Vol 19 No 2 March-April 2022 100 Risk Factors for Failure of Endoscopic Management of Stone-related Ureteral Strictures Teruaki Sugino1, Kazumi Taguchi1*, Shuzo Hamamoto1, Tomoki Okada1, Masahiko Isogai1, Yutaro Tanaka1, Rei Unno1, Yasuhiro Fujii1,2, Takashi Hamakawa1,3, Ryosuke Ando1, Atsushi Okada1, Takahiro Yasui1 Purpose: To investigate factors determining the outcomes of endoscopic management for stone-related ureteral stricture. Materials and Methods: Data of patients who underwent endoscopic surgery for ureteral stricture due to stones from January 2016 to April 2020 were retrospectively analyzed. We compared cases successfully treated with endoscopic surgery with cases that resulted in failure. We focused on factors associated with treatment success, in- cluding cause and length of stricture, methods of stricture treatment, surgical time, and duration of hydronephrosis before the treatment. Treatment success was defined as improvement in hydronephrosis status. Results: Nineteen patients were treated for stone-related ureteral stricture. Hydronephrosis was successfully im- proved in 12 patients (63.2%). Seven patients with failed endoscopic management had ureteroscopic lithotrip- sy-related stricture, whereas 3/12 (25.0%) patients with ureteroscopic lithotripsy-related stricture and 7/12 (58.3%) patients with impacted stone-related stricture were successfully treated by endoscopic management (P = .004). The prevalence of stricture length > 15 mm was significantly higher in the patients with failed management than in the patients with successful management (71.4 vs 16.6%, P = .046). Intraoperative endoscopic observation demon- strated that the mucosa of the ureteroscopic lithotripsy-related stricture had ischemic appearance with relatively long stricture length (P = 0.13) compared to the impacted stone-related stricture. No association was observed between treatment outcome and method of endoscopic management, including laser incision, balloon dilation, or both. Conclusion: Ureteroscopic lithotripsy as a cause and stricture length > 15 mm could affect the success rate of endoscopic management of ureteral stricture. In such cases, reconstructive management should probably be con- sidered in the early stages. Keywords: hydronephrosis; impacted stones; ureteral stricture; ureteroscopy INTRODUCTION In recent years, the prevalence of ureteral stones has been consistently increasing in the world due to the effects of the increasing incidence of obesity and changes in dietary habits.(1,2) Ureteroscopic lithotripsy (URSL) has become a common treatment for middle and lower ureteral stones.(3,4) Although it is effective and minimally invasive, it could cause significant complications such as intraoperative ureteral injury, bleeding, infection, and postoperative ureteral strictures (US).(5) US is reported to occur in 1–4% of patients after ordinary URSL; however, it occurs in 7.8–24% of patients when URSL is performed for impacted stones. (6–8) Moreover, there are non-iatrogenic ureteric stric- tures such as those associated with impacted stones or chronic inflammatory disorders.(9,10) The main purpose of the management of US is to im- prove hydronephrosis and protect renal function.(11) Recently, a wide variety of therapeutic options have become available to urologists, such as endoscopic management and open/laparoscopic/robot-assisted re- construction. Laser incision (LI) and balloon dilation (BD) as endoscopic management techniques for benign US have been described in previous reports; Razdan et al. reported that these techniques had a success rate of 74% in 50 patients.(9) Further, May et al. reported that 27.5% of 40 patients were successfully managed with endoscopic techniques.(12) The factors that influence the success rate of the endoscopic management of US (e.g., the cause and length of the stricture, the duration of hy- dronephrosis, the surgical management technique, and the number of placed ureteral stents) are controversial. To identify the factors associated with successful endo- scopic management of US, we retrospectively investi- gated patients who underwent endoscopic management for benign US related to ureteral stones and/or their treatments. MATERIALS AND METHODS Study population The present cross-sectional study was approved by the Institutional Review Board of the Nagoya City Univer- sity Hospital. All patients provided informed consent for the use of their data. 1Department of Nephro-urology, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan. 2Department of Urology, Social Medical Corporation Kojunkai Daido Hospital, Daido Clinic, Nagoya, Japan. 3Department of Urology, Nagoya City East Medical Center, Nagoya, Japan. *Correspondence: Department of Nephro-urology, Nagoya City University, Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Tel.: +81-52-853-8266x, Fax: +81-52-852-3179, E-mail: ktaguchi@med.nagoya-cu.ac.jp. Received February 2021 & Accepted July 2021 ENDOUROLOGY AND STONE DISEASE Urology Journal/Vol 19 No. 2/ March-April 2022/ pp. 95-100. [DOI: 10.22037/uj.v18i.6697] Patients who underwent endoscopic management for US between January 2016 and April 2020 were ana- lyzed. These patients were referred to our hospital for endoscopic management of ureteral stricture due to im- pacted stones or postoperative complications after laser ureteric lithotripsy. They underwent LI and/or BD man- agement and one or two ureteral stents or a nephrosto- my catheter were placed at the end of the surgery. Pa- tients with a solitary kidney, urinary diversion, poorly controlled diabetes, and those who were pregnant were excluded from this study. We obtained patients’ demo- graphics, such as sex, age, and body mass index (BMI), from the medical records. Additionally, the laterality, location, cause, and length of the US, as well as the status of hydronephrosis were also captured. The US related to URSL was defined as follows: US with dam- age caused by either the laser or access sheath during URSL, which was not detected during previous surgery. In contrast, the US related to an impacted stone was de- fined as follows: US following stone impaction without damage caused by either the laser or access sheath dur- ing URSL, which was detected during previous surgery. Regarding hydronephrosis, Grade 0 hydronephrosis was defined as no swelling of the renal pelvis or ca- lyx, Grade 1 as swelling of the renal pelvis, Grade 2 as swelling of the renal calyx, Grade 3 as swelling of the renal pelvis and calyx, and Grade 4 as swelling of the renal pelvis and calyx with bending of the ureter. Surgical parameters, including surgical time, and suc- cess or failure of treatment were analyzed. Success of treatment was defined as improvement in the status of hydronephrosis examined by either ultrasonography or computed tomography conducted 3 months after re- moving the ureteral stents. The urine flow through the treated ureter was confirmed by retrograde pyelography when the ureteral stents were removed. Surgical techniques All patients were placed under general anesthesia, and the operation was performed in the lithotomy position. Before treatment, the status of the stricture was con- firmed using retrograde ureteropyelography. A 6.0 Fr semi-rigid ureteroscope (Olympus, Tokyo, Japan) was inserted and used to observe the stricture site. Then, we inserted a 0.035-inch hydrophilic guide wire through the stricture site. BD was conducted when the diameter of the stricture allowed the insertion of the URO MAX Ultra™ before inflation; otherwise, LI was performed instead. In contrast, both procedures were conducted with mucosal findings of rigid appearance. As for the LI procedure, we cut the mucosa and muscular layer of the stricture site (including 5 mm before and after) using a 272 μm fiber (Cyber Ho, Quanta system, Milan, Italy) until we could visualize the fat tissue outside of the ure- ter. The energy setting was 6.0 W (1.0 J × 6 Hz) and the incision was conducted using the ‘Soft Tissues’ mode. For the BD, we dilated the ureteral lumen up to 15 Fr using a balloon catheter (URO MAX Ultra™; Boston Scientific Japan, Tokyo, Japan). One or two double-J ureteral stents (4.7 or 6.0 Fr, INLAY OPTIMA™, BD, Franklin Lakes, NJ and 4.8 Fr, Tria™, Boston Scien- tific, Marlborough, MA), chosen by the main operator, were placed into the ureter at the end of procedures. Endoscopic management of ureteral strictures-Sugino et al. Table 1. Patient characteristics, surgical data, and treatment classifications (success or failure) Factor Overall (n = 19) Failure (n = 7) Success (n = 12) P valueb Age (years)a 69 [58, 73] 71.5 [58.0, 75.3] 60.0 [58.0, 66.0] 0.253 Sex Male 12 (63.2%) 3 (42.9%) 9 (75.0%) 0.326 Female 7 (36.8%) 4 (57.1%) 3 (25.0%) BMI (kg/m2) a 24 [21, 26.9] 25.0 [24.0, 26.9] 23.5 [20.8, 26.5] 0.611 Preoperative hydronephrosis Grade 1 3 (15.8%) 0 (0.0%) 3 (25.0%) 0.61 Grade 2 5 (26.3%) 2 (28.6%) 3 (25.0%) Grade 3 5 (26.3%) 2 (28.6%) 3 (25.0%) Grade 4 6 (31.6%) 3 (42.9%) 3 (25.0%) Duration of hydronephrosis before 4.0 [2.5, 5.5] 5.0 [3.5, 5.0] 4.0 [2.0, 7.5] 0.898 surgery (months) a Laterality Right 11 (57.9%) 3 (42.9%) 8 (66.7%) 0.38 Left 8 (42.1%) 4 (57.1%) 4 (33.3%) Location Proximal 7 (36.8%) 2 (28.6%) 6 (50.0%) 0.63 Distal 12 (63.2%) 5 (71.4%) 6 (50.0%) Cause of stricture URSL 10 (52.6%) 7 (100%) 3 (25.0%) 0.004 Impacted stone 7 (36.8%) 0 (0.0%) 7 (58.3%) Other 2 (10.6%) 0 (0.0%) 2 (16.7%) Length of stricture (> 15 mm) 7 (36.8%) 5 (71.4%) 2 (16.6%) 0.045 Prestenting 5 (26.3%) 0 (0.0%) 5 (41.7%) 0.106 Surgical time (min) a 71.0 [64.5, 93.5] 69.0 [64.5, 83.5] 76.0 [63.8, 95.0] 0.554 Endoscopic management Laser incision (LI) and balloon dilation (BD) 8 (42.1%) 4 (57.1%) 4 (33.3%) 0.481 LI 2 (10.6%) 0 (0.0%) 2 (16.6%) BD 3 (15.8%) 0 (0.0%) 3 (25.0%) Drainage Single stent 8 (42.1%) 1 (14.3%) 7 (58.3%) 0.12 Double stents 9 (47.3%) 4 (57.1%) 5 (41.7%) Nephrostomy tube 1 (5.3%) 1 (14.3%) 0 (0.0%) Duration of the post-surgery follow-up (days) a 654[546, 1134.5] 618[516.5, 652] 563[877.5, 1304] 0.384 Abbreviations: BMI, body mass index; URSL, ureteroscopic lithotripsy; LI, laser incision; BD, balloon dilation aMedian [25%, 75% interquartile range]. bComparison between the failure and success groups Endourology and Stones diseases 96 Vol 19 No 2 March-April 2022 100 Statistical analysis Non-normally distributed variables are expressed as medians (25%, 75% interquartile range). Categorical variables are presented as frequencies (percentages). Data were analyzed using EZR for R (R project 3.6.3, R Foundation for Statistical Computing, Vienna, Austria) (13). To compare the patients with failed or successful management and the factors associated with the cause of US, the Fisher’s exact test and Mann-Whitney U tests were used. The correlation coefficient between the length of US and perioperative parameters was comput- ed using Spearman's rank correlation coefficient. RESULTS A total of 19 patients were identified as having under- gone endoscopic treatment for US after laser lithotripsy for ureteral stones. The characteristics of the patients and surgical data are summarized in Table 1. Preopera- tive hydronephrosis was Grade 1 in 3 patients (15.8%), Grade 2 in 5 (26.3%), Grade 3 in 5 (26.3%), and Grade 4 in 6 (31.6%). The median duration of hydronephro- sis before surgery was 4.0 months. The stricture cause was identified as URSL in 10 patients (52.6%), impact- ed stone in 7 (36.8%), and chronic inflammatory dis- orders in 2 (10.5%). Seven patients had a US longer Figure 1. (A) Findings from ureteroscopy of URSL-related US. The ureteral mucosa appeared white and poor blood vessels were ob- served. (B) Findings from ureteroscopy of impacted stone-related US. Relatively normal blood vessels were observed on the mucosa. URSL, ureteroscopic lithotripsy; US, ureteral stricture Figure 2. (A) Correlation between length of US and BMI, duration of hydronephrosis and surgical time. The correlation coefficient (r) was computed using Spearman's rank correlation coefficient. (B) Comparison of perioperative parameters between URSL-related and impact stone-related US. BMI, body mass index; URSL, ureteroscopic lithotripsy; US, ureteral stricture Endoscopic management of ureteral strictures-Sugino et al. Vol 19 No 2 March-April 2022 97 Endourology and Stones diseases 98 than 15 mm. Prestenting 3 months before surgery was performed in 5 patients (26.3%). Eight patients (42.1%) underwent both LI and BD. Two patients (10.6%) underwent LI alone, while 3 (15.8%) underwent BD alone. A single stent was placed in 8 patients (42.1%) and double stents were placed in 9 (47.3%). We were unable to perform LI or BD in 3 patients (15.8%) as the stricture was too severe. Specifically, although we were able to insert the guidewire in 1 patient, imaging of the direction of incision was not possible and we placed a ureteral stent. In the other 2 patients, we were not able to insert the guidewire at all and we placed a nephrostomy tube in 1 patient. The median duration of the post-surgery follow-up was 654 days. Table 1 also classifies the data as treatment success or failure. The success rate of the treatment was 63.2% (12/19). URSL-related US occurred in 7 and 3 patients in the failure and success groups, respectively (P = .004). The ureteral mucosa appeared to become white in color and poor blood vessels were observed in UR- SL-related US (Figure 1A). Contrarily, all 7 patients with impacted stone-related US were successfully treat- ed with endoscopic management. Relatively normal blood vessels were observed on the mucosa in the im- pacted stone-related US (Figure 1B). Five patients in the failure group (71.4%) had a US longer than 15 mm, whereas only 2 patients in the success group (16.6%) had a US longer than 15 mm (P = .045). Based on the post-surgery follow-up, 2 patients in the success group (16.6%) underwent re-treatment. Specifically, 1 patient had the ureteral stent replaced and the other had LI at 1257 and 1735 days, respectively, from the first endo- scopic surgery. Furthermore, 3 patients in the failure group (42.9%) underwent open surgeries and 1 patient (14.3%) underwent BD again. The correlation between length of US and other peri- operative parameters, as well as the comparison of pe- rioperative parameters between URSL-related and im- pacted-stone related US are shown in Figure 2A and 2B. The correlation coefficients between length of US and BMI, duration of hydronephrosis, and surgical time were 0.023, 0.097, and 0.078, respectively (P = .93, .69, and .75). The median BMI, duration of hydronephro- sis, surgical time, and length of US in the patients with URSL-related and impacted stone-related US were 24.4 and 26.6 kg/m2, 4.5 and 4.0 months, 70.5 and 77.5 min- utes, and 17.0 and 7.0 mm, respectively (P = .67, .69, .81, and .13). DISCUSSION The development and innovation of endourologic tools has enabled urologists to choose endoscopic manage- ment techniques, such as endoureterotomy and endo- scopic dilation, for patients with US.(14) These tech- niques are safer and less invasive than open surgical repair; however, success rates vary widely between reports.(9,15) We would investigate the factors that influ- ence the success rate of the management for stone-re- lated US. Intraoperative ureteral damage during URSL is one of the causes of US.(6) US caused by ureteral damage is as- sociated with ischemic changes, which results in lower success rates following treatment for US.(7) On the other hand, it is reported that stones embedded in the ureteral mucosa stimulate inflammation, which might result in US.(16) US caused by stones embedded in the ureteral wall does not always involve ischemic changes; there- fore, relatively normal blood vessels may be observed on the mucosa (Figure 1B) and it is likely to be curable with additional treatment.(11) Netto et al. reported that the success rates of BD for non-ischemic and ischem- ic US were 89 and 29%, respectively(17). In the current study, 52.6% of the USs were related to URSL; the success rate of the management for URSL-related US was significantly lower compared to that of the man- agement for impacted stone-related US. The mucosal change in URSL-related US indicated ischemic change, which could result in a poor success rate. There were no significant differences in perioperative parameters, including the length of US, between the patients with URSL-related and impacted stone-related US. These data suggest that treating URSL-related US with endo- scopic management is challenging. US length is thought to be an important predictor of the outcome after endoscopic management for US in sever- al reports. Netto et al. reported a lower success rate for the management of USs longer than 10 mm.(17) Thomas et al. reported a poorer outcome of BD for USs longer than 15 mm.(18) Meretyk et al. reported that the 20 mm length was the most reliable predictor of success rate of LI.(15) The current study demonstrated that more than 70% of patients in whom endoscopic treatment failed had a US longer than 15 mm. Moreover, the length of US poorly correlated with other perioperative parame- ters. According to these data, which are consistent with previous reports, our study revealed that a length of 15 mm was likely to be an important factor to affect suc- cess rate of endoscopic treatment. Prior studies report that the duration of the US is associ- ated with the success rate for endoscopic management. Byun et al. reported that the duration of US (shorter or longer than 3 months) was an important factor that affected the success rate.(19) In contrast, Wolf et al. re- ported that the duration of the US did not significantly affect the success rate of US treatment.(20) In the current study, the median duration of hydronephrosis before surgery was not significantly different between the pa- tients with endoscopic treatment failure and success. The success rate of LI using a holmium YAG laser was reported to be 67-68.4%.(21,22) Moreover, previous re- ports demonstrated that the success rate of BD for US was 50-76%.(23,24) A Holmium YAG laser with both cutting and coagulating functions provides precise in- cision to a depth of the fat tissue outside of the ureter with effective hemostatic effect.(25) We assumed that the combination of LI and BD enabled the equally centered expansion of the lumen on the incision line, which pre- vented restenosis. However, the current study showed that there were no significant differences in the man- agement between the patients with success or failure; 57% patients underwent both LI and BD in the failure group, whereas 33.3% patients underwent both proce- dures in the success group. Ureteral stents are preoperatively used for avoiding in- fection and kidney failure before the management of urolithiasis. They dilate the ureteral lumen and straight- en the ureter, which makes it easy to insert a ureter- oscope or ureteral access sheath.(26) For these reasons, prestenting would also elevate the success rate of endo- scopic management for US. In our study, all 5 patients with prestenting had successful endoscopic manage- ment; therefore, we believe prestenting could contribute Endoscopic management of ureteral strictures-Sugino et al. Vol 19 No 2 March-April 2022 100 to improved treatment success rates. The placement of two ureteral stents was first reported in cases of malignant obstruction.(27) The authors sug- gested that two stents have more power to stand up to the comprehensive force of the tumor than one thick stent. The use of two ureteral stents has been applied for the management of benign US.(9,28,29) Some urolo- gists prefer to insert as large of a ureteral stent as possi- ble; however, larger stents cause ischemia of the ureter, which tend to develop restenosis.(29) It is reported that two stents slide against each other via peristalsis of the ureter, which maintain the expanded lumen.(30) This mo- tion may prevent ischemia or pressure necrosis of the ureter, which is believed to result in a better success rate; however, our study showed no statistical differ- ence in treatment success rates between the patients with single and double stents. Our study is limited by its relatively small number of pa- tients. Due to the nature of the disease, it was difficult to collect a large number of cases, even in this multicenter study. Therefore, we could not perform the multivari- ate logistic regression and interaction analysis of risk factors for unsuccessful treatment and care should be taken when interpreting the results. However, the sig- nificance of this study lies in the fact that it focused on the stricture associated with urinary stones and identi- fied a lower success rate of US endoscopic management following damage during URSL. Moreover, given that identifying the beginning of US development was dif- ficult without close monitoring, we may not have been able to provide an accurate estimate of the US duration. Furthermore, although improvement of hydronephrosis was defined as successful in this study, other factors, e.g., change in split renal function, should have been assessed as well. 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