Abstract
Hemorrhagic cystitis is an inflammatory condition caused by infectious and non-infectious (radiation, drugs) factors. Hematuria is the most important sign. Clinical course ranges from asymptomatic microscopic hematuria to massive bleeding. Fulminating hemorrhagic cystitis is a life-threatening condition. There is a wide variety of treatments like saline irrigation, intravesical instillation of a great class of drugs, systemic drugs, hyperbaric oxygen therapy, and even surgery (angioembolization, urinary diversion, and cystectomy). The main purpose of this article is to review etiology and treatment options available for HC, focusing latest updates and tendencies.
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Elliott SP, Malaeb BS. Long-term urinary adverse effects of pelvic radiotherapy. World J Urol. 2011;29(1):35–41. Epidemiologic review of pelvic radiotherapy and its consequences grouping many kind of pelvic malignancies.
Alesawi AM, El-Hakim A, Zorn KC, Saad F. Radiation-induced hemorrhagic cystitis. Curr Opin Support Palliat Care. 2014;8(3):235–40.
Smit SG, Heyns CF. Management of radiation cystitis. Nat Rev Urol. 2010;7(4):206–14.
Linder BJ, Tarrell RF, Boorjian SA. Cystectomy for refractory hemorrhagic cystitis: contemporary etiology, presentation and outcomes. J Urol. 2014;192(6):1687–92. The largest and latest series of cystectomy for hemorrhagic cystitis.
Pode D, Perlberg S, Steiner D. Busulfan-induced hemorrhagic cystitis. J Urol. 1983;130(2):347–8.
Islam R, Isaacson BJ, Zickerman PM, Ratanawong C, Tipping SJ. Hemorrhagic cystitis as an unexpected adverse reaction to temozolomide: case report. Am J Clin Oncol. 2002;25(5):513–4.
Mohammadianpanah M, Shirazi M, Mosalaei A, Omidvari S, Ahmadloo N. Hemorrhagic cystitis in a patient receiving conventional doses of dacarbazine for metastatic malignant melanoma: case report and review of the literature. Clin Ther. 2007;29(6):1161–5.
Kim MK, Kang CK, Kim MJ, Jun KI, Lee YK, Jeong SJ, et al. Penicillin G-induced hemorrhagic cystitis: a case and review of the literature. Korean J Intern Med. 2013;28(6):743–5.
Martinez-Suarez HJ, Wang R, Faerber GJ. Atorvastatin-induced hemorrhagic cystitis: a case report. Urology. 2009;73(3):681.e5–6.
Arnold H, Bourseaux F, Brock N. Chemotherapeutic action of a cyclic nitrogen mustard phosphamide ester (B 518-ASTA) in experimental tumours of the rat. Nature. 1958;181(4613):931.
Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol. 2009;6(11):638–47.
Cox PJ. Cyclophosphamide cystitis—identification of acrolein as the causative agent. Biochem Pharmacol. 1979;28(13):2045–9.
Korkmaz A, Topal T, Oter S. Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation. Cell Biol Toxicol. 2007;23(5):303–12.
Monach PA, Arnold LM, Merkel PA. Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: a data-driven review. Arthritis Rheum. 2010 Jan;62(1):9–21. Erratum in: Arthritis Rheum. 2010;62(8):2555. Dosage error in article text.
Le Guenno G, Mahr A, Pagnoux C, Dhote R, Guillevin L. French Vasculitis Study Group. Incidence and predictors of urotoxic adverse events in cyclophosphamide-treated patients with systemic necrotizing vasculitides. Arthritis Rheum. 2011;63(5):1435–45.
Tsuboi K, Kishi K, Ohmachi K, et al. Multivariate analysis of risk factors for hemorrhagic cystitis after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003;32:903–7.
Gonella S, di Pasquale T, Palese A. Preventive measures for cyclophosphamide-related hemorrhagic cystitis in blood and bone marrow transplantation: an Italian multicenter retrospective study. Clin J Oncol Nurs. 2015;19(1):E8–14. New retrospective study showing prevalency efficacy of preventive measures after BMT.
Droller MJ, Saral R, Santos G. Prevention of cyclophosphamide-induced hemorrhagic cystitis. Urology. 1982;20:256–8.
Turkeri LN, Lum LG, Uberti JP, et al. Prevention of hemorrhagic cystitis following allogeneic bone marrow transplant preparative regimens with cyclophosphamide and busulfan: Role of continuous bladder irrigation. J Urol. 1995;153:637–40.
Hadjibabaie M, Alimoghaddam K, Shamshiri AR, et al. Continuous bladder irrigation prevents hemorrhagic cystitis after allogeneic hematopoietic cell transplantation. Urol Oncol. 2008;26:43–6.
Brock N, Pohl J, Stekar J. Detoxification of urotoxic oxazaphosphorines by sulfhydryl compounds. J Cancer Res Clin Oncol. 1981;100:311–20.
Hows JM, Mehta A, Ward L, et al. Comparison of mesna with forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplantation: a prospective randomised study. Br J Cancer. 1984;50:753–6.
Shepherd JD, Pringle LE, Barnett MJ, Klingemann HG, Reece DE, Phillips GL. Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation. J Clin Oncol. 1991;9:2016–20.
Cesaro S, Hirsch HH, Faraci M, Owoc-Lempach J, Beltrame A, Tendas A, et al. Cidofovir for BK virus-associated hemorrhagic cystitis: a retrospective study. Clin Infect Dis. 2009;49(2):233–40.
Leung AY, Yuen KY, Kwong YL. Polyoma BK virus and haemorrhagic cystitis in haematopoietic stem cell transplantation: a changing paradigm. Bone Marrow Transplant. 2005;36(11):929–37.
Akiyama H, Kurosu T, Sakashita C, et al. Adenovirus is a key pathogen in hemorrhagic cystitis associated with bone marrow transplantation. Clin Infect Dis. 2001;32:1325–30.
Tutuncuoglu SO, Yanovich S, Ozdemirli M. CMV-induced hemorrhagic cystitis as a complication of peripheral blood stem cell transplantation: case report. Bone Marrow Transplant. 2005;36:265–6.
Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet. 1971;297:1253–7.
Pinto M, Dobson S. BK and JC virus: a review. J Infect. 2014;68 Suppl 1:S2–8.
Cesaro S, Facchin C, Tridello G, et al. A prospective study of BK-virusassociated haemorrhagic cystitis in pediatric patients undergoing allogeneic stem cell transplantation. Bone Marrow Transplant. 2008;41:363–70.
Laskin BL, Denburg M, Furth S, Diorio D, Goebel J, Davies SM, et al. BK viremia precedes hemorrhagic cystitis in children undergoing allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19(8):1175–82. New research confirming the relationship between BK viremia and HC after HSCT.
Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31:1341–6.
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. National Cancer Institute. 2009;4:59–60.
LENT SOMA scales for all anatomic sites. Int J Radiat Oncol Biol Phys. 1995;31:1049–1091.
Suzuki S, Chino A, Fukui I, Hayashi T, Kozuka T, Suganuma T, et al. Successful use of endoscopic argon plasma coagulation for hemorrhagic radiation cystitis: a case report. Jpn J Clin Oncol. 2014;44(7):692–5. Interesting case report evaluating argon plasma coagulation. This is a innovative technique for hemorrhagic cystitis but it is known for actinic proctitis.
Talab SS, McDougal WS, Wu CL, Tabatabaei S. Mucosa-sparing, KTP laser coagulation of submucosal telangiectatic vessels in patients with radiation-induced cystitis: a novel approach. Urology. 2014;84(2):478–83. Innovative technique for hemorrhagic cystitis.
Ravi R. Endoscopic neodymium:YAG laser treatment ofradiation induced haemorrhagic cystitis. Lasers Surg Med. 1994;14:83–7.
Kaplan JR, Wolf Jr JS. Efficacy and survival associated with cystoscopy and clot evacuation for radiation or cyclophosphamide induced hemorrhagic cystitis. J Urol. 2009;181(2):641–6.
Choong SK, Walkden M, Kirby R. The management of intractable haematuria. BJU Int. 2000;86(9):951–9.
Kumar AP, Wrenn Jr EL, Jayalakshmamma B, Conrad L, Quinn P, Cox C. Silver nitrate irrigation to control bladder hemorrhage in children receiving cancer therapy. J Urol. 1976;116:85–6.
Ragavaiah NV, Soloway MS. Anuria following silver nitrate irrigations for intractable bladder hemorrhage. J Urol. 1977;118:681–2.
Fall M, Pettersson S. Ureteral complications after intravesical formalin instillation. J Urol. 1979;122(2):160–2.
Donahue LA, Frank IN. Intravesical formalin for hemorrhagic cystitis: analysis of therapy. J Urol. 1989;141(4):809–12.
Laszlo D, Bosi A, Guidi S, Saccardi R, Vannucchi AM, Lombardini L, et al. Prostaglandin E2 bladder instillation for the treatment of hemorrhagic cystitis after allogeneic bone marrow transplantation. Haematologica. 1995;80(5):421–5.
Nakaseko C, Oh H, Sato H, Cho R, Ishii A, Ikegami T, et al. Prostaglandin E1 bladder instillations for late-onset hemorrhagic cystitis following allogeneic bone marrow transplantation. Rinsho Ketsueki. 1995;36(8):728–34.
Levine LA, Jarrard DF. Treatment of cyclophosphamide-induced hemorrhagic cystitis with intravesical carboprost tromethamine. J Urol. 1993;149(4):719–23.
Singh I, Laungani GB. Intravesical epsilon aminocaproic acid in management of intractable bladder hemorrhage. Urology. 1992;40(3):227–9.
Shao Y, Lu GL, Shen ZJ. Comparison of intravesical hyaluronic acid instillation and hyperbaric oxygen in the treatment of radiation-induced hemorrhagic cystitis. BJU Int. 2012;109(5):691–4. The first comparison between hyaluronic acid and hyperbaric oxygen therapy in HC.
Tirindelli MC, Flammia GP, Bove P, Cerretti R, Cudillo L, De Angelis G, et al. Fibrin glue therapy for severe hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20(10):1612–7. New feasible and effective weapon against refractory HC after HSCT.
Palma PC, Villaca CJ, Netto NR. N-acetylcysteine in the prevention of cyclophosphamide induced haemorrhagic cystitis. Int Surg. 1986;71:36–7.
Czibere A, Bruns I, Graef T, Fenk R, Zohren F, Safaian N, et al. Treatment of severe hemorrhagic cystitis after allogeneic stem cell transplantation with palifermin, a recombinant human keratinocyte growth factor. Biol Blood Marrow Transplant. 2007;13(7):872–4.
Bhaskaran S, Abu-Arja RF, Abusin G, Cabral L, Nagle K, Ahuja S, et al. Recombinant human keratinocyte growth factor: successful treatment of severe, refractory hemorrhagic cystitis after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2014;49(12):1550–1. This article uses concepts of gene therapy, which could represent promising future perspective to the topic.
Wang Y, Chen F, Gu B, Chen G, Chang H, Wu D. Mesenchymal stromal cells as an adjuvant treatment for severe late-onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. Acta Haematol. 2015;133(1):72–7. This article uses concepts of gene therapy, which could represent promising future perspective to the topic.
Vose JM, Reed EC, Pippert GC, et al. Mesna compared with continuous bladder irrigation as uroprotection during high-dose chemotherapy and transplantation: a randomized trial. J Clin Oncol. 1993;11:1306–10.
Pyeritz RE, Droller MJ, Bender WL, Saral R. An approach to the control of massive haemorrhage in cyclophosphamide-induced cystitis by intravenous vasopressin: a case report. J Urol. 1978;120:253–4.
Heath JA, Mishra S, Mitchell S, Waters KD, Tiedemann K. Estrogen as treatment of hemorrhagic cystitis in children and adolescents undergoing bone marrow transplantation. Bone Marrow Transplant. 2006;37(5):523–6.
Liu YK, Harty JI, Steinbock GS, Holt Jr HA, Goldstein DH, Amin M. Treatment of radiation or cyclophosphamide induced hemorrhagic cystitis using conjugatedestrogen. J Urol. 1990;144(1):41–3.
Vance BJ. Hemorrhagic cystitis: failure of estrogen treatment. Urology. 1990;36(6):561.
Rodriguez Luna JM, Teruel JL, Vallejo J, Burgos FJ, Lovaco F, Mayayo T. Control of massive hematuria in idiopathic hemorrhagic cystitis after administration of conjugated estrogen. J Urol. 1992;148(5):1524–5.
Miller J, Burfield GD, Moretti KL. Oral conjugated estrogen therapy for treatment of hemorrhagic cystitis. J Urol. 1994;151(5):1348–50.
Ordemann R, Naumann R, Geissler G, Bornhause RM, Schuler U, Ehninger G. Encouraging results in the treatment of haemorrhagic cystitis with estrogen—report of 10 cases and review of the literature. Bone Marrow Transplant. 2000;25:981–5.
Hassan Z. Management of refractory hemorrhagic cystitis following hematopoietic stem cell transplantation in children. Pediatr Transplant. 2011;15(4):348–61. This is a great review emphasizing pediatric management of HC.
Gaziev J, Paba P, Miano R, Germani S, Sodani P, Bove P, et al. Late-onset hemorrhagic cystitis in children after hematopoietic stem cell transplantation for thalassemia and sickle cell anemia: a prospective evaluation of polyoma (BK) virus infection and treatment with cidofovir. Biol Blood Marrow Transplant. 2010;16(5):662–71.
Savona MR, Newton D, Frame D, Levine JE, Mineishi S, Kail DR. Low-dose cidofovir treatment of BK virus associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant. Bone Marrow Transplant. 2007;39:783–7.
Faraci M, Cuzzubbo D, Lanino E, Di Marco E, Cirillo C, Dallorso S, et al. Low dosage cidofovir without probenecid as treatment for BK virus hamorrhagic cystitis after hemopoietic stem cell transplant. Pediatr Infect Dis J. 2009;28:55–7.
Cesaro S, Pillon M, Tridello G, Aljurf M, Martino R, Schroyens W, et al. Relationship between clinical and BK virological response in patients with late hemorrhagic cystitis treated with cidofovir: a retrospective study from the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2013;48(6):809–13. This retrospective study shows the action of cidofovir agaisnt BK virus, the possible mechanism of reducing HC.
Chen XC, Liu T, Li JJ, He C, Meng WT, Huang R. Efficacy and safety of leflunomide for the treatment of BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients. Acta Haematol. 2013;130(1):52–6. The latest study evaluating the role of leflunamide in HC.
Miller AN, Glode A, Hogan KR, Schaub C, Kramer C, Stuart RK, et al. Efficacy and safety of ciprofloxacin for prophylaxis of polyomavirus BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transplant. 2011;17(8):1176–81. Retrospective study showing a reduced rate of HC in patients who received prophylactic ciprofloxacin.
Toptas T, Kaygusuz-Atagunduz I, Kani HT, Adiguzel C, Firatli-Tuglular T. Levofloxacin for the treatment of severe refractory BK virus-associated hemorrhagic cystitis in hematopoietic stem cell transplantation recipients: a report of three cases. Oncol Lett. 2014;8(4):1775–7.
Haldar S, Dru C, Bhowmick NA. Mechanisms of hemorrhagic cystitis. Am J Clin Exp Urol. 2014;2(3):199–208. Great review of pathophysiology of HC.
Dellis A, Deliveliotis C, Kalentzos V, Vavasis P, Skolarikos A. Is there a role for hyberbaric oxygen as primary treatment for grade IV radiation-induced haemorrhagic cystitis? A prospective pilot-feasibility study and review of literature. Int Braz J Urol. 2014;40(3):296–305. Excelent article. The most complete e meticulous review about hyperbaric oxygen therapy for hemorrhagic cystitis.
Yoshida T, Kawashima A, Ujike T, Uemura M, Nishimura K, Miyoshi S. Hyperbaric oxygen therapy for radiation-induced hemorrhagic cystitis. Int J Urol. 2008;15:639–41.
Neheman A, Nativ O, Moskovitz B, Melamed Y, Stein A. Hyperbaric oxygen therapy for radiation-induced haemorrhagic cystitis. BJU Int. 2005;96:107–9.
Del Pizzo JJ, Chew BH, Jacobs SC, Sklar GN. Treatment of radiation induced hemorrhagic cystitis with hyperbaric oxygen: long-term followup. J Urol. 1998;160:731–3.
Matsuo H, Shinomiya N, Suzuki S. Hyperbaric stress during saturation diving induces lymphocyte subset changes and heat shock protein expression. Undersea Hyperb Med. 2000;27:37.
Gökçe M, Akçay A, Tuğcu D, Erdemir M, Mirasoğlu B. Hyperbaric oxygen therapy for hemorrhagic cystitis. Exp Clin Transplant. 2014;12(3):279–80. Good case report evaluating data about time to improve hematuria after HOT.
Dodds PR, Papowitz AJ. Re: treatment of radiation induced hemorrhagic cystitis with hyperbaric oxygen. J Urol. 2004;171(4):1637. author reply 1637.
Bae SH, Han DK, Baek HJ, Park SJ, Chang NK, Kook H, et al. Selective embolization of the internal iliac arteries for the treatment of intractable hemorrhage in children with malignancies. Korean J Pediatr. 2011;54(4):169–75. This is a recent paper showing the safety and efficacy of selective embolization for controlling acute intractable hemorrhage in pediatric malignancy patients.
McIvor J, Williams G, Southcott RD. Control of severe vesical haemorrhage by therapeutic embolisation. Clin Radiol. 1982;33(5):561–7.
Han Y, Wu D, Sun A, Xie Y, Xu J, Zhou J, et al. Selective embolization of the internal iliac arteries for the treatment of severe hemorrhagic cystitis following hematopoietic SCT. Bone Marrow Transplant. 2008;41(10):881–6.
Liguori G, Amodeo A, Mucelli FP, Patel H, Marco D, Belgrano E, et al. Intractable haematuria: long-term results after selective embolization of the internal iliac arteries. BJU Int. 2010;106(4):500–3. The latest paper confirming the efficacy and safety of embolization in patients with pelvic malignancy, and indicating that this technique should be considered before surgery.
Eigner EB, Freiha FS. The fate of the remaining bladder following supravesical diversion. J Urol. 1990;144:31.
Fazili T, Bhat TR, Masood S, et al. Fate of the leftover bladder after supravesical urinary diversion for benign disease. J Urol. 2006;176:620.
Adeyoju AB, Thornhill J, Lynch T, Grainer R, McDermott R, Butler MR. The fate of the defunctionalized bladder following supravesical urinary diversion. Br J Urol. 1996;78:80.
Koc S, Hagglund H, Ireton RC, et al. Successful treatment of severe hemorrhagic cystitis with cystectomy following matched donor allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2000;26:899.
Stillwell TJ, Benson Jr RC. Cyclophosphamide induced hemorrhagic cystitis. A review of 100 patients. Cancer. 1988;61:451.
Sebe P, Garderet L, Traxer O, Nouri M, Gluckman E, Gattegno B. Subtotal cystectomy with ileocystoplasty for severe hemorrhagic cystitis after bone marrow transplantation. Urology. 2001;57(1):168.
Rowley MW, Clemens JQ, Latini JM, et al. Simple cystectomy: outcomes of a new operative technique. Urology. 2011;78:942–5. This small retrospective case series shows an alternative to conventional cystectomy. This technique can be performed quickly with minimal blood loss and complications.
Linn JF, Hohenfellner M, Roth S, et al. Treatment of interstitial cystitis: comparison of subtrigonal and supratrigonal cystectomy combined with orthotopic bladder substitution. J Urol. 1998;159:774–8.
Peeker R, Aldenborg F, Fall M. The treatment of interstitial cystitis with supratrigonal cystectomy and ileocystoplasty: difference in outcome between classic and nonulcer disease. J Urol. 1998;159:1479–82.
Neulander EZ, Rivera I, Eisenbrown N, et al. Simple cystectomy in patients requiring urinary diversion. J Urol. 2000;164:1169–72.
Osborn DJ, Dmochowski RR, Kaufman MR, Milam DF, Mock S, Reynolds WS. Cystectomy with urinary diversion for benign disease: indications and outcomes. Urology. 2014;83(6):1433–7.
Kumar S, Sharma AP, Bahuguna P. Re: Cystectomy for Refractory Hemorrhagic Cystitis: Contemporary Etiology, Presentation and Outcomes: B. J. Linder, R. F. Tarrell and S. A. Boorjian J Urol 2014;192: 1687–1692. J Urol. 2015;193(6):2153–4. Excelent and critical comment about the largest series of cystectomy in HC.
Alkan I, Jeschke S, Leeb K, Albquami N, Janetschek G. Treatment of radiation-induced hemorrhagic cystitis with laparoscopic cystoprostatectomy. Urol Int. 2006;77(2):190–2.
Fergany AF, Moussa AS, Gill IS. Laparoscopic cystoprostatectomy for radiation-induced hemorrhagic cystitis. J Endourol. 2009;23(2):275–8.
Al Hussein Al Awamlh B, Lee DJ, Nguyen DP, Green DA, Shariat SF, Scherr DS. Assessment of the quality-of-life and functional outcomes in patients undergoing cystectomy and urinary diversion for the management of radiation-induced refractory benign disease. Urology. 2015;85(2):394–400. Important and inedited paper analyzing quality-of-life post-treatment in HC.
Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205–13.
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Juliano Cesar Moro, Eder Silveira Brazão Junior, Cassio Luis Zanettini Riccetto, and Paulo Palma declare that they have no conflict of interest.
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Moro, J.C., Junior, E.S.B., Riccetto, C.L.Z. et al. Fulminating Hemorrhagic Cystitis: New Trends from Etiology to Treatment. Curr Bladder Dysfunct Rep 10, 212–221 (2015). https://doi.org/10.1007/s11884-015-0305-8
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DOI: https://doi.org/10.1007/s11884-015-0305-8