Long-term Renal Function After Urinary Diversion by Ileal Conduit or Orthotopic Ileal Bladder Substitution

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1 EUROPEAN UROLOGY 61 (2012) available at journal homepage: Platinum Priority Bladder Cancer Editorial by Ja Hyeon Ku and Seth P. Lerner on pp of this issue Long-term Renal Function After Urinary Diversion by Ileal Conduit or Orthotopic Ileal Bladder Substitution Xiao-Dong Jin a,b,1, Simone Roethlisberger c,1, Fiona C. Burkhard a, Frédéric Birkhaeuser a, Harriet C. Thoeny d, Urs E. Studer a, * a Department of Urology, University of Bern, Bern, Switzerland; b Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People s Republic of China; c Department of Nephrology and Hypertension, University of Bern, Bern, Switzerland; d Department of Radiology, University of Bern, Bern, Switzerland Article info Article history: Accepted September 2, 2011 Published online ahead of print on September 15, 2011 Keywords: Glomerular filtration rate Kidney function test Urinary diversion Urinary tract infection Please visit europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Background: Data on long-term renal function are scarce for ileal conduit diversion (ICD) and even rarer for orthotopic ileal bladder substitution (BS). Objective: Explore the changes in renal function of patients who lived 10 yr with an ICD or BS and determine the risk factors contributing to renal function deterioration. Design, setting, and participants: Fifty consecutive ICD patients and 111 consecutive BS patients who lived 10 yr after undergoing surgery between January 1985 and December 2000 were retrospectively analyzed. Measurements: The glomerular filtration rate (GFR) was calculated with the Modification of Diet in Renal Disease (MDRD) equation before and 10 yr after surgery. Decreased renal function was defined as a decrease in GFR >10 ml/min per 1.73 m 2 in 10 yr. Results and limitations: Median GFR values in patients with ICD or BS decreased from 65.5 (range: 23 90) to 57 (range: 7 100) ml/min per 1.73 m 2 and from 68 (range: ) to 66 (range: ) ml/min per 1.73 m 2, respectively. Eighteen ICD patients (36%) and 23 BS patients (21%) had deteriorating renal function. Seven of 12 ICD patients with obstruction (ureteroileal stricture, stomal stenosis/parastomal hernia) (58%) had renal function deterioration, as did 17 of 46 BS patients with obstruction (ureteroileal/nipple stricture and/or bladder outlet obstruction) (37%). Logistic regression analysis confirmed that obstruction was the leading, and an independent, risk factor for renal function deterioration for both ICD patients ( p = 0.045) and BS patients ( p = 0.002). Patients with diabetes or hypertension were significantly more likely to have deterioration of renal function if they had ICD ( p = and p = 0.05, respectively). The limitation of the study is its retrospective nature and its composition that included many patients who did not survive 10 yr. Conclusions: Urinary tract obstruction was the leading cause of long-term renal function impairment, regardless of whether the patient had ICD or BS. ICD patients with predisposing risk factors, such as diabetes or hypertension, were at increased risk for impaired renal function. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. 1 These authors contributed equally to this work. * Corresponding author. Department of Urology, University Hospital Bern, 3010 Bern, Switzerland. Tel ; Fax: address: urology.berne@insel.ch (U.E. Studer). 1. Introduction Ileal conduit diversion (ICD) and orthotopic ileal bladder substitution (BS) are the two most frequently used urinary diversions after cystectomy [1,2]. ICD has long been considered the gold standard of urinary diversion, although several long-term studies have reported a high incidence of renal impairment in ICD patients [3,4]. In contrast, severe /$ see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 492 EUROPEAN UROLOGY 61 (2012) renal impairment in patients with orthotopic low-pressure neobladder seems to be less frequent, but long-term data on changes in the glomerular filtration rate (GFR) of these patients are lacking [5,6]. Most studies have evaluated renal function based on mean serum creatinine values or morphologic changes noted on intravenous urography or sonography [5,7,8]. However, serum creatinine is not a sensitive marker for deterioration of renal function, remaining within normal limits until it is reduced by approximately 50% [9], and a dilated extrarenal urinary tract does not necessarily indicate reduced renal function. In this study, we analyze the changes in GFR values 10 yr after ICD or BS urinary diversion and elucidate the risk factors for long-term deterioration of renal function. 2. Patients and methods 2.1. Patient selection [(Fig._1)TD$FIG] Between January 1985 and December 2000, 617 patients underwent radical cystectomy in our department and received either an ICD or BS diversion. Patients with nephrectomy owing to tumor recurrence during follow-up or who died within 10 yr were excluded. Many patients were lost to follow-up. Finally, 50 ICD patients and 111 BS patients who had lived with the ICD or BS for 10 yr were included (Fig. 1) Surgical technique In an ileal segment cm long was isolated approximately 25 cm proximal to the ileocecal valve. Ureters were split and anastomosed separately by two running sutures using the Nesbit technique in an open end-to-side fashion. The ileal segment was anastomosed to the abdominal wall in a nipple-to-stoma fashion. In the ileal reservoir, together with the afferent tubular segment, was constructed from an ileal segment cm long, which was resected approximately 25 cm proximal to the ileocecal valve. The distal cm were detubularized and reconstructed into a low-pressure reservoir, as has been described [10,11]. Theproximal cm of ileum was left intact, and the ureters were implanted into its most proximal part, initially either with a nonrefluxing intussuscepted nipple or an open refluxing anastomosis like that of the ICD [12]. 280 pts with ICD 337 pts with BS 1 pt on hemodialysis before surgery 11 pts undiverted to ICD 290 eligible pts with ICD 326 eligible pts with BS 30 pts lost to follow-up 4 pts lost to follow-up 198 pts died within 203 pts died within 1 pt received nephrectomy within 3 pts received nephrectomy within 61 pts with ICD survived 10 yr 116 pts with BS survived 10 yr 11 pts with incomplete data set 5 pts with incomplete data set 50 pts with ICD were evaluable 111 pts with BS were evaluable Fig. 1 CONSORT diagram of eligible patients. ICD = ileal conduit diversion; BS = bladder substitution; pts = patients.

3 EUROPEAN UROLOGY 61 (2012) Patient follow-up and data collection Patients were followed regularly in the outpatient clinic or by practicing urologists at 1, 3, and 6 mo; then every 6 mo up to 5 yr; and then annually thereafter. At each visit blood pressure, serum creatinine, glucose, urine culture, and residual urine were determined, and renal ultrasonography was performed. All patients with confirmed mechanical obstruction (ureteroileal or nipple stenosis, stomal obstruction, or bladder outlet obstruction [BOO] [13]) were reoperated and the obstruction resolved. Chronic urinary tract infection (UTI) was defined as bacteriuria of 10 5 colony-forming units lasting 3 mo or three or more briefer episodes in a year Evaluation of renal function GFR was calculated applying the Modification of Diet in Renal Disease (MDRD) equation [14]: GFR (ml/min per 1.73 m 2 ) = 175 (serum creatinine) (age) (0.742 if female). We defined decreased renal function or increased renal function as a decrease or increase in GFR >10 ml/min per 1.73 m 2 before and 10 yr after surgery. Chronic kidney disease (CKD) stages were also used to classify renal function Definition of obstruction In the ICD group, ureteroileal stricture and/or a stomal obstruction by stricture or parastomal hernia was classified as obstruction. In the BS group, ureteroileal stricture or BOO was classified as obstruction Statistical analysis Statistical analysis was performed by the Institute of Mathematical Statistics and Actuarial Sciences, University of Bern, Switzerland, with the statistical software R. A two-tailed Z test was used to compare proportions, with logistic regression to determine risk factors for renal function deterioration. Statistical significance was defined as p < Results 3.1. Patient characteristics The causes of death of the patients surviving < 10 yr and therefore excluded from this analysis were similar in both Table 1 Causes of death of patients who survived <10 yr Cause of death n = 197 n = 203 Urinary diversion, related causes, no. (%) 11 (5.5) 6 (3) Renal failure, no. (%) 3 (1.5) 1 (0.5) Urosepsis, no. (%) 6 (3) 4 (2) Other, no. (%) 2 (1) 1 (0.5) Urinary diversion, unrelated causes, no. (%) 186 (94.5) 197 (97) Urothelial carcinoma, no. (%) 86 (43) 112 (55) Other cancers, no. (%) 22 (11) 26 (13) Cardiovascular disease, no. (%) 21 (11) 28 (14) Gastrointestinal bleeding, no. (%) 0 (0) 3 (1.5) Intracerebral bleeding, no. (%) 2 (1) 0 (0) Pulmonary diseases, no. (%) 2 (1) 7 (3.5) Other infections, no. (%) 7 (3.5) 6 (3) Suicide, no. (%) 0 (0) 4 (2) Unknown, no. (%) 46 (23) 11 (5) ICD = ileal conduit diversion; BS = bladder substitution. Table 2 Characteristics of ileal conduit diversion and bladder substitution patients at the time of surgery Characteristic groups (Table 1). The ICD group tended to have more deaths related to urinary diversion, although its 23% of patients with unknown cause of death leaves the exact percentage of diversion-related deaths unknown. For the evaluable patients, the median age and indications for cystectomy were comparable for both groups (Table 2). ICD patients had significantly more diabetes compared with BS patients ( p = 0.003) and tended to have more hypertension Renal function n =50 Ten years after surgery, the median GFR values had decreased from 65.5 (range: 23 90) to 57 (range: 7 100) ml/min per 1.73 m 2 in ICD patients and from 68 (range: ) to 66 (range: ) ml/min per 1.73 m 2 in BS patients. Eighteen ICD patients (36%) and 23 BS patients (21%) had deteriorating renal function. GFR values in 4 ICD patients and 15 BS patients had improved 10 yr after surgery (Fig. 2). Thirteen ICD patients (26%) and 19 BS patients (17%) had newly developed CKD stage III V (GFR <60 ml/min per 1.73 m 2 )after10yr(fig. 3). Two ICD patients needed hemodialysis 10 yr after surgery; no BS patients did Factors influencing renal function Median age, yr (range) 65 (38 80) 63 (37 79) Gender Male, no. (%) 21 (42) 99 (89) Female, no. (%) 29 (58) 12 (11) <0.001 Comorbidity at time of operation Hypertension, no. (%) 22 (43) 35 (32) Diabetes, no. (%) 14 (27) 7 (6) Loss of a renal unit, no. (%) 0 (0) 1 (1) Hydronephrosis, no. (%) 6 (12) 7 (6) Indications for cystectomy Bladder cancer, no. (%) 42 (84) 105 (94.5) Shrunken bladder, no. (%) 4 (8) 5 (4.5) Hemorrhagic cystitis, no. (%) 3 (6) 0 (0) Neurogenic bladder, no. (%) 1 (2) 1 (1) ICD = ileal conduit diversion; BS = bladder substitution. Ten of 18 ICD patients (56%) with decreasing renal function had diabetes, and only 4 ICD patients with diabetes had stable renal function ( p = 0.020), a difference not seen in the BS group (Table 3). Twelve of 50 ICD patients (24%) and 46 of 111 BS patients (41%) experienced outlet obstruction at any level of the urinary tract (1 BS patient with ureteroileal stricture and BOO was counted only once). One ICD patient (2%) had a ureteroileal stricture, while 11 patients (22%) had stomal obstruction. Thirteen BS patients (12%) had an obstruction of the upper urinary tract either because of ureteroileal stricture, stenosis of the antireflux

4 494 [(Fig._2)TD$FIG] EUROPEAN UROLOGY 61 (2012) pts (36%) with decreased RF 23 pts (21%) with decreased RF 28 pts (56%) with stable RF 73 pts (66%) with stable RF 15 pts (13%) with improved RF n= 50 4 pts (8%) with improved RF Fig. 2 The change in renal function (RF) in patients with ileal conduit diversion (ICD) or bladder substitution (BS) I10 yr after surgery. Decreased renal function is defined as a decrease in glomerular filtration rate (GFR) >10 ml/min per 1.73 m 2 in 10 yr. Improved RF is defined as an increase in GFR >10 ml/min per 1.73 m 2 in 10 yr. Because of the disparity between the 2 patient groups and the relatively small sample size, no direct comparison is made. pts = patients. [(Fig._3)TD$FIG] n = 50 Preoperative At 10 yr Preoperative At 10 yr GFR 60 ml/min per 1.73 m 2 (CKD stage I II) 34 68% % 86 77% % 3 10 GFR <60 ml/min per 1.73 m 2 (CKD stage III IV) 16 32% % 25 33% % Fig. 3 Chronic kidney disease (CKD) stages in patients with ileal conduit diversion (ICD) or bladder substitution (BS) before and 10 yr after urinary diversion. Thirteen of 34 ICD patients (38%) and 19 of 86 BS patients (22%) with a preoperative glomerular filtration rate (GFR) >60 ml/min per 1.73 m 2 developed CKD stage III V. Because the two groups are not necessarily comparable, no comparative computation is made. Numbers in the columns indicate the number of patients. nipple used earlier in a randomized trial, or stenosis of the afferent limb; 34 BS patients (31%) experienced BOO that required treatment at least once. Causes of BOO were anastomotic stricture (n =15), mucosa prolapse (n =10), urethral stricture (n = 6), and prostate growth (n =3).All were incised/resected endoscopically [15]. Seven of 12 ICD patients (58%) and 17 of 46 BS patients (37%) with obstruction had renal function deterioration. Urinary tract obstruction was an independent risk factor for renal function deterioration in both ICD and BS patients (Table 4). Neither nephrolithiasis nor chemotherapy appeared to negatively affect renal function. Relief of preoperative ureteral obstruction after surgery was the main reason for improved renal function in both ICD and BS patients (Table 5). In both groups, chronic UTI was associated with a worse renal outcome. ICD patients had a high incidence of chronic UTI (15 of 50 patients, or 30%). Twelve of 15 patients (80%) had renal function deterioration, while only 3 patients had stable renal disease ( p < 0.001). In 5 of 15 ICD patients (33%), chronic UTI was associated with urinary tract obstruction, in 8 patients (53%) with recurrent pyelonephritis. Of the 16 BS

5 EUROPEAN UROLOGY 61 (2012) Table 3 Incidence of decreased or stable/improved glomerular filtration rate according to risk factors for renal function deterioration in patients with ileal conduit diversion or bladder substitution n =50 Risk factors Pts per 18 pts (36%) with decreased GFR (>10ml/min per 10 yr), no. (%) Pts per 32 pts (64%) with stable/improved GFR, no. (%) Pts per 23 pts (21%) with decreased GFR (>10ml/min per 10 yr), Pts. per 88 pts (79%) with stable/improved GFR, no. (%) no. (%) Diabetes 10 (56) 4 (13) (13) 4 (5) Hypertension 13 (72) 9 (28) (35) 27 (31) Nephrolithiasis 2 (11) 2 (6) (9) 3 (3) Pyelonephritis 9 (50) 6 (19) (40) 16 (18) Hydronephrosis * 1 (6) 4 (13) (4) 3 (3) Chronic UTI 12 (67) 3 (9) < (48) 5 (6) <0.001 Loss of a renal unit 1 (6) 0 (3) 0 (0) 1 (1) before diversion Chemotherapy 3 (17) 2 (6) (4) 5 (6) Ureteroileal obstruction 1 (6) 0 (0) 6 (26) 7 (8) Stomal obstruction 6 (33) 5 (16) BOO 12 (5) 22 (25) Total urinary tract obstructions ** 7 (39) 5 (16) 17 (74) 29 (33) ICD = ileal conduit diversion; BS = bladder substitution; pt = patient; GFR = glomerular filtration rate; UTI = urinary tract infection; BOO = bladder outlet obstruction. The ICD group had a significant proportion of patients with decreased renal function after 10 yr who had diabetes and chronic UTI. Hypertension and obstructions were more common in ICD patients with decreased GFR. In the BS group, UTI and ureteroileal stricture were significantly associated with a worse renal outcome. BOO and pyelonephritis were more common in BS patients with decreased GFR (statistically not significant). * Only patients without apparent ureteroileal stricture/stenosis. ** Total urinary tract obstruction in the ICD group includes patients with ureteroileal stricture or stomal obstruction; total urinary tract obstruction in the BS group includes patients with ureteroileal stricture/nipple obstruction and/or BOO; one patient with ureteroileal stricture and BOO was counted only once. Table 4 Significant risk factors for renal function deterioration in patients with ileal conduit diversion or bladder substitution as assessed by logistic regression analysis Probability of observing a renal function deterioration Coefficient Estimate In ICD patients Urinary tract obstruction * Diabetes Hypertension In BS patients Urinary tract obstruction ** ICD = ileal conduit diversion; BS = bladder substitution. * Urinary tract obstruction in the ICD group includes patients with ureteroileal stricture or stomal obstruction. ** Urinary tract obstruction in the BS group includes patients with ureteroileal stricture/nipple obstruction and/or bladder outlet obstruction. Table 5 Reasons for improved renal function n =50 Patients with improved RF, no. (%) 4 (8) 15 (14) Reasons Preoperative ureteral obstruction, no. (%) 2 (4) 5 (5) Shrunken bladder with low compliance, no. (%) 1 (2) 1 (1) BOO with large PVR before surgery, no. (%) 1 (1) Stopped intake of nephrotoxic medication, no. (%) 2 (2) Unknown, no. (%) 1 (2) 6 (5) ICD = ileal conduit diversion; BS = bladder substitution; RF = renal function; BOO = bladder outlet obstruction; PVR = postvoid residual. patients (14%) with chronic UTI, 11 patients (69%) experienced diminished renal function, and 5 patients had stable renal disease ( p < 0.001). Most chronic UTIs (11 of 16 UTIs, or 69%) were secondary to ureteroileal obstruction or BOO in the BS group (Table 3). In the ICD group, 72% of hypertensive patients had diminished renal function, and 28% had stable GFR ( p = 0.07). In the BS group, 35% of hypertensive patients had decreased GFR.

6 496 EUROPEAN UROLOGY 61 (2012) Discussion Preservation of renal function is of paramount importance following urinary diversion. So far, most studies assessing renal function have simply compared median or mean GFR values before surgery and at various average times after surgery, not taking into account that in some patients GFR improves after the alleviation of obstruction or that the inclusion of good short-term results may mask poorer longterm results. In the Mayo Clinic series, 20% of ICD patients developed moderate to severe CKD (stage III V) after a median follow-up of only 5.8 yr [16], whereas in our series, 13 of 50 ICD patients (26%) and 19 of 111 BS patients (17%) had developed CKD stage III V 10 yr after surgery. It is noteworthy that most patients already had CKD stage II before surgery. Samuel et al. detected a worsening of GFR by >5% in 52 of 178 ICD patients (29%) a mean 8.2 yr after surgery [3]. Eisenberg and colleagues reported that 30% of BS patients (45 of 148 patients) with a preoperative calculated GFR (egfr) >60 ml/min showed a decrease in egfr below 60 ml/min at 3 yr [17]. Mansour et al. found a mean 13% decline in GFR values in 113 BS patients after 10 yr [18]. Because there is a ml/min per 1.73 m 2 agedependent physiologic decrease in GFR per year [19,20],we only considered a decline in GFR >10 ml/min per 1.73 m 2 over 10 yr as significant. This is a more objective criterion for evaluating renal function deterioration than are changes in CKD stages, because a GFR decrease from, for example, 85 ml/min to 65 ml/min would still be considered stable (CKD stage II), while a decrease from 65 to 55 ml/min would be classified as aggravated CKD from stage II to stage III. GFR was calculated with the MDRD formula, although the gold standard for GFR measurement is still urinary inulin clearance. In the original MDRD study, the measured urinary creatinine clearance was not more accurate than the egfr [21]. Several other studies have shown poorer accuracy with nuclear imaging than with egfr [22]. The present study clearly shows that both ICD and BS patients with urinary tract obstruction are at high risk of developing renal function deterioration, regardless of the level at which the obstruction occurs (ureteroileal anastomosis, ileal conduit, BOO). To avoid irreversible renal damage, patients must be regularly followed up and any obstruction treated early. The higher incidence of ureteroileal stricture in BS patients (12%) was partially due to their being part of an earlier prospective randomized study in which half of patients received an intussuscepted antireflux nipple valve; these patients had a high stricture/obstruction rate, as reported previously [12]. Furthermore, the true incidence of outlet obstruction in the ICD patients may be underestimated because of nonstandardized follow-up examinations in this regard. Both ICD and BS patients with chronic UTI were likely to develop renal function deterioration. In the BS group, 69% of patients (11 of 16 patients) with chronic UTI had the UTI secondary to ureteroileal stricture or BOO. Whether the chronic UTI was a consequence of outlet obstruction or whether the outlet obstruction itself was the leading cause of renal function deterioration is difficult to assess. Interestingly, 66% of ICD patients with chronic UTI had no obstruction. In the Samuel et al. series, recurrent UTI was significantly more common in patients with worsening GFR than in patients with stable GFR, but only 36% had urinary tract obstruction [3]. This report accords with our findings. Whether chronically infected urine itself, without outlet obstruction, plays a role in long-term renal function impairment in ICD patients is unclear. A surprising finding was that diabetes and hypertension were risk factors for renal function deterioration in ICD patients but not in BS patients. Samuel et al. found hypertension to be an independent predictor of GFR decrease in ICD patients as well [3]. Kim et al. reported hypertension as a significant risk factor for worsening of CKD stage following radical cystectomy, but they did not distinguish between types of diversion [16]. Our findings suggest that it is safer for patients with known renal deterioration risk factors (eg, diabetes and hypertension) to undergo BS than to receive an ICD. This issue requires further elucidation. The main limitation of our study is that it is retrospective, with incomplete follow-up for many ICD patients. The unknown causes of death (23%) occurring after <10 yr in the ICD group may mask additional cases of urinary diversion related death. It is currently unclear to what extent creatinine and urea are reabsorbed by the ileal neobladder and whether creatinine can be used to assess kidney function. Animal models suggest that much of the creatinine is reabsorbed by solvent drag, a glucose-dependent way of transport. Creatinine is reabsorbed less well by an active carriermediated transport [23]. As urine normally does not have large amounts of glucose, creatinine may be resorbed to a lesser degree. Rinnab et al. showed reabsorption of creatinine and urea in 50% of patients with an ileal neobladder, but 27% of the patients simultaneously excreted creatinine and resorbed urea, while 10% of the patients showed the reverse response [24]. It remains unclear whether there is significant reabsorption of urea and creatinine in BS or ICD patients. As the contact time of urine is shorter and the reabsorbing surface of an ICD is smaller than that of a reabsorption of creatinine would be expected to be more pronounced in BS patients, their serum creatinine levels would be expected to be higher, and hence their GFR could be falsely lower [25]. Despite this, our BS patients showed an opposite trend, which would rather speak in favor of BS diversion. 5. Conclusions The present findings show that a substantial proportion of both ICD and BS patients experienced renal function deterioration during a. Urinary tract obstruction at any level was the leading cause of impaired long-term renal function. UTI also appears to play an important role in renal function deterioration, especially when combined with obstruction. We observed better

7 EUROPEAN UROLOGY 61 (2012) long-term renal function after orthotopic ileal BS than after ICD in patients with predisposing risk factors for CKD, namely, diabetes or hypertension. Author contributions: Urs E. Studer had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Studer, Jin, Roethlisberger. Acquisition of data: Jin, Roethlisberger, Burkhard, Birkhaeuser, Thoeny. Analysis and interpretation of data: Jin, Roethlisberger, Studer. Drafting of the manuscript: Jin, Roethlisberger. Critical revision of the manuscript for important intellectual content: Studer. Statistical analysis: None. Obtaining funding: None. Administrative, technical, or material support: Burkhard. Supervision: Studer. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Lowrance WT, Rumohr JA, Clark PE, et al. Urinary diversion trends at a high volume, single American tertiary care center. J Urol 2009; 182: [2] Kassouf W, Hautmann RE, Bochner BH, et al. A critical analysis of orthotopic bladder substitutes in adult patients with bladder cancer: is there a perfect solution? Eur Urol 2010;58: [3] Samuel JD, Bhatt RI, Montague RJ, et al. 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