The immunosuppression in transplant patients increases the risk of opportunistic infection, and polyoma viruses (BK and JC virus) along with adenoviruses are the most common causative agent of HC in this population. Infection with polyoma virus is opportunistic, as up to 80 % of all adults are colonized. The virus infects many different cell types including urothelial cells of the renal pelvis, ureters, and bladder [4–6]. In immunocompetent hosts, they lie dormant following infection – viral reactivation requires a combination of predisposition to reactivation, target organ damage, and host immune dysfunction.

Adenovirus represents another common infectious agent associated with HC in immunocompromised patients. The incidence of adenovirus infection ranges from 10 to 20 %, with renal transplant patients being at increased risk of HC associated with infection [7, 8]. Children have been shown to have onset of symptoms sooner than adults (30 vs. 90 days) [9].

While polyoma virus and adenovirus infection cause HC in immunocompromised hosts, infection with cytomegalovirus (CMV) has recently been shown to cause HC despite seemingly normal immune function. In one report, an otherwise healthy 3-year-old boy with gross hematuria had cystoscopic evidence of HC – bladder biopsy was consistent with CMV infection and viral DNA was present in both serum and urine samples. In this patient, symptoms resolved spontaneously with conservative management 1 month after onset [10].

While viral HC is most common, bacterial, fungal, and parasitic infection can also cause HC. Bacterial cystitis, though usually a benign disease, has been reported in rare but severe cases to progress to HC with potentially fatal outcomes including spontaneous bladder perforation [29]. The most common bacterial causes are E. coli, Proteus spp., Klebsiella spp., and S. saprophyticus [30]. There is a recent report of a patient with acalculous cholecystitis and acute HC caused by S. typhi [31]. Regardless of the causative agent, management of bacterial HC relies on culture-driven antimicrobial therapy along with symptom control.

HC is also a known sequelae of tuberculosis of the bladder. This is seen in the immigrant population and affected individuals usually have concurrent renal tuberculosis [32].

Fungal causes of HC are rare and usually associated with treatment of bacterial cystitis [33]. Organisms reported to cause hemorrhagic complications include Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, and Torulopsis glabrata. Characteristic findings include white plaques overlying the urothelium. As with bacterial cystitis, symptoms resolve following treatment of the underlying infection [34]. In the United States, parasitic HC is rare. However, bladder schistosomiasis is a serious health concern in developing nations, primarily in Africa [35]. Infection starts with exposure to contaminated water, where larvae penetrate the skin. Following maturation in the lungs and liver, adult worms travel to the pelvic veins and deposit eggs in the bladder wall. The eggs incite an inflammatory reaction with subsequent fibrosis. During the inflammatory phase, nodular bladder wall thickening is seen on CT urography. In the chronic fibrotic phase, bladder volume is decreased and imaging shows a thickened calcified bladder [36].

Treatment with praziquantel will treat the infection but the chronic fibrotic changes cannot be reversed [37]. In rare cases, hemorrhagic cystitis has been noted in association with hydatid cyst disease caused by Echinococcus granulosus [38]. Treatment with albendazole leads to resolution of symptom.

Radiation-induced cystitis is seen in adult patients with pelvic malignancy and pediatric patients following whole-body radiation in preparation for bone marrow transplantation. Its presentation can be divided into acute and late radiation cystitis.

The overall incidence of radiation cystitis ranges from 5 to 10 %. This number varies greatly depending on the series and the patient population studied. Patients receiving larger doses of radiation or radiation directed at the bladder have an increased risk of developing radiation cystitis of worsening severity [39]. It is therefore not surprising that patients who have undergone radiation treatment for bladder cancer have the highest rates of radiation cystitis, with almost 10 % of patients having small shrunken bladders [40]. Patients treated with radiation for either prostate or cervical cancer have a 6–8 % risk of grade III/IV HC [41, 42]. Acute radiation cystitis occurs either during or shortly after radiation therapy (usually within 3 months) and is caused by injury to the fast dividing cells of the bladder mucosa. The symptoms are typically self-limiting and include dysuria, urgency, and frequency. These can usually be managed conservatively. In the acute phase, imaging findings are similar to those seen in infectious HC. Late radiation cystitis develops anywhere between 6 months and 20 years after therapy. It is caused by damage to vascular and connective tissues, which have a much slower cell turnover rate than the bladder mucosa. Endothelial cell damage and perivascular fibrosis are seen months to years after radiation and can result in vascular occlusion/bladder ischemia [43]. The vascular ischemia causes late bladder fibrosis and contraction which can be seen on CT imaging. Radiation also damages smooth muscle cells, causing them to be replaced by fibroblasts, which will lead to decreased bladder compliance. Histologically, these late changes present as a progressive obliterative endarteritis that leads to mucosal ischemia, cellular depletion, and fibrosis. The hypoxia results in tissue breakdown and sloughing of the necrotic bladder mucosa, which leads to hematuria. Telangiectasia also develops which can further contribute to the hematuria. The impaired tissue healing and fibrosis lead to a reduction in bladder capacity and can cause LUTS [44].

The initial management of HC begins with careful history, physical examination, and labs as needed to determine not only the underlying etiology but also the degree of the blood loss, as patients should be resuscitated appropriately with fluids and/or blood product based on standard critical care guidelines. Urinalysis and urine culture should be performed, and all patients should be presumed to have urinary tract infection until culture data shows otherwise. Diagnosis should rule out other conditions including medical renal disease, UTI, urolithiasis, coagulopathy, and neoplasm of the bladder or upper urinary tract. In cases of bleeding caused by these mechanisms, treatment of the underlying disorder leads to resolution of symptoms. Even in such cases, hemorrhage itself must be managed and can be done so using the same algorithm used in all other forms of HC.

In determining appropriate management strategies, it is important to understand the severity as well as chronicity of the symptoms. In grade I and II hematuria, management involves treating the underlying cause combined with increased fluid intake. Increased fluids dilute the urokinase found in urine allowing bleeding to resolve with normal coagulation. In patients with grade III and IV HC (Table 24.1), treatment by a urologist is often necessary. These patients are characterized by hemorrhage severe enough to cause urinary retention secondary to clot obstruction of the bladder neck and urethra.

Of course, the ideal strategy would be that of prevention. For patients undergoing radiation treatment, this involves tailoring the treatment as much as possible to the region of interest and limiting the dose delivered to the bladder. For chemical-induced cystitis, such as that caused by acrolein, minimizing exposure through treatments that are very effective (i.e., mesna) is the best treatment as it prevents HC. In many patients, once chronic changes are present, they are irreversible and the effect of urokinase in the urine on the underlying bladder muscle and vasculature propagates a cycle of irritation, causing hemorrhage that is very difficult to control.