Isao Kuroda md, Department of Urology, Kidney Disease Center, Saitama Medical School, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan. Email: VEQ01625@nifty.ne.jp
A 49-year-old man with Wegener's granulomatosis, who had been treated with cyclophosphamide, was admitted to our hospital experiencing gross hematuria. The hemorrhage was refractory to multiple conventional treatments. It progressed but later was resolved after a course of hyperbaric oxygen therapy.
Cyclophosphamide (CPA) is a well-known cause of hemorrhagic cystitis(HC). It is usually treated with an intravesical instillation of hydrotalcite and PGF2α. These treatments are often unsatisfactory, and consequently some patients require urinary diversions. In the present case, hyperbaric oxygen therapy (HBO) was effective in treating intractable HC and preserving the bladder. There are few reported cases of hemorrhagic cystitis being cured by HBO in patients with collagen disease treated with CPA. Here in we report our case and findings.
A 49-year-old man was admitted to our hospital suffering macrohematuria.The patient had received various immunosuppresive drugs since he had been diagnosed with Wegener's granulomatosis in 1983, including 360 g CPA. On 26 April 2001, the patient under went cystoscopy, which revealed mild HC without active bleeding. We initiated an intravesical instillation of sodium carbazocromsulfonate; however, bleeding became more severe each day. We then attempted repeat bladder instillations of sodium aluginate, but achieved no results. Vasodilation and bleeding from the bladder mucosa worsened and the patient suffered frequent episodes of bladder tamponade (Fig. 1).
Pathological and cytological findings did not suggest a malignancy in either the upper or lower urinary tracts. After reaching the diagnosis of progressive HC induced by CPA, we treated the patient with HBO (2.7 ATA 60 min per day × 5days per week for 4 weeks). On day 3 the bladder tamponade was resolved; on day 15 the macrohematuria disappeared; and on day 20 the microhematuria disappeared. Complete normalization of the intention of the bladder was confirmed by cystoscopy 2 weeks after HBO therapy ended.
Cyclophosphamide is an oxazaphosphorinate alkilate drug. It was developed in 1958 and has been widely used as an anticancer and immunosuppressive drug for self-immune diseases and transplants.1 Cyclophosphamide-induced HC was first recognized in 19592 and has been observed in approximately 2–40% of the patients.1 Most of the cases are resolved naturally by ceasing medication, but some cases are more complicated, like the present one.
Cyclophosphamide is metabolized in the liver and produces acrolein, which is excreted into the urine, coming into contact with the uroepithelium and inducing necrosis and edematous change. Although regeneration of the uroepithelium occurs during recovery, the regenerated mucusis not thick enough and suffers vasodilation and angiogenesis, which results in easy bleeding.3
General treatments for HC are shown in Table 1. As a preventative measure, hydration reduces the chance of acrolein coming into contact with the uroepithelium. Mesna contains a sulfhydryl compound that binds acrolein within the urinary collecting system and detoxifies it, resulting in inert thioether, which is then passed innocuously into the urine without damaging the uroepithelium.4 Prophylactic cystoscopies are also recommended for patients receiving CPA because early mucosal lesion of the bladder, which will most likely be followed by CPA-induced HCC, may develop prior to the appearance of microhematuria.5 Intravesical instillations of hydrotalcite and PGF2a are widely used to treat CPA-induced HC.1,6,7 Although intravesical instillations of phenol and formalin are relatively effective,8,9 they are not usually performed because of the risk of severe complications like an atrophic bladder and high grade VUR.3,10 As a result, increasing number of cases, like ours, in which conventional intravesical instillation therapies using PGF2a cannot resolve HC,HBO is used before administering phenol or formalin.11,12
Table 1. Treatment for hemorrhagic cystitis (HC)
Reduced chance of acrolein contacting uroepithelium.
Compound sulfhydryl binds and detoxifies acrolein.
Simple; safe; no anesthesia
Allergic reaction; encephalopathy
Inhibited transcapillary movement of plasma protein; reduced local edema, inflammation and exudation.
Multiple instillation required
No systemic side effects; available commercially
Bladder spasm; expensive
Local vasoconstriction and platelet aggregation regulate mucous barrier.
Rare systemic side effects
Effective for intractable HC especially when PGF2α fails.
Good success rate
Pain; general or regional anesthesia; atrophic bladder
Similar chemical structure to acrolein; heals bladder mucosa to prevent HC progression.
Hyperbaric oxygen therapy is a relatively new treatment for radiation cystitis. Several prospective studies of radiation-induced cystitis treated with HBO13–15 have revealed a beneficial effect on cystitis cases that had been refractory to all previous treatments.
Hyperbaric oxygen therapy elevates the oxygen gradient between the damaged hypoxic urothelium and the normal tissues surrounding it. This stimulates a macrophage invasion, producing macrophage-derived growth factors, such as macrophage-derived angiogenetic factor, which in turn stimulate angiogenesis.16 Hyperbaric oxygen therapy is, therefore, the first available treatment that can potentially modify the disease. Moreover, this mechanism is independent of the effect of mesna, and combined HBO and mesna treatment is thought to be more effective in animal models.17,18
Today HBO is clinically used for carbon monoxide poisoning, acute peripheral circulation failure, caisson sickness, and in the treatment of radiation cystitis and Fourier's Gangrene in the field of urology.19 Recently, it has been reported that the application of HBO was also effective in patients with HC who had undergone bone marrow transplantation and received CPA for immunosuppression.6,20,21
The present case strongly suggests that HBO is the reasonable choice of treatment for patients with intractable CPA-induced HC.