Haemorrhagic Cystitis

Haemorrhagic cystitis is diffuse bladder mucosal inflammation with bleeding from the bladder surface. Severity ranges from microscopic haematuria to life threatening haemorrhage with clot retention. The incidence after allogeneic stem cell transplantation is 10 to 25 percent, and 2 to 40 percent following high dose cyclophosphamide without mesna.

Causes:

• Infectious: adenovirus types 11 and 21, BK polyomavirus and, to a lesser extent, cytomegalovirus, in haematopoietic stem cell and kidney transplant recipients. Bacterial infections with Escherichia coli, Proteus. Schistosomiasis in endemic areas, with Schistosoma haematobium, with bladder squamous cell carcinoma risk. Tuberculosis. Fungal.
• Chemical and drug induced: cyclophosphamide and ifosfamide, which produce the toxic metabolite acrolein. Also busulfan, thiotepa, penicillins, danazol, and intravesical agents such as BCG.
• Radiation (late).
• Others: chemical irritants, bladder tumours, coagulopathy, systemic diseases.

In transplant recipients, early onset disease (within 1 to 2 weeks after conditioning) results from direct toxicity. Late onset (after engraftment) results from BK virus reactivation in the setting of immune suppression.

Complications: clot retention, anaemia, renal obstruction and failure, bladder contracture, and death in severe cases.

• Dysuria, urinary frequency, urgency, suprapubic pain, bladder spasms, macroscopic haematuria, clots, and urinary retention.
• Graded severity: grade I microscopic haematuria; grade II macroscopic haematuria; grade III macroscopic haematuria with clots; grade IV haematuria with clots causing urinary tract obstruction requiring intervention.
• Fever and malaise with infection; anaemia and haemodynamic instability with severe blood loss.
• Hydronephrosis and flank pain from clot obstruction of the ureters.
• Symptoms of the underlying cause: history of cyclophosphamide, transplant, or exposure in a schistosomiasis endemic area (swimming in fresh water).

• History of risk factors and medication exposure.
• Urinalysis (red cells, no casts), urine culture, urine cytology, and polymerase chain reaction for BK virus, adenovirus and cytomegalovirus in urine and blood (BK viruria above 10^7 copies/mL with viraemia correlates with haemorrhagic cystitis); urine microscopy for schistosome eggs (terminal spined eggs) and serology.
• Blood: haemoglobin, platelets, clotting profile, creatinine and blood group with crossmatch.
• Renal and bladder ultrasound for clots, bladder wall thickening and hydronephrosis; CT urography when tumour or stones are suspected.
• Cystoscopy: diffuse mucosal oedema, erythema, haemorrhagic or ulcerated areas and clots, with evacuation and biopsy where indicated.

• Resuscitation and supportive care: intravenous fluids, transfusion (red cell for haemoglobin below 7 g/dL, platelets above 50 x 10^9/L during active bleeding), correction of coagulopathy and platelet count, analgesia, antispasmodics (oxybutynin 5 mg three times daily), and withdrawal of the offending drug.
• Catheterisation with a large bore three way catheter (22 to 24 Fr) and continuous bladder irrigation with normal saline to prevent clot formation. Use manual irrigation or cystoscopic clot evacuation under anaesthesia, with fulguration of bleeding points.
• Prevention of chemical haemorrhagic cystitis: vigorous hydration (3 L/m2 per day) and frequent voiding. Give mesna 60 to 100 percent of the ifosfamide or cyclophosphamide dose in divided doses (for example 20 percent of the dose at the time of chemotherapy, then 4 and 8 hours later, or by continuous infusion). Use bladder irrigation in high dose cyclophosphamide regimens.
• Viral haemorrhagic cystitis: reduction of immunosuppression where feasible, hydration, and antiviral therapy.
• Cidofovir 5 mg/kg intravenously weekly with probenecid 2 g before and 1 g at 2 and 8 hours after the infusion (4 g in total) and prehydration with saline. Alternatively, low dose 1 mg/kg three times a week, or intravesical cidofovir 5 mg/kg in 100 mL saline instilled for 60 minutes weekly (less nephrotoxic). Monitor renal function.
• Adenovirus specific T-cell therapy and virus specific cytotoxic T-lymphocytes (posoleucel) for refractory disease. Brincidofovir where available. Fluoroquinolones have been used for BK virus prophylaxis with limited benefit. Leflunomide 20 mg daily.
• Antifibrinolytics: tranexamic acid 1 g three times a day orally or intravenously for 5 to 7 days (caution with thrombosis risk and clots in the ureters), or aminocaproic acid 5 g load then 1 g per hour.
• Intravesical therapy for persistent bleeding: alum 1 percent solution irrigation at 200 to 300 mL/hour for 24 to 48 hours, hyaluronic acid 40 mg weekly, prostaglandin or carboprost instillations (carboprost 0.8 mg/L, 100 mL/hour for 4 hours), silver nitrate 0.5 to 1 percent, and aminocaproic acid solution.
• Formalin 1 to 10 percent for refractory cases under anaesthesia. Exclude vesicoureteral reflux and use caution, as it risks bladder contracture, fistula and renal damage.
• Hyperbaric oxygen therapy 2.0 to 2.5 atmospheres for 90 to 120 minutes daily for 20 to 40 sessions (resolution in 60 to 80 percent).
• Interventional radiology: selective embolisation of the vesical arteries. Surgery: cystectomy and urinary diversion (rare) or bilateral nephrostomies and ureteric diversion as a last resort. Conservative measures usually suffice.
• Schistosomiasis: praziquantel 40 mg/kg orally in two divided doses on one day (or 40 mg/kg as a single dose), with follow up at 3 months, and treatment for urinary obstruction.
• Bacterial infection: culture directed antibiotics (for example ciprofloxacin 500 mg twice daily or nitrofurantoin 100 mg twice daily for 7 days).
• Follow up: monitor blood count, creatinine, and ultrasound for hydronephrosis, and long term cystoscopy surveillance in chronic disease (radiation, schistosomiasis).