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Analysis of Renal Functional Outcomes After Radical or Partial Nephrectomy for Renal Masses ≥7 cm Using the RENAL Score
Oncology Analysis of Renal Functional Outcomes After Radical or Partial Nephrectomy for Renal Masses ‡7 cm Using the RENAL Score Ryan P. Kopp, Michael A. Liss, Reza Mehrazin, Song Wang, Hak J. Lee, Ramzi Jabaji, Hossein S. Mirheydar, Kyle Gillis, Nishant Patel, Kerrin L. Palazzi, Jim Y. Wan, Anthony L. Patterson, and Ithaar H. Derweesh OBJECTIVE
METHODS
RESULTS
CONCLUSION
To determine if partial nephrectomy (PN) confers a renal functional benefit compared to radical nephrectomy (RN) for clinical T2 renal masses (T2RM) when adjusting for tumor complexity characterized by the RENAL nephrometry score. A 2-center study of 202 patients with T2RM undergoing RN (122) or PN (80) (median follow-up, 41.5 months). RN and PN cohorts were subanalyzed according to RENAL sum as a categorical variable of <10 or 10. Primary outcome was median change in estimated glomerular filtration rate (DeGFR) between preoperative to 6 months postoperative. Logistic regressioneidentified prognostic factors and survival models analyzed association between the RENAL sum and the freedom from de novo chronic kidney disease (CKD; eGFR<60 mL/min/1.73m2). No significant differences existed between PN and RN for RENAL score. DeGFR was greater in RN (19.7) vs PN (11.9; P ¼ .006). De novo CKD was 40.2% after RN vs 16.3% after PN (P <.001). RENAL score 10 (odds ratio, 6.67; P ¼ .025) and RN among patients with RENAL score <10 (odds ratio, 24.8; P <.001) were independently associated with de novo CKD at 6 months by logistic regression. Among patients with RENAL score <10, median CKD-free survival was PN 38 vs RN 16 months (P ¼ .001). Cox proportional hazard demonstrated decreasing risk of CKD for PN vs RN from RENAL 10 (hazard ratio, 0.836) to RENAL 6 (hazard ratio, 0.003; P ¼ .001). RN is independently associated with decreased renal function compared to PN for T2RM with RENAL sum 10, but not >10, with larger relative decrease in eGFR for each decrease in RENAL sum. Further investigation is required to determine optimal candidates for PN in T2RM. UROLOGY -: -e-, 2015. 2015 Elsevier Inc.
P
artial nephrectomy (PN) is a preferred option for clinical T1 renal masses, by which a large amount of parenchyma may often be spared.1-6 The role of PN for renal functional preservation in clinical T2 renal masses (T2RM) is unclear. Radical nephrectomy (RN) and PN may be oncologically similar, and it is possible that PN might have superior overall survival through long-term preservation of renal function.7,8 This
Ryan P. Kopp and Michael A. Liss contributed equally to this work. Financial Disclosure: The authors declare that they have no relevant financial interests. Funding Support: This study was supported by Stephen Weissman Kidney Cancer Research Fund. From the Department of Urology, Moores Cancer Center, UC San Diego Health System, La Jolla, CA; and the Department of Urology, University of Tennessee Health Science Center, Memphis, TN Address correspondence to: Ithaar H. Derweesh, M.D., Department of Urology, Moores Cancer Center, UC San Diego Health System, 3855 Health Sciences Drive, Mail Code: 0987, La Jolla, CA 92093-0987. E-mail: [email protected] Submitted: November 1, 2014, accepted (with revisions): February 3, 2015
ª 2015 Elsevier Inc. All Rights Reserved
thought is controversial after results of a prospective randomized trial demonstrated similar survival for RN and PN in the renal cell carcinoma population.9 The body of literature on PN for T2RM is growing despite there being no consensus opinion on utility of PN in this setting.10-16 Comparative studies of RN and PN for T2RM that specifically examine renal functional outcomes are limited. RENAL nephrometry score includes additional measures of anatomic differences between tumors, in addition to the tumor-parenchyma relationship, which correlates with renal functional outcomes and procedure selection.3,4,17,18 We recently demonstrated the use of RENAL score to control for variability of T2RM for oncologic outcomes.16 We aim to translate this methodology to elucidate if there is a tumor size or anatomic complexity threshold at which point renal functional benefit from PN reaches a plateau—this may aid in http://dx.doi.org/10.1016/j.urology.2015.02.067 0090-4295/15
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patient selection for PN among those with T2RM and in prognostication of renal functional outcomes.
METHODS Study Patients An institutional review boardeapproved retrospective study of patients with T2RM who underwent RN or PN at 2 institutions (UC San Diego Health System and University of Tennessee Health Sciences Center) from July 2002 to June 2012 (median follow-up, 41.5 months) was carried out. Evaluation, management, and follow-up of T2RM have been previously published.16 Imperative indications led to PN (n ¼ 80) in 20 patients (25%); this included (chronic kidney disease [CKD] or an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73m2 [n ¼ 20], solitary kidney [n ¼ 7], bilateral tumors [n ¼ 6]). Relative indications weighted surgeon recommendation toward PN in 29 patients (36%; multiple risk factors for CKD, including diabetes mellitus or proteinuria, severe hypertension, body mass index [BMI] >35 kg/m2, GFR <70 mL/min/1.73 m2]). Elective PN included 31 cases (39%). Of those who underwent RN (n ¼ 122), 20 (16.3%) had eGFR <60 mL/min/1.73 m2. There were no RN for solitary kidney; 7 patients underwent RN for T2RM with PN of contralateral T1 mass. Sixteen patients (13.1%) with relative indications elected RN over PN. Laparoscopic surgery candidacy was determined by operating surgeons. There were no conversions from PN to RN. Cases with preoperative estimates of ischemia time <30 minutes used warm ischemia and cold ischemia if estimates were 30 minutes.
Variables and Outcomes We recorded patient demographics, clinical characteristics, and renal function (serum creatinine, eGFR [mL/min/1.73 m2] calculated by Modification of Diet in Renal Disease equation).19 Renal mass parameters included tumor size (cm), renal cell carcinoma grade or histology, RENAL nephrometry score,17 and American Joint Committee on Cancer (AJCC) stage.20 Analysis of perioperative outcomes included surgical approach, operative time, estimated blood loss (mL), ischemia time (PN), and complications (Clavien).21 Primary outcome was median change of eGFR (DeGFR) between preoperative to 6 months postoperatively, with secondary outcomes being median change in creatinine level (DCr) from preoperative to 6 months postoperative, de novo CKD, and time to CKD. We excluded all perioperative laboratory test results during inpatient admission and laboratory test results obtained before 6 months. De novo CKD, defined as development of stage III CKD,4-6,19,22 with 2 consecutive eGFR values <60 mL/min/1.73m2 no less than 3 months apart and no greater than 6 months apart. The date of earliest value between the 2 (6 months postoperative) was listed as the date of de novo CKD. Patients who never recovered eGFR to 60 by 6 months postoperative were listed as de novo CKD at 6 months.
Statistical Analysis Clinical characteristics, RENAL scores, and functional outcomes were analyzed within subgroups of RN and PN using chi-square and Fisher exact tests for categorical variables and Mann-Whitney test and t test for continuous variables. RN and PN cohorts were then analyzed within RENAL sum as categorical variable of <10 or 10. Before analysis, we designated 10 as threshold to create groups of similar size and 2
to separate simple and intermediate masses from complex masses based on previous publications (simple, 4-6; intermediate, 7-9; and complex, 10-12).16-18 We conducted further analysis by individual total RENAL sum by Cox proportional hazard models (described below) to determine most appropriate prognostic groups. We used binary logistic and linear regression models to determine association between surgery type and renal functional outcomes. Logistic regression model included procedure, RENAL score, and outcome of de novo CKD. Kaplan-Meier survival estimates for freedom from CKD through the date of last follow-up were constructed to assess for durable renal function using the time to event and were analyzed with logrank test among RN vs PN overall and stratified by RENAL sum (<10 vs 10). Cox proportional hazard analysis was carried out using RENAL sum as a continuous variable to represent a continuous spectrum of risk, with hazard ratios generated at each RENAL sum. Analysis used SPSS (version 17.0; Chicago, IL, SPSS, Inc.), with P <.05 defining significant.
RESULTS Participants Two hundred two patients with cT2RM underwent RN (122) or PN (80). Demographic characteristics were similar between groups. Hypertension was more common in PN (P ¼ .05), whereas preoperative renal function and other comorbidities were not significantly different between groups (Table 1). Perioperative Outcomes Patients who underwent PN were more likely to have open surgery (97.5%) compared to those who underwent RN (62.3%; P <.001; Table 1). Cold ischemia was used in 42 PN patients (median time, 48 min; interquartile range [IQR], 39-54). Warm ischemia was used in 35 patients who underwent PN (median time, 24 min; IQR, 19-27). Clampless (nonischemic) technique was used in 3. Operative time and estimated blood loss were significantly higher for PN. PN and RN had similar transfusion rates and length of stay. Clavien 3 complications were more common in PN (n ¼ 14, 17.5%) vs RN (n ¼ 3, 2.5%; P <.001). Urinary fistula occurred in 8 (10%) PN patients, and these patients were managed with combination of stents and percutaneous drains. Additional renal complications included acute kidney injury in 1 RN patient, temporary dialysis in 1 PN patient (solitary kidney or preexisting CKD), and renal pseudoaneurysm in 3 PN patients requiring selective angioembolization—patients had imperative (2) or relative (1) indication for PN, and all had complex (10-12) RENAL sum. At the last follow-up, serum creatinine level (mg/dL) had increased by 0.2 in 1 patient and by 0.3 and 0.4 in the other 2. Remaining complications for this cohort were described previously.16 Tumor Size and Morphology RENAL score was available for 105 RN and 73 PN patients (Table 2). Mean tumor size (cm) was smaller in PN (8.8) vs RN patients (10.2; P <.001). There was no UROLOGY
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Table 1. Clinical, perioperative, and pathologic variables Variable Age, (y), mean SD Gender, n (%) Male Female Race, n (%) Caucasian African American/Latino/Asian/other BMI (kg/m2), mean SD Hypertension, n (%) Diabetes, n (%) Coronary artery disease, n (%) Tumor size (cm) from CT, mean SD Preoperative creatinine, median (IQR) Clinical T stage, n (%) cT2a cT2b Preoperative eGFR <60 mL/min/1.73m2, n (%) Approach, n (%) Open Laparoscopic OR time (min), mean SD Estimated blood loss (mL), median (IQR) Ischemia time (min), median (IQR) Days in hospital, median (IQR) Transfusion, n (%) Pathology, n (%) Benign tumors Malignant tumors Positive margins, n (%) Complications, n (%) Low-grade complication, n (%) High-grade complication, n (%) Urine leak
RN (n ¼ 122)
PN (n ¼ 80)
P Value
58 9.0
58 12.4
.751 .550
77 (63.1) 45 (36.9)
54 (67.5) 26 (32.5)
62 (52.1) 57 (47.9) 29.2 5.1 73 (59.8) 24 (19.7) 5 (11.9) 10.2 2.7 1.0 (0.9-1.2)
37 (46.3) 43 (53.8) 30.1 4.6 59 (73.8) 23 (28.8) 6 (13.0) 8.8 1.6 1.1 (0.9-1.3)
78 (63.9) 44 (36.1) 20 (16.3)
62 (77.5) 18 (22.5) 20 (25)
.471
76 (62.3) 46 (37.7) 153 57 225 (100-400) 6 (4-14) 20 (16.4) 4 118 2 30 28 3
(3.3) (96.7) (1.7) (24.6) (23.0) (2.5) 0
78 (97.5) 2 (2.5) 221 59 325 (200-500) 29 (25-47) 7 (6-10) 13 (16.3) 10 69 2 30 20 14 8
(12.7) (87.3) (2.9) (37.5) (25.0) (17.5) (10.0)
.208 .050 .173 .525 <.001 .320 .059 .103 <.001 .011 .005 .331 1.000 .020 .627 .059 .739 <.001 <.001
BMI, body mass index; CT, computed tomography; eGFR, estimated glomerular filtration rate; IQR, interquartile range; OR, operation room; PN, partial nephrectomy; RN, radical nephrectomy; SD, standard deviation.
Table 2. Tumor size and RENAL nephrometry scores Variable Tumor size (cm), mean SD Total nephrometry score, mean SD Nephrometry sum, n (%) <10 10 R score, n (%) R ¼ 3 (7 cm) E score, n (%) E ¼ 1 (exophytic 50%) E ¼ 2 (endophytic 50%) E ¼ 3 (entirely endophytic) N score, n (%) N ¼ 1 (7 mm) N ¼ 2 (>4 to <7 mm) N ¼ 3 (4 mm) A score, n (%) A (anterior) P (posterior) X (indeterminate) L score, n (%) L ¼ 1 (above/below) L ¼ 2 (crosses pole) L ¼ 3 (>50% crosses pole/crosses midline/between poles)
RN (n ¼ 105)
PN (n ¼ 73)
P Value
10.2 2.7 9.9 1.3
8.8 1.6 9.7 1.3
<.001 .209 .526
35 (33.3) 70 (66.7)
28 (38.4) 45 (61.6)
105 (100)
73 (100)
29 (27.6) 59 (56.2) 17 (16.2)
24 (32.9) 43 (58.9) 6 (8.2)
2 (1.9) 27 (25.7) 76 (72.4)
3 (4.1) 20 (27.4) 50 (68.5)
30 (28.6) 31 (29.5) 44 (41.9)
16 (21.9) 25 (34.2) 32 (43.8)
14 (13.3) 48 (45.7) 43 (41.0)
10 (13.9) 34 (47.2) 28 (38.9)
1.000 .276
.643
.583
.963
Abbreviations as in Table 1.
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significant difference in mean RENAL score between RN and PN patients (9.9 vs 9.7; P ¼ .209). Renal Functional Outcomes For RN and PN, there were no significant differences in median times to first and second creatinine checks (7 and 12 months for both; P ¼ .743 and 0.299, respectively) and preoperative median creatinine (P ¼ .320), eGFR (P ¼ .541), and eGFR <60 (RN, 16.4% vs PN, 25.0%; P ¼ .151; Table 3). Median Dcreatinine (baseline 6 months postoperative) and median DeGFR (baseline 6 months) were higher in RN patients (Dcreatinine: RN, 0.3 vs PN, 0.2; P ¼ .003; DeGFR: RN, 19.7 vs PN, 11.9; P ¼ .006), and de novo eGFR <60 (RN, 40.2% vs PN, 16.3%; P <.001) was significantly higher for RN patients. Subanalysis of preoperative renal function for RENAL sum <10 patients (RN ¼ 35; PN ¼ 28; Table 3) demonstrated similar median preoperative eGFR (P ¼ .450) and preoperative eGFR <60 (RN, 8.6% vs PN, 21.4%; P ¼ .170). Postoperatively, we observed significantly greater median DeGFR (RN, 32.6 vs PN, 9.3; P <.001) for RN patients; de novo eGFR <60 (RN, 65.7% vs PN, 7.1%; P <.001) was greater for RN patients. Subanalysis of RENAL sum 10 patients (RN ¼ 70; PN ¼ 45; Table 3) demonstrated no significant difference for preoperative values, median DeGFR (P ¼ .596), and de novo eGFR <60 (RN, 31.4% vs PN, 22.2%; P ¼ .394). Linear regression (data not shown) demonstrated RN for RENAL <10 was associated with average DeGFR 21.3 compared to PN among RENAL <10 (P <.001). Subanalysis of preoperative renal function for patients with baseline eGFR 60 (RN ¼ 102; PN ¼ 60; Table 3) demonstrated similar median preoperative creatinine (P ¼ .762) and eGFR (P ¼ .508). Postoperatively, significantly greater median DeGFR was noted for RN (21.2) vs PN (11.5; P ¼ .008). Multivariate logistic regression analysis for factors associated with de novo eGFR <60 is demonstrated in Table 3. One hundred five RN and 97 PN patients had complete data (including RENAL nephrometry) and were entered into analysis. Factors entered into the model included BMI, history of hypertension, history of diabetes mellitus, type of procedure (RN vs PN), approach (open vs laparoscopic), and nephrometry sum. Age, sex, and race were not included in the model as these factors are incorporated into MDRD eGFR equation.19 Nonsignificant variables were removed from the model. Procedure was not associated with eGFR <60. RENAL 10 (odds ratio [OR], 6.67; P ¼ .025) and RN only among RENAL <10 (OR, 24.8; P ¼ .001) were independently associated with de novo eGFR <60. Kaplan-Meier analysis (Fig. 1A-C) demonstrates that PN patients had superior freedom from CKD over time compared to RN patients (log rank P ¼ .0002); within the subgroup RENAL <10, median interval of freedom from CKD was RN 16 months (IQR, 10-31 months) and PN 38 months (IQR, 28-61 months; P ¼ .001). Cox proportional hazard model with RENAL sum as a 4
continuous variable (Fig. 1D) demonstrated decreasing risk of CKD for PN vs RN patients, starting at RENAL 10 (hazard ratio, 0.836; 95 confidence interval, 0.3631.928), down to RENAL 6 (hazard ratio, 0.003; 95% confidence interval, 0-0.107; P ¼ .001).
COMMENT The present study suggests that PN may attenuate renal function decline in T2RM with renal functional benefit in the nonimperative setting; however, we note that the benefit is negated in more complex tumors defined by RENAL score >10. This was demonstrated by multiple measures, and the benefit of PN for freedom from CKD increased as RENAL sum decreased. Among patients with RENAL sum <10, PN had a significant 22-month freedom from CKD benefit over RN patients, and on average, RN patients lost more than 20 units in GFR relative to PN patients when DeGFR was analyzed as a continuous outcome by linear regression. These findings demonstrate that assignment of RENAL score may help identify candidates with T2RM who are most likely to benefit from PN and conversely, identify patients in elective circumstances where PN would not yield significant benefit and may expose the patient to increased risk. This is a novel finding for cT2RM, and therefore RENAL score, as an indicator of preservable parenchyma, may provide renal functional prognostic information. Renal functional advantages of PN over RN for T1 tumors are suggested by multiple studies.5-7,22,23 Less is known regarding larger masses; however, there is growing evidence for PN both for imperative and elective indications.14-17,24 These studies suggest that tumor size should not be an independent contraindication to PN.11,12,16 Previous studies have not clearly defined if there is a tumor size and complexity plateau at which point PN may not confer renal functional benefit over RN. We aimed to build on previous reports of renal functional outcomes after PN for T2RM by using RENAL score to better describe the tumor-parenchyma relationship and effect on renal function. A total of 4 other studies have examined renal functional outcomes for PN for renal masses 7 cm. In our cohort overall, DeGFR (mL/min/1.73m2) was significantly greater in RN (19.7) vs PN patients (11.9; P ¼ .006). Another comparative analysis in the literature between pT2þ RN (207) vs PN (69) was conducted by Breau et al,11 who revealed similar significant difference in change in renal function at median follow-up of 3.2 years, noting a reduction in creatinine of 9.5% for PN vs 33% for RN patients (P <.001). Our findings are also similar to those of Becker et al,24 who analyzed 91 patients who underwent elective PN for tumors 7 cm and noted DeGFR of 11.1 mL/min/ 1.73m2 with a median follow-up of 28 months, and to the findings of Karellas et al,12 who analyzed 37 cases with PN for tumor 7 cm and noted DeGFR of 10 between preoperative and postoperative values. Long et al13 analyzed 46 patients with renal masses 7 cm who were treated UROLOGY
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Table 3. Renal functional outcomes RN (n ¼ 122)
Total cohort Preoperative creatinine (mg/dL), median (IQR) Creatinine 6 months postoperation (mg/dL), median (IQR) DCreatinine (baseline 6 month), median (IQR) Preoperative eGFR (mL/min/1.73m2), median (IQR) eGFR 6 months postoperation (mL/min/1.73m2), median (IQR) DeGFR (baseline 6 month), median (IQR) Preoperative eGFR <60 mL/min/1.73m2, n (%) eGFR <60 mL/min/1.73m2 at last follow-up, n (%) De novo eGFR <60 mL/min/1.73m2, n (%) Time to de Novo eGFR <60 mL/min/1.73m2 (mo), median (IQR) RENAL Sum <10
PN (n ¼ 80)
1.0 (0.9-1.2) 1.3 (1.1-1.5)
1.1 (0.9-1.3) 1.3 (1.0-1.6)
.320 .665
0.3 (0.1-0.5) 79 (64-91) 59 (48-70)
0.2 (0.1-0.3) 78 (59-89) 66 (57-75)
.003 .541 .003
19.7 20 69 49 20
(33.4 to 8.0) (16.4) (56.6) (40.2) (11-37)
11.9 20 33 13 16
RN (n ¼ 35)
Preoperative creatinine (mg/dL), median (IQR) Creatinine 6 months postoperation (mg/dL), median (IQR) DCreatinine (baseline 6 month), median (IQR) Preoperative eGFR (mL/min/1.73m2), median (IQR) eGFR 6 months postoperation (mL/min/1.73m2), median (IQR) DeGFR (baseline 6 month), median (IQR) Preoperative eGFR <60 mL/min/1.73m2, n (%) eGFR <60 mL/min/1.73m2 at last follow-up, n (%) De novo eGFR <60 mL/min/1.73m2, n (%) Time to de novo eGFR <60 mL/min/1.73m2 (mo), median (IQR) RENAL Sum 10
Baseline eGFR 60
PN (n ¼ 28)
.006 .151 .044 <.001 .165 P Value
1.0 (0.8-1.1) 1.1 (1.0-1.3)
.522 <.001
0.5 (0.4-0.6) 90 (76-102) 54 (46-61)
0.1 (0.1-0.2) 82 (74-97) 72 (61-86)
<.001 .450 <.001
32.6 3 26 23 16
(45.2 to 22.4) (8.6) (74.3) (65.7) (10-31)
9.3 6 8 2 38
(19.0 to 7.1) (21.4) (28.6) (7.1) (28-61)
PN (n ¼ 45)
<.001 .170 <.001 <.001 .001 P Value
1.1 (0.9-1.2) 1.3 (1.2-1.5)
1.2 (1.0-1.4) 1.5 (1.3-1.7)
.077 .011
0.2 (0.1-0.4) 73 (64-85) 59 (49-66)
0.3 (0.1-0.4) 69 (58-80) 55 (46-63)
.216 .219 .086
12.1 12 34 22 21
(25.2 to 6.7) (17.1) (48.6) (31.4) (11-37)
RN (n ¼ 102)
Preoperative creatinine (mg/dL), median (IQR) Creatinine 6 months postoperation (mg/dL), median (IQR) DCreatinine (baseline 6 mo), median (IQR) Preoperative eGFR (mL/min/1.73m2), median (IQR) eGFR 6 months postoperation (mL/min/1.73m2), median (IQR) DeGFR (baseline 6 month), median (IQR) Preoperative eGFR <60 mL/min/1.73m2 eGFR <60 mL/min/1.73m2 at last follow-up, n (%) De novo eGFR <60 mL/min/1.73m2, n (%) Time to de novo eGFR <60 (mo), median (IQR)
(19.3 to 7.0) (25.0) (41.3) (16.3) (36-71)
0.9 (0.8-1.1) 1.5 (1.2-1.6)
RN (n ¼ 70)
Preoperative creatinine (mg/dL), median (IQR) Creatinine 6 months postoperation (mg/dL), median (IQR) DCreatinine (baseline 6 month), median (IQR) Preoperative eGFR (mL/min/1.73m2), median (IQR) eGFR 6 months postoperation (mL/min/1.73m2), median (IQR) DeGFR (baseline 6 months), median (IQR) Preoperative eGFR <60 mL/min/1.73m2, n (%) eGFR <60 mL/min/1.73m2 at last follow-up, n (%) De novo eGFR <60 mL/min/1.73m2, n (%) Time to de novo eGFR <60 (mo), median (IQR)
P Value
14.0 12 22 10 18
(20.6 to 9.5) (26.7) (48.8) (22.2) (13-25)
PN (n ¼ 60)
.596 .482 1.000 .394 .290 P Value
1 (0.9-1.1) 1.3 (1.1-1.5)
1 (0.8-1.1) 1.1 (1.0-1.4)
.762 .077
0.3 (0.2-0.5) 81 (71.6-93.6) 60.2 (51.9-67.5)
0.2 (0.1-0.3) 81.9 (74-99.5) 70.4 (54.5-78.5)
.002 .508 .018
21.2 (41.2 to 11.3) 0 49 (48.0) 49 (48.0) 18 (8-24)
11.5 (20.6 to 7.5) 0 13 (21.7) 13 (21.7) 24 (12-36)
.008 .001 .001 .087
Multivariate Logistic Regression for Variables Associated With De novo eGFR <60 mL/min/1.73 m2 95.0% CI for HR Partial (radical nephrectomy ¼ ref) Nephrometry (10, <10 ¼ ref) Radical and nephrometry <10
HR
Lower
Upper
P Value
0.97 6.67 24.78
0.37 1.27 3.68
2.55 35.04 167.06
.950 .025 .001
CI, confidence interval; HR, hazard ratio; ref, reference group. Other abbreviations as in Table 1.
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Figure 1. (A) Kaplan-Meier analysis for freedom from de novo CKD for RN and PN. (B) Kaplan-Meier analysis from freedom from de novo CKD for RN and PN for RENAL sum <10. (C) Kaplan-Meier analysis for freedom from de novo CKD for RN and PN for RENAL sum 10. (D) Plot of hazard ratios depicting risk of CKD for RN vs PN for increasing RENAL score. CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; LCL, lower confidence limit; PN, partial nephrectomy; RN, radical nephrectomy; UCL, upper confidence limit.
with PN and with median follow-up 13.1 months and demonstrated 8.2% upward migration from stage I to stage III CKD and 2.0% upward migration from stage III to stage IV CKD. In our analysis with longer median follow-up (41.5 months), we demonstrated a higher de novo rate of CKD for RN (40.2%) and PN (16.3%) patients, with a 22-month benefit to median freedom from CKD among PN patients with RENAL sum <10. Increasingly, renal functional outcomes after renal surgery are seen as the product of an interaction of a variety of factors: nonmodifiable factors (such as age, baseline eGFR, BMI, and comorbid conditions) and “quantity” of preservable parenchyma, which in PN is primarily influenced by tumor size and its location, which is inherently also nonmodifiable.1 Furthermore, data suggest that the effect of a modifiable factor such as ischemia time appears somewhat limited in the long run, especially if kept under 20-25 minutes warm with cold ischemic protection extending time of acceptable ischemia to 2 hours.25 In our series, median ischemic time was 24 minutes for the warm group and 48 minutes for the cold group, and therefore, significant effect of ischemia time on worsening renal functional outcomes in our PN group is not likely.2,26,27 6
Simmons et al2 introduced volumetric analysis to measure preoperative and postoperative kidney volume and also demonstrated that volume loss or “quantity” of preserved nephrons was the primary determinant of renal function after PN. Recognizing that renal function after PN is multifactorial and that PN carries increased surgical risk than RN even in T1 renal mass5 nonetheless begs the question: In the clinical setting, can we efficiently identify larger renal masses for which PN may confer a renal functional benefit, and conversely, can we identify factors associated with lack of benefit for PN in the elective setting and where PN, even if feasible, may not provide benefit to offset increased risk of complications? RENAL score is easy to assign and is associated with the selection of performing RN or PN,15 correlates with the risk of postoperative complication and urine leak,28,29 and was therefore included to account for surgeon selection bias. On Cox analysis, significant differences in renal functional outcomes persisted for RN vs PN for RENAL score 10 but not for RENAL score >10; freedom from CKD over time was significantly poorer for RN among patients with RENAL score <10. For large masses, RENAL score may have UROLOGY
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substantial prognostic value for renal functional outcomes. Correlation of RENAL score with functional volume and association with postoperative renal function is supported by other studies with various tumor sizes. Simmons et al3 compared the RENAL and centrality index (C-index) scoring systems in 299 patients with a contralateral normal kidney who underwent PN. They noted on multivariable analysis that “R” and “N” components of the RENAL score correlated with percent functional volume preservation and that diameter and overall RENAL scores also significantly correlated with long-term percentage GFR preservation.3 Mehrazin et al4 examined the association of renal morphology with renal function after 322 PNs and noted on linear regression analysis that for each 1-point increase in RENAL score, there was a 2.5% decrease in eGFR and for each 1-cm increase in diameter, there was a 1.8% decrease in eGFR. Furthermore, they found that increasing RENAL score was independently associated with CKD after PN (OR, 1.24; P ¼ .046). The findings of Simmons et al and Mehrazin et al suggest that RENAL nephrometry may be a useful adjunct to tumor size when attempting to assess ultimate renal function outcome of PN. Similarly, in our series of cT2 tumors, renal functional benefit conferred by PN declined with increasing nephrometry score, that is, increasing RENAL score may correlate with decreasing amount of preservable parenchyma, and at some point, as suggested by our Cox analysis, the likely breakpoint is RENAL 10; the amount of preservable parenchyma becomes insignificant in the setting of a 2-kidney system, and therefore, renal functional benefit may not be realized in PN vs RN. Overall, our cohorts of PN and RN had relatively similar comorbidities, anatomic characteristics measured by RENAL score, and tumor pathology despite the slightly larger tumors in the RN group. Nonetheless, larger size in RN group is suggestive of inherent selection bias that cannot be eliminated in a retrospective study. However, procedure selection is associated with RENAL score, which was statistically similar in our cohort, as was preoperative CKD between RN and PN, and we used multivariate analysis to control for a variety of factors associated with potential selection bias. Furthermore, eGFR is an estimate of renal function based on serum creatinine and less accurate than quantitative assessments using radioisotope clearance or formulas including additional data such as weight. Nonetheless, eGFR is widely used as a surrogate for renal function in studies such as ours which have sought to examine the effect of surgical nephron loss and coexisting comorbid factors. Ultimately, these data argue for a prospective study in which renal function is determined preoperatively and postoperatively by scintigraphic studies in addition to serum creatinine and eGFR. Indeed, eGFR of <60 mL/min/1.73m2 may not be an effective marker in and of itself.19 For this reason, we chose our primary end point to be a change in eGFR to gage the degree of functional preservation. We UROLOGY
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did not include percent parenchyma spared, which may have also added to the robustness of our analysis. Our utilization of RENAL score as a surrogate for tumor complexity and parenchyma spared (and a more important factor than ischemia time or other perioperative variables) has been confirmed in other analyses by our group and others and validates our findings.2-4,27 Although median follow-up was 41.5 months, longer follow-up (5 year) is necessary for robust renal and oncologic survival outcomes. Nonetheless, our analysis represents the most in-depth examination of renal functional outcomes using one of the largest series of PN and RN for cT2 renal mass reported in the literature.16 The high percentage of cT2 PN is a reflection of the main surgeon’s referral practice and supports a randomized clinical trial to compare renal functional outcomes between RN and PN for larger tumors, which should include prospective assessment of the clinical utility of RENAL sum in stratification of risk and outcomes in cT2RM.30
CONCLUSION Our data suggest that RN is independently associated with decreased renal function measured by continuous eGFR, development of CKD at 6 months, and nearly 2-year loss in CKD-free interval compared to PN for T2RM with RENAL sum 10. However, renal functional benefit was not realized by PN in more complex tumors, and caution should be exercised in offering PN in elective circumstances to this group. Prospective investigation with further follow-up is needed to determine utility of PN for T2RM. References 1. Lane BR, Russo P, Uzzo RG, et al. Comparison of cold and warm ischemia during partial nephrectomy in 660 solitary kidneys reveals predominant role of nonmodifiable factors in determining ultimate renal function. J Urol. 2011;185:421-427. 2. Simmons MN, Hillyer SP, Lee BH, et al. Functional recovery after partial nephrectomy: effect of volume loss and ischemic injury. J Urol. 2012;187:1667-1673. 3. Simmons MN, Hillyer SP, Lee BH, et al. Diameter-axial-polar nephrometry: integration and optimization of R.E.N.A.L. and centrality index scoring systems. J Urol. 2012;188:384-390. 4. Mehrazin R, Palazzi KL, Kopp RP, et al. Impact of tumour morphology on renal function decline after partial nephrectomy. BJU Int. 2013;111:E374-382. 5. Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. J Urol. 2009;182:12711279. 6. Ljungberg B, Cowan NC, Hanbury DC, et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol. 2010;58:398-406. 7. Thompson RH, Boorjian SA, Lohse CM, et al. Radical nephrectomy for pT1a renal masses may be associated with decreased overall survival compared with partial nephrectomy. J Urol. 2008;179: 468-471. 8. Tan HJ, Norton EC, Ye Z, et al. Long-term survival following partial vs radical nephrectomy among older patients with early-stage kidney cancer. JAMA. 2012;307:1629-1635. 9. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical
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nephrectomy for low-stage renal cell carcinoma. Eur Urol. 2011;59: 543-552. Becker F, Roos FC, Janssen M, et al. Short-term functional and oncologic outcomes of nephron-sparing surgery for renal tumours 7 cm. Eur Urol. 2011;59:931-937. Breau RH, Crispen PL, Jimenez RE, et al. Outcome of stage T2 or greater renal cell cancer treated with partial nephrectomy. J Urol. 2010;183:903-938. Karellas ME, O’Brien MF, Jang TL, et al. Partial nephrectomy for selected renal cortical tumours of 7 cm. BJU Int. 2010;106:14841487. Long CJ, Canter DJ, Kutikov A, et al. Partial nephrectomy for renal masses 7 cm: technical, oncological and functional outcomes. BJU Int. 2012;109:1450-1456. Jeldres C, Patard JJ, Capitanio U, et al. Partial versus radical nephrectomy in patients with adverse clinical or pathologic characteristics. Urology. 2009;73:1300-1305. Peycelon M, Hupertan V, Comperat E, et al. Long-term outcomes after nephron sparing surgery for renal cell carcinoma larger than 4 cm. J Urol. 2009;181:35-41. Kopp RP, Mehrazin R, Palazzi KL, et al. Survival outcomes after radical and partial nephrectomy for clinical T2 renal tumors categorized by RENAL nephrometry score. BJU Int. 2014;114:708-718. Kutikov A, Smaldone MC, Egleston BL, et al. Anatomic features of enhancing renal masses predict malignant and high-grade pathology: a preoperative nomogram using the RENAL nephrometry score. Eur Urol. 2011;60:241-248. Tobert CM, Kahnoski RJ, Thompson DE, et al. RENAL nephrometry score predicts surgery type independent of individual surgeon’s use of nephron-sparing surgery. Urology. 2012;80: 157-161. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-S266. AJCC. Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205-213. Huang WC, Levey AS, Serio AM, et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. Lancet Oncol. 2006;7:735-740. Malcolm JB, Bagrodia A, Derweesh IH, et al. Comparison of rates and risk factors for developing chronic renal insufficiency, proteinuria and metabolic acidosis after radical or partial nephrectomy. BJU Int. 2009;104:476-481. Becker F, Siemer S, Hack M, et al. Excellent long-term cancer control with elective nephron-sparing surgery for selected renal cell carcinomas measuring more than 4 cm. Eur Urol. 2006;49:1058-1063. Becker F, Van Poppel H, Hakenberg OW, et al. Assessing the impact of ischaemia time during partial nephrectomy. Eur Urol. 2009;56:625-635. Yossepowitch O, Eggener SE, Serio A, et al. Temporary renal ischemia during nephron sparing surgery is associated with shortterm but not long-term impairment in renal function. J Urol. 2006;176:1339-1443. Kopp RP, Mehrazin R, Palazzi K, et al. Factors affecting renal function after open partial nephrectomy—a comparison of clampless and clamped warm ischemic technique. Urology. 2012;80: 865-870. Stroup SP, Palazzi K, Kopp RP, et al. RENAL nephrometry score is associated with operative approach for partial nephrectomy and urine leak. Urology. 2012;80:151-156. Bruner B, Breau RH, Lohse CM, et al. RENAL nephrometry score is associated with urine leak after partial nephrectomy. BJU Int. 2011; 108:67-72. Weight CJ, Miller DC, Campbell SC, et al. The management of a clinical T1b renal tumor in the presence of a normal contralateral kidney. J Urol. 2013;189:1198-1202.
EDITORIAL COMMENT The authors1 should be congratulated for this significant contribution to the partial nephrectomy (PN) literature. The present study was a retrospective analysis evaluating renal function outcomes after open PN compared with radial nephrectomy (RN) stratified by RENAL sum for renal masses >7 cm (T2RMs). As expected, the DeGFR was greater in RN (19.7) vs PN (11.9) and the de novo chronic kidney disease was significantly delayed in PN verses RN. Interestingly, they demonstrated equivalent renal function outcomes for PN and RN if RENAL score 10, whereas PN was associated with greater complication rates. To understand renal function after PN, baseline renal function, ischemic injury, amount of healthy tissue removed, and reconstructive injury (renorrhaphy) must all be considered. Cold and warm ischemia median times were 48 and 24 minutes, respectively, which appear to be in the acceptable ranges for T2RMs. Maximally preserving renal function would require small resection margins and atraumatic reconstruction techniques. Significant injury from cortical renorrhaphy can occur with even small renal masses. A recent study attributed a 12% loss in ipsilateral renal volume to cortical renorrhaphy on adjusted analysis.2 Reconstructive injury is thought to be due to ligation of segmental vessels in addition to strangulated parenchyma, which has been shown to be worse with more central tumors (higher RENAL score).3 It is important to note that the DeGFR was greater with RN when the RENAL sum was <10 vs 10 (12.1 vs 32.6, respectively) and appears slightly worse for PN at 14.0 vs 9.3, respectively. This suggests that T2RMs with RENAL sum of <10 have more functional renal parenchyma that is lost during an RN and T2RMs with RENAL sum 10 require more involved PN, leading to greater loss of renal function. The functional assessment combined with the complication rate of PN and RN for T2RMs would suggest that a rationale approach would be open PN when and RENAL sum <10 and RN when RENAL sum is 10 and imperative indications are not present. This approach maximizes renal function with acceptable complications and may maximize the use of laparoscopic RN approaches for patients who may not benefit from open PN approach. Several limitations exist in this study. Spot serum creatinine was used to estimate renal function. This is an insensitive tool compared with 24 h urine collection, renal radioisotope clearance, or volumetric analysis.4 Overall, this study is hypothesis generating. Suggesting that instead of an absolute “size limit,” a “complexity limit” may be more appropriate with understanding that size and complexity are not exclusive. Future prospective, volumetric studies may help further define the tipping point for PN based on mass complexity that maximizes renal preservation while limiting associated complications. Thomas Allen Gardner, M.D., Clinton D. Bahler, M.D., and Paul Gillhaus, M.D., Indiana University
References 1. Kopp RP, Liss MA, Mehrazin R, et al. Analysis of renal functional outcomes after radical or partial nephrectomy for renal masses 7 cm using the RENAL score. Urology. In press. 2. Bahler CD, Dube HT, Flynn KJ, et al. Feasibility of omitting cortical renorrhaphy during robotic partial nephrectomy: a matched analysis. J Endourol. 2015;29:548-555.
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3. Simmons MN, Hillyer SP, Lee BH, et al. Nephrometry score is associated with volume loss and functional recovery after partial nephrectomy. J Urol. 2012;188:39. 4. Goh YS, Wu MW, Tai BC, et al. Comparison of creatinine based and kidney volume based methods of estimating glomerular filtration rates in potential living kidney donors. J Urol. 2013;190:1820.
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REPLY The use of partial nephrectomy (PN) for larger masses has increased in recent years, primarily driven by the increasing experience with the procedure on the whole, emerging data suggesting oncologic equivalence to radical nephrectomy, and a growing awareness of the potential deleterious long-term consequences of nephron loss and chronic renal insufficiency.1 PN for larger masses is not without controversy, given increased risk of procedure-specific complications and doubts about the renal functional benefit of nephron-sparing surgery for larger masses.2 Our data suggest that a subset of patients may receive renal functional benefit from PN for larger masses but that this benefit may be limited by overall tumor complexity. We agree with the opinion that our findings are essentially hypothesis generating, and although they may provide additional information to aid in decision making with respect to whether to perform a PN in the setting of a larger (ie, cT2) tumor, there are nonetheless many gray areas, which await further delineation and refinement; for example, what do in the setting of elective or relative indications where benefit may be more incremental (ie, a RENAL score of 10, where our Cox proportional hazard analysis demonstrated decreasing risk of CKD for PN vs RN starting at RENAL score of 10 [hazard ratio, 0.836]). Indeed, not all RENAL scores of 10 may have the same impact on final renal function. Much work needs to be done to further refine criteria and “tipping points” on whether PN may yield benefit. Indeed, although emerging data point to the dominant role of
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nonmodifiable factors such as percent parenchymal volume preserved and presence of baseline drivers toward chronic renal insufficiency when ischemia time is limited,3 RENAL score nonetheless remains an overarching surrogate marker for both quantity of preserved nephrons as well as quality of the preservation4 (with respect to the effect of tumor location on prolonging ischemia time and its potential deleterious effects and volume loss in post PN because of the effects of the reconstruction in more complex renal masses). Ultimately, our findings compel us to agree with, and to call for prospective investigation into the physiologic, anatomical, and technical factors, which may affect renal functional outcomes and for the use of predictive volumetric analysis of renal function as the lynchpin of such integrated decision-making tool(s).5 Even with this approach, RENAL score is a unique marker of tumor complexity and perioperative risk. Ithaar H. Derweesh, M.D., Department of Urology, UC San Diego Health System, La Jolla, CA
References 1. Alanee S, Nutt M, Moore A, et al. Partial nephrectomy for T2 renal masses: contemporary trends and oncologic efficacy. Int Urol Nephrol. 2015; [Epub ahead of print]. 2. Tomaszewski JJ, Smaldone MC, Uzzo RG, Kutikov A. Is radical nephrectomy a legitimate therapeutic option in patients with renal masses amenable to nephron-sparing surgery? BJU Int. 2015;115: 357-363. 3. Thompson RH, Lane BR, Lohse CM, et al. Renal function after partial nephrectomy: effect of warm ischemia relative to quantity and quality of preserved kidney. Urology. 2012;79:356-360. 4. Mehrazin R, Palazzi KL, Kopp RP, et al. Impact of tumour morphology on renal function decline after partial nephrectomy. BJU Int. 2013;111:E374-E382. 5. Meyer A, Woldu SL, Weinberg AC, et al. Predicting renal parenchymal loss following nephron sparing surgery. J Urol. 2015; [Epub ahead of print].
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METHODS
RESULTS
CONCLUSION
To determine if partial nephrectomy (PN) confers a renal functional benefit compared to radical nephrectomy (RN) for clinical T2 renal masses (T2RM) when adjusting for tumor complexity characterized by the RENAL nephrometry score. A 2-center study of 202 patients with T2RM undergoing RN (122) or PN (80) (median follow-up, 41.5 months). RN and PN cohorts were subanalyzed according to RENAL sum as a categorical variable of <10 or 10. Primary outcome was median change in estimated glomerular filtration rate (DeGFR) between preoperative to 6 months postoperative. Logistic regressioneidentified prognostic factors and survival models analyzed association between the RENAL sum and the freedom from de novo chronic kidney disease (CKD; eGFR<60 mL/min/1.73m2). No significant differences existed between PN and RN for RENAL score. DeGFR was greater in RN (19.7) vs PN (11.9; P ¼ .006). De novo CKD was 40.2% after RN vs 16.3% after PN (P <.001). RENAL score 10 (odds ratio, 6.67; P ¼ .025) and RN among patients with RENAL score <10 (odds ratio, 24.8; P <.001) were independently associated with de novo CKD at 6 months by logistic regression. Among patients with RENAL score <10, median CKD-free survival was PN 38 vs RN 16 months (P ¼ .001). Cox proportional hazard demonstrated decreasing risk of CKD for PN vs RN from RENAL 10 (hazard ratio, 0.836) to RENAL 6 (hazard ratio, 0.003; P ¼ .001). RN is independently associated with decreased renal function compared to PN for T2RM with RENAL sum 10, but not >10, with larger relative decrease in eGFR for each decrease in RENAL sum. Further investigation is required to determine optimal candidates for PN in T2RM. UROLOGY -: -e-, 2015. 2015 Elsevier Inc.
P
artial nephrectomy (PN) is a preferred option for clinical T1 renal masses, by which a large amount of parenchyma may often be spared.1-6 The role of PN for renal functional preservation in clinical T2 renal masses (T2RM) is unclear. Radical nephrectomy (RN) and PN may be oncologically similar, and it is possible that PN might have superior overall survival through long-term preservation of renal function.7,8 This
Ryan P. Kopp and Michael A. Liss contributed equally to this work. Financial Disclosure: The authors declare that they have no relevant financial interests. Funding Support: This study was supported by Stephen Weissman Kidney Cancer Research Fund. From the Department of Urology, Moores Cancer Center, UC San Diego Health System, La Jolla, CA; and the Department of Urology, University of Tennessee Health Science Center, Memphis, TN Address correspondence to: Ithaar H. Derweesh, M.D., Department of Urology, Moores Cancer Center, UC San Diego Health System, 3855 Health Sciences Drive, Mail Code: 0987, La Jolla, CA 92093-0987. E-mail: [email protected] Submitted: November 1, 2014, accepted (with revisions): February 3, 2015
ª 2015 Elsevier Inc. All Rights Reserved
thought is controversial after results of a prospective randomized trial demonstrated similar survival for RN and PN in the renal cell carcinoma population.9 The body of literature on PN for T2RM is growing despite there being no consensus opinion on utility of PN in this setting.10-16 Comparative studies of RN and PN for T2RM that specifically examine renal functional outcomes are limited. RENAL nephrometry score includes additional measures of anatomic differences between tumors, in addition to the tumor-parenchyma relationship, which correlates with renal functional outcomes and procedure selection.3,4,17,18 We recently demonstrated the use of RENAL score to control for variability of T2RM for oncologic outcomes.16 We aim to translate this methodology to elucidate if there is a tumor size or anatomic complexity threshold at which point renal functional benefit from PN reaches a plateau—this may aid in http://dx.doi.org/10.1016/j.urology.2015.02.067 0090-4295/15
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patient selection for PN among those with T2RM and in prognostication of renal functional outcomes.
METHODS Study Patients An institutional review boardeapproved retrospective study of patients with T2RM who underwent RN or PN at 2 institutions (UC San Diego Health System and University of Tennessee Health Sciences Center) from July 2002 to June 2012 (median follow-up, 41.5 months) was carried out. Evaluation, management, and follow-up of T2RM have been previously published.16 Imperative indications led to PN (n ¼ 80) in 20 patients (25%); this included (chronic kidney disease [CKD] or an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73m2 [n ¼ 20], solitary kidney [n ¼ 7], bilateral tumors [n ¼ 6]). Relative indications weighted surgeon recommendation toward PN in 29 patients (36%; multiple risk factors for CKD, including diabetes mellitus or proteinuria, severe hypertension, body mass index [BMI] >35 kg/m2, GFR <70 mL/min/1.73 m2]). Elective PN included 31 cases (39%). Of those who underwent RN (n ¼ 122), 20 (16.3%) had eGFR <60 mL/min/1.73 m2. There were no RN for solitary kidney; 7 patients underwent RN for T2RM with PN of contralateral T1 mass. Sixteen patients (13.1%) with relative indications elected RN over PN. Laparoscopic surgery candidacy was determined by operating surgeons. There were no conversions from PN to RN. Cases with preoperative estimates of ischemia time <30 minutes used warm ischemia and cold ischemia if estimates were 30 minutes.
Variables and Outcomes We recorded patient demographics, clinical characteristics, and renal function (serum creatinine, eGFR [mL/min/1.73 m2] calculated by Modification of Diet in Renal Disease equation).19 Renal mass parameters included tumor size (cm), renal cell carcinoma grade or histology, RENAL nephrometry score,17 and American Joint Committee on Cancer (AJCC) stage.20 Analysis of perioperative outcomes included surgical approach, operative time, estimated blood loss (mL), ischemia time (PN), and complications (Clavien).21 Primary outcome was median change of eGFR (DeGFR) between preoperative to 6 months postoperatively, with secondary outcomes being median change in creatinine level (DCr) from preoperative to 6 months postoperative, de novo CKD, and time to CKD. We excluded all perioperative laboratory test results during inpatient admission and laboratory test results obtained before 6 months. De novo CKD, defined as development of stage III CKD,4-6,19,22 with 2 consecutive eGFR values <60 mL/min/1.73m2 no less than 3 months apart and no greater than 6 months apart. The date of earliest value between the 2 (6 months postoperative) was listed as the date of de novo CKD. Patients who never recovered eGFR to 60 by 6 months postoperative were listed as de novo CKD at 6 months.
Statistical Analysis Clinical characteristics, RENAL scores, and functional outcomes were analyzed within subgroups of RN and PN using chi-square and Fisher exact tests for categorical variables and Mann-Whitney test and t test for continuous variables. RN and PN cohorts were then analyzed within RENAL sum as categorical variable of <10 or 10. Before analysis, we designated 10 as threshold to create groups of similar size and 2
to separate simple and intermediate masses from complex masses based on previous publications (simple, 4-6; intermediate, 7-9; and complex, 10-12).16-18 We conducted further analysis by individual total RENAL sum by Cox proportional hazard models (described below) to determine most appropriate prognostic groups. We used binary logistic and linear regression models to determine association between surgery type and renal functional outcomes. Logistic regression model included procedure, RENAL score, and outcome of de novo CKD. Kaplan-Meier survival estimates for freedom from CKD through the date of last follow-up were constructed to assess for durable renal function using the time to event and were analyzed with logrank test among RN vs PN overall and stratified by RENAL sum (<10 vs 10). Cox proportional hazard analysis was carried out using RENAL sum as a continuous variable to represent a continuous spectrum of risk, with hazard ratios generated at each RENAL sum. Analysis used SPSS (version 17.0; Chicago, IL, SPSS, Inc.), with P <.05 defining significant.
RESULTS Participants Two hundred two patients with cT2RM underwent RN (122) or PN (80). Demographic characteristics were similar between groups. Hypertension was more common in PN (P ¼ .05), whereas preoperative renal function and other comorbidities were not significantly different between groups (Table 1). Perioperative Outcomes Patients who underwent PN were more likely to have open surgery (97.5%) compared to those who underwent RN (62.3%; P <.001; Table 1). Cold ischemia was used in 42 PN patients (median time, 48 min; interquartile range [IQR], 39-54). Warm ischemia was used in 35 patients who underwent PN (median time, 24 min; IQR, 19-27). Clampless (nonischemic) technique was used in 3. Operative time and estimated blood loss were significantly higher for PN. PN and RN had similar transfusion rates and length of stay. Clavien 3 complications were more common in PN (n ¼ 14, 17.5%) vs RN (n ¼ 3, 2.5%; P <.001). Urinary fistula occurred in 8 (10%) PN patients, and these patients were managed with combination of stents and percutaneous drains. Additional renal complications included acute kidney injury in 1 RN patient, temporary dialysis in 1 PN patient (solitary kidney or preexisting CKD), and renal pseudoaneurysm in 3 PN patients requiring selective angioembolization—patients had imperative (2) or relative (1) indication for PN, and all had complex (10-12) RENAL sum. At the last follow-up, serum creatinine level (mg/dL) had increased by 0.2 in 1 patient and by 0.3 and 0.4 in the other 2. Remaining complications for this cohort were described previously.16 Tumor Size and Morphology RENAL score was available for 105 RN and 73 PN patients (Table 2). Mean tumor size (cm) was smaller in PN (8.8) vs RN patients (10.2; P <.001). There was no UROLOGY
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Table 1. Clinical, perioperative, and pathologic variables Variable Age, (y), mean SD Gender, n (%) Male Female Race, n (%) Caucasian African American/Latino/Asian/other BMI (kg/m2), mean SD Hypertension, n (%) Diabetes, n (%) Coronary artery disease, n (%) Tumor size (cm) from CT, mean SD Preoperative creatinine, median (IQR) Clinical T stage, n (%) cT2a cT2b Preoperative eGFR <60 mL/min/1.73m2, n (%) Approach, n (%) Open Laparoscopic OR time (min), mean SD Estimated blood loss (mL), median (IQR) Ischemia time (min), median (IQR) Days in hospital, median (IQR) Transfusion, n (%) Pathology, n (%) Benign tumors Malignant tumors Positive margins, n (%) Complications, n (%) Low-grade complication, n (%) High-grade complication, n (%) Urine leak
RN (n ¼ 122)
PN (n ¼ 80)
P Value
58 9.0
58 12.4
.751 .550
77 (63.1) 45 (36.9)
54 (67.5) 26 (32.5)
62 (52.1) 57 (47.9) 29.2 5.1 73 (59.8) 24 (19.7) 5 (11.9) 10.2 2.7 1.0 (0.9-1.2)
37 (46.3) 43 (53.8) 30.1 4.6 59 (73.8) 23 (28.8) 6 (13.0) 8.8 1.6 1.1 (0.9-1.3)
78 (63.9) 44 (36.1) 20 (16.3)
62 (77.5) 18 (22.5) 20 (25)
.471
76 (62.3) 46 (37.7) 153 57 225 (100-400) 6 (4-14) 20 (16.4) 4 118 2 30 28 3
(3.3) (96.7) (1.7) (24.6) (23.0) (2.5) 0
78 (97.5) 2 (2.5) 221 59 325 (200-500) 29 (25-47) 7 (6-10) 13 (16.3) 10 69 2 30 20 14 8
(12.7) (87.3) (2.9) (37.5) (25.0) (17.5) (10.0)
.208 .050 .173 .525 <.001 .320 .059 .103 <.001 .011 .005 .331 1.000 .020 .627 .059 .739 <.001 <.001
BMI, body mass index; CT, computed tomography; eGFR, estimated glomerular filtration rate; IQR, interquartile range; OR, operation room; PN, partial nephrectomy; RN, radical nephrectomy; SD, standard deviation.
Table 2. Tumor size and RENAL nephrometry scores Variable Tumor size (cm), mean SD Total nephrometry score, mean SD Nephrometry sum, n (%) <10 10 R score, n (%) R ¼ 3 (7 cm) E score, n (%) E ¼ 1 (exophytic 50%) E ¼ 2 (endophytic 50%) E ¼ 3 (entirely endophytic) N score, n (%) N ¼ 1 (7 mm) N ¼ 2 (>4 to <7 mm) N ¼ 3 (4 mm) A score, n (%) A (anterior) P (posterior) X (indeterminate) L score, n (%) L ¼ 1 (above/below) L ¼ 2 (crosses pole) L ¼ 3 (>50% crosses pole/crosses midline/between poles)
RN (n ¼ 105)
PN (n ¼ 73)
P Value
10.2 2.7 9.9 1.3
8.8 1.6 9.7 1.3
<.001 .209 .526
35 (33.3) 70 (66.7)
28 (38.4) 45 (61.6)
105 (100)
73 (100)
29 (27.6) 59 (56.2) 17 (16.2)
24 (32.9) 43 (58.9) 6 (8.2)
2 (1.9) 27 (25.7) 76 (72.4)
3 (4.1) 20 (27.4) 50 (68.5)
30 (28.6) 31 (29.5) 44 (41.9)
16 (21.9) 25 (34.2) 32 (43.8)
14 (13.3) 48 (45.7) 43 (41.0)
10 (13.9) 34 (47.2) 28 (38.9)
1.000 .276
.643
.583
.963
Abbreviations as in Table 1.
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significant difference in mean RENAL score between RN and PN patients (9.9 vs 9.7; P ¼ .209). Renal Functional Outcomes For RN and PN, there were no significant differences in median times to first and second creatinine checks (7 and 12 months for both; P ¼ .743 and 0.299, respectively) and preoperative median creatinine (P ¼ .320), eGFR (P ¼ .541), and eGFR <60 (RN, 16.4% vs PN, 25.0%; P ¼ .151; Table 3). Median Dcreatinine (baseline 6 months postoperative) and median DeGFR (baseline 6 months) were higher in RN patients (Dcreatinine: RN, 0.3 vs PN, 0.2; P ¼ .003; DeGFR: RN, 19.7 vs PN, 11.9; P ¼ .006), and de novo eGFR <60 (RN, 40.2% vs PN, 16.3%; P <.001) was significantly higher for RN patients. Subanalysis of preoperative renal function for RENAL sum <10 patients (RN ¼ 35; PN ¼ 28; Table 3) demonstrated similar median preoperative eGFR (P ¼ .450) and preoperative eGFR <60 (RN, 8.6% vs PN, 21.4%; P ¼ .170). Postoperatively, we observed significantly greater median DeGFR (RN, 32.6 vs PN, 9.3; P <.001) for RN patients; de novo eGFR <60 (RN, 65.7% vs PN, 7.1%; P <.001) was greater for RN patients. Subanalysis of RENAL sum 10 patients (RN ¼ 70; PN ¼ 45; Table 3) demonstrated no significant difference for preoperative values, median DeGFR (P ¼ .596), and de novo eGFR <60 (RN, 31.4% vs PN, 22.2%; P ¼ .394). Linear regression (data not shown) demonstrated RN for RENAL <10 was associated with average DeGFR 21.3 compared to PN among RENAL <10 (P <.001). Subanalysis of preoperative renal function for patients with baseline eGFR 60 (RN ¼ 102; PN ¼ 60; Table 3) demonstrated similar median preoperative creatinine (P ¼ .762) and eGFR (P ¼ .508). Postoperatively, significantly greater median DeGFR was noted for RN (21.2) vs PN (11.5; P ¼ .008). Multivariate logistic regression analysis for factors associated with de novo eGFR <60 is demonstrated in Table 3. One hundred five RN and 97 PN patients had complete data (including RENAL nephrometry) and were entered into analysis. Factors entered into the model included BMI, history of hypertension, history of diabetes mellitus, type of procedure (RN vs PN), approach (open vs laparoscopic), and nephrometry sum. Age, sex, and race were not included in the model as these factors are incorporated into MDRD eGFR equation.19 Nonsignificant variables were removed from the model. Procedure was not associated with eGFR <60. RENAL 10 (odds ratio [OR], 6.67; P ¼ .025) and RN only among RENAL <10 (OR, 24.8; P ¼ .001) were independently associated with de novo eGFR <60. Kaplan-Meier analysis (Fig. 1A-C) demonstrates that PN patients had superior freedom from CKD over time compared to RN patients (log rank P ¼ .0002); within the subgroup RENAL <10, median interval of freedom from CKD was RN 16 months (IQR, 10-31 months) and PN 38 months (IQR, 28-61 months; P ¼ .001). Cox proportional hazard model with RENAL sum as a 4
continuous variable (Fig. 1D) demonstrated decreasing risk of CKD for PN vs RN patients, starting at RENAL 10 (hazard ratio, 0.836; 95 confidence interval, 0.3631.928), down to RENAL 6 (hazard ratio, 0.003; 95% confidence interval, 0-0.107; P ¼ .001).
COMMENT The present study suggests that PN may attenuate renal function decline in T2RM with renal functional benefit in the nonimperative setting; however, we note that the benefit is negated in more complex tumors defined by RENAL score >10. This was demonstrated by multiple measures, and the benefit of PN for freedom from CKD increased as RENAL sum decreased. Among patients with RENAL sum <10, PN had a significant 22-month freedom from CKD benefit over RN patients, and on average, RN patients lost more than 20 units in GFR relative to PN patients when DeGFR was analyzed as a continuous outcome by linear regression. These findings demonstrate that assignment of RENAL score may help identify candidates with T2RM who are most likely to benefit from PN and conversely, identify patients in elective circumstances where PN would not yield significant benefit and may expose the patient to increased risk. This is a novel finding for cT2RM, and therefore RENAL score, as an indicator of preservable parenchyma, may provide renal functional prognostic information. Renal functional advantages of PN over RN for T1 tumors are suggested by multiple studies.5-7,22,23 Less is known regarding larger masses; however, there is growing evidence for PN both for imperative and elective indications.14-17,24 These studies suggest that tumor size should not be an independent contraindication to PN.11,12,16 Previous studies have not clearly defined if there is a tumor size and complexity plateau at which point PN may not confer renal functional benefit over RN. We aimed to build on previous reports of renal functional outcomes after PN for T2RM by using RENAL score to better describe the tumor-parenchyma relationship and effect on renal function. A total of 4 other studies have examined renal functional outcomes for PN for renal masses 7 cm. In our cohort overall, DeGFR (mL/min/1.73m2) was significantly greater in RN (19.7) vs PN patients (11.9; P ¼ .006). Another comparative analysis in the literature between pT2þ RN (207) vs PN (69) was conducted by Breau et al,11 who revealed similar significant difference in change in renal function at median follow-up of 3.2 years, noting a reduction in creatinine of 9.5% for PN vs 33% for RN patients (P <.001). Our findings are also similar to those of Becker et al,24 who analyzed 91 patients who underwent elective PN for tumors 7 cm and noted DeGFR of 11.1 mL/min/ 1.73m2 with a median follow-up of 28 months, and to the findings of Karellas et al,12 who analyzed 37 cases with PN for tumor 7 cm and noted DeGFR of 10 between preoperative and postoperative values. Long et al13 analyzed 46 patients with renal masses 7 cm who were treated UROLOGY
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Table 3. Renal functional outcomes RN (n ¼ 122)
Total cohort Preoperative creatinine (mg/dL), median (IQR) Creatinine 6 months postoperation (mg/dL), median (IQR) DCreatinine (baseline 6 month), median (IQR) Preoperative eGFR (mL/min/1.73m2), median (IQR) eGFR 6 months postoperation (mL/min/1.73m2), median (IQR) DeGFR (baseline 6 month), median (IQR) Preoperative eGFR <60 mL/min/1.73m2, n (%) eGFR <60 mL/min/1.73m2 at last follow-up, n (%) De novo eGFR <60 mL/min/1.73m2, n (%) Time to de Novo eGFR <60 mL/min/1.73m2 (mo), median (IQR) RENAL Sum <10
PN (n ¼ 80)
1.0 (0.9-1.2) 1.3 (1.1-1.5)
1.1 (0.9-1.3) 1.3 (1.0-1.6)
.320 .665
0.3 (0.1-0.5) 79 (64-91) 59 (48-70)
0.2 (0.1-0.3) 78 (59-89) 66 (57-75)
.003 .541 .003
19.7 20 69 49 20
(33.4 to 8.0) (16.4) (56.6) (40.2) (11-37)
11.9 20 33 13 16
RN (n ¼ 35)
Preoperative creatinine (mg/dL), median (IQR) Creatinine 6 months postoperation (mg/dL), median (IQR) DCreatinine (baseline 6 month), median (IQR) Preoperative eGFR (mL/min/1.73m2), median (IQR) eGFR 6 months postoperation (mL/min/1.73m2), median (IQR) DeGFR (baseline 6 month), median (IQR) Preoperative eGFR <60 mL/min/1.73m2, n (%) eGFR <60 mL/min/1.73m2 at last follow-up, n (%) De novo eGFR <60 mL/min/1.73m2, n (%) Time to de novo eGFR <60 mL/min/1.73m2 (mo), median (IQR) RENAL Sum 10
Baseline eGFR 60
PN (n ¼ 28)
.006 .151 .044 <.001 .165 P Value
1.0 (0.8-1.1) 1.1 (1.0-1.3)
.522 <.001
0.5 (0.4-0.6) 90 (76-102) 54 (46-61)
0.1 (0.1-0.2) 82 (74-97) 72 (61-86)
<.001 .450 <.001
32.6 3 26 23 16
(45.2 to 22.4) (8.6) (74.3) (65.7) (10-31)
9.3 6 8 2 38
(19.0 to 7.1) (21.4) (28.6) (7.1) (28-61)
PN (n ¼ 45)
<.001 .170 <.001 <.001 .001 P Value
1.1 (0.9-1.2) 1.3 (1.2-1.5)
1.2 (1.0-1.4) 1.5 (1.3-1.7)
.077 .011
0.2 (0.1-0.4) 73 (64-85) 59 (49-66)
0.3 (0.1-0.4) 69 (58-80) 55 (46-63)
.216 .219 .086
12.1 12 34 22 21
(25.2 to 6.7) (17.1) (48.6) (31.4) (11-37)
RN (n ¼ 102)
Preoperative creatinine (mg/dL), median (IQR) Creatinine 6 months postoperation (mg/dL), median (IQR) DCreatinine (baseline 6 mo), median (IQR) Preoperative eGFR (mL/min/1.73m2), median (IQR) eGFR 6 months postoperation (mL/min/1.73m2), median (IQR) DeGFR (baseline 6 month), median (IQR) Preoperative eGFR <60 mL/min/1.73m2 eGFR <60 mL/min/1.73m2 at last follow-up, n (%) De novo eGFR <60 mL/min/1.73m2, n (%) Time to de novo eGFR <60 (mo), median (IQR)
(19.3 to 7.0) (25.0) (41.3) (16.3) (36-71)
0.9 (0.8-1.1) 1.5 (1.2-1.6)
RN (n ¼ 70)
Preoperative creatinine (mg/dL), median (IQR) Creatinine 6 months postoperation (mg/dL), median (IQR) DCreatinine (baseline 6 month), median (IQR) Preoperative eGFR (mL/min/1.73m2), median (IQR) eGFR 6 months postoperation (mL/min/1.73m2), median (IQR) DeGFR (baseline 6 months), median (IQR) Preoperative eGFR <60 mL/min/1.73m2, n (%) eGFR <60 mL/min/1.73m2 at last follow-up, n (%) De novo eGFR <60 mL/min/1.73m2, n (%) Time to de novo eGFR <60 (mo), median (IQR)
P Value
14.0 12 22 10 18
(20.6 to 9.5) (26.7) (48.8) (22.2) (13-25)
PN (n ¼ 60)
.596 .482 1.000 .394 .290 P Value
1 (0.9-1.1) 1.3 (1.1-1.5)
1 (0.8-1.1) 1.1 (1.0-1.4)
.762 .077
0.3 (0.2-0.5) 81 (71.6-93.6) 60.2 (51.9-67.5)
0.2 (0.1-0.3) 81.9 (74-99.5) 70.4 (54.5-78.5)
.002 .508 .018
21.2 (41.2 to 11.3) 0 49 (48.0) 49 (48.0) 18 (8-24)
11.5 (20.6 to 7.5) 0 13 (21.7) 13 (21.7) 24 (12-36)
.008 .001 .001 .087
Multivariate Logistic Regression for Variables Associated With De novo eGFR <60 mL/min/1.73 m2 95.0% CI for HR Partial (radical nephrectomy ¼ ref) Nephrometry (10, <10 ¼ ref) Radical and nephrometry <10
HR
Lower
Upper
P Value
0.97 6.67 24.78
0.37 1.27 3.68
2.55 35.04 167.06
.950 .025 .001
CI, confidence interval; HR, hazard ratio; ref, reference group. Other abbreviations as in Table 1.
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Figure 1. (A) Kaplan-Meier analysis for freedom from de novo CKD for RN and PN. (B) Kaplan-Meier analysis from freedom from de novo CKD for RN and PN for RENAL sum <10. (C) Kaplan-Meier analysis for freedom from de novo CKD for RN and PN for RENAL sum 10. (D) Plot of hazard ratios depicting risk of CKD for RN vs PN for increasing RENAL score. CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; LCL, lower confidence limit; PN, partial nephrectomy; RN, radical nephrectomy; UCL, upper confidence limit.
with PN and with median follow-up 13.1 months and demonstrated 8.2% upward migration from stage I to stage III CKD and 2.0% upward migration from stage III to stage IV CKD. In our analysis with longer median follow-up (41.5 months), we demonstrated a higher de novo rate of CKD for RN (40.2%) and PN (16.3%) patients, with a 22-month benefit to median freedom from CKD among PN patients with RENAL sum <10. Increasingly, renal functional outcomes after renal surgery are seen as the product of an interaction of a variety of factors: nonmodifiable factors (such as age, baseline eGFR, BMI, and comorbid conditions) and “quantity” of preservable parenchyma, which in PN is primarily influenced by tumor size and its location, which is inherently also nonmodifiable.1 Furthermore, data suggest that the effect of a modifiable factor such as ischemia time appears somewhat limited in the long run, especially if kept under 20-25 minutes warm with cold ischemic protection extending time of acceptable ischemia to 2 hours.25 In our series, median ischemic time was 24 minutes for the warm group and 48 minutes for the cold group, and therefore, significant effect of ischemia time on worsening renal functional outcomes in our PN group is not likely.2,26,27 6
Simmons et al2 introduced volumetric analysis to measure preoperative and postoperative kidney volume and also demonstrated that volume loss or “quantity” of preserved nephrons was the primary determinant of renal function after PN. Recognizing that renal function after PN is multifactorial and that PN carries increased surgical risk than RN even in T1 renal mass5 nonetheless begs the question: In the clinical setting, can we efficiently identify larger renal masses for which PN may confer a renal functional benefit, and conversely, can we identify factors associated with lack of benefit for PN in the elective setting and where PN, even if feasible, may not provide benefit to offset increased risk of complications? RENAL score is easy to assign and is associated with the selection of performing RN or PN,15 correlates with the risk of postoperative complication and urine leak,28,29 and was therefore included to account for surgeon selection bias. On Cox analysis, significant differences in renal functional outcomes persisted for RN vs PN for RENAL score 10 but not for RENAL score >10; freedom from CKD over time was significantly poorer for RN among patients with RENAL score <10. For large masses, RENAL score may have UROLOGY
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substantial prognostic value for renal functional outcomes. Correlation of RENAL score with functional volume and association with postoperative renal function is supported by other studies with various tumor sizes. Simmons et al3 compared the RENAL and centrality index (C-index) scoring systems in 299 patients with a contralateral normal kidney who underwent PN. They noted on multivariable analysis that “R” and “N” components of the RENAL score correlated with percent functional volume preservation and that diameter and overall RENAL scores also significantly correlated with long-term percentage GFR preservation.3 Mehrazin et al4 examined the association of renal morphology with renal function after 322 PNs and noted on linear regression analysis that for each 1-point increase in RENAL score, there was a 2.5% decrease in eGFR and for each 1-cm increase in diameter, there was a 1.8% decrease in eGFR. Furthermore, they found that increasing RENAL score was independently associated with CKD after PN (OR, 1.24; P ¼ .046). The findings of Simmons et al and Mehrazin et al suggest that RENAL nephrometry may be a useful adjunct to tumor size when attempting to assess ultimate renal function outcome of PN. Similarly, in our series of cT2 tumors, renal functional benefit conferred by PN declined with increasing nephrometry score, that is, increasing RENAL score may correlate with decreasing amount of preservable parenchyma, and at some point, as suggested by our Cox analysis, the likely breakpoint is RENAL 10; the amount of preservable parenchyma becomes insignificant in the setting of a 2-kidney system, and therefore, renal functional benefit may not be realized in PN vs RN. Overall, our cohorts of PN and RN had relatively similar comorbidities, anatomic characteristics measured by RENAL score, and tumor pathology despite the slightly larger tumors in the RN group. Nonetheless, larger size in RN group is suggestive of inherent selection bias that cannot be eliminated in a retrospective study. However, procedure selection is associated with RENAL score, which was statistically similar in our cohort, as was preoperative CKD between RN and PN, and we used multivariate analysis to control for a variety of factors associated with potential selection bias. Furthermore, eGFR is an estimate of renal function based on serum creatinine and less accurate than quantitative assessments using radioisotope clearance or formulas including additional data such as weight. Nonetheless, eGFR is widely used as a surrogate for renal function in studies such as ours which have sought to examine the effect of surgical nephron loss and coexisting comorbid factors. Ultimately, these data argue for a prospective study in which renal function is determined preoperatively and postoperatively by scintigraphic studies in addition to serum creatinine and eGFR. Indeed, eGFR of <60 mL/min/1.73m2 may not be an effective marker in and of itself.19 For this reason, we chose our primary end point to be a change in eGFR to gage the degree of functional preservation. We UROLOGY
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did not include percent parenchyma spared, which may have also added to the robustness of our analysis. Our utilization of RENAL score as a surrogate for tumor complexity and parenchyma spared (and a more important factor than ischemia time or other perioperative variables) has been confirmed in other analyses by our group and others and validates our findings.2-4,27 Although median follow-up was 41.5 months, longer follow-up (5 year) is necessary for robust renal and oncologic survival outcomes. Nonetheless, our analysis represents the most in-depth examination of renal functional outcomes using one of the largest series of PN and RN for cT2 renal mass reported in the literature.16 The high percentage of cT2 PN is a reflection of the main surgeon’s referral practice and supports a randomized clinical trial to compare renal functional outcomes between RN and PN for larger tumors, which should include prospective assessment of the clinical utility of RENAL sum in stratification of risk and outcomes in cT2RM.30
CONCLUSION Our data suggest that RN is independently associated with decreased renal function measured by continuous eGFR, development of CKD at 6 months, and nearly 2-year loss in CKD-free interval compared to PN for T2RM with RENAL sum 10. However, renal functional benefit was not realized by PN in more complex tumors, and caution should be exercised in offering PN in elective circumstances to this group. Prospective investigation with further follow-up is needed to determine utility of PN for T2RM. References 1. Lane BR, Russo P, Uzzo RG, et al. Comparison of cold and warm ischemia during partial nephrectomy in 660 solitary kidneys reveals predominant role of nonmodifiable factors in determining ultimate renal function. J Urol. 2011;185:421-427. 2. Simmons MN, Hillyer SP, Lee BH, et al. Functional recovery after partial nephrectomy: effect of volume loss and ischemic injury. J Urol. 2012;187:1667-1673. 3. Simmons MN, Hillyer SP, Lee BH, et al. Diameter-axial-polar nephrometry: integration and optimization of R.E.N.A.L. and centrality index scoring systems. J Urol. 2012;188:384-390. 4. Mehrazin R, Palazzi KL, Kopp RP, et al. Impact of tumour morphology on renal function decline after partial nephrectomy. BJU Int. 2013;111:E374-382. 5. Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. J Urol. 2009;182:12711279. 6. Ljungberg B, Cowan NC, Hanbury DC, et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol. 2010;58:398-406. 7. Thompson RH, Boorjian SA, Lohse CM, et al. Radical nephrectomy for pT1a renal masses may be associated with decreased overall survival compared with partial nephrectomy. J Urol. 2008;179: 468-471. 8. Tan HJ, Norton EC, Ye Z, et al. Long-term survival following partial vs radical nephrectomy among older patients with early-stage kidney cancer. JAMA. 2012;307:1629-1635. 9. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical
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nephrectomy for low-stage renal cell carcinoma. Eur Urol. 2011;59: 543-552. Becker F, Roos FC, Janssen M, et al. Short-term functional and oncologic outcomes of nephron-sparing surgery for renal tumours 7 cm. Eur Urol. 2011;59:931-937. Breau RH, Crispen PL, Jimenez RE, et al. Outcome of stage T2 or greater renal cell cancer treated with partial nephrectomy. J Urol. 2010;183:903-938. Karellas ME, O’Brien MF, Jang TL, et al. Partial nephrectomy for selected renal cortical tumours of 7 cm. BJU Int. 2010;106:14841487. Long CJ, Canter DJ, Kutikov A, et al. Partial nephrectomy for renal masses 7 cm: technical, oncological and functional outcomes. BJU Int. 2012;109:1450-1456. Jeldres C, Patard JJ, Capitanio U, et al. Partial versus radical nephrectomy in patients with adverse clinical or pathologic characteristics. Urology. 2009;73:1300-1305. Peycelon M, Hupertan V, Comperat E, et al. Long-term outcomes after nephron sparing surgery for renal cell carcinoma larger than 4 cm. J Urol. 2009;181:35-41. Kopp RP, Mehrazin R, Palazzi KL, et al. Survival outcomes after radical and partial nephrectomy for clinical T2 renal tumors categorized by RENAL nephrometry score. BJU Int. 2014;114:708-718. Kutikov A, Smaldone MC, Egleston BL, et al. Anatomic features of enhancing renal masses predict malignant and high-grade pathology: a preoperative nomogram using the RENAL nephrometry score. Eur Urol. 2011;60:241-248. Tobert CM, Kahnoski RJ, Thompson DE, et al. RENAL nephrometry score predicts surgery type independent of individual surgeon’s use of nephron-sparing surgery. Urology. 2012;80: 157-161. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-S266. AJCC. Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205-213. Huang WC, Levey AS, Serio AM, et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. Lancet Oncol. 2006;7:735-740. Malcolm JB, Bagrodia A, Derweesh IH, et al. Comparison of rates and risk factors for developing chronic renal insufficiency, proteinuria and metabolic acidosis after radical or partial nephrectomy. BJU Int. 2009;104:476-481. Becker F, Siemer S, Hack M, et al. Excellent long-term cancer control with elective nephron-sparing surgery for selected renal cell carcinomas measuring more than 4 cm. Eur Urol. 2006;49:1058-1063. Becker F, Van Poppel H, Hakenberg OW, et al. Assessing the impact of ischaemia time during partial nephrectomy. Eur Urol. 2009;56:625-635. Yossepowitch O, Eggener SE, Serio A, et al. Temporary renal ischemia during nephron sparing surgery is associated with shortterm but not long-term impairment in renal function. J Urol. 2006;176:1339-1443. Kopp RP, Mehrazin R, Palazzi K, et al. Factors affecting renal function after open partial nephrectomy—a comparison of clampless and clamped warm ischemic technique. Urology. 2012;80: 865-870. Stroup SP, Palazzi K, Kopp RP, et al. RENAL nephrometry score is associated with operative approach for partial nephrectomy and urine leak. Urology. 2012;80:151-156. Bruner B, Breau RH, Lohse CM, et al. RENAL nephrometry score is associated with urine leak after partial nephrectomy. BJU Int. 2011; 108:67-72. Weight CJ, Miller DC, Campbell SC, et al. The management of a clinical T1b renal tumor in the presence of a normal contralateral kidney. J Urol. 2013;189:1198-1202.
EDITORIAL COMMENT The authors1 should be congratulated for this significant contribution to the partial nephrectomy (PN) literature. The present study was a retrospective analysis evaluating renal function outcomes after open PN compared with radial nephrectomy (RN) stratified by RENAL sum for renal masses >7 cm (T2RMs). As expected, the DeGFR was greater in RN (19.7) vs PN (11.9) and the de novo chronic kidney disease was significantly delayed in PN verses RN. Interestingly, they demonstrated equivalent renal function outcomes for PN and RN if RENAL score 10, whereas PN was associated with greater complication rates. To understand renal function after PN, baseline renal function, ischemic injury, amount of healthy tissue removed, and reconstructive injury (renorrhaphy) must all be considered. Cold and warm ischemia median times were 48 and 24 minutes, respectively, which appear to be in the acceptable ranges for T2RMs. Maximally preserving renal function would require small resection margins and atraumatic reconstruction techniques. Significant injury from cortical renorrhaphy can occur with even small renal masses. A recent study attributed a 12% loss in ipsilateral renal volume to cortical renorrhaphy on adjusted analysis.2 Reconstructive injury is thought to be due to ligation of segmental vessels in addition to strangulated parenchyma, which has been shown to be worse with more central tumors (higher RENAL score).3 It is important to note that the DeGFR was greater with RN when the RENAL sum was <10 vs 10 (12.1 vs 32.6, respectively) and appears slightly worse for PN at 14.0 vs 9.3, respectively. This suggests that T2RMs with RENAL sum of <10 have more functional renal parenchyma that is lost during an RN and T2RMs with RENAL sum 10 require more involved PN, leading to greater loss of renal function. The functional assessment combined with the complication rate of PN and RN for T2RMs would suggest that a rationale approach would be open PN when and RENAL sum <10 and RN when RENAL sum is 10 and imperative indications are not present. This approach maximizes renal function with acceptable complications and may maximize the use of laparoscopic RN approaches for patients who may not benefit from open PN approach. Several limitations exist in this study. Spot serum creatinine was used to estimate renal function. This is an insensitive tool compared with 24 h urine collection, renal radioisotope clearance, or volumetric analysis.4 Overall, this study is hypothesis generating. Suggesting that instead of an absolute “size limit,” a “complexity limit” may be more appropriate with understanding that size and complexity are not exclusive. Future prospective, volumetric studies may help further define the tipping point for PN based on mass complexity that maximizes renal preservation while limiting associated complications. Thomas Allen Gardner, M.D., Clinton D. Bahler, M.D., and Paul Gillhaus, M.D., Indiana University
References 1. Kopp RP, Liss MA, Mehrazin R, et al. Analysis of renal functional outcomes after radical or partial nephrectomy for renal masses 7 cm using the RENAL score. Urology. In press. 2. Bahler CD, Dube HT, Flynn KJ, et al. Feasibility of omitting cortical renorrhaphy during robotic partial nephrectomy: a matched analysis. J Endourol. 2015;29:548-555.
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3. Simmons MN, Hillyer SP, Lee BH, et al. Nephrometry score is associated with volume loss and functional recovery after partial nephrectomy. J Urol. 2012;188:39. 4. Goh YS, Wu MW, Tai BC, et al. Comparison of creatinine based and kidney volume based methods of estimating glomerular filtration rates in potential living kidney donors. J Urol. 2013;190:1820.
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REPLY The use of partial nephrectomy (PN) for larger masses has increased in recent years, primarily driven by the increasing experience with the procedure on the whole, emerging data suggesting oncologic equivalence to radical nephrectomy, and a growing awareness of the potential deleterious long-term consequences of nephron loss and chronic renal insufficiency.1 PN for larger masses is not without controversy, given increased risk of procedure-specific complications and doubts about the renal functional benefit of nephron-sparing surgery for larger masses.2 Our data suggest that a subset of patients may receive renal functional benefit from PN for larger masses but that this benefit may be limited by overall tumor complexity. We agree with the opinion that our findings are essentially hypothesis generating, and although they may provide additional information to aid in decision making with respect to whether to perform a PN in the setting of a larger (ie, cT2) tumor, there are nonetheless many gray areas, which await further delineation and refinement; for example, what do in the setting of elective or relative indications where benefit may be more incremental (ie, a RENAL score of 10, where our Cox proportional hazard analysis demonstrated decreasing risk of CKD for PN vs RN starting at RENAL score of 10 [hazard ratio, 0.836]). Indeed, not all RENAL scores of 10 may have the same impact on final renal function. Much work needs to be done to further refine criteria and “tipping points” on whether PN may yield benefit. Indeed, although emerging data point to the dominant role of
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nonmodifiable factors such as percent parenchymal volume preserved and presence of baseline drivers toward chronic renal insufficiency when ischemia time is limited,3 RENAL score nonetheless remains an overarching surrogate marker for both quantity of preserved nephrons as well as quality of the preservation4 (with respect to the effect of tumor location on prolonging ischemia time and its potential deleterious effects and volume loss in post PN because of the effects of the reconstruction in more complex renal masses). Ultimately, our findings compel us to agree with, and to call for prospective investigation into the physiologic, anatomical, and technical factors, which may affect renal functional outcomes and for the use of predictive volumetric analysis of renal function as the lynchpin of such integrated decision-making tool(s).5 Even with this approach, RENAL score is a unique marker of tumor complexity and perioperative risk. Ithaar H. Derweesh, M.D., Department of Urology, UC San Diego Health System, La Jolla, CA
References 1. Alanee S, Nutt M, Moore A, et al. Partial nephrectomy for T2 renal masses: contemporary trends and oncologic efficacy. Int Urol Nephrol. 2015; [Epub ahead of print]. 2. Tomaszewski JJ, Smaldone MC, Uzzo RG, Kutikov A. Is radical nephrectomy a legitimate therapeutic option in patients with renal masses amenable to nephron-sparing surgery? BJU Int. 2015;115: 357-363. 3. Thompson RH, Lane BR, Lohse CM, et al. Renal function after partial nephrectomy: effect of warm ischemia relative to quantity and quality of preserved kidney. Urology. 2012;79:356-360. 4. Mehrazin R, Palazzi KL, Kopp RP, et al. Impact of tumour morphology on renal function decline after partial nephrectomy. BJU Int. 2013;111:E374-E382. 5. Meyer A, Woldu SL, Weinberg AC, et al. Predicting renal parenchymal loss following nephron sparing surgery. J Urol. 2015; [Epub ahead of print].
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