Bladder cancer is the fourth leading cause of cancer in men. Improvements in cancer care have led to patients living longer. Five-year relative survival rates in patients with localized and regional bladder cancer have been reported to be 69 and 34%, respectively . Depending on tumor characteristics, many patients require radical cystectomy with lymph node dissection and urinary diversion. For diversion, various techniques including ileal conduit, orthotopic neobladder (ONB) and continent cutaneous urinary diversion (CCUD) may be utilized based on patient characteristics and surgeon preferences. Although the proportion of patients undergoing incontinent diversions has been reported to be as high as 92% , recent data from high-volume centers suggests that both ONB and CCUD are commonly performed . The purpose of this article is to review long-term complications of different diversion types following radical cystectomy and strategies to prevent or treat them. A systematic search of Medline, Embase, and Scopus electronic databases was conducted to retrieve English language original and review articles addressing different categories of long-term complications after radical cystectomy for bladder cancer.
RENAL FUNCTION DETERIORATION
Renal function deterioration rate after urinary diversion ranges from 20% to more than 70% in different series [4–7,8▪,9] (Table 1). This wide range is because of variations in definition, measurements, and length of follow-up in different studies. Some studies have considered a 25% decline in estimated glomerular filtration rate (eGFR) compared with baseline as a sign of renal function deterioration [8▪] whereas others defined renal function deterioration as more than 10 ml/min/1.73 m2 reduction in eGFR [5–7]. Various methods have also been applied to assess renal function. Recent studies have employed Chronic Kidney Disease Epidemiology Collaboration equation to calculate eGFR that provides the most precise assessment of renal function [7,9].
Deterioration of renal function after urinary diversion may be a consequence of complications related to the diversion including recurrent urinary tract infections (UTIs), obstructive uropathy, and factors impertinent to urinary diversion, such as age, medications, hypertension, and diabetes mellitus. In a recent study, assessing 322 patients with urinary diversion, longer follow-up was associated with a higher rate of renal function deterioration. Risk of renal function deterioration at 1, 3, and 5 years after CCUD was 24, 29, and 42%, respectively, which was comparable with other diversion methods . Eisenberg et al.  in a study with a median follow-up of 10.5 years revealed that risk of renal function decline is 71 and 74% in patients with incontinent and continent urinary diversions, respectively. Therefore, irrespective of diversion type, a significant number of patients may experience renal function deterioration; however, rate of end-stage renal disease remains quite low [4,7]. Despite the relatively younger age and more favorable baseline renal function in patients with continent diversions, studies assessing long-term changes in renal function have failed to show the type of urinary diversion as a significant predictor of postoperative renal function deterioration [5–7,8▪]. Deterioration of renal function after radical cystectomy and urinary diversion requires special attention as some studies have demonstrated a significantly higher risk of cardiovascular disease and subsequent mortality in patients with chronic kidney disease .
Voiding dysfunction in ONB patients is divided into problems of filling (storage) and voiding (emptying). In several large series addressing functional outcomes of ONB, continence rate ranges between 57 and 100% [11–21] (Table 2). Daytime continence initially improves followed by nocturnal control as the capacity of neobladder increases. In a series of 166 patients, the Copenhagen group, reported night-time continence rates of 75 and 94% at 1 and 3 years, respectively . Failure of emptying may also occur in patients with ONB. Urinary retention usually appears months after orthotopic diversion; however, it can even occur years after good neobladder function . It occurs more frequently in women and the incidence varies from 11 to 70% in the literature [22▪▪]. Anderson et al.  assessed 49 women with ONB for a mean follow-up period of 3.1 years; daytime incontinence, night-time incontinence, and emptying failure occurred in 43, 55, and 31% of women, respectively. They also noted that incontinence is associated with a history of concurrent or previous hysterectomy. Although the cause is not established, it might be related to posterior prolapse of the neobladder during the valsalva maneuver and consequent kinking of the urethra. Utilizing peritoneal or omental flap to fill the posterior pelvis as well as anterior and superior fixation of the reservoir may prevent prolapse and decrease hypercontinence rate . Inadequate emptying is uncommon in men with ONB diversion. In a series of 655 men, Simon et al.  observed residual urine volume of above 100 ml in 11.5% of men with ONB diversion. Mechanical obstruction (i.e., benign neovesicourethral anastomosis strictures or local tumor recurrence) was the major cause of incomplete emptying, although we have not observed this in our series. In a randomized trial comparing Studer versus T pouch, a total of 179 patients were assessed for voiding dysfunction in a mean follow-up period of 4.5 years . Seventy patients (39.7%) reported daily urinary leakage and 30 (16.8%) had no control/frequent dribbling during the day. Intermittent catheterization was necessary in 17 (9.5%) patients. Age and diabetes mellitus were predictors of voiding dysfunction whereas pouch type did not . However, applying colonic segments and non-nerve-sparing techniques have been suggested as risk factors for urinary incontinence after ONB reconstruction . Lifestyle modification and behavioral therapy, that is, limited fluid intake at night, timed voiding, double voiding, and pelvic floor muscle training have been proposed as therapeutic strategies to improve functional outcomes after ONB diversion.
Stoma-related complications are among the most frequent complications in patients with CCUD and ileal conduit; the incidence has been reported to be as high as 60% .
Stomal stenosis is uncommon in patients with ileal conduit and the incidence ranges from 0 to 3% [4,7,25]. One of the largest studies to date at Mayo clinic reported conduit stricture in 2.4% of 1057 patients at a median follow-up of 9.4 years . Nevertheless, complications pertinent to catheterizable stoma are among the most frequent and troublesome complications in patients with CCUD. Stomal stenosis and difficult catheterization occurs in up to 30% of patients with CCUD . Nieuwenhuijzen et al.  noted that stomal stenosis requiring surgical revision occurred in 3 and 13% of patients after ileal conduit and Indiana pouch urinary diversion, respectively. Continence rate varies from 57 to 97.3% of CCUDs [26–28]. Continence mechanism utilized in CCUD may also affect the rate of stenosis in patients with CCUD. Vergho et al.  reported stenosis rate of 30 and 2.7% in 486 patients with appendicoumblical stoma and intussuscepted ileal nipple after a mean follow-up period of 90.3 months, respectively. Urinary leakage with a CCUD may occur as a consequence of incompetent continence mechanism, uninhibited contractions, or poor compliance reservoir. A trial of anticholinergics may be beneficial in patients with high-pressure, poor compliant reservoirs. When the problem is refractory, surgical intervention to increase the capacity becomes necessary.
Parastomal hernia leads to protrusion of peritoneal content through the abdominal wall defect next to stoma with incidence ranging from 2.3 to 48% [29–32]. This variation may be related to different clinicoradiological criteria used to define the parastomal hernia. Parastomal hernia can negatively impact the quality of life as it could be associated with discomfort and improper fitting of the ostomy appliance. Occasionally, parastomal hernia leads to urinary or bowel obstruction, strangulation, and bowel perforation. Parastomal hernia is a clinical diagnosis; however, radiologic evaluation is more accurate. Moreno-Matias et al. proposed a clinicoradiological classification system to determine three different types of parastomal hernia. In type 1, hernia sac contains the prolapsed bowel loop forming the stoma. Type 2 contains abdominal fat or omentum and type 3 has herniated bowel loops other than the stoma . Donahue et al.  used this classification system and showed that types 1, 2, and 3 parastomal hernia developed in five (4%), 90 (66%), and 41 (30%) patients 2 years after ileal conduit urinary diversion, respectively. On multivariable analysis, female sex, higher BMI, and lower preoperative albumin were significantly associated with risk of parastomal hernia . In a study from the University of Southern California with more than 15 years follow-up, parastomal hernia was found to be the most common stoma-related complication occurring in 30% of patients with ileal conduit . In a retrospective analysis of Indiana University cystectomy database, Liu et al.  showed that the cumulative risk of parastomal hernia formation was 12.2 and 22.5%, at 1 and 2 years after cystectomy, respectively. Multivariable analysis showed that prior laparotomy and severe obesity were predictors of parastomal herniation. Surgical repair of parastomal hernia is a challenging procedure and may be associated with unsatisfactory results and high recurrence rate. Approximately half of patients require surgery because of abdominal discomfort and/or intestinal complications .
Ureteroenteric stricture (UES) usually occurs within a few months after radical cystectomy [37▪▪]. In a large series of 1964 open radical cystectomy patients from the University of Southern California, 49 patients and 51 (2.6%) renal units were retrospectively identified with benign UES, with a median follow-up period of 12.4 years [37▪▪]. UES is more common on the left side and usually presents with flank pain and/or UTI and, however, could be asymptomatic up to one-third of cases [37▪▪]. In a study by Richards et al. , overall stricture rate per ureter was 5.9% on the right versus 10.0% on the left. Shah et al. [37▪▪] used a multivariate logistic regression model that revealed no association between age, BMI, comorbidity, perioperative radiation or chemotherapy, and risk of UES formation. Surgical technique seems to play an important role in occurrence of UES and benign UES is uncommon when a consistent meticulous surgical technique is used [37▪▪]. Anderson et al.  reported a UES rate of 8.5 and 12% in 375 and 103 patients who underwent open and robot-assisted laparoscopic radical cystectomy, albeit the difference was not statistically significant. Both endourological and open approaches have been utilized for treating UES. The overall success rates seem to be lower with endourological procedures with 50% retreatment rate .
Bowel obstruction is a common cause of readmission in patients after radical cystectomy . In a large series of 1057 patients, bowel obstruction was found to be the most common complication occurring in 16% of patients at a median follow-up period of 1.7 years . In another study of 1000 radical cystectomy patients, bowel obstruction was observed in 3.6% of patients 20 years postoperatively . Late-onset bowel obstruction may be a consequence of stenosis of the ileoileal anastomosis or intraperitoneal adhesion bands. Nevertheless, peritoneal carcinomatosis should also be ruled out, if indicated.
Both neobladder-vaginal and entero-neobladder fistula may occur as a complication of urinary diversion. In a report of 51 women who underwent radical cystectomy and ONB, neobladder-vaginal fistula was reported in three (6%) women . Entero-neobladder fistula usually occurs between small bowel anastomosis and neobladder and presents with fecaluria, pneumaturia, and recurrent UTIs . Large series have reported an incidence of less than 3% for entero-neobladder fistula [4,42]. Total parenteral nutrition and urinary catheter drainage are the mainstay in conservative management of fistula. However, the majority of patients require open surgical correction and recurrent cancer must be ruled out in suspicious cases .
Neobladder/pouch perforation is a rare complication associated with urinary diversion and has been described in several small case series. Perforation may occur by traumatic catheterization or blunt trauma to a full neobladder/pouch. Immediate laparotomy and repair of the neobladder/pouch is necessary as the rupture usually occurs intraperitoneally . However, there are some reports of conservative management in the literature .
Urinary diversion is associated with acid base and electrolyte abnormalities. Several factors including the segment of the bowel used for diversion, the surface area of the bowel, and the amount of time the urine is exposed to the enteric segment influence the severity of metabolic consequences. Ileum absorbs chloride and excretes bicarbonate that results in metabolic acidosis. Metabolic acidosis has been reported to be the principal cause of readmissions in patients after radical cystectomy . Although chronic metabolic acidosis exists in more than 70% of patients with urinary diversion , severe metabolic acidosis occurs in 1% of patients. In a series of 363 men with ONB, Hautmann et al.  reported that nearly one-half of all patients required some form of alkalinizing treatment. In response to metabolic acidosis, bone buffers the excess protons and releases calcium. Moreover, chronic metabolic acidosis inhibits osteoblast activity, stimulates osteoclast bone resorption, and might lead to osteoporosis. A population-based study using SEER-Medicare database evaluated the incidence of fracture in 50 520 patients of whom 4878 had cystectomy and revealed that cystectomy is associated with a 21% greater risk of fracture .
Metabolic complications occur less frequently in patients with incontinent diversion. In a large series of 1057 patients who underwent radical cystectomy with conduit urinary diversion using ileum or colon, Shimko et al.  reported that metabolic abnormalities were among the least common complications occurring in 12.8% of patients. Resection of terminal ileum also leads to B12 deficiency with incidence of 0–33% [4,11,12]. This variability may be due to the differences in length of resected ileum, assessment methods, and follow-up. Symptomatically, when body supply is depleted megaloblastic anemia and severe neurologic injuries may occur. It has been suggested to monitor vitamin B12 annually beginning 3–5 years after surgery .
Patients with urinary diversions are susceptible to bacteriuria and developing pyelonephritis. Wood et al.  reported asymptomatic bacteriuria in 78% of their patients with ONB and only half of them developed symptomatic UTI. Pyelonephritis has been reported to be among the most common causes of admissions in patients with urinary diversion . Up to 17% of patients with conduits experience acute pyelonephritis with subsequent renal function deterioration especially when the affecting organism is proteus or pseudomonas . The rate of UTI has been reported to be similar between various types of diversion . Moreover, age, sex, intermittent catheterization, bowel segment used for reconstruction, and perioperative chemotherapy has no effect on rates of UTI . Urosepsis usually occurs in the context of recurrent symptomatic UTIs. Therefore, suppressive or prophylactic antibiotic therapy may be unnecessary unless a history of recurrent UTIs exists .
Patients with urinary diversion are more likely to develop urolithiasis. Metabolic acidosis and short bowel syndrome may result in hypocitraturia and hyperoxaluria, respectively . Struvite stones may also form because of infection or bacterial colonization of the reservoir. Moreover, exposed staples represent a nidus and facilitate stone formation in patients with diversion. Ferriero et al.  assessed the risk of stone formation in stapled neobladder in 445 consecutive patients with ONB diversion. At a median follow-up of 41 months, neobladder stone formation occurred in 41 (9.2%) patients. Risk of stone formation increased over time and was 8, 19.5, and 24.9% at 3, 5, and 7-year follow-up, respectively. Cystoscopic evaluation revealed that staple lines were usually covered by ileal mucosa. However, in 15 cases (36.6%), the stones were anchored to titanium staples. Although the effect of staples in stone formation within reservoirs has not been evaluated in randomized studies, slightly higher incidence of stone formation has been reported in series using staples [12,50] compared with hand-sewn reservoirs [11,14].
Risk of urolithiasis seems to be similar between various types of urinary diversion . Nevertheless, female sex has been postulated to be a risk factor for stone formation within ONB that is consistent with higher need for intermittent catheterization . Treating metabolic and electrolyte disturbances are important preventive measures. In addition, patient counseling for appropriate hydration and adequate reservoir emptying is of value in patients with continent diversion.
The overall long-term complication rate of urinary diversion has been reported to be as high as 60%. Stoma-related complications followed by UTI are among the most common complications. This emphasizes on importance of long-term, regular follow-ups in these patients.
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