| Abstract|| |
It is known that high dose cyclophosphamide (cycloph), through its metabolite acrolein can cause hemorrhagic cystitis (HC) which can be a serious and life threatening complication. We decided to perform an analysis of risk factors for the development of HC in patients receiving cycloph as part of their conditioning regimen for bone marrow transplantation (BMT). A total of 45 patients (25 males &. 20 females) underwent BMT as treatment for hematological and malignant diseases. The median age was 12 years (range 2-43). The conditioning regimen was either cycloph 120 mg/kg over two days and total body irradiation 1440 mg/kg over four days, or cycloph 200 mg/kg over four days and Busulfan, 14 mg/kg over four days. The uroprotective measures taken included Mesna 160% of the cycloph dose with fluid hydration (120 ml/m2/hr) over two days. The overall incidence of hematuria was 60% (31% microscopic and 29% gross hematuria) and the median onset was at day three post start of chemotheraphy (range 1-33 days). We found no difference between the two groups (HC or non-HC) in respect of age, conditioning regimen, frequency of bladder emptying and fluid input (p values > 0.05). The only significant difference was in the mean urine output; 3200 ml/m2/day (133 ml/m2/hr) for HC and 3560 ml/m2/day (150 ml/m2/hr) for non HC (p values = 0.02). We advise prolonging the IV fluid hydration to a total of three days and maintaining a high urine output more than 3560 ml/m2 /day (150 ml/m2 /hr) during cycloph administration.
Keywords: Hemorrhagic cystitis, Cyclophosphamide, Bone marrow transplantation.
|How to cite this article:|
Haddadin I. Hemorrhagic Cystitis Following Bone Marrow Transplantation. Saudi J Kidney Dis Transpl 1997;8:429-32
| Introduction|| |
Allogenic bone marrow transplantation (BMT) is being applied as a treatment of choice for many hematological and malignant diseases. The drugs most commonly used inthe conditioning regimen are alkylating agents; cyclophosphamide (cycloph) and busulfan with or without total body irradiation ,, . Hemorrhagic cystitis (HC) is a well known, potentially life threatening, complication of high dose cycloph through its metabolite acrolein. The incidence of HC ranges from 6.5 to 52% even with use of the uroprotective compound 2-mercaptoethane (Mesna), bladder irrigation and hyperhydration regimens , . Many studies have been carried out to compare the use of different regimens in order to decrease or prevent this serious complication , . We performed an analysis of the known risk factors such as the conditioning regimen used, age of the patients, the disease status, the amount of hydration given, the frequency of bladder emptying and the urine output, on the occurrence of HC.
| Patients and Methods|| |
The records of 45 patients who underwent BMT at Bristol Bone Marrow Transplant Unit, U.K. were reviewed during an eight month period from October 1994 to May 1995. The patients included 25 males and 20 females with a median age of 12 years (range 2-43 years). A total of 42 patients received HLA matched or one antigen mismatched unrelated donors, and three received auto-logous BMT. The conditioning regimen was with either high dose cycloph, 120 mg/kg given over two days and fractionated total body irradiation 1440 cGY in eight fractions given over four days or cycloph, 200 mg/kg over four days and busulfan 14 mg/kg over four days. Mesna was given in the dose of 160% of cycloph dose (20% of total Mesna with cycloph over one hour and 80% over the next 23 hours). Fluid hydration therapy was started 12 hours before cycloph administration at a rate of 80 ml/m2 /hr and increased to 120 ml/m2 /hr at four hours before and continued at the same rate until 24 hrs after cycloph administration. As cycloph has an anti-diuretic effect, careful assessment of fluid balance was undertaken. In the event of fluid retention a small dose of i.v. frusemide was given in the first instance. If hematuria was detected, mesna and hydration were continued for a further 48 hours.
The oral and i.v. fluid intake and urine output were recorded by the nursing staff and a dip-stick urinalysis was performed daily on all urine samples collected before, during and after cycloph administration. All patients were asked to report any urinary symptoms, passage of red urine or clots. Also, urinalysis was performed daily and in cases of hematuria, a mid-stream urine specimen was collected for culture and sensitivity. Accurate fluid balance at 0700, 1200, 1600, 2000 hours were calculated and a medical staff was notified if no urine was passed in eight hours.
Grading of Hematuria
The diagnosis of hematuria was established on urinary sediment examination and the degree was assessed according to the number of red blood cells per high power field (RBC/hpf). The grading of hematuria was as follows:
1 10-100(microscopic hematuria)
2 > 100 (gross hematuria)
3 Severe + Clots
| Results|| |
A total of 27 patients developed HC, 16 males and 11 females (ratio 1.45:1) yeilding an overall incidence of 60%. Microscopic hemturia occurred in 31% (RBC/hpf = 10 - 100) and lasted a few days and gross hematuria occurred in 29% (RBC/hpf > 100). Frequent bladder irrigation due to clot formation and obstruction was required in some patients of the latter group. The median onset of HC was at day three after commencing high dose cycloph (range 1-33 days). None of the study patients had thrombocytopenia (mean platelet count at onset was 71 x 109 /L). As in the BMT protocol, all urine samples were sent for bacteriological and virological studies. Cytomegalovirus (CMV) was isolated from one patient when he had hematuria and CMV and polyoma viruses were isolated from seven patients when there was no hematuria. We performed an analysis of several risk factors that predispose to HC. The underlying diseases in the study patients had no statistically significant correlation with the development of hematuria [Figure - 1]. Also, we analyzed other factors such as the use of T-cell depleted marrow, the median age of the patients, CMV status and the conditioning regimens used in both groups. We found no significant difference in these parameters in both study groups [Table - 1]. The frequency of bladder emptying (X) was assessed from the fluid balance sheet and we recorded how many times each patient emptied his bladder during the time of cycloph infusion and hydration. The mean frequency of bladder emptying in the group with HC was 1.97 hours and in the group without HC, was 1.88 hours with the range being 1.15-2.88 hours and 1.23-2.65 hours respectively. The difference between the two groups was not statistically significant (p = 0.3). The total fluid input (oral + i.v.) for HC patients was 3300 ml/m2/day and for the group without HC was 3450 ml/m2 /day during cycloph infusion. There was no significant difference between the two groups (p = 0.1). Frusemide 1 mg/kg i.v. once or twice was given in 11 patients (61%) of no HC group and 15 patients (55%) of the HC group without any statistically significant difference between the two groups. The only significant difference found was in the mean urine output, which was 3200 ml/m2 /day (133 ml/m2/hr) for HC and 3560 ml/m2/day (150 ml/m2/hr) for the no HC group ( p value = 0.02) [Table - 2]. The significance of urine output is also shown in the Box and Whisker plot which shows the range, median, 25 and 75 percentiles in both groups [Figure - 2].
The microscopic hematuria resolved within few days while gross hematuria required more attention and treatment with i.v. hydration and Mesna. The grade three hematuria, which is life-threatening due to severe bleeding and urinary obstruction caused by clot formation, required several days of bladder irrigation, hyperhydration with Mesna and blood transfusion.
| Discussion|| |
In our unit, the majority of BMT are from voluntary unrelated donors, but we also have autologous and peripheral blood stem transplantation. We did not include the third group in our study because high dose cycloph is not used in their conditioning regimens. The distribution of different hernatological and malignant diseases like ALL, AML, NHL, CLL, CGL, solid tumors and aplastic anaemia was nearly equal in the groups with or without HC with no effects of the disease status on the incidence of hematuria. Similar results have been found in many reviews  . The incidence of hematuria would vary according to the conditioning regimen used and the combination of high dose cycloph and busulfan could increase the incidence. However, in our study, this regimen was used in only five patients and we found no significant increase in the incidence of HC. Also, the cycloph + TBI regimen which was used in the majority of both groups had no influence on the development of hematuria; however, we did not test the effect of adding TBI to the regimen on the occurrence of HC. It has been shown that previous bladder irradiation can increase the incidence of hematuria  . The role of previous chemotherapy was not looked at in detail because most of the cases had leukemia and cycloph was not included in their treatment regimens. Another risk factor that was not looked into was graft versus host disease. Although other workers have found that older age has increased incidence of hematuria, our results did not support this  .
The role of several viruses particularly adeno virus type II and BK virus, in inducing HC has been reported in the literature ,, . Thus, viruses can potentiate the occurrence of hematuria in BMT patients, specially the late onset hematuria beyond 2-4 weeks of cycloph administration.
The importance of frequent bladder emptying to shorten the contact time between the toxic metabolites of cycloph and bladder mucosa has been proved  . We found no difference between the mean frequency of bladder emptying in both groups. The toxic metabolites of cycloph can be detected up to 36-48 hr after administration, as shown in several pharmacokinetic studies of the drug , . The protective measures in our conditioning regimen covered only 24 hrs after cycloph infusion. The next 24 hr of cycloph infusion was therefore, left unprotected from the toxic metabolites, which could explain the occurrence of hematuria in the majority of patients at day 3 of commencing cycloph infusion. In our opinion, it is wise to extend the period of hydration with Mesna to cover day 3 of commencing cycloph infusion in order to decrease the incidence of hematuria. Also, ensuring high urine output is essential because the more diluted the urine, the less likely it is to injure the bladder mucosa as a result of toxic metabolites.
In conclusion, to decrease the incidence of HC in BMT recipients we recommend maintaining the urine output above 150ml/m2/hr during cycloph administration and if it falls below this rate to give boluses of fluid. Also, considering the median onset of hematuria of three days from the start of cycloph infusion, it is wise to prolong hydration therapy, along with Mesna, up to a total of 3 to 5 days after the last dose of cycloph.
| Acknowledgement|| |
I would like to thank the team of bone marrow transplant unit at Bristol Royal Hospital for Sick Children for their help during my stay in the unit. I also thank Bob Thorne and Issa Hazin for their statistical advice and help.
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Pediatric Hematologist Oncologist, King Hussein Medical Center, P.O. Box 926119, Amman 11110
[Figure - 1], [Figure - 2]
[Table - 1], [Table - 2]