burden can be significant. Patients need clear communication, prompt investigation to provide reassurance, and appropriate counselling.