Stesura Seveso 313Archivio Italiano di Urologia e Andrologia 2021; 93, 3 ORIGINAL PAPER No conflict of interest declared. for larger volume stones, but with few severe complica- tions (4, 5); on the other hand, other studies described also life threatening complications of RIRS. In every day practice is RIRS a really uncomplicated tech- nique? What are the real risks? The purpose of this study is to report the stone free rate (SFR) and clinical complications in patients submitted to RIRS. MATERIALS AND METHODS Outcomes of 514 (mean age was 55 yrs; range: 24-84) consecutive patients (313 males and 201 females) who underwent RIRS for renal stones from January 2014 to February 2020 have been retrospectively analyzed. 213 (41.4%) vs 301 (68.6%) stones were located in the right and left kidney; in detail, 213 (41.3%) vs 101 (19.5%) vs 75 (10.6%) vs 239 stones (46.6%) were located in the lower pole vs the middle pole vs the upper pole vs the renal pelvis, respectively. The median stone size was 1.3 cm (range 0.6-3 cm), in 128/514 (24.9%) cases the stones were multiple; CT stone density (HU) 859 (range 436 - 1674). Preintervention double-J stenting was performed in 208/571 (36.5%) cases. Overall SFR was evaluated after 3 months following the procedure by means of a non-contrast computed tomography (N-CCT). Patients who were not considered stone free at the end of the procedure were rescheduled for second look. Success was considered as stone-free status or ≤ 0.4 cm fragments Clinically Insignificant Residual Fragments (CIRF). The 30 days complication rate was classified according to the Clavien-Dindo (CD) classification system (6). Surgical technique All patients were operated in the standard lithotomy posi- tion, under general or spinal anesthesia according to anesthetist-patients counseling. Preliminary semirigid ureteroscopy (using a 6.5-7 F. ureterorenoscope) was performed to observe the ureter and obtain a precondi- tioning ureteral dilation. A ureteral access sheath (UAS) was positioned (10/12 or 12/14 F - Retrace® Coloplast; 9.5/11.5 or 10.7/12.7 F - Flexor® Cook Urological) depending on the ureteral diam- Introduction: The purpose of this study is to report the stone free rate (SFR) and clinical complications in patients submitted to retrograde intrarenal sur- gery (RIRS). Materials and methods: A total of 571 procedures of upper uri- nary stones treated using flexible ureteroscopy and holmium laser lithotripsy from January 2014 to February 2020 have been analyzed. Overall SFR was evaluated after 3 months following the procedure by means of a non-contrast computed tomogra- phy. Success was considered as stone-free status or ≤ 0.4 cm fragments. Results: The overall SFR was 92.3% in group 1 (stone size: < 1 cm), 88.3% in group 2 (stone size: > 1 ≤ 2 cm), 56.7% in group 3 (stone size: 2-3 cm) and 69.6% in group 4 (multiple stones). Post-operative complications, according to the Clavien- Dindo (CD) classification system, were recorded in 32 (5.6%) procedures. The major complications recorded were: one case of subcapsular hematoma (SRH) associated with pulmonary embolism two days after the procedure (CD Grade IIIa) treated conservatively and one case of hemorrhagic shock 2 hour with multiple renal bleedings requiring urgent nephrectomy (CD Grade IVA). Conclusions: The RIRS is an effective and safe procedure with a high SFR significantly correlated with the stone size; at the same time, RIRS could be characterized by severe clinical com- plications that require rapid diagnosis and prompt treatment. Key wORDS: RIRS; Complications; Stone free rate. Submitted 18 March 2021; Accepted 7 May 2021 INTRODUCTION The retrograde intrarenal surgery (RIRS) was introduced in 2008 as an alternative to extracorporeal shock wave lithotripsy (ESWL) and percutaneous nephrolithotomy (PNL) in patients with ESWL-refractory and lower pole stones; today, according to the more recent European Guidelines (EAU guidelines), RIRS represents one of the first line treatments for < 2 cm renal stones (1, 2). In fact, in 2013 EAU guidelines RIRS has been reported as an effective and definitive therapeutic option for renal stones with higher stone free rate (SFR) and low rate of complications (3). Many studies have compared RIRS to percutaneous surgery (PNL) with results that seem to be similar even Stone free rate and clinical complications in patients submitted to retrograde intrarenal surgery (RIRS): Our experience in 571 consecutive cases Orazio Maugeri 1, Ettore Dalmasso 2, Dario Peretti 2, Fabio Venzano 2, Germano Chiapello 2, Carlo Ambruosi 2, Claudio Dadone 2, Astrid Bonaccorsi 1, Pietro Pepe 1, Letterio D’Arrigo 1, Michele Pennisi 1 1 Urology Unit - Cannizzaro Hospital, Catania, Italy; 2 Urology Unit - S. Croce and Carle Hospital, Cuneo, Italy. DOI: 10.4081/aiua.2021.3.313 Summary Archivio Italiano di Urologia e Andrologia 2021; 93, 3 O. Maugeri, E. Dalmasso, D. Peretti 314 eter and compliance. The length of the UAS inserted was 35 cm for women, 45 cm for men. Fluoroscopy was always performed in all cases for instrumentation and control. A 7.5 F flexible fiberoptic ureteroscope and a 200 or 272 micron fiber were used depending on the type of laser. Stone treatment consisted in fragmentation and/or dusting, performed by Sphinx® Jr 30W Ho:YAG laser system (LISA laser) (412 cases; 72.1%), or 120-W high-power Ho:YAG laser system (Lumenis® Ltd.,) (104 cases; 18.2%) or Dornier Medilas H Solvo 30 Watt Holmium:YAG laser (Olympus®) (55 cases; 9.6%), depending on the availability of the different lasers case by case. The most appropriate setting and technique depended on stone size and hardness and on the laser used (Table 4). For stone size < 1 cm the treatment of choice was frag- mentation and complete extraction of the fragments using a zero tip 1.9 Fr nitinol basket. For stone size > 1 or ≤ 3 cm RIRS procedure was com- posed by 3 phases: 1) First phase: stone dusting using low energy, high fre- quency and long pulse width with a persistent contact between laser fiber and stone. 2) Extraction of fragments: the major fragments derived from stone dusting were extracted using a zero tip 1.9 Fr nitinol basket. All fragments were conserved for stone analysis. 3) Second stage: “popcorn effect”: high energy, high fre- quency and short pulse duration. Continuous irrigation with gravity drainage (40 to 50 cm H2O) and syringe-based systems were gently applied to obtain and sustain a clear the operative field. At the end of the procedure a 4.8-6 Fr double J stent was placed in radioscopy, with or without strings depending removal time (cut-off was 7 days). In 48 procedures (9.3%), UAS could not be applied and consequently the procedure was performed without access sheath. We used: UAS 9.5 Fr (n = 33), 10-12 Fr (n = 158), 10.7- 12.7 Fr (n = 43), 12-14 (n = 195). RESULTS RIRS was performed in 514 patients for a total of 571 pro- cedures (54 second look and 3 third look); preoperative assessment included physical examination, routine urine culture, and N-CCT. RIRS was performed on standard antibiotic prophylaxis (according to local guidelines) or on targeted antibiotic therapy in case of preoperative positive urine culture (in this case therapy was started 5 days before surgery and continued for 3 more days). Preoperative urine cultures were positive in 103 patients (20%). All the infec- tions were treated by specific antibiotic therapy. Mean operative time was 67 minutes (range: 17-172); 351 (61.4%) patients underwent RIRS under spinal anes- thesia, while 220 (38.5%) patients were operated under general anesthesia. The median period between interven- tion and JJ stent removal was 7 days (Interquartile range - IQR 1-66). Median post-operative stay was 1.8 days (IQR 1-19). At 3 months N-CCT, the overall success rate was 82.8% (426/514 cases); after the first RIRS 345/514 patients were completely free from urolithiasis (SFR: 67.1%), while 72/514 patients had ≤ 4 mm stone frag- ments in the same renal localization of previously treated lithiasis (CIRF rate: 14%). 54 patients had residual stones requiring second-look and three needed a third-look for significant residual fragments. Table 1 shows success rate, stone free rate and CIRF after first treatments according to stone volume and number; the stone composition by spectrophotometric analysis is reported in Table 2. Intraoperative complications were reported in 4 patients: – Intraoperative bleeding: one during laser lithotripsy and one after placement of the UAS. In both cases bleeding led to poor visibility and abortion of the pro- cedure that was rescheduled. – Two ureteral wall injuries secondary to UAS place- ment: a grade 2 lesion according to Traxer classifica- tion (6) were treated with a double J stent for a long period; a grade 3 lesion required percutaneous drain- ing of the kidney. No subsequent strictures were noted during follow up (13 and 18 months). Post-operative complications were recorded in 31 (5.4%) procedures (Table 3): Table 1. Stone free rate in the 514 patients submitted to RIRS. Number of stone Single < 1 cm Single 1-2 cm Single 2-3 cm Multiple Number of patients 202 247 37 128 Overall Success rate, pt (%) 186 (92.3%) 130 (88.3%) 21 (56.7%) 89 (69.6%) Overall Stone free rate, pt (%) 175/186 (94%) 89/130 (68.4%) 14/21 (66.6%) 67/89 (75.2%) Overall CIRF rate, pt (%) 11/186 (5.9%) 41/130 (31.5%) 7/21 (33.3%) 22/89 (24.7%) Stone free rate after I look pt (%) 158/175 (90.2%) 71/89 (79.7%) 6/14 (42.8%) 44/67 (65.6%) Stone free rate after II look pt (%) 17/175 (9.7%) 18/89 (20.2%) 8/14 (57.1%) 23/67 (34.3%) Stone free rate after III look pt (%) - - - - CIRF rate after I look pt (%) 11/11 (100%) 35/41 (85.3%) 5/7 (71.4%) 21/22 (95.4%) CIRF rate after II look pt (%) - 6/41 (14.6%) - - CIRF rate rate after III look pt (%) - - 2/7 (14,2%) 1/22 (4.5%) Table 2. Stone composition to spectrophotometric analysis. Stone composition. no. (%) Value Calcium oxalate monohydrate 194 (37.7%) Calcium oxalate dihydrate 102 (19.8%) Uric acid 88 (17.1%) Mixed 87 (16.9%) Calcium oxalate and phosphate (68) Calcium oxalate and uric acid (19) Carbapatite 17 (3.3%) Brushite 4 (0.7%) Urate ammonium 6 (1.1%) Cystine 4 (0.7%) Struvite 2 (0.3%) Various types 10 (1.9%) 315Archivio Italiano di Urologia e Andrologia 2021; 93, 3 Stone free rate and complications of RIRS – one patient (0.1%) had a cerebrospinal fluid leak after spinal anesthesia causing headache (CD Grade I) treat- ed with bed rest and paracetamol/caffeine; – eleven patients (1.9%) had post-operative nausea and vomiting requiring specific therapy; – fifteen patients (2.6%), developed urosepsis, defined as clinical signs of bacterial infections with positive blood culture (CD Grade II-IIIA). Among them, twelve (2.8%) required antibiotic therapy (CD Grade II), while in three (0,5%) double J was replaced due to concomitant hydronephrosis with double J displace- ment (CD Grade IIIA); – two patients (0.3%) on antiplatelet therapy had post- operative hematuria which required bladder irrigation and prolonged catheterization (CD Grade II). – two patients had hemorrhagic events (0.3%) at the sec- ond look of complex multiple kidney stones: 1) Subcapsular hematoma (SRH) associated with pul- monary embolism two days after the procedure (CD Grade IIIa). Treatments consisted in two blood unit transfusion and angiography, which did not show any blood spill. Inferior vena cava filter was placed and anticoagulant therapy was continued for 6 months. 6 months follow up CT scan shows a complete reab- sorption of the hematoma (Figure 1). 2) Hemorrhagic shock 2 hour after RIRS due to massive renal bleeding (CD Grade IVa) (Figure 2). CT scan and angiography showed multiple renal bleedings requiring urgent nephrectomy; – Eight patients complained severe pain and/or urinary urgency probably as a double J related side effect. DISCUSSION In the last years, RIRS has become increasing- ly popular and probably the more common procedure for kidney stones up to 2 cm (7); the high SFR with minimal invasiveness and the outpatient setting have been pointed out as specific benefits by several authors (8, 9). Standard success rates range between 65% and 92%. In our study SFR was 86% with a mean operative time of 72 minutes. Figure 1. Subcapsular hematoma (SRH) of left kidney (a: CT axial evaluation) (b: CT coronal evaluation). Figure 2. Kidney hematoma with multiple renal bleedings following RIRS. a: multiple stones of left kidney (preoperative CT evaluation); b: hematoma of left kidney (CT ev-aluation); c: rupture of left kidney (CT evaluation); d: kidney specimen. Table 3. Clinical complications following RIRS classified according to Clavien-Dindo Grading System. Clavien-Dindo N° of Description Treatment Grade System patients Grade I 12 11 nausea and vomiting Anti-emetics and supportive care 1 cefalea Grade II 14 12 urosepsis Antibiotic therapy 2 haematuria Bladder irrigation and prolonged catheterization Grade III a 4 3 urosepsis with double J displacement Antibiotic therapy + double J substitution 1 subcapsular renal haematoma (SRH) Selective artery embolisation + inferior associated with pulmonary embolism vena cava filter and anticoagulation therapy Grade III b - - - Grade IV a 1 Multiple subcapsular haematoma Urgent left nephrectomy Table 4. Setting laser. Energy (Joule) Frequency (Hertz) Pulse width 30W Ho:YAG laser system Sphinx® Jr (LISA laser) Fragmentation 0,8/1J 10/15 Hz Short pulse (300 μs) Dusting 0,5/0,8 J 18/20 Hz Long pulse (650 μs) Pop corn 0,8/1J 15/18 Hz Short pulse (450 μs) 120-W high-power Ho:YAG laser system (Lumenis®) Fragmentation 1J/1,5 J 25/30 Hz Long Pulse (650 μs) Dusting 0,2/0,5 J 50/70 Hz Long Pulse (1000 μs) Pop-dusting 0,5 J 80 Hz Short Pulse (300 μs) 30 W Ho:YAG laser Medilas H Solvo (Dornier, Olympus®) Fragmentation 0,8/1J 10/15 Hz - Dusting 0,5/0,8 J 18/20 Hz - Pop corn 0,8/1J 15/18 Hz - a. b. a. b. c. d. Archivio Italiano di Urologia e Andrologia 2021; 93, 3 O. Maugeri, E. Dalmasso, D. Peretti 316 These results are comparable to the main previous litera- ture (10-12). Even if RIRS is generally considered a safe procedure, a wide spectrum of intra and mostly post-operative severe events must be considered. Literature is weak about detailed analysis of complica- tions even if some reports deal with serious and life threatening complications. Cindolo et al. in 2016 (13) in a multi-institutional study reporting fatal cases after RIRS, highlighted how this “safe” procedure hides potentially dramatic and fatal complications and the need of a care- ful post-operative patient monitoring: four patients died for septic complications, one for a cardiac event and one due to hemorrhagic complication. Cindolo et al. (14) eval- uated life-threatening complications after ureteroscopy for lithiasis, reporting 12 cases of serious complications requiring urgent treatment and even one fatal case. Ureteral injury is the most common intraoperative com- plication; beneficial effects and convenience of using access sheaths have been debated. UAS main purpose is to facilitate reentries into renal collecting system, theoret- ically reducing possible injuries to ureter and urethra. In recent studies, the routine intraoperative use of UAS dur- ing RIRS was recommended because it decreases duration of the interventions, with a minimal morbidity associated (14, 15). In our series, we used ureteral access sheaths for nearly all patients, recording two significant ureteral damage correlated to UAS (16). Proper management of such complications is crucial to avoid further short- and long- term complications. The urinary tract infection is the most common event (2- 28% of the cases) (17); in our study, 15 (2.6%) patients experienced these clinical complications; all the cases required specific antibiotic therapy with no need of inten- sive care support (CD II and IIIa). Double J displacement, noted in three patients, could have been the reason of post-operative infection. We suggest to check its position by X ray in case of infection, especially when antibiotic therapies are not effective. Bleeding and renal rupture are less frequent but could lead to serious consequences. In our series two patients had serious hemorrhagic compli- cations; subcapsular hematoma after RIRS is rarely described in the literature and its etiology is not perfectly known (18). Various authors have tried to understand what is the cause of subcapsular renal hematoma: increase intrarenal pressure leading to rupture of the fornix and separation of the capsule from the parenchyma, urinary infection and infiltration of leukocytes into the parenchyma which can be damaged by irrigation, laser and guide wires (19- 22). The sudden expansion and rupture of renal parenchyma is probably the most likely explanation of our cases. Chronic hydronephrosis was present in our two haemorrhagic cases; sudden increase in intrarenal pressure was showed to cause twisting, stretching and /or obstruction of the main intrarenal vessels (23). It is remarkable that retrograde pyelogram performed at the end of the procedure didn’t show any leak or renal absorption of contrast dye; clinical complications were suspected for an uncontrolled renal pain, hypotension and hemoglobin drop. In conclusion, RIRS should be considered an effective and safe procedure in the treatment of renal stones, but a wide spectrum of complications must be considered. Even if rare, complications could lead to life-threatening conditions requiring quick diagnosis and prompt treat- ment. Intraoperative signs of possible post-operative complica- tions may be missing and a careful monitoring is crucial to recognize these events as early as possible. REFERENCES 1. Tiselius HG, Alken P, Buck C, et al. Guidelines on urolithiasis. Arnhem, the Netherlands: European Association of Urology. 2008. 2. Türk C, Knoll T, Petrik A, et al. EAU Guidelines. Urolithiasis. 2013. 3. Bas O, Bakirtas H, Sener NC, et al. Comparison of shock wave lithotripsy, flexible ureterorenoscopy and percutaneous nephrolithotripsy on moderate size renal pelvis stones. Urolithiasis. 2014; 42:115-20. 4. Knoll T, Jessen JP, et al. Flexible ureterorenoscopy versus minia- turized PNL for solitary renal calculi of 10-30 mm size World J Urol. 2011; 29:755-59. 5. Dindo D, Demartines N, Clavien PA. Classification of surgical complications. A new proposal with evaluation in a Cohort of 6336 patients and results of survey. Ann Surgery. 2004; 2:205-213. 6. Traxer O, Thomas A. Prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. J Urol. 2013; 189:580- 84. 7. Elbir F, Basıbüyük I, Topaktas R, et al. Flexible ureterorenoscopy results: Analysis of 279 cases. Turk J Urol. 2015; 41:113-18. 8. Breda A, Angerri O. Retrograde intrarenal surgery for kidney stones larger than 2.5 cm. Curr Opin Urol. 2014; 24:179-83. 9. Breda A, Ogunyemi O, Leppert JT, et al. Flexible ureteroscopy and laser lithotripsy for multiple unilateral intrarenal stones. Eur Urol. 2009; 55:1190-96. 10. Riley JM, Stearman L, Troxel S. Retrograde ureteroscopy for renal stones larger than 2.5 cm. J Endourol. 2009; 23:1395-8. 11. Hyams ES, Munver R, Bird VG, et al. Flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone bur- dens that measure 2 to 3 cm: a multi-institutional experience. J Endourol. 2010; 24:1583-88. 12. Di Mauro D, La Rosa VL, Cimino S, Di Grazia E. Clinical and psychological outcomes of patients undergoing Retrograde Intrarenal Surgery and Miniaturised Percutaneous Nephrolithotomy for kidney stones. A preliminary study. Arch Ital Urol Androl. 2020; 91:256-260. 13. Cindolo L, Castellan P, Scoffone CM, et al. Mortality and flexi- ble ureteroscopy: analysis of six cases. World J Urol. 2016; 34:305- 10. 14. Kourambas J, Byrne RR, Preminger GM. Does a ureteral access sheath facilitate ureteroscopy? J Urol. 2001; 165:789-93. 15. Karaaslan M, Tonyali S, Yilmaz M, et al. Ureteral access sheath use in retrograde intrarenal surgery. Arch Ital Urol Androl. 2019; 91:112-114. 16. Rapoport D, Perks AE, Teichman JM. Ureteral access sheath use and stenting in ureteroscopy: effect on unplanned emergency room visits and cost. J Endourol. 2007; 21:993-97. 317Archivio Italiano di Urologia e Andrologia 2021; 93, 3 Stone free rate and complications of RIRS 17. De S, Autorino R, Kim FJ, et al. Percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and meta- analysis. Eur Urol. 2015; 67:125-37. 18. Bai J, Li C, Wang S, et al. Subcapsular renal haematoma after holmium:yttrium-aluminum-garnet laser ureterolithotripsy. BJU Int. 2012; 109:1230-41. 19. Tao W, Cai CJ, Sun CY, et al. Subcapsularrenal hematoma after ureteroscopy with holmium:yttrium-aluminum-garnet laser lithotripsy. Lasers Med Sci. 2015; 30:1527-32. 20. Hyams ES, Munver R, Bird VG, et al. Flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone bur- den\s that measure 2 to 3 cm: a multi-institutional experience. J Endourol. 2010; 24:1583-88. 21. Riley JM, Stearman L, Troxel S. Retrograde ureteroscopy for renal stones larger than 2.5 cm. J Endourol. 2009; 23:1395-98. 22. Di Mauro D, La Rosa VL, Cimino S, Di Grazia E. Clinical and psychological outcomes of patients undergoing Retrograde Intrarenal Surgery and Miniaturised Percutaneous Nephrolithotomy for kidney stones. A preliminary study. Arch Ital Urol Androl. 2020; 91:256- 260.   23. Nuttall MC, Abbaraju J, Dickinson IK, et al. A review of studies reporting on complications of upper urinary tract stone ablation using the holmium:YAG laser. Br J Med Surg Urol. 2010; 3:151-59. Correspondence Orazio Maugeri, MD (Corresponding Author) omaugeri@gmail.com Bonaccorsi Astrid, MD Pietro Pepe, MD piepepe@hotmail.com D’Arrigo Letterio, MD Michele Pennisi, MD Urology Unit - Cannizzaro Hospital, Via Messina 829, Catania (Italy) Dalmasso Etttore, MD Peretti Dario, MD Venzano Fabio, MD Chiapello Germano, MD Ambruosi Carlo, MD Dadone Claudio, MD Urology Unit - S. Croce and Carle Hospital, Cuneo, (Italy)