Functional Recovery After Partial Nephrectomy: Effects of Volume Loss and Ischemic Injury

Functional Recovery After Partial Nephrectomy: Effects of Volume Loss and Ischemic Injury Matthew N. Simmons,* Shahab P. Hillyer, Byron H. Lee, Amr F. Fergany, Jihad Kaouk and Steven C. Campbell From the Sections of Urologic Oncology and Minimally Invasive and Robotic Urologic Surgery, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio Purpose: We used what is to our knowledge a new method to estimate volume loss after partial nephrectomy to assess the relative contributions of ischemic injury and volume loss on functional outcomes. Materials and Methods: We analyzed the records of 301 consecutive patients who underwent conventional partial nephrectomy between 2007 and 2010 with available data to meet inclusion criteria. Percent functional volume preservation was measured at a median of 1.4 years after surgery. Modification of diet in renal disease-2 estimated glomerular filtration rate was measured preoperatively and perioperatively, and a median of 1.2 years postoperatively. Statistical analysis was done to study associations. Results: Hypothermia or warm ischemia 25 minutes or less was applied in 75% of cases. Median percent functional volume preservation was 91% (range 38% 107%). Percent glomerular filtration rate preservation at nadir and late time points was 77% and 90% of preoperative glomerular filtration rate, respectively. On multivariate analysis percent functional volume preservation and warm ischemia time were associated with nadir glomerular filtration rate while only percent functional volume preservation was associated with late glomerular filtration rate (each p 0.001). Late percent glomerular filtration rate preservation and percent functional volume preservation were directly associated (p 0.001). Recovery of function to 90% or greater of percent functional volume preservation predicted levels was observed in 86% of patients. In patients with de novo postoperative stage 3 or greater chronic kidney disease, percent functional volume preservation and Charlson score were associated with late percent glomerular filtration rate preservation. Warm ischemia time was not associated with late functional glomerular filtration rate decreases in patients considered high risk for ischemic injury. Conclusions: In this cohort volume loss and not ischemia time was the primary determinant of ultimate renal function after partial nephrectomy. Technical modifications aimed at minimizing volume loss during partial nephrectomy while still achieving negative margins may result in improved functional outcomes. Abbreviations and Acronyms CIT cold ischemia time CKD chronic kidney disease GFR glomerular filtration rate PFVP percent functional volume preservation PGP percent GFR preservation PN partial nephrectomy RENAL (R)adius (tumor size as maximal diameter), (E)xophytic/ endophytic properties of tumor, (N)earness of tumor deepest portion to collecting system or sinus, (A)nterior (a)/posterior (p) descriptor and (L)ocation relative to polar line WIT warm ischemia time Submitted for publication August 30, 2011. Study received institutional review board approval. * Correspondence: Center for Urologic Oncology, Cleveland Clinic Glickman Urological and Kidney Institute, 9500 Euclid Ave., Suite Q10-1, Cleveland, Ohio 44195 (telephone: 216-636-0066; FAX: 216-445-7031; e-mail: simmonm2@ccf.org). Financial interest and/or other relationship with Intuitive, Healthtronic and Covidien. Key Words: kidney, nephrectomy, cold ischemia, warm ischemia, kidney function tests IT is widely accepted that renal parenchymal volume preservation equates to improved functional outcomes, which explains the emergence of PN as the standard of care for localized renal masses. 1 Despite this little attention has been paid to assessing volume loss after PN, mostly due to difficulty in measuring 0022-5347/12/1875-1667/0 Vol. 187, 1667-1673, May 2012 THE JOURNAL OF UROLOGY Printed in U.S.A. 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI:10.1016/j.juro.2011.12.068 www.jurology.com 1667

1668 FUNCTIONAL RECOVERY AFTER PARTIAL NEPHRECTOMY this parameter. Volume loss after PN occurs partly as the result of parenchymal removal and reconstruction associated with tumor excision, and partly during tissue remodeling during the weeks to months after renorrhaphy. Volumetric analysis has been used to measure volume changes after PN but this requires sophisticated software and technical expertise. 2 4 We recently developed a mathematical method to manually estimate PFVP using standard preoperative and postoperative computerized tomography. 5 Analysis of 39 cases using this methodology revealed that volume loss correlated strongly with long-term function after PN. In this study we more completely characterized renal functional recovery as it relates to volume loss and ischemia-reperfusion injury. Most prior studies of the relationship of ischemia time with functional outcomes did not consider volume loss. 6 8 We examined the differential contribution of volume loss and ischemia time on nadir and long-term kidney function in a large contemporary PN cohort, including open, laparoscopic and robotic cases. METHODOLOGY Patient Population Patient data were obtained from an institutional review board approved, prospectively maintained database in conformity with Health Insurance Portability and Accountability Act regulations. We selected 301 of 855 consecutive patients treated with open, laparoscopic or robotic PN between January 2007 and May 2010 according to the study inclusion criteria of age greater than 18 years, a contralateral kidney that was symmetrical on radiology or data that quantified the contralateral functional contribution, single tumor excision, availability of creatinine data before and after surgery, and availability of preoperative and postoperative cross-sectional imaging. Exclusion criteria included PN done for a nononcological condition and the presence of postoperative hydronephrosis. Volumetric Analysis All patients underwent contrast enhanced computerized tomography or magnetic resonance imaging a median of 1 month (range 0 to 9) before surgery and at a late date after surgery (median 1.2 years, range 0.2 to 3.8). PFVP was measured using cylindrical volume ratio methodology. 5 Syngo Studio imaging software (Siemens, Washington, D.C.) was used for all analyses. Kidney Function Evaluation Serum creatinine was measured using standard laboratory methodology 1 to 3 days before surgery and perioperatively. Late measurements were made a median of 1.4 years (range 0.2 to 4.3) after PN. Data on patient age, BMI, gender and ethnicity were used to calculate GFR using the modified diet in renal disease-2 equation. 9 Percent GFR preservation was calculated by dividing nadir or late GFR by preoperative GFR. PFVP predicted GFR was calculated by multiplying preoperative GFR times PFVP. Statistical Analysis Parametric data are shown as the mean SD. The Student t test and 1-way ANOVA were used to test differences in means. All nonparametric data are expressed as the median and range. Bland-Altman analysis was used to assess agreement between groups. Univariate and multivariate linear regression analysis was done to assess correlations of PFVP with demographic, pathological and operative data. The null hypothesis was rejected at p 0.05. RESULTS Table 1 lists study cohort demographic, pathological and operative data. Figure 1, A shows cohort functional and volume changes. Function, defined as PGP, showed a nadir at 77% (range 19% to 117%) at a median of 1 day and recovered to 90% (range 44% to 130%) at a median of 1.4 years. Median PFVP was 91% (range 38% to 107%), which correlated with late Table 1. Demographic, pathological and operative data on 301 patients Median age (range) 59 (18 86) No. male (%) 181 (60) No. rt side (%) 143 (48) Median kg/m 2 BMI (range) 29 (18.1 54.5) Median Charlson score (range) 4 (1 12) Median cm tumor diameter (range) 3.2 (0.85 9.56) Median centrality index (range) 2.2 (0.52 9.69) Median RENAL score (range) 7 (4 11) No. solitary kidneys (%) 17 (6) No. malignant tumors (%) 274 (91) No. tumor stage (%): pt1a 200 (66) pt1b 67 (23) pt2 10 (3) pt3a 23 (8) Median Fuhrman grade (range) 2 (1 4) No. PN technique (%): Open 141 (47) Laparoscopic 100 (33) Robotic 60 (20) Median PFVP (range): 91 (38 107) Open PN 90 (52 107) Laparoscopic PN 93 (68 106) Robotic PN 91 (61 104) Median GFR (range): Preop (ml/minute/1.73 m 2 ) 83.2 (32 195) Time to nadir (days) 1 (0 11) Nadir (ml/minute/1.73 m 2 ) 65 (11.4 137) % Nadir preservation 77 (19 117) Time to late (yrs) 1.4 (0.2 4.3) Late (ml/minute/1.73 m 2 ) 76.5 (16 142) % Late preservation 90 (40 129) No. stage 3 or greater CKD (%): Preop 41 (13) Postop 79 (26) Ischemia: No. zero (%) 19 (6) No. warm (%) 226 (75) Median mins WIT (range) 21 (7 60) No. cold (%) 57 (19) Median mins CIT (range) 40 (25 77)

FUNCTIONAL RECOVERY AFTER PARTIAL NEPHRECTOMY 1669 Figure 1. Correlation between observed function and volume. A, median PGP was 77% at median of 1 day after PN. Median late PGP was 90% at median of 1.4 years. Median PFVP was 91% (dashed line), correlating with late PGP (p 0.001). Pre-op, preoperative. B, linear regression analysis shows observed late vs volume predicted GFR (r 2 0.88, p 0.001). C, Bland-Altman analysis of agreement between observed late and volume predicted GFR (CI 0.75, 95% CI 0.14, p 0.02). PGP (r 2 0.5, p 0.001). Late PGP was 90% or greater of PFVP in 259 patients (86%). PFVP was multiplied by preoperative GFR to calculate volume predicted GFR. Figure 1, B and C shows agreement between PFVP predicted GFR and observed late GFR. Multivariate regression analysis was done for 244 patients who underwent warm ischemia for a median of 21 minutes (range 0 to 60) to identify factors associated with functional decrease (table 2). PFVP, preoperative GFR and WIT were associated with nadir GFR (r 2 0.77, each p 0.001). PFVP and preoperative GFR were associated with late GFR (r 2 0.88, each p 0.001). WIT was not associated with late GFR (p 0.585). On analysis using nadir and late PGP as dependent variables PFVP and WIT were associated with nadir PGP (r 2 0.27, p 0.001 and 0.009, respectively). PFVP was strongly associated with late PGP (r 2 0.5, p 0.001) but WIT was not (p 0.433). Briefly, ultimate renal function in this cohort was determined primarily by the quantity of parenchyma preserved with a minimal long-term effect of ischemic injury. The relationship of PFVP with ischemia type and duration was assessed (table 3). Figure 2, A shows functional trends for 224 patients who underwent WIT (median 24 minutes, range 7 to 60) vs 57 with CIT (median 41 minutes, range 25 to 77). Late PGP in the CIT and WIT groups was 87% to 89%, which correlated with the median PFVP of 89%, suggesting almost complete recovery from ischemic insult in most patients. Figure 2, B shows PGP trends for patients grouped by no ischemia (19 or 6%), and warm ischemia 25 minutes or less (151 or 50%) and greater than 25 minutes (74 of 25%). Those with zero ischemia had the highest nadir and late PGP (88% and 97%, respectively). Patients with WIT 25 or less minutes had higher nadir PGP than the group with WIT greater than 25 minutes (67% vs 62%, p 0.02) but the 2 groups had equivalent late PGP (75% vs 76%). Observed late PGP correlated with predicted PFVP in all 3 groups. Mean PFVP was 97%, 90%, 88% and 89%, in the groups with zero ischemia, WIT 25 minutes or less, WIT greater than 25 minutes and CIT, respectively (p 0.001). Analysis was performed to identify factors associated with de novo postoperative stage 3 or greater CKD. A total of 39 patients with normal preoperative kidney function, ie GFR 60 ml/minute/1.73 m 2 or greater, showed progression to stage 3 or greater CKD, ie GFR less than 60 ml/minute/1.73 m 2,atthe Table 2. Multivariate regression analysis Dependent Variable p Value Nadir egfr Late egfr Nadir PGP Late PGP Tumor 0.134 0.281 0.13 0.608 diameter PFVP 0.001 0.001 0.001 0.001 Age 0.5 0.008 0.553 0.049 BMI 0.061 0.82 0.031 0.577 Charlson score 0.272 0.055 0.343 0.731 WIT 0.001 0.585 0.009 0.433 Preop GFR 0.001 0.001 0.694 0.476

1670 FUNCTIONAL RECOVERY AFTER PARTIAL NEPHRECTOMY Table 3. Ischemia type and duration Mean SD WIT Mean SD Zero Ischemia 25 Mins or Less Greater Than 25 Mins Mean SD Cold Ischemia p Value No. pts 19 151 74 57 Age 58.4 9.2 57.5 12.6 58 13.2 58.7 13 0.937 % Male 0.63 0.5 0.6 0.5 0.58 0.5 0.6 0.5 0.981 BMI (kg/m 2 ) 30.9 6.7 29.6 6.2 30.1 5.8 30.6 5.8 0.647 Charlson score 3.9 1.1 4.2 1.7 4.2 1.7 4.5 2.1 0.556 Tumor diameter (cm) 2.6 1.4 3.3 1.4 3.8 1.5 3.9 1.6 0.001 PFVP 0.97 0.06 0.9 0.08 0.88 0.11 0.89 0.08 0.001 Centrality index 4.3 2.1 2.8 1.6 2.13 1.3 1.8 0.9 0.001 RENAL score 4.8 1.1 7 1.9 7.9 1.9 8.2 1.7 0.001 GFR: Preop (ml/min/1.73 m 2 ) 91.2 21 85.9 24 86.2 26 80.8 21 0.335 Nadir (ml/min/1.73 m 2 ) 80.9 25 66.9 21 62.3 23 56.6 22 0.026 % Nadir preservation 0.88 0.11 0.77 0.15 0.72 0.16 0.68 0.2 0.001 Late (ml/min/1.73 m 2 ) 88.5 23 75.2 23 75.7 26 72.5 21 0.081 % Late preservation 0.97 0.08 0.87 0.12 0.87 0.14 0.89 0.12 0.008 Ischemia time (mins) 0 17.4 4.7 33.5 7.3 43.2 12.6 0.001 late time point. Patients without CKD demonstrated 92% late PGP, consistent with the 91% volume predicted level (p 0.001, fig. 3). In contrast, patients with postoperative CKD had 77% late PGP, significantly short of the volume predicted 84% level. Multivariate analysis was done to identify factors associated with this hindered recovery (tables 4 and 5). Tumor diameter and PFVP were associated with nadir PGP (p 0.004 and 0.02, respectively). PFVP and Charlson score were associated with late PGP (p 0.03 and 0.05, respectively). WIT was not associated with late PGP (p 0.46). Analysis was done to assess the impact of WIT and PFVP in additional patient subsets considered at high risk for ischemic injury. Patients were grouped by age 70 years or less vs greater than 70, preoperative GFR 60 ml per minute per 1.73 m 2 or less vs greater than 60 and Charlson score 5 or less vs greater than 5. Similar to the CKD cohort (fig. 3), patients in the high risk groups had larger tumor diameter, lower PFVP and longer WIT (data not shown). Equivalent results were noted on multivariate analysis, namely that PFVP and Charlson score but not WIT were associated with late PGP. DISCUSSION Introducing volumetric data into functional outcome analysis revealed that volume loss had a more direct, predictable effect on ultimate GFR than ischemia time. The GFR decrease immediately after PN was associated with volume loss and ischemia but the association of ischemia time was lost at the late time point. These data challenge the prevailing and long held notion that ischemic injury is the primary determinant of ultimate function after PN. Numerous prior studies have shown associations of functional decline with ischemia duration but most were not adjusted for volume loss. 6,7,10,11 Figure 2, B shows the importance of this adjustment. Based on a graph lacking volume loss data one would conclude that WIT is primarily associated with decreased GFR. However, after volume data are introduced it becomes clear that volume loss is directly associated with late function. In this study cohort WIT was associated with increased tumor diameter, central location and volume loss (each p 0.001). In this regard WIT was a surrogate for PFVP and not a primary instigator of decreased function except in the shortterm phase after surgery. These data are supported by prior studies showing an association of functional outcome with volume loss estimates. 4,12,13 A limitation of some of these studies was reliance on a visual estimation of the volume decrease, which can be inaccurate and subjective. Our series confirms the essential findings of these prior studies using a consistent quantitative measure of volume change. These data lead to a refined mechanistic model for post-pn injury and functional recovery. An injury phase is initiated at surgery. The magnitude of the decrease in GFR appears to be influenced by 3 factors, including 1) functional volume loss, 2) ischemia related acute kidney injury and 3) mechanical trauma effects. Volume loss occurs partly as the result of excising normal tissue adjacent to the tumor margin but also to a large extent to collateral damage sustained during renorrhaphy, namely ligation of adjacent arteries, tissue compression and necrosis at the renorrhaphy site as well as pyramidal atrophy due to calyceal ligation. Ischemia-reperfusion injury has well characterized detrimental effects and is proportional to ischemia duration. 14 Mechanical trauma effects were

FUNCTIONAL RECOVERY AFTER PARTIAL NEPHRECTOMY 1671 Figure 3. Incomplete functional recovery in patients with de novo stage 3 or greater CKD. PGP was plotted for 232 patients without and 39 with de novo stage 3 or greater CKD at preoperative (Pre-op), nadir and late time points. Patients with de novo CKD had decreased PGP at nadir and late points relative to those without CKD, who had late functional recovery to 91% volume predicted level. Patients with CKD did not achieve volume predicted level (PFVP 84%, observed PGP 77%, p 0.008). Figure 2. PGP impact of ischemia type and time. A, 224 patients with median 21-minute WIT and 57 with median 40-minute CIT at preoperative (Pre-op), nadir and late time points. At nadir CIT group had lower PGP than WIT group (p 0.001). PFVP (dashed lines) correlated strongly with late PGP in each group. B, patients with zero, 25 or less and greater than 25-minute WIT at preoperative, nadir and late time (t) points. At nadir and late point 25 or less and greater than 25-minute WIT groups had significantly decreased function than zero ischemia group (p 0.001). PFVP (dashed lines) correlated strongly with late function in all groups. observed in the patient subset with zero ischemia, who showed a 12% temporary decrease in function at the nadir time point. Potential mechanisms of trauma effects include but are not limited to disruption of osmotic gradients by localized edema, cytokine inhibitory effects and alteration of regional microvascular blood flow. Ischemia may amplify the severity of trauma related effects, in addition to inducing injury. The recovery phase follows the injury phase in the weeks to months after surgery. During this time it appears that the effects of trauma and ischemia are reversed and kidneys recover to a new functional baseline determined primarily by the amount of remaining functional volume. Contemporary data support that specific patient subsets, such as the elderly population, those with major medical comorbidities and those with preoperative CKD, may be more vulnerable to ischemic injury. 6 8 In this study patients with de novo CKD did not completely recover to volume predicted levels (fig. 3). Analysis was done to determine whether this was due to increased vulnerability to ischemic injury. Those at high risk had higher sensitivity to WIT at the nadir but not at the late time point. The effects of WIT and PFVP were examined in additional patient subsets thought to be at high risk for ischemic injury, namely the elderly population (age greater than 70 years), those with preoperative stage 3 or greater CKD and those with major medical comorbidities (Charlson score greater than 5). Those at high risk had a relatively larger tumor diameter, lower PFVP and longer WIT (data not shown). Table 4. Postoperative stage 3 or greater CKD NonCKD CKD p Value No. pts 232 39 Mean SD age 55.5 12.6 63.85 10 0.001 Mean SD % male 0.6 0.5 0.56 0.5 0.64 Mean SD BMI (kg/m 2 ) 29.6 5.8 29.7 6 0.92 Mean SD Charlson score 3.8 1.5 5.2 2.1 0.001 Mean SD tumor diameter 3.4 1.4 3.4 1.4 Not applicable (cm) Mean SD PFVP 0.91 0.09 0.77 0.13 0.001 Mean SD Centrality index 2.6 1.6 2.4 1.4 0.46 Mean SD GFR: Preop 94.4 20.6 68.3 6.7 0.001 Nadir 73.3 19.3 46.8 12.6 0.001 % Nadir preservation 0.78 0.15 0.68 0.16 0.002 Late 85.8 18.1 52.2 7.6 0.001 % Late preservation 0.92 0.11 0.77 0.13 0.001 Ischemia: No. warm 20 22 Mean SD WIT (mins) 18 0.07 33 10.2 0.33 No. cold 42 44 Mean SD CIT (mins) 42 13.7 6 12.9 0.74

1672 FUNCTIONAL RECOVERY AFTER PARTIAL NEPHRECTOMY Table 5. Multivariate regression analysis with percent GFR preservation as dependent variable % Nadir GFR Preservation p Value % Late GFR Preservation p Value NonCKD CKD NonCKD CKD No. pts 180 32 180 32 Tumor diameter 0.031 0.004 0.082 0.649 PFVP 0.002 0.023 0.001 0.031 Age 0.721 0.324 0.001 0.064 Gender 0.234 0.324 0.001 0.064 BMI 0.392 0.599 0.970 0.310 Charlson index 0.213 0.087 0.317 0.046 WIT 0.016 0.114 0.461 0.458 Multivariate analysis revealed a consistent theme in these high risk groups, in which PFVP and Charlson score but not WIT were associated with late PGP. This suggests that in such vulnerable populations incomplete recovery from ischemic injury may have a role but other factors, such as increased volume loss and perhaps age related or illness related factors, may also contribute substantially to the inequitable recovery. While these data appear to decrease the impact of ischemic injury on late functional recovery, they do not prove an absent effect. An effect of ischemia was clearly observed at the nadir time point. It is reasonable to expect that it would have a durable impact on late GFR in certain patients, particularly if WIT is continued to extended intervals. This cohort was limited, in that there were relatively few patients with prolonged ischemia since 25% had WIT greater than 25 minutes and only 6% had WIT greater than 40 minutes. Adequate evaluation of the impact of prolonged ischemia would require more patients with prolonged WIT, ideally in a solitary kidney, in which analysis of decreased renal function is more straightforward. What can be concluded from the current study is that there was a negligible impact of limited warm ischemia or hypothermia on ultimate renal function even in patients considered at high risk for ischemic injury. Overall the cohort was reasonably healthy and of average age for elective PN, and had a low incidence of preoperative CKD. Also, the cohort included patients treated with open, laparoscopic and robotic PN with ischemia times commensurate with those commonly reported in the literature. Since PFVP was equivalent at 90% to 93% in the open, laparoscopic and robotic PN groups, all patients were included in analysis. The cohort had a median tumor centrality index of 2.5 and a median RENAL score of 7, indicating an intermediate degree of resection difficulty. All of these factors indicate that this cohort is likely representative of most patients treated at academic centers and in the community. Thus, data from this study can be generalized to most practice settings. Optimizing the precision of excision and reconstruction could yield substantial improvement in functional outcomes after PN and may provide greater yield than a further decrease in ischemic time from conventional standards, namely limited warm ischemia or liberal hypothermia use. Technical modifications that could decrease PN associated volume loss include high resolution radiological tumor mapping, refined live image guided tumor excision, avoidance of the occlusion of adjacent end arteries and minimization of the amount of tissue incorporated into renorrhaphy. Emerging surgical techniques go to great lengths to minimize or eliminate ischemia. 15 17 Data from this study show that direct comparison of functional outcomes from emerging techniques relative to traditional PN techniques involving limited WIT or hypothermia will require volumetric data. Limitations of this study include its retrospective nature, reliance on GFR estimation from serum creatinine, heterogeneity in various aspects of the study cohort and the presence of compensatory function from normal contralateral kidneys in most patients. Studies would ideally include more patients with a solitary kidney and/or direct GFR measurement using 125 I-iothalamate clearance measurement. A key issue relating to the validity of this study is the accuracy of the volume estimation method. To estimate measurement error we divided PFVP by late PGP. The SD of differences in these values was 11%. Despite a modest degree of measurement error associations were highly statistically significant. It is expected that more sophisticated, accurate volume measurement methods would only further corroborate our findings. CONCLUSIONS Decreased function immediately after PN was associated with volume preservation and ischemia time. In contrast, the percent decrease in GFR at late time points was associated only with volume preservation, implying that ischemia effects were transient and reversible. Most study patients had a median WIT of less than 25 minutes or hypothermia and the implications of this study should not be generalized beyond these parameters. New techniques that optimize tissue preservation while still achieving negative margins may lead to improved functional outcomes after PN.

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