A Bladder Matter: Redefining the Grading System for Pediatric Hemorrhagic Cystitis

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Robey, Michelle Higgins, Mohammad Elmojtaba Gumma, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7567918/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Introduction: Pediatric hemorrhagic cystitis (HC) is a morbid, understudied condition ranging from microscopic hematuria to life-threatening hemorrhage. Existing grading systems, based on adult populations, fail to account for pediatric-specific factors and lack predictive value. This study aimed to identify risk factors for severe HC and propose a modernized, predictive grading scale. Methods: We retrospectively reviewed patients ≤ 18 years with gross hematuria due to HC at our institution (2014–2024). Bladder toxic exposures, treatments, and outcomes were analyzed. Existing grading systems were applied to assess utility. Chi-square, Mann-Whitney, and logistic regression identified predictors of surgical intervention (p < 0.05). Results: Ninety-three patients were included. The strongest predictors of surgical intervention were male sex ( p = 0.023), history of bone marrow transplantation (BMT) ( p = 0.031), busulfan exposure ( p = 0.011), graft versus host disease (GVHD) ( p = 0.027), BK virus ( p = 0.01), AML ( p = 0.043), and clot volume of >/= 10% of estimated bladder capacity (OR 34.8, p < 0.0001). Conclusion: We propose an updated grading system incorporating ultrasound findings to guide management. This revised scale improves risk stratification, guides timely urologic consultation, and standardizes clinical decision-making. Prospective validation is warranted. Figures Figure 1 Introduction Pediatric hemorrhagic cystitis (HC) is a highly morbid yet understudied condition, with incidence rates varying widely. ( 1 ) The severity of HC ranges from microscopic hematuria to life-threatening bladder hemorrhage and is currently graded on a scale of 1–4 with 4 being the most severe of cases. ( 2 ) The existing grading system for HC is largely based on two studies: one from 1982 by Dr. Droller and colleagues, which defined severity for adult patients undergoing a prevention regimen for cyclophosphamide-induced HC, and another from 1986 by Dr. Arthur and colleagues, which described severity in patients with HC secondary to BK virus. ( 3 , 4 ) While these studies provided a critical framework for classifying HC severity within their respective studies, these grades were created for the grouping of their results for internal purposes and not subjected to validation in independent cohorts In addition, these grades did not account for characteristics inherent to pediatric patients—such as limited bladder capacity that predisposes to rapid obstruction from even modest clot burden, or anatomic constraints that often preclude the use of minimally invasive evacuation techniques—both of which may necessitate earlier urologic intervention. More recent research has highlighted the importance of factors like laboratory parameters, bladder toxic chemotherapies, graft-versus-host disease (GVHD), and BK virus positivity in predicting disease severity and the need for surgical intervention. ( 5 , 6 ) The current outdated classification systems fail to incorporate emerging predictors of severity and intervention needs identified in these newer studies. A modernized grading scale that leverages recent findings and predictive analytics can significantly improve early intervention strategies, guide urologic referrals, and reduce invasive procedures in pediatric HC patients. As new insights continue to emerge, grading systems must evolve to reflect the latest evidence, ensuring that clinical practice is aligned with the most accurate and effective risk assessment models. This study aims to identify risk factors predictive of severe disease and redefine grading for hemorrhagic cystitis to facilitate earlier urologic consultation and intervention. Ultimately, our findings will provide a foundation for standardizing care pathways and strengthening multidisciplinary collaboration in the management of pediatric HC. Materials/Methods We performed a retrospective chart review of patients diagnosed with hemorrhagic cystitis (HC) at our institution between 2014 and 2024. The study focused on patients with gross hematuria aged 18 years or younger. Exclusion criteria encompassed individuals with concurrent urinary tract infections, alternate sources of bleeding (i.e. bladder mass, upper tract bleeding), or incomplete data. Comprehensive demographic data were collected, including race, ethnicity, age at HC onset, and primary diagnosis. Relevant medical history, such as prior chemotherapy and/or radiation exposure, BMT status, and exposure to HC-inducing agents, was documented. Clinical data was also collected including Foley catheter use, initiation of continuous bladder irrigation (CBI), usage of intravesical therapies, urology consultations, and surgical interventions. Ultrasounds were reviewed for blood clot and volume was calculated according to the Eq. 0.52 x coronal diameter x sagittal diameter x coronal diameter. To account for age-related variation in bladder capacity, clot burden was expressed as a percentage of estimated bladder capacity (EBC) (EBC = (Age + 2) x 30), with adult capacity defined as 420 mL at age 12. Statistical analysis was performed using XLSTAT (Addinsoft, France). Univariate analyses were performed to identify variables associated with clot formation, with categorical and continuous variables assessed using Chi-square/Fisher’s Exact and Mann–Whitney U tests, respectively. Continuous predictors were dichotomized using Youden’s Index to optimize sensitivity and specificity Results Cohort Characteristics Primary Diagnosis ALL 29 AML 21 Benign Blood Dyscrasia 11 Brain Tumor 1 Ewing’s Sarcoma 4 Lymphoma 6 Neuroblastoma 5 Osteosarcoma 3 Other Autoimmune Disease 4 Rhabdomyosarcoma 9 Clinical Features of HC Episodes Patient Age at HC Onset, average (years) 12.8 Episode Duration, average (days) 18.3 Number of inpatient urology consults 23 Time to urology consult from onset, average (days) 14.4 Number of patients requiring operative intervention 11 Total number of all operative interventions 13 Time to operative intervention from urology consult, average (days) 4.6 Number of patients requiring nephrostomy tubes 5 Number of patients requiring bladder embolization 3 Ultrasound Findings Average clot volume (% of EBC) 38.4% Average clot size, operative intervention 58% Average clot size, no operative intervention 4% Table 1: Cohort Characteristics Cohort characteristics and clinical parameters of pediatric patients with HC. Abbreviations: ALL = acute lymphocytic leukemia; AML = acute myeloid leukemia; Cr = creatinine; HC = hemorrhagic cystitis; Hct = hematocrit; Hgb = hemoglobin; Plt = platelet; pRBC = packed red blood cells. A total of 93 patients were included in our analysis. Most patients in our cohort were male (60.2%), white (50.5%), and non-Hispanic (69.8%) with an average age of 12.8 years. The most common diagnosis was acute lymphocytic leukemia (ALL) (32%) followed by acute myeloid leukemia (AML) (22.5%). Sixty one percent of patients had undergone BMT, 15% had prior pelvic radiation (pXRT), and 100% had exposure to at least one bladder toxic chemotherapy. A full breakdown of patient characteristics can be found in Table 1. Multiple factors were found to be significantly associated with the need for operative intervention in patients with HC. The presence of measurable clot emerged as the strongest predictor, with affected patients being 34.8 times more likelyto require surgery ( p < 0.0001 ). Clot volume dichotomized using Youden’s Index as above yielding an optimum cut off threshold of 10% of EBC. Additional predictors of operative intervention included male sex ( p = 0.023, OR 2.9 ), platelet nadir ( p = 0.029 ), busulfan exposure ( p = 0.011, OR 3.15 ), history of BMT ( p = 0.031, OR 2.77 ), Graft-versus-Host Disease (GVHD) ( p = 0.027, OR 3.52 ), andBK virus positivity ( p = 0.01, OR 3.37 ). Among disease-specific factors, AML was associated with increased odds of surgical intervention ( p = 0.043, OR 2.58 ). Discussion Given the limitations of the current grading systems, there is a clear need for a grading scale that is both predictive and clinically actionable. A more effective grading criterion would incorporate predictive markers that help differentiate cases that require urgent intervention from those that can be managed conservatively, optimizing resource allocation and treatment outcomes. A Refined Grading System Our study identified organized clot presence on ultrasound as the strongest predictor of operative intervention. The key distinction in this revised system lies in Grade 4 designation, which is no longer assigned retrospectively based on intervention status, but rather prospectively based on ultrasound-confirmed clot presenc e . Although several clinical variables were found to be significantly associated with an increased likelihood of requiring operative intervention, these factors were not incorporated into the final grading scale. While predictive of outcomes, they do not directly capture the physiologic burden or clinical severity of hemorrhagic cystitis in the same way that clot burden does. These predictors may function as important modifiers of risk but lack the capacity to quantify the immediate clinical challenge posed by HC. In contrast, clot volume provides a direct and reproducible measure of disease severity that aligns with the need for intervention. Thus, we prioritized variables with the greatest clarity, objectivity, and applicability at the bedside in constructing a grading system intended to standardize severity assessment and guide management decisions. Based on our findings, we propose a modified grading system that incorporates both clinical presentation and ultrasound findings to improve risk stratification (Figure 1): Grade 1 : Microscopic hematuria Grade 2 : Gross hematuria without clots Grade 3 : Gross hematuria with passage of clots (/=10% on US) By integrating imaging findings into HC severity classification, this new grading scale offers several advantages over existing systems: Predictive Value for Surgical Intervention: The presence and size of an organized clot provide an objective measure that correlates with operative management, allowing for earlier risk stratification. Improved Urologic Referral Strategies: Patients classified as Grade 4 based on this system may benefit from earlier urology involvement, potentially reducing delays in intervention. Standardized Clinical Decision-Making: A refined grading scale may facilitate more consistent communication between oncologists, hematologists, and urologists regarding HC severity and management plans. While our proposed grading system represents an improvement over prior models, further validation is needed in prospective cohorts to confirm its predictive accuracy across diverse patient populations. Additionally, longitudinal studies could assess whether early identification of Grade 4 disease based on ultrasound leads to improved patient outcomes and resource allocation. Future Directions Delayed recognition of clot formation may result in prolonged hematuria, urinary retention, and increased need for invasive interventions. Given the observed role of measurable clot on ultrasound in predicting progression to operative intervention, future research should seek to identify predictive measures for clot formation. Conclusion The current classification systems for pediatric HC lack predictive utility and fail to integrate modern imaging and laboratory-based risk factors. By incorporating organized clot presence and size on ultrasound, our proposed grading scale offers a more clinically meaningful framework for risk stratification. Adoption of this model could streamline urologic referral pathways, enhance decision-making, and ultimately improve patient outcomes in the management of pediatric hemorrhagic cystitis. During the preparation of this work the author(s) used OpenAI (2025, San Francisco, CA) to support grammar editing, clarity improvements. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication. Declarations Ethical Approval This study was conducted in accordance with international, national, and/or institutional guidelines for research reporting, including the Declaration of Helsinki where applicable. Approval was obtained from the Institutional Review Board (IRB) (Approval No. IRB00479060 ). Funding Statement This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors Author Contribution Catherine Robey wrote the main manuscript text and prepared figures 1 and table 3.Michelle Higgins contributed to data collection and analysisMohammad Elmojtabla Gumma contributed to data collection and analysisTanisha Martheswaran contributed to data collection and analysisMing Wang reviewed and edited the main manuscriptKenneth R Cooke reviewed and edited the main manuscriptChad Crigger reviewed and edited the main manuscript and served as senior author to the project References Umeda K, Kato I, Kawaguchi K et al (2018) High incidence of BK virus-associated hemorrhagic cystitis in children after second or third allogeneic hematopoietic stem cell transplantation. Pediatr Transpl 22(4):e13183. 10.1111/petr.13183 Schneidewind L, Neumann T, Kranz J et al (2017) Nationwide survey of BK polyomavirus associated hemorrhagic cystitis in adult allogeneic stem cell transplantation among haematologists and urologists. Ann Hematol 96(5):797–803. 10.1007/s00277-017-2935-8 Droller MJ, Saral R, Santos G (1982) Prevention of cyclophosphamide-induced hemorrhagic cystitis. Urology 20(3):256–258. 10.1016/0090-4295(82)90633-1 Arthur RR, Shah KV, Baust SJ, Santos GW, Saral R (1986) Association of BK viruria with hemorrhagic cystitis in recipients of bone marrow transplants. N Engl J Med 315(4):230–234. 10.1056/NEJM198607243150405 Johnston D, Schurtz E, Tourville E, Jones T, Boemer A, Giel D (2016) Risk Factors Associated with Severity and Outcomes in Pediatric Patients with Hemorrhagic Cystitis. J Urol 195(4 Pt 2):1312–1317. 10.1016/j.juro.2015.11.035 Lunde LE, Dasaraju S, Cao Q et al (2015) Hemorrhagic cystitis after allogeneic hematopoietic cell transplantation: risk factors, graft source and survival. Bone Marrow Transpl 50(11):1432–1437. 10.1038/bmt.2015.162 Pereira M, Rodrigues N, Godinho I et al (2017) Acute kidney injury in patients with severe sepsis or septic shock: a comparison between the 'Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease' (RIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease: Improving Global Outcomes (KDIGO) classifications. Clin Kidney J 10(3):332–340. 10.1093/ckj/sfw107 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 16 Mar, 2026 Reviews received at journal 10 Mar, 2026 Reviewers agreed at journal 09 Feb, 2026 Reviews received at journal 28 Dec, 2025 Reviews received at journal 04 Dec, 2025 Reviewers agreed at journal 18 Nov, 2025 Reviewers agreed at journal 15 Nov, 2025 Reviewers invited by journal 16 Sep, 2025 Editor assigned by journal 11 Sep, 2025 Submission checks completed at journal 10 Sep, 2025 First submitted to journal 08 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) The severity of HC ranges from microscopic hematuria to life-threatening bladder hemorrhage and is currently graded on a scale of 1\u0026ndash;4 with 4 being the most severe of cases. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) The existing grading system for HC is largely based on two studies: one from 1982 by Dr. Droller and colleagues, which defined severity for adult patients undergoing a prevention regimen for cyclophosphamide-induced HC, and another from 1986 by Dr. Arthur and colleagues, which described severity in patients with HC secondary to BK virus. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) While these studies provided a critical framework for classifying HC severity within their respective studies, these grades were created for the grouping of their results for internal purposes and not subjected to validation in independent cohorts\u003c/p\u003e\u003cp\u003eIn addition, these grades did not account for characteristics inherent to pediatric patients\u0026mdash;such as limited bladder capacity that predisposes to rapid obstruction from even modest clot burden, or anatomic constraints that often preclude the use of minimally invasive evacuation techniques\u0026mdash;both of which may necessitate earlier urologic intervention.\u003c/p\u003e\u003cp\u003eMore recent research has highlighted the importance of factors like laboratory parameters, bladder toxic chemotherapies, graft-versus-host disease (GVHD), and BK virus positivity in predicting disease severity and the need for surgical intervention. (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) The current outdated classification systems fail to incorporate emerging predictors of severity and intervention needs identified in these newer studies. A modernized grading scale that leverages recent findings and predictive analytics can significantly improve early intervention strategies, guide urologic referrals, and reduce invasive procedures in pediatric HC patients. As new insights continue to emerge, grading systems must evolve to reflect the latest evidence, ensuring that clinical practice is aligned with the most accurate and effective risk assessment models.\u003c/p\u003e\u003cp\u003eThis study aims to identify risk factors predictive of severe disease and redefine grading for hemorrhagic cystitis to facilitate earlier urologic consultation and intervention. Ultimately, our findings will provide a foundation for standardizing care pathways and strengthening multidisciplinary collaboration in the management of pediatric HC.\u003c/p\u003e"},{"header":"Materials/Methods","content":"\u003cp\u003eWe performed a retrospective chart review of patients diagnosed with hemorrhagic cystitis (HC) at our institution between 2014 and 2024. The study focused on patients with gross hematuria aged 18 years or younger. Exclusion criteria encompassed individuals with concurrent urinary tract infections, alternate sources of bleeding (i.e. bladder mass, upper tract bleeding), or incomplete data.\u003c/p\u003e\u003cp\u003eComprehensive demographic data were collected, including race, ethnicity, age at HC onset, and primary diagnosis. Relevant medical history, such as prior chemotherapy and/or radiation exposure, BMT status, and exposure to HC-inducing agents, was documented. Clinical data was also collected including Foley catheter use, initiation of continuous bladder irrigation (CBI), usage of intravesical therapies, urology consultations, and surgical interventions. Ultrasounds were reviewed for blood clot and volume was calculated according to the Eq.\u0026nbsp;0.52 x coronal diameter x sagittal diameter x coronal diameter. To account for age-related variation in bladder capacity, clot burden was expressed as a percentage of estimated bladder capacity (EBC) (EBC = (Age\u0026thinsp;+\u0026thinsp;2) x 30), with adult capacity defined as 420 mL at age 12.\u003c/p\u003e\u003cp\u003eStatistical analysis was performed using XLSTAT (Addinsoft, France). Univariate analyses were performed to identify variables associated with clot formation, with categorical and continuous variables assessed using Chi-square/Fisher\u0026rsquo;s Exact and Mann\u0026ndash;Whitney U tests, respectively. Continuous predictors were dichotomized using Youden\u0026rsquo;s Index to optimize sensitivity and specificity\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eCohort Characteristics\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"416\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary Diagnosis\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eALL\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e29\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAML\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBenign Blood Dyscrasia\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBrain Tumor\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEwing’s Sarcoma\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLymphoma\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNeuroblastoma\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOsteosarcoma\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOther Autoimmune Disease\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRhabdomyosarcoma\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical Features of HC Episodes\u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePatient Age at HC Onset, average (years)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12.8\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEpisode Duration, average (days)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18.3\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNumber of inpatient urology consults\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e23\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTime to urology consult from onset, average (days)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNumber of patients requiring operative intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTotal number of all operative interventions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTime to operative intervention from urology consult, average (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNumber of patients requiring nephrostomy tubes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNumber of patients requiring bladder embolization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUltrasound Findings\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAverage clot volume (% of EBC)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e38.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAverage clot size, operative intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e58%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAverage clot size, no operative intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1: Cohort Characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCohort characteristics and clinical parameters of pediatric patients with HC.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eALL = acute lymphocytic leukemia; AML = acute myeloid leukemia; Cr = creatinine; HC = hemorrhagic cystitis; Hct = hematocrit; Hgb = hemoglobin; Plt = platelet; pRBC = packed red blood cells.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp; A total of 93 patients were included in our analysis. Most patients in our cohort were male (60.2%), white (50.5%), and non-Hispanic (69.8%) with an average age of 12.8 years. The most common diagnosis was acute lymphocytic leukemia (ALL) (32%) followed by acute myeloid leukemia (AML) (22.5%). Sixty one percent of patients had undergone BMT, 15% had prior pelvic radiation (pXRT), and 100% had exposure to at least one bladder toxic chemotherapy. A full breakdown of patient characteristics can be found in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMultiple factors were found to be significantly associated with the need for operative intervention in patients with HC. The presence of measurable clot emerged as the strongest predictor, with affected patients being 34.8 times more likelyto require surgery\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003ep \u0026lt; 0.0001\u003cstrong\u003e).\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClot volume dichotomized using Youden’s Index as above yielding an optimum cut off threshold of 10% of EBC.\u003c/p\u003e\n\u003cp\u003eAdditional predictors of operative intervention included male sex\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003ep = 0.023, OR 2.9\u003cstrong\u003e),\u0026nbsp;\u003c/strong\u003eplatelet nadir\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003ep = 0.029\u003cstrong\u003e),\u0026nbsp;\u003c/strong\u003ebusulfan exposure\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003ep = 0.011, OR 3.15\u003cstrong\u003e),\u0026nbsp;\u003c/strong\u003ehistory of BMT\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003ep = 0.031, OR 2.77\u003cstrong\u003e),\u0026nbsp;\u003c/strong\u003eGraft-versus-Host Disease (GVHD)\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003ep = 0.027, OR 3.52\u003cstrong\u003e),\u0026nbsp;\u003c/strong\u003eandBK virus positivity\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003ep = 0.01, OR 3.37\u003cstrong\u003e).\u003c/strong\u003e Among disease-specific factors, AML was associated with increased odds of surgical intervention\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003ep = 0.043, OR 2.58\u003cstrong\u003e).\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eGiven the limitations of the current grading systems, there is a clear need for a grading scale that is both predictive and clinically actionable. A more effective grading criterion would incorporate predictive markers that help differentiate cases that require urgent intervention from those that can be managed conservatively, optimizing resource allocation and treatment outcomes. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eA Refined Grading System\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study identified organized clot presence on ultrasound as the strongest predictor of operative intervention. The key distinction in this revised system lies in Grade 4 designation, which is no longer assigned retrospectively based on intervention status, but rather prospectively based on ultrasound-confirmed clot presenc\u003cstrong\u003ee\u003c/strong\u003e.\u0026nbsp;Although several clinical variables were found to be significantly associated with an increased likelihood of requiring operative intervention, these factors were not incorporated into the final grading scale. While predictive of outcomes, they do not directly capture the physiologic burden or clinical severity of hemorrhagic cystitis in the same way that clot burden does. These predictors may function as important modifiers of risk but lack the capacity to quantify the immediate clinical challenge posed by HC. In contrast, clot volume provides a direct and reproducible measure of disease severity that aligns with the need for intervention. Thus, we prioritized variables with the greatest clarity, objectivity, and applicability at the bedside in constructing a grading system intended to standardize severity assessment and guide management decisions. Based on our findings, we propose a modified grading system that incorporates both clinical presentation and ultrasound findings to improve risk stratification (Figure 1):\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eGrade 1\u003c/strong\u003e: Microscopic hematuria\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGrade 2\u003c/strong\u003e: Gross hematuria without clots\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGrade 3\u003c/strong\u003e: Gross hematuria with passage of clots (\u0026lt;10% EBC on US)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGrade 4\u003c/strong\u003e: Gross hematuria with passage of clots (\u0026gt;/=10% on US)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eBy integrating imaging findings into HC severity classification, this new grading scale offers several advantages over existing systems:\u0026nbsp;\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003ePredictive Value for Surgical Intervention: The presence and size of an organized clot provide an objective measure that correlates with operative management, allowing for earlier risk stratification.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eImproved Urologic Referral Strategies: Patients classified as Grade 4 based on this system may benefit from earlier urology involvement, potentially reducing delays in intervention.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eStandardized Clinical Decision-Making: A refined grading scale may facilitate more consistent communication between oncologists, hematologists, and urologists regarding HC severity and management plans.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eWhile our proposed grading system represents an improvement over prior models, further validation is needed in prospective cohorts to confirm its predictive accuracy across diverse patient populations. Additionally, longitudinal studies could assess whether early identification of Grade 4 disease based on ultrasound leads to improved patient outcomes and resource allocation. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFuture Directions\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDelayed recognition of clot formation may result in prolonged hematuria, urinary retention, and increased need for invasive interventions. Given the observed role of measurable clot on ultrasound in predicting progression to operative intervention, future research should seek to identify predictive measures for clot formation. \u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe current classification systems for pediatric HC lack predictive utility and fail to integrate modern imaging and laboratory-based risk factors. By incorporating organized clot presence and size on ultrasound, our proposed grading scale offers a more clinically meaningful framework for risk stratification. Adoption of this model could streamline urologic referral pathways, enhance decision-making, and ultimately improve patient outcomes in the management of pediatric hemorrhagic cystitis.\u003c/p\u003e\u003cp\u003eDuring the preparation of this work the author(s) used OpenAI (2025, San Francisco, CA) to support grammar editing, clarity improvements. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eEthical Approval\u003c/h2\u003e\u003cp\u003e This study was conducted in accordance with international, national, and/or institutional guidelines for research reporting, including the Declaration of Helsinki where applicable. Approval was obtained from the Institutional Review Board (IRB) (Approval No. \u003cem\u003eIRB00479060\u003c/em\u003e).\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding Statement\u003c/h2\u003e\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eCatherine Robey wrote the main manuscript text and prepared figures 1 and table 3.Michelle Higgins contributed to data collection and analysisMohammad Elmojtabla Gumma contributed to data collection and analysisTanisha Martheswaran contributed to data collection and analysisMing Wang reviewed and edited the main manuscriptKenneth R Cooke reviewed and edited the main manuscriptChad Crigger reviewed and edited the main manuscript and served as senior author to the project\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eUmeda K, Kato I, Kawaguchi K et al (2018) High incidence of BK virus-associated hemorrhagic cystitis in children after second or third allogeneic hematopoietic stem cell transplantation. Pediatr Transpl 22(4):e13183. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/petr.13183\u003c/span\u003e\u003cspan address=\"10.1111/petr.13183\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchneidewind L, Neumann T, Kranz J et al (2017) Nationwide survey of BK polyomavirus associated hemorrhagic cystitis in adult allogeneic stem cell transplantation among haematologists and urologists. Ann Hematol 96(5):797\u0026ndash;803. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00277-017-2935-8\u003c/span\u003e\u003cspan address=\"10.1007/s00277-017-2935-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDroller MJ, Saral R, Santos G (1982) Prevention of cyclophosphamide-induced hemorrhagic cystitis. 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J Urol 195(4 Pt 2):1312\u0026ndash;1317. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.juro.2015.11.035\u003c/span\u003e\u003cspan address=\"10.1016/j.juro.2015.11.035\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLunde LE, Dasaraju S, Cao Q et al (2015) Hemorrhagic cystitis after allogeneic hematopoietic cell transplantation: risk factors, graft source and survival. Bone Marrow Transpl 50(11):1432\u0026ndash;1437. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/bmt.2015.162\u003c/span\u003e\u003cspan address=\"10.1038/bmt.2015.162\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePereira M, Rodrigues N, Godinho I et al (2017) Acute kidney injury in patients with severe sepsis or septic shock: a comparison between the 'Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease' (RIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease: Improving Global Outcomes (KDIGO) classifications. Clin Kidney J 10(3):332\u0026ndash;340. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ckj/sfw107\u003c/span\u003e\u003cspan address=\"10.1093/ckj/sfw107\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjur","sideBox":"Learn more about [World Journal of Urology](https://link.springer.com/journal/345)","snPcode":"345","submissionUrl":"https://submission.nature.com/new-submission/345/3","title":"World Journal of Urology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7567918/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7567918/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e\u003cp\u003ePediatric hemorrhagic cystitis (HC) is a morbid, understudied condition ranging from microscopic hematuria to life-threatening hemorrhage. Existing grading systems, based on adult populations, fail to account for pediatric-specific factors and lack predictive value. This study aimed to identify risk factors for severe HC and propose a modernized, predictive grading scale.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e\u003cp\u003eWe retrospectively reviewed patients\u0026thinsp;\u0026le;\u0026thinsp;18 years with gross hematuria due to HC at our institution (2014\u0026ndash;2024). Bladder toxic exposures, treatments, and outcomes were analyzed. Existing grading systems were applied to assess utility. Chi-square, Mann-Whitney, and logistic regression identified predictors of surgical intervention (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e\u003cp\u003eNinety-three patients were included. The strongest predictors of surgical intervention were male sex (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023), history of bone marrow transplantation (BMT) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031), busulfan exposure (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011), graft versus host disease (GVHD) (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.027), BK virus (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01), AML (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043), and clot volume of \u0026gt;/= 10% of estimated bladder capacity (OR 34.8, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e\u003cp\u003e We propose an updated grading system incorporating ultrasound findings to guide management. This revised scale improves risk stratification, guides timely urologic consultation, and standardizes clinical decision-making. Prospective validation is warranted.\u003c/p\u003e","manuscriptTitle":"A Bladder Matter: Redefining the Grading System for Pediatric Hemorrhagic Cystitis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-26 10:46:45","doi":"10.21203/rs.3.rs-7567918/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-16T09:12:40+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-10T05:21:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"301182602761317192411039455837351956328","date":"2026-02-09T14:11:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-28T17:48:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-04T18:14:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223249976413050002258626532928477135112","date":"2025-11-18T17:12:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"117784874720419759465558279251224456190","date":"2025-11-15T17:23:10+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-16T13:56:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-11T05:15:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-10T17:46:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"World Journal of Urology","date":"2025-09-08T23:51:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjur","sideBox":"Learn more about [World Journal of Urology](https://link.springer.com/journal/345)","snPcode":"345","submissionUrl":"https://submission.nature.com/new-submission/345/3","title":"World Journal of Urology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ba31be3b-cf0c-4feb-8975-9a2fa63cedb0","owner":[],"postedDate":"September 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-22T17:08:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-26 10:46:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7567918","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7567918","identity":"rs-7567918","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}