Long-Term Renal Function Outcomes after Radical Cystectomy

Long-Term Renal Function Outcomes after Radical Cystectomy Manuel S. Eisenberg, R. Houston Thompson, Igor Frank,* Simon P. Kim, Katherine J. Cotter, Matthew K. Tollefson, Dharam Kaushik, Prabin Thapa, Robert Tarrell and Stephen A. Boorjian† From the Departments of Urology (MSE, RHT, IF, MKT, DK, SAB) and Health Sciences Research (PT, RT), Mayo Clinic, Rochester and Department of Urology, University of Minnesota (KJC), Minneapolis, Minnesota, and Department of Urology, Yale University (SPK), New Haven, Connecticut

Purpose: We evaluated the long-term natural history of renal function after radical cystectomy with urinary diversion and determined factors associated with decreased renal function. Materials and Methods: We reviewed the records of 1,631 patients who underwent radical cystectomy between 1980 and 2006. The estimated glomerular filtration rate was calculated preoperatively and at various intervals after surgery. A renal function decrease was defined as a greater than 10 ml per minute/ 1.73 m2 reduction in the estimated glomerular filtration rate. Multivariate analysis was done to evaluate the association of clinicopathological features, incontinent vs continent diversion type and postoperative complications with decreased renal function. Results: A total of 1,241 patients (76%) underwent incontinent diversion and 390 (24%) underwent continent diversion. Median followup after radical cystectomy in patients alive at last followup was 10.5 years (IQR 7.1, 15.3). The median preoperative estimated glomerular filtration rate was higher in the continent diversion cohort (67 vs 59 ml per minute/1.73 m2, p <0.0001). This difference was maintained until 7 years postoperatively, after which no difference was noted in renal function by diversion type. By 10 years after radical cystectomy the risk of a renal function decrease was similar for incontinent and continent diversion (71% and 74%, respectively, p ¼ 0.13). On multivariate analysis risk factors associated with decreased renal function included age (HR 1.03, p <0.0001), preoperative estimated glomerular filtration rate (HR 1.05, p <0.0001), chronic hypertension (HR 1.2, p ¼ 0.01), postoperative hydronephrosis (HR 1.2, p ¼ 0.03), pyelonephritis (HR 1.3, p ¼ 0.01) and ureteroenteric stricture (HR 1.6, p <0.0001). Conclusions: Decreased renal function is noted in most patients during longterm followup after radical cystectomy. Postoperative hydronephrosis, pyelonephritis and ureteroenteric stricture represent potentially modifiable factors associated with a decrease. Choice of urinary diversion was not independently associated with decreased renal function.

Abbreviations and Acronyms CD ¼ continent diversion CKD ¼ chronic kidney disease eGFR ¼ estimated GFR GFR ¼ glomerular filtration rate ID ¼ incontinent diversion RC ¼ radical cystectomy RF ¼ renal function UD ¼ urinary diversion Accepted for publication September 4, 2013. Study received institutional review board approval. * Financial interest and/or other relationship with Rochester Medical. † Correspondence: 200 First St. Southwest, Rochester, Minnesota 55905 (telephone: 507284-3982; FAX: 507-284-4951; e-mail: boorjian. [email protected]).

Key Words: urinary bladder neoplasms; urinary diversion; renal insufficiency, chronic; cystectomy; postoperative complications IN 2013 bladder cancer represented the fifth most commonly diagnosed malignancy in the United States.1 RC

with UD remains the standard of care for muscle invasive bladder cancer and high risk nonmuscle invasive

0022-5347/14/1913-0619/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.

http://dx.doi.org/10.1016/j.juro.2013.09.011 Vol. 191, 619-625, March 2014 Printed in U.S.A.

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disease.2 Nevertheless, RC is associated with significant risks of perioperative and long-term morbidity and mortality.3,4 UD is particularly associated with subsequent deterioration in RF.36 RF deterioration is particularly concerning, given the noted association between severe CKD and all cause mortality.4,6e11 The etiology of an RF decrease after RC is likely multifactorial, including age related changes, potential nephrotoxic chemotherapy, the impact of patient comorbidities, which are frequent in such a population, and postoperative urinary tract obstruction and infectious related complications. However, in most studies of RF after UD to date serum creatinine was used as the measure of RF.4,8,10e13 Serum creatinine is influenced by numerous factors, including age, gender, hydration level and muscle mass, and it often overestimates the GFR. Because most patients treated with RC and UD are elderly, in this population serum creatinine may be particularly inaccurate. Quantifying RF by eGFR is a more accurate measure of RF since it accounts for additional relevant variables such as age, race and gender.14 In this context we determined the long-term natural history of RF, as measured by eGFR in patients who underwent RC with UD. We also identified potentially modifiable factors associated with worsening RF in these patients.

MATERIALS AND METHODS After receiving institutional review board approval we identified 2,472 patients treated with RC and UD for pTanyNanyM0 bladder cancer at our institution between 1980 and 2006. Of these patients we excluded 236 without serum creatinine measurement within 90 days preoperatively, 589 without serum creatinine measurement 90 days or greater postoperatively and 16 without research authorization, leaving 1,631 available for analysis. All patients underwent RC using standard techniques. The ID group consisted of those who received an ileal conduit while the CD group included 5 patients with cutaneous CD and 385 with orthotopic neobladder diversion. The ureteroenteric anastomosis was formed using a freely refluxing technique for ID and CD. Evaluated clinical variables included age, race, gender, ECOG (Eastern Cooperative Oncology Group) performance status, preoperative chronic hypertension, type 2 diabetes, preoperative hydronephrosis, baseline and followup eGFR, receipt of perioperative systemic chemotherapy and UD type. When evaluating postoperative complications, we focused on those related to renal obstruction or infection, that is hydronephrosis, pyelonephritis, urolithiasis, recurrent urinary tract infection (4 or more per year), ureteroenteric stricture, stomal stenosis and renal unit loss. The designation of hydronephrosis was based on abnormal upper tract imaging in patients

with or without documentation of a ureteroenteric stricture. Pyelonephritis was defined as a febrile episode with a positive urine culture in the absence of another indication for fever. We previously reported our method of identifying long-term complications of UD.4 The retrospective nature of our study precluded standardized postoperative surveillance in all patients. However, followup after RC at our institution is recommended quarterly for the first 2 years after surgery, semiannually for the next 2 years and annually thereafter in patients without evidence of recurrence. For patients followed elsewhere the cystectomy registry at our institution monitors outcomes annually by correspondence with the patient and treating physician. The primary outcome measure was eGFR. It was calculated using the CKD Epidemiology Collaboration (CKD-EPI) equations because these equations provide the most accurate assessment of RF, with the best prediction of long-term patient outcome and the least bias over a large eGFR range.1417 To evaluate factors associated with a decrease in eGFR we compared preoperative eGFR to values obtained at subsequent postoperative visits. For the 6-month postoperative time point we used serum creatinine measurements made 3 to 9 months after surgery. For the 1-year time point we evaluated serum creatinine measured 9 to 18 months postoperatively. For all subsequent time points values obtained within 6 months of the given time point were considered. If multiple serum creatinine values were available for a given time point, we used the median for analysis. We assessed for a RF decrease, defined as a greater than 10 ml per minute/1.73 m2 reduction in eGFR from baseline during followup to be consistent with a recent similar analysis.18 On time dependent analysis we evaluated the time since surgery for the RF decrease. Continuous variables are shown using summary statistics and categorical variables are shown as the frequency. Median eGFR values were compared using the Wilcoxon rank sum test. The rate of RF decreasefree survival was estimated using the Kaplan-Meier method and compared using the log rank test. Cox proportional hazards regression models were used to assess the association of clinicopathological variables with decreased RF. Statistical analysis was done using SASÒ and R (R Foundation for Statistical Computing, Vienna, Austria) with 2-sided p <0.05 considered statistically significant.

RESULTS Table 1 lists patient clinicopathological features. A total of 1,241 and 390 patients underwent ID and CD, respectively. Demographic differences between the ID and CD cohorts were noted for almost all evaluated variables, including age at surgery, preoperative eGFR, T and N stage, functional status and comorbidities. Of 1,631 patients 192 (12%) received chemotherapy perioperatively, including cisplatinum based regimens in 146 (76%). Overall 888 patients (54%) experienced 1 or more

LONG-TERM RENAL FUNCTION OUTCOMES AFTER RADICAL CYSTECTOMY

621

Table 1. Clinicopathological demographics Overall No. pts Median age (IQR) No. female (%) No. white (%)* No. ECOG performance status (%):† 0 1 2 or Greater No. chronic hypertension (%) No. type 2 diabetes (%) No. preop hydronephrosis (%) Median mg/dl preop creatinine Median ml/min/1.73 m2 preop eGFR (IQR) Median yrs followup (IQR) No. pathological stage (%):‡ pT0 pTa/is/1 pT2 pT3-4 pNþ§ No. periop chemotherapy (%) No. postop renal complications (%): Hydronephrosis Renal unit loss Urolithiasis Pyelonephritis Recurrent urinary tract infections Ureteroenteric stricture Stomal stenosis * Of † Of ‡ Of § Of

1,629 1,630 1,369 1,408

1,631 68 288 1,538

ID

(61, 74) (18) (94)

1,334 (82) 233 (14) 63 (4) 650 (40) 168 (27) 404 (25) 1.2 (1.0, 1.4) 61.6 (49.8, 72.5) 10.5 (7.1, 15.3)

1,241 69 247 1,180

CD (63, 76) (20) (95)

390 63 41 358

p Value

(56, 68) (11) (92)

965 (78) 214 (17) 61 (5) 514 (41) 138 (34) 331 (27) 1.2 (1.0, 1.4) 59.2 (47.6, 71.2) 11.2 (7.4, 16.1)

369 (95) 19 (5) 2 (0.5) 136 (35) 30 (14) 73 (19) 1.1 (1.0, 1.3) 67.2 (58.1, 74.7) 9.6 (6.8, 14.1)

<0.0001 <0.0001 0.01 <0.0001

0.02 <0.0001 0.002 0.007 <0.0001 0.01 <0.0001

163 521 240 445 300 192

(12) (38) (18) (33) (21) (12)

102 399 169 357 262 147

(10) (39) (16) (35) (25) (12)

61 122 71 88 38 45

(18) (36) (21) (26) (11) (12)

<0.0001 0.87

623 43 212 231 173 244 24

(38) (3) (13) (14) (11) (15) (1)

450 35 157 162 103 191 21

(36) (3) (13) (13) (8) (15) (2)

173 8 55 69 70 53 3

(44) (2) (14) (18) (18) (14) (1)

0.004 0.39 0.07 0.03 <0.0001 0.14 0.29

patients. patients. patients. patients.

obstructive or infectious related complication postoperatively. Hydronephrosis (44% vs 36%, p ¼ 0.004), pyelonephritis (18% vs 13%, p ¼ 0.03) and recurrent urinary tract infections (18% vs 8%, p <0.0001) were more likely to develop in patients who underwent CD. Median followup after RC in patients alive at last followup was 10.5 years (IQR 7.1, 15.3). The overall survival rate was 59% and 42% at 5 and 10 years, respectively. Interestingly, preoperatively and up to year 6 after RC the median eGFR was higher in CD

Table 2. eGFR by year after RC stratified by UD type Median eGFR (ml/min/1.73 m2) Postop Yr

Overall

ID

CD

p Value

Baseline 0.5 1 2 3 4 5 6 7 8 9 10

62 60 57 57 56 56 55 55 54 53 53 51

59 58 57 57 56 54 53 54 54 53 52 52

67 63 59 60 59 58 57 56 54 54 55 50

<0.0001 <0.0001 0.003 0.002 0.01 0.01 0.02 0.04 0.80 0.27 0.08 0.87

cases (table 2). However, beginning 7 years postoperatively we detected no significant difference in eGFR between CD and ID cases. Preoperatively 642 of 1,241 patients with ID (52%) and 115 of 390 with CD (29%) were classified with stage 3 CKD, defined as eGFR less than 60 ml per minute/1.73 m2 (p <0.0001). Notably, of patients with eGFR 60 ml/ minute/1.73 m2 or greater before surgery new onset stage 3 CKD was detected postoperatively in 326 of 599 (54%) with ID and 156 of 275 (57%) with CD (p ¼ 0.52). The incidence of postoperative hemodialysis was similar in patients with ID and CD, that is 45 of 1,241 (3.6%) and 12 of 390 (3.1%), respectively (p ¼ 0.61). Figure 1 shows time to event analysis for RF decrease-free survival. One, 3, 5 and 10 years postoperatively the risk of a greater than 10 ml/ minute/1.73 m2 decrease in eGFR was 26%, 44%, 54% and 71%, respectively, in patients with ID. This was not statistically significantly different from the 31%, 47%, 57% and 74% rate of decreased RF, respectively, in patients with CD (p ¼ 0.13). Of patients with preoperative stage 3 CKD 191 of 642 (30%) with ID and 45 of 115 (39%) with CD showed improvement in eGFR to 60 ml per minute/ 1.73 m2 or greater during followup (p ¼ 0.05). We further noted that 337 of 1,241 patients (27%) with

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LONG-TERM RENAL FUNCTION OUTCOMES AFTER RADICAL CYSTECTOMY

Figure 1. RF decrease-free survival by UD type

ID and 87 of 390 (22%) with CD showed an improvement in eGFR of 10 ml per minute/1.73 m2 or greater at some point during postoperative followup (p ¼ 0.06). A postoperative, RF related complication was associated with a significantly increased risk of decreased RF (fig. 2). This association was maintained regardless of UD choice. Thus, in patients with ID with any renal complication the 5-year RF decrease-free rate was 42% vs 53% in those with ID who remained free of post-RC complications (p ¼ 0.002). An even greater difference in RF decrease-free survival was seen at 5 years in patients with CD who did vs did not experience a renal complication (34% vs 62%, p <0.0001). We observed no difference in RF decrease-free survival between patients with ID vs CD who were free of renal complications (p ¼ 0.18). On multivariate analysis greater patient age (HR 1.03, p <0.0001), greater preoperative eGFR (HR 1.05, p <0.0001) and chronic hypertension (HR 1.2, p ¼ 0.01) were independently associated with decreased RF (table 3). Decreased RF was also significantly associated with postoperative hydronephrosis (HR 1.2, p ¼ 0.03), pyelonephritis (HR 1.3, p ¼ 0.01) and ureteroenteric stricture (HR 1.6, p <0.0001). Importantly, the choice of UD was

not independently associated with the subsequent patient risk of a RF decrease.

DISCUSSION In a large cohort of patients with long-term followup the overall rate of decreased RF approached 72% 10 years after RC. We identified nonmodifiable and potentially modifiable risk factors associated with poor RF outcome. Specifically, older age, higher preoperative eGFR, chronic hypertension, postoperative hydronephrosis, ureteroenteric anastomotic stricture and pyelonephritis were associated with an increased risk of subsequent decreased RF. Importantly, UD type was not independently associated with the risk of a postoperative eGFR decrease. Several findings emerge from our data that are of particular clinical relevance for patients undergoing UD. Decreased RF was noted in about 72% of patients after UD with an increasing risk with time. To our knowledge the current study represents the first long-term, year-by-year report of median eGFR and RF decrease-free survival. One, 5 and 10 years after UD median eGFR was 57, 55 and 51 ml per minute/1.73 m2 with a 27%, 54% and 72% risk of decreased RF, respectively. The apparent

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Figure 2. RF decrease-free survival by postoperative renal related complications and UD type

discrepancy between the modest change in median eGFR and the increased risk of RF decrease-free survival may be explained by the inherent survivorship bias of reporting median eGFR or the RF rate at a specific time point, especially as the time from RC increases. That is, only the most fit patients are represented at the later time points while less fit patients who may have experienced a more significant RF decrease are increasingly underrepresented. Previous studies of decreased RF after UD were largely limited by short followup or by reporting RF at a single time point rather than as a dynamic process.4e6,10e12 Furthermore, while prior series showed decreased RF after RC in 5% to 27% of patients,8,11,13 the generalizability of these findings

is limited. Most patients in each cohort were excluded from final analysis since they did not attain the prespecified followup duration and, thus, RF was not assessed. For example, Jin et al recently reported a RF decrease in 25% of patients after RC at a minimum 10-year followup.18 However, the RF decrease was not provided in patients with less than 10-year followup, who represented 74% of the cohort. The difference in the decreased RF rate between our study and that by Jin et al may be attributable to differences in patient selection, exclusion criteria, different ratios of ID to CD and different methods used to calculate eGFR. Another important finding in our study was that similar decreased RF rates were noted in the ID and

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LONG-TERM RENAL FUNCTION OUTCOMES AFTER RADICAL CYSTECTOMY

Table 3. Multivariate analysis of clinicopathological features and complications associated with greater than 10 ml/minute/ 1.73 m2 eGFR decrease

Age Gender (referent female) Preop eGFR/1 ml/min/1.73 m2 increase Chronic hypertension Type 2 diabetes Preop hydronephrosis pT stage (referent pTa/is/1): pT2 pT3-4 pN1þ (referent pN0) Periop chemotherapy UD type (referent ID) Postop renal related complication: Hydronephrosis Renal unit loss Urolithiasis Pyelonephritis Recurrent urinary tract infections Ureteroenteric stricture Stomal stenosis

HR (95% CI)

p Value

1.03 (1.02e1.04) 1.1 (0.9e1.4) 1.05 (1.05e1.06) 1.2 (1.0e1.4) 1.1 (0.9e1.4) 0.9 (0.8e1.1)

<0.0001 0.31 <0.0001 0.01 0.44 0.59

1.1 1.1 1.1 1.1 1.1

(0.9e1.3) (0.9e1.3) (0.9e1.4) (0.8e1.4) (0.9e1.3)

0.39 0.51 0.27 0.49 0.28

1.2 1.3 0.9 1.3 1.2 1.6 1.1

(1.0e1.4) (0.9e1.8) (0.8e1.2) (1.1e1.6) (1.0e1.5) (1.3e2.0) (0.6e1.9)

0.03 0.22 0.52 0.01 0.07 <0.0001 0.79

CD groups. Notably, most previous groups evaluated RF for only a single UD type4,5,8e13 so that comparisons between ID and CD are limited. Our data substantiate prior assertions that eGFR and the risk of decreased RF are not worse in patients with CD than in those with ID.12,13,19 When offering patients CD vs ID, the inherent selection bias may possibly mask a true difference in postoperative RF but we noted no association between UD type and RF when adjusting for associated clinicopathological factors. However, potential differences in contact time may exist between urine and the bowel surface for CD vs ID, allowing for greater creatinine reabsorption by the CD. Such a difference may have contributed to the noted equilibration in median eGFR between diversions during the first 7 years after cystectomy. We also report the significant impact of renal related complications on long-term RF. Indeed, previous studies identified decreased RF as one of the most common adverse events after RC.4e6,8e12 However, a limitation of many of these studies is the lack of evaluation of the relationship of longterm RF outcomes in relation to other, potentially modifiable risk factors, such as post-RC complications. Jin et al reported that 10 years after RC urinary tract obstruction was significantly associated with a RF decrease in ID and CD cases while diabetes and hypertension were contributing factors in ID but not in CD cases.18 Samuel et al reported that hypertension and recurrent urinary tract infections were risk factors for worsening GFR after ID while obstruction was the most common underlying cause of decreased RF in those patients.9 Recurrent urosepsis, hypertension and an immediate postoperative GFR of less than 50 ml

per minute/1.73 m2 were also associated with a long-term RF decrease.9 We similarly found that obstruction at the ureteroenteric anastomosis and pyelonephritis were predictive of decreased RF. Interestingly, we also noted that postoperative hydronephrosis was predictive of an RF decrease even after controlling for a documented ureteroenteric anastomotic stricture, possibly indicating a role for increased surveillance for the clinically common finding of upper tract dilatation in the absence of stricture. Recognition of these postoperative conditions and early intervention may offer an opportunity to impact long-term renal outcomes. Our study is limited by its retrospective, nonrandomized design. We further acknowledge the potential for underestimating renal related postoperative complications, given the tertiary referral nature of our center, since patients frequently undergo followup locally. Additionally, excluding patients from analysis when they did not have longterm RF data available may have introduced selection bias. Those on whom RF data were and were not recorded in our registry may have had clinically relevant clinicopathological differences that would have impacted an RF decrease. While we mirrored clinical practice by determining RF with eGFR, we did not evaluate the gold standard measures of inulin clearance or creatinine clearance under diuretic conditions and we recognize the potentially limited accuracy of measuring serum creatinine in patients after UD due to creatinine reabsorption.20 Moreover, we acknowledge the lack of a control population that did not undergo surgery to assess the comparative impact of RC and UD on a RF decrease. Notably, we could not examine the effects of medical or surgical intervention for renal related complications on subsequent RF. Our data also did not allow us to assess the impact of different types of ureterointestinal anastomoses or different bowel segments on subsequent RF, as reported previously.2123

CONCLUSIONS Most patients experienced a decrease in RF during long-term followup after RC, although no difference was seen at 10 years between patients with IC vs CD. Age, preoperative kidney function and chronic hypertension, and the postoperative complications of hydronephrosis, pyelonephritis and ureteroenteric anastomotic stricture were associated with an increased risk of decreased RF. These data emphasize the importance of continuing to monitor eGFR after RC and identifying and treating renal related complications early to limit RF deterioration.

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