EUROPEAN UROLOGY 58 (2010)

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1 EUROPEAN UROLOGY 58 (2010) available at journal homepage: Kidney Cancer Renal Damage Caused by Warm Ischaemia During Laparoscopic and Robot-Assisted Partial Nephrectomy: An Assessment Using Tc 99m-DTPA Glomerular Filtration Rate Jae Duck Choi a, Jong Wook Park b, Joon Young Choi c, Hong Seok Kim a, Byong Chang Jeong a, Seong Soo Jeon a, Hyun Moo Lee a, Han Yong Choi a, Seong Il Seo a, * a Department of Urology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea b Department of Urology, Korea Cancer Centre Hospital, Seoul, Republic of Korea c Department of Nuclear Medicine, Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Article info Article history: Accepted August 26, 2010 Published online ahead of print on September 15, 2010 Keywords: Partial nephrectomy Warm ischaemia Radionuclide imaging Renal function Robotics Abstract Background: Few studies assessing the functional change of each kidney following warm ischaemia after partial nephrectomy are available. Objectives: Our aim was to identify the effects of the warm ischaemic time (WIT) on renal function after partial nephrectomy under the pneumoperitoneum. Design, setting, and participants: Forty-four consecutive patients who underwent laparoscopic partial nephrectomy (LPN) or robot-assisted partial nephrectomy (RAPN) from June 2008 to May 2009 for a single ct1 renal tumour were included in this prospective protocol. Measurements: Technetium Tc 99m-diethylenetriaminepentaacetic acid (Tc 99m-DTPA) renal scintigraphy was used to determine the glomerular filtration rate (GFR) of both kidneys and each kidney individually. Tc 99m-DTPA GFR was performed preoperatively and 3 mo postoperatively. In addition, we analysed Tc 99m-DTPA scintigraphy GFR regionally in the healthy areas of the affected kidney. Results and limitations: Patients with WIT >28 min had a significantly greater decrease in the GFR of the affected kidney ( p = 0.031). The GFR of the affected kidney showed a significant decrease perioperatively ( to ml/min per 1.73 m 2 ; p = 0.003). The functional change of the nonaffected kidney showed an increasing trend ( to ml/min per 1.73 m 2 ), although it was not statistically significant ( p = 0.103). Regional Tc 99m-DTPA GFR of both affected kidney and nonaffected kidney showed no significant differences perioperatively ( to ml/min per 1.73 m 2 ; p =0.641; to ml/min per 1.73 m 2 ; p = 0.200). On multivariate analysis, preoperative GFR, resected volume of marginal healthy tissue, and WIT were independent predictors for functional reduction of the affected kidney ( p < 0.05). The study was limited by small numbers and short follow-up periods. Conclusions: Stationary overall renal function after LPN or RAPN is masked possibly by functional compensation of the contralateral healthy kidney. The damage of the affected kidney estimated by scintigraphy occurs when WIT exceeds 28 min during partial nephrectomy under the pneumoperitoneum. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Samsung Medical Centre, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul, , Republic of Korea. Tel ; Fax: address: siseo@skku.edu (S.I. Seo) /$ see back matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 EUROPEAN UROLOGY 58 (2010) Introduction Laparoscopic partial nephrectomy (LPN) and robot-assisted partial nephrectomy (RAPN) have been accepted as surgical options for the treatment of small renal tumours with adequate oncologic results [1,2]. During these surgical procedures, renal hilar clamping is usually employed to achieve the bloodless field. Major concerns persist regarding ischaemic renal injury following the interruption of renal circulation. Moreover, there are ongoing arguments about maximal tolerable warm ischaemic time (WIT) during partial nephrectomy exacerbated by a lack of sufficient studies evaluating the function of each kidney separately. The evaluation of ischaemic renal injury after partial nephrectomy via measurement of glomerular filtration rate (GFR) by using technetium Tc 99m-diethylenetriaminepentaacetic acid (Tc 99m-DTPA) has rarely been studied [3,4]. This is an accurate method for evaluation of GFR independently of serum creatinine levels and considered the gold standard method for measuring GFR [5]. Therefore, we prospectively evaluated changes in renal function caused by warm ischaemia using Tc 99m-DTPA GFR before and after LPN or RAPN, including the evaluation of each kidney separately. 2. Materials and methods 2.1. Patients, image protocol, and pathology assessment Between June 2008 and May 2009, 44 consecutive patients who underwent LPN or RAPN by a single surgeon were enrolled in this prospective study. All patients underwent spiral computerised tomography before surgery. Patients showing preoperative renal dysfunction or tumour >7 cm were excluded. Informed consent was obtained for preoperative and postoperative renal scan studies. Tc 99m-DTPA renal scans were performed preoperatively and 3 mo postoperatively in all 44 patients. Following the intravenous administration of 370 MBq of Tc 99m-DTPA, posterior dynamic images were acquired using a gamma camera (Infinia; GE Healthcare, USA) with a low-energy general-purpose collimator in a matrix with a frame rate of 1 s/frame for 60 frames and 20 s/frame for 60 frames. The GFR of each kidney was measured by gamma camera estimation using Gates s method [6]. GFR was normalised by body surface area (1.73 m 2 ). We measured regional uptake and calculated regional GFR for both kidneys, and the region of interest (ROI) was set as 4 4 pixels ( mm) in a surgically nonaffected area. We measured regional uptake twice for each kidney and averaged the value for regional GFR calculation. Pathology assessment included histology of the lesion and the calculation of the volume of marginal healthy renal tissue. We evaluated the excised volume of marginal healthy tissue by subtracting the tumour volume from the total volume of the resected specimen calculated by the ellipsoid formula Surgical technique A transperitoneal approach was used for all procedures. Techniques and trocar arrangement for RAPN and LPN have been previously described in the literature [7,8]. However, some important modifications in our surgical technique are described. A laparoscopic bulldog clamp was placed across the full length of the renal artery by the assistant surgeon. The tumour was excised with approximately 5-mm margins from the tumour. The cut inner surface was sutured with 3-0 polyglactin running suture, and LAPRA-TY clips (Ethicon, Cincinnati, OH, USA) were used to fix the sutures. Renal parenchymal approximation sutures (2-0 polyglactin) were placed and Hem-o-Lok clips were used to fix the sutures Statistics Pearson chi-square, student t tests, Fisher exact tests, and Mann- Whitney U tests were used to compare categorical and continuous variables. Paired t tests and Wilcoxon signed rank tests were used for perioperative comparison of renal functional change. All data are reported as mean plus or minus standard deviation. Correlations were assessed by the Spearman rank correlation coefficient. Multivariate regression was used for the determination of independent factors predictive of renal function reduction. All tests were two sided, and p values < 0.05 were considered statistically significant. All statistical analyses were performed using SPSS software (SPSS Inc, Chicago, IL, USA). 3. Results LPN and RAPN were successfully completed in all patients, and conversion to open surgery did not occur in any case. No operative complications were observed in any patients. Table 1 summarises the patient and renal tumour data. There were no significant differences in preoperative characteristics between the two procedure groups (Table 1). The mean serum creatinine level was similar between before and 3 mo after surgery ( p =0.527;Table 2). The GFR of the operated kidney measured by Tc 99m-DTPA scintigraphy decreased significantly from ml/min per 1.73 m 2 preoperatively to ml/min per 1.73 m 2 3 mo postoperatively ( p = 0.003). The total Tc 99m-DTPA GFR was similar before and 3 mo after the operation. Mean GFR was ml/min per 1.73 m 2 preoperatively and ml/min per 1.73 m 2 3 mo postoperatively ( p = 0.124; Table 2). The Tc 99m-DTPA GFR of the contralateral kidney increased from ml/min per 1.73 m 2 preoperatively to ml/min per 1.73 m 2 3 mo postoperatively (p = 0.103). We also assessed the regional Tc 99m-DTPA GFR of both kidneys. Regional GFR of both kidneys showed no significant changes perioperatively ( p < 0.05; Table 2). There was a significant negative correlation between the length of ischaemic time and the Tc 99m-DTPA GFR of the operated kidney: the longer the ischaemic time, the greater the decrease in Tc 99m-DTPA GFR (R 2 = 0.386, p = 0.009; Fig. 1). However, there was neither correlation between the length of ischaemic time and the regional Tc 99m-DTPA GFR of the operated kidney nor of the contralateral kidney. We subdivided the patients into two groups using the length of WIT to determine the maximum WIT that resulted in the most significant functional decrease on Tc 99m-DTPA GFR or regional GFR of operated kidney. The greatest difference of GFR was found at WIT of 28 min ( p = 0.031). However, these differences were not observed in regional GFR. We grouped patients by cut-off WIT (28 min and >28 min of ischaemic time) to compare patient characteristics. Preoperative GFR, tumour size, estimated blood loss, and operative time were similar between groups, respectively (Table 3). The percentage change of Tc 99m-DTPA GFR

3 902 EUROPEAN UROLOGY 58 (2010) Table 1 Patients and operative characteristics * LPN (n = 31) RAPN (n = 13) All (n = 44) p value Patient age, yr (21 71) (24 81) (21 81) Sex Male Female BMI, kg/m ( ) ( ) ( ) Side Right Left Tumour size, cm ( ) ( ) ( ) Tumour location Upper Mid Lower Ischaemic time, min (19 57) (25 58) (19 58) EBL, ml (20 800) (50 600) (20 800) Operative time, min ( ) ( ) ( ) Resected healthy tissue volume, cm ( ) ( ) ( ) Tumour pathology RCC AML Others AML = angiomyolipoma; BMI = body mass index; EBL = estimated blood loss; GFR = glomerular filtration rate; LPN = laparoscopic partial nephrectomy; RAPN = robot-assisted partial nephrectomy; RCC = renal cell carcinoma. * Values given as mean plus or minus standard deviation (range). Table 2 Comparison of preoperative and postoperative renal function Preoperative Postoperative 3 mo p value Serum creatinine, mg/ml ( ) ( ) GFR of operated kidney, ml/min per 1.73 m ( ) ( ) GFR of total kidney, ml/min per 1.73 m ( ) ( ) GFR of contralateral kidney, ml/min per 1.73 m ( ) ( ) r-gfr of operated kidney, ml/min per 1.73 m ( ) ( ) r-gfr of contralateral kidney, ml/min per 1.73 m 2 ) ( ) ( ) GFR = glomerular filtration rate; r-gfr = regional glomerular filtration rate. of the operated kidney in patients with >28 min of WIT decreased to 79.6% when evaluated 3 mo postoperatively, but in the group with 28 min of WIT it decreased only to 99.1% ( p = 0.013; Table 3). When we compared the [(Fig._1)TD$FIG] compensatory increase of Tc 99m-DTPA GFR in the contralateral kidney between two ischaemic time groups, significant differences were not observed in the percentage of functional increase ( p = 0.580; Table 3). On multivariate analysis, preoperative GFR, resected volume of marginal healthy tissue, and WIT were independent predictors for functional reduction of the affected kidney ( p < 0.05; Table 4). 4. Discussion Fig. 1 The relationship between ischaemic time and glomerular filtration rate (GFR) as measured by technetium Tc 99mdiethylenetriaminepentaacetic acid renal scans in the operated kidney. LPN has recently allowed WIT to approximate the mean ischaemic times of open partial nephrectomy [9 11]. In addition, RAPN has enabled more urologists to overcome the challenges associated with complex laparoscopic reconstructive procedures [12]. However, LPN or RAPN still may result in some decreases in overall renal function. During partial nephrectomy, WIT is considered to be one of the few modifiable risk factors for the development of renal damage. However, the technically feasible maximal WIT that has the least effect on renal function remains controversial.

4 EUROPEAN UROLOGY 58 (2010) Table 3 Patient characteristics divided by a cut-off ischaemic time of 28 minutes for ischaemic renal damage WIT 28 min (n = 31) WIT >28 min (n = 13) p value Age, yr (21 81) (35 71) Tumour size, cm ( ) ( ) Preoperative serum creatinine, mg/dl ( ) ( ) Preoperative total GFR, ml/min per 1.73 m ( ) ( ) EBL, ml (50 400) (20 800) Operative time, min ( ) ( ) Warm ischaemic time, min (19 28) (29 58) Operative methods LPN RAPN 11 2 Postoperative change in percentage of operated kidney GFR, % 99.1 ( ) 79.6 ( ) Postoperative change in percentage of contralateral kidney GFR, % ( ) ( ) EBL = estimated blood loss; GFR = glomerular filtration rate; LPN = laparoscopic partial nephrectomy; RAPN = robot-assisted partial nephrectomy; WIT = warm ischaemic time. Table 4 Factors related to percentage glomerular filtration rate change of operated kidney 3 months after surgery: univariate and multivariate analysis Univariate Multivariate Coefficient (95% CI) p value Coefficient (95% CI) p value Age, yr 0.1 ( 0.6, 0.5) Gender, female referent 5.8 ( 9.4, 21.2) BMI, kg/m ( 3.5, 0.9) Preoperative GFR, ml/min per 1.73 m ( 0.6, 0.1) ( 0.6, 0.1) Tumour size, cm 8.2 ( 14, 1.6) ( 0.6, 0.2) EBL, ml 0.02 ( 0.1, 0.2) Operative time, min 0.02 ( 0.09, 0.1) WIT, min 0.9 ( 1.7, 0.1) ( 0.9, 0.1) Resected healthy tissue volume, cm ( 1.5, 0.4) ( 1.4, 0.2) BMI = body mass index; CI = confidence interval; EBL = estimated blood loss; GFR = glomerular filtration rate; WIT = warm ischaemic time. Nguyen and Gill introduced an early unclamping technique that reduces ischaemia time from an average of 31.1 to 13.9 min. However, the technique involves a risk for bleeding and additional ischaemia (in cases of reclamping) [9]. Therefore complete arteriovenous hilar clamping during laparoscopic partial nephrectomy is more desirable because it provides a bloodless operative field and optimal visualisation. Additionally, placement of bolster suture is more effective, especially once the clamp is removed. The importance of evaluating the renal function of the affected kidney separately from total renal function can be explained by considering those patients in whom a functioning remnant kidney could be affected by comorbidities that might impair total renal function in the future, such as medical renal diseases or an additional renal surgery. Few studies have assessed functional compensation by the normal contralateral kidney or functional decreases in the operated kidney specifically in a prospective manner using GFR [4,13,14]. Most studies have reported that partial nephrectomy does not have an effect on renal function using the serum creatinine level as an indicator [15,16]. We prospectively measured renal function before and 3 mo after surgery by using Tc 99m-DTPA GFR to assess ischaemic renal injury during LPN and RAPN. Shekarriz et al prospectively evaluated renal function by renal scan in patients who underwent LPN with hilar clamping and a functioning contralateral kidney. They reported a negative association between hilar clamp time and change in renal function, and a positive correlation between clamp time and change in total GFR [4]. However, these results were not statistically significant. Our data showed a statistically significant positive correlation between WIT and a reduction of GFR estimated by using Tc 99m-DTPA scans on the operated kidney (R 2 = 0.386; p = 0.009, Fig. 1). Because functional adaptation may occur, we evaluated the contralateral kidney. Tc 99m-DTPA GFR of the contralateral kidney was generally increased at 3 mo after surgery. Comparing the two groups based on the 28 min of cut-off ischaemic time, some compensatory hyperfunctioning of the contralateral kidney was observed in both groups, although significant differences between the two groups were not detected. According to previous studies, the safe upper limit of WIT in humans is likely to be 30 min [17,18]. Although laparoscopic surgeons are more and more ambitious, wanting to perform partial nephrectomy for larger and deeper tumours, the 30-min cut-off still remains the accepted safe time limit beyond which irreversible kidney damage may occur in the absence of renal cooling

5 904 EUROPEAN UROLOGY 58 (2010) [13,19,20]. Other studies have suggested the extension of the upper limit of WIT up to 55 min or even longer [21,22]. However, extending the WIT caused a significantly greater decrease in renal function [23]. When determining the maximum cut-off time, our results showed that functional changes of the affected kidney were most significant at the 28-min WIT cut-off. When we divided the patients into two groups according to an ischaemic cut-off time of 28 min, we detected no differences in tumour size. Funahashi et al evaluated 32 patients including open and laparoscopic partial nephrectomy patients, and they reported that regional technetium Tc 99m-mercaptoacetlytriglycine-3 (MAG-3) uptake of the operated kidney decreased significantly postoperatively, for a cut-off ischaemic time of 25 min [14]. Furthermore, regional Tc 99m-MAG-3 uptake decreased less in the laparoscopic group compared with the open group, and ischaemic time was equal between the groups. LPN offers intraoperative conditions such as the pneumoperitoneum that may affect renal function differently than those of open surgery even though renal blood flow is clamped without cooling the kidney during open partial nephrectomy. It may be necessary to consider the pneumoperitoneal effect to determine the maximum cut-off time in this study. Unlike previous studies, our results showed no significant changes of regional GFR in the affected kidney according to Tc 99m-DTPA evaluation before and after surgery. These inconsistent results may be due to differing methods of measuring renal function or delineating the ROI around kidneys between studies. Determination of ROI is subjective and examiner dependent, and it can vary with minute differences in body position. The amount of renal rotation after surgery may also affect ROI. In a previous study, Abuelo concluded that nephron damage mainly takes place in the endothelial cells of the peritubular capillaries, especially those in the outer medulla, which is marginally oxygenated under normal circumstances [24]. Thus it is possible that regional renal function could be overestimated using ROI or underestimated according to ROI location, and further clinical studies are needed. The present study had several limitations. The first was the small sample size and the short length of follow-up. We used a follow-up of 3 mo for evaluating renal functional damage related to WIT. This time frame of 3 mo was based on the discovery that recovery from acute renal damage was completed within weeks even after 60 min of ischaemia in an animal study [16]. So a period of 3 mo could be reasonable for an assessment of ischaemic renal damage after partial nephrectomy. However, there are still undisclosed issues in human investigations regarding whether the ischaemic damage of the affected kidney would be reversible or whether the damage would be permanent if WIT is prolonged. Porpiglia et al demonstrated that mild recovery was found 1 yr after surgery, even with prolonged WIT. However, this finding was only about the change the operated kidney contributed to the total renal function [13]. Thus it would be worth investigating this functional damage of the affected kidney with a longer follow-up period. Secondly, we could not isolate the extent of renal damage caused only by the warm ischaemia. The renal damage is probably due to the amount of resected healthy renal tissue and to WIT. It could also be affected by the preoperative renal function. Lastly, functional adaptation could develop in both the affected and contralateral kidney. Further studies are necessary to determine whether the damaged function of the affected kidney will recover in the future, especially above the maximal time point. 5. Conclusions We found that as WIT increased, greater amounts of ischaemic renal damage resulted. The observed changes in renal function may have included the effects of functional compensation by the contralateral kidney. When either LPN or RAPN is performed, adequate renal function in the affected kidney may not be maintained if WIT is >28 min. Author contributions: Seong Il Seo had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Seo, J.D. Choi, Park. Acquisition of data: J.D. Choi, Kim. Analysis and interpretation of data: J.D. Choi. Drafting of the manuscript: J.D. Choi. Critical revision of the manuscript for important intellectual content: Seo, Park, J.D. Choi, Lee, H.Y. Choi, Jeon, Jeong. Statistical analysis: J.D. Choi. Obtaining funding: None. Administrative, technical, or material support: J.Y. Choi, Hyun. Supervision: Seo. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Aron M, Koenig P, Kaouk JH, Nguyen MM, Desai MM, Gill IS. Robotic and laparoscopic partial nephrectomy: a matched-pair comparison from a high-volume centre. BJU Int 2008;102: [2] Benway BM, Bhayani SB, Rogers CG, et al. 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