Journal Article Page
European UrologyVolume 62, issue 1, pages e1-e30, July 2012
Long-Term Functional Evaluation of the Treated Kidney in a Prospective Series of Patients Who Underwent Laparoscopic Partial Nephrectomy for Small Renal Tumors
Accepted 5 February 2012, Published online 14 February 2012, pages 130 - 135
Renal scintigraphy may allow long-term monitoring of ischemic damage after partial nephrectomy (PN).
Evaluate use of renal scintigraphy for evaluating long-term effects of warm ischemia on renal function in patients with a normal contralateral kidney.
Design, setting, and participants
We prospectively examined kidney function of 54 patients who underwent laparoscopic PN (LPN). Minimum follow-up time was 4 yr.
LPN was performed with warm ischemia by transperitoneal or retroperitoneal approach.
Demographic, perioperative, and pathologic data and postoperative complications were registered. Split renal function (SRF) and effective renal plasma flow (ERPF) were evaluated by renal scintigraphy preoperatively, at 3 and 12 mo postoperatively, then yearly. Baseline weighted differentials (b-WDs) of both SRF and ERPF in the affected kidney were calculated between baseline condition and every time point. Multivariate linear regression was used to find independent variables for increased b-WDs at 3 and 48 mo. P values <0.05 were considered significant.
Results and limitations
The SRF and ERPF of kidneys treated by LPN decreased significantly at month 3 and subsequently remained stable through the duration of follow-up. Conversely, neither serum creatinine nor estimated glomerular filtration rate changed significantly during follow-up. The regression model showed statistical significance at month 3 for warm ischemia time (WIT) and age, whereas at 48 mo, statistical significance was reached by WIT alone. No new onset of cardiovascular disease was registered. No evidence of local recurrence was recorded with computed tomography scan. Our study may be underpowered due to small sample size; however, this is one of the largest long-term prospective series using renal scintigraphy to evaluate the renal function after LPN.
WIT contributes to irreversible kidney damage observed at month 3 that does not appear to worsen.
Elective partial nephrectomy (PN) is considered the gold standard of treatment for renal tumors ≤7 cm . Most surgeons prefer the use of vascular clamping to improve visualization of the tumor limits, facilitating complete tumor resection and minimizing the risk of positive surgical margin (PSM). A bloodless field allows precise surgical closure of the collecting system and parenchymal defects . The most common method used to perform ischemia is clamping of the renal artery with or without the renal vein (warm ischemia). Warm ischemia time (WIT) was identified as the most important surgery-related factor affecting renal function in patients who underwent PN . Moreover, ischemic damage and postischemic renal failure may be involved in hypertension development and cardiovascular diseases (CVDs) .
Few studies have evaluated the long-term effect of WIT on treated kidney function in patients who underwent elective PN , , , and . Moreover, most of the available studies evaluated kidney function using serum creatinine (SCr) and/or estimated glomerular filtration rate (eGFR), underestimating the importance of the normal contralateral kidney in masking biochemical changes. Renal scintigraphy (RS) is the only method that allows clinicians to quantify real changes in the amount of renal-function loss of the treated kidney  and . To contribute to this discussion, we planned the present prospective study with two aims. The first was to evaluate the long-term effect of WIT on renal function, using split renal function (SRF) and effective renal plasmatic flow (ERPF) estimated by radionuclide technetium Tc 99m–mercaptoacetyl-triglycine (99mTc-MAG-3) RS, in a series of patients who underwent elective LPN for renal tumors. The second aim was to identify the predictors of renal damage following LPN.
2. Patients and methods
We prospectively enrolled all patients who underwent LPN between July 2004 and December 2007. All patients signed a written informed consent approved by the ethics committee of our center. Abdominal computed tomography (CT) scan and RS using radionuclide 99mTc-MAG-3 were performed preoperatively in every patient.
2.1. Inclusion criteria
We enrolled all patient candidates for LPN of renal tumors ≤4 cm, with baseline eGFR (modification of diet in renal disease [MDRD] formula) ≥60 ml/min  (stage I/II chronic kidney disease [CKD] according to the Kidney Disease Outcomes Quality Initiative), and baseline SRF ranging from 45% to 55% in the treated kidney. Only patients with minimum follow-up of 4 yr were included in the analysis.
2.2. Exclusion criteria
Patients with a solitary or horseshoe-shaped kidney and/or kidney scars at the preoperative CT scan were excluded. In addition, patients who experienced complications potentially affecting kidney function, such as significant bleeding (causing severe hypotension), urinary fistula, kidney infection, or any other condition different from the intervention itself were excluded from the analysis.
All patients underwent LPN performed by a single surgeon using the technique described previously . In all cases, the renal artery alone was clamped with a bulldog clamp and declamped at the end of the renal parenchyma reconstruction.
For each patient, we prospectively collected the following variables in a dedicated database: demographic data including comorbidities classified according to Charlson comorbidity index (CCI) , and clinical tumor size, side, and location according to the RENAL nephrometry score ; perioperative data; pathologic data; and postoperative complications classified according to the Clavien system . Moreover, CCI and new onset of CVDs were recorded at each time point. Body mass index (BMI) also was recorded to assess whether LPN influenced patients’ body build, a possible confounder of eGFR assessment .
Patients with a final diagnosis of renal cell carcinoma were generally observed every 3 to 4 mo for the first year after LPN and every 6 mo from the second through the fifth years. Oncologic follow-up consisted of a history, a physical examination, and an abdominal evaluation using ultrasound or CT scan. Elective bone scan, chest CT, and magnetic resonance imaging were performed when clinically indicated.
2.5. Evaluation of renal function
SCr and eGFR (abbreviated MDRD formula) were assessed by serial measurements; SRF and ERPF were evaluated by 99mTc-MAG-3 RS. All renal scintigraphies were performed at our institution and read by a dedicated nuclear-medicine doctor. The measures were conducted preoperatively, at the 3rd and 12th postoperative months (POMs), and then yearly for a minimum of 4 yr.
A normal range does not exist for SRF and ERPF calculated by RS and there is variability among patients, so we created a new variable called baseline weighted differential (b-WD) that represented the percentage of loss of SRF or ERPF, considering the baseline value. This variable was used in statistical analysis to eliminate the possible confounder of a different patient's scintigraphic baseline value in the preoperative setting, with 1) b-WD of SRF = (n POM SRF − baseline SRF)/baseline SRF, where n = 3, 12, 24, 36, and 48, respectively, and 2) b-WD of ERPF = (n POM ERPF − baseline ERPF)/baseline ERPF, where n = 3, 12, 24, 36, and 48, respectively.
2.6. Pathology assessment
A dedicated uropathologist analyzed fresh-tissue specimens from the operative room and assigned extension of the primary tumor according to the 2009 version of TNM classification . After fixation in a 10% formalin solution, all specimens were step-sectioned at 5-mm intervals and the entire specimen was analyzed, including the distance between the inked margin and the tumor, with the aim of assigning the mean value of the thickness of the peritumoral healthy tissue . Histologic subtypes and nuclear grade were defined according to the World Health Organization classification  and to the Fuhrman classification , respectively. PSM was defined as cancer cells at the level of inked parenchymal excision surface .
2.7. Statistical analysis
Means and standard deviations were used to report continuous variables. Frequencies and proportions were used for categoric variables. The means of continuous variables were compared using the student t test after verifying that variables to be analyzed were approximately normally distributed. Analysis of variance (ANOVA) was used to compare the means of more than two groups. Multivariable linear regression analysis was used to identify independent predictors of SRF and ERPF b-WD changes. All variables potentially influencing postoperative renal function were included in the models.
All tests were two sided, and p values <0.05 were considered significant. All statistical analyses were performed using Statistic 6 (Statsoft Inc.; Tulsa, OK, USA).
Seventy-five patients were enrolled during the specified period. Three patients were excluded: One patient was not analyzed due to horseshoe-shaped kidney, and two patients had early postoperative complications (one had acute bleeding causing severe hypotension and one had a urinary fistula) and were excluded from undergoing following scintigraphic controls. Of 72 analyzable patients, 54 reached the minimum follow-up of 4 yr and were considered the population of the study. Table 1 shows the demographic, perioperative, and pathologic findings of these patients.
|Patients (n = 54)|
|Age, yr, mean (SD)||57.61 (13.92)|
|Males, no. (%)||38 (70.4)|
|BMI, kg/m2, mean (SD)||26.61 (3.40)|
|CCI, mean (SD)||0.90 (1.40)|
|SCr, mg/dl, mean (SD)||0.97 (0.23)|
|EGFR, ml/min, mean (SD)||85.76 (25.71)|
|SRF, %, mean (SD)||48.05 (4.33)|
|ERPF, ml/min × 1.73 m2, mean (SD)||182.70 (34.01)|
|ASA score ≥3 (SD)||27 (50.0)|
|Right-sided LPN, no. (%)||23 (42.6)|
|Transperitoneal approach, no. (%)||39 (72.2)|
|CT scan size, cm, mean (SD)||3.69 (1.39)|
|RENAL nephrometry score, mean (SD)||5.00 (1.39)|
|Operative time, min, mean (SD)||121.02 (34.52)|
|WIT, min, mean (SD)||27.98 (11.12)|
|WIT, min, range||9–60|
|EBL, ml, mean (SD)||127.89 (82.73)|
|Intraoperative complications, no. (%)||0 (0)|
|Postoperative complications, no. (%)||4 (7.4)|
|Thickness of peritumoral healthy tissue rim, mm, mean (SD)||4.40 (3.12)|
|Malignant lesions, no. (%)||41 (76.0)|
|Positive surgical margins, no. (%)||0 (0)|
BMI = body mass index; CCI = Charlson comorbidity index; SCr = serum creatinine; eGFR = estimated glomerular filtration rate; SRF = split renal function; ERPF = effective renal plasmatic flow; ASA = American Society of Anesthesiology; LPN = laparoscopic partial nephrectomy; CT = computed tomography; WIT = warm ischemia time; EBL = estimated blood loss; SD = standard deviation.
Observed postoperative complications (n = 4; 7.4%) were grade 1–2, according to Clavien classification. Specifically, two patients required transfusion for postoperative bleeding, one patient was medically treated for pneumonia, and one patient was treated for pleural effusion. During oncologic follow-up, no patient showed local recurrence or distant progression. No patient died during the follow-up period.
Neither SCr nor eGFR changed significantly during follow-up (Table 2). Conversely, either the mean value or the value at 3 mo after LPN, both for SFR (48.05 ± 4.33 vs 44.76 ± 2.40; p = 0.0030) (Fig. 1a) and ERPF (182.70 ± 34.01 vs 153.54 ± 42.34; p = 0.0001) (Fig. 1b) of the operated kidney decreased significantly in comparison with their baseline values. This decrease remained stable for follow-up measurements. Accordingly, no differences were found among the five postoperative functional measurements (Table 2). Moreover, SRF b-WD (Fig. 1c) and ERPF b-WD (Fig. 1d) were comparable at every time point.
|Baseline (0)||3rd POM (1)||12th POM (2)||24th POM (3)||36th POM (4)||48th POM (5)||ANOVA test||t test|
|Overall (baseline and postoperative controls; 0 vs 1 vs 2 vs 3 vs 4 vs 5)||Only postoperative controls (1 vs 2 vs 3 vs 4 vs 5)||Baseline vs mean postoperative value|
|SCr, mg/dl, mean (SD)||0.97 (0.23)||0.96 (0.14)||0.99 (0.23)||0.99 (0.22)||0.98 (0.34)||0.97 (0.18)||0.1912||0.1611||0.8292|
|EGFR, ml/min, mean (SD)||85.76 (25.71)||88.22 (24.01)||84.50 (26.03)||84.46 (25.85)||84.04 (24.20)||85.15 (24.76)||0.1407||0.1046||0.9205|
|SRF, %, mean (SD)||48.05 (4.33)||44.76 (6.71)||44.52 (6.20)||44.91 (5.89)||45.26 (5.80)||45.78 (5.02)||<0.0001||0.2851||0.0048|
|ERPF, ml/min × 1.73 m2, mean (SD)||182.70 (34.01)||153.54 (42.34)||150.59 (41.87)||152.87 (40.41)||155.57 (41.12)||157.31 (38.90)||<0.0001||0.3263||0.0001|
POM = postoperative month; ANOVA = analysis of variance; SCr = serum creatinine; eGFR = estimated glomerular filtration rate; SRF = split renal function; ERPF = effective renal plasmatic flow; SD = standard deviation.
At multivariable analysis (Table 3), age (p = 0.03) and WIT (p = 0.03) turned out to be independent predictors of SRF b-WD increasing 3 mo after LPN. Only WIT was a predictor of ERPF b-WD increasing (p = 0.0210) 3 mo after LPN, while 4 yr after PN, only WIT predicted ERPF b-WD increasing. Conversely, no risk factor for worsening of SRF b-WD was detected.
|SRF b-WD||ERPF b-WD|
|3rd POM||48th POM||3rd POM||48th POM|
|p value||p value|
|CT scan size, cm||0.2079||0.7326||0.2442||0.1536|
|Peritumoral healthy tissue rim thickness, mm||0.4865||0.2845||0.7518||0.8570|
SRF = split renal function; ERPF = effective renal plasmatic flow; b-WD = baseline-weighted differential; POM = postoperative month; CCI = Charlson comorbidity index; BMI = body mass index; CT = computed tomography; WIT = warm ischemia time.
BMI and CCI did not change statistically at the measured time points. No new onset of CVDs was registered.
Many studies evaluating functional outcomes after LPN have been performed in patients either with a solitary kidney or with a normal contralateral kidney. These studies used different markers of kidney function, mainly aiming to identify a safe WIT cut-off. Results have varied based on the individual experience of the surgeons involved, the patient population size, and the markers used. Although some authors suggested that every minute counts when the renal hilum is clamped , the majority of these studies indicate a safe WIT cut-off range between 20 and 25 min , , and . In previous studies, the 25-min WIT cut-off appeared to be the most clinically helpful , , and .
It is well known that warm ischemia (WI) causes a direct hypoxic injury to the kidney , but the natural history of this recorded damage is not well understood. The aim of the present prospective study was to better elucidate this natural history.
We analyzed 54 patients who underwent LPN performed with WI and we evaluated renal function by using SCr, eGFR and, specifically, RS. This nuclear-medicine technique has been used in various studies in the urologic literature , , and  to estimate renal damage of operated kidney after intervention by using SRF and ERPF.
All analyzed patients reached a minimum follow-up time of 4 yr and we considered this length of follow-up sufficient to study the history of renal function following LPN.
Our results confirmed that SCr and derived measures have low sensitivity for evaluating kidney damage in cases presenting normal or moderately reduced kidney function (CKD stage I/II) at follow-up. In contrast, by using SRF and ERPF estimated by RS, we recorded loss of renal function at the third POM with respect to baseline. This loss remained stable over time as confirmed by follow-up measurements of SRF and ERPF and b-WD variables. Thus we can state that major loss of kidney function is recorded by the third POM, whereas kidney function remains stable over further follow-up. These findings may suggest that future studies of early kidney damage should focus on the results of RS and should accurately record SRF and ERPF data.
Confirming literature findings, the multivariable linear regression analysis evaluating our data at postoperative months 3 and 48 indicated that WIT plays a crucial role in predicting worsening of scintigraphic parameters after LPN. Moreover, age was statistically significant on third-POM analysis based on SRF b-WD, confirming that unmodifiable parameters also have an important impact on renal function . In the present study, all other parameters demonstrated no statistical significance in predicting kidney function impairment over the course of a series of long-term follow-ups.
One of the concerns with long-term kidney damage is that pathogenic insult (eg, WIT) may trigger a mechanism of renal damage maintained by cytokines produced by cells of the distal tubuli that are able to exacerbate the inflammatory response, stimulating further injury  and . This is not supported by our findings. On the contrary, our results support the hypothesis of limited damage, remaining stable over time.
With regard to comorbidities, we recorded neither an increase in CCI nor a new onset of CVDs with respect to the baseline conditions. According to our data at the fourth postoperative year, we can state that the limited injury to kidney parenchyma following LPN is not sufficient to trigger mechanisms involved in hypertension development and following CVDs or comorbidities related to postischemic renal failure.
We did not record any local recurrence or evidence of new-onset parenchymal scars among patients who had a histologic diagnosis of malignant tumor and underwent CT scan during follow-up. The absence of any parenchymal scar indirectly confirmed that there is not a fibrogenic response to ischemia and may suggest that there is not progressive involvement of the whole parenchyma.
In patients who undergo LPN performed with WI, the majority of renal damage detected by RS is recorded within the third POM without further worsening over time. WI seems to be the most important independent variable for predicting renal damage and surgeons should make every effort to minimize WI intervals. Moreover, it seems that renal ischemia does not trigger any mechanism leading to new onset of morbidities after LPN.
Author contributions: Francesco Porpiglia 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: Porpiglia.
Acquisition of data: Bertolo, Angusti, Podio.
Analysis and interpretation of data: Porpiglia, Fiori, Bertolo.
Drafting of the manuscript: Porpiglia, Fiori, Bertolo.
Critical revision of the manuscript for important intellectual content: Piccoli, Morra.
Statistical analysis: Bertolo, Russo.
Obtaining funding: None.
Administrative, technical, or material support: None.
Other (specify): None.
Financial disclosures: Francesco Porpiglia certifies 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.
-  B. Ljungberg, N.C. Cowan, D.C. Hanbury, et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol. 2010;58:398-406 Abstract, Full-text, PDF, Crossref.
-  M. Colombel, M. Timsit, L. Badet. Chirurgie conservatrice et hypothermie renale: bases physiologiques et technique operatoire. Annales d’Urologie. 2007;41:2-22
-  K. Touijer, B. Guillonneau. Advances in laparoscopic partial nephrectomy. Curr Opin Urol. 2004;14:235-237 Crossref.
-  A.S. Go, G.M. Chertow, D. Fan, C.E. McCulloch, C.Y. Hsu. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-1305 Crossref.
-  R.H. Thompson, B.R. Lane, C.M. Lohse, et al. Every minute counts when the renal hilum is clamped during partial nephrectomy. Eur Urol. 2010;58:340-345 Abstract, Full-text, PDF, Crossref.
-  I.S. Gill, L.R. Kavoussi, B.R. Lane, et al. Comparison of 1,800 laparoscopic and open partial nephrectomies for single renal tumors. J Urol. 2007;178:41-46 Crossref.
-  A.C. Novick. Renal hypothermia: in vivo and ex vivo. Urol Clin North Am. 1983;10:637-644
-  M.A. Clark, S. Shikanov, J.D. Raman, et al. Chronic kidney disease before and after partial nephrectomy. J Urol. 2011;185:43-48 Crossref.
-  B.R. Lane, I.S. Gill, A.F. Fergany, B.T. Larson, S.C. Campbell. Limited warm ischemia during elective partial nephrectomy has only a marginal impact on renal functional outcomes. J Urol. 2011;185:1598-1603 Crossref.
-  S. Iida, T. Kondo, H. Amano, et al. Minimal effect of cold ischemia time on progression to late-stage chronic kidney disease observed long term after partial nephrectomy. Urology. 2008;72:1083-1087
-  O. Yossepowitch, S.E. Eggener, A. Serio, et al. Temporary renal ischemia during nephron sparing surgery is associated with short-term but not long-term impairment in renal function. J Urol. 2006;176:1339-1343 Crossref.
-  Y. Shirasaki, T. Saika, T. Tsushima, Y. Nasu, R. Arata, H. Kumon. Predicting postoperative renal insufficiency in patients undergoing nephrectomy for renal malignancy: assessment by renal scintigraphy using 99mtechnetium-mercaptoacetyltriglycine. J Urol. 2005;173:388-390 Crossref.
-  F. Porpiglia, J. Renard, M. Billia, et al. Is renal warm ischemia over 30 minutes during laparoscopic partial nephrectomy possible? One-year results of a prospective study. Eur Urol. 2007;52:1170-1178 Abstract, Full-text, PDF, Crossref.
-  F. Porpiglia, A. Volpe, M. Billia, J. Renard, R.M. Scarpa. Assessment of risk factors for complications of laparoscopic partial nephrectomy. Eur Urol. 2008;53:590-598 Abstract, Full-text, PDF, Crossref.
-  M. Nuttalla, J. van der Meulena, M. Embertona. Charlson scores based on ICD-10 administrative data were valid in assessing comorbidity in patients undergoing urological cancer surgery. J Clin Epidemiol. 2006;59:265-273
-  A. Kutikov, R.G. Uzzo. The R.E.N.A.L. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. J Urol. 2009;182:844-853 Crossref.
-  D. Dindo, N. Demartines, P.A. Clavien. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205-210
-  H. Moch, W. Artibani, B. Delahunt, et al. Reassessing the current UICC/AJCC TNM staging for renal cell carcinoma. Eur Urol. 2009;56:636-643 Abstract, Full-text, PDF, Crossref.
-  A. Minervini, C. di Cristofano, A. Lapini, et al. Histopathologic analysis of peritumoral pseudocapsule and surgical margin status after tumor enucleation for renal cell carcinoma. Eur Urol. 2009;55:1410-1418 Abstract, Full-text, PDF, Crossref.
-  Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Pathology and genetics of tumours of the urinary system and male genital organs. World Health Organization classification of tumours. Lyon, France: IARC Press; 2004. p. 10–87.
-  S.A. Fuhrman, L.C. Lasky, C. Limas. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982;6:655-663
-  F. Porpiglia, C. Fiori, R. Bertolo, et al. The effects of warm ischaemia time on renal function after laparoscopic partial nephrectomy in patients with normal contralateral kidney. World J Urol. 2012;30:257-263 Crossref.
-  F. Becker, H. Van Poppel, O.W. Hakenberg, et al. Assessing the impact of ischaemia time during partial nephrectomy. Eur Urol. 2009;56:625-635 Abstract, Full-text, PDF, Crossref.
-  I.H. Derweesh, A.C. Novick. Mechanisms of renal ischaemic injury and their clinical impact. BJU Int. 2005;95:948-950 Crossref.
-  B.R. Lane, P. Russo, R.G. Uzzo, et al. Comparison of cold and warm ischemia during partial nephrectomy in 660 solitary kidneys reveals predominant role of nonmodifiable factors in determining ultimate renal function. J Urol. 2011;185:421-427 Crossref.
-  R.G. Uzzo, A.C. Novick. Nephron sparing surgery for renal tumours: indications, techniques and outcomes. J Urol. 2001;166:1264-1266
a Division of Urology, University of Turin, “San Luigi Gonzaga” Hospital, Orbassano, Turin, Italy
b Department of Public Health, University of Turin, Turin, Italy
c Division of Nephrology, University of Turin, “San Luigi Gonzaga” Hospital, Orbassano, Turin, Italy
d Division of Nuclear Medicine, “San Luigi Gonzaga” Hospital, Orbassano, Turin, Italy
Corresponding author. Division of Urology, Department of Clinical and Biological Sciences, University of Turin, “San Luigi Gonzaga” Hospital, Regione Gonzole 10, 10043 Orbassano (Turin), Italy. Tel. +39 0119026557; Fax: +39 0119026244.
© 2012 European Association of Urology, Published by Elsevier B.V.
Recommend this article
Currently this article has a rating of 1. Please log in to recommend it.