Development Of Hemorrhagic Cystitis Research Articles

BK Polyomavirus Diversity After Hematopoietic Stem Cell Transplantation.

BK polyomavirus (BKPyV) infection is common after hematopoietic stem cell transplantation (HSCT) and is associated with the development of hemorrhagic cystitis (HC). The role that BKPyV plays in the pathogenesis of HC is not well characterized. We investigated the impact of BKPyV diversity on the development of HC using a previously established cohort of pediatric HSCT patients. There were 147 urine samples with quantifiable BKPyV at month 1 after HSCT; 137 (93.2%) were amplified using our in-house polymerase chain reaction approach and sent for next-generation sequencing. Subtype Ia was most frequent (61.3%), followed by subtype Ib1 (31.4%). The median viral load of subtype Ia samples was higher than for subtype Ib1 at month 1. Across the protein coding regions, APOBEC-induced mutations and signature patterns associated with HC were identified. This is the largest sequencing study of a single cohort of HSCT patients, providing a vast resource of sequence data for future analyses.

Urotoxicity and safety data of low-dose intravenous cyclophosphamide therapy for rheumatic diseases: A Single-Center retrospective cohort study

Despite its effectiveness in rheumatic diseases, cyclophosphamide (CYC) treatment should be used with caution due to its side effects. CYC is thought to pose a risk in the development of hemorrhagic cystitis and bladder cancer. This study aims to determine the incidence of hemorrhagic cystitis and bladder cancer with intravenous low-dose CYC therapy used in the treatment of rheumatic diseases. A total of 211 adult patients with rheumatic disease treated with intravenous CYC were evaluated in this retrospective study conducted between January 2006 and May 2021. Patient data including cumulative CYC dose, treatment frequency, duration of treatment, side effects, such as hemorrhagic cystitis and bladder cancer were acquired from medical archives. The mean follow-up period was 48.5 (3–180) months, and the mean cumulative CYC dose was 5g (2–19g). None of the patients received mesna therapy concurrent with CYC therapy. 11 patients developed hemorrhagic cystitis (5.2%). Hemorrhagic cystitis was found to be statistically significantly associated with the number of CYC cycles (p=0.04). All patients were asymptomatic. No statistically significant difference was observed between hemorrhagic cystitis, treatment duration, and cumulative dose for CYC therapy in rheumatic diseases. Malignancy developed in 12 patients (5.7%) after CYC treatment. Bladder cancer was observed in 1 patient. According to our findings, the only risk factor for hemorrhagic cystitis in patients receiving CYC was the number of CYC cycles. Intravenous CYC regimen did not cause symptomatic hemorrhagic cystitis. Low-dose IV CYC may be safe in terms of serious urotoxic side effects when used at the appropriate dose, duration and frequency.

#94: BK Virus (BKV) Infections in Pediatric Allogeneic Hematopoietic Cell Transplant (Allo-HCT) Patients: A Single-center Experience

Abstract Background BK virus infection in Allo-HCT pediatric patients is associated with the development of hemorrhagic cystitis (HC) leading to increased morbidity and prolonged hospitalization. We described the baseline characteristics, clinical presentation, and outcomes associated with recent BK virus infections at St. Jude Children’s Research Hospital. Methods We identified all pediatric Allo-HCT recipients with a positive blood or urine test for BKV at St. Jude between 2010 and 2018. A retrospective review of the electronic medical records (EMR) was conducted for demographics, signs, and symptoms associated with BKV infection, complications, and outcomes. Descriptive statistics were used to summarize the cohort. Results Of 475 patients who received an Allo-HCT during the study period, 209 (44%) had at least one positive test for BKV. Most were male (60%) and mean age was 12.4 years. BKV was most common in haploidentical transplants (n = 65), followed by match unrelated donor and matched sibling donor. Sixty-seven (32%) had only viruria, 5 (2%) had only viremia, and 137 (66%) had both. Of those with a positive result for BKV, 169 (80%) presented with hematuria or were diagnosed with HC. Urologic interventions were required by 22% of the patients; 40 required continuous bladder irrigation and 9 underwent cystoscopy. Despite having BKV detected in urine and/or blood, 17% had no symptoms. Conclusions A large proportion of Allo-HCT patients developed BKV associated HC. Morbidity associated with HC is important, with 1 in 5 patients requiring urology intervention.

Incidence of hemorrhagic cystitis after cyclophosphamide therapy with or without mesna: A cohort study and comprehensive literature review.

Cyclophosphamide is an alkylating agent associated with significant toxicities, most importantly hemorrhagic cystitis. Many approaches including mesna use were established to reduce this toxicity. However, data on mesna efficacy are conflicting. To investigate the incidence of hemorrhagic cystitis in patients receiving cyclophosphamide therapy with or without mesna. A retrospective chart review was done on all adult patients receiving cyclophosphamide therapy with or without mesna at the King Saud University Medical City. The incidence of hemorrhagic cystitis was recorded. Patients receiving mesna were compared with those not receiving mesna. Data were reported as numbers and percentages, and appropriate statistical tests of association were used. This step was followed by a comprehensive literature review using appropriate keywords in PubMed from the inception of the database until August 2019. All studies of interest were reported. A total of 718 patients' medical records were reviewed. The majority of the patients received mesna (n = 433, 60%). The mesna group had a greater incidence of hemorrhagic cystitis (3.5% vs. 0.4%, p < 0.004) and received a significantly larger cumulative dose (3103 ± 1696 vs. 2465 ± 1528, p < 0.001) mg of cyclophosphamide therapy. Our literature review revealed large differences in the conclusions of published trials with highly diverse study designs and populations, emphasizing on the need of large prospective trials to address this topic.Conclusion and relevance: Our study results do not support the use of mesna in preventing hemorrhagic cystitis. We found that the only influential factor in the development of hemorrhagic cystitis was the dose of cyclophosphamide therapy.

Effect of Cyclophosphamide on Hemorrhagic Cystitis Following Haploidentical Related Compared to Matched Related/Unrelated Donor Hematopoietic Stem Cell Transplantation: A 7-Year Tertiary Center Analysis

Introduction: Hemorrhagic cystitis (HC) is a serious and common complication of hematopoietic cell transplantation (HCT) affecting both allogeneic (alloHCT) and haploidentical HCT recipients. Early urinary bleeding after transplant is usually attributed to toxic effects of cyclophosphamide (Cy) or other agents used in the conditioning regimen or for graft-versus-host disease (GVHD) prevention. HC occurring beyond 3 to 4 weeks after HCT is usually attributed to BK polyoma virus or other viruses, e.g. cytomegalovirus or adenovirus. The aims of this study were to determine the incidence, risk factors, severity, morbidity pattern and toxicity of treatment, and outcome of HC in recipients of HSCT at a single tertiary transplant center. Methods: We analyzed all patients undergoing haploidentical (haploHCT) or MRD/MUD alloHCT at our bone marrow transplant unit from September 2012 through June 2019. In alloHCT group, 70% (n=205) of the patients received myeloablative conditioning consisted of Cy and only six patients (2%) received identical GVHD prevention with a post-transplant Cy-based regimen. Conversely; in haploHCT group, use of Cy-containing preparative regimen was not often (22.9 % (n=8)) but 77.1% (n=27) of the patients received post-transplant Cy. Grading of HC was based on the system used by Droller et al. and classified as grade I if the hematuria was microscopic and grade II if macroscopic. The presence of clots in the urine was regarded as grade III and obstructive uropathy with or without renal impairment as grade IV HC, respectively. All patients with a clinical diagnosis of HC had urine and blood analyzed for presence of BK virus by PCR. Results: A total of 328 HSCTs were performed during the study period, of which 169 (51.5%) alloHSCT from MUD, 124 (37.8%) alloHCT from MRD and 35 (10.7%) haploHCT. Baseline characteristics of the patients were similar among two groups with regarding to age, diagnosis, disease status and intensity of conditioning (Table 1). Hemorrhagic cystitis was diagnosed in 78 of 328 patients (23.8%) with a median follow up 7.4 months. Disease status at transplant, recipient age, cytomegalovirus antigenemia and the intensity of conditioning regimen were not associated with the development of HC. In addition, use of bone marrow versus peripheral blood had no influence on development of hemorrhagic cystitis (p=0.16). The incidence of HC was significantly higher in patients who received grafts from haploidentical donors compared to those receiving grafts from MRD/MUDs (54.3% (n=19) vs 20.1% (n=59), p&lt;0.001). Interestingly, the incidence of Grade III-IV HC was higher in the alloHCT compared to the haploHCT groups (37.2% vs 2.1%, p&lt;0.001). In multivariate analysis of risk factors associated with HC, receiving conditioning regimen including Cy and the use of a haploidentical donor was not significantly associated with HC. The incidence HC with BK viruria at the time of diagnosis of HC was higher in the cohort of patients receiving grafts from MRD/MUD donors (61% vs 47%, p=0.04). and BK viruria was not associated with HC severity. We identified no significant association between adenovirus, HHV-6 or CMV in HC patients comparing the onset and resolution of HC. Neither HC nor grades III-IV HC was associated with overall survival. Conclusion: Conditioning regimen is an important factor in the development of HC and its mechanism has been well described. In our study, we could not demonstrate the increased HC risk of conditioning regimens including cyclophosphamide. We also showed that cyclophosphamide in MAC had similar HC risk compared with RIC containing cyclophosphamide. BK virus was frequently found to be a risk factor for HC. In this retrospective analysis, BK virus was detected 45 patients out of 78 patients with HC and BK viruria was not associated with HC severity. Table 1 Disclosures Özcan: Amgen: Honoraria, Other: Travel support; Novartis: Research Funding; Celgene Corporation: Research Funding, Travel support; MSD: Research Funding; AbbVie: Other: Travel support, Research Funding; Jazz: Other: Travel support; Janssen: Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; Archigen: Research Funding; Roche: Other: Travel support, Research Funding; Bayer: Research Funding; Sanofi: Other: Travel support; Abdi Ibrahim: Other: Travel support; BMS: Other: Travel support. Beksac:Celgene: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Incidence and Morbidity of Radiation-Induced Hemorrhagic Cystitis in Prostate Cancer

OBJECTIVETo determine if reported incidence rates of hemorrhagic cystitis after radiation therapy for prostate cancer are accurate, to investigate the effect of different radiation modalities on the development of hemorrhagic cystitis and to assess its morbidity and treatment. MATERIALS AND METHODSA retrospective chart review was completed of 709 patients at 2 Detroit Medical Center hospitals who underwent radiation therapy for prostate cancer between January 2000 and September 2015. In patients who developed hemorrhagic cystitis, we analyzed the incidence, radiation modality, morbidity, treatment, and complications. RESULTSThe incidence rate of hemorrhagic cystitis after radiation for prostate cancer was 11.1%. There was no significant difference between external beam and intensity-modulated radiation therapy and the development of hemorrhagic cystitis (P = .18). Patients developed hemorrhagic cystitis an average of 79.1 months (4-230 months) after radiation. The average number of admissions was 2.5 (1-9) with an average length of stay of 7.6 days (1-42 days). Fifty-two percent of patients required blood transfusion with an average of 4.3 units transfused per patient (1-33U). The most common treatment was cystoscopy with fulguration/clot evacuation in 86% of patients. Complications included urinary tract infection, acute kidney injury, urosepsis, and even death. CONCLUSIONThe incidence of hemorrhagic cystitis following radiation therapy for prostate cancer is under-reported in the literature. Hemorrhagic cystitis is associated with high morbidity and complications for patients, requiring multiple hospitalizations, blood transfusions, and procedures. Advances in radiation have not significantly reduced the risk of developing hemorrhagic cystitis.

Sulfated glycosaminoglycans in bladder tissue and urine of rats after acute exposure to paraoxon and cyclophosphamide

Glycosaminoglycans (GAGs) in the urine of Wistar rats, and on the surface of the epithelium and lamina propria of the bladder, were quantitatively assessed before and after acute intoxication with paraoxon or cyclophosphamide. Paraoxon was administered subcutaneously (s.c.) twice with an interval of 1h to a final dose of 275mg/kg; cyclophosphamide was administered intraperitoneally (i.p.) with a single dose of 100mg/kg or to a final dose of 240mg/kg (three times per 80mg/kg every 12h). GAGs on the surface of the epithelium and lamina propria of the urinary bladder of rats were quantitatively determined by Alcian blue dye staining. GAGs in the urine were determined spectrophotometrically with 1-9-dimethyl methylene blue. By 48–96h after intoxication with either paraoxon or cyclophosphamide, statistically significant increases in the concentration of GAGs were obtained both for the tissues of the bladder and the urine of rats. Cyclophosphamide, in contrast to paraoxon, caused the development of hemorrhagic cystitis in the animals. The synthesis of GAGs is considered to be compensatory response to the toxic xenobiotics.

Hemorrhagic cystitis in children treated with alkylating agent cyclophosphamide: The experience of a medical center in Taiwan

Hemorrhagic cystitis is a common complication with chemotherapeutic alkylating agents. We investigated the possible prognostic factors of cyclophosphamide-induced hemorrhagic cystitis in children. Medical records of children (< 18 years old) with cyclophosphamide-related hemorrhagic cystitis were collected retrospectively from January 2000 to December 2010 in a tertiary care center. We also prospectively enrolled children (< 18 years old) with cyclophosphamide treatment. The retrospective study consisted of 23 patients whose median age was 11 years. The median day of onset time was 1 day after cyclophosphamide usage. The hemato-oncological diseases included acute leukemia (39.1%), lymphoma (13%), blastoma (13%), sarcoma (13%), aplastic anemia (13%), and others (8.7%). Patients who received bone marrow transplantation (BMT) had significantly longer duration of hemorrhagic cystitis than those who did not receive BMT (p < 0.05). Serum uric acid, checked prior to and after the onset of hemorrhage cystitis, was significantly lower after the development of hemorrhagic cystitis (p < 0.05). In the prospective study, 11 children were enrolled with a median age of 5 years. The urinary nitrite/nitrate and 8-iso-prostaglandin F2α levels increased significantly after cyclophosphamide usage (p < 0.05). Alteration serum uric acid level and BMT could be indicators for severe hemorrhagic cystitis. The elevated levels of urinary nitrite/nitrate and 8-iso-prostaglandin F2α may indicate the essential roles played by nitric oxide syntheses and reactive oxidative stress in cyclophosphamide-induced hemorrhagic cystitis. These findings may help clinicians formulate a better strategy for treating cyclophosphamide-induced hemorrhagic cystitis.

BK-virus-associated Hemorrhagic Cystitis in Children After Hematopoietic Stem Cell Transplantation

BK-virus-induced hemorrhagic cystitis (BK-HC) is a serious complication in children undergoing hematopoietic stem cell transplantation (HSCT). Data of BK-HC in children undergoing HSCT are still limited. To describe the epidemiology, clinical course, and outcome of children with BK-HC after HSCT. The medical records of all children aged 0 to 20 years, who underwent HSCT at Schneider Children's Medical Center between 2000 and 2008 and were diagnosed with BK-HC, were reviewed for demographic, clinical, and microbiological data. Patients in whom BK-HC had developed were compared with patients in whom it did not. Seventeen children (5.3%) acquired BK-HC at 10 to 180 days after HSCT (mean, 57 d); 9 had grade 3 to 4 disease. Bleeding lasted for 4 to 42 days (mean, 14). All patients but 1, who died of unrelated causes, recovered. Follow-up ranged from 6 to 91 months (mean, 35 months). Acute myeloid leukemia, use of cyclophosphamide in the conditioning regimen, unrelated donor, and older age were associated with the development of hemorrhagic cystitis (HC). The incidence of BK-HC in children after HSCT is relatively low. Its rate of successful resolution is very high. Further prospective studies are required to determine optimal therapy.

Polyomavirus BK-specific CD8+ T cell responses in patients after allogeneic stem cell transplant

Polyomavirus BK (BKV) is known as an important etiologic agent in the development of hemorrhagic cystitis (HC) after allogeneic stem cell transplant (SCT). To define T cell epitopes of the BKV proteins VP1 and sT, eight potential HLA-A2-binding peptides were synthesized based on computer algorithms. These peptides were co-incubated with CD8 + T cells from the peripheral blood (PB) of 25 healthy volunteers and seven patients suffering from HC after allogeneic SCT in a mixed-lymphocyte peptide culture (MLPC), which were subsequently screened by enzyme-linked immunospot (ELISPOT) assays and fluorescence-activated cell sorting (FACS) analysis. We found that CD8 + T cells from five of seven (71%) patients with HC presensitized with the BKV peptide VP1 p108 (LLMWEAVTV) specifically recognized T2 cells pulsed with VP1 p108. In contrast, only seven of 25 (28%) healthy volunteers had CD8 + T cells reactive with VP1 p108-pulsed T2 cells. The presence of VP1 p108-specific T cells could be confirmed by FACS analysis. The BKV peptide VP1 p108 seems to play an important role as an immunodominant peptide in the pathogenesis of HC in patients after allogeneic SCT, and might be a promising target for immunotherapies or even strategies to prevent the development of BKV-associated HC.

Adenovirus‐associated hemorrhagic cystitis in a pediatric renal transplant recipient

Adenovirus infection has been associated with the development of hemorrhagic cystitis in bone marrow transplant recipients. However, limited information exists regarding adenovirus-associated hemorrhagic cystitis in solid organ transplantation, especially in renal transplant recipients. In most cases, the disease is self-limited. However, some patients may have a protracted course. Although no particular antiviral agent has been identified as the gold standard of therapy, cidofovir has been found to be effective in a number of bone marrow transplant recipients. In this study, we report a five-yr-old boy who presented with adenovirus-associated hemorrhagic cystitis 68 days after renal transplant and was successfully treated with reduction of immunosuppression and an intermediate dose of intravenous cidofovir.

DETECTION OF BK VIRUS AND ADENOVIRUS IN THE URINE FROM CHILDREN AFTER ALLOGENEIC STEM CELL TRANSPLANTATION

The development of hemorrhagic cystitis (HC) and urinary excretion of polyoma BK virus (BKV) and adenovirus (ADV) was investigated by polymerase chain reaction in 20 children undergoing allogeneic stem cell transplantation. Five children developed HC, and all of them excreted BKV; however, only 1 excreted ADV, suggesting that BKV is more significant cause of HC than ADV in children undergoing stem cell transplantation.

Cistitis hemorrágica por poliomavirus bk y jc en pacientes sometidos a trasplante de médula ósea: aspectos clínicos y manejo urológico

IntroductionDifferential diagnosis of hematuria after bone marrow transplantation (B.M.T.) may include polyomavirus (BK and JC)-associated haemorrhagic cystitis. Many reports have implied BK virus as the major pathogen in the development of haemorrhagic cystitis after BMT. BK viruria is also associated with ureteric stenosis in renal allografts recipients. Viral urinary tract infections are uncommon in healthy individuals, but we can find them frequently in patients under immunosuppressive conditions. Material and methodsRetrospective study of 123 consecutive B.M.T. recipients in the period from 1995 to 2000, evaluating those with polyomavirus-associated haemorrhagic cystitis. We present patient´s characteristics, primary disease, clinical features, diagnosis aspects and treatment of these “hidden hosts of urinary tract”. Results7 patients (5.7% of B.M.T.) developed BK or JC virus-associated haemorhagic cystitis; 3 men and 4 women; median patient age was 29 years (range 14 to 45 years). Bacterial, mycobacterial and parasitic urine cultives had negative results in all of them. The clinical course was characterized by a late onset of haemorrhagic cystitis (days +30 to +132 after BMT). All 7 patients developed macroscopic haematuria (duration 3 to 30 days). In 6 cases Graft Versus Host Disease (G.V.H.D.) criteria were found. Ultrasonographic studies revealed diffuse thickening of bladder wall in 5 patients. Hematuria was managed by hyperhidratation, blood transfusions, transurethral catheter and evacuation of blood clots, continuous bladder irrigation, urine alkalinization and antiviral therapy. No other more aggressive measures were required to stop the bledding. Only 1 case of transient elevated creatinine. ConclusionsPolyomavirus-associated haemorrhagic cystitis must be considered in differential diagnosis of hematuria in bone marrow transplantation recipients. Urological management, according with the severity and duration of hematuria, is frequently required.

Clinical course and treatment of haemorrhagic cystitis associated with BK type of human polyomavirus in nine paediatric recipients of allogeneic bone marrow transplants.

Of a total of 117 bone marrow transplant (BMT) recipients in the period from August 1988 to November 1995, 9 (7.7%) developed haemorrhagic cystitis. This condition was characterized in all nine patients by late onset (day +24 to +50 post-BMT), long duration (1 to 7 weeks), and the excretion of BK virus in the urine, as confirmed by electron microscopy, DNA hybridization and PCR analysis. Adenovirus was not involved. The serological assessment of BK virus-specific IgM and IgG pre- and post-BMT is consistent with viral reactivation in all patients, although a primary infection cannot be absolutely excluded in a single patient. A significant correlation between the use of high-dose busulphan (16 mg/kg) in the preparative regimen and development of haemorrhagic cystitis (P = 0. 0003) was evident. The severe course of the disease in two patients resulted in bladder tamponade; bleeding could not be inhibited with coagulation and laser treatment. Deterioration was prevented by bladder irrigation via a suprapubic catheter. Remission occurred spontaneously in all patients. BK virus induced haemorrhagic cystitis in a paediatric bone marrow transplantation recipients is characterized by late onset, long duration, viral reactivation and correlates to high-dose busulphan. Severe bleeding could not be influenced by surgical intervention.

Dithio-bis-mercaptoethanesulphonate (DIMESNA) does not prevent cellular damage by metabolites of ifosfamide and cyclophosphamide in LLC-PK1 cells.

Ifosfamide (IF) is an alkylating cytostatic with urotoxic (haemorrhagic cystitis) and nephrotoxic (Fanconi syndrome) side effects. Cyclophosphamide (CP), a structural isomer of IF, shows urotoxic but no nephrotoxic side effects. The development of haemorrhagic cystitis during therapy with IF or CP can be prevented by the uroprotective drug sodium-2-mercaptoethanesulphonate (MESNA). However, even in the presence of MESNA, Fanconi syndrome may still develop after therapy with IF. Using the renal tubular cell line LLC-PK1, we investigated whether there is a protective effect of either MESNA or of its major metabolite DIMESNA, in combination with metabolites of IF or CP, on thymidine incorporation, uridine incorporation or total protein. DIMESNA, the dimer of MESNA, is the dominant form of the molecule in the circulation; the proximal tubular cell must convert this back to MESNA at the expense of glutathione, before it can exert its uroprotective action. We did not find a protective effect of DIMESNA under any of the experimental conditions tested. LLC-PK1 cells exposed to 3 mmol/l DIMESNA did not convert DIMESNA to MESNA. The toxic effect of the CP metabolite 4-OOH-CP was more pronounced in the presence of DIMESNA than in its absence. MESNA completely prevented the toxic effects of acrolein and of 4-OOH-CP. The toxic effects of 4-OOH-IF and of chloracetaldehyde, two major metabolites of IF, were significantly reduced in the presence of MESNA. However, even at 30-fold molar excess of MESNA over a 4-OOH_IF, thymidine incorporation remained reduced by 40% compared with controls, indicating incomplete protection of tubular cells against metabolites of IF. Similarly, the effect of chloracetaldehyde was not completely reversed by MESNA.(ABSTRACT TRUNCATED AT 250 WORDS)