Risk Factors of Ureteral Stenosis After Percutaneous Microwave Ablation of Renal Tumor, a Single-Center Experience

Background Ureteral stenosis after percutaneous microwave ablation (MWA) of renal tumor is a rare but severe complication, and its risk factors are not apparent. Purpose This study aimed to investigate the risk factors for stenosis of ureter after MWA treatment of the renal tumor that is a rare complication. Materials and Methods Data of 211 patients who underwent MWA for the treatment of renal tumor were retrospectively analyzed from September 2006 to August 2019. Demographic characteristics, clinical features, ablation parameters, and outcomes were analyzed to find out the potential risk factors of this complication. P < 0.05 is considered significant. Results Six of 211 patients developed ureter stenosis, and the rate of this complication is 2.84%. The median time of emergence of hydronephrosis was 226 (range, 3–390) days. Univariate analysis shows the distance between ureter and tumor (P = 0.225) or ablation zone (P = 0.089) is not related to this complication. Postoperative urine routine (red blood cell, P = 0.001; white blood cell, P = 0.035) and R.E.N.A.L. score (P < 0.001) is related to this complication. But after multivariate logistic analysis, only R.E.N.A.L. score (P = 0.004) is associated with this complication. The location and growth pattern of tumor and the energy of ablation were not related to this complication independently. Conclusion The stenosis of the ureter after MWA of renal tumor is not associated with the tumor size, location, or the distance between the ureter and tumor and ablation site independently. But R.E.N.A.L. score is associated with ureter stenosis after MWA for the treatment of renal tumor, which combines the information of location, depth, and size of tumor. Preoperative evaluation of the tumor is necessary for avoiding ureter stenosis. Further studies should focus on these risk factors of this complication.


INTRODUCTION
The renal tumor is one of the fatal urological malignancies. The incidence of the renal tumor has been growing. However, the survival rate of the renal tumor has increased (1,2). Although surgical resection is considered as the principal treatment for renal tumor (3), since Zegel used cryoablation (CA) for renal tumor for the first time (4), ablative technique, as a minimally invasively therapy for the treatment of the renal tumor, has been used in the treatment of renal tumors widely and included in the guidelines for the treatment of renal tumors (5).
Microwave ablation (MWA) for the renal tumor is a minimally invasive therapy, which can be performed under the guidance of ultrasound (US) or computed tomography (CT) during the operation or percutaneously directly. It has been proved in the previous study that MWA can achieve a similar effect and lower rate of complication compared with laparoscopic radical nephrectomy and open radical nephrectomy (6)(7)(8). The rate of major complications was 1.8%; the rate of minor complication was 17.5% (9). Injury or stenosis of the ureter away from ablation zone after MWA for the renal tumor is a rare but severe complication, and this complication might induce a decrease in quality of life because they might always suffer double-J stent placement or percutaneous puncture catheter drainage (PPCD) caused by the complication. To the best of our knowledge, there are rarely researches of this complication after MWA for renal tumor. Even there appeared reports about this complication, none of these articles investigate the risk factors of this complication (10)(11)(12). Here, we report six cases with injury or stenosis of the ureter after MWA for renal tumor and try to find potential risk factors.

Patients
This study is approved by institutional review board at Chinese PLA General Hospital. This retrospectively study enrolled the 211 patients in the Interventional Ultrasound Department of Chinese PLA General Hospital from September 2006 to August 2019 who had undergone MWA for the treatment of renal tumor. All the patients had signed the informed consent form. The institutional database was queried to identify incident patients and collect baseline clinical data including age, sex, comorbidity, lesion location, ablation time, ablation power, the maximum diameter of the tumor and ablation zone, preoperative, postoperative and follow-up imaging examination, and laboratory examination. Our study was approved by the institutional review board. The collected criteria were as follows: (1) conformed to the treatment guidelines of NCCN (5), (2) refusal of surgery or inability of operation, and (3) stenosis of the ureter after MWA therapy. R.E.N.A.L. score (13) was used to evaluate the tumor size, location, and depth. Because all of the tumors were less than 4 cm, all the scores of tumor size were 1 point. To evaluate exophytic or endophytic property, tumors that are 50% or more exophytic are assigned 1 point, tumors less than 50% exophytic are assigned 2 points, and those that are entirely endophytic are assigned 3 points. To quantitate the distance between collecting system and tumor, the distances that are more than 7 mm is assigned 1 point; 4 to 7 mm, 2 points; and less than 4 mm, 3 points. To evaluate the location of tumor, tumors that are entirely above the upper polar line or below the lower polar line are assigned 1 point. If the mass crossed the polar line, a score of 2 points is given. A tumor that has greater than 50% of the diameter across either polar line, crossed the renal axial midline, or is fully contained between the polar lines is assigned 3 points.

Technique and Procedure
All the patients are treated with percutaneous MWA under US guidance by experienced doctors. The microwave unit (KY-2000, Kangyou Medical, Nanjing, China) is capable of producing 100 W of power at 2,450 MHz. An automatic biopsy gun with an 18gage cutting needle to puncture the biopsy for two to three times to achieve tumor tissue was used, followed by 1% lidocaine local anesthesia (Yiyou, Beijing, China). A protective temperaturemeasured device was inserted to control the temperature of the surrounding tissue. The antenna was then inserted into the mass and placed at a proper location under US guidance. After antennas were placed, intravenous anesthesia was administered by a combination of propofol (Diprivan; Zeneca Pharmaceuticals, Wilmington, DE, United States), and ketamine (Shuanghe Pharmaceuticals, Beijing, China) via the peripheral vein.
Hydrodissection technique is a protective measure to reduce the heat injury of surrounding tissues, and this method has proven its efficiency to avoid the damage to the intestinal tract and renal sinus around (14)(15)(16). For patient 2, because the tumor was entirely in the pelvis, saline was injected into the renal pelvis continuously during the ablation procedure.

Patient Characteristic and Follow-Up
Preoperative imaging examination, such as US, contrastenhanced US, and contrast-enhanced CT/magnetic resonance imaging (MRI), was retrospectively analyzed to determine the tumor location, the diameter of the tumor, and the relationship between the lesion and adjacent structure. The distance between the ureter and tumor or ablation site was measured on MRI/CT. Postoperative first urine routine was collected to analyze potential risk factors. Postoperative imaging examination was retrieved to measure the diameter of the ablation zone and judge if there was stenosis of ureter and secondary hydronephrosis and record the occurrence time of complication. For patient 2, hydronephrosis was detected by US 180 days after ablation, and she accepted percutaneous nephrostomy (Figure 1). Patient 6 complained of abdominal pain 3 days after ablation; CT showed ureterectasia of the upper ureter and hydronephrosis, considering ureter stenosis because of inflammatory edema. After double-J stent placement, abdominal pain achieved relief.

Statistical Analysis
The data were expressed as median or mean ± SD. The correlation between this complication and clinical characteristics was analyzed using a χ 2 test or Fisher exact test for categorical variables and Mann-Whitney U test for continuous variables. Variables in which P value is less than 0.2 or clinically considered meaningful were included into multivariable logistic regression. The statistical analysis was calculated by SPSS 18.0 software package (Chicago, IL, United States) and R (version 3.6.1). P < 0.05 was considered significant. The receiver operating characteristic curve was plotted by R (version 3.6.1).

Complication
Six of 211 patients developed ureter stenosis, and the rate of this complication is 2.84%. The characteristic baseline is given in Table 1, and complication-related information of these six patients and tumors is given in Table 2. Of these six patients, the mean distance between tumor and ureter is 22.2 mm (range, 12.0-35.0 mm). The mean distance between ablation site and ureter is 20.1 mm (range, 10.6-32.1 mm). Four of six patients developed hydronephrosis. The median time of emergence of hydronephrosis was 226 (range, 3-390) days. After ablation, two patients showed macroscopic hematuria. Minor and major complication is shown in Supplementary Table 1. The patients who had severe hydronephrosis and accepted double-J stent placement or PPCD and accepted medical image examination every 3 months. After double-J stent or drainage catheter placement, the hydronephrosis was relieved. During the followup time, the drainage might cause blockage or exodus. And catheter placement again under US guidance was considered.

Multivariate Analysis of Risk Factors
After univariate risk factor analysis, R.E.N.A.L. score (P < 0.001), diameter of tumor (P = 0.093), and ablation zone (P = 0.123), postoperative urine routine (RBC, P = 0.001; WBC, P = 0.255; and urine protein, P = 0.035), the distance between the ureter and tumor (P = 0.225), or ablation zone (P = 0.089), and total energy (P = 0.739) were included in the multivariate analysis of risk factors. After multivariate logistic regression analysis, only R.E.N.A.L. score (P < 0.001) was related to this complication. The ROC curve is shown in Figure 2. The AUC value was 0.942. The cutoff was 8. The 95% confidence interval was 0.833 to 0.922.  12) reported one case and two cases ureteropelvic junction stricture after MWA, respectively. Schmitz et al. (18) have reported two cases of ureteropelvic junction stricture remote from the ablation site, which is similar to our study. All of these studies did not report the incidence rate and potential risk factors of this complication. Our results showed that the R.E.N.A.L. score is associated with this complication. In contrast to previous research, which concluded the location of the tumor and growth pattern were independent predictors of developing stenosis of ureter (19). Our research did not find the location of tumor and growth pattern were related to it independently. Statistical analysis showed the diameter of the tumor is not associated with this complication. It is consistent with previous studies using MWA to treat renal mass (20)(21)(22). These studies did not report stenosis of ureter after MWA. This complication is irrelevant to ablation energy but relevant to the comprehensive information of location, and the distance between tumor and renal pelvis might indicate the reason of developing stenosis of the ureter is influenced not only by energy but also by the location of the lesion. It is possible for the heat to be transferred from the ablation zone to renal pelvis and heated the urine. Superheating urine injures the muscular layer and submucosa of the ureter and induces the stenosis of the ureter. Preoperative double-J stent placement may also help to avoid this complication after ablation, which might cause the superheating urine be carried away and the decrease in the rate of injury of the ureter. All of these patients did not experience the preoperative double-J stent placement, which might be the potential factor of this postoperative delayed complication. Hydrodissection was needed to protect the ureter. Previous research has proved that hydrodissection was an effective measure for protecting the tract adjacent renal mass (15). The combination of hydrodissection and preoperative double-J stent placement might be a better choice (23). Additionally,   retrograde cold saline perfusion may also be a feasible method to decrease the temperature of urine and injury of the ureter (24). But there is no clear recommended flow rate. Moreover, placing the protective temperature-monitoring device into the renal pelvis to control the temperature of the urine could help the operator master the critical temperature precisely. Abnormal postoperative urine routine could indicate the ablation zone is communicated with the renal pelvis and inflammatory response because of injury of the ureter. Three of these patients were diagnosed with stenosis of the ureter more than 4 months after MWA therapy. There was no symptom of injury of the ureter after operation immediately, demonstrating that the stenosis of the ureter is delayed progress, which is corresponding to the previous study (25). One patient complained of abdominal pain 3 days after ablation because of ureterectasia of the upper ureter and achieved relief after accepted Double-J stent. Hence, postoperative double-J stent placement is also a remedial measure to alleviate the degree of stenosis of the ureter. It was also the treatment after injury of the ureter during surgical operation (26). Further study should focus on the protective measure of the ureter during ablation to minimize this complication, such as the combination of various protective methods. There are still some limitations to this study-first, the nature of the retrospective study, which might affect the evaluation of outcomes. Second, because the stenosis of the ureter remote from the ablation site after MWA is a rare complication, the series of this complication is still limited; the power of evidence of risk factors is still low. Third, the experience of doctors and single-center study could impact the outcome.

DISCUSSION
In conclusion, R.E.N.A.L. score is associated with ureter stenosis after MWA for the treatment of renal tumor, which combines the information of location, depth, and size of tumor. Preoperative evaluation of the tumor is necessary for avoiding ureter stenosis. Moreover, the combination of various preoperative protective methods might be sufficient to reduce the rate of this complication such as preoperative double-J stent placement, hydrodissection technique, and retrograde cold saline perfusion. In addition, the postoperative remedy is also necessary to decrease the degree of stenosis of the ureter.

DATA AVAILABILITY STATEMENT
The datasets analyzed in this manuscript are not publicly available. Requests to access the datasets should be directed to wjpdabao@gmail.com.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by Ethics Committee of PLA General Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

AUTHOR CONTRIBUTIONS
JW: protocol and project development, methodology, data collection, manuscript writing, and manuscript editing. JY and ZC: protocol and project development, and methodology. ZH and XY: protocol and project development, and data management. KL and PH: data collection and management. FL and PL: protocol and project development, and manuscript review. All authors contributed to the article and approved the submitted version.