Pediatric hemorrhagic cystitis

Journal of Pediatric Urology (2009) 5, 254e264

REVIEW ARTICLE

Pediatric hemorrhagic cystitis Daniel B. Decker a,*, Jose A. Karam a, Duncan T. Wilcox b a

Children’s Medical Center at Dallas, University of Texas Southwestern Medical Center, Department of Urology, 5323 Harry Hines Boulevard, Dallas, TX 75390-9110, USA b The Children’s Hospital, University of Colorado at Denver, 13123 East 16th Avenue, B463 Aurora, CO 80045, USA Received 6 October 2008; accepted 13 February 2009 Available online 19 March 2009

KEYWORDS Hemorrhagic cystitis; Pediatric; Bone-marrow transplant; BK virus; Cidofovir; Hyperbaric oxygen

Abstract Purpose: To review the current literature as it pertains to hemorrhagic cystitis (HC) in the pediatric bone-marrow transplant (BMT) population. By reviewing the pathophysiology of the disease, preventive methods, and therapeutic options, urologists may be better equipped to manage this challenging clinical scenario. Materials and methods: The HC literature was reviewed using a MEDLINE/PubMed literature search, specifically focusing on the pediatric BMT population as it pertains to the incidence, pathophysiology, prevention, and treatment of HC. Results: Conservative estimates of HC incidence in recent retrospective studies of pediatric BMT populations still approach 10e20%. Several high-volume pediatric BMT centers have reported contemporary data on their experience with HC providing increased insight into incidence and pathophysiology. Accumulating evidence linking BK virus to HC is a significant development warranting further investigation. Other contributing agents/risk factors need identification in the likely multifactorial etiology of HC. Preventive and therapeutic strategies have made modest advances, but certainly need further validation with prospective randomized studies. Conclusions: Pediatric BMT patients are susceptible for HC development despite preventive measures and improved insight into the pathophysiology. Unfortunately, there are no evidence-based treatment guidelines for this difficult clinical issue that frequently requires prolonged care and multiple treatment modalities necessitating judicious patience in the application of more aggressive interventions. ª 2009 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Introduction * Corresponding author. Tel.: þ1 (336) 721 1487; fax: þ1 (214) 648 8786. E-mail addresses: [email protected] (D.B. Decker), jose.karam @UTSouthwestern.edu (J.A. Karam), [email protected] (D.T. Wilcox).

Hemorrhagic cystitis (HC) is a condition of diffuse vesical bleeding that can be one of the most challenging clinical issues for the urologist to manage. With severe HC there are often significant morbidity, prolonged hospitalization and occasional mortality. While the potential causes of HC are

1477-5131/$36 ª 2009 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jpurol.2009.02.199

Pediatric hemorrhagic cystitis numerous, chemotherapeutic agents and radiation account for the majority of cases of severe bladder hemorrhage. Some of the most severe cases of HC have been reported in pediatric populations following bone-marrow transplant (BMT) [1]. With the increasing prevalence of transplantation of allogenic stem cells or bone-marrow, hemorrhagic cystitis is a noteworthy complication particularly in this pediatric population where incidence has been reported in the literature to range from 10% to 70% depending upon definition and grading [2e5]. Furthermore, the potential for life-long sequelae from fibrosis and contracture of the bladder is of great consequence in pediatric populations. As with any complicated disease process, understanding of the pathophysiology underlying HC is the foundation for management strategies. In terms of treatment, it is paramount for a favorable outcome to not only have an adequate knowledge of possible therapeutic options but to also have a judicious approach with timely application and escalation of intervention when necessary. Although this review focuses upon HC in BMT pediatric populations, much of the pathophysiology, preventive strategies and treatment paradigms translate and apply to HC from other causes and in adult populations.

Definition and grading HC is defined as the presence of sustained hematuria and LUTS (lower urinary tract symptoms, e.g. dysuria, frequency, urgency) in the absence of other conditions, such as vaginal bleeding, generalized bleeding diathesis, and bacterial or fungal UTI [2]. In order for clarity, consistency, and standardization within the literature a HC grading system has been proposed by Droller et al. [6] (Table 1).

Pathophysiology Various causative etiologies may directly contribute to the development of hemorrhagic cystitis in pediatric and adult populations. Damage to the bladder transitional epithelium and blood vessels by toxins, drugs, radiation, and viruses/ bacteria may lead to HC. The pediatric oncology patient undergoing BMT may be exposed to all of these factors. Therefore, as previously mentioned, this review will focus upon the often severe (grades IIIeIV) HC in pediatric BMT patients who frequently necessitates urologic intervention. In these patients, the use of alkylating chemotherapeutic agents in conditioning regimens may cause initial damage to the bladder epithelium since the bladder is the end-

Table 1 Grade I Grade II Grade III Grade IV

Grading system for hemorrhagic cystitis. Microscopic hematuria Macroscopic hematuria Macroscopic hematuria with small clots Gross hematuria with clots causing urinary tract obstruction requiring instrumentation for clot evacuation

255 organ in prolonged contact with the toxic substance [2,3,6e8]. Additionally, the total body irradiation dosing for BMT conditioning may have slight direct deleterious effects upon the bladder but more importantly contributes to the overall immunosuppressive state [9]. Ultimately this depleted T-cell state and impaired immune response may facilitate a subsequent cytopathic effect from viral infection or latent reactivation [1,8,10]. An immune reaction against the virus possibly secondary to or exacerbated by graft-versus-host disease (GVHD) may lead to profound damage to the bladder mucosa. The resulting hematuria may be further exacerbated by thrombocytopenia as well as any co-morbidity-related coagulopathy [2,3,8,10,11]. Several published series have reinforced this theoretical framework for the pathophysiology of HC in pediatric BMT populations. Recently in a large retrospective study, Hassan et al. [3] analyzed 834 patients who underwent BMT between 1990 and 2005. All patients in this cohort received mesna (2-mercaptoethane sodium sulfonate), alkalization of the urine, and hyperhydration with forced diuresis for HC prophylaxis. Ultimately 109 patients (13.1%) developed grades IIeIV HC. Busulfan-based conditioning, myeloablative conditioning, and cytomegalovirus (CMV) infection were found to be risk factors for grades IIeIV HC. In multivariate analysis, bacteremia and severe acute GVHD were the significant risk factors for development of severe HC (grades IIIeIV). Severe HC in this cohort had a delayed onset starting on a median of 35 days and a longer duration persisting for a median of 23 days. Of significant prognostic importance, this study found that transplant-related mortality was 21% in patients without HC versus 71% of those with grades IIIeIV HC [3]. In 2003, Hale et al. [1] reported their experience with 245 pediatric BMT patients. In this cohort, 27 (11%) patients developed severe HC with a median duration of 73 days (range: 5e619 days). Of note, 12 patients had ongoing refractory HC at the time of death. This study did confirm a theme that has been noted in other large retrospective series. That is, there is an increased risk of severe HC in unrelated donor grafts likely from the T-cell depletion which can ultimately be reflective of an increased immunocompromised state which might predispose to a cytopathic viral infection (although no testing for polyomaviruses, BK and JC virus, was performed in this cohort) [1]. In another series, Gorczynska et al. [2] retrospectively analyzed 106 children who underwent allogenic BMT and reported that HC (grades IIeIV) was diagnosed in 26 patients (25.5%). All children in this study were prospectively screened for BK virus, JC virus and adenovirus with a PCR-based assay. Interestingly, in all 26 patients with HC, viral DNA was excreted by the kidney with BK virus being the most commondpresent in the urine of 21/26 (80.8%) children with HC. Overall, 48 patients in this series had BK viruria; 10 of these (20.8%) also had BK viremia with 21/48 (43.7%) viruria patients and 8/10 (80%) viremia patients going on to develop delayed onset HC (median 45 days). Also, these authors noted application of cidofovir in 20 patients with BK virus-positive HC, indicating its safety as well as its possible prevention of disease progression and death thereby warranting further studies [2].

256 Thus in the context of pediatric BMT populations, early onset HC that occurs within the first 2e3 days after the graft is thought to be a complication of thrombocytopenia and conditioning regimens containing high-dose cyclophosphamide and busulfan with additional bladder damage possibly from irradiation for myeloablation [9]. The development of delayed onset HC, which is frequently more severe and occasionally fatal [4,12], usually occurs several weeks after the BMT and is likely immune related. That is, depressed cellular immunity, donor T-cell depletion, and GVHD may lead to infections from viruses such as BK virus, adenovirus 11, and CMV, ultimately leading to, exacerbating, or at least complicating the HC [1,9,11,13]. The exact viral mechanisms contributing to the pathophysiology of HC as well as the etiologic potential for viruses such as JC virus, adenovirus, and CMV remain to be elucidated. There is, however, accumulating evidence linking BK virus and HC.

BK virus and HC BK virus is a double-stranded DNA polyomavirus which was first isolated in 1971 from a urine sample obtained from a renal transplant recipient after whom the virus was named [14]. Up to 90% of adults are seropositive for BK virus antibody while primary infection is generally asymptomatic and occurs in childhood [15]. The most common symptoms when symptoms are noted are fever and upper respiratory tract infection. BK virus generally remains latent in kidney following primary infection but may also be found in brain, liver, lung, and eye. Route of transmission is not clear although respiratory transmission, as well as sexual, fecal, and transplacental transmission, are hypothesized. In states of mild immune impairment (such as pregnancy, diabetes, the elderly) or with depressed cellular immunity, reactivation with increased virus replication and viruria may be seen. Of urologic importance, BK virus excretion has been implicated in ureteric stenoses in renal allograft recipients and cystitis in immunodeficient and normal children [16]. There is accumulating evidence within the literature that supports a strong association of BK virus with various diseases (frequently urinary tract pathology due to the urotropic nature of the virus) [16e19]. However, further elucidation regarding the pathogenesis of BK virus is clearly necessary. BK virus infection is not specific or universal for any disease process thereby supporting a more contributory or inciting role of the virus in the predisposed immunodeficient with likely unrecognized cofactors necessary for pathogenesis. The association of BK virus with persistent HC was originally documented by Arthur et al. [20] in 1986. The authors prospectively monitored urinary excretion for BK virus using ELISA and DNA hybridization assays in 53 consecutive bonemarrow transplant patients (adult and pediatric). In 19 (36%) of these patients BK viruria lasted 7 days or longer and in 15 (79%) HC developed. This led the authors to conclude that BMT recipients who excrete BK virus in the urine had a four-fold increased incidence of HC compared to those without BK viruria [20]. In a randomized trial, Bedi et al. [21] prospectively evaluated 95 consecutive adult and pediatric BMT recipients for BK virus. Urinary excretion of BK virus was

D.B. Decker et al. demonstrated in 50 (53%) of 95 patients, while 38 patients had persistent BK viruria. HC occurred in 19 of 38 patients with persistent BK viruria while no HC occurred in the 45 who did not excrete BK virus. This study also demonstrated that shedding of BK virus had a strong temporal correlation with onset of HC. Median onset of HC was 26 days while median onset BK viruria was 21 days. This led the authors to reasonably conclude that the previously demonstrated cytopathic effects of BK virus on uroepithelial cells in vivo and in vitro, as well as the strong association and temporal correlation between BK viruria and HC, strongly implicate BK virus in the etiology of HC [21]. A more recent small prospective study by Cesaro et al. further reinforced this concept by finding that of the 74 pediatric BMT patients analyzed those who had two consecutive BK virus-positive urine samples had a sensitivity of 100% and specificity of 82% for developing HC [22]. It is evident that BK viremia is less common than BK viruria and most studies have shown a nearly universal association of BK viruria following those patients with documented BK viremia. It would therefore intuitively follow that BK viremia might have a stronger association with HC. Erard et al. [23] performed a case control study to determine the association of BK viremia with HC. They found that BK viremia detected during the disease was independently associated with HC (Odds ratio Z 30, P < 0.001) and that the higher the viral load the higher the HC risk. Also, BK viremia even before the onset of clinical symptoms of HC is implicated as a risk factor for HC (Odds ratio Z 11, P < 0.001). Subsequently, the authors noted the potential utility of BK virus as a marker or predictor of HC [23]. While there is accumulating evidence for the involvement of BK virus in the etiology of HC [2,10,17,20e24], the multifactorial nature of the disease must be kept in mind. It is apparent that BK virus is not the sole cause of HC as 50e100% of patients undergoing BMT have BK viruria while with even the higher estimates of incidence only about 25% of this patient population develops HC [2,10,25]. Because of this poor specificity for disease, some authors have even questioned the pathogenesis of BK virus in HC [26]. In any case, the probable contributory role of BK virus in HC certainly warrants further study. In conclusion, BK virus is ubiquitous in nature but may become a clinical concern for the urologist in the immunosuppressed. Its strong association with HC is fairly welldocumented but the exact extent of this clinical issue as well as other related issues in the urologic spectrum needs to be elucidated. Further preventative strategies for HC, and specifically for BK virus, are necessary as treatment options are limited for both.

Prevention High-dose cyclophosphamide is one of the most commonly used chemotherapeutic agents in BMT conditioning protocols and its propensity to cause HC has been well-docum ented [27e30]. The urotoxicity observed with cyclophosphamide is thought to be due to its liver metabolite, acrolein [27]. Another alkylating agent, busulfan, may be used alone or in conjunction with cyclophosphamide and can also induce HC [7].

Pediatric hemorrhagic cystitis The three main approaches for prophylaxis of cyclophosphamide-induced HC include mesna, hyperhydration with forced diuresis, and continuous bladder irrigation (CBI) [5,27,30e33]. There have been several studies which have sought to evaluate and compare the overall efficacy of these prophylaxis regimens in order to better define the optimal preventive modality, timing, and dosing. Turkeri et al. [34] reasoned that CBI may diminish HC by diluting the toxic metabolites of chemotherapy and thereby decreasing their contact with the urothelium. The authors investigated this theory by retrospectively analyzing 199 adult and pediatric patients who underwent allogeneic BMT. They found that of 117 patients who underwent a conditioning regimen with both cyclophosphamide and busulfan, 20/87 (25%) with CBI prophylaxis developed HC versus 16/30 (53%) without CBI prophylaxis. CBI prophylaxis consisted of normal saline (NS) infused at a constant rate of 180 cc/m2 via three-way catheter, starting 12 h before chemotherapy and lasting 36 h after conditioning. This led the authors to propose that CBI prophylaxis is a welltolerated and safe regimen with no increased risk of UTIs and should therefore be considered as a preventive regimen for BMT patients [34]. Conflicting conclusions regarding the utility of CBI were made in a separate study. Vose et al. [5] prospectively randomized 200 adult patients receiving high-dose cyclophosphamide for their BMT to either hyperhydration with CBI or hyperhydration with continuous mesna infusion. The CBI consisted of 200 cc/h of NS prior to chemotherapy and lasting 12 h after the last dose of cyclophosphamide. This study found that the incidence of hematuria of any grade was diminished in the mesna group (76% versus 53%, P Z 0.007). More importantly the incidence of severe HC (grade III/IV) was the same in both groups at 18% but the authors reported less discomfort and less frequent UTIs in the mesna group versus the CBI group [5]. Additionally, the authors did not find any increased rate of graft rejection with mesna as had been reported to be a concern with mesna prevention in BMT populations [32]. More recently Hadjibabaie et al. [35] performed a nonrandomized caseecontrol study that sought to investigate the role of CBI in addition to mesna, hydration, and alkalization in the prevention of HC after BMT. Forty adult patients underwent this combined regimen (CBI at 300 cc/h started 12 h before chemo and lasting 48 h after) versus 40 historical controls who did not receive CBI. This study found that HC grades IIeIV occurred in 50% of the controls compared to 32.5% of the treatment group (CBI, hydration, mesna, alkalization for HC prevention). The duration of late-onset HC as well as the duration of hospitalization were significantly shorter in the treatment groups (10 versus 18 days; 30 versus 40 days, respectively). Contrary to previously reported poor tolerance and increased UTIs with CBI [5], the authors noted that the preventive regimen was generally well-tolerated without a significant increase in UTIs [35]. While this study does report relatively high incidences of BMT-related HC in small cohorts, it is unique in showing that combined preventive strategies with CBI may be additionally beneficial. From these data it is evident that the current preventive strategies might be marginally effective in reducing the incidence of HC, but clearly there is no single preventive

257 strategy with proven superiority, and other approaches to further prevent HC should be investigated. On this note, Giraud et al. [24] reviewed 90 adult and pediatric allogeneic BMT patients of whom 15 developed HC. The authors found that a reduced intensity conditioning (RIC) regimen with decreased total body irradiation (from 12 to 6 Gy) and fludarabine decreases the risk of HC. In a later retrospective publication from the same group, they reported a relatively low overall rate of HC grades IIeIV of 109/834 (13.1%) with only 27/834 (3.2%) as the more severe HC requiring interventions. The authors postulated that RIC may have contributed to this apparent reduction in the probability of developing HC after BMT in their series [3]. Additional evidence from other centers has supported the possible protective effect of RIC. Although it is apparent that HC occurs as a result of the interplay between multiple factors, it does appear that the intensity of conditioning treatment may have a role. In a prospective study of 58 BMT patients, Chakrabarti et al. [11] found that even in the presence of prolonged polyoma viruria there was no association with HC in those patients with a non-myeloablative conditioning protocol [11]. Consequently, immunosuppression for BMT at a lower rate of toxicity may have promise as a further HC preventive strategy.

Diagnostic considerations In the pediatric BMT population, the presence of sustained hematuria with lower urinary tract symptoms may often make the diagnosis of HC self-evident. In the case of grade III or greater HC, it may be beneficial to follow BK virus titers given the preponderance of evidence linking BK virus and HC as well as the accumulating evidence demonstrating the benefit of treatment (see below). There is less information regarding the utility of monitoring other viral cultures (e.g. JC virus, adenovirus, CMV). BK virus titers are commonly followed in the blood and urine using DNA PCA assays. In our anecdotal experience, peaks in BK virus titers tend to correspond to worsening symptoms. Therefore, by measuring periodic BK virus levels, the overall course and progression of HC may be monitored and also assist in guiding therapy. Ultrasonography of the kidneys and bladder may be useful as a baseline study in order to objectively characterize clotting within the bladder and evaluate for upper tract dilation (possibly indicating an obstructive process). Along these same lines, laboratory assessment of biological renal function should be followed along with hematologic measurements (Fig. 1).

Treatment Since 1990 when deVries and Freiha [36] reviewed the urologic management of HC, there have been numerous treatment modalities reported; however no single standardized and evidence-based approach has been adopted. Because the disease occurs on a spectrum of severity, a multimodality stepwise approach with judicious escalation in therapy appears warranted (Fig. 1). Once HC is established the treatment principles are generally the same despite the etiology.

258

D.B. Decker et al. HC Grade III/IV: Proposed Treatment Algorithm Clot retention H20 Hand Irrigation; NS CBI

Cystoscopy/Clot evaluation/Fulguration +/- SP tube

Increased morbidity with escalation in treatment

Intravesical therapy: Alum, Cidofovir1, Prostaglandins

IV/Oral therapy: Elmiron/Estrogen Other: HBO

Consider fibrin sealant

Consider surgical options2

Figure 1 Symptom progression: If HC persists over 3e4 days, continues to require blood products, or evidence of obstructive uropathy (e.g. upper tract dilation on ultrasonography or laboratory evidence of declining renal function). Symptom progression: If HC persists over 7e10 days, continues to require blood products, or evidence of obstructive uropathy (e.g. upper tract dilation on ultrasonography or laboratory evidence of declining renal function). (1) Consider antiviral therapy with elevated BK virus titers. (2) Invasive surgical options: bilateral percutaneous nephrostomy tubes  ureteral occlusion; selective arterial embolization; or cystectomy/diversion.

Conservative therapy Initially, HC grades IeIII may be conservatively managed with intensive intravenous hydration, forced diuresis, analgesia, and spasmolytic drugs, especially in pediatric populations in whom more aggressive measures should be more cautiously employed than in adult patients. However, progression of hematuria and even possibly clot retention often necessitate more invasive intervention. In our experience, three-way catheter drainage is often difficult in pediatric populations and it should be stressed that conservative treatment with hyperhydration may promote passage of large clots as a first-line therapy.

due to the potential for otherwise extended urethral catheterization as well as technical difficulties with and limited availability of three-way catheter in pediatric populations. In the initial management of HC, it is imperative to also be cognizant of the often obvious need for medical support with interventions such as platelet transfusions, blood transfusions, and IV hydration. Given the aforementioned links with infectious agents in an immunosuppressed state, the use of prophylactic antimicrobials (e.g. penicillins, cephalosporins, trimethoprimesulfamethoxazole, fluconazole) may also be warranted due to the risk of sepsis from frequent and vigorous bladder irrigation.

Normal saline continuous bladder irrigation

Cystoscopy, clot evacuation, and fulguration

If conservative therapy proves unsuccessful, the next course of treatment involves insertion of a large-bore three-way catheter and NS CBI. Vigorous hand irrigation and evacuation of clots prior to therapy are vital as the success of subsequent irrigation often depends upon the thoroughness of the preceding clot evacuation. Caution is needed in pediatric bladders given the risk of overdistention and rupture [1]. The use of appropriate analgesia during irrigation is important. Additionally, with hand irrigation, clot lysis may be best achieved with sterile water as the irrigant. NS CBI is often a mainstay of HC management, used throughout the treatment course to prevent clot retention and renal insufficiency/failure. Therefore, some advocate the use of a suprapubic tube for this procedure

Due to the relatively non-invasive nature of the procedure and practicality of the therapy, cystoscopy with clot evacuation and fulguration should be considered a first-line surgical treatment if an escalation from more conservative measures becomes necessary. To begin with, the utility of cystoscopy in ruling out any concomitant neoplasm (although relatively uncommon in pediatric populations) should be emphasized. Secondly, the importance of removing all clots before any initiation of intravesical irrigation cannot be overstated. Aggressive bedside irrigation with sterile water to maximally dissolve clots can be effective, yet in our experience it is often difficult to ensure complete clot evacuation without direct bladder visualization. While ultrasonography can be a useful and

Pediatric hemorrhagic cystitis

259

non-invasive adjunct to evaluate clot burden within the bladder (as well as evaluating for upper tract dilation), cystoscopy additionally affords one the opportunity to fulgurate any localized mucosal bleeding. Aggressive fulguration should be avoided to prevent bladder shrinkage/contraction.

cytoprotective and anti-inflammatory properties prostaglandins also have the extra benefit of no coagulum formation. However, flushing and severe bladder spasms are possible with prostaglandin therapy [47]. The efficacy, optimal dose, and timing of prostaglandin intravesical therapy have yet to be established in randomized studies.

Intravesical therapy

E-aminocaproic acid (Amicar) Aminocaproic acid is an inhibitor of plasmindthereby preventing clot lysis and possibly counteracting urokinase. While it may be given orally or intravenously there is a risk of thrombosis and rhabdomyolysis with Amicar usage. Aminocaproic acid creates large adhesive clots that are difficult to remove and with any upper tract bleeding this may lead to loss of that renal unit from obstruction [49]. Lakhani et al. [50] reported complete resolution of intractable BMT-related HC in an adult patient with the use of intravesicular Amicar 2.5 g/100 cc NS solution for 1 h three times daily [50]. The authors advocated that local instillation of Amicar in the bladder is safe and has no side effects. Therefore intravesical therapy may be the safer alternative but caution should still be exercised in pediatric patients as this is yet another therapy where the safety and efficacy have yet to be established in randomized studies.

In a stepwise progression of care, initiation of intravesical agents is often necessary with continued HC. A number of intravesical agents have been utilized with varying reports of success and complications. Historically, formalin instillation has been touted as an effective therapy [37,38]. Prior to instillation a VCUG is necessary to rule out reflux and general anesthesia is often required due to pain associated with instillation. Ureteral occlusion balloons may be used to minimize concerns of reflux. However, the pain associated with the therapy as well as the possibility of bladder scarring, contracture and fibrosis make intravesical formalin inadvisable in pediatric populations. The use of silver nitrate as an intravesical therapy for HC tends to have the same complicating factors [39]. Therefore, while some authors have reported upon the effectiveness of intravesical formalin and silver nitrate in severe HC with adults [40], use in the pediatric population should be avoided secondary to the potential of long-term bladder sequelae. One percent alum (aluminum potassium sulfate) Intravesical alum has been reported as an efficacious therapy with minimal side effects and without bladder changes or scarring [41]. It is an astringent that causes protein precipitation over bleeding surfaces. A 1% alum solution (10 g aluminum potassium sulfate in 1 L distilled water) may be administered continuously via a three-way hematuria catheter at a maximal rate of 300 cc/h. The therapy may take several days to stop the hematuria and can create large clots that clog the catheter. The treatment is not painful and may be administered even if VUR is present [42]. There have, however, been reports of elevated aluminum levels causing encephalopathy, seizures, and acidosis particularly, but not only, in patients with renal insufficiency [43e45]. While systemic absorption of intravesical alum is generally thought to be minimal, the use of 1% alum in those patients with renal insufficiency should generally be avoided. Prostaglandin (prostaglandin E1/E2, F2a/carboprost) Although the exact mechanism is not known, intravesical prostaglandins have had success in small series and anecdotally in treating HC. It is postulated that prostaglandins may work by causing smooth muscle contraction of the blood vessels in the mucosa/submucosa, through membrane stabilization, or by induction of hemostasis with platelet aggregation [46]. Various prostaglandins (E1, E2, F2a) have been used for intravesical HC therapy [47,48]. A small adult series demonstrated the beneficial effects of a prostaglandin F2a analog (carboprost tromethamine) with a recommended starting dose of 0.8e1.0 mg/dL for 60 min every 6 h intravesically [46]. While additionally providing

Cidofovir Cidofovir is a cytidine nucleoside analog that has in vitro activity against polyomavirus and adenovirus [51,52]. Its efficacy in the clinical setting for the treatment of BK and adenovirus infections has also been reported [2,53e55]. However, systemic use of cidofovir is sometimes limited due to its nephrotoxicity [56] and additionally patients with HC may often have acute renal failure as a result of their disease which may also preclude its use in that population. While some institutions have reported positive responses and minimal nephrotoxicity with low-dose intravenous cidofovir (1 mg/kg weekly) in adult BMT populations with BK virus-associated HC, the efficacy and safety have not been proven in prospective trials [57]. Nonetheless, intravesical cidofovir treatment remains an attractive option. Bridges et al. [58] described a single adult patient with severe HC who improved after two once-weekly doses of 5 mg/kg intravesically administered cidofovir in 60 mL of normal saline with clamping of the Foley catheter for 1 h after administration [58]. When nephrotoxicity is a concern, intravesical cidofovir has been reported as a possible therapy for BK- or adenovirusassociated HC with minimal co-morbidity [59]. Direct application of cidofovir to the bladder, the end-organ site of injury, makes intuitive sense and appears to be promising in terms of safety and efficacy. Given the urotropic nature of BK virus, which may be excreted from the kidney and shed distally, the possibility of combined lowdose intravenous cidofovir and intravesical cidofovir is another possible strategy warranting further investigation. Furthermore, cidofovir has been proposed to be applied as a preventive or early, pre-emptive therapy for polyomavirus-associated HC [11], yet once again further prospective studies are needed prior to widespread application.

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Oral/IV therapy Pentosanpolysulphate (PPS/Elmiron) Pentosanpolysulphate is a semisynthetic glycosaminoglycan similar to heparin with anticoagulant properties and fibrinolytic effects. Currently, it is indicated for acute and maintenance treatment of patients with interstitial cystitis [60]. There is minimal published literature on the use of pentosanpolysulphate (PPS/Elmiron) for HC and no reports to our knowledge on pediatric patients with HC. Most reported applications of the therapy are in adults with radiation cystitis and cyclophosphamide-induced HC [61,62]. The mechanism of action is unclear, but PPS is thought to adhere to the bladder wall glycosaminoglycan layer and replace damaged segments of this mucus lining of the bladder. The glycosaminoglycan layer protects and buffers the bladder from the caustic effects of urine, bacteria and other irritants. Although PPS has very mild anticoagulant properties as well as fibrinolytic effectsdit appears from several case reports that it might be counterintuitively effective and improve HC [63,64]. While not reported in the literature, the possible application of intravesical PPS for HC should be considered. A main disadvantage of PPS as an oral therapy is the low concentration of the active drug reaching the bladder (1e3%) resulting in a long lag time prior to clinical improvement. Compared to oral therapy alone, intravesical therapy might provide the benefit of establishing a higher concentration directly into the bladder with a minimum risk of systemic side effects. Overall, there have been very limited reports regarding the use of oral PPS in HC (and no intravesical applications). Additionally, the safety and efficacy of PPS in pediatric patients have not been established, yet PPS therapy remains a promising therapeutic option pending further studies. Estrogen Oral or intravenous estrogen has been proposed as a safe and efficacious intervention for HC. Similar to other proposed therapies, there is limited single-center anecdotal experience with estrogen. There are several postulated mechanisms by which estrogens are thought to act including stabilization of microvasculature, altering immune responses, and/or promoting damaged tissue repair [65e68]. A number of investigators have reported success in their limited experience with oral and intravenous estrogens in the treatment of BMT-related HC in adult and pediatric populations. To summarize, various investigators have documented case series ranging from five to 10 patients in which there was a positive response (improvement or resolution of hematuria) rate of greater than 70% over a duration of treatment ranging from several days to several weeks [67e70]. Concerns with estrogen therapy include liver dysfunction, hypercoagulability, hypertension, flushing, feminization in males, and malignant transformation. In the aforementioned reports of the application of estrogen therapy for HC, it was generally well-tolerated with only one possible instance of reversible hepatotoxicity [67]. While with long-term exposure of exogenous estrogen there is a recognized increased risk of cancer [71], the potential

D.B. Decker et al. carcinogenicity of high-dose estrogen administration in a short-term setting has not been documented and remains unknown [68]. Nonetheless, the possibility of estrogen being a safe, feasible, efficacious, and inexpensive treatment as part of the combined treatment of HC remains attractive pending further validation. Other intravesical/oral/IV agents Throughout the literature there are other reported agents for HC therapy which warrant mentioning. That is, intravesical sodium hyaluronate [72,73], oral risperidone [73], intravenous activated recombinant factor VII [74], and even tissue repair using intravenous allogeneic mesenchymal stem cells [75] have been cited as possible intravesical agents with promising results or proposed efficacy for HC therapy in small cohorts (adult and pediatric).

Systemic therapy Hyperbaric oxygen (HBO) Hyperbaric oxygen has emerged as a possible treatment modality for refractory HC. It is hypothesized that HBO induces healing of damaged tissues, decreases edema and promotes capillary angiogenesis by the elevation of the oxygen gradient between the damaged hypoxic urothelium and normal tissue surrounding itdresulting in permanent tissue healing. Originally applied to the treatment of radiation-induced HC in adults in the 1980s [76], multiple publications have since advocated HBO for this indication [77e80]. There have, however, been limited reports of HBO therapy in pediatric populations [81] and even fewer specifically in pediatric HC. Furness et al. [82] first reported a pediatric case in which HBO therapy was effective for severe, recalcitrant HC that was secondary to chemotherapy/ radiation [82]. More recently, in 2004, Bratsas et al. [83] described HBO application in a case report of a pediatric oncology patient treated with cyclophosphamide who developed intractable HC which persisted for over 3 months and was recalcitrant to multiple treatment modalities. This index patient subsequently underwent HBO therapy for 60 min twice a day. After several weeks of treatment the patient had significantly reduced hematuria allowing for the bladder catheter to be removed. The patient’s urine ultimately cleared and there were no further episodes of hematuria on 2 years of follow-up [83]. While clearly an anecdotal case report of successful treatment of pediatric HC, HBO remains an attractive option given the non-invasiveness of the therapy. However, there remain several issues which might preclude more widespread application of HBO for HC in pediatric BMT patients. Besides logistic concerns of possible transfers and placing a likely immunosuppressed pediatric patient in a hyperbaric chamber, contraindications for HBO include active cancer and active viral infection which as previously discussed are commonly present in this patient population. Complications from HBO therapy have been reported in a patient with Fanconi anemia raising concerns regarding this modality in that subset of patients [84]. Additionally, the duration of therapy has not been elucidated in pediatric populations due to its limited application.

Pediatric hemorrhagic cystitis Recently, Corman et al. [78] published a retrospective 13-year, 57-patient experience of HBO therapy for radiation-induced HC in a mostly adult population. These authors postulated that although it is estimated that 40 hyperbaric treatments are the optimal number for acute resolution and durable long-term results, it may also be cost-effective by limiting long-term sequelae despite the fact that a complete course may cost approximately $20,000 in the United States [78]. By inducing neovascularity and permanent tissue healing while preserving bladder function, HBO therapy for HC certainly has promise. Overall, there are accumulating reports regarding the utility of HBO for the treatment of radiation-induced HC in adult populations, yet there appears to be limited application in pediatric BMT patient populations.

Surgical therapy Fibrin sealant Novel surgical approaches to manage the refractory bleeding of HC using fibrin sealant have been reported [85e 87]. In the patient with severe, persistent hematuria requiring constant blood transfusions an intensification of care appears warranted. In an escalation of the care treatment model (Fig. 1), fibrin sealant has a possible niche as a relatively ‘less-invasive’ surgical option. For example, Purves et al. [87] reported a case describing this novel application of fibrin glue in an 11-year-old male with leukemia who underwent an allogeneic BMT and developed refractory HC. The patient experienced 3 months of severe HC which did not respond to multiple therapeutic modalities. The authors described fibrin glue application to the CO2-insufflated bladder via a suprapubic tract under the guidance of a urethral cystoscope. Without any urinary diversion, the use of temporary ureteral stents to avoid occlusion of the ureteral orifices while the fibrin glue solidifies (approximately 5 min) was mentioned as a possibility. The authors noted complete resolution of HC following the above intervention with no recurrence at 12 months’ followup [87]. Although there is obviously limited reported experience of this novel approach, it is intuitively promising and may have an increased role in the management of HC pending further studies demonstrating safety and efficacy. Supravesical urinary diversion, vesical artery embolization, and cystectomy While there are multiple less invasive options, the treatment for severe, life-threatening HC may occasionally necessitates more aggressive measures. It remains imperative to adhere to a relative scale of treatment (Fig. 1) based upon the associated morbidity. On the other hand, the potential for mortality from HC with a rate approaching 4% [36] must be kept in mind. When less morbid treatment options fail, there remain additional options for refractory bleeding from HC. Supravesical urinary diversion may be an effective means of treating severe, refractory HC. It is hypothesized that urokinases, which are proteolytic enzymes in the urine, contribute to the pathophysiology of HC. The urine urokinases have intrinsic fibrinolytic activity that ultimately degrades fibrinogen and fibrin clots. This inhibits clotting

261 and can perpetuate HC [88]. Therefore, by removing urokinases from contact with the injured bladder mucosa, the normal clotting mechanism may be restored. In addition, complete supravesical urinary diversion prevents bladder overdistention and subsequent bleeding of friable blood vessels. The traditional method of supravesical urinary diversion might entail laparotomy and urinary diversion with a conduit or cutaneous ureterostomies. However, the patient with severe, refractory HC is likely to have multiple co-morbidities often precluding those approaches. A less invasive option for supravesical urinary diversion with bilateral percutaneous nephrostomy tubes to control intractable HC has been previously described with varied success [89,90]. Gonzalez et al. [91] took this concept a step further by describing a technique for complete supravesical urinary diversion using ‘less-invasive’ techniques. In this case report, the authors describe a very poor operative candidate with refractory, life-threatening HC in whom bilateral percutaneous nephrostomy tubes were placed and complete ureteral occlusion performed by collagen injection at the ureteral orifices resulting in resolution of HC and no further symptoms at 21 months’ follow-up [91]. Vesical artery embolization for refractory HC has been successfully performed under local anesthesia with a good response and minimal morbidity. Several investigators have reported upon this treatment option specifically for adult patients with BMT-related HC [92e94]. Although long-term data and follow-up are lacking, with an experienced interventional radiology team this is an option to keep in mind after failure of less invasive therapy. Additionally, more aggressive measures to manage grade IV HC have been described. In very severe cases of HC, cystectomy with urinary diversion has been reported as a therapeutic option [95,96].

Conclusions With the increasing use of radiation, toxic chemotherapeutics and stem cell/bone-marrow transplantation (which often incorporates both), HC is a clinical entity that will continue to demand attention. The pediatric BMT population is particularly susceptible to HC and the importance of further elucidating the disease process in these patients is evident in the fact that the developed treatment paradigms and lessons learned from this group may be applied to HC from other etiologies (e.g. radiation cystitis in adults). There is a relative paucity of prospective studies to provide scientific guidelines for treatment. Furthermore, HC is an extremely difficult clinical issuednot only for the patient but also for the treating multimodality team (e.g. urologist, oncologist, nephrologist, pediatrician, social worker, parents, etc.). Multiple therapeutic modalities are often necessary and many may have significant morbidity. There is little evidence-based medicine on the subject as most applications of treatment are anecdotal. While it is evident that multiple therapies have been described, no one definitive therapy for HC has been established. Therefore, judicious clinical acumen remains paramount and the urologist should be prepared to play an active role

262 in treating patients who experience this complication. A comprehensive knowledge of the incidence, pathophysiology, and possible preventive measures for HC, as well as a familiarity with the various tools available in the treatment armamentarium, is crucial.

Conflict of interest There are no conflicts of interest to report.

Funding None.

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