The PRECISE-study: an investigation into combined kidney stone surgery

The lifetime risk of urolithiasis is around 8%. Most patients who suffer from kidney stones are in the productive age, where pain, diagnostics and interventions related to kidney stone disease have an additional societal burden, as well as a great personal burden. Stone formers have a 5-year chance of recurrence of 50%, and of all patients suffering from urolithiasis, 10-20% necessitaties surgical kidney stone removal. Achieving a stone free situation during the operation is important as residual fragments will increase the chance of (faster) recurrences of symptoms. Percutaneous nephrolithotomy (PCNL) is the most effective therapy with CT-controlled stone free rates between 45% and 91%. By combining two treatment modalities, (ureterorenoscopy (URS) and PCNL, which is generally called endoscopic combined intrarenal surgery (ECIRS)), these percentages could be improved. However, ECIRS has not been properly investigated yet. Only one single center randomized controlled trial has been published, but the trial only included patients with partial staghorn stones and their endpoint has been the presence of postoperative residual fragments on X-ray. The population size is too small to draw conclusions on whether these patients also suffer less stone related events after treatment with ECIRS when compared to PCNL. The study also does not entail quality of life measurements. Additionally, the study used kidney-ureter-bladder plain X-ray to investigate postoperative residual fragments, but this method is not nearly as sensitive as a CT-scan, which is the standard in contemporary care. Our study aims to include all patients with urolithiasis in which the indication for PCNL has been established, and quality of life measurements and stone-related events will be included as secondary endpoints. Additionally, post-operative evaluation of residual fragments will be performed with a CT-scan instead of X-ray.

The primary objective of the study is to determine whether ECIRS, the combined procedure of PCNL and URS, is superior in stone extraction when compared to PCNL. This will be determined by investigating the difference in percentage of stone free patients based on a postoperative CT-scan 4 weeks after the procedure, a scan which is already standard during regular follow-up independent of any associated studies. Our secondary objectives are differences in postoperative stone volume between the two procedures, differences in stone free rates after 1 year, differences in stone related events (urinary tract infections, emergency department visits because of recurrence of pain, additional operations or additional interventions in terms of ECIRS, PCNL, URS, placement of nephrotomy tubes or double J catheters) after 1 year, 3 year and 5 years, differences in quality of life outcomes after 1 and 5 years, differences in radiation exposure, differences in complications and differences in costs and carbon footprints.

This study is an unblinded multicenter randomized controlled trial. The inclusion and performance of operations will take place in four centers that are responsible for the urology residency program in the North-Eastern region of the Netherlands (OOR NO). All these centers have experienced surgeons that regularly perform PCNL and ECIRS. These four centers are also members of the regional research initiative ROUND. These hospitals are:

1. University Medical Center Groningen (UMCG)
2. Isala Hospital Zwolle
3. Martini Hospital Groningen (Martini Ziekenhuis; MZH)
4. Hospital Group Twente (Ziekenhuisgroep Twente; ZGT)

Patients will be counseled for inclusion for the study when the indication has been confirmed according to the European Association of Urology (EAU) to perform a percutaneous kidney stone treatment. After inclusion, the patients will be randomized to either one of the two study arms: one arm will undergo ECIRS, whether the other arm will undergo PCNL. Patients will then be scheduled for the specific operative procedure. The preparation for the surgery will be equal for both arms. The surgery procedure will be different for each arm. The patients randomized to the ECIRS group will undergo PCNL, but with an additional retrograde URS. This necessitates presence of an ureterorenoscopic set in the operating theatre, as well as a second urological surgeon (urologist or senior resident). It is hypothesized that the ECIRS procedure will take more time, while it necessitates less radiation exposure and probably leads to a higher percentage of patients in which all stone material can be extracted. There is no known difference is postoperative complication rates between ECIRS and PCNL. Patients will be extensively counseled on the differences between ECIRS and PCNL.
Patients in both groups will be subject to regular follow-up which is already in place independently of any research studies. This contain follow-up appointments with a CT-scan after 4 weeks and 1 year, and consults by phone after 3 and 5 years. At these regular follow-up points, the urologists will also pay attention to record quality of life (with the EuroQol EQ-5D-5L questionnaire) and stone-related events.

The investigational treatment is ECIRS. This is a combined treatment of PCNL and URS. Isolated retrograde URS is already commonly used in daily urological practice for less complex kidney stones which do not require treatment with PCNL. ECIRS will be compared with PCNL monotherapy. This allows for percutaneous antegrade stone retrieval, but also for retrograde retrieval of stones. Additionally, several techniques can be performed which are only possible when there is both antegrade and retrograde access to the urinary tract. These techniques pertain endoscopic retrograde guidance of establishing antegrade percutaneous access to the kidney, such as puncturing the kidney under direct retrograde endoscopic vision, as well as introducing guidewires and dilators under endoscopic vision. This might result in better punctures, less necessity to establish multiple percutaneous access tracts and less radiation exposure, since with PCNL, fluoroscopic and ultrasonic guidance has to be used. Additionally, ECIRS allows for combined fragmentation of stones through antegrade ballistic, laser and basket techniques via the nephroscope, while also using retrograde laser and basket techniques with the flexible ureterorenoscope. The so called pass the ball technique can be used, where the ureterorenoscope is used to grasp stones with a basket from different kidney calices in order to present them to the rigid nephroscope from which the stones can easily be removed.

As patients already undergo both PCNL and ECIRS frequently at Dutch hospitals, this study does not presuppose any additional (major) risks. The main goal of the study is to determine to which effect ECIRS is superior or inferior when compared to PCNL, since PCNL is at this time considered to be the standard procedure for complex or large kidney stones.
When comparing the two procedures in terms of risks, the conclusion can be made that the literature has shown that there is no reason to presuppose that one procedure suffers from more postoperative complications when compared to the other, but that ECIRS might be a procedure that takes longer than PCNL, which increases anesthesia time. Additionally, with ECIRS, technically, the chance of tissue damage of the urethra, bladder or ureter might increase since an ureterorenoscope has to be inserted, but during PCNL, this chance might be as high since the bladder is often also entered cystoscopically to insert an ureteral catheter, besides, an indwelling catheter is also often placed. The preliminary literature even suggests a decrease in postoperative complications and duration of hospital stay in favor of ECIRS.
Additionally, with ECIRS, patients might suffer from less radiological exposure since needle, guidewire and dilator placement can be guided endoscopically and does not necessitate fluoroscopic guidance. Secondly, since antegrade and retrograde approaches allow for treatment of kidney stones, less percutaneous tracts might be necessary, which technically decreases chances of (major) hemorrhage and additional radiological exposure. Additionally, the hypothesis of the researchers is that ECIRS results in less additional operative and radiological interventions because it achieves a higher percentage of stone-free patients.