311 Central European Journal of Urology ORIGINAL PAPER UROLITHIASIS Definition of clinically insignificant residual fragments after percutaneous nephrolithotomy among urologists: a world-wide survey by EAU-YAU Endourology and Urolithiasis Working Group Senol Tonyali1,13, Esteban Emiliani2,13, Tarik Emre Şener3,13, Amelia Pietropaolo4,13, Mehmet Ӧzsoy5,13, Omar Aboumarzouk6,13, Bhaskar Somani4,13, Panagiotis Kallidonis7,13, Vincent M.J. De Coninck8,13, Michele Talso9,13, Etienne Xavier Keller10,13, Nicola Macchione11,13, Thomas Tailly12,13 1 Department of Urology, Istanbul University Istanbul School of Medicine, Istanbul, Turkey 2 Department of Urology, Fundacio Puigvert, Autonomous University of Barcelona, Barcelona, Spain 3 Department of Urology, Marmara University School of Medicine, Istanbul, Turkey 4 Department of Urology, University Hospital Southampton NHS Trust, Southampton, United Kingdom 5 Department of Urology, Medical University of Vienna, Vienna, Austria 6 Department of Urology, Queen Elizabeth University Hospital, Glasgow, United Kingdom 7 Department of Urology, University of Patras School of Medicine, Patras, Greece 8 Department of Urology, AZ KLINA, Brasschaat, Belgium 9 Department of Urology, ASST Fatebenefratelli-Sacco, Luigi Sacco University Hospital, Milan, Italy 10 Department of Urology, University Hospital Zurich, University of Zurich, Zurich, Switzerland 11 Department of Urology, ASST Santi Paolo E Carlo, Università Degli Studi Di Milano, Milan, Italy 12 Department of Urology, University Hospital of Ghent, Ghent, Belgium 13 European Association of Urology – Young Academic Urologists Endourology and Urolithiasis Working Group Citation: Tonyali S, Emiliani E, Şener TE, et al. Definition of clinically insignificant residual fragments after percutaneous nephrolithotomy among urologists: a world-wide survey by EAU-YAU Endourology and Urolithiasis Working Group. Cent European J Urol. 2022; 75: 311-316. Article history Introduction The aim of this article was to evaluate the current perception of urologists as to what Submitted: June 2, 2022 size is considered as a clinically insignificant residual fragment (CIRF). Accepted: July 28, 2022 Material and methods A survey was globally distributed to the members of the Endourological Society Published online: Aug. 18, 2022 via SurveyMonkey. Results A total of 385 participants responded to the survey on CIRF. Most participants considered 2 mm (29%) as CIRF threshold, followed by 3 mm (24%), 4 mm (22%), 0 mm (14%), 5 mm (8%) and 1 mm (3%). North American urologists considered CIRF to be smaller than urologists from Asia, Eurasia and South Corresponding author America, (p-values ≤0.001, 0.037 and 0.015 respectively). European urologists identified smaller CIRF Senol Tonyali Istanbul University Istanbul in comparison to Asian urologists (p-value = 0.001). Urologists mainly using a pneumatic lithotripter School of Medicine accepted larger fragments as CIRF, compared to urologists mainly using ultrasonic devices or a combina- Department of Urology tion of ultrasonic and pneumatic devices (p-value = 0.026 and 0.005 respectively). Similarly, urologists Topkapı Mah. Turgut Özal mainly performing X-Ray and ultrasound as post-operative imaging accepted larger fragments as CIRF Millet Cad. in comparison to urologists mainly performing non-contrast computed tomography (p-value = 0.001). Üroloji Anabilim Dalı Fatih 34093 Istanbul, Turkey Conclusions What is considered as CIRF varies between urologist from different continents and seems phone: +90 535 625 7440 to be associated with the lithotripter used and the post-operative imaging modality of preference senoltonyali@hotmail.com to assess treatment success. Key Words: percutaneous nephrolithotomy ‹› survey ‹› clinically insignificant residual fragment ‹› imaging Cent European J Urol. 2022; 75: 311-316 This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 doi: 10.5173/ceju.2022.0115 International (CC BY-NC-SA 4.0). License (http://creativecommons.org/licenses/by-nc-sa/4.0/) 312 Central European Journal of Urology INTRODUCTION Urolithiasis is a major health problem all around the world with a steady increasing prevalence re- ported to be as high as 20.1% [1]. Given the im- provements in technology and development of new devices, open surgery has become obsolete and minimally invasive approaches including extra- corporeal shockwave lithotripsy (ESWL), uretero- renoscopy (URS) and percutaneous nephrolithot- omy (PCNL) are standard treatments for urinary stone disease. Obtaining a stone-free status is one of the main parameters of surgical success and outcomes besides complications, hospital stay and renal function [2]. Although the stone-free rate is often used to compare effectiveness of differ- ent treatment modalities, there is no consensus on what constitutes a successful procedure or a stone-free status and, on the type and timing of imaging modality used to assess this status. While some clinicians would define stone-free sta- tus as having no visible or measurable fragments Figure 1. The distribution of perception of clinically insignifi- on follow-up imaging, others may suggest that the cant residual fragments. post-operative presence of small asymptomatic re- sidual fragments (RF) smaller than 2 mm, 4 mm or 5 mm may still be considered a successful proce- Statistical analysis dure or a stone-free patient [3, 4]. These fragments that are neither obstructing nor symptomatic are IBM Statistical Package for Social Sciences (SPSS) traditionally referred to as clinically insignificant version 25.0 (Armonk, New York, USA) was used for residual fragments or CIRF. Although urinary stone statistical analysis and p-values of <0.05 were con- disease is prone to recurrence, the presence of CIRF sidered significant. Shapiro Wilk was used to evalu- in comparison to a true stone-free status may lead ate normal distribution of continuous variables. to earlier stone related symptoms, complications Non-normally distributed variables were analyzed and re-interventions [3]. with Mann-Whitney-U test or Kruskal-Wallis test In this study, we aimed to evaluate the current per- where appropriate and results presented as medians ception of urologists as to what constitutes a success- with interquartile ranges. For multiple group com- ful procedure and which size of RFs can be perceived parisons, post-hoc analysis, with adjustment of the as clinically insignificant. p-value with Bonferroni correction was performed. The comparison of categorical variables was per- MATERIAL AND METHODS formed with Chi squared and Fisher’s exact tests and results presented as percentages. A survey, developed by EAU-YAU Endourology and Urolithiasis Working Group, was globally distribut- RESULTS ed to the members of the Endourological Society via SurveyMonkey. A total of 385 urologists completed the survey The survey questions included: respondent demo- on CIRF. Most of the respondents considered 2 mm graphics, country of practice, years of experience, (29%) as CIRF threshold, followed by 3 mm (23.6%) type of workplace, whether endourology fellowship and 4 mm (22%). A less conspicuous number of uro- trained or not, annual number of PCNL cases, intra- logists considered CIRF as 0 mm (14%), 1 mm (3.4%) operative lithotripsy method, post-operative imaging or 5 mm (7.8%) (Figure 1). The majority of the re- modality and post-operative imaging time. (Appen- spondents were from North America or Europe dix 1). (31.4% and 23.9%, respectively), fellowship trained Ethics committee approval is waived because survey (59.2%) and working at an academic center (56.9%) research that does not impose risks on participants (Table 1). There was no significant difference be- and that only enrolls competent adults. tween urologists working in academic versus non- 313 Central European Journal of Urology Table 1. Demographics and characteristics of the survey respon- Urologists mainly using a pneumatic lithotriptor ac- dents included the analysis cept larger fragments as CIRF (median/[IQR] = 3 mm Variables N (%) [3–4]) in comparison to urologists mainly using ul- trasonic devices only (median/[IQR] = 3 mm/[3–4], Age (years) 25–30 9 (2.3) p-value = 0.026) or a combination of ultrasonic 31–35 39 (10.1) and pneumatic devices (median/[IQR] = 2 mm/[2–3] 36–40 66 (17.1) p-value = 0.005). 41–45 87 (22.6) 46–50 50 (13) Urologists mainly performing non-contrast comput- 51–55 56 (14.5) ed tomography (NCCT) as post-operative imaging 56–60 33 (8.6) tolerate smaller fragments as CIRF in comparison 61–65 25 (6.5) >65 20 (5.2) to urologists mainly performing X-Ray of kidneys ureters and bladder (KUB) and ultrasound (US) Gender Female 21 (5.5) as post-operative imaging (median/[IQR] =2 mm/[1–3] Male 364 (94.5) vs 3 mm/[2–4], p-value = 0.001). The majority of Continent urologists prefer post-operative imaging to be per- Asia 72 (18.7) formed prior to discharge (43.2%), within 2 weeks Africa 12 (3.1) (13.6%) or within 1 month (22.8%) of the procedure. Oceania 8 (2.1) Eurasia 24 (6.2) The remainder would perform imaging between Europe 92 (23.9) 6 weeks and 3 months after the procedure. North America 121 (31.4) South America 56 (14.5) DISCUSSION Years in practice Junior resident 3 (0.8) Senior resident 8 (2.1) The term clinically insignificant residual fragment Fellow 11 (2.9) was first introduced in peer-reviewed literature 0–5 64 (16.6) 6–10 61 (15.8) by Kulb et al., discussing residual fragments after 11–20 114 (29.6) ESWL [5]. In this early era of ESWL, before current >20 124 (32.2) endoscopic and imaging technologies were widely Practice setting available, the term was suggested, trying to identi- Academic 219 (56.9) fy a cutoff below which further interventions could Community hospital 53 (13.8) Military hospital 6 (1.6) be avoided [5, 6]. Given the lack of a standardized Private hospital 73 (19) method for postoperative imaging modality, time of VA 3 (0.8) imaging and the threshold for CIRF size, its current Other 31 (8.1) utility and validity is contentious. N – number; VA – veterans affairs Despite an extensive body of literature having been dedicated to defining the cutoff size of clinical sig- nificance of RFs and their natural history, our data academic centers (p = 0.602), between fellowship demonstrates that there is no globally accepted cut- trained versus not fellowship-trained urologists off for CIRF size. Additionally, there appear to be (p = 0.104) and according to annual PCNL caseload geographical differences that may stem from dif- in terms of CIRF size perception (p = 0.982). There ferences in clinical practice such as differences in was no significant association with physician’s age tract size or lithotripter use. Physicians preferring and the perception of what size of RF is considered a NCCT for post-operative imaging seem to be more clinically insignificant [p = 0.604]. stringent, allowing significantly smaller fragments We did however find a significant geographical differ- as CIRF in comparison to physicians using X-Ray ence in perception of CIRF (P <0.0001). Urologists and US. Although the cause and effect of this as- from North America (median/[IQR] = 2 mm/[1–3]) con- sociation remains elusive, it seems conceivable that sidered CIRF to be smaller than urologists working in if a more accurate means of detecting fragments Asia (median/[IQR] = 3 mm/[2–4], p <0.001), Eurasia is used, larger fragments may not be considered to be (median/[IQR] = 3 mm/[3–4], p = 0.037) and South clinically insignificant. America (median/[IQR] = 3 mm/[2–4], p = 0.015). The ideal timepoint for post-operative imaging is Similarly, European urologists considered a smaller also a topic of debate. The end of the first month af- threshold for CIRF compared to Asian urologists (me- ter surgery seems reasonable to avoid false positive dian/[IQR] = 2 mm/[2–3] vs 3 mm/[2–4], p = 0.001). results as a consequence of stone dust or residual North American and European urologists did not have fragments that pass spontaneously at early post-op- a significantly different perception on CIRF size. erative period [7]. 314 Central European Journal of Urology Given the differences in perception of CIRF and than determining smaller RF thresholds. Similar what constitutes a successful procedure, several sug- to the aforementioned study, Kang et al. suggested gestions have been proposed to standardize the re- to achieve complete stone free status following en- porting of this most important outcome after stone doscopic lithotripsy methods using holmium laser. surgery. In a short communication, Somani et al. Fragments of 1 mm and <3 mm had passed spon- proposed to report the size of the RF and the imaging taneously after a 2-year follow-up in only 40% and modality used to assess this [8]. In search of consen- 21.4% respectively [14]. In addition, although stone sus using the Delphi method, a panel of experts con- growth was apparent in 18.1% and 26.6% respective- cluded that treatment success and stone-free status ly, only 4 patients (3.2%) experienced a stone related are separate outcomes [4]. The panel agreed (82.1% event. Rebuck et al. [15] investigated the fate of RFs consensus) that stone-free status after PCNL must ≤4 mm in 51 patients following ureteroscopy and be defined as the complete clearance of any RFs, holmium laser stone fragmentations. The authors as assessed by means of computed tomography (CT) reported that about 1 in 5 of those patients expe- scan (76.2% consensus). Among 44 experts who se- rienced a stone event over the following 1.6 years, lected a cut-off size of CIRF, 56.8% voted for 4 mm, while 21.7% became stone-free via spontaneous pas- 11.4% voted for 3 mm and 31.8% voted for 2 mm [4]. sage and 58.7% remained asymptomatic [15]. Our data confirms the lack of a consensus on CIRF Evaluating the fate of patients with RFs after size and demonstrates that we are still in dire need PCNL, Emmott et al. demonstrated that 16.9% and of a standardized way and a definition to report this 28.2% of patients with RFs of <4 mm and ≥4 mm re- most important outcome. spectively required a reintervention over time. Ka- The results of the expert panel from Opondo et al. plan-Meier survival analysis also identified patients are somewhat reflected in published literature as with larger fragments to recur faster than patients a CIRF threshold of 4 mm is widely accepted in with smaller fragments [16]. Using 2 mm as a cut- several studies [4, 9, 10]. In a study by Altunrende off for CIRF, Raman et al. concluded that patients et al. employing a pneumatic lithotripter for stone with RFs larger than 2 mm after PCNL had signifi- fragmentation, KUB or CT for postoperative evalu- cantly lower 3 and 5-year stone event-free survival ation and a cutoff of 4 mm for CIRF, they evaluated rates compared to patients with RFs smaller than 38 patients that had CIRF after PCNL with at least 2 mm [17]. 24 months follow-up [9]. They concluded that CIRF It is clear from all these studies that leaving even with struvite stone composition was the main risk small fragments appears to carry a higher risk factor for progression of stone disease. Gokce et al. of eventually having a recurrence or a clinical event assessed the sensitivity and specificity of follow-up as compared to being completely stone-free. imaging to detect CIRF with a cutoff of 4 mm. Using In fact, the term CIRF could or even should be con- NCCT as the gold standard, KUB and US demon- sidered a misnomer as every currently clinically in- strated a sensitivity of 85.7% and 57.1% respectively significant residual fragment can become clinically to detect stones >4 mm [10]. In a retrospective study significant over time. However, similar to its mean- Osman et al. questioned the clinical insignificance ing after ESWL, a CIRF after PCNL can be con- of single residual stones smaller than 5 mm following sidered a residual fragment that does not currently PCNL [11]. They found fragments <5 mm to result require or warrant an auxiliary procedure but does in active intervention in one third of the patients on carry the risk of recurrence. As many CIRF do not intermediate follow-up longer than 12 months. Thus, become symptomatic over time, the active treatment different from the aforementioned studies, they sug- of these fragments, reaching for a 100% stone-free, gested that the threshold of CIRF might be ≤3 mm. may be an overtreatment in a large portion of this In a study comparing the stone related events after population and the harms of such procedure should RIRS between RF smaller than 4 mm and 4 to 7 mm, be weighed against the benefits. The term clinically authors reported that RFs larger than 4 mm were acceptable residual fragment (CARF) may therefore more prone to cause stone related events [12]. Chew be a more accurate description of the entity. et al. reported that RFs >4 mm after RIRS were What the ideal cutoff is for a CIRF or CARF after more likely to grow with time and were more associ- endoscopic stone treatment and how these patients ated with complications [13]. The authors addition- should be reported in published literature, remains ally found that even RF larger than 2 mm were likely a topic of debate and requires more high-quality re- to grow with time, but were not associated with search with larger populations. In the meantime, at- complications. As such, they concluded that achiev- taining a true stone-free status, as assessed by NCCT ing complete stone-free status is a better strategy within 1 month of surgery, is the goal to be achieved to prevent stone events after ureteroscopy rather with endoscopic stone treatment. 315 Central European Journal of Urology Our study is also not without limitations. The rela- constitutes a clinically insignificant or acceptable re- tively low rate of response to the survey might be sidual fragment. the most important limitation of the study. However, we think that global participation might have over- Conflicts of interest come this issue. The authors declare no conflicts of interest. CONCLUSIONS Statement of ethics Study approval statement: No formal ethical approval was necessary The definition of CIRF is still uncertain today. What to conduct the study. Consent to participate statement: Consent was is considered as CIRF varies between urologists implied by participation. from different continents and seems to be associated with the modality of post-operative imaging to as- Funding sources sess treatment success. As CIRF is one of the most No funding was received for this work. important outcome variables reported in endouro- logical literature, this variation causes heterogeneity Data availability statement in data and difficulty in comparing results. There is The data that support the findings of this study are available upon a dire need for a consensus on a definition of what request to corresponding author. Questions of the distributed survey pertaining to CIRF assessment 1) Age: 25–30, 31–35, 36–40, 41–45, 46–50, 51–55, 56–60, >60 2) Sex: Male/ Female 3) Country of clinical practice 4) Years in practice: I am a junior resident/ I am a senior resident/ I am a fellow/ 0–5, 6–10, 11–20, >20 years 5) You work predominantly in: an academic hospital/ community hospital/ private hospital / Veterans Affairs hospital / military hospital 6) Do you have fellowship training in Endourology/stone treatment? Yes/No 7) How many PCNL procedures do you personally perform annually? <10 10–20 21–50 51–100 >100 8) Please indicate the lithotripsy modality you use Never <25% >25%, <50% Approx. 50% >50%, <75% >75% Always Ultrasound Pneumatic Laser Electro-hydraulic Combined ultrasound/pneumatic No lithotripsy PCNL – percutaneous nephrolithotomy; CIRF – clinically insignificant residual fragment; KUB – kidneys ureters and bladder; CT – computed tomography 9) At what time post-operatively do you usually perform imaging to determine stone-free status? Prior to discharge Two weeks 1 month 316 Central European Journal of Urology 6 weeks 2 months 3 months 10) Which imaging modality do you use to determine stone free status after PCNL? Never <25% >25%, <50% Approx. 50% >50%, <75% >75% Always Nephrostogram X-Ray KUB X-Ray KUB and ultrasound Digital tomosynthesis Non-contrast CT Contrast-enhanced CT PCNL – percutaneous nephrolithotomy; CIRF – clinically insignificant residual fragment; KUB – kidneys ureters and bladder; CT – computed tomography 11) What do you consider to be a clinically insignificant fragment? 0 mm: clinically insignificant fragments don’t exist 1 mm 2 mm 3 mm 4 mm 5 mm Other: Please specify: References 1. Bartoletti R, Cai T, Mondaini N, Melone F, 7. Skolarikos A, Papatsoris AG. Diagnosis 13. Chew BH, Brotherhood HL, Sur RL, et al. Travaglini F, Carini M, Rizzo M. Epidemiology and management of postpercutaneous Natural History, Complications and and risk factors in urolithiasis. Urol Int. nephrolithotomy residual stone fragments. Re-Intervention Rates of Asymptomatic 2007; 79 (Suppl 1): 3-7. J Endourol. 2009; 23: 1751-1755. Residual Stone Fragments after Ureteroscopy: a Report from the EDGE 2. 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