Approach to Hematuria

Evaluation & Workup

This section covers the definition and epidemiology of hematuria, the risk factors that raise concern for malignancy, and the AUA risk-stratified workup and follow-up.

Epidemiology

• AUA definition: 3+ RBCs on microscopic UA warrant assessment and potential hematuria workup, single urinalysis with RBCs is all that is required for a hematuria workup, dipstick alone is not adequate for diagnosis
• Prevalence: 6.5% healthy patients have microscopic hematuria on screening tests
• Malignancy prevalence: 1-3.1% w/ microscopic hematuria, 13.2% w/ gross hematuria
• Unknown cause: 33-67% patients do not have diagnosable cause of hematuria (positional, physical activity, recent intercourse)

Risk Factors

• Smoking: increases risk of bladder cancer
• Radiation: XRT cystitis, secondary malignancy, fistula
• Chemotherapy: cyclophosphamide can lead to hemorrhagic cystitis
• UTI: hematuria may be a presenting symptom
• Chronic catheter: irritation or development of SCC bladder cancer
• Chemical exposure: benzenes, aromatic amines increases risk of bladder cancer
• Hx stones, BPH, trauma: benign causes of hematuria
• Dysuria: in absence of UTI, may be presenting symptom of carcinoma in situ
• Hx cancer: either GU-specific or syndromic (Lynch, VHL)

Risk Groups

Risk	Needs all criteria?	Gender/Age	Smoking (packyears)	# RBC (UA x1)	Urothelial cancer risk factors*	Prior hematuria
Low	Yes	Women < 60, Men < 40	< 10	3-10	None	No
Intermediate	No	Women > 60, Men 40-59	10-30	11-25	1+	Persistent 3-25 RBC
High	—	Men 60+	> 30	> 25	1+ (needs another high risk feature)	Gross

*Risk factors include irritative voiding symptoms, prior pelvic radiation, prior cyclophosphamide, history urothelial cancer or Lynch syndrome, prior occupational exposures, and chronic indwelling foreign body

Recommendations

• Low: 0.2-0.5% probability of malignant cause — repeat UA in 6mo
• Intermediate: 1.3-1.6% probability of malignant cause — cysto + RBUS; can offer cytology/urine tumor markers
• High: 10.8-11.1% probability of malignant cause — cysto + CTU

Considerations

• UTI: hematuria in setting of UTI does not warrant workup, perform workup if hematuria persists after treatment (wait 3wks-3mo)
• Anticoagulation: patients on anticoagulation should undergo same workup
• If benign cause identified and treatment, discuss with patient whether further workup is warranted
• Nephrologic cause suspected: perform full workup, increased risk for GU cancers in setting of decreased renal function
• Family history: if history of RCC, genetic renal tumor syndrome, Lynch syndrome, patients should undergo cross-sectional imaging regardless of other risk factors

Workup Components

• Upper tract imaging: CTU, MRU, renal US + retrograde pyelograms
• Renal US: less sensitive for upper tract urothelial cancer but very sensitive for renal neoplasms, recommended option for intermediate risk patients
• Cystoscopy: perform without enhancement (blue light), preferable as screening test
• If persistent/worsening hematuria after renal US, obtain cross-sectional imaging
• Cytology/tumor markers: do not use for low or high risk patients (except if equivocal workup and persistent hematuria/irritative symptoms), do not obtain after otherwise normal cystoscopy, can use for intermediate risk patients instead of cystoscopy (but proceed with cystoscopy if repeat UA shows hematuria 12mo after initial evaluation)

Follow-up

• Probability of subsequent cancer: less than 1% if negative initial workup, equivalent to general population risk for developing GU cancer
• Negative workup: consider annual microscopic UA
• Worsening hematuria or urologic symptoms: obtain further workup

Management

This section covers the acute management of gross hematuria and clot retention, cause-specific management by source, and the treatment of hemorrhagic cystitis.

Initial Evaluation of Gross Hematuria

• Safe to discharge: able to empty bladder (check bladder scan), no blood clots (check urine appearance), not actively bleeding (stable Hgb, non-hypotensive)
• Retention with mild bleeding: likely prostatic origin, attempt regular catheter placement (often results in clear yellow urine, catheter bypasses prostatic bleeding)
• Retention likely secondary to clot burden: likely prior XRT or surgery, place large 3-way Rusch catheter, manually irrigate, start continuous bladder irrigation (CBI)
• Persistent bleeding despite CBI: consider traction, OR clot evacuation, other cause-specific treatments

BPH

• Cause: increased vascularity in hyperplastic tissue secondary to VEGF
• Finasteride: inhibits androgen-stimulated angiogenesis and decreases VEGF expression, 90% symptom improvement, decreased need for surgical intervention, can take 2 weeks to 9 months to take effect
• Refractory hematuria: best managed with surgical outlet procedures

Prostate Cancer

• Usually caused by locally advanced cancer with bladder invasion
• Management: consider ADT, palliative XRT, channel TURP, cystoprostatectomy w/ diversion

Urethrorrhagia

• Trauma: most common non-gender specific cause, maintain catheter for 3-7 days
• Urethritis can be infectious or chemical induced
• Urethral tumors: consider if history urothelial cancer

Upper Tract Causes

• Presentation: clot colic, anemia, and wormlike clots in urine
• Nephropathies: look for dysmorphic RBCs and casts on UA, systemic symptoms
• Papillary necrosis: sickle cell, NSAID use
• Localized management: may require embolization or partial/total nephrectomy

Random Causes of Hematuria to Rule Out

• TB/Schistosomiasis: travel to endemic areas
• ADPKD: family history
• Endometriosis or uterouro fistula: cyclical hematuria during menstrual cycle
• Ureteroiliac fistula: hx vascular surgery, chronic ureteral stents, pelvic XRT
• Arteriovenous malformation: may occur if recent renal procedure, treat w/ embolization
• Nutcracker syndrome: compression of renal vein between aorta and SMA

Hemorrhagic Cystitis — Common Causes

• XRT: seen in up to 5% after pelvic XRT
• Chemotherapy: seen in 2-40% after cyclophosphamide, ifosfamide, resolves in 60-90% with mesna
• Viral (BK polyoma): more common in children or immunocompromised

Hemorrhagic Cystitis — Medical Management

Drug	Mechanism	Dosing	Considerations	Needs OR/Anesthesia?	Contraindications	Side effects
Alum (aluminum ammonium sulfate / aluminum potassium sulfate)	Protein precipitation, vasoconstriction	1% solution (10g/L) run at 200-300mL/hr	Success: 45-100%; no need for anesthesia; can give with VUR	No	None	Aluminum toxicity
Amicar (aminocaproic acid)	Inhibits fibrinolysis	1g/L intravesical; 5g PO loading dose + 1g/hr; give for 24hr after hematuria resolves	Success: up to 92%	—	Bladder clots present (causes them to harden), DIC, upper tract bleeding (causes glomerular thrombosis), risk factors for thrombosis	Rhabdomyolysis (monitor CPK if used for > 24hr), hypotension, GI effects
Silver Nitrate	Chemical coagulation	0.5-1% instilled for 10-20 minutes, rinse out with saline	Mix with water (will precipitate in saline)	Sometimes (if high concentrations)	Extravasation, VUR (need to occlude ureters), inability to tolerate general/spinal anesthesia	Bladder scarring, ureteral strictures if VUR
Formalin	Cellular protein precipitation	1-4% solution 300mL or up to bladder capacity, hold for 10-15 minutes, irrigate bladder with 1L water/saline	Success: 80-90%	Yes	—	—

Hyperbaric Oxygen

• Technique: 100% O2 at 2-3 atm, 90 minutes, 30-40 sessions
• Benefits: enhances angiogenesis, vasoconstriction, antibiotic efficacy, neutrophil function
• Absolute contraindications: cisplatin/doxorubicin treatment, untreated pneumothorax, active viral infections
• Relative contraindications: seizure risk, poorly controlled DM, emphysema, optic neuritis, glaucoma, current pregnancy, fever, active malignancy, hx sinus/ear surgery, hx spontaneous pneumothorax, spherocytosis, claustrophobia
• Success for XRT cystitis: 80-90% response rate, but 5yr success only 27%
• Side effects: claustrophobia (20%), otalgia (17%), seizures (rare)

Surgical/Procedural Interventions

Treatment	Tips
Nephrostomy tubes	Avoids bladder exposure to urokinase, allowing clots to form; can be performed with ureteral coiling
Internal iliac artery embolization	Can be performed unilaterally/bilaterally; posterior occlusion results in significant gluteal pain; success up to 90%
Cystectomy + Urinary Diversion	Complications in up to 80% if bladder not removed; high risk of complications