Preoperative factors predicting spontaneous clearance of residual stone fragments after flexible ureteroscopy

bs_bs_banner International Journal of Urology (2015) 22, 372 377 doi: 10.1111/iju.12690 Original Article: Clinical Investigation Preoperative factors predicting spontaneous clearance of residual stone fragments after flexible ureteroscopy Hiroki Ito, 1,2 Shinnosuke Kuroda, 1 Takashi Kawahara, 2 Kazuhide Makiyama, 2 Masahiro Yao 2 and Junichi Matsuzaki 1 1 Department of Urology, Ohguchi East General Hospital, and 2 Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan Abbreviations & Acronyms AUROC = area under the receiver operating characteristics BMI = body mass index furs = lithotripsy with flexible ureteroscopy KUB = kidney ureter bladder NCCT = non-contrast computed tomography PCNL = percutaneous nephrolithiaisis POD = postoperative day POM = postoperative month RF = residual fragment SCRF = the spontaneous clearance of residual renal fragments SF = stone free SWL = shock-wave lithotripsy URS = ureteroscopy Correspondence: Hiroki Ito M.D., Department of Urology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama City, Kanagawa 236-0012, Japan. Email: pug_daikichi@yahoo.co.jp Received 22 July 2014; accepted 9 November 2014. Online publication 19 January 2015 Objective: To investigate factors predicting spontaneous clearance of residual renal fragments after flexible ureteroscopy. Methods: Among 546 patients who underwent lithotripsy with flexible ureteroscopy, 81 had residual renal fragments, as determined by kidney ureter bladder films on postoperative day 1. The final outcome was determined at 3 months after the last flexible ureteroscopy session using non-contrast computed tomography. Patient characteristics and preoperative factors were analyzed using the unpaired t-test and 2 -test. Correlations between the possible predictive factors and the spontaneous clearance of residual renal fragments after flexible ureteroscopy were analyzed using a multivariate logistic regression model with backward selection. Results: Non-contrast computed tomography at postoperative month 3 showed that 33 cases (40.7%) had spontaneous clearance of residual renal fragments, whereas 48 (59.3%) showed non-clearance. Significant differences were found between these cases in terms of stone number, stone location, presence of lower pole calculi and preoperative stent placement. Multivariate assessment showed that stone number (P = 0.004), presence of lower pole calculi (P = 0.021) and presence of hydronephrosis (P = 0.024) were independent predictors of the spontaneous clearance of residual renal fragments after flexible ureteroscopy. Conclusions: Stone number, presence of lower pole calculi and presence of hydronephrosis are independent predictive factors of the spontaneous clearance of residual renal fragments after flexible ureteroscopy. Key words: computed tomography, helical, kidney stone, lithotripsy, multivariate analysis, ureteroscopy. Introduction Achieving a SF status is important for preventing postoperative events related to residual stone fragments after endourological procedures, and considerable attention is now being paid to identifying what constitutes clinically insignificant residual renal fragments after these procedures. 1 7 Some studies have evaluated the natural history of residual fragments after SWL and PCNL. 1,2 These studies showed that some patients with residual fragments who experience a symptomatic episode require additional intervention within 2 3 years of SWL or PCNL. 1,2 In contrast, the natural history of residual stone fragments after URS has not been examined extensively. In their study of 46 patients with post-urs renal stone fragments 4 mm, Rebuck et al. suggested that approximately one in five (or 19.6%) patients experience a stone-related event in the 1.6 years after URS. 4 The remaining patients either become stone free through spontaneous passage or retain asymptomatic fragments of stable size. 4 However, studies with a larger patient population are required to determine the rate of SCRF after URS. Recently, with the development of the ureteroscope and assistant technical devices, lithotripsy with furs has become the standard treatment option for urinary stones, similar to SWL or PCNL. 8 12 Accurate pre-furs prediction of the rate of SCRF would definitely help surgeons determine the possible outcomes of furs, and thereby select optimal treatment options preoperatively. However, to our knowledge, no studies have been carried out to identify factors that predict SCRF after endourological surgeries, including furs. 372 2015 The Japanese Urological Association

Predicting clearance of residual stone fragments To this end, the present study determined both the rate of SCRF after furs and the factors that predict SCRF after furs. To our knowledge, this is the first study to identify the preoperative predictors of SCRF after furs. presence of hydronephrosis and lower pole calculi, and stone location were evaluated on preoperative NCCT images and before the furs procedures. For all procedures, stone status was decided by the same urologist (HI). Methods We retrospectively reviewed the cases of 546 patients treated with furs with or without semi-rigid URS procedures for urinary stones between December 2009 and December 2012 at Ohguchi East General Hospital, Japan. Second- and thirdstage URS was carried out in five and one patients, respectively. The primary options for the treatment of urinary stones were SWL for patients with urinary stones <10 mm diameter and PCNL for renal stones >20 mm diameter. For all patients, URS was offered as the first or second option. The final choice of treatment modality depended on the patients decision and the surgeon s preference. 13 15 The present study was approved by the ethics committee of Ohguchi East General Hospital. Written informed consent was obtained from all patients for their data to be used for research purposes. Surgical techniques The surgical procedures used are described elsewhere. 16 Briefly, URS was carried out with a 6/7.5-Fr or 8/9.8-Fr semirigid ureteroscope (Richard-Wolf, Knittlingen, Germany), a 6-Fr flexible ureteroscope (Flex-X2; STORZ, Tuttlingen, Germany or Olympus P-5; Olympus, Tokyo, Japan), or both, with a 200 550 μm holmium:yttrium-aluminum-garnet laser. During all procedures, ureteral access sheaths (12/14-Fr or 14/16-Fr from Cook Medical, Bloomington, IN, USA or 11/13 or 13/15-Fr from Boston Scientific, Natick, MA, USA) were used to facilitate stone extraction and reduce the intrarenal pressure. For stone removal and clearance of residual fragments, 1.5-Fr or 2.2-Fr tipless nitinol baskets were used in all procedures. Before fragmentation, lower pole stones were relocated using these baskets. If the operation time exceeded 120 min, the procedure was stopped to minimize perioperative complications. Pre- and postoperative evaluation Stone status was routinely evaluated on KUB films on POD 1. SF status was defined as no visible stones; when residual stone fragments 4 mm were detected, the outcome was recorded as RF status. The final outcome of furs was decided on NCCT carried out 3 months after the last furs session. The preoperative factors analyzed were stone diameter (mm), stone volume (mm 3 ), stone number, stone side (right or left), age, sex, height, bodyweight, BMI, presence of hydronephrosis (including partial hydronephrosis), presence of lower pole calculi, preoperative placement of ureteral stent and stone location (ureter stones, renal stones, or both). Stone volume was determined on 5 mm axial and 3.5 mm reconstructed coronal NCCT images, as described previously. 13 The number of stones, Statistical analysis Statistical analysis was carried out using Statistical Package for Social Sciences, version 21 (SPSS, Chicago, IL, USA). Patient characteristics and preoperative factors were analyzed using the unpaired t-test and 2 -test. The AUROC was used to evaluate the predictive potential of age, BMI, stone burden and stone number. The cut-off points used for categorizing stone number were set depending on the highest value of both sensitivity and specificity determined from the ROC curve. The cut-off points of stone volume and Hounsfield units were set at 1000 mm 3 and 1500 HU, respectively. The operators were eight urologists. A multivariate logistic regression model with backward selection was also used for statistical analysis. 15,17,18 All variables that showed significant correlation in the full multivariate model (P < 0.15) were included in the reduced multivariate model. In all statistical tests, P < 0.05 was considered significant. Results Patient characteristics and surgical outcomes Among a total of 546 URS procedures carried out, 342 were found to be have SF status as the outcome, 123 were considered failures and 81 had RF status (fragments 4 mm) on POD 1. The 81 patients with RF status were subsequently further analyzed. NCCT in POM 3 showed that of these 81 cases, 33 cases (40.7%) showed SCRF and 48 (59.3%) showed non-scrf. In all 81 cases, the procedures were carried out under general anesthesia. Flexible URS with lithotripsy alone was carried out in 54 procedures, whereas the other 27 procedures involved both semirigid and flexible URS with lithotripsy. Postoperative ureteral stent placement was carried out in all procedures to reduce the risk of complications; the stents were removed at approximately POM 1, when we were certain that the bypass was no longer necessary. Medical expulsive treatment, including an alpha 1 blocker, was not administered up to POM 3 in any of the cases. Table 1 shows a comparison of patient characteristics and treatment outcomes according to SCRF observed in POM 3. Significant differences were found between the SCRF and non-scrf groups in stone number (P = 0.019), stone location (P = 0.042), presence of lower pole calculi (P = 0.025) and preoperative stent placement (P = 0.010). In terms of postoperative complications, high-grade fever occurred in four patients, and they received conservative treatment (Clavien classification, grade II). Ureteral stricture developed in two patients, neither of whom had any obvious perioperative problems. Balloon dilation of the ureter was carried out in both cases, and a successful outcome was obtained in one patient (Clavien classification, grade III). In the second patient, as the balloon dilation failed, permanent double-j stents were placed (Clavien classification, grade III). 2015 The Japanese Urological Association 373

HITOET AL. Table 1 Comparison of patient outcomes in POM 3 and stone data between the SCRF group and non-scrf group SCRF Non-SCRF P-value No. patients 33 (40.7%) 48 (59.3%) Age (years) 57.17 ± 11.56 58.63 ± 11.91 0.586 Sex (n) Female 6 15 0.187 Male 27 33 Side (n) Right 19 29 0.798 Left 14 19 Height (cm) 167.36 ± 9.10 164.42 ± 10.02 0.181 Bodyweight (kg) 64.45 ± 13.34 66.11 ± 13.30 0.583 BMI (cm/kg 2 ) 22.85 ± 3.42 24.35 ± 3.78 0.072 Stage 1 32 43 0.082 2 0 5 3 1 0 Semi-rigid URS (n) Without 18 31 0.364 With 15 17 No. stones 2.24 ± 1.86 3.44 ± 2.43 0.019* Stone burden Diameter (mm) 22.82 ± 12.68 26.70 ± 11.18 0.161 Volume (mm 3 ) 1124.05 ± 800.09 1341.94 ± 857.33 0.258 Stone location Ureter 8 4 0.042* Kidney 20 27 Ureter + kidney 5 17 Lower pole calculi Absent 17 13 0.025* Present 16 35 Hounsfield unit Maximum 1353.61 ± 410.51 1296.23 ± 359.69 0.507 Mean 1111.48 ± 356.33 1056.81 ± 335.70 0.484 Hydronephrosis (n) 14 34 0.133 Preoperative stenting Cases 11 30 0.010* Indwelling duration (months) 2.45 ± 3.03 1.97 ± 2.04 0.563 Size 5-Fr 1 2 0.074 6-Fr 6 12 7-Fr 2 3 8-Fr 2 13 SWL failure (n) 9 19 0.252 Operation time (min) 102.45 ± 29.37 108.56 ± 29.51 0.362 Laser use (kj) 2.85 ± 2.56 3.78 ± 4.42 0.288 Operator 50 URS performed 27 35 0.353 <50 URS performed 6 13 Postoperative admission days 4.69 ± 5.49 3.69 ± 1.57 0.236 Postoperative fever (n) 1 3 0.511 Postoperative ureteral 2 0 0.084 stricture (n) Stone composition Calcium oxalate 11 25 0.269 Calcium phosphate 1 0 Uric acid 1 0 Mixed 18 23 Other 1 0 Unclear 1 2 *Significant differences between two groups as determined by unpaired t-test or 2 -test. ROC curve analysis of outcome predictors ROC curves for SCRF after furs are shown in Figure 1. The AUROC curves were higher for stone number (0.657) than for any other parameters (Table 2). As the stone number that showed the highest sensitivity and specificity in the ROC curves was four, this value was set as the cut-off for stone number. presence of hydronephrosis (P = 0.045) were significantly associated with SCRF after furs (P < 0.15; Table 3). Additionally, reduced multivariate assessment showed that stone number (P = 0.004), presence of lower pole calculi (P = 0.021) and presence of hydronephrosis (P = 0.024) were independent predictors of SCRF after furs (Table 3). Multivariate analysis of outcome predictors Full multivariate assessment showed that stone number (P = 0.022), presence of lower pole calculi (P = 0.148) and Discussion The primary aim of the present study was to assess early stone history after furs, whereas the secondary aim was to 374 2015 The Japanese Urological Association

Predicting clearance of residual stone fragments Fig. 1 Receiver operating characteristic curves for SCRF after URS: stone number and stone volume. Cut-off point of stone number is four. ( ), Stone number; ( ), stone volume; ( ), reference. Table 2 AUROC curve for preoperative parameters in cases of SCRF in POM 3 Parameter AUROC Stone number 0.657 Stone volume 0.572 BMI 0.587 Age 0.547 determine the predictors of SCRF 4 mm, as measured on KUB films at POD 1 after furs. NCCT at POM 3 showed that among the 81 patients with RF status, 33 patients (40.7%) showed SCRF, whereas 48 (59.3%) did not. Our main findings were that stone number, the presence of lower pole calculi and the presence of hydronephrosis were significant, independent factors predicting SCRF after URS. To our knowledge, this is the first study to successfully identify predictive factors of SCRF after furs. Among patients with residual renal stone fragments 4 mm at POD 1, most (59.3%) could not spontaneously pass the fragments by POM 3, because of which they showed non-sf status on NCCT. To our knowledge, one previous study has investigated the natural stone history after URS. That study analyzed natural stone history for a longer time than the present study did, and the results predicted that among 46 patients with post-urs renal stone fragments 4 mm, approximately one in five (or 19.6%) would experience a stone event over the next 1.6 years. 4 We believe that the current early stone history investigation was better able to reflect SCRF after furs, as early stone history cannot be influenced by de novo stone formation or stone recurrence. A previous study showed that the lack of active retrieval of fragments during URS is associated with a higher risk of unplanned medical visits than complete intraoperative extraction. 19 As aforementioned, previous findings also suggested that residual renal stone fragments 4 mm after furs required careful follow up or secondary interventions, such as SWL, second URS or PCNL. 1 4 The low SCRF rate after furs observed in the present study was consistent with that noted in previous reports, and suggests that active retrieval of fragments during Table 3 Multivariate logistic regression analysis of SCRF after furs Parameter Category Multivariate Full Reduced P OR 95% CI P OR 95% CI Age <60 years 1 X 60 years 0.514 1.46 0.47 4.50 Body mass index (cm/kg 2 ) <25 1 X 25 0.268 2.06 0.57 7.39 No. stones 1 3 1 1 4 0.022 7.5 1.34 41.90 0.004 10.29 2.12 50.00 Stone location Ureter 0.838 1 X Renal 0.555 1.79 0.26 12.36 Ureter + renal 0.651 1.60 0.21 12.24 Lower pole calculi Absent 1 1 Present 0.148 3.07 0.67 14.09 0.021 3.98 1.23 12.86 Stone volume (mm 3 ) <1000 1 X 1000 0.91 1.07 0.32 3.57 Hounsfield unit maximum <1500 1 X 1500 0.63 1.33 0.41 4.31 Hydronephrosis Absent 1 1 Present 0.045 3.67 1.03 13.06 0.024 4.00 1.21 13.31 Stenting Absent 1 X Present 0.221 2.06 0.65 6.55 n =81 2015 The Japanese Urological Association 375

HITOET AL. furs is essential to avoid postoperative stone events or additional interventions, particularly for the treatment of stones with unfavorable predictors of SCRF. Both the AUROC curves and multivariate logistic analysis showed that stone number was the strongest predictor of SCRF after furs. Multiple stones indicate the complex anatomy of the intrarenal cavity, which can make stone passage after URS difficult. Interestingly, the ROC curve showed that a value of more than four stones was strongly associated with unsuccessful SCRF after furs, and in the multivariate analysis as well, this cut-off point of four for stone number showed a significant correlation with unsuccessful SCRF. Many previous reports showed that stone volume is the strongest predictive indicator of successful outcome of furs. 13,15 However, the present results showed that stone volume had a low predictive value in this regard. Many studies have reported the presence of lower pole calculi as a significant indicator of URS failure, and on this basis, several guidelines for stone management do not recommend URS as the first choice for the treatment of lower pole calculi. 13,15,20,21 In the present study also, we found that the presence of lower pole calculi was associated with unsuccessful postoperative stone passage, as well as the failure of URS itself. One of the possible reasons for the failure of SCRF in lower pole calculi was that the lower pole anatomy had a significant impact on stone clearance, as shown in previous studies. 22,23 Our findings support the common recommendation that lower pole calculi, which often require PCNL, be removed more completely than other stones. 20,21 In the present study, we also found the presence of hydronephrosis to be an independent predictor of SCRF. This factor has also been reported to be one of the predictors of furs failure. 15 Additionally, the presence of hydronephrosis was reported as one of the predictors of PCNL success and the risk of perioperative complications with PCNL. 24,25 In the present study, the presence of hydronephrosis was found to be associated with unsuccessful postoperative stone passage as well as furs failure. The presence of hydronephrosis shows that the intrarenal cavity is large, and this could lead to difficulties not only in stone removal during surgical intervention, but also in spontaneous stone passage after furs and PCNL. Thus, all the three independent predictors of SCRF after furs namely, stone number, presence of lower pole calculi and hydronephrosis represent the complex and large intrarenal anatomical characteristics that might promote failure of stone removal and passage from the intrarenal cavity after furs. These findings, which suggest that the anatomical characteristics play an important role in predicting SCRF after furs, could help physicians in predicting the occurrence of stone events after furs, in choosing the optimal treatment option, and in informing patients with complex and large intrarenal anatomy regarding the associated risks. In certain rodent experiments, the long-term insertion of a ureteral stent decreased ureteral peristalsis, and often even caused aperistalsis. 26 28 Based on these results, Kinn and Andersen suggested that ureteral stenting might prolong the time required for a stone to pass to the bladder. 28 Consistent with these hypotheses, the present study showed that the rate of preoperative stenting was higher in the non-scrf group than in the SCRF group, although multivariate analysis showed that preoperative stenting was not a predictor of SCRF. The exact reason for the higher rate of preoperative stenting in the non- SCRF group is not clear, although this could presumably be a result of the decreased ureteral peristalsis in that group. The present study had a few limitations. First, this was a retrospective study. Furthermore, this was a short study, and a longer study duration might have been beneficial, preferably over a few years, in order to determine the natural history of stones after URS, including SCRF. However, as aforementioned, we believe that the present findings reflect early stone history after URS, which is not affected by de novo stone formation or stone recurrence. Conflict of interest None declared. References 1 Streem SB, Yost A, Mascha E. Clinical implications of clinically insignificant store fragments after extracorporeal shock wave lithotripsy. J. Urol. 1996; 155: 1186 90. 2 Raman JD, Bagrodia A, Gupta A et al. Natural history of residual fragments following percutaneous nephrostolithotomy. J. 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