Complete intraureteral stent placement relieves daytime urinary frequency compared with conventional placement in patients with an indwelling ureteral stent: post-hoc analysis of a randomized, controlled trial

A previous randomized, controlled trial had demonstrated that complete intraureteral stent placement (CIU-SP) was superior to conventional stent placement (C-SP) in terms of improvement of stent-related urinary symptoms. However, it is unclear as to which subdomain symptom and cohort could benefit the most from CIU-SP compared to C-SP in urinary symptoms while considering the baseline urinary status. To determine this, a post-hoc analysis was performed using data from a previous study (CIU-SP group, n = 39; C-SP group, n = 41). We assessed the mean changes in the International Prostate Symptom Score (I-PSS) and the Overactive Bladder Symptom Score (OABSS) from baseline to day 14. Statistical comparison between the two groups was performed using analysis of covariance with adjustment of baseline urinary status as a covariate. Among 80 patients, the total I-PSS was significantly lower in the CIU-SP group than in the C-SP group in the cohort with mild urinary symptoms (P = 0.005), but not in those with moderate/severe symptoms (P = 0.521). The CIU-SP group showed significantly improved I-PSS and OABSS daytime frequencies, with the highest t statistic (2.47 and 2.10, respectively) among subdomains of both symptom scores compared with the C-SP group (both P < 0.001). In multivariate regression analysis, the stent placement method (CIU-SP vs. C-SP) was independently associated with the I-PSS daytime frequency on day 14 (P = 0.017). This study suggests that CIU-SP significantly improved stent-related daytime frequency compared with C-SP, and it may benefit especially those patients who have mild urinary symptoms before the placement of ureteral stents.

Changes in urinary symptom scores from baseline to day 14 due to stent placement. The mean changes in the I-PSS and OABSS in all patients are shown in Fig. 1 and Table 2. The total mean I-PSS, I-PSS voiding symptom subscore (Q1 + Q3 + Q5 + Q6), I-PSS storage symptom subscore (Q2 + Q4 + Q7), and total OABSS on day 14 were significantly increased compared with baseline (all P < 0.05; Fig. 1A). Although there was no significant difference between the voiding and storage symptom subscores (P = 0.884, Fig. 1A and Table 2), the storage symptom subscore was independently associated with deterioration of the I-PSS QoL index due to stent placement (β = 0.382, standard error [SE] = 0.042, t statistic = 5.682, P < 0.001; Fig. 1B). Analysis of the correlation between baseline symptom scores and the mean change in scores from the baseline revealed that lower baseline scores were significantly correlated with worse urinary symptom outcome in both I-PSS (|r| = 0.44, P < 0.001; Fig. 1C) and OABSS (|r| = 0.41, P < 0.001; Fig. 1D).

Multivariate analysis of clinical factors associated with daytime frequency of the i-pSS or
OABSS on day 14. According to the results from simple regression analysis described above, multiple regression analysis was performed to investigate the relationships between potential clinical variables and I-PSS/ OABSS daytime frequency. Body mass index (β = − 0.160, SE = 0.045, t statistic = − 3.456, P = 5.859 × 10 −4 ) and stent placement method (β = 0.853, SE = 0.349, t statistic = 2.402, P = 0.017) were significantly associated with the I-PSS daytime frequency (Table 3). No factors were significantly correlated with the OABSS daytime frequency, with only a tendency for the stent placement method (β = 0.257, SE = 0.141, t statistic = 1.859, P = 0.072) ( Table 3).

Discussion
In the present study, we focused on stent-related urinary symptoms in patients with an indwelling ureteral stent after URS. The I-PSS storage symptom subscore was correlated with the I-PSS QoL index rather than its voiding symptom subscore. A novel placement technique, CIU-SP, was significantly superior to C-SP in terms of improving the total I-PSS score, daytime frequency, storage symptom subscore, and QoL index. Patients having mild urinary symptoms at the baseline could more benefit from CIU-SP than from C-SP. Daytime frequency in the I-PSS and OABSS was the most relevant subdomain that was improved by CIU-SP compared with C-SP. Finally, the stent placement method (CIU-SP vs. C-SP) was an independent clinical factor for predicting improvement of the I-PSS daytime frequency. In contrast to our previous report 6 , this post-hoc analysis had several strengths for accurately evaluating stent-related LUTS for the following reasons: (1) measuring the mean change in urinary symptoms from baseline to day 14; (2) applying analysis of covariance for adjusting baseline covariates; (3) selecting day 14 as the final evaluation date for minimizing the confounding effect of discomfort of the URS procedure 13 ; and (4) examining details regarding stent-related LUTS using the validated LUTS-specific indicators 11,12 . Therefore, our results have added new evidence on management of improving stent-related urinary discomfort and QoL. www.nature.com/scientificreports/ In the field of LUTS research, storage-related symptoms are the most clinically bothersome and affect patients' QoL in those with benign prostatic hyperplasia (BPH)/LUTS or overactive bladder (OAB) [14][15][16][17] . Charles et al. found that nocturia and daytime frequency were the primary and secondary chief complaints, respectively, based on the American Urological Association Symptom Index in 1240 men with BPH 15 . McVary et al. suggested that the symptom of bother and QoL were affected two-fold by storage I-PSS questions (Q2, Q4, Q7) vs. questions on voiding symptoms (Q1, Q3, Q5, Q6) 16 . OAB, namely a storage symptom disorder, affected patients' mental health, work productivity, and health-related QoL, regardless of sex 17 .
In the present study, we found that patients' QoL was affected approximately three-fold by a storage symptom compared with a voiding symptom, despite the fact that both symptoms equally occurred because of stent placement. Similar to the approach for BPH/LUTS or OAB, management of storage symptoms is important in controlling ureteral stent-related urinary discomfort. Physical or chemical stimulation on the bladder wall causes release of chemicals, including ATP, acetylcholine, prostaglandins, and nitric oxide, which modulate the activity of either afferent nerves or muscular components of the bladder wall 18 . According to such underlying mechanism(s), CIU-SP may be a reasonable placement method because of not presenting the distal end of the stent. This can prevent iatrogenic physical irritation on the bladder wall. Notably, in our study, CIU-SP significantly reduced daytime frequency among urinary symptom subdomains compared with C-SP, whereas the rate of nocturia was equal in both groups. Based on the mechanism(s) mentioned above, these findings are easy to understand because the absence of a distal tip of the stent might reduce physical stimulus on the bladder during daytime activities.
Furthermore, we also found a negative correlation between the degree of the urinary status at baseline and the change in urinary symptoms after ureteral stent placement. Indeed, patients who had mild urinary symptoms could benefit from CIU-SP, whereas those with moderate/severe symptoms showed little impact, regardless of placement techniques. Thus, the clinical significance of CIU-SP demonstrated in our previous study 6 could be attributed to the inclusion of more than half of the patients with favorable urinary symptoms before the URS surgery in the study. In other words, patients who have moderate or more urinary symptoms could tolerate even   To date, many studies have attempted to alleviate stent-related discomfort by agents, such as alpha-1 blockers, anticholinergics, and beta-3 adrenergic receptor agonists 13,[19][20][21][22] . These results regarding improvement of urinary symptoms are conflicting, and negative results have been found in several randomized, controlled trials 13,[20][21][22] . We believe that trials using medication should consider not only improvement of stent-related irritation, but also urinary symptoms that the patient has 23 . Nevertheless, most ureteral stent studies did not take into account the change from baseline or baseline LUTS status 13,[19][20][21][22] . Therefore, actual results of previous studies may change if considering these factors for statistical analysis. Unlike trials of medications, we focused on examining the pure effect of stent placement methods on urinary symptoms, and found that CIU-SP was a better placement technique than C-SP. Unfortunately, even when using CIU-SP, some patients still suffer from stent-related urinary symptoms. Therefore, further investigations are required to determine the mechanism(s) that are associated with these symptoms (i.e., extraction string, intravesical inflammation, or irradiation pain), for providing a more comfortable method for patients who require ureteral stent placement.  We acknowledge several limitations that should be interpreted with caution. First, this post-hoc study was not intended to be designed when performing the primary study. Therefore, there was a lack of calculation of required sample size for this study. Second, we used only the loop type of stents instead of double j stents, which are commonly used. Although this study could not determine the best management for using double j stents, we believe that our findings could be useful for developing a new stent design that can reduce irritation of the bladder wall. Finally, as we previously mentioned 6 , we did not assess the safety of CIU-SP in patients with distal ureteral stones. Therefore, further studies including patients with distal ureteral stones are required in the future.

conclusion
This study highlights the asymmetrical relationship between ureteral stent-related storage and voiding LUTS for patients' urinary QoL. CIU-SP may be a more beneficial strategy for patients who have mild urinary symptoms at baseline than for those who have moderate/severe symptoms. Furthermore, CIU-SP might help reduce ureteral stent-related storage symptoms compared with C-SP, especially in terms of improving daytime frequency.

Methods participants and study design.
This was a post-hoc analysis that used the same data of a previous prospective, single-blind, randomized, clinical trial, which was registered at the University Hospital Medical Information Network (UMIN00017067) 6 . This study was approved by the ethics board of Kansai Medical University (IRB No. 2016503), and all patients provided written informed consent. This trial strictly followed the 2010 Consolidated Standards of Reporting Trials (CONSORT) statement guidelines 24 . Details of this trial, and inclusion and exclusion criteria were described previously 6 . Briefly, patients who were aged > 20 years who underwent unilateral URS with planned ureteral stent insertion were included. However, patients who had concomitant use of alpha-1 blockers, anticholinergics, corticosteroids, calcium channel blockers, and analgesics, distal ureteral stones, and preoperative ureteral stenting were excluded. Patients were equally randomized in a 1:1 ratio into the CIU-SP and C-SP groups. The modified intention-to-treat population, except for those without follow-up, sufficient clinical data, or those who withdrew consent after randomization, was used for analysis (Supplementary Figure 1).
intervention. For all patients, the I-PSS (mild: ≤ 7, moderate: 8-19, severe: ≥ 20) 11 and the OABSS (mild: ≤ 5, moderate: 6-11, severe: ≥ 12) 12 at baseline and day 14 were obtained (Supplementary Figure 1). The details of surgical intervention of this study were also described previously 6 . Briefly, all patients underwent unilateral URS under spinal anesthesia with or without a ureteral access sheath. After URS, a Polaris Loop Ureteral Stent (Boston Scientific, Malborough, MA, USA) with a string was inserted by the two placement methods (i.e., CIU-SP and C-SP) according to the actual ureteral length. Finally, the stent string was cut approximately 10 cm from the tip of the urethra after insertion of the urethral catheter. For discharge medication, only oral diclofenac sodium 25 mg was allowed to be used during the study period (use of antimuscarinics or alpha-blockers were prohibited). On day 14, the ureteral stent was removed at the outpatient clinic with the extraction string. endpoints. The primary endpoint was the mean change in the total I-PSS and OABSS from baseline to day 14. The secondary endpoints were the mean change in the I-PSS and OABSS subscores from baseline to day 14. These analyses were not part of the protocol-specified primary or secondary endpoints of the previous study 6 . Statistical analysis. Continuous data are expressed as mean ± standard deviation. The Chi-square test was used to compare nominal variables, and the paired or non-paired t test was used to compare continuous variables. The correlations between data were evaluated using Spearman's rank correlation test. For analysis of endpoints, ANCOVA was applied for comparison between the two groups (the placement group as a factor and baseline as a covariate). Simple or multiple linear regression analysis was applied to assess the association between the urinary symptom scores and potential factors, with 15 subjects per variable as the minimum required sample size 25 . The t statistic in linear regression analysis, which was calculated as the ratio of an estimated coefficient (β) to its standard error, was used to test the hypothesis that a coefficient is equal to zero. All statistical analyses were performed using EZR version 1.37 (Saitama Medical Center, Jichi, Japan) 26 . A two-sided P value of < 0.05 was considered statistically significant.