Materials and Methods: Our health center"s archive system was scanned retrospectively for the time interval between January 2006- January 2021 for patients operated with partial nephrectomy for renal mass. History, comorbidities and laboratory results, operational information, tumor morphologies in radiographic images and its specified scores (R.E.N.A.L. score, PADUA score, C-index), peroperative and postoperative complications and pathology results of 148 regularly followed-up patients were analyzed.
Results: Mean age of the patients was 55.04±10.91 years, ratio of male to female was 1.27 and mean tumor size was 3.56 cm. Mean follow-up period was 55.53±42.26 months. Postoperative creatinine value in the 6th month showed an increase of 0.18 mg/dl compared to preoperative value. Estimated glomerular filtration rate (eGFR) also decreased by an average of 18.3%. Operation of grade 4 tumors significantly affected the postoperative renal function. PADUA score (p=0.023) had a significant effect on postoperative GFRs and duration of ischemia. Also, difference in pre-and postoperative GFRs and its percentage change were significantly affected by C-index (p=0.035, p=0.042). Pathological size (p=0.038), R.E.N.A.L. score (p=0.001), PADUA score (p<0.001), duration of ischemia (p=0.045) had a positively and C-index (p=0.001) had a negatively significant correlation with Modified Clavien-Dindo Complication Scoring System.
Conclusion: All nephrometry scores, duration of ischemia and tumor size were associated with the complication rates according to Clavien classification. Tumor grade, PADUA score and C-index are valuable parameters for predicting renal dysfunction after partial nephrectomy.
Renal functions may be affected at various levels in patients undergoing PN due to morphological features of the tumor and operational techniques [5,6]. Nephrometry scores (R.E.N.A.L. score, PADUA score and C-index) announced by various centers are frequently used as predictors of outcomes after PN. Lately, studies about this subject are drawing attention and in the current study, our aim is to evaluate and sum up the factors affecting complications and renal function loss during and after PN.
Demographics, habits, comorbidities, clinical and laboratory results, tumor morphology in radiologic images (computerized tomography or magnetic-resonance imaging), surgical information (type of operation, duration of ischemia, and amount of bleeding), tumor pathology and follow-up data were recorded. Creatinine values of patients were evaluated preoperatively and postoperatively at the 6th month. Estimated glomerular filtration rate (eGFR) values were calculated with the Cockcroft-Gault formula. Peri-/post-operative complications were evaluated via the Modified Clavien-Dindo Complication Scoring System [7].
Patients without any symptoms were noted as incidental cases. Hematuria and flank pain were the mostly encountered localized symptoms. Most common systemic symptoms were fever, weight-loss and fatigue. All patients were evaluated with contrast-enhanced abdominal computerized tomography (CT) or magnetic resonance imaging (MRI) prior to surgery. Thorax CT was used for thoracic evaluation. For pathological classification, TNM (tumor-node-metastasis) 2017 criteria were used [8]. Largest size, stage and Furhman grades of the tumor were noted postoperatively. European Association of Urology (EAU) 2020 guidelines were taken into consideration to followup the patients according to their tumor stage [2].
Surgical Method
All surgeries (both open and laparoscopic) were performed
by a highly experienced urology team with specialized assistants
and nurses. During open PN, subcostal/transcostal flank incision
was done with the patient in lateral decubitis position. All
adipose tissues excepting those around the tumor were dissected.
Zero-ischemia was used for small tumors with convenient
localization. Renal artery clamping with mannitol infusion and
renal cooling with ice-slush was used to excise bigger tumors
in unsuitable locations. Masses were wedge-resected with
leaving at least 0.5cm safe surgical margin. Bleeding vessels
were ligated with 4/0 polyglactin sutures and hemostatic agents
(Surgicel and Spongostan, Ethicon® Inc., Somerville, NJ, USA)
placed between U sutures was used for the closure of the renal
parenchymal defect. All procedures were done retroperitoneally,
primary repair of peritoneum was performed if peritoneal defects
were encountered.
During laparoscopic PN, three or four ports were placed transperitoneally. Tumors were resected using similar techniques as in open PN, with zero-ischemia or clamping renal artery depending on the size and localization of the tumor. Defect in the renal parenchyma was repaired with V-Loc (Covidien™, Ireland) sutures.
Radiological Evaluation and Nephrometry Scoring
Systems
Patients with accessible pre-operative contrast enhanced
(CT/MRI) images were included in the study. These images
were evaluated by two urologists from the study team in terms
of the complexity of renal anatomy and nephrometry scores
(R.E.N.A.L. score, PADUA score and C-index).
R.E.N.A.L. scoring system: First defined by Kutikov and Uzzo in 2009, and five characteristic features of the tumor are evaluated.
(R) Radius: Maximum tumor diameter (cm), 1 point is given if the tumor is ≤4 cm, 2 points if between 4.1-7 cm and 3 points if >7cm.
(E) Exophytic/endophytic localization: 1 point if the tumor is ≥50% exophytic, 2 points if ≤50% exophytic, 3 points if completely endophytic.
(N) Nearness: Proximity of the tumor to the collecting system or renal sinus (mm), 1 point if ≥7mm, 2 points if 4.1-6.9 mm, 3 points if ≤4mm.
(A) Anterior/posterior: No scoring is made for this. Only letters of a&p are given to the total score.
(L) Localization: 1 point if the tumor is completely above or below the polar line, 2 points if the tumor crosses the polar line, 3 points if 50% of the tumor crosses the polar line or completely fills the middle of the polar line.
According to this scoring, those with a total score between 4-6 are grouped as low, those between 7-9 as medium, and those between 10-12 as high risk group [9].
PADUA scoring system: Defined by Ficarra et al. at the same year as the R.E.N.A.L. score. It takes its name from the initials of Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) classification of renal tumors, adapted to the city of Padua/Italy. While all other parameters are similar to the R.E.N.A.L. score, there are two differences. One is the use of the axial polar line to evaluate polar localization. The other is to evaluate laterality and renal sinus involvement with respect to the renal edge. According to this classification, kidney tumors score between 6 and 14. Depending on their anatomical localization, and 6-7 points are considered low, 8-9 points medium, and >10 points high-risk group [10].
C-index: Simmons et al. defined this index in 2010, one year after other scoring systems were introduced. The aim is to determine the difficulty level of the tumor resection. It measures the tumor size and the distance from the outer margin of the tumor to the center in sagittal section. The center of the kidney is calculated by taking the exact midpoint of the section where the kidney was first and last seen (distance x). With the same method, the exact midpoint of the tumor is also calculated (distance y). When these points are combined to form a right triangle, the "C-index" is calculated by dividing the length of the hypotenuse (found according to the Pythagorean theorem) by the radius (r) of the tumor. According to this formula, as the C-index value decreases, tumor resection becomes more challenging. A cut-off value of 2.5 was determined by authors, and the surgery was considered easier at a value of >2.5, while it was stated that a more difficult and complex surgery was required when C-index <2.5 [11].
Calculation methods of R.E.N.A.L. and PADUA scoring systems, and C-index are shown in Figure 1.
Figure 1: Calculations of nephrometry scores A) R.E.N.A.L. Score B) PADUA Score C) C-Index
Statistical Method
According to the distribution of variables, differences
between two groups were analyzed using Student-T test
and Mann- Whitney U test. For more than two groups, One-
Way ANOVA and Kruskal- Wallis test was used. Bonferroni
correction was used for evaluating multiple nonparametric
subgroups. The values presented as ratios were analyzed by chisquare test. Correlations between parameters were evaluated
with Spearman"s rho correlation analysis. p<0.05 level was
considered statistically significant. For all statistical analysis,
SPSS 17.0 (IBM SPSS Statistics Corp., Armonk, NY, USA)
software was used.
Hundred and seventeen patients had open PN and 31 had laparoscopic PN. Mean ischemia time of all operations was 13.23±11.59 minutes. There were no statistically significant difference between surgical methods in terms of R.E.N.A.L. scores, C-Indices, operative time, timing of surgery (mandatory/ elective), comorbidity rate or age of the patients. Duration of ischemia (p=0.003) was significantly shorter in open surgery compared to laparoscopic procedures. In three cases, operation was converted from laparoscopic to open surgery. One of these patients had ureteral injury, the tumor of the second patient was suspected to be of splenic origin and in the third case surgical margin was violated.
Postoperatively, Clavien grade I-II-IIIA, IIIB, and IVA complications were observed in 55, 17, 3, 7, 1 patients, respectively. Embolization was performed in two patients with Clavien IIIA complications, and perioperatively-placed double J (JJ) stent in one patient was removed. Four patients with grade IIIB complications underwent JJ stenting under general anesthesia due to discharge coming from the wound or drain site in postoperative period. One patient had persistent urinary leakage from the drain and inserted JJ stent could not solve the problem so the patient was explored. One patient was converted to open surgery because of ureteral injury during laparoscopic PN. One patient with grade IVA complications had renal loss because of postoperative renal vein thrombosis. Clavien classification was positively associated with pathological size (p=0.038), R.E.N.A.L. score (p=0.001), PADUA score (p<0.001), duration of ischemia (p=0.045) and negatively associated with C-index (p=0.001) (Table 1).
Table 1: Comparison of complications with nephrometry scores, tumor size and ischemia times
Postoperative GFR changes and creatinine levels are shown in Table 2. In Grade 4 tumors, postoperative creatinine levels were significantly higher than other tumor grades (Table 3). Correlations between nephrometry scores and renal functions are given in Table 4. Postoperative GFRs were significantly affected by PADUA scores (p=0.023). Additionally, PADUA scores over 10 significantly altered the duration of ischemia (p=0.008). Also, difference between pre-and post-operative average GFR values, and its percentage change were significantly affected by C-index (p=0.035, p=0.042).
Table 3: Comparison of tumor grade groups according to postoperative creatinine levels
Table 4: Relationship between renal functions and nephrometry scores
Although the results of postoperative GFR, difference between pre-, and post-operative GFR values, and decrease rates in postoperative GFR were relatively more physiologic in zeroischemia group than 0-20 min-, and >20 min- ischemia groups without any statistically significant intergroup differences (Table 5).
Table 5: Relationship between ischemia times and renal functions
PN instead of RN in T1 tumors has been shown to prevent the development of long-term renal injury in the postoperative period and consequently reduce mortality rates from cardiovascular disease [3]. Since there is a significant relationship between duration of ischemia and postoperative renal injury, ischemia times should not exceed 20-25 minutes. Thompson et al. stated each minute over 25 minutes increases the risk of acute renal injury and subsequent development of chronic renal injury by 5-6% [14]. In a multi-institutional study by the same author concerning ischemia times during PN performed in patients with solitary kidneys, warm ischemia times over 20 minutes was associated with an increased risk of chronic renal failure and permanent requirement for dialysis [15]. Simmons et al. evaluated parenchymal atrophy measuring pre-, and post-operative parenchymal thickness, and reported development of severe parenchymal atrophy when duration of ischemia exceeded 40 minutes [16]. In a review in 2016 by Rod et al. [17] which evaluated postoperative renal functions according to duration of ischemia, zero ischemia was not superior to ischemia lasting less than 25 minutes. Gupta et al. indicated also age, comorbidity, preoperative GFR, tumor complexity, type and duration of ischemia as independent parameters affecting postoperative GFR [18]. Diversely, Çömez et al. reported no significant difference between pre-and postoperative eGFRs [19]. In our study, as the duration of ischemia increased, renal functions started to deteriorate but there were no statistically significant difference between ischemia times and postoperative GFRs, pre-, and post-operative GFRs, decreasing rates in postoperative GFRs and amount of transfused blood and/or solutions. These results we obtained in our study may be associated with very limited number of our patients had ischemia times over 25 minutes.
Nephrometry scores have been put forward to predict postoperative renal function in patients undergoing PN. C-index is associated with glomerular filtration rate and its decrease percentage. In cases with a C-index of 2.5 or less, the risk of 30% functional loss increased 2.2-fold [20]. In our study, postoperatively GFR decreasing rates were found to be significantly different between C-index (<2.5 vs ≥2.5) and between PADUA score subgroups (6-9 vs 10-12). This significance was detected in difference in GFRs and GFR percentage change for C-index and only postoperative GFR for PADUA scores. Even though there still is a higher numerical GFR difference and percentage change in PADUA 10-12 subgroup, this insignificance may caused by the asymmetrical distribution of the subgroups regarding PADUA scores (116 vs. 32). Additionally, no significant difference was detected between R.E.N.A.L. score subgroups.
Tatsugami et al. found no significant difference in postoperative renal functions between patients undergoing open/laparoscopic PN [21]. In our study, although there was a statistically significant difference between the duration of ischemia depending on the type of operation; there was no statistically significant difference between type of surgery and postoperative creatinine, pre-, and post-operative GFR values, GFR decrease and GFR decrease rates similar to the literature. Toosy et al. showed pneumoperitoneum created during laparoscopy protects the kidney from ischemia and reperfusion injury in rats [22]. Although the duration of ischemia in the laparoscopic group is increased, pneumoperitoneum created during LPN may explain the fact that ischemia time has no impact on postoperative GFR. Also, clinical studies have shown that at postoperative 6th month, renal function is not affected up to 55 minutes of ischemia times in laparoscopic cases [23]. Adamy et al. evaluated 987 patients operated by open/laparoscopic methods, stating that the average duration of ischemia was 40 min for open and 35 min for laparoscopic surgeries [24]. They also reported that the postoperative eGFR value of laparoscopically-treated patients was significantly higher compared to open surgery.
Complications such as hemorrhage, renal injury and urinary fistula may occur after PN. R.E.N.A.L., PADUA, and C-index scores may predict complications after PN. Ficarra et al. who first mentioned the concept of PADUA scoring, demonstrated that those with PADUA scores of 6-7 had 14 times lower risk of complications than those with 8-9 and risk increased by 30 times in those with >10 [10]. In recent years, Draeger et al. reported that PADUA scores were more related to complication severity rather than complication rates [25]. Rosevear et al. reported that patients who developed complications after PN had higher R.E.N.A.L. scores [26]. Similarly, in our study, a statistically significantly positive correlation was found between PADUA and R.E.N.A.L. scores and severity of complications. We also found a negative association between C-index and severity of complications.
Gill et al. reported that complications of 1800 patients undergoing open/laparoscopic PN were comparable [27]. In our study, no association was found between open/laparoscopic surgery and Clavien classification. As Patard et al. suggested, tumor size had no effect on surgical and medical complications, but they found that the blood transfusion rate was significantly higher in the group with larger tumors [28]. The reason for this discrepancy is that they had not considered blood transfusion as a complication (normally counted as Clavien II complication). We also found a statistically significant association between Clavien classification and tumor size. The main reason for this relationship is the greater amount of blood loss in large tumors. We believe excessive bleeding may be due to increased angiogenesis in large tumors.
In literature, multivariate analysis of various factors has been investigated as prognostic factors in nephron-sparing surgeries. However, to determine the values that can predict the outcomes, number of cases and regularly followed-up patients should be also considered. Even though this study has one of the longest follow-up span in the literature, low number of cases can be asserted as the main limitation of this study. This study also has the feature of being supplementary to our recent study about the prognostic factors indicating surgical margin status and recurrence in partial nephrectomy patients [29]. The number of patients have increased throughout the years, enriching this study. Our clinic is an experienced, high-load center but unreachable data of especially patients included earlier in the study, and the change of achiving systems are responsible for inadequate sample size. Also, our results are mostly descriptive and bivariate as the study was planned. These comparative results has the potential to be coincidental and multivariate logistic regression analysis of these findings will give more comprehensive outcomes. In recent years, performance scoring, such as Eastern Cooperative Oncology Group (ECOG), has an important role in evaluation of candidates for PN. Due to the retrospective design of the study, lack of performance scores is another limitation.
Ethics Committee Approval: The study was approved by the Ethics Committee of University of Health Sciences, Sisli Hamidiye Etfal Training and Research Hospital (Approval date, and Registration number: 07.07. 2020/2888).
Informed Consent: An informed consent was obtained from all patients.
Publication: The results of the study were not published elsewhere in full or in part in form of abstracts.
Peer-review: Externally peer-reviewed.
Authorship Contributions: All authors contributed to the study conception and design. Preparation of the material used and data collection: HCD, SC, AHY and SLK. Analysis of data: ST, AHY and ET. The first draft of manuscript was written by HCD and ET and edited by SLK and SC. This study was supervised by KH and all authors have read and approved the final manuscript.
Conflict of Interest: The authors declare that they have no conflict of interest.
Financial Disclosure: The authors declare that this study received no financial support.
Acknowledgments: Thanks to Naz Demirel for illustration of nephrometry scoring systems.
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