european urology 52 (2007)

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1 european urology 52 (2007) available at journal homepage: Kidney Cancer Functional Significance of Using Tissue Adhesive Substance in Nephron-Sparing Surgery: Assessment by Quantitative SPECT of 99m Tc-Dimercaptosuccinic Acid Scintigraphy Guy Hidas a, *, Liad Lupinsky a, Alexander Kastin a, Boaz Moskovitz a, David Groshar b, Ofer Nativ a a Department of Urology, Bnai-Zion and Medical Center, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel b Department of Nuclear Medicine, Bnai-Zion and Medical Center, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel Article info Article history: Accepted December 4, 2006 Published online ahead of print on December 11, 2006 Keywords: Kidney neoplasm Nephron-sparing surgery Tissue sealants Abstract Objectives: To compare changes in renal function following nephronsparing surgery (NSS) using tissue adhesive only versus NSS using standard suturing technique, as measured by quantitative SPECT of 99m Tc-dimercaptosuccinic acid uptake by the kidney (QDMSA). Materials and methods: QDMSA was done before and 3 6 mo after the operation in 32 patients who underwent standard suturing technique and in 24 patients in whom tissue adhesive sealant (19 with albumin glutaraldehyde tissue adhesive [BioGlue]; 5 with CoSeal) was used to close the parenchymal defect. Individual kidney uptake was measured and retrospectively compared between the two groups. Results: Average tumor diameter was 3.4 cm (range: 2.2 6) in the suture group and 3.56 (range: 1.7 6) in the tissue sealant group. In the tissue sealant group following surgery, we observed an average individual renal function loss of 11.49% compared with the suture group in whom an average individual renal function loss of 20.36% ( p=0.02) was measured by 99m Tc-DMSA. Conclusions: The use of tissue sealant to close the parenchymal defect during NSS demonstrated a statistically significant advantage in reducing functioning renal loss as measured by the absolute uptake of QDMSA. Further clinical studies are required to establish the role of tissue sealants in NSS. # 2006 Published by Elsevier B.V. on behalf of European Association of Urology. * Corresponding author. Hbosem Street 15/1, Mevaseret Zion, Israel. Tel ; Fax: address: guy@hidas.net (G. Hidas) /$ see back matter # 2006 Published by Elsevier B.V. on behalf of European Association of Urology. doi: /j.eururo

2 786 european urology 52 (2007) Introduction Nephron-sparing surgery (NSS) entails complete resection of a renal tumor while leaving the largest possible amount of normal functioning parenchyma in the involved kidney. Because of improvements in early diagnosis and advanced surgical techniques, the use of NSS has become the standard of care for localized renal lesions [1]. Previously we have shown the ability of albumin glutaraldehyde tissue adhesive sealant to provide adequate hemostasis during NSS. In this pilot study the use of tissue sealant significantly decreased blood loss and transfusion rate, as well as renal ischemic period and operative time, without increasing the risk of urinary leakage [2]. Quantitative single photon emission computed tomography (SPECT) measurement of 99m Tcdimercaptosuccinic acid (QDMSA) is a noninvasive reproducible method that can be used reliably to monitor serial changes in individual renal function [3]. In a previous study [4] describing our initial experience with standard suture technique, we showed by QDMSA an average loss of 17.8% in parenchymal volume and 20.7% loss in individual renal function. The aim of this study was to evaluate by QDMSA the amount of functioning renal mass removed during NSS using only tissue adhesive compared with the mass removed by NSS using the standard suture technique. 2. Material and methods Between February 1993 and June 2006, 248 NSS procedures for renal lesions were performed at our institute. Tissue adhesive sealant was used in 61 cases. Two sequential QDMSA examinations were available for 24 patients who underwent NSS with the aid of tissue sealant (Sealant group), 19 with albumin glutaraldehyde tissue adhesive (BioGlue; Cryolife, Atlanta, GA, USA) and 5 with polyethylene glycol polymers (CoSeal; Baxter Deutschland GmbH, Germany). These results were retrospectively compared with 32 patients who underwent traditional NSS (Suture group). The first QDMSA scan was performed before surgery; the second scan occurred 3 6 mo after the operation. Patient and tumor characteristics are summarized in Table 1. All procedures were performed by a single surgeon after obtaining institutional review board approval. Operative technique was carried out in the same way as in the previous study [2]. Briefly, after exposure of the kidney through a flank approach, vascular clamping of both the renal artery and the renal vein was performed, followed by local hypothermia for 20 min. Enucleation of the tumor involved circumferential incision followed by blunt dissection between the fibrous pseudocapsule and the renal parenchyma. The resected surface of the kidney was thoroughly dried to ensure adherence of the glue to the tissue, The collecting system was closed by continued, 4-0, absorbable sutures if necessary; then 2 5 ml of tissue sealant was slowly applied over the tumor bed. Quantitative SPECT of 99m Tc-DMSA uptake by the kidney was done as described previously [4,5]: The patient was injected with MBq (2 4 mci) 99m Tc-DMSA, and SPECT was performed after 4 6 h. We used a rotating single-head gamma camera with a low-energy collimator (Apex 415-ECT; Elscint, LTD, Haifa, Israel). Data were accumulated from 120 projections 38 apart; the process lasted for about 20 min. Raw data were reconstructed by filtered back projections with a Hann filter (cutoff point: 0.5 cycle per centimeter). Following reconstruction each image was sectioned at 1-pixel (0.68-cm) intervals in transaxial, coronal, and sagittal planes by using a byte matrix. Kidney volumes and radioactive concentration measurements were calculated on the reconstructed data by using the threshold method with a 43% threshold value that is known to best fit the target to nontarget ratio of DMSA in the kidney [6]. Data analysis was automated and operator independent; the operator chose the slice that best defined the kidney and drew a region of interest (ROI) around it. Volume measurement was calculated by the sum of pixels in all sections multiplied by slice thickness. Concentration measurement used all pixels within the ROI that had a higher reading than the threshold. Counts per voxel were converted into concentration units (MBq/cm 3 [mci/cm 3 ]) by using the regression line obtained by previous phantom measurements. The injected dose density (%ID per cubic centimeter of renal tissue) was calculated by using this value corrected for radioactive decay. Multiplying kidney volume by %ID per cubic centimeter gave kidney uptake. Data are presented as the change of postoperative kidney function from baseline. Samples were analyzed with the use of mean 1 SD. Student t test was used to evaluate significant differences between the values before and after operation, and between the two groups. A p value of less than 0.05 was considered statistically significant. 3. Results Mean patient age was 60.4 yr in the tissue sealant group and 61.2 yr in the suture group ( p = 0.66). As shown in Table 1, all other patient and tumor characteristics were similar in both groups; the only difference was the proportion of centrally located tumors, which was higher in the tissue sealant group (37.5% vs. 25%), and the warm ischemic time, which was significantly shorter in the sealant group (19 min vs min, p = 0.02). The results of the two sequential QDMSA renal scans are summarized in Tables 2 and 3. Table 2 demonstrates the results of the operated kidney. In the tissue adhesive group following surgery, we observed a decrease in the mean absolute uptake of 1.36% (1.57%) in the operated kidney (from 12.7% [4.31%] before surgery to 11.34% [4.34D] after

3 european urology 52 (2007) Table 1 Patient and tumor characteristics Variable Sealant group Suture group Patient (n) Mean age (yr) (n [range]) 60.4 (31 84) 61.2 (29 80) Sex (n) Male 9 17 Female Mean tumor size (n [range]) 3.56 (2.2 6) 3.4 (1.7 6) Tumor location (n) Upper pole 5 13 Midsegment 9 10 Lower pole 10 9 Tumor deepness (n) Peripheral Central 9 8 Tumor side (n) Right Left Mean warm ischemic time (min) surgery; p=0.278). Such a difference yields an average individual renal function loss of 11.49% (11.9%) as measured by 99m Tc-DMSA. In the suture group the mean decrease in kidney absolute uptake following surgery was 2.41% ( 2.05%) (from 11.42% [2.57%] before surgery to 9.02% [2.49%] after surgery; p < ), indicating an average individual renal function loss of 20.36% (15.4%) as measured by 99m Tc-DMSA. In other words, when using adhesive material, we were able to decrease the amount of functioning tissue loss by 53% compared with our standard Fig. 1 Differences in functional changes of the operated kidney after tumor enucleation: comparison between tissue sealant and suture groups. suture technique (11.49% vs %, respectively, p = 0.02; Fig. 1). As shown in Table 3, mild compensatory changes were found only in the contralateral kidney in the suture group with an average 3.59% (18.78%) increase in the individual renal function. However this difference was not statistically significant ( p = 0.602). 4. Discussion NSS is now an acceptable approach for the treatment of localized renal lesions. Recent publications have led to expanding the indications for partial Table 2 Results of QDMSA before and after tumor enucleation in the operated kidney Variable Sealant group (% [SD]) Suture group (% [SD]) Preoperative mean absolute uptake (4.31) (2.57) Postoperative mean absolute uptake (4.34) 9.02 ( 2.49D) Mean absolute uptake decrease 1.36 (1.57) 2.41 ( 2.05) Mean individual renal function loss (11.9) (15.4) p value QDMSA = quantitative SPECT of 99m TC-dimercaptosuccinic acid uptake by the kidney. Table 3 Results of QDMSA before and after tumor enucleation in the contralateral kidney Variable Tissue sealant group (% [SD]) Suture group (% [SD]) Preoperative mean absolute uptake 13.5 (4.65) (2.58) Postoperative mean absolute uptake (4.31) (3.32) Mean absolute uptake change ( ) 0.63 (2.13) (+) 0.38 (2.29) Mean individual renal function change ( ) 3.13 (14.5) (+) 3.59 (18.78) p value QDMSA = quantitative SPECT of 99m TC-dimercaptosuccinic acid uptake by the kidney.

4 788 european urology 52 (2007) nephrectomy to include centrally located lesions as well as larger tumors up to 7 cm [7,8]. Typically renal cell carcinoma is diagnosed in the sixth and seventh decades of life when the prevalence of comorbidities like hypertension, diabetes, tobacco smoking, and other risk factors that can reduce renal function are higher [9]. In those patients the rationale for NSS is to minimize the risk of chronic renal failure by preserving as much functional renal tissue as possible. Lau et al. [10] have shown in a retrospective, longterm, follow-up study from the Mayo Clinic that the risk for proteinuria and chronic renal failure is higher after radical nephrectomy compared with NSS (22.4% and 11.6%, respectively). McKiernan et al. [11] compared the incidence of newly developed renal insufficiency in 173 patients undergoing radical nephrectomy and 117 patients undergoing NSS. They found a higher level of mean postoperative serum creatinine in patients treated by radical nephrectomy compared with those who underwent NSS (1.5 mg/dl and 1 mg/dl, respectively). Like Lau et al they also noted a significant higher risk of chronic renal insufficiency in the radical nephrectomy group. The standard technique to close the renal defect following tumor resection is by approximating the transected margins with various suture techniques usually together with hemostatic substances [12]. The tension of the sutures on the frail renal parenchyma and the distortion of the normal renal anatomy may result in blood vessels kinking and further ischemic loss of viable tissue. By contrast the use of tissue sealant, which fills up the cavity in the enuclation site, will result in maximal parenchymal preservation. In a previous pilot study we demonstrated the advantage of albumin glutaraldehyde tissue adhesive (BioGlue) alone in NSS to provide adequate hemostasis as well as decreased blood loss and transfusion rate. Furthermore the simplicity of using tissue adhesive substances significantly shortens the renal ischemic period by 8.8 min (17.2 min vs. 26 min, p=0.002). Tissue sealant also was found to be a highly effective hemostatic agent during laparoscopic partial nephrectomy [13,14]. BioGlue is an admixture of bovine serum albumin (45% w/v) and glutaraldehyde (10% w/v) in a 4:1 ratio. They bind to each other and to the tissue, creating a strong covalent bond. CoSeal is completely synthetic and comprises two distinct polyethylene gycol polymers that chemically bond together to form the sealant. It must be emphasized that adequate closure of the collecting system is a prerequisite for successful application of tissue sealant. Because the renal lesion is not expected to contribute to the kidney filtration and the surrounding compressed renal parenchyma is also nonfunctional, the only consequence of NSS to renal function would be caused by either distortion of the peritumoral parenchyma or by irreversible ischemic renal damage. We assumed that these two limitations of the suture approach could be overcome when a tissue adhesive substance is used. In the current study the proportion of centrally located tumors was higher in the tissue sealant group (37.5% vs. 25%). Despite the fact that removal of central lesions is associated with more tissue loss, this group of patients had better postoperative functional outcome, which further emphasized the advantage of tissue adhesive materials in NSS. DMSA scan is a noninvasive reproducible method for monitoring serial changes in individual renal function [5]. The renal uptake of 99m Tc-DMSA correlates well with the effective renal plasma flow, glomerular filtration rate, and creatinine clearance. Thus, the renal uptake of 99m Tc-DMSA provides a practical index for evaluating individual renal function [15,16]. In a previous study we evaluated by DMSA scan the amount of functioning renal mass removed and the amount of remaining individual renal function after NSS. Twenty-four patients who underwent traditional suture technique were examined with DMSA scan before and 1 6 mo after surgery, by the same method used in this study. A decrease of 20.7% in the individual renal function was observed after tumor enucleation [4]. In these two studies, comparing the individual renal function before and after surgery allowed each case to serve as its own control. This approach enabled correction for confounding risk factors for impairment of kidney function (hypertension, diabetes, nephrolithiasis, etc) that could influence the results of the QDMSA examination. The present study shows further improvement of renal function preservation using tissue sealants. In the tissue adhesive group we observed an average individual renal function loss of about 11.5% compared with an average individual renal function loss of 20.4% in the suture group, as measured by 99m Tc-DMSA. Therefore, when using adhesive material we were able to decrease the amount of functioning tissue loss by more than 50% compared with our standard suture technique ( p=0.02). Another proof of the advantage of kidney function preservation using tissue sealants is the

5 european urology 52 (2007) fact that compensated contralateral postoperative hyperfunction was observed only in the suture group in whom the decreased functioning parenchyma was more prominent (Table 3). 5. Conclusions In our experience, the use of tissue sealant in NSS demonstrated a statistically significant advantage in reducing functioning renal loss, as measured by the absolute uptake of QDMSA. Although our findings were statistically significant, further prospective randomized studies with a larger sample size are required to validate our initial results and to determine the exact role of tissue sealants in this procedure. References [1] Uzzo RG, Novick AC. Nephron sparing surgery for renal tumors: indications, techniques and outcomes. J Urol 2001;166:6 18. [2] Hidas G, Kastin A, Mullerad M, et al. Sutureless nephronsparing surgery: use of albumin glutaraldehyde tissue adhesive (BioGlue). Urology 2006;67: [3] Groshar D, Frankel A, Iosilevsky G, et al. Quantitation of renal uptake of Tc-99m-DMSA using SPECT. J Nucl Med 1989;30: [4] Groshar D, Moskovitz B, Kastin A, et al. Renal function after tumor enucleation: assessment by quantitative SPECT of 99mTc-dimercaptosuccinic acid uptake by the kidneys. J Nucl Med 1999;40: [5] Groshar D, Moskovitz B, Issaq E, et al. Quantitative SPECT of DMSA uptake by the kidneys: assessment of reproducibility. Kidney Int 1997;52: [6] Iosilevsky G, Israel O, Frenkel A, et al. A practical SPECT technique for quantitation of drug delivery to human tumors and organ absorbed radiation dose. Semin Nucl Med 1989;19: [7] Leibovich BC, Blute ML, Cheville JC, et al. Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7 cm results in outcome similar to radical nephrectomy. J Urol 2004;171: [8] 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: [9] Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med 1996;335: [10] Lau WK, Blute ML, Weaver AL, et al. Matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc 2000;75: [11] McKiernan J, Simmons R, Katz J, et al. Natural history of chronic renal insufficiency after partial and radical nephrectomy. Urology 2002;59: [12] Novick AC. Renal-sparing surgery for renal cell carcinoma. Urol Clin North Am 1993;20: [13] Nadler RB, Loeb S, Rubenstein RA, et al. Use of BioGlue in laparoscopic partial nephrectomy. Urology 2006;68: [14] Bernie JE, Ng J, Bargman V, et al. Evaluation of hydrogel tissue sealant in porcine laparoscopic partial-nephrectomy model. J Endourol 2005;19: [15] Taylor Jr A. Quantitation of renal function with static imaging agents. Semin Nucl Med 1982;12: [16] Groshar D, Embon OM, Frenkel A, et al. Renal function and Tc-99m-DMSA uptake in single kidneys: the value of in vivo SPECT quantitation. J Nucl Med 1991;32: Editorial Comment Luigi Da Pozzo, Department of Urology, University Vita-Salute, Scientific Institute San Raffaele, Via Olgettina 60, Milan, Italy dapozzo.luigi@hsr.it Nephron-sparing surgery has become a standard surgical option for low-stage renal tumours. Nevertheless, it has to be noted that no prospective randomised study has yet demonstrated that long-term oncologic results are equivalent to those obtained with radical nephrectomy [1]. Among rationales to perform nephron-sparing surgery, preservation of long-term renal function as much as possible is one of the most important. It is thus not only reasonable but also mandatory to investigate new techniques aimed at this end point. Tissue sealant agents have undoubtedly ameliorated and enhanced nephron-sparing procedures by reducing blood loss, transfusion rate, and renal ischaemic time. To my knowledge, this elegant study also demonstrates for the first time a clinical advantage of their use over standard suture techniques by preserving long-term renal function. Although data reported need to be confirmed in a larger prospective randomised study and the optimal and most effective tissue adhesive substance (organic or synthetic) still has to be defined, this study strongly supports the use of sealant agents when performing nephron-sparing surgery. In my opinion, such haemostatic technique should become a standard procedure when conservative surgery is conducted in a solitary kidney as well as in patients with preoperative renal failure or risk factors for it. The use of tissue sealant agents is also particularly attractive in the scenario of laparoscopic surgery [2]. Indeed, laparoscopic nephron-sparing procedures are gaining increasing popularity even if they are currently routinely performed only in

6 790 european urology 52 (2007) selected cases and experienced centres. Reducing ischaemic times and extending chances to preserve renal function by using tissue sealants will extend indications for conservative laparoscopic procedures in the near future. References [1] Van Poppel H, Da Pozzo L, Albrecht W, et al., for the European Organization for Research and Treatment of Cancer (EORTC), National Cancer Institute of Canada Clinical Trials Group (NCIC CTG), Southwest Oncology Group (SWOG), the Eastern Cooperative Oncology Group (ECOG). A prospective randomized EORTC intergroup phase 3 study comparing the complications of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2007;51: [2] Schips L, Dalpiaz O, Cestari A, et al. Autologous fibrin glue using the Vivostat system for hemostasis in laparoscopic partial nephrectomy. Eur Urol 2006;50:801 5.