Risk factors of bladder stones in neurogenic lower urinary tract dysfunction: A real‐world study

Abstract Objective The objective of this study is to investigate the incidence and risk factors for stone formation and recurrence in patients with neurogenic lower urinary tract dysfunction (NLUTD) in a real‐world cohort. Materials and methods A retrospective cohort study was conducted on all patients with NLUTD who underwent bladder stone treatment between 2010 and 2022. Univariate and multivariate Cox models were used to identify the potential risk factors for stone recurrence. Results Among 114 patients included in the study, 30% experienced stone recurrence. The most common stone components were carbonate apatite phosphate and magnesium ammonium phosphate. The overall recurrence rate was 14 cases per 100 patient years. Neurogenic detrusor overactivity had the highest recurrence rate. Risk factors for stone recurrence in the multivariate analysis were intermittent and suprapubic catheterization, and recurrent urinary tract infection (rUTI). Conclusions Patients experienced multiple bladder stone recurrences. Close monitoring of bladder pressure and UTI with restrictive catheter application may reduce the risk of stone recurrence.

metabolic anomalies, urine parameters and stone composition are conflicting. 7,10,11mitations exist in previous studies that investigated urinary stones in patients with NLUTD.Several of these studies were relatively outdated, 4,12 included kidney stones, 7 or were examined for only one underlying disease, 8,13 rather than providing insight into the real-world NLUTD cohort typically observed by urologists.Consequently, the incidence and risk factors cannot often be determined, and apart from individual recommendations, 14,15 specific guidelines do not currently exist. 16,17e present study was conducted to characterize bladder stones and stone recurrence in a real-world NLUTD cohort and assess the potential risk factors for recurrent stone formation.

| Study design and setting
This retrospective cohort study was performed at the Department of Urology of REHAB Basel, Basel, Switzerland, a neurorehabilitation and paraplegiology centre.
The Ethics Committee of Northwestern and Central Switzerland approved the study protocol and waived the requirement for informed consent (no.2022-00365).This study was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki.We adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines when reporting study results.

| Patient selection
All consecutive patients with NLUTD who received neuro-urological care at REHAB were screened.Between 2010 and 2022, 4049 patients with NLUTD were seen in 10 650 consultations, of whom 114 (2.81%) had bladder stones and were eligible for inclusion in this study.Kidney stones were not a factor.The exclusion criteria were: missing outcome data (e.g.stone composition or urine results) or refusal to participate in any clinical study project involving the secondary use of routine healthcare data.

| Data collection and definitions
Patients were identified from ongoing case statistics on stone analyses and inquiries at the laboratory where the stones were analysed.
Stone clearance was checked endoscopically, and all stones were analysed.The stone size varied between 3 cm and a few millimetres.
Urine composition and urine culture results were obtained.Blood parameters were not recorded.The entire cohort of patients with NLUTD was identified at the REHAB Basel.Two independent investigators (S.M. and S.F.) collected and reviewed all relevant data obtained from the in-house electronic medical records or paper archives.The records were entered into a study database via electronic case report forms.
All the patients underwent regular examinations at our centre, including video-urodynamics, endoscopy, laboratory tests and ultrasonography. 17Since 2010, an extended follow-up regimen has been implemented as recommendations from Ord et al. 14

and Ost and
Lee 15 for patients with permanent catheters.These patients underwent cystoscopy every 1-1.5 years if possible and annual sonography of the urinary tract.Patients without indwelling catheters underwent cystoscopy if clinically necessary, for example, in the case of macrohematuria or suspected stone formation.We only use silicone indwelling catheters, and they are routinely changed every 6 weeks in our patients with an uncomplicated urological course and earlier in case of clinical need.Radiography/CT was performed if stones were suspected in the upper urinary tract.
Our primary objective was to analyse bladder stones and stone recurrence in patients with NLUTD.The second objective was to identify potential risk factors for stone recurrence.At first stone occurrence, patient characteristics (e.g.age, sex, underlying disease, bladder function and bladder management) were assessed.Underlying diseases were categorized as spinal (congenital or acquired SCI), supraspinal (i.e.traumatic brain injury, cerebral palsy, wakeful coma and cerebral perfusion disorder) and multiple sclerosis (MS).We found no isolated peripheral neuropathies or Parkinson's disease.Nevertheless, the study population can be considered a real-world cohort.UTIs were defined in accordance with European Association of Urology's (EAU) guidelines 17 and diagnosed by urologists.
Routine clinical follow-up was scheduled according to the treating physician's recommendations or when the patient had physical complaints; however, all patients were followed.The same data were collected for all the recurrences.

| Statistical analysis
Continuous variables are presented as mean with standard deviation (SD) if normally distributed, or as median with interquartile range (IQR) if skewed.Categorical variables are presented as numbers with percentages with comparisons based on Fisher's exact test, or as nonparametric trends, if explicitly mentioned.
Regarding the primary aim of the study, stone composition was described as the number of occurrences of specific components and cross-tabulated with patient and disease characteristics.
To investigate the risk of stone recurrence, event rates were calculated with 95% confidence intervals (CIs) for the entire study cohort, underlying disease and bladder dysfunction type.Univariate Cox regression analyses were conducted with multiple events and hazard ratios (HRs) determined for age, sex, underlying disease, bladder function, bladder management, rUTI and median urine pH values 3 months preoperatively, which were modelled as time-varying covariates.Furthermore, underlying disease, bladder function, bladder management, rUTI and median urine pH values 3 months preoperatively were included as covariates in the multivariable Cox regression analysis.To reduce bias and avoid loss of statistical power, multiple imputations were conducted using chained equations, adding 100 imputations for each missing value.Statistical significance was set at p < 0.05.
All analyses were performed using Stata 16.0 (StataCorp LLC, College Station, TX, USA).An overview plot was created using R (The R Project for Statistical Computing, https://www.r-project.org,version 4.1).

| Basic characteristics
The study included 114 patients with 206 stone episodes and 161 stone composition analyses.
The mean patient age at the time of the first stone surgery was 54 years (SD, 16 years), and 48 patients were female.The interval between the onset of underlying neurological disease and first stone ranged from 32 days to 59.1 years (median 9.2 years), and the majority of first stones occurred >1 year after disease onset.
An underlying spinal disease was observed in 49% of the patients (n = 56).Furthermore, none of the following comorbidities were present: gout, hyperparathyroidism or chronic inflammatory bowel disease.
Patients tended to be severely affected neurologically and limited in their ability to work.The median functional independence measure (FIM) assessment score was 48, IQR 30 to 75, and ranged from 19 to 126 points.
After the first stone event, recurrences occurred in 30% (n = 34) with an average of 0.8 stones recurring in all patients.A single stone recurrence occurred in 15% of patients; another 15% experienced more than one stone recurrence (up to 9; Table 1A; Figure S1).Among the stones, 19% had only one component.The most frequent stone component was carbonate apatite phosphate, present in 88% of stones.A summary of the stone composition is presented in Table 1B.

| Stone recurrence
Stone recurrence tended to increase in SPC patients (Table 2B).
Both calcium phosphate and magnesium ammonium phosphate stones recurred more than once (Table 2B).Table S1 shows the stone Patients with rUTI were more likely to experience >1 episode of recurrence (Table 2B).The underlying uropathogens are listed in Table S2.In most cases, these were either obligate or facultative urease-forming bacteria (Table S2).The presence of magnesium ammonium phosphate stones was significantly associated with rUTI.
The association between carbonate apatite phosphate stones and rUTI was not statistically significant (Table S3).

| Risk factors for stone recurrence
In the univariate analysis, a higher mean urine pH 3 months preoperatively significantly increased the risk of stone recurrence, with an HR of 1.23 by unit increase.rUTI was associated with a double risk of stone recurrence.After adjusting for underlying disease, urine pH and rUTI, multivariate analysis showed that patients with both CIC and SPC had a triple risk of stone recurrence.After adjustment, the rUTI nearly doubled the risk of recurrence (Table 3).

| DISCUSSION
The results of this study revealed frequent stone recurrences in patients with NLUTD in a real-world setting.Therefore, close and long-term monitoring should be performed in at-risk patients (e.g.NDO, catheterization and rUTI).
To the best of our knowledge, this is the largest real-world NLUTD bladder stone cohort study to date, in which an extended stone analysis was performed.The limitations of previous studies were the lack of distinction between the bladder and upper urinary tract, date of recurrence and stone analysis, and inclusion of only one neurological disease, without considering the entire NLUTD spectrum. 6,13,14e real-world cohort in the present study consisted of 49% of patients with acquired or congenital SCI, 28% with various brain injuries up to wakeful coma and 23% with MS, representing a broad NLUTD spectrum.This cohort composition allows for the assessment of neurological diseases as risk factors for stone formation.
Most bladder stones in the NLUTD cohort were diagnosed at a later stage (>1 year after the neurological onset).In recent studies on patients with SCI, bladder stones were more likely to occur in the chronic phase than in the acute and post-acute phases. 4,13erefore, long-term monitoring of patients with NLUTD is warranted.
The chemical composition of the stones in the NLUTD cohort differed significantly from that in the general population, indicating that other factors may have caused stone formation.Although 19% of NLUTD stones in our study consisted of only one component, this rate was much higher in the general population (81%). 16Calcium oxalate stones were observed more frequently in the general population (41% vs. 70.4%).Carbonate apatite phosphate stones (dahllite) were more common in NLUTD patients (88% vs. 4.8%). 18 previous NLUTD studies, stones were either not completely analysed 4,12,13 or information was not provided regarding mixed stones, 12 and only infectious and non-infectious stones 7 or apatite and infectious stones were distinguished. 6Differentiating between partially infectious (carbonate apatite phosphate, i.e. dahllite) and non-infectious (calcium hydrogen phosphate dihydrate, i.e. brushite) calcium phosphate (i.e.apatite) stones is necessary. 19,20In the present study, dahllite and struvite were found in 88% and 42% of stones, respectively.A high prevalence (98% 12 to 100% 6 ) of infectious stones has been reported in paraplegic patients.Furthermore, when comparing bladder stones between MS and non-MS patients, significantly more infectious stones were detected in patients with neurological disease. 7In the present study, infectious stones were found to contribute significantly to stone recurrence.These findings indicate that rUTI plays a significant role in stone formation and recurrence in patients with NLUTD.
The overall risk of urinary stone recurrence in the general population is high (50%). 21,22However, for bladder stones, data on the recurrence rates in both the general population and patients with NLUTD are scarce.Owing to the heterogeneity of the NLUTD cohort, most studies have focussed on urinary stones in general, 13,15 specific diseases such as SCI, 6,14 or only certain subgroups (e.g.women with indwelling catheters). 23Therefore, previously described recurrence rates varied between 16% 14 and 23%. 6e third of the study cohort had recurrent stones, of which 50% had >1 recurrence.This high rate can be explained by the large number of catheterized patients, rUTI and stringent follow-up.Owing to rigorous screening, some stones were detected before they became symptomatic.
T A B L E 1 (Continued) When recurrence rates were analysed in specific subgroups, similar data were observed in groups of patients with spinal, supraspinal and MS diseases, supporting the decision to study the NLUTD cohort as a whole.Recurrence has been shown to be associated with bladder (dys-)function rather than with the underlying disease.The highest recurrence rates were observed in patients with NDO and DSD.One reason for the association between stone recurrence and NDO and DSD could be the high intravesical pressure that results in hypoperfusion of the urothelium, which is prone to bacterial infection. 24rUTI was detected in 44% and 17% of the patients with NDO and NDU, respectively.Furthermore, DSD can cause a post-void residual volume and increase the risk of rUTI. 25More than one third (37%) of the study cohort had rUTI.In the literature, this rate has been reported to be slightly higher during the first rehabilitation of SCI patients (43%). 26In the present study, rUTI led to >1 stone recurrence, and rUTI was a risk factor for stone recurrence in multivariate analysis.
Infectious stones were the most common stones in patients with NLUTD.
Spontaneous micturition and incontinence were associated with the lowest risks of recurrence.SPC and CIC showed more recurrences and almost tripled the risk of recurrence.These findings are in agreement with those of a previous study that included patients with SCI, indicating a higher risk of stones with CIC and permanent catheters. 13wever, in an earlier SCI study (1985-1990), 14 an increased number of stones with transurethral catheters and SPC was observed; still, recurrence did not increase compared with CIC.Regarding the risk of stone recurrence in SCI patients, Bartel et  The heterogeneous results for different modes of bladder management in the literature may be explained by the lack of assessment of bladder pressure reduction.The role of a potentially inadequate or unattenuated high-pressure bladder when supplied with an indwelling catheter versus the mandatory attenuated bladder when using CIC cannot be assessed.However, because spontaneous and reflex emptying into the urinary condom has the lowest recurrence rate, the catheter itself may also be a risk factor.Incontinence tends to have fewer recurrences with the use of urinary condoms than with absorbent materials, which may be due to lower infection rates and the need to reduce incontinence pressure before reflex emptying into the urinary condom. 27,28e present study has several limitations.First, the study was conducted at a single centre.Second, the sample size may not have allowed the detection of small effects.Third, this study may be limited by its retrospective design, and prospective multicentre investigations are needed to integrate this premise into current clinical practice.
Fourth, the risk factors studied may not be completely independent of each other.Therefore, a multivariate analysis with appropriate correction was performed.Fifth, several parameters, particularly bladder function, are not static and may be affected by medication or bladder management.The specific influence of these parameters should be studied prospectively.Sixth, not all potential risk factors could be assessed, such as, for example, the hydration status of the patients or residual urine in patients without indwelling catheter.

| CONCLUSION
Patients with NLUTD are at high risk of stone formation.The risk of recurrence is particularly high in rUTI (almost doubled), SPC and CIC (tripled), but also NDO with DSD and evidence of infection-associated stones pose significant risks.These patients may require lifelong close monitoring and preventive measures to reduce their risk of stone formation, as mentioned in the Section 2: regular control cystoscopies for patients with indwelling catheters, in our centre every 12-18 months if feasible.Close control of bladder pressure and UTI with cautious application of catheters could help reduce the risk.

Figure
Figure S1 shows stone recurrences during the observation period and the underlying diseases.The overall recurrence rate was 14 per 100 patient years and was similar among the underlying diseases.The highest recurrence rate was observed in patients with NDO and DSD, at 17 per 100 patient years (Table2A).
Patient characteristics and (B) stone characteristics showing stone composition and patient characteristics per included stone.
(Continues) composition per episode and proportion of stone components relative to the first episode.
26.6reported the highest recurrence rates in patients with transurethral catheters, followed by SPC and CIC, with no increased risk of reflex emptying with the use of urinary condoms. Tefore, CIC is a reliable risk factor for recurrent stones because of the significantly increased rate of rUTI.26TA B L E 2 (A) First and any recurrence in relation to underlying disease and bladder function.(B) Stone recurrence in relation to bladder management, stone composition and recurrent urinary tract infections.