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Partial vs. radical nephrectomy and the risk of all-cause mortality, cardiovascular, and nephrological outcomes

Introduction: The study’s objective was to examine the effects of renal preservation surgery on long-term mortality, cardiovascular outcomes, and renal-related outcomes. Methods: We performed a retrospective cohort study of all partial (n=575) and radical nephrectomies (n=882) for tumors ≤7 cm in diameter between 2002 and 2010 across three academic centers in Ontario, Canada. We linked records from provincial databases to assess patient characteristics and outcomes (median seven years’ followup using retrospective data). A weighted propensity score was used to reduce confounding. The primary outcome was all-cause mortality. Secondary outcomes included hospitalization with major cardiovascular events, noncancer related mortality, kidney cancer-related mortality, and dialysis. Results: Mean one-year postoperative estimated glomerular filtration rate (eGFR) was 71 mL/min/1.73 m2 in the partial group and 52 mL/min/1.73 m2 in the radical group. Partial nephrectomy was associated with a lower risk of all-cause mortality in the first five years after surgery (hazard ratio [HR] 0.42; 95% confidence interval [CI] 0.27–0.66), which did not extend beyond five years (HR 1.01; 95% CI 0.68–1.49). Kidney cancer-related mortality was lower in the partial compared to the radical group for the first four years after surgery (HR 0.16; 95% CI CUAJ – Original Research Breau et al Effects of renal-preservation surgery on long-term mortality, CV, & renal outcomes 2 © 2020 Canadian Urological Association 0.04–0.72). There were no significant differences between the groups for cardiovascular outcomes or non-cancer related deaths. Conclusions: Overall survival and cancer-specific survival was reduced in radical nephrectomy patients. However, despite reduced renal function in the radical nephrectomy group, non-cancer related death, cardiovascular events, and dialysis were not significantly different between groups. Long-term benefits of partial nephrectomy may be less than previously believed. Introduction Partial nephrectomy is the preferred treatment for localized renal masses because of equivalent cancer control and improved post-operative renal function compared with radical nephrectomy.(1–3) In non-surgical patients, lower renal function is associated with higher cardiovascular events and shorter survival, hence, partial nephrectomy has been considered to be potentially protective against renal failure and future cardiovascular morbidity(4–7) This is supported by cohort studies and a recent systematic review demonstrating lower cardiovascular related events for partial nephrectomy.(8–10),(11) Surprisingly, the only randomized trial of partial versus radical nephrectomy showed that partial nephrectomy resulted in greater mortality.(12) It is possible that the prognostic significance of surgically induced renal function loss differs from a medical renal loss from conditions such as diabetic nephropathy and its association with a higher risk of cardiovascular disease.(5) Using a large cohort of patients undergoing surgery for renal cell carcinoma (RCC), we examined the association between surgery and mortality, long-term cardiovascular events, and renal related events. We hypothesized that partial nephrectomy versus radical nephrectomy would be associated with reduced mortality owing to fewer cardiovascular complications and reduced need for renal replacement therapy.


Introduction
Partial nephrectomy is the preferred treatment for localized renal masses because of equivalent cancer control and improved post-operative renal function compared with radical nephrectomy. (1)(2)(3) In non-surgical patients, lower renal function is associated with higher cardiovascular events and shorter survival, hence, partial nephrectomy has been considered to be potentially protective against renal failure and future cardiovascular morbidity(4-7) This is supported by cohort studies and a recent systematic review demonstrating lower cardiovascular related events for partial nephrectomy. (8)(9)(10) , (11) Surprisingly, the only randomized trial of partial versus radical nephrectomy showed that partial nephrectomy resulted in greater mortality. (12) It is possible that the prognostic significance of surgically induced renal function loss differs from a medical renal loss from conditions such as diabetic nephropathy and its association with a higher risk of cardiovascular disease. (5) Using a large cohort of patients undergoing surgery for renal cell carcinoma (RCC), we examined the association between surgery and mortality, long-term cardiovascular events, and renal related events. We hypothesized that partial nephrectomy versus radical nephrectomy would be associated with reduced mortality owing to fewer cardiovascular complications and reduced need for renal replacement therapy.

Study design and setting
Residents of Ontario, Canada have universal access to hospital care and physician services covered under the Ontario Health Insurance Plan program. These healthcare encounters are recorded in large population-based databases, which are linked using unique, encoded identifiers and held at the ICES (formerly known as the Institute for Clinical Evaluative Sciences). This study was completed through the ICES Kidney, Dialysis and Transplantation research program and all analyses were performed at the ICES Western site in London, Ontario. This study was approved by the University of Western Ontario (#102933), the Hamilton Integrated (#14-283-D), and the Ottawa Health Science Network (#20140446-01H)Research Ethics Boards. We followed the reporting guidelines for observational studies (see Supplementary Table 1). (13)

Patients and exposure status Only patients from surgical RCC databases were included in the study
The date of the partial or radical nephrectomy procedure was the index date. Patients were excluded from the study if they had a tumor size larger than seven centimeters (partial nephrectomy is rarely performed for stages higher than Stage 2 RCC), if the surgery date was not between a hospital admission and discharge date (to ascertain hospitalization characteristics and eliminate any recording errors), if patients had evidence of receiving dialysis in the previous year, if they had a kidney transplant, if there was tumor thrombus, or metastatic disease. If patients had more than one nephrectomy during the study period, the first surgery was considered the index procedure.

Outcomes
Patient outcomes were assessed from index date until end of follow-up, with the latest possible follow-up date of March 31, 2015. Emigration from Ontario is very low (0.1%/year) and was the only reason for lost study follow-up. (14) The primary outcome was all-cause mortality. The secondary outcomes were hospitalization with a major cardiovascular event (myocardial infarction, stroke, coronary artery bypass surgery, coronary angioplasty), a composite of death or hospitalization with major cardiovascular event, non-cancer related mortality, kidney cancerrelated death, any dialysis, and nephrologist visits. Tertiary outcomes were non-cancer related deaths stratified by pre-operative estimated glomerular filtration rate (eGFR). All analyses were censored for death where relevant.
Pre-specified sub-group analyses for the primary outcome of all-cause mortality were completed for pre-operative eGFR (<45 versus ≥45 mL/min/1.73m 2 ) and tumor size (≤4 cm versus >4 cm) in order to assess whether pre-existing medical renal disease and tumor stage affected the impact of partial versus radical nephrectomy on survival. Post-hoc sub-group

Analysis
All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC). Baseline characteristics were compared between partial and radical nephrectomy groups, where a twosided p-value less than 5% was considered statistically significant with no adjustment for multiple testing. A multivariable logistic regression model including 11 baseline characteristics was used to calculate propensity scores for the probability of receiving a radical versus a partial nephrectomy. These 11 variables were age, sex, tumor size, hospital centre, surgery type, surgery year, pre-operative eGFR, ADG score, previous carotid ultrasound, previous prescription for nitrates, and previous prescription for statins. These characteristics were included either because they were significantly different between the two groups or there was previous evidence of an association with the exposure it was forced into the model. Using this propensity score, we created inverse probability of treatment weights (IPTW) in order for the radical group to better resemble the partial group across the measured baseline characteristics. This 'weighted sample' is essentially a pseudo-sample of people in the radical group who have a similar distribution of baseline characteristics as the partial group. This eliminates some of the potential for confounding based on differences in the characteristics between the two groups, so the associations between groups and the outcomes are less biased, while not excluding any individuals from the analysis. (19) IPTW weights were trimmed at the 1 st and 99 th percentiles to limit the influence of instable weights. (20) Hazard ratios were estimated using Cox proportional hazards regression models, accounting for weighting. To test for proportionality we created a time dependent covariate by

CUAJ -Original Research
Breau et al Effects of renal-preservation surgery on long-term mortality, CV, & renal outcomes 5 © 2020 Canadian Urological Association modelling an interaction of procedure type and log-transformed follow-up time. If this time dependent covariate was significant, then the proportionality assumption was considered violated. (21) For outcomes where the proportionality assumption did not hold, the Cox models were time-stratified using Heaviside functions such that the proportionality assumption was met within each time period. Kaplan-Meier curves were generated to visualize differences in survival time between partial and radical nephrectomy groups. As a sensitivity analysis, we repeated analyses using Fine and Gray's model with death as a competing event.

Baseline characteristics
There were 2108 nephrectomy procedures abstracted from three academic hospitals, and 1457 patients in the cohort after the exclusion criteria were applied (Supplementary Figure 1). The baseline characteristics between the two groups prior to and after propensity score weighting are presented in Table 1. Prior to weighting, the partial nephrectomy group was younger, more likely to have an open procedure, more likely to have smaller tumors, and had higher pre-operative eGFR. After propensity score weighting, the groups were well-balanced across the measured health characteristics, with the exception of a slightly higher eGFR (81 [20.7] versus 78 [16.9] mL/min/1.73 m 2 ) for the partial compared to the radical group.

Postoperative outcomes
Peri-operative and post-operative outcomes at 30 days and one year are presented in Table 2. The mean (SD) one-year post-operative eGFR values for the weighted cohort were 71 (22.3) and 52 (13.4) mL/min/1.73 m 2 for the partial and radical groups, respectively (p<0.0001). The proportion of patients who received a nephrology consultation within the year after nephrectomy was 9.4% for the partial group versus 18.8% for the radical group (p<0.0001), but the need for chronic dialysis was similar, and very low in both groups (Table 3).

Mortality and cardiovascular outcomes
Patients were followed for a median (25th, 75 th percentile) of 6.9 (5.2, 8.5) years overall, with a maximum follow-up of 13.8 years (Supplementary Table 3). Patients were followed until mortality or March 31, 2015, whatever date came first. The incidence of all-cause mortality was significantly lower in the partial nephrectomy group compared to the radical nephrectomy group during the first five years of follow-up: 20.4 versus 31.5 deaths per 1000 person-years after weighting (HR 0.42, 95% CI 0.27-0.66, p=0.0001). However, the association was not evident beyond five years (HR 1.01, 95% CI 0.68-1.49, p=0.98). The Kaplan-Meier curve showing allcause survival probabilities following partial and radical nephrectomy procedures is presented in Figure 1. Cumulative incidence of all-cause mortality at 1, 5 and 9 years is shown in Supplementary Table 4. There was a significant interaction effect by sex after 5 years or more

CUAJ -Original Research
Breau et al Effects of renal-preservation surgery on long-term mortality, CV, & renal outcomes 6 © 2020 Canadian Urological Association follow-up, where for females, partial versus radical nephrectomy had a protective effect, which was reversed in males (interaction p=0.0006 for 5+ years; Supplementary Figure 2). Partial (vs. radical) nephrectomy did not associate with a different risk of hospitalization with a major cardiovascular event: 10.2 versus 8.4 events per 1000 person-years in the weighted analysis (HR 1.22, 95% CI 0.75-1.96, p=0.43). The incidence of all-cause mortality or major cardiovascular events for the weighted analysis was 29.0 events per 1000 person-years for the partial group and 38.8 events per 1000 person-years for the radical group. This difference was statistically significant in the first four years of follow-up (HR 0.68, 95% CI 0.48-0.96, p=0.029) but not after four years (HR 0.97, 95% 0.67-1.43, p=0.90). In the weighted analysis, the incidence of non-cancer related deaths was not significantly different between patients in the partial or radical groups (HR 0.88, 95% CI 0.62-1.25, p=0.49; see Figure 2). The incidence of kidney cancer-related mortality was 1.5 and 5.1 events per 1000 person-years for the partial and radical groups, respectively (see Figure 3). This difference was statistically significant in the first four years of follow-up (HR 0.16, 95% CI 0.04-0.72, p=0.017) but not beyond 4 years (HR 0.83 (95% CI 0.20, 3.42), p=0.80).
Pre-operative renal function significantly modified the association of nephrectomy type (partial compared to radical) and all-cause mortality in the first five years of follow-up, with a significant association observed in those with eGFR ≥45 mL/min/1.73 m 2 (HR 0.36, 95% CI 0.21-0.62, interaction p=0.0025). No significant associations were observed after five years of follow-up, however there was a trend towards higher risk of all-cause mortality for eGFR <45 mL/min/1.73 m 2 and lower risk for eGFR ≥45 mL/min/1.73 m 2 ; a significant interaction by preoperative eGFR status was observed (p<0.0001). Importantly, Figure 4 demonstrates that partial nephrectomy does not significantly reduce non-cancer related mortality over radical nephrectomy whether pre-operative eGFR is less than or greater than 45 mL/min/1.73 m 2 .
Given that partial nephrectomy patients had smaller tumors on average, we hypothesized that tumor related confounding may explain the association between partial nephrectomy and overall survival. To explore this hypothesis, patients were stratified into tumors ≤4 cm and >4 cm. However, no significant interactions were observed when stratified by tumor size (interaction p=0.32 for both <5 and 5+ year follow-up intervals; Supplementary Figure 3). The Fine and Gray's model to account for a competing risk of death showed similar results for secondary outcomes (Supplementary Table 5).

Discussion
Several studies have demonstrated a significant association of cardiovascular events, hospitalization, and even death with the reduction of eGFR in the analyses of large high risk population databases.(5-7) Therefore, despite showing that partial nephrectomy conferred superior renal function compared with radical nephrectomy, we were surprised to show that there was not a difference in the long-term need for dialysis, nor was there a difference in cardiovascular events or non-cancer related mortality between partial and radical nephrectomy

CUAJ -Original Research
Breau et al Effects of renal-preservation surgery on long-term mortality, CV, & renal outcomes 7 © 2020 Canadian Urological Association groups. However, the aforementioned studies were performed in community-based populations with the majority of patients having medical renal disease as the cause of lower eGFR. Indeed, in our current study, patients with pre-operative eGFR <45 ml/min/1.73m 2 had inferior all-cause mortality irrespective of operative intervention, illustrating the impact of medical renal disease on overall health. In contrast, healthy patients with significant acute renal loss from nephrectomy (donor nephrectomy), do not have a long-term higher risk of death, cardiovascular events or hospitalization compared with the general population. (22) Although there may be a higher risk of renal replacement therapy long-term, this risk is relatively low. (23) Therefore, there appears to be a distinct difference in the impact of long-standing medical renal disease versus surgical renal loss with regards to general cardiovascular and renal health.
Compared with patients undergoing donor nephrectomy, patients with RCC are older, and have a more significant history of smoking, hypertension, obesity, and diabetes.(24) As well, a number of patients undergoing extirpative surgery for RCC have impaired renal function, with 19% being classified as stage 3 chronic kidney disease or greater in our population, preoperatively. In fact, we have shown that the presence of diabetes and lower pre-operative eGFR are independent predictors of ongoing long-term renal functional loss in patients undergoing radical nephrectomy.(24) These patients may theoretically be at heightened risk for hyperfiltration injury and accelerated renal loss to end-stage kidney disease. Nevertheless, in this population of patients with coexisting medical renal disease, the impact of the degree of surgical renal loss (radical versus partial nephrectomy) on the acceleration of cardiovascular morbidity and mortality risk was unknown.
For patients with renal tumors, partial nephrectomy has been shown to be associated with better renal function preservation compared to radical nephrectomy, while achieving equivalent oncologic outcomes. (1,11) However, the long-term impact of this renal function preservation has not been established and the only randomized controlled trial (EORTC) revealed worse survival in the partial nephrectomy arm. (12) This study has been criticized for a lengthy and limited patient accrual and it is possible that this study was biased by clinicians accruing patients that were healthier, with superior pre-operative renal function than 'real world' patients with RCC. For the first time, we have shown that although there is a higher proportion of patients with stage 3 chronic kidney disease or greater one year following radical nephrectomy, non-cancer related mortality and cardiovascular events were not different compared to the partial nephrectomy group after a 5-year minimum follow-up. Furthermore, while the proportion of patients requiring nephrology consultation was higher in the radical nephrectomy group, the rate of renal replacement therapy was similarly low in both groups. Even in a subset of patients with stage 3 chronic kidney disease pre-operatively (eGFR<45), there was no difference in non-cancer related mortality between groups. Another study using the ICES databases found an association between partial nephrectomy and reduced need for dialysis. (25) While that study evaluated all patients in the Ontario, the analysis was limited because of lack of baseline renal function data.

CUAJ -Original Research
Breau et al Effects of renal-preservation surgery on long-term mortality, CV, & renal outcomes 8 © 2020 Canadian Urological Association Unlike the previous EORTC randomized trial comparing partial and radical nephrectomy, we found that cancer-related mortality was higher in the radical nephrectomy group within the first four years of follow-up. (12) This trend persisted even when we analyzed the data in tumors ≤4 cm and >4 cm subsets. This was not explained by a higher early complication rate or mortality (<30 day). We believe that this finding may be the result of residual confounding, despite use of propensity score weighting, with higher risk patients receiving radical nephrectomy. This hypothesis, could not be examined in more detail because we did not capture post-operative tumor type, tumor grade, or tumor stage, all factors associated with cancer prognosis.(26) It is likely that radical nephrectomy was performed in patients with more central tumors or with tumors with a more aggressive radiologic appearance. As central tumors are associated with poorer prognosis, this may explain the inferior oncologic outcomes in the radical nephrectomy group. (27) In addition to the lack of detailed baseline tumor information, this study should be interpreted with caution because of the lack of long-term reassessment of renal function through the ICES database. While the length of follow-up is longer than most studies in this field, the time to cardiovascular events may be longer than what we were able to observe and the protective effect of partial nephrectomy may emerge with longer follow-up.

Conclusions
Based on this analysis, the type of extirpative procedure was not associated with non-cancer related mortality, cardiovascular events or renal outcomes. This indicates that the hyperfiltration effect from greater surgical renal loss (radical nephrectomy) may not have the same implications with the progressive effect associated with medical renal disease.

Access to data
The data set from this study is held securely in coded form at the Institute for Clinical Evaluative Sciences (ICES). While data sharing agreements prohibit ICES from making the data set publicly available, access can be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/DAS. The full data set creation plan is available from the authors upon request. Effects of renal-preservation surgery on long-term mortality, CV, & renal outcomes 11 © 2020 Canadian Urological Association Fig. 1. Kaplan-Meier curve of survival time following partial and radical procedures. CI: confidence interval; HR: hazard ratio.     2 After weighing, the frequency/sample size in the radical group was 490. 3 Missing income inputted into income quintile 3. 4 A rural location is defined as populations <10 000. 5 The mean time between the baseline serum creatinine measurement date and the surgery date was 12 for the group and 13 for the group, which did not change after propensity weighting. 6 eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; all patients were assumed to be non-black in the CKD-EPI equation, given the lack of data for race (a reasonable assumption since less than 5% of the Ontario population is of black race). 7 All comorbidities were assessed in the past 5 years from the surgery date. 8 Percentages calculated from participants >66 years only, as this is the segment of the population that has universal drug benefits. ACE: angiotensin-converting enzyme; ADG: aggregated diagnostic group; ARB: angiotensin receptor blocker; eGFR: estimated glomerular filtration rate; SD: standard deviation.  1 After weighing, the frequency/ sample size in the radical group was 490. eGFR: estimated glomerular filtration rate; IQR: interquartile range; SD: standard deviation.   A n a l y s i s Bias 9

Figures and Tables
Describe any efforts to address potential sources of bias.
A n a l y s i s Study size 10 Explain how the study size was arrived at. N / A