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Recent scoring systems predicting stone-free status after retrograde intrarenal surgery; a systematic review and meta-analysis

Introduction Several scoring systems and nomograms have been developed to predict the success of retrograde intrarenal surgery. But no meta-analysis for the performance of scoring systems has yet been performed. The aim of this study was to compare predictive ability of recent scoring systems for stone-free rate of retrograde intrarenal surgery. Material and methods PubMed and Web of Science databases were searched systematically between April and May 2021. The scoring systems which were validated externally or studied at least by two different researcher groups were selected for further analysis. Of 59 records, 14 studies met the inclusion criteria (n = 4137). Area under curve (AUC) values of selected scoring systems were pooled in random or fixed effects. The I2 test was used to quantify heterogeneity. Results Eight, 5, 8, 4 and 3 studies included in meta-analyses for the modified Seoul National University Renal Stone Complexity Score (S-ReSC), R.I.R.S., Resorlu-Unsal Score (RUS), S.T.O.N.E., and Ito’s Nomogram, respectively. We found pooled AUC values 0.709 (95% CI 0.670–0.748), 0.704 (95% CI 0.668–0.739), 0.669 (95% CI 0.646 to 0.692), and 0.771 (95% CI 0.724 to 0.818), for first four of them, respectively. Heterogeneity was very high to pool AUC values for Ito’s nomogram. Conclusions Although S.T.O.N.E. score showed higer pooled AUC value, this systematic review and meta-analysis has not revealed superiority of any scoring system. High heterogeneity between studies and dependencies between scoring systems make it difficult to design a comparative statistical model to generalize the findings. Also, limitations aside, neither scoring system has demonstrated good predictive/discriminative performance.


INTRODUCTION
Advances in surgical techniques and urological devices have made minimal invasive surgery for kidney stones more preferred in recent years. Shock wave lithotripsy, retrograde intrarenal surgery (RIRS), and percutaneous nephrolithotomy (PNL) have replaced open kidney stone surgery in many cases [1]. Which treatment should be chosen for which stone in the kidney is of critical importance. The key is to use the right weapon at the right time. Retrograde intrarenal surgery stands out with its low complication rate and high stone-free rate (SFR), especially for stones up to 2 cm [2]. It is known that the success rate of RIRS depends on multiple factors, such as stone burden, number, localization, renal calyceal anatomy [3]. Several scoring systems and nomograms have been developed with these factors to predict the success of RIRS [3]. Emerging data suggest that scoring systems might provide a preoperative prediction for the outcome of RIRS but none of them gained popularity and were not widely used. Similar findings have been reported from different authors for several scoring systems [4,5]. To date, no meta-analysis for the performance of scoring systems has yet been performed. We therefore aimed to compare predictive ability of the scoring systems for SFR of RIRS.

Search strategy and selection criteria of studies and scoring systems
This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [6]. Study protocol was registered with PROSPERO (number: CRD42021252873). PubMed and Web of Science databases were searched systematically between April and May 2021. The search strategy was developed with keywords in accordance with Population Intervention Comparison Outcomes (PICO) strategy. All keywords and details of the search strategy can be found in Table 1-2. For each database, the search strategy, removal of duplicates, title-abstract screening were performed by 2 different authors independently (OÖ and ÖÇ). After the resolution of discrepancies by head-to-head meeting, the remaining articles were evaluated by OÖ based on full text. Full text versions of studies were requested from the authors if needed. Finally, reference lists of all full texts were reviewed for further relevant studies. The scoring systems which were validated externally or studied at least by two different researcher groups were selected for further analysis. First research strategy was validated by second research strategy including names of selected scoring systems in 'Comparison' components instead of general relevant keywords. But no additional articles were found. Only original studies which have area under curve (AUC) metadata of ROC curve analysis and written in English were included in the meta-analysis. Studies including patients who underwent bilateral RIRS or had a different simultaneous surgical procedure

Quality assessment
Included studies were assessed by two reviewers (HÇ and OÖ) independently. The risk of bias assessments were done according to modified version of the Quality In Prognostic Studies (QUIPS) tool's six criteria; study participation, study attrition, prognostic factor measurement, outcome measurement, confounding, and statistical analysis and reporting [7]. Final decisions about discrepancies were made after a head-to-head discussion between the scorers. Surgical outcome evaluations by kidney, ureter, and bladder (KUB) imaging, ultrasonography (US), computed tomography (CT), or second-look flexible ureterorenoscopy were considered to be appropriate. Because of consensus lack on the exact diameter of significant residual fragments in the literature, any cut-off value was not took account during quality assessment of reported outcomes.  [9,10,11]. Also one nomogram which developed for pediatric patients and one nomogram predicting perioperative complications were excluded [12,13]. After exclusion of 7 article in the full-text evalua-

Data extraction and analysis
Area under the ROC curve were pooled in random or fixed effects for five scoring systems separately. The I 2 test was used to quantify heterogeneity. A fixed-effects model was used where the I 2 was below 30%; otherwise, a random-effects model was used [8]. Area under curve values were pooled in MedCalc Statistical Software version 20 (MedCalc Software bv, Ostend, Belgium). An AUC of ≥0.800 was considered to denote reasonable/favourable discriminating ability. p values under 0.05 were considered statistically significant.

RESULTS
Study selection flow chart, derived from the PRIS-MA 2020 Flow Diagram can be seen in Figure 1 [22].
systems were summarized in Table 3. These can be classified in three categories; stone related parameters (stone burden, localization, density etc.), anatomic parameters (infundibular measurements, hydronephrosis, abnormal anatomy etc.), and surgeon related parameter (experience).

Quality assessment
The risks of bias assessments were displayed in Table 5. Prognostic factor and outcome measurements were the most poorly rated domains among six criteria of QUIPS tool. Except two of them, retrospective design of included studies caused a scoring system calculation bias risk. There weren't clear statements indicating exact calculation time of scoring systems in validation studies (preoperatively or in the retrospective study period). More importantly, most of the studies didn't report inter-/intraobserver variability analyses. Thus, most of the studies showed poor quality in terms of prognostic factor measurement criteria. Another common lack that reduces the quality of the studies was the non-standard outcome measurement.

Data analysis
Relevant metadata which extracted from selected studies for each scoring system and results of metaanalyses with pooled data can be seen in Table 6. All scoring systems' AUC values showed statistical-  the respect of hydronephrosis degree. (N)umber of stone is scored as 1 stone = 1 point, 2 stones = 2 points, >2 stones = 3 points. Finally, (E)valuation of HU is included in the scoring system as follows; <750 HU = 1 point, 750-1000 HU = 2 points and >1000 HU = 3 points. Ito's nomogram. The only nomogram which was included in the systematic review was Ito's. It was introduced by Ito and colleagues in 2014 [19]. Stone volume (≤500, 500< × ≤1000, 1000< × ≤2000, >2000 mm 3 ), lower pole calculi, operator experience (<50, ≥50), hydronephrosis, and number of stones are the parameters of nomogram. A total score is calculated according to these parameters (total score 0-25). This systematic review and meta-analysis has not revealed superiority of any scoring system which aimed to predict surgical outcomes of RIRS. Statistically significant heterogeneity prevented results of analysis from interpreting predictive/discriminative ability of all recent scoring systems. Although heterogeneity was resolved to certain extent by the exclusion of some studies, following evident clinical obstacles will continue to be a source of heterogeneity for further studies; the inter-/intra-observer variability of scores which were calculated by many different scorers, retrospective calculation bias, discordance between studies for the exact diameter of significant residual fragments and surgical outcome assessment methods. Furthermore, some controversial parameters of scoring systems could have contributed the heterogeneity. Stone burden was the most included parameter. Its high predictive performance is still valid but there are controversies about the calculation method of it [27]. Similar to literature, stone burden unit (mm, mm 2 , cm 3 ) showed variety among included studies. Also, heterogeneity aside, any scoring system did not demonstrate good predictive/discriminative performance (pooled AUC ≥0.800).
Ozbek's study was a strong source of heterogeneity for three scoring systems; S-ReSC, R.I.R.S. and RUS [20]. AUC values for these scoring systems were reported higher in Ozbek's study than other studies. Xiao's study which was another cause of heterogeneity for R.I.R.S. and RUS scores, was the only article reporting higher AUC values than Ozbek's study [16]. This two studies were responsible a high amount of heterogeneity.
After the exclusion of studies which were source of heterogeneity for each scoring system, S.T.O.N.E. score had higher pooled AUC value (0.771) than S-ReSC, R.I.R.S., and RUS scores (0.709, 0.704 and 0.669, respectively). High heterogeneity could not be resolved by exclusion of any study for Ito's nomogram. Thus, it was not involved further interpretation.

DISCUSSION
There were five scoring systems which had been validated externally and well-studied; S-ReSC, R.I.R.S., S.T.O.N.E. scores, RUS and Ito's nomogram. S-ReSC score. This scoring system was introduced firstly for the prediction of SFR after percutaneous nephrolithotomy [14]. Then it was modified for outcomes of RIRS by Jung and colleagues [15]. The modified S-ReSC score is calculated sum of 1 points attended for each of following stone locations: the renal pelvis (#1), superior and inferior major calyceal groups (#2-3), and anterior and posterior minor calyceal groups of the superior (#4-5), middle (#6-7), and inferior calyx (#8-9). If the stone is in the inferior sites (#3, #8-9), one additional point per site is added. R.I.R.S. score. Xiao and colleagues developed R.I.R.S. score in 2017 [16]. This score is assigned according to following criteria; (R)enal stone density ≤1000 Hounsfield Unit (HU) (1 point) or >1000 HU (2 points), the renal infundibulopelvic angle (RIPA, defined as the inner angle of the intersection of ureteropelvic axis and the axis of the lower renal calyx) of the (I)nferior pole stone (scored from 1 to 3 points as determined by a non-inferior pole stone or inferior pole stone with RIPA >30° or ≤30°), (R)enal infundibular length (RIL, the distance from most distal point at bottom stone-containing calix to midpoint of lip of renal pelvis) >25 mm (2 points) or ≤25 mm (1 point), (S)tone burden (1 to 3 points for stone burden according to cumulative stone diameter ≤10 mm, >10 mm and ≤20 mm, and >20 mm, respectively). RUS score. The first developed and validated scoring system for RIRS was introduced by Resorlu and colleagues in 2012 [17]. There are four criteria have equal weight (1 point for each); stone size >20 mm, lower pole stone location and RIPA <45°, stone number in different calyces >1, abnormal renal anatomy (horseshoe kidney or pelvic kidney). S.T.O.N.E. score. This scoring system was derived from pre-operative radiological features of stones [18]. Name of the scoring system is an acronym of included parameters. (S) represents stone size; 1, 2 and 3 points for stones <5 mm, 5-10 mm, and Most selected studies had reported the UAS/basket usage. But there was no enough metadata about pre/ postoperative double j stent insertion rates. This was another cause for heterogeneity and poor quality beyond all the statistical and reporting problems discussed above.

Strengths and limitations
This is the first systematic review and meta-analysis on comparison of recent scoring systems predicting outcomes of RIRS. We only used AUC metadata from studies to provide inclusive findings. More reliable metadata (for example multivariable analysis results) were not exist in most of the studies. Other limitations were poor quality, the heterogeneity between the studies, cohorts differencies and dependencies between scoring systems preventing further comparisons. All of these limitations affected the generalizability of the findings.

Future research
Despite abundance of scoring system and nomogram studies, ideal system to predict surgical outcomes of RIRS is still an unmet need. A scorer friendly system showing low inter-/intraobserver variability, high discriminative/predictive ability may gain popularity and may be used widely.

CONCLUSIONS
There was no superiority of any current scoring system which aimed to predict surgical outcomes of RIRS. Although S.T.O.N.E. score showed highest AUC value, high heterogeneity between studies and dependencies between scoring systems make difficult to design a comparative statistical model to generalize these findings. Also, limitations aside, neither scoring system has demonstrated good predictive/ discriminative performance.