ENDOUROLOGY AND STONE DISEASE Evaluation of Nephrolithometric Scoring Systems to Predict Outcomes of Retrograde Intrarenal Surgery Nejdet Karsiyakali1, Emre Karabay2*, Erkan Erkan3, Mustafa Kadıhasanoglu3 Purpose: The aim of the study was to evaluate the predictive value of nephrolithometric scoring systems used to predict the complexity of renal stones for the outcomes of retrograde intrarenal surgery (RIRS). Materials and Methods: A total of 81 patients who underwent RIRS for nephrolithiasis between January 2013 and October 2017 were reviewed in this retrospective study. Guy’s Stone Score (GSS), the S.T.O.N.E., Clinical Research Office of the Endourologic Society (CROES), and Seoul National University Renal Stone Complexity (S-ReSC) nephrolithometry scores were assessed by same researcher for each patient from preoperative non-con- trast enhanced computed tomography scans. These nephrolithometric scores, stone characteristics and complica- tions were compared in patients with/without residual stone. Results: The median (IQR) age of patients (37 female/44 male) was 45 (20) years. The median (IQR) stone bur- den was 139.4 (125.4) mm2 and the mean Hounsfield unit (HU) value was 1034.46 ± 239.56. The stone burden, S.T.O.N.E. and S-ReSC scores were statistically significantly higher and the CROES score was significantly lower in patients with a residual stone (p < 0.001, for all). The incidence of residual stones was statistically significantly higher in patients with Grade 3 GSS (p = 0.018). While S.T.O.N.E., S-ReSC and CROES were significantly cor- related with stone-free rates, GSS failed to correlate with stone-free status. According to the receiver operating characteristic (ROC) curve analysis, the predictive value of stone burden was higher for residual stones, compared to S-ReSC scoring (p < 0.05). Conclusion: Nephrolithometric scoring systems nomograms used to predict the PCNL success were not superior to stone burden in predicting the RIRS success. Keywords: percutaneous nephrolithotomy; kidney stone; nephrolithiasis; retrograde intrarenal surgery; flexible ureteroscopy INTRODUCTION Urinary system stone disease is the third most com-mon disorder following urinary tract infections and prostate diseases in urological complaints. Its inci- dence varies between 2 and 20% with a lifelong risk of 12% in men and 6% in women.(1) With the technological advances in the field of med- icine, urinary system stone disease can be treated us- ing non-invasive or minimally invasive methods. According to the European Association of Urology (EAU) guidelines, extracorporeal shock wave litho- tripsy (SWL), ureteroscopic lithotripsy (URS-L), ret- rograde intrarenal surgery (RIRS), and percutaneous nephrolithotomy (PCNL) are the first-line treatment methods for the removal of kidney stones with varying sizes and localization.(2) The EUA guidelines state that stones smaller than 2 cm can be effectively treated us- ing RIRS, although there are several studies reporting favorable results for stones larger than 2 cm, as well.(3,4) Over the past few decades, RIRS has become wide- spread thanks to sophisticated flexible ureteroreno- scopes and other instruments and increased experience. 1Cukurca State Hospital, Department of Urology, Hakkari, Turkey. E-mail: nkarsiyakali@hotmail.com 2Haydarpasa Numune Training and Research Hospital, Department of Urology, Istanbul, Turkey. 3Istanbul Training and Research Hospital, Department of Urology, Istanbul, Turkey. *Correspondence: Haydarpasa Numune Training and Research Hospital, Department of Urology, Telephone number: +905053858965. E-mail: emrekarabay@gmail.com. Adress: Tibbiye Street. No: 23 34668 Uskudar / Istanbul TR Received April 2019 & Accepted December 2019 Currently, RIRS is an alternative to SWL and PCNL with high stone-free status and low morbidity rates in the treatment of urinary system stone disease.(5) In ad- dition, RIRS has been shown to be a safe method with minimal complication rates.(6,7) The stone-free rate is the most significant factor of successful nephrolithotomy. To date, several scoring systems have been developed to predict the success of PCNL and to minimize procedure-related complications including Guy’s Stone Score (GSS), the S.T.O.N.E. nephrolithometry score, Clinical Research Office of the Endourologic Society (CROES) nephrolithometric nomogram, and Seoul National University Renal Stone Complexity (S-ReSC) score.(8-11) The Resorlu-Unsal Stone Score (RUUS) is the first scoring system described in the literature for predicting the stone-free rate after RIRS.(12) Moreover, the S-ReSC scoring system has been modified for predicting RIRS success.(13) In this context, the Xiao et al. developed the R.I.R.S. scoring system to estimate the stone-free rate after RIRS.(14) However, these scoring systems has not been externally validated. Urology Journal/Vol 17 No. 4/ July-August 2020/ pp. 346-351. [DOI: 10.22037/uj.v0i0.5256 ] To the best of our knowledge, there is no study or head- to-head comparison evaluating the predictive value of common nephrolithometric scoring systems for RIRS success. In the present study, therefore, we aimed to evaluate the predictive value of nephrolithometric scor- ing systems which are commonly used in PCNL for RIRS success. PATIENTS AND METHODS Study Population In this retrospective study, a total of 102 patients who underwent RIRS for kidney stones between January 2013 and October 2017 were analyzed. All steps of the study were planned and performed according to the World Medical Association Declaration of Helsinki. All patients signed the informed consent demonstrating the permission of the patients to usage of their clinical data in future clinical studies. Patients with urinary system anomalies and bleeding diatheses, need for anticoagulants, pregnant patients and patients under 18 years old were excluded from the study. Twenty-one patients whose preoperative com- puted tomography (CT) scans were not available were excluded. Finally, a total of 81 patients were included in the study. Preoperative Evaluation and Calculation of Scoring Systems When the preoperative urine culture of the patients was positive, the patients were treated preoperatively with appropriate antibiotic on the basis of antimicrobial susceptibility test for no less than 7 days. The patients whose control urine cultures were found to be sterile were scheduled for RIRS. Data including preoperative routine biochemistry anal- ysis, complete blood count, coagulation tests, urine cul- ture, and non-contrast CT scans were retrospectively analyzed. Non-contrast CT scans were reviewed by the same researcher who was blind to the patients’ char- acteristics. He analyzed the stone volume, Hounsfield units (HU), and location of the stones. In case of mul- tiple stones, total stone volume was the sum of each stone volume. The mean HU value was calculated from non-contrast enhanced CT scans showing maxi- mum axial diameter of the stone on bone window using maximum diameter in the elliptic plane.(15) The GSS, S.T.O.N.E. nephrolithometry score, CROES nephro- lithometric nomogram, and S-ReSC scores were also calculated using preoperative non-contrast CT scans described by their authors. Surgical Procedure All patients received prophylactic single-dose intrave- nous antibiotherapy (cefazolin sodium 1 g) preopera- tively. Surgery was performed under general anesthesia. The patient was placed in the semi-lithotomy position on the operating table with a fluoroscope depending on the affected side. The operation was initiated in a stand- ard fashion using semi-rigid ureteroscopy (URS) and a 0.038-inch polytetrafluoroethylene-coated guidewire was advanced through the upper urinary system under the visual and fluoroscopic guidance. A ureteral access sheath compatible with the ureter diameter was placed over the guidewire (10/12-Fr or 12/14-Fr, Re-trace Ure- teral Access Sheath, Coloplast, Humlebaek, Denmark). The 7.5-Fr flexible URS device (Karl Storz Endoskope, FLEX-X2, Tuttlingen, Germany) was used in all pa- tients. During lithotomy, holmium-yttrium aluminum RIRS Outcomes with Nephrolithometry Scores-Karsiyakali et al. Variable n (%) Age (year) Median (IQR) 45 (20) Sex Female 37 (45.7) Male 44 (54.3) Stone features and scoring systems Side Right 48 (59.3) Left 33 (40.7) Stone localizations Upper pole 7 (8.6) Middle pole 5 (6.2) Lower pole 10 (12.3) Renal pelvis 17 (21.0) Kidney + proximal ureter 20 (24.7) Multiple calyces 22 (27.2) Stone burden (mm2) Median (IQR) 139.4 (125.4) Hounsfield unit Mean ± SD 1034.46 ± 239.56 Residual stone Yes 21 (25.9) No 60 (74.1) GSS Grade 1 42 (51.9) Grade 2 36 (44.4) Grade 3 3 (3.7) S.T.O.N.E. score Mean±SD 6.48 ± 1.00 S-ReSC score Median (IQR) 1 (1) S-ReSC risk group Low 73 (90.1) Middle 7 (8.6) High 1 (1.2) CROES score Mean ± SD 194.64 ± 49.71 CROES probability of stone-free status (%) Mean ± SD 82.23 ± 10.38 Complication No 78 (96.3) Pyelonephritis 2 (2.5) DJS migration to bladder 1 (1.2) Table 1. Demographic characteristics of patients, baseline stone status, and scores of scoring systems. Abbreviations: Min, minimum; Max, maximum; SD, standard deviation; GSS, Guy’s Stone Score; S.T.O.N.E. stone size (S), tract length (T), obstruction (O), number of involved calices (N), and essence or stone density (E); CROES, Clinical Research Office of the Endouro- logic Society; S-ReSC, Seoul National University Renal Stone Complexity; DJS, double J stent. Vol 17 No 04 July-August 2020 347 garnet (YAG) laser using 270 µm or 365 µm fiber at an energy of 0.6 to 0.8 Joule and frequency of 8-10 Hertz was applied. Pieces of stones were removed using stone basket, if applicable. Surgery was terminated, once the absence of opacity was confirmed through fluoroscopy. A 4.8-Fr double-J stent was inserted in all patients at the end of surgery. Postoperative Period On the next day of surgery, all patients underwent ultra- sonography (USG) and kidney- ureter- bladder graphy (KUB). Double J-stent was retrieved under local anes- thesia one month after surgery in all patients. The stone-free status was defined as no evidence of opacity on KUB or stones or the presence of clinically insignificant residual fragment stones <4 mm on CT.(16) The treatment success was evaluated using KUB at one month postoperatively. The presence of hydronephrosis was assessed using non-contrast enhanced CT, if KUB showed no opacity but hydronephrosis in USG. Statistical Analysis Statistical analysis was performed using the Number Cruncher Statistical System (NCSS) 2007 statistics software (NCSS, LLC, Kaysville, UT, USA). The Kolmogorov-Smirnov test was used to analyze the normality of the distribution of variables. The Stu- dent’s t-test was used to compare normally distributed quantitative data, while the Mann-Whitney U test was used to compare non-normally distributed quantitative data between the groups. The Pearson chi-square test, Fisher-Freeman-Halton exact test, and Fisher’s exact test were used to compare qualitative data between the groups. The Spearman correlation analysis was per- formed to evaluate relationships between the variables. The receiver operating characteristic (ROC) curve anal- ysis was conducted to estimate optimal cut-off values including sensitivity, specificity, positive predictive value, and negative predictive value. The ROC curve analysis was used to predict the presence of residual stones and the results were compared using binomial exact test. Chi-sqaure test was performed to evaluate the consistency between the presence of residual stones and stone-free status according to the CROES. A p val- ue of <0.05 was considered statistically significant. RESULTS Of the patients, 37 were females and 44 were males with a median (IQR) age of 45 (20) years. Right-sid- ed operation was performed in 48 patients (59.3%) and left-sided operation in 33 patients (40.7%). The me- dian (IQR) stone burden was 139.4 (125.4) mm2 and the mean Hounsfield unit (HU) value was 1034.46 ± 239.56. Demographic characteristics of the patients, baseline stone status, and scores of the scoring systems are shown in Table 1. The incidence of residual stones was statistically sig- nificantly higher in the patients with increased stone burden (P < 0.05). However, there was no significant relationship between the presence of residual stones and HU (P > 0.05) (Table 2). The incidence of resid- ual stones was statistically significantly higher in pa- tients with grade 3 GSS (P < 0.05). The stone burden, S.T.O.N.E. and S-ReSC scores were statistically signif- icantly higher and the CROES score was significantly Endourology and Stones diseases 348 Table 2. Relationship of stone types and scoring systems with residual stones. Residual Stone p-value No (n,%=60, 74.1%) Yes (n,%=21, 25.9%) Stone burden (mm2) Median (IQR) 97.02 (104.77) 266.35 (232.41) c0.001** Hounsfield units Mean ± SD 1013.58 ± 229.28 1094.10 ± 263.51 c0.099 GSS (n,%) Grade 1 34 (56.7) 8 (38.1) d0.018* Grade 2 26 (43.3) 10 (47.6) Grade 3 0 (0) 3 (14.3) S.T.O.N.E. score Mean ± SD 6.17 ± 0.83 7.38 ± 0.92 c0.001** S-ReSC score Median (IQR) 1 (1) 2 (2) c0.004** S-ReSC risk group (n,%) Low 58 (96.7) 15 (71.4) e0.003** Middle/High 2 (3.3) 6 (28.6) CROES score Mean ± SD 207.13 ± 43.76 158.95 ± 49.30 c0.001** CROES probability of stone-free status (%) Median (IQR) 90 (9) 72 (22) c0.001** cMann-Whitney U Test, dFisher-Freeman-Halton Exact Test, eFisher’s Exact Test. *p < 0.05, **p < 0.01 Abbreviations: Min, minimum; Max, maximum; SD, standard deviation; GSS, Guy’s Stone Score; S.T.O.N.E. stone size (S), tract length (T), obstruction (O), number of involved calices (N), and essence or stone density (E); CROES, Clinical Research Office of the Endouro- logic Society; S-ReSC, Seoul National University Renal Stone Complexity. Diagnostic Screening ROC Curve ap Cut-off Sensitivity Specificity Positive Predictive Value Negative predictive value Stone burden (mm2) ≥166.2 80.95 71.67 50.00 91.49 0.866 0.783-0.949 0.001** S.T.O.N.E. score ≥ 7 95.24 70.00 52.63 97.67 0.837 0.737-0.937 0.001** S-ReSC score ≥ 2 61.90 68.33 40.63 83.67 0.687 0.544-0.829 0.011* CROES score ≤ 191 76.19 70.00 47.06 89.36 0.767 0.640-0.894 0.001** aComparisons of cut-off values of each nomograms and stone-burden separately, *p < 0.05, **p < 0.01 Abbreviations: ROC, receiver operating characteristic; AUC, area under the curve; CI, confidence interval; S.T.O.N.E. stone size (S), tract length (T), obstruction (O), number of involved calices (N), and essence or stone density (E); CROES, Clinical Research Office of the Endourologic Society; S-ReSC, Seoul National University Renal Stone Complexity. Table 3. Diagnostic screening tests and ROC curve analysis for stone burden, S.T.O.N.E., S-ReSC, and CROES scoring systems. RIRS Outcomes with Nephrolithometry Scores-Karsiyakali et al. lower in patients with a residual stone (P < 0.05, for all). The incidence of residual stones was also statistically significantly higher in patients with an intermediate/ high S-ReSC risk and a low CROES stone-free rate (P < 0.05, for both) (Table 2). No residual stone was observed in 60 patients (74.1%) with ≥ 90% stone-free rate according to the CROES, while 21 patients (25.9%) with <90% stone-free rate had residual stones. According to the CROES stone-free rate estimation, 31 patients were at no risk for residual stone development with ≥ 90% probability and no re- sidual stone was observed in 28 of these patients while residual stone was present in three patients. According to the CROES stone-free rate estimation, 50 patients were at risk for residual stone development with < 90% probability; however, residual stones were observed in only 18 patients, while no residual stone was observed in 32 of these patients. These findings revealed no sta- tistically significant consistency between the actual re- sidual stone rate and CROES stone-free rate (P < 0.05). Stone burden and S.T.O.N.E., S-ReSC and CROES scoring systems according to the ROC curve analysis are presented in Figure 1. A cut-off value of ≥ 166.2 mm2 was calculated for the stone burden according to the presence of residual stones. The odds ratio (OR) for residual stones was 10.75 (95% CI 3.15 to 36.61) in pa- tients with a stone burden of ≥ 166.2 mm2 (Table 3). A cut-off value of ≥ 7 was calculated for the S.T.O.N.E. scoring system according to the presence of residual stones. The OR for residual stones was 46.66 (95% CI 5.81 to 374.62) in patients with ≥ 7 S.T.O.N.E. scores (Table 3). A cut-off value of ≥ 2 was calculated for the S-ReSC scoring system according to the presence of residual stones. The OR for residual stones was 3.50 (95% CI 1.24 to 9.87) in patients with ≥ 2 S-ReSC scores (Table 3). A cut-off value of ≤ 191 was calcu- lated for the CROES scoring system according to the presence of residual stones. The OR for residual stones was 7.46 (95% CI 2.374 to 23.486) in patients with ≤ 191 CROES scores (Table 3). The ROC curve analysis revealed that the predictive value of stone burden was higher for residual stones, compared to S-ReSC scoring (P < 0.05). There was no statistically significant difference between the other variables (P > 0.05) (Table 4). DISCUSSION In our study, we found a statistically significant rela- tionship between the scoring systems used to predict the PCNL success and stone-free status following RIRS. However, ROC curve analysis revealed that these nom- ograms were not superior to stone burden in predicting the RIRS success and that even the predictive value of S-ReSC was lower than stone burden for the postopera- tive stone-free status. In the present study, we evaluated the predictive val- ue of percutaneous nephrolithotomy scoring systems which are commonly used in PCNL for RIRS success. The PCNL is the gold standard treatment for complex kidney stones and stones larger than 2 cm; however, it is associated with certain minor and major complications including intra- or postoperative urinary extravasation, bleeding requiring transfusion, postoperative fever, sepsis, or colon or pleural injury.(17,18) The addition of new ports to the new-generation flexible URS devices with thinner device size and sophisticated optical sys- tems allows clearer visualization and RIRS, therefore, has become an alternative to PCNL for the treatment of kidney stones larger than 2 cm.(19) On the other hand, compared to PCNL, the main disadvantage of RIRS is the requirement for a additional sessions. In recent years, predicting stone-free rate and possible complications before surgery has generated great inter- est in endourology and several nomograms have been developed to predict the success rate of SWL, URS, PCNL, and RIRS.(8-14,20,21) The GSS which is a simple and reliable tool for predicting success rate considers location of the stone and renal anatomy. Higher scores indicate low stone-free rates. The stone-free rate is also independent on the stone burden, experience of the surgeon, age, body weight and comorbidities of the pa- tient.(8) In a review including PCNL scoring systems, the stone-free rate ranged from 0 to 100% for GSS.(22) In our study, the incidence of residual stones was higher in patients with Grade 3 GSS. However, we believe that GSS is not useful to predict the success rates following RIRS. Using the GSS, it is likely to classify a stone as grade 1 in the lower pole and as grade 2 in the upper pole of the kidney. During RIRS, it is more difficult to reach the stone localized in the lower pole using a flex- ible URS due to the deflection angle. In addition, RIRS is not a feasible alternative for Grade 4 staghorn stones. Pairwise Comparison of AUC AUC p Stone burden - S.T.O.N.E. 0.866 – 0.837 0.594 Stone burden - S-ReSC 0.866 – 0.687 0.008** Stone burden - CROES 0.866 – 0.767 0.099 S.T.O.N.E. - S-ReSC 0.837 – 0.687 0.057 S.T.O.N.E.- CROES 0.837 – 0.767 0.335 S-ReSC - CROES 0.687 – 0.767 0.117 Table 4. Pairwise comparisons of AUC of ROC curve and stone burden. Binomial Exact test. **p < 0.01 Abbreviations: ROC, receiver operating characteristic; AUC, area under the curve; S.T.O.N.E. stone size (S), tract length (T), ob- struction (O), number of involved calices (N), and essence or stone density (E); CROES, Clinical Research Office of the Endourologic Society; S-ReSC, Seoul National University Renal Stone Com- plexity. Figure 1. ROC curve analysis of stone burden and nomograms according to residual stone. RIRS Outcomes with Nephrolithometry Scores-Karsiyakali et al. Vol 17 No 04 July-August 2020 349 The significant relationship found in our study can be attributed to the small sample size with Grade 3 GSS. The S.T.O.N.E. nephrolithometry score, which is a sim- ple tool for predicting the success rate of PCNL, con- siders stone size (S), tract length (T), obstruction (O), number of involved calices (N), and essence or stone density (E).(11) The scores vary from 5 to 13 and lower scores indicate less complex stone, while higher scores indicate more complex scenario. In the present study, we found a statistically significant relationship between the S.T.O.N.E. scores and stone-free status. However, we observed no significant relationship between the HU, one of the parameters used in this scoring system, and stone-free status. In addition, tract length is not a helpful measure to predict the success rate of RIRS. Nonetheless, the area under the ROC curve for the S.T.O.N.E. scoring system in terms of the stone burden was the closest compared to the area under the ROC curve for other scoring systems. Thus, this finding sug- gests that the S.T.O.N.E. scoring system is superior to the other scoring systems in predicting stone-free status following RIRS and that modified version of the system can be used for this purpose. The CROES nephrolithometric nomogram in predicting PCNL outcomes is an also reliable tool which incorpo- rates several variables such as stone burden, location of the stone, the presence of staghorn stones, previous sur- gery due to urolithiasis, and case volume per year of the center. Higher scores indicate higher stone-free rates.(9) In our study, we considered that all these variables were helpful in predicting RIRS outcomes and found statisti- cally significantly lower CROES scores in patients with residual stones. However, we found no statistically sig- nificant consistency between the actual residual stone rate and CROES stone-free rate. This can be attributed to the fact that our sample size is small and that scoring based on the location of the stone using CROES system is not feasible for RIRS. The S-ReSC scoring system, which is also useful in pre- dicting the post-PCNL stone-free rate, is solely based on stone distribution as assessed by the cumulative number of calyces involved.(10) It is a 9-point system with 1 point assigned to 9specific locations. A score of 1 to 2 is considered low, 3 to 4 is medium, and ≥ 5 is high. In a study involving 327 patients undergo- ing PCNL, the stone-free rate was found to be 65.4%, indicating that the S-ReSC scoring system is useful in predicting the post-PCNL outcomes.(23) In our study, the incidence of residual stones was also statistically signif- icantly higher in patients with an intermediate/high or high S-ReSC risk compared to low-risk patients. How- ever, the ROC curve analysis revealed that the S-ReSC is the least sensitive scoring system in predicting stone- free status, compared to other nomograms. This can be explained by the fact that the S-ReSC nomogram considers equal scoring for all calyces and lacks higher scores for hard-to-reach calyces in the lower pole dur- ing RIRS. Nonetheless, this study has some limitations, which have to be pointed out. First, it was a retrospective study with a relatively small sample size and the inherent ret- rospective and non-randomized nature might have led to selection bias. Second, non-contrast CT scan was not used in all patients to detect the clinically insig- nificant residual stones and to evaluate the outcomes of RIRS. Third, all nomograms evaluated in this study were originally designed to predict the PCNL success. Hence, these nomograms may not be useful in predict- ing RIRS outcomes. 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