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Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor
YJPSU-58955; No of Pages 5 Journal of Pediatric Surgery xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor Silvia Ceccanti a, Francesco Cozzi a, Alice Cervellone a, Augusto Zani b, Denis A. Cozzi a,⁎ a b
Pediatric Surgery Unit, Sapienza University of Rome, Rome, Italy Division of General and Thoracic Surgery, Department of Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Canada
a r t i c l e
i n f o
Article history: Received 23 October 2018 Accepted 30 October 2018 Available online xxxx Key words: Wilms' tumor Renal carcinoma Nephron-sparing surgery Renal function Cystic nephroma Renal volume
a b s t r a c t Aim: We sought to assess the magnitude of functional decline and the natural history of the operated kidney residual function after zero-ischemia nephron-sparing surgery (Z-NSS) in children with unilateral renal tumor (URT). Patients and methods: 50 children were treated for URT at our surgical unit between 1992 and 2016. Of these 12 who underwent Z-NSS were available for the current analysis. Operated kidney function was assessed by 99mTcdimercapto-succinic acid (DMSA) renal scintigraphy. Operated kidney volume was assessed by renal ultrasonography. Results: A positive correlation between split renal function and split renal volume was found (P = 0.001). The subset of patients with ≥40% preservation of operated kidney function/volume (OKF/V) had no-time dependent changes during adolescence. The subset of patients with b 40% OKF/V preservation had a catch-up growth that after puberty reached values not much different from those with ≥ 40% OKF/V preservation. At 5 years of follow-up, 3 of 5 patients with baseline dysfunction (eGFR between 40.8 and 89.4 ml/min/1.73 m2) presented with a global renal function within normal range. After puberty, all patients presented with global renal function within normal values (eGFR between 95 and 151 ml/min/1.73 m2). Conclusions: In children with URT who underwent Z-NSS, the pattern of OKF/V recovery suggests that compensatory catch-up growth capacity during childhood minimizes OKF/V decline more than Z-NSS. Level of evidence: Level I prognosis study — prospective cohort study with N 80% follow-up and all patients enrolled at same time point in disease. © 2018 Elsevier Inc. All rights reserved.
In 1992, our group started a prospective study to investigate whether enucleative surgery was safe and feasible in children with stage I unilateral renal tumor (URT) [1]. Following the first three patients treated by zero-ischemia nephron-sparing surgery (Z-NSS), we decided to excise the tumor with a rim of normal parenchyma (partial nephrectomy), whenever feasible, to avoid more aggressive postoperative chemotherapy. Z-NSS was always performed with parenchymal compression and without hypothermia or vascular occlusion. This was done to avoid an irreversible damage of the ipsilateral kidney, which could have diminished the added benefit of preserving the ipsilateral renal parenchyma. The term “zero-ischemia partial nephrectomy”, has previously been used not only for selective branch microdissection of the renal artery and
vein, but also for excision of Wilms' tumors with vascular control obtained by compressing the surrounding parenchyma [2]. Recently, we have reported that all children who underwent Z-NSS were able to achieve or maintain a two-kidney global estimated glomerular filtration rate (eGFR) [3]. However, it could be that the assessment of global renal function may have masked the postoperative renal damage of the operated kidney, owing to the hypertrophy of the healthy contralateral kidney [4]. In the present study, we attempted for the first time to assess the magnitude of functional decline of the operated kidney after Z-NSS in children with URT. In addition, we investigated the natural history of the operated kidney residual volume and function after Z-NSS, which has not been extensively studied. 1. Materials and methods
Abbreviations: Z-NSS, Zero-ischemia nephron-sparing surgery; URT, Unilateral renal tumor; DMSA, 99mTc-dimercapto-succinic acid; USS, Ultrasonography; eGFR, Estimated glomerular filtration rate; OKF/V, Operated kidney function/volume. ⁎ Corresponding author at: Pediatric Surgery Unit, Sapienza University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy. Tel./fax: +39 06 499 79349. E-mail address: [email protected] (D.A. Cozzi).
From January 1992 to December 2016, 50 children with URT and a normal contralateral kidney were consecutively operated at our Institution. Fifteen (30%) patients who successfully underwent Z-NSS were prospectively enrolled at the time of diagnosis. Patient selection criteria
https://doi.org/10.1016/j.jpedsurg.2018.10.095 0022-3468/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: S. Ceccanti, F. Cozzi, A. Cervellone, et al., Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2018.10.095
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S. Ceccanti et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
included stage I Wilms' tumor, benign tumor, and the clinical judgment on the feasibility of Z-NSS. We excluded from the analysis three patients: one patient developed a metachronous Wilms' tumor; one patient with Wilms' tumor after multiple enucleations underwent an unnecessary nephrectomy elsewhere; one patient with Wilms' tumor had a lymph node recurrence after partial nephrectomy, requiring a complete nephrectomy. All procedures were performed without hypothermia or vessels clamping. Local ischemia was obtained with digital or vascular clamp compression of the renal parenchyma. Thirty-five patients underwent primary nephrectomy. The histopathological features of children who underwent Z-NSS included 8 stage I Wilms' tumor, 1 stage I Wilms' tumor with aniridia, 1 with stage I Wilms' tumor with hyperplastic multifocal nephroblastomatosis, 1 cystic nephroma, and 1 oncocytoma. The operated kidney function was evaluated by quantitative 99mTcdimercapto-succinic acid (DMSA) renal scintigraphy in the first 8 patients who underwent Z-NSS. Planar imaging was obtained 3 to 4 h after intravenous injection of DMSA (120 MBq/1.73 m 2). Images were recorded with the patient lying over the gamma camera, equipped with a high-resolution collimator. Five-minute posterior and 30° posterior oblique scintigrams were recorded, collecting 200,000–300,000 counts per view, depending on the patient's size. After body background correction, total counts obtained from posterior-view scintigrams were used to quantify the relative percentage function of the kidney remnant [(count of kidney remnant × 100) ÷ (sum of counts of kidney remnant and contralateral kidney)]. Initially, the DMSA scan was part of the follow-up protocol for children who had undergone Z-NSS at our institution. This investigation was scheduled to be obtained both at short and long-term run. On the same day of the scintigraphy, we also assessed our patients by ultrasonography (USS) for volume measurement of the kidney remnant. Sonograms were performed by using 3.5–5.0 MHz convex probes, depending on the patient's size. The approach was always anterior, focusing on the renal structures to avoid geometrical distortion, and renal measurements were all made by the same radiologists to minimize interobserver variation. Kidney volume was calculated by using the formula for a prolate ellipsoid (maximum bipolar length × maximum width × maximum depth × 0.532). Estimates of renal volume based on sonographic findings were used to calculate the relative percentage volume of the operated kidney [(volume of the operated kidney × 100) ÷ (sum of volumes of the operated kidney and the contralateral kidney)]. Percentages of relative operated kidney volume were obtained by the ellipsoid formula on kidney diameters measured by USS. Values of the kidney relative volume in children can be regarded as normal if the volume of the right kidney ranges between 36 cm3 and 57 cm3 and that of the left kidney measures at 47 cm3 [5]. We considered ≥40% as a normal split function. Since 2004, we abandoned DMSA scintigraphy because it was believed to be too invasive and expensive. Therefore, kidney volume/function of our patients was followed-up using USS alone. The estimated glomerular filtration rate (eGFR) was regarded as the best measure of renal function. In patients ≤17 years old, eGFR was calculated using the update bedside Schwartz equation, GFR = 0.413 × height (cm)/serum creatinine (mg/dl) [6]. In patients who were 18 years or older, eGFR was calculated with the abbreviated Modification of Diet in Renal Disease Study equation, GFR = 32.788 × serum creatinine −1.15 × age−0.203 × 0.742 for female and/or × 1.212 for black patients [7]. Evaluations of relative and absolute renal function/volume were carried out on a regular basis during follow-up. 1.1. Statistical analysis Relative function and volume of the operated kidneys at different follow-up are shown as median (range) and compared by nonparametric Wilcoxon matched pairs test. Pearson's correlation coefficient was used to evaluate the relationship between relative renal function and relative renal volume of the operated and contralateral kidney. The
Table 1 Patient characteristics of 12 children with unilateral renal tumor who underwent zero-ischemia nephron-sparing surgery. Patient Sex Age Preop eGFR (months) (ml/min/1.73 m2)
Preop CHT
Side
Tumor size (cm)
NSS
1 2 3 4 5 6 7 8 9 10 11 12
yes yes yes no yes yes no no yes yes yes yes
right left left left left right left right right right right left
4.5 7 12 10 1.2 12 8 3.5 4.5 3.5 4.8 5
E E E E PN PN PN PN PN PN PN PN
M F F M M F F F F M F F
29 23 22 20 51 24 155 9 48 44 6 47
41 80 116 70 114 54 94 99 116 125 89 145
NSS = nephron-sparing surgery; E = enucleation; PN = partial nephrectomy; CHT = chemotherapy.
hypothesis of no difference between 2 categories was rejected only if the P value ≤ 0.05. Statistical analysis was performed using GraphPad Instat 3.0 and SPSS 13.0 statistical softwares. Data are expressed as median (range). 2. Results In the present cohort of 12 children with URT who underwent ZNSS, there was a strong female preponderance (8/12) (Table 1). Patients underwent surgery at a 26.5 (6–155) months. Nine underwent preoperative chemotherapy according to the SIOP protocol (2001). Five presented before surgery with a renal dysfunction (eGFR b90 ml/min/ 1.73 m 2). Four underwent enucleation of the tumor, and 8 underwent partial nephrectomy. No side preponderance was found. Median tumor size was 4.9 (1.2–12) cm; with 2/3 having a diameter of N4 cm. In one child a CT scan showed a tiny slice of viable renal parenchyma compressed by a giant cystic nephroma (10 × 7 × 8 cm). Enucleation of the tumor was followed by preservation of 14% of function of the operated kidney. In a child with preoperative renal dysfunction (Table 1: patient 4) even such a small contribution of the operated kidney function was very useful to obtain a global renal function within the normal range (Table 2). Three patients after partial nephrectomy had positive surgical margins. All patients who underwent NSS presented with normal renal function despite two or more drugs postoperative chemotherapy. No patients underwent radiotherapy. At a median follow-up of 2 (1–40) months, 8 children underwent DMSA scan showing that four had an operated kidney function b 40%, and 4 an operated kidney function ≥40%, including two children who Table 2 Natural history of global renal function in 12 children with unilateral renal tumor who underwent zero-ischemia nephron-sparing surgery. Patient
1 2 3 4 5 6 7 8 9 10 11 12
eGFR ml/min/1.73 m2 5 years follow-up
10 years follow-up
last follow-up
142 79 87 101 99 76 99 59 127 91 102 na
124 94 112 107 110 98 103 na 122 na na na
150 109 106 107 140 120 111 95 151 102 102 142
Age at last follow-up (years)
27 26 20 12 19 20 26 16 21 10 6 5
na = not available.
Please cite this article as: S. Ceccanti, F. Cozzi, A. Cervellone, et al., Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2018.10.095
S. Ceccanti et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
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0.03) (Tables 1 and 2). Indeed, at 5 years of follow-up, 2 of 5 children with baseline renal dysfunction presented with persistent renal dysfunction. After puberty, all these 5 had an eGFR between 95 and 151 ml/min/1.73 m 2. In contrast, all patients without preoperative renal dysfunction had a stable global renal function (chronic kidney disease stage I) (Table 2). 3. Discussion
Fig. 1. Relationship of ultrasound (USS) measured renal volume and DMSA uptake at a median follow-up of 2 months (range, 1 to 40) after zero-ischemia nephron-sparing surgery in the first 8 patients of our series.
underwent tumor enucleation. We found a very strong correlation between renal function (DMSA) and renal volume (USS) of the operated and contralateral kidney (Fig. 1). Patients with ≥ 40% preservation of operated kidney function/volume (OKF/V) showed a no time-dependent significant changes up during adolescence and remained within normal values. Patients with OKF/ V preservation b40% presented a very significant difference from patients with OKF/V preservation ≥40% at median follow-up of 2 (1–40) months (Fig. 2). Operated kidney of patients with b 40% OKF/V preservation presented a progressive catch-up growth trend. At the last followup of 18 (2–24) years, the difference between b 40% and ≥ 40% OKF/V preservation was no longer significant (Fig. 2). Overall, at a median follow-up of 2 (1–40) months, the median renal function of the operated kidney measured by DMSA in the first 8 patients was 36% (12–48). At last follow-up of 18.5 (2–26) years, the median volume of the operated kidney, measured by USS in all 12 children, was 40% (range, 14 to 57). The trend of operated kidney renal function natural history was not much different from the trend of global renal function natural history. Actually, the global renal function showed a continuous improvement in eGFR during adolescence from 96 (41 to 145) ml/min/1.73 m2 before surgery to 110.2 (95 to 151) ml/min/1.73 m2 at the last follow-up (P =
In the present study, we found a strong correlation between the residual renal volume measured by USS and the renal function measured by DMSA in 8 children after Z-NSS (Fig. 1). Similarly, we previously reported that in children with URT who underwent Z-NSS (10 patients) or nephrectomy (16 patients), there was a significant correlation between renal function measured by creatinine standard deviation scores and total residual renal volume (operated kidney / operated + contralateral kidney) measured by USS [8]. These data strongly support the old concept that the assessment of renal volume may replace the assessment of renal function [5,9]. Accordingly, in children with primary vesicoureteral reflux, a strong correlation was found between split renal function assessed by scintigraphy and by ultrasonography [10]. This concept appears relevant, as highlighted by a recent literature review on the best methods for renal function assessment of the operated kidney in adults with kidney tumor [4]. This study concluded that scintigraphy should be considered the best method to measure split renal function of operated kidney [4]. In our opinion, the split renal function assessed by scintigraphy may be replaced by the split renal function assessed by USS, which has the advantage of being a less invasive and expensive method. In the present study, we assessed the longterm split renal function by ultrasonography (Fig. 2). In the present cohort of patients, we found that the median renal volume of the operated kidney after puberty was about 40% and ranged from 14 to 57%. In the literature, there is only one study that investigated a technique called “zero-ischemia laparoscopic assisted partial nephrectomy” in children with URT. However, in this study the split renal function or split renal volume of the operated kidney was not analyzed [2]. A review of the literature in adults with renal carcinoma suggests that nonclamped partial nephrectomy does not provide a better recovery of operated kidney in comparison with clamped partial nephrectomy. Actually, in adults with renal carcinoma and a normal contralateral kidney, the decline in function of the operated kidney averages about 20% after partial nephrectomy with or without renal vessels clamping [11]. Present findings indicate that the difference in the magnitude of functional decline after Z-NSS between the cohort in this study and adults is not because of the impact of a smaller renal tumor diameter. Indeed, partial nephrectomy in adults is usually reserved to patients with b4 cm tumor in diameter. In the present cohort of children, the mean
Fig. 2. Natural history of the operated kidney renal function/volume after zero-ischemia nephron-sparing surgery for unilateral renal tumor. Measurements were based on scintigrams at a median follow-up of 2 months and 5 years, respectively, and on sonograms at last follow-up.
Please cite this article as: S. Ceccanti, F. Cozzi, A. Cervellone, et al., Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2018.10.095
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S. Ceccanti et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
diameter was 6.33 ± 3.49 cm, and 2/3 of patients had N4 cm tumor in diameter. The lower degree of operated kidney decline in children may be because of a greater ability of children to undergo compensatory renal hypertrophy rather than to Z-NSS. Another new finding of the present study was that the subset of children with OKF/V preservation ≥40% showed a no-time dependent volume change during adolescence and remained within normal limits. Conversely, the subset of children with OKF/V preservation b40% showed a continue catch-up growth during adolescence (Fig. 2). Claësson et al. previously emphasized the importance of a long-term follow-up to detect a late catch-up growth of the scarred kidney in children with urinary tract infection and unilateral renal scarring. Indeed, a “conspicuous growth spur was observed at puberty” [12]. Similarly, the present global renal function had a continuous improvement in eGFR up during adolescence. The result of this type of compensatory catch-up growth was that even patients with preoperative renal dysfunction (5 patients) progressively recovered after puberty to a global renal function within normal range values. Noteworthy, at 5 years followup only three patients with baseline renal dysfunction had a two healthy kidney global renal function (Table 2). This pattern of recovery of absolute and relative renal function/volume strongly suggests that, more than Z-NSS, it is the great renal function reserve of children that plays an important role in reducing the postsurgery renal function decline. In the present study, all patients with or without preoperative renal dysfunction presented with CKD stage I (eGFR N 90 ml/min/1.73 m 2) after puberty. The natural history of adults with renal tumor undergoing partial nephrectomy is quite different from that of the present cohort of children. Clark et al. in a multi-institutional cohort study (1228 adult patients) found that, at a follow-up between 3 and 18 months post partial nephrectomy, 37% of patients remained at CKD stage I, 53% developed CKD stage II, 10% developed CKD stage III, and 1% developed CKD stage IV. Interestingly, only 5% of patients with preoperative renal dysfunction improved their renal function down to CKD stage I [13]. Conversely, in our present cohort, all patients with preoperative renal dysfunction who underwent Z-NSS were able to recover to an eGFR N 90 ml/min/1.73 m 2. More recently, Mason et al. reported the natural history of renal function after partial nephrectomy in a multi-institutional cohort of 565 adult patients with renal cell carcinoma at a median follow-up of 26 months. In this Canadian study, 40% of patients remained at CKD stage I, 49% of patients developed CKD stage II, 7.8% developed CKD stage III, and 1.5% developed a stage IV. Interestingly, only 8.6% of patients with preoperative renal dysfunction improved renal function to CKD stage I [14]. Moreover, this latter prevalence of adult patients recovering to CKD stage I is much lower than that found in the present cohort of patients. No longer follow-up data are available. However, Davidek et al. have recently concluded that renal function recovery after partial nephrectomy in adults does not continue to improve at 1year postoperative follow-up [15]. The age-related compensatory adaptation to ablation of 50% of renal mass is not surprising. Animal experiments indicate that after nephrectomy the compensatory renal growth was inversely related to the age [16,17]. However, the greater hypertrophy of the nonoperated kidney after nephrectomy was associated with a greater focal glomerulosclerosis in the group of immature rats [17]. The main advantage of NSS over nephrectomy is that excision of b 50% of renal mass is associated with a limited compensatory hypertrophy and hyperfiltration of the nonoperated kidney in comparison with nephrectomy [8,18]. We are well aware that the main limitations of present study are the small number of patients and the single institution experience analysis. Furthermore, the present study does not include a comparison group of children with similar characteristics who were operated with the clamping technique. Therefore, we cannot conclude that the renal function following Z-NSS is better than that following clamping techniques.
Clearly, studies are required to confirm the greater benefit of Z-NSS in children, in comparison with adults. In addition, the potential advantage of nonclamped vs. clamped conservative surgery in children with URT requires confirmation by multi-institutional prospective studies. Another limitation is that the assessment of renal volume by ultrasonography may be operator-dependent. However, in our cohort of patients, the assessment of renal volume by ultrasonography was performed by the same operators. Measurement of three rather than two kidney diameters, may reduce the operator-dependent differences in assessing kidney volume. Despite the difficulties in defining the margins of operated kidneys, we found a good agreement between relative renal volume and relative renal function. The small differences between sonographic measurement of kidney volume and scintigraphic measurements of renal function may be clinically irrelevant [5]. These limitations are practically inevitable owing to the very limited investigational experience with a nephron-sparing approach in children with URT. Nonetheless, we believe that the present results may contribute to a better knowledge of the magnitude of renal function decline of the operated kidney and of the natural history of the operated kidney renal function after Z-NSS. These data may serve to establish the most effective treatment of unilateral nonsyndromic Wilms' tumor. In conclusion, in children with URT, undergoing Z-NSS, the renal function of the operated kidney strongly correlates with the renal volume. The natural history of the operated kidney is different in patients with or without OKF/V preservation ≥40%. Patients with b 40% OKF/V preservation have a trend towards continuous function recovery, whereas patients with OKF/V preservation ≥40% have no significant changes. The natural history of the operated kidney function is not different from that of the global renal function. Indeed, patients with preoperative global renal dysfunction, at long term follow-up, are able to restore a global renal function not much different from that of normal subjects with two-kidney function. Therefore, a follow-up of long duration is important to detect the late renal function recovery after loss of renal parenchyma. Role of the Funding Source This work was supported, in part, by the Nando and Elsa Peretti Foundation (NEPF), Vaduz, Liechtenstein [grant No. 2018–006]. The NEPF did not have any role in study design, data collection and analysis, data interpretation, writing of the manuscript, or the decision to submit the manuscript for publication. Appendix A. Discussion Presenter: Silvia Ceccanti Q: Abraham Cherian (GOSH, London) • Do you get a sense from your study now that you have in renal ultrasound a reliable modality to assess kidney volume? What do you think is the minimum renal volume required to make nephron-sparing surgery possible? A: Silvia Ceccanti (Roma) • There are no fixed protocols. For instance SIOP has decided in their guidelines to allow surgeons to perform nephron-sparing surgery if you are able to maintain 50% of the kidney function. We disagree because as I showed there are also remnants with 30% or even 10% function that may still contribute in a certain way give help to residual kidney function. So I don't think it is a matter of percentage of the kidney you can spare.
References [1] Cozzi F, Schiavetti A, Bonanni M, et al. Enucleative surgery for stage I nephroblastoma with a normal contralateral kidney. J Urol 1996;156:1788–91. [2] Lopes RI, Ming J, Koyle MA, et al. "Zero-ischemia" laparoscopic-assisted partial nephrectomy for the management of selected children with Wilms' tumor following neoadjuvant chemotherapy. Urology 2017;100:103–10.
Please cite this article as: S. Ceccanti, F. Cozzi, A. Cervellone, et al., Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2018.10.095
S. Ceccanti et al. / Journal of Pediatric Surgery xxx (xxxx) xxx [3] Cozzi DA, Ceccanti S, Cozzi F. Renal function recovery after nephrectomy or nephron-sparing surgery in children with unilateral renal tumor. Eur J Pediatr Surg 2017;27:74–80. [4] Bertolo RG, Zargar H, Autorino R, et al. Estimated glomerular filtration rate, renal scan and volumetric assessment of the kidney before and after partial nephrectomy: a review of the current literature. Minerva Urol Nefrol 2017;69:539–47. [5] Sargent MA, Gupta SC. Sonographic measurement of relative renal volume in children: comparison with scintigraphic determination of relative renal function. Am J Roentgenol 1993;161:157–60. [6] Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009;20:629–37. [7] Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461–70. [8] Cozzi F, Zani A, Schiavetti A, et al. Compensatory renal growth in children with unilateral renal tumor treated by nephron-sparing surgery or nephrectomy. Eur J Pediatr Surg 2007;17:382–6. [9] Troell S, Berg U, Johansson B, et al. Ultrasonographic renal parenchymal volume related to kidney function and renal parenchymal area in children with recurrent urinary tract infections and asymptomatic bacteriuria. Acta Radiol Diagn (Stockh) 1984;25:411–6.
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[10] Weitz M, Licht C, Müller M, et al. Renal ultrasound volume in children with primary vesicoureteral reflux allows functional assessment. J Pediatr Urol 2013;9:1077–83. [11] Mir MC, Ercole C, Takagi T, et al. Decline in renal function after partial nephrectomy: etiology and prevention. J Urol 2015;193:1889–98. [12] Claësson I, Jacobsson B, Jodal U, et al. Compensatory kidney growth in children with urinary tract infection and unilateral renal scarring: an epidemiologic study. Kidney Int 1981;20:759–64. [13] Clark MA, Shikanov S, Raman JD, et al. Chronic kidney disease before and after partial nephrectomy. J Urol 2011;185:43–8. [14] Mason R, Kapoor A, Liu Z, et al. The natural history of renal function after surgical management of renal cell carcinoma: results from the Canadian Kidney Cancer Information System. Urol Oncol 2016;34:486.e1–7. [15] Dawidek MT, Chan E, Boyle SL. Assessing time of full renal recovery following minimally invasive partial nephrectomy. Urology 2018;112:98–102. [16] Larsson L, Aperia A, Wilton P. Effect of normal development on compensatory renal growth. Kidney Int 1980;18:29–35. [17] O'Donnell MP, Kasiske BL, Raij L, et al. Age is a determinant of the glomerular morphologic and functional responses to chronic nephron loss. J Lab Clin Med 1985;106:308–13. [18] Takagi T, Mir MC, Sharma N, et al. Compensatory hypertrophy after partial and radical nephrectomy in adults. J Urol 2014;192:1612–8.
Please cite this article as: S. Ceccanti, F. Cozzi, A. Cervellone, et al., Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2018.10.095
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor Silvia Ceccanti a, Francesco Cozzi a, Alice Cervellone a, Augusto Zani b, Denis A. Cozzi a,⁎ a b
Pediatric Surgery Unit, Sapienza University of Rome, Rome, Italy Division of General and Thoracic Surgery, Department of Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Canada
a r t i c l e
i n f o
Article history: Received 23 October 2018 Accepted 30 October 2018 Available online xxxx Key words: Wilms' tumor Renal carcinoma Nephron-sparing surgery Renal function Cystic nephroma Renal volume
a b s t r a c t Aim: We sought to assess the magnitude of functional decline and the natural history of the operated kidney residual function after zero-ischemia nephron-sparing surgery (Z-NSS) in children with unilateral renal tumor (URT). Patients and methods: 50 children were treated for URT at our surgical unit between 1992 and 2016. Of these 12 who underwent Z-NSS were available for the current analysis. Operated kidney function was assessed by 99mTcdimercapto-succinic acid (DMSA) renal scintigraphy. Operated kidney volume was assessed by renal ultrasonography. Results: A positive correlation between split renal function and split renal volume was found (P = 0.001). The subset of patients with ≥40% preservation of operated kidney function/volume (OKF/V) had no-time dependent changes during adolescence. The subset of patients with b 40% OKF/V preservation had a catch-up growth that after puberty reached values not much different from those with ≥ 40% OKF/V preservation. At 5 years of follow-up, 3 of 5 patients with baseline dysfunction (eGFR between 40.8 and 89.4 ml/min/1.73 m2) presented with a global renal function within normal range. After puberty, all patients presented with global renal function within normal values (eGFR between 95 and 151 ml/min/1.73 m2). Conclusions: In children with URT who underwent Z-NSS, the pattern of OKF/V recovery suggests that compensatory catch-up growth capacity during childhood minimizes OKF/V decline more than Z-NSS. Level of evidence: Level I prognosis study — prospective cohort study with N 80% follow-up and all patients enrolled at same time point in disease. © 2018 Elsevier Inc. All rights reserved.
In 1992, our group started a prospective study to investigate whether enucleative surgery was safe and feasible in children with stage I unilateral renal tumor (URT) [1]. Following the first three patients treated by zero-ischemia nephron-sparing surgery (Z-NSS), we decided to excise the tumor with a rim of normal parenchyma (partial nephrectomy), whenever feasible, to avoid more aggressive postoperative chemotherapy. Z-NSS was always performed with parenchymal compression and without hypothermia or vascular occlusion. This was done to avoid an irreversible damage of the ipsilateral kidney, which could have diminished the added benefit of preserving the ipsilateral renal parenchyma. The term “zero-ischemia partial nephrectomy”, has previously been used not only for selective branch microdissection of the renal artery and
vein, but also for excision of Wilms' tumors with vascular control obtained by compressing the surrounding parenchyma [2]. Recently, we have reported that all children who underwent Z-NSS were able to achieve or maintain a two-kidney global estimated glomerular filtration rate (eGFR) [3]. However, it could be that the assessment of global renal function may have masked the postoperative renal damage of the operated kidney, owing to the hypertrophy of the healthy contralateral kidney [4]. In the present study, we attempted for the first time to assess the magnitude of functional decline of the operated kidney after Z-NSS in children with URT. In addition, we investigated the natural history of the operated kidney residual volume and function after Z-NSS, which has not been extensively studied. 1. Materials and methods
Abbreviations: Z-NSS, Zero-ischemia nephron-sparing surgery; URT, Unilateral renal tumor; DMSA, 99mTc-dimercapto-succinic acid; USS, Ultrasonography; eGFR, Estimated glomerular filtration rate; OKF/V, Operated kidney function/volume. ⁎ Corresponding author at: Pediatric Surgery Unit, Sapienza University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy. Tel./fax: +39 06 499 79349. E-mail address: [email protected] (D.A. Cozzi).
From January 1992 to December 2016, 50 children with URT and a normal contralateral kidney were consecutively operated at our Institution. Fifteen (30%) patients who successfully underwent Z-NSS were prospectively enrolled at the time of diagnosis. Patient selection criteria
https://doi.org/10.1016/j.jpedsurg.2018.10.095 0022-3468/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: S. Ceccanti, F. Cozzi, A. Cervellone, et al., Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2018.10.095
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included stage I Wilms' tumor, benign tumor, and the clinical judgment on the feasibility of Z-NSS. We excluded from the analysis three patients: one patient developed a metachronous Wilms' tumor; one patient with Wilms' tumor after multiple enucleations underwent an unnecessary nephrectomy elsewhere; one patient with Wilms' tumor had a lymph node recurrence after partial nephrectomy, requiring a complete nephrectomy. All procedures were performed without hypothermia or vessels clamping. Local ischemia was obtained with digital or vascular clamp compression of the renal parenchyma. Thirty-five patients underwent primary nephrectomy. The histopathological features of children who underwent Z-NSS included 8 stage I Wilms' tumor, 1 stage I Wilms' tumor with aniridia, 1 with stage I Wilms' tumor with hyperplastic multifocal nephroblastomatosis, 1 cystic nephroma, and 1 oncocytoma. The operated kidney function was evaluated by quantitative 99mTcdimercapto-succinic acid (DMSA) renal scintigraphy in the first 8 patients who underwent Z-NSS. Planar imaging was obtained 3 to 4 h after intravenous injection of DMSA (120 MBq/1.73 m 2). Images were recorded with the patient lying over the gamma camera, equipped with a high-resolution collimator. Five-minute posterior and 30° posterior oblique scintigrams were recorded, collecting 200,000–300,000 counts per view, depending on the patient's size. After body background correction, total counts obtained from posterior-view scintigrams were used to quantify the relative percentage function of the kidney remnant [(count of kidney remnant × 100) ÷ (sum of counts of kidney remnant and contralateral kidney)]. Initially, the DMSA scan was part of the follow-up protocol for children who had undergone Z-NSS at our institution. This investigation was scheduled to be obtained both at short and long-term run. On the same day of the scintigraphy, we also assessed our patients by ultrasonography (USS) for volume measurement of the kidney remnant. Sonograms were performed by using 3.5–5.0 MHz convex probes, depending on the patient's size. The approach was always anterior, focusing on the renal structures to avoid geometrical distortion, and renal measurements were all made by the same radiologists to minimize interobserver variation. Kidney volume was calculated by using the formula for a prolate ellipsoid (maximum bipolar length × maximum width × maximum depth × 0.532). Estimates of renal volume based on sonographic findings were used to calculate the relative percentage volume of the operated kidney [(volume of the operated kidney × 100) ÷ (sum of volumes of the operated kidney and the contralateral kidney)]. Percentages of relative operated kidney volume were obtained by the ellipsoid formula on kidney diameters measured by USS. Values of the kidney relative volume in children can be regarded as normal if the volume of the right kidney ranges between 36 cm3 and 57 cm3 and that of the left kidney measures at 47 cm3 [5]. We considered ≥40% as a normal split function. Since 2004, we abandoned DMSA scintigraphy because it was believed to be too invasive and expensive. Therefore, kidney volume/function of our patients was followed-up using USS alone. The estimated glomerular filtration rate (eGFR) was regarded as the best measure of renal function. In patients ≤17 years old, eGFR was calculated using the update bedside Schwartz equation, GFR = 0.413 × height (cm)/serum creatinine (mg/dl) [6]. In patients who were 18 years or older, eGFR was calculated with the abbreviated Modification of Diet in Renal Disease Study equation, GFR = 32.788 × serum creatinine −1.15 × age−0.203 × 0.742 for female and/or × 1.212 for black patients [7]. Evaluations of relative and absolute renal function/volume were carried out on a regular basis during follow-up. 1.1. Statistical analysis Relative function and volume of the operated kidneys at different follow-up are shown as median (range) and compared by nonparametric Wilcoxon matched pairs test. Pearson's correlation coefficient was used to evaluate the relationship between relative renal function and relative renal volume of the operated and contralateral kidney. The
Table 1 Patient characteristics of 12 children with unilateral renal tumor who underwent zero-ischemia nephron-sparing surgery. Patient Sex Age Preop eGFR (months) (ml/min/1.73 m2)
Preop CHT
Side
Tumor size (cm)
NSS
1 2 3 4 5 6 7 8 9 10 11 12
yes yes yes no yes yes no no yes yes yes yes
right left left left left right left right right right right left
4.5 7 12 10 1.2 12 8 3.5 4.5 3.5 4.8 5
E E E E PN PN PN PN PN PN PN PN
M F F M M F F F F M F F
29 23 22 20 51 24 155 9 48 44 6 47
41 80 116 70 114 54 94 99 116 125 89 145
NSS = nephron-sparing surgery; E = enucleation; PN = partial nephrectomy; CHT = chemotherapy.
hypothesis of no difference between 2 categories was rejected only if the P value ≤ 0.05. Statistical analysis was performed using GraphPad Instat 3.0 and SPSS 13.0 statistical softwares. Data are expressed as median (range). 2. Results In the present cohort of 12 children with URT who underwent ZNSS, there was a strong female preponderance (8/12) (Table 1). Patients underwent surgery at a 26.5 (6–155) months. Nine underwent preoperative chemotherapy according to the SIOP protocol (2001). Five presented before surgery with a renal dysfunction (eGFR b90 ml/min/ 1.73 m 2). Four underwent enucleation of the tumor, and 8 underwent partial nephrectomy. No side preponderance was found. Median tumor size was 4.9 (1.2–12) cm; with 2/3 having a diameter of N4 cm. In one child a CT scan showed a tiny slice of viable renal parenchyma compressed by a giant cystic nephroma (10 × 7 × 8 cm). Enucleation of the tumor was followed by preservation of 14% of function of the operated kidney. In a child with preoperative renal dysfunction (Table 1: patient 4) even such a small contribution of the operated kidney function was very useful to obtain a global renal function within the normal range (Table 2). Three patients after partial nephrectomy had positive surgical margins. All patients who underwent NSS presented with normal renal function despite two or more drugs postoperative chemotherapy. No patients underwent radiotherapy. At a median follow-up of 2 (1–40) months, 8 children underwent DMSA scan showing that four had an operated kidney function b 40%, and 4 an operated kidney function ≥40%, including two children who Table 2 Natural history of global renal function in 12 children with unilateral renal tumor who underwent zero-ischemia nephron-sparing surgery. Patient
1 2 3 4 5 6 7 8 9 10 11 12
eGFR ml/min/1.73 m2 5 years follow-up
10 years follow-up
last follow-up
142 79 87 101 99 76 99 59 127 91 102 na
124 94 112 107 110 98 103 na 122 na na na
150 109 106 107 140 120 111 95 151 102 102 142
Age at last follow-up (years)
27 26 20 12 19 20 26 16 21 10 6 5
na = not available.
Please cite this article as: S. Ceccanti, F. Cozzi, A. Cervellone, et al., Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2018.10.095
S. Ceccanti et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
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0.03) (Tables 1 and 2). Indeed, at 5 years of follow-up, 2 of 5 children with baseline renal dysfunction presented with persistent renal dysfunction. After puberty, all these 5 had an eGFR between 95 and 151 ml/min/1.73 m 2. In contrast, all patients without preoperative renal dysfunction had a stable global renal function (chronic kidney disease stage I) (Table 2). 3. Discussion
Fig. 1. Relationship of ultrasound (USS) measured renal volume and DMSA uptake at a median follow-up of 2 months (range, 1 to 40) after zero-ischemia nephron-sparing surgery in the first 8 patients of our series.
underwent tumor enucleation. We found a very strong correlation between renal function (DMSA) and renal volume (USS) of the operated and contralateral kidney (Fig. 1). Patients with ≥ 40% preservation of operated kidney function/volume (OKF/V) showed a no time-dependent significant changes up during adolescence and remained within normal values. Patients with OKF/ V preservation b40% presented a very significant difference from patients with OKF/V preservation ≥40% at median follow-up of 2 (1–40) months (Fig. 2). Operated kidney of patients with b 40% OKF/V preservation presented a progressive catch-up growth trend. At the last followup of 18 (2–24) years, the difference between b 40% and ≥ 40% OKF/V preservation was no longer significant (Fig. 2). Overall, at a median follow-up of 2 (1–40) months, the median renal function of the operated kidney measured by DMSA in the first 8 patients was 36% (12–48). At last follow-up of 18.5 (2–26) years, the median volume of the operated kidney, measured by USS in all 12 children, was 40% (range, 14 to 57). The trend of operated kidney renal function natural history was not much different from the trend of global renal function natural history. Actually, the global renal function showed a continuous improvement in eGFR during adolescence from 96 (41 to 145) ml/min/1.73 m2 before surgery to 110.2 (95 to 151) ml/min/1.73 m2 at the last follow-up (P =
In the present study, we found a strong correlation between the residual renal volume measured by USS and the renal function measured by DMSA in 8 children after Z-NSS (Fig. 1). Similarly, we previously reported that in children with URT who underwent Z-NSS (10 patients) or nephrectomy (16 patients), there was a significant correlation between renal function measured by creatinine standard deviation scores and total residual renal volume (operated kidney / operated + contralateral kidney) measured by USS [8]. These data strongly support the old concept that the assessment of renal volume may replace the assessment of renal function [5,9]. Accordingly, in children with primary vesicoureteral reflux, a strong correlation was found between split renal function assessed by scintigraphy and by ultrasonography [10]. This concept appears relevant, as highlighted by a recent literature review on the best methods for renal function assessment of the operated kidney in adults with kidney tumor [4]. This study concluded that scintigraphy should be considered the best method to measure split renal function of operated kidney [4]. In our opinion, the split renal function assessed by scintigraphy may be replaced by the split renal function assessed by USS, which has the advantage of being a less invasive and expensive method. In the present study, we assessed the longterm split renal function by ultrasonography (Fig. 2). In the present cohort of patients, we found that the median renal volume of the operated kidney after puberty was about 40% and ranged from 14 to 57%. In the literature, there is only one study that investigated a technique called “zero-ischemia laparoscopic assisted partial nephrectomy” in children with URT. However, in this study the split renal function or split renal volume of the operated kidney was not analyzed [2]. A review of the literature in adults with renal carcinoma suggests that nonclamped partial nephrectomy does not provide a better recovery of operated kidney in comparison with clamped partial nephrectomy. Actually, in adults with renal carcinoma and a normal contralateral kidney, the decline in function of the operated kidney averages about 20% after partial nephrectomy with or without renal vessels clamping [11]. Present findings indicate that the difference in the magnitude of functional decline after Z-NSS between the cohort in this study and adults is not because of the impact of a smaller renal tumor diameter. Indeed, partial nephrectomy in adults is usually reserved to patients with b4 cm tumor in diameter. In the present cohort of children, the mean
Fig. 2. Natural history of the operated kidney renal function/volume after zero-ischemia nephron-sparing surgery for unilateral renal tumor. Measurements were based on scintigrams at a median follow-up of 2 months and 5 years, respectively, and on sonograms at last follow-up.
Please cite this article as: S. Ceccanti, F. Cozzi, A. Cervellone, et al., Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2018.10.095
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S. Ceccanti et al. / Journal of Pediatric Surgery xxx (xxxx) xxx
diameter was 6.33 ± 3.49 cm, and 2/3 of patients had N4 cm tumor in diameter. The lower degree of operated kidney decline in children may be because of a greater ability of children to undergo compensatory renal hypertrophy rather than to Z-NSS. Another new finding of the present study was that the subset of children with OKF/V preservation ≥40% showed a no-time dependent volume change during adolescence and remained within normal limits. Conversely, the subset of children with OKF/V preservation b40% showed a continue catch-up growth during adolescence (Fig. 2). Claësson et al. previously emphasized the importance of a long-term follow-up to detect a late catch-up growth of the scarred kidney in children with urinary tract infection and unilateral renal scarring. Indeed, a “conspicuous growth spur was observed at puberty” [12]. Similarly, the present global renal function had a continuous improvement in eGFR up during adolescence. The result of this type of compensatory catch-up growth was that even patients with preoperative renal dysfunction (5 patients) progressively recovered after puberty to a global renal function within normal range values. Noteworthy, at 5 years followup only three patients with baseline renal dysfunction had a two healthy kidney global renal function (Table 2). This pattern of recovery of absolute and relative renal function/volume strongly suggests that, more than Z-NSS, it is the great renal function reserve of children that plays an important role in reducing the postsurgery renal function decline. In the present study, all patients with or without preoperative renal dysfunction presented with CKD stage I (eGFR N 90 ml/min/1.73 m 2) after puberty. The natural history of adults with renal tumor undergoing partial nephrectomy is quite different from that of the present cohort of children. Clark et al. in a multi-institutional cohort study (1228 adult patients) found that, at a follow-up between 3 and 18 months post partial nephrectomy, 37% of patients remained at CKD stage I, 53% developed CKD stage II, 10% developed CKD stage III, and 1% developed CKD stage IV. Interestingly, only 5% of patients with preoperative renal dysfunction improved their renal function down to CKD stage I [13]. Conversely, in our present cohort, all patients with preoperative renal dysfunction who underwent Z-NSS were able to recover to an eGFR N 90 ml/min/1.73 m 2. More recently, Mason et al. reported the natural history of renal function after partial nephrectomy in a multi-institutional cohort of 565 adult patients with renal cell carcinoma at a median follow-up of 26 months. In this Canadian study, 40% of patients remained at CKD stage I, 49% of patients developed CKD stage II, 7.8% developed CKD stage III, and 1.5% developed a stage IV. Interestingly, only 8.6% of patients with preoperative renal dysfunction improved renal function to CKD stage I [14]. Moreover, this latter prevalence of adult patients recovering to CKD stage I is much lower than that found in the present cohort of patients. No longer follow-up data are available. However, Davidek et al. have recently concluded that renal function recovery after partial nephrectomy in adults does not continue to improve at 1year postoperative follow-up [15]. The age-related compensatory adaptation to ablation of 50% of renal mass is not surprising. Animal experiments indicate that after nephrectomy the compensatory renal growth was inversely related to the age [16,17]. However, the greater hypertrophy of the nonoperated kidney after nephrectomy was associated with a greater focal glomerulosclerosis in the group of immature rats [17]. The main advantage of NSS over nephrectomy is that excision of b 50% of renal mass is associated with a limited compensatory hypertrophy and hyperfiltration of the nonoperated kidney in comparison with nephrectomy [8,18]. We are well aware that the main limitations of present study are the small number of patients and the single institution experience analysis. Furthermore, the present study does not include a comparison group of children with similar characteristics who were operated with the clamping technique. Therefore, we cannot conclude that the renal function following Z-NSS is better than that following clamping techniques.
Clearly, studies are required to confirm the greater benefit of Z-NSS in children, in comparison with adults. In addition, the potential advantage of nonclamped vs. clamped conservative surgery in children with URT requires confirmation by multi-institutional prospective studies. Another limitation is that the assessment of renal volume by ultrasonography may be operator-dependent. However, in our cohort of patients, the assessment of renal volume by ultrasonography was performed by the same operators. Measurement of three rather than two kidney diameters, may reduce the operator-dependent differences in assessing kidney volume. Despite the difficulties in defining the margins of operated kidneys, we found a good agreement between relative renal volume and relative renal function. The small differences between sonographic measurement of kidney volume and scintigraphic measurements of renal function may be clinically irrelevant [5]. These limitations are practically inevitable owing to the very limited investigational experience with a nephron-sparing approach in children with URT. Nonetheless, we believe that the present results may contribute to a better knowledge of the magnitude of renal function decline of the operated kidney and of the natural history of the operated kidney renal function after Z-NSS. These data may serve to establish the most effective treatment of unilateral nonsyndromic Wilms' tumor. In conclusion, in children with URT, undergoing Z-NSS, the renal function of the operated kidney strongly correlates with the renal volume. The natural history of the operated kidney is different in patients with or without OKF/V preservation ≥40%. Patients with b 40% OKF/V preservation have a trend towards continuous function recovery, whereas patients with OKF/V preservation ≥40% have no significant changes. The natural history of the operated kidney function is not different from that of the global renal function. Indeed, patients with preoperative global renal dysfunction, at long term follow-up, are able to restore a global renal function not much different from that of normal subjects with two-kidney function. Therefore, a follow-up of long duration is important to detect the late renal function recovery after loss of renal parenchyma. Role of the Funding Source This work was supported, in part, by the Nando and Elsa Peretti Foundation (NEPF), Vaduz, Liechtenstein [grant No. 2018–006]. The NEPF did not have any role in study design, data collection and analysis, data interpretation, writing of the manuscript, or the decision to submit the manuscript for publication. Appendix A. Discussion Presenter: Silvia Ceccanti Q: Abraham Cherian (GOSH, London) • Do you get a sense from your study now that you have in renal ultrasound a reliable modality to assess kidney volume? What do you think is the minimum renal volume required to make nephron-sparing surgery possible? A: Silvia Ceccanti (Roma) • There are no fixed protocols. For instance SIOP has decided in their guidelines to allow surgeons to perform nephron-sparing surgery if you are able to maintain 50% of the kidney function. We disagree because as I showed there are also remnants with 30% or even 10% function that may still contribute in a certain way give help to residual kidney function. So I don't think it is a matter of percentage of the kidney you can spare.
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Please cite this article as: S. Ceccanti, F. Cozzi, A. Cervellone, et al., Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2018.10.095
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Please cite this article as: S. Ceccanti, F. Cozzi, A. Cervellone, et al., Volume and function of the operated kidney after nephron-sparing surgery for unilateral renal tumor, Journal of Pediatric Surgery, https://doi.org/10.1016/j.jpedsurg.2018.10.095