Suction Mini-Percutaneous Nephrolithotomy Versus Standard Percutaneous Nephrolithotomy for the Management of 2-4 cm Kidney Stones: Study Protocol for an International, Multicenter, Parallel-group, Noninferiority, Randomized Controlled Trial
Suction Mini-Percutaneous Nephrolithotomy Versus Standard Percutaneous Nephrolithotomy for the Management of 2-4 cm Kidney Stones: Study Protocol for an International, Multicenter, Parallel-group, Noninferiority, Randomized Controlled Trial
Percutaneous nephrolithotomy (PCNL) is recommended as the first-line treatment choice for kidney stones larger than 2cm in international guidelines . However, tract-related complications affecting renal parenchymal and blood vessels have always been a concern . The mini-PCNL technique which uses a smaller tract (≤18 Fr) has been introduced to decrease tract-related complications . Nevertheless, the smaller mini-PCNL tract necessitates fragmentationi of stones into smaller pieces before extraction, potentially prolonging the operative time. Additionally, higher pressure irrigation is often required to flush out fragments by vacuum cleaner effect. If the drainage of irrigation fluid is insufficient via a smaller tract, the intrarenal pressure (IRP) may build up, leading to pyelovenous backflow and infectious complications.
Suction application in mini-PCNL has the potential to enhance stone fragments removal efficiency, maintain low IRP, and decrease potential postoperative infection complications. In the pre-suction era, mini-PCNL achieved noninferior stone-free rates (SFR) and operative times compared to standard PCNL, along with benefits of reduced bleeding, less postoperative pain, and shorter hospital stay. However, high-level evidence regarding whether suction mini-PCNL can attain comparable outcomes to standard PCNL is still lacking.
Therefore, we have designed this multicenter, international, randomized controlled noninferiority trial comparing suction mini-PCNL with standard PCNL in the management of 2-4 cm kidney stones.
Study Objectives:
The objective of the present study is to determine whether suction mini-PCNL is noninferior to standard PCNL in terms of surgical efficiency in the management of 2-4 cm kidney stones.
The primary outcomes are the immediate postoperative stone-free rate (SFR) and operative time. Secondary outcomes include the final SFR at 1 month, length of hospital stay, postoperative complications, and quality of life.
Study Overview:
The present study is an international, multicenter, prospective, parallel group, noninferiority, randomized controlled trial.
Setting:
This study will be conducted in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Medical Research Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University: #2021(81). The study will be carried out in 20 urological institutes across the world, including 6 in Europe, 4 in America and 10 in Asia. Each participating urologist is required to possess significant experience of both suction mini-PCNL and standard PCNL, conducting ≥100 cases per annum.
Sample Size:
The reported SFRs following suction mini-PCNL and standard PCNL for 2-4 cm renal stones are 83% and 86% respectively. We hypothesize that the SFR following suction mini-PCNL is noninferior to standard PCNL. The noninferiority margin is prespecified at -10%, based on clinical consensus and prior randomized controlled trial. Assuming a one-sided α of 0.025, a power of 80%, and a noninferiority margin of -10%, the minimum required sample size per group is calculated to be 419. Considering an anticipated withdrawal and loss to follow-up rates of approximately 10%, this is adjusted to 480 participants per group, resulting in a total sample size of 960.
The reported operative times for mini-PCNL and standard PCNL in the management of 2-4 cm kidney stones are comparable [15]. Since suction mini-PCNL is faster than mini-PCNL, we conservatively assume that there is no difference in operative time between suction mini-PCNL and standard PCNL. The reported standard deviation is approximately 15 minutes. Our hypothesis is that the operative time for suction mini-PCNL is noninferior to that of standard PCNL. Assuming a one-sided α of 0.025, a power of 80%, and a noninferiority margin of -10 minutes, the minimum required sample size per group is calculated to be 43, which is smaller than the sample size determined based on SFR.
Thus, the final total sample size is set at 960.
Patients population:
The inclusion criteria are as follow: (1) Adults aged 18-70 years; (2) American Society of Anesthesiology (ASA) score of 1-2; (3) Kidney stones measuring 2-4 cm in diameter on non-contrast computer tomography; (4) Ability to provide written informed consent and adhere to trial requirements.
The exclusion criteria are as follow: (1) Anatomy abnormalities, such as urinary diversion, horseshoe kidney, transplanted kidney, or ureteropelvic junction obstruction; (2) Untreated acute urinary tract infection (UTI); (3) Patients on anticoagulant/antithrombotic therapy, or with uncorrected coagulopathies; (4) Patients who decline trial enrolment or cannot adhere to trial requirements.
Screening and Enrollment of Participants:
All participating centers will follow a standardized process to conduct this study. Clinicians or designated personnel will assess patients with suspected renal stones as part of routine clinical practice. Once renal stones are confirmed by CT scan and patients are fully evaluated for PCNL, eligible patients screened from the inclusion and exclusion criteria will be well informed of the trial and offered an information leaflet, detailing the potential benefits and drawbacks of the two different PCNL techniques. Patients will have ample opportunity to discuss with the local clinical team, and those who choose to participate will be able to do so. A log will be kept of all patients assessed to document reasons for their non-inclusion in the study to inform the CONSORT diagram. In addition to regular coverage, additional medical insurance and perioperative care would be provided for these candidates. Signed informed consent forms will be obtained from all participants prior to any study-specific procedures. Following consent, participants will be randomized to one of the two treatment groups.
Randomization and Allocation and Blinding:
Participants will be randomized in a 1:1 ratio to either standard PCNL or suction mini-PCNL. Stratified randomization will be performed according to the participating centers. Randomization sequence generation will be performed electronically using random block sizes of 4 and 6 prior to patient enrolment. Random sequence allocation and concealment will be implemented using consecutively numbered, opaque, tamper-proof envelopes.
Patients will be blinded to the intervention, however blinding of surgeons will not feasible due to the nature of the procedures. Radiologists evaluating the postoperative CT scans will be blinded to the intervention received. The postoperative clinical assessment will be performed by investigators blinded to the intervention and not involved in the surgical interventions. Blinded statistical analyses will be conducted with the code of intervention arm assignment remaining concealed until the analyses and interpretation have been completed.
Surgical protocol:
A standardized operative protocol will be established to ensure uniformity across all centers. Periodic protocol monitoring visits will be conducted to ensure its adherence at all participating centers.
Postoperative Evaluation and Follow-up:
Operative details including operative time will be timely documented. All intraoperative complications including bleeding, collecting system perforation, organ injury or other perioperative complications will be evaluated using the Clavien-Dindo grading system.
Complete blood count and electrolyte biochemical tests will be performed within 2 hours after surgery. Patients with a hemoglobin level <70g/l will receive blood transfusion.
KUB will be obtained on the morning of postoperative day one to evaluate the stone-free status, stent and nephrostomy tube status. A low-dose NCCT scan with 2mm slice thickness will be conducted within 72 hours after the operation to evaluate the postoperative immediate SFR. If residual fragments ≧4mm are present, any information concerning auxiliary treatments will be recorded, including the size of residual stones, type of auxiliary treatment and final outcome.
If nephrostomy tube is placed, it will be removed in the absence of significant bleeding or complications, followed by patient discharge. The double-J stent will be removed after 2 weeks.
Pain visual analog scale (VAS) will be evaluated at three time points, namely pre-operatively, post-operatively 6 hours, and 24 hours respectively. Postoperative analgesia requirement will be documented to reflect postoperative pain and recovery. Quality of life (QoL) scores will be assessed by Wisconsin Stone Quality of Life questionnaire (WISQOL) pre-operatively, as well as 4 weeks postoperatively.
Data Collection and Quality Control:
Patients' demographics and all clinical outcomes will be recorded in the pre-established case report forms (CRF). Two urologists will take turns recording and verifying work for each recruited case. The data of each participating center will be uploaded and summarized weekly, and on-site verification will be conducted periodically to ensure data authenticity and accuracy. Reassessment will be required if summarized data deviate significantly from the median level in the preliminary statistics analysis.
Stone-free status will be evaluated by blinded radiologist from 2mm slice NCCT scan performed postoperatively within 72 hours and at 1 month. Stone size will be defined as the largest diameter for a single stone or the sum of the largest diameters for multiple stones. Stone size and Hounsfield units (HU) will be measured consistently using the same software across all centers. S.T.O.N.E. score will be used for evaluation of stone complexity. Operative time will be calculated from the percutaneous puncture to completion of double-J or nephrostomy tube placement. Hospital stay will be calculated from the day of surgery to the day of discharge and rounded up to the nearest whole day. Intraoperative and postoperative complications will be documented and graded according to the Clavien-Dindo classification.
Each recruited case will have three CRFs completed by its participating center: one at randomization, one after the intervention, and one at 1-month follow-up, including details of any additional interventions and complications.
Statistical Analysis:
Intention-to-treat analysis will be performed. All enrolled participants with complete data will be included in the analysis. Statistical analyses will be conducted using Statistical Package for Social Sciences (SPSS) 22.0 or above and R software version 4.3.1 or above (R Foundation for Statistical Computing). Continuous data will be presented as median (IQR) and analyzed using Student's t test or Mann-Whitney U test, as appropriate. Categorical data will be expressed as n (%) and compared using the χ2 test or Fisher's exact test, as appropriate.
Pre-specified sensitivity analyses will be performed to assess the robustness of the primary findings under alternative, clinically plausible noninferiority margins. These sensitivity analyses will include SFR noninferiority margins of -5% and operative time noninferiority margins of -5 and -10 minutes, respectively. These analyses will be exploratory in nature and are intended to evaluate the consistency of conclusions across different noninferiority thresholds, rather than to redefine the primary hypotheses or decision criteria. Subgroup analyses will be performed to explore potential effect modification by stone location, stone density and lithotripsy energy modality. Logistic regression and linear regression models including a treatment-by-subgroup interaction term will be used to evaluate the interaction effect on SFR and operative time, respectively.
This trial includes two co-primary endpoints: postoperative SFR and operative time. To control the overall type I error rate, a joint noninferiority testing strategy based on the intersection-union principle will be applied. Noninferiority of suction mini-PCNL will be concluded only if both co-primary endpoints independently satisfy their respective noninferiority criteria. Specifically, for SFR, non-inferiority is defined if the lower bound of the 95% confidence interval for the absolute risk difference exceeds -10%. For operative time, non-inferiority is defined if the lower bound of the 95% confidence interval for the mean difference below 10 minutes. For all other analyses, a two-sided p-value of < 0.05 will be regarded as statistically significant.
Inclusion Criteria:
Exclusion Criteria: