Treatment of Upper Urinary Tract Stones With a Diameter≤2cm by Intelligent Pressure-controlled Flexible Ureteroscope

1. Background Urinary stone is a common disease with a prevalence rate of 5-15%. It has a recurrence rate of 50% for 5-10 years, and about 75% for 20 years. It is a heavy healthy burden to the population. Flexible ureteroscope lithotripsy(f-URL) is a first-line treatment for renal stone ≤ 2cm in diameter. It has the advantage of less trauma, low complications and fast recovery. It is also suitable for upper ureteral calculi, residual calculi after percutaneous nephrolithotomy (PCNL) It can also be combined with PCNL for the treatment of complex renal calculi.

   The postoperative stone free rate of f-URL varies drastically due to different sizes of residual stone. The Chinese consensus of flexible ureteroscopy recommended that stone ≤ 4mm in diameter should be considered as clinical insignificant residual stone. When residual stone was defined as ≤ 3mm, the stone free rate for one-month was 90% of renal stones ≤ 20 mm, and was 74.4% for stone of 10-25 mm. It would not cause significant symptoms when the residual stone ≤ 2 mm. Based on this definition, Fatih A's randomized trial showed that the stone free rate of f-URL for renal calculi ≤ 20 mm was 85.7%. It was only 30% for stone > 20 mm of single procedure，86.6% of secondary procedure, and 100% for tertiary procedure. When the residual stone was defined as ≤ 1 mm, the stone free rate of f-URL was 64.7% for a single procedure, 92% for secondary procedure, and the overall stone free rate was 85.1% and 100% for stone > 20 mm and ≤ 20 mm respectively by a retrospective study. When the stone free rate was defined as complete stone clearance, it was 71% after one month of single f-URL for renal stone >30mm .

   Postoperative infection is a common complication of f-URL. The key point to avoid postoperative infection includes to treat urinary infection, to keep a low flow perfusion and renal pelvic pressure (RPP) during operation, and to control the operation time. The renal pelvic pressure depends on the size of ureteral sheath and flexible ureteroscope, the flow of perfusion and outflow of traditional f-URL. It is difficult to realize real-time monitoring and regulation of renal pelvic pressure during the operation.

   To realize a high stone free rate and a low postoperative infection rate of f-URL, a new system named flexible ureteroscope with intelligent control of renal pelvic pressure (FURL-ICP) is designed and used. It has an irrigation and suctioning control platform, uses a ureteral access sheath with a pressure-sensitive tip, enables regulation of the infusion flow precisely, and controls the vacuum suctioning by computerized real-time recording and monitoring of RPP. A stable RPP is kept within a pre-set safe range by pressure feedback technology. The stone power could be sucked out during operation. Previous data showed that postoperative stone free rate was 90% for one day, and 95.6% for one month after operation respectively, and the overall complication rate was 14.4%. The aim of this study is to compare the efficacy and safety for FURL-ICP and f-URL in the treatment of upper urinary calculi with diameter ≤ 2cm.

2. Objective To compare the efficacy and safety of FURL-ICP and traditional FURL for the treatment of ≤ 2cm upper urinary stones.

3. Trial Design and Participants The trial is designed as a multicenter, parallel, randomized controlled trial with two arms. Patients will be recruited from 12 Chinese tertiary medical centers. Each participating center performed >50 f-URLs per month. Patients with upper urinary tract stones scheduled for f-URL will be invited in this study.

4. Randomization and masking Central randomized allocation will be used without stratification. Participants will be assigned by a simple random sampling technique with a rate of 1:1. A randomization list is generated by a statistician and securely stored at a password-protected computer of the sponsor's center. Only one protocol-blinded coordinator will know the password and reveal the assignments in sequence to each center. The allocation is revealed before the surgery day. One-side superiority test is designed to compare the efficacy and safety of FURL-ICP and f-URL.

5. Sample size Sample size is estimated by SFR of one month for f-URL. Complete stone free is defined as residual stone ≤ 2mm in diameter. The SFRs of FURL-ICP and traditional f-URL are presumed to be 90% (PT) and 75% (PC) respectively, based on previous data. 5% is considered as an inferior margin. The sample size is calculated with the formulas of a one-side superiority test comparing two proportions. The minimum sample size for each group was 224, and at least 449 cases are needed in the study. (https://www.cnstat.org/statx/compute.html).

6. Intervention methods:

（1）Operation methods of intervention group(FURL-ICP)： Each procedure is completed under general anesthesia in supine lithotomy position with 60-90° oblique on the affected side upward. A semi-rigid ureteroscopy is used to check the urinary tract system and to place a 0.032-inch guidewire. A pressure measuring ureteral access sheath (UAS) (11/13.8Fr) is inserted into the proximal ureter along the guidewire without fluoroscopic guidance. A 7.5 Fr flexible ureteroscopy is used to check the delivery location of the UAS, mucosa of renal pelvis and ureter. After adjusting the UAS in suitable position, the pressure sensory and suctioning channels are connected to the irrigation and suctioning platform. After being injected with water, a zero calibration is performed for the pressure sensory system. A fully automatic mode is selected on the platform. The perfusion flow is set between 50 to 150 mL/min. The RPP control value is set between -15 to -5 mmHg. The renal pelvic pressure alarm value is set between 20 to 30mmHg. During the operation, a holmium laser is used to break stones into powder (fiber diameter 200 µm), and the flexible ureteroscopy is moved back and forward slightly to suck out the stone particles inside the sheath gap. Particles larger than the sheath gap but smaller than the UAS is sucked out by intermittently withdrawing the flexible ureteroscopy without basketing. A 4-6Fr ureteral stent is left for 2 weeks after the operation. Stone composition is analyzed. If the UAS is failed to be placed, ureteral stent will be placed for 2 weeks and a second stage FURL-ICP will be performed.

（2）Operation methods of control group（traditional f-URL）： Each procedure is completed under general anesthesia in lithotomy position. A semi-rigid ureteroscopy is used to place a 0.032-inch guidewire. A pressure measuring ureteral access sheath (UAS) (11/13.8Fr) is inserted into the proximal ureter along the guidewire without fluoroscopic guidance. The irrigation and suctioning platform will be not used. A 7.5 Fr flexible ureteroscopy is used to break the stone with a holmium laser (fiber diameter 200 µm). A basket is used to remove the stone fragments. A 4-6Fr ureteral stent is left for 2 weeks after the operation. Stone composition is analyzed. If the UAS is failed to be placed, ureteral stent will be placed for 2 weeks and a second stage traditional f-URL will be performed.