A Patient-Prioritized Research Agenda for Clinical Trials in Kidney Stone Disease.

PURPOSE: To ensure that research on kidney stones provides meaningful impact for the kidney stone community, patients and caregivers should be engaged as stakeholders in clinical trial design, starting at study inception. This project aimed to elicit, refine, and prioritize research ideas from kidney stone stakeholders to develop a patient-centered research agenda for clinical trials. MATERIALS AND METHODS: The Kidney Stone Engagement Core, a group of patients, caregivers, advocates, clinicians, and researchers, executed an iterative process of surveys and focus groups to elicit and refine research themes, which were then translated into research questions. A separate group of patients, caregivers, and clinicians prioritized these questions through parallel modified Delphi and crowd-sourced digital platforms. A research agenda was developed by the Kidney Stone Engagement Core based on the highest rated questions during a hybrid virtual/in-person capstone session. RESULTS: A total of 70 individuals (57 patients and caregivers, 13 researchers and clinicians) participated in the elicitation, 20 individuals (15 patients and caregivers, 5 researchers and clinicians) participated in refinement, and an additional 80 individuals (81 patients and caregivers, 9 researchers and clinicians) participated in prioritization. Key novel themes emerged from elicitation and refinement: ureteral stents, genetic evaluation, shared surgical decision-making, key subgroups, cumulative disease burden, genetic evaluation, and psychosocial support. Stakeholders generated 6 proposed trials from these themes focused on surveillance, surgical intervention, and medical prevention. CONCLUSIONS: Patients and caregivers valued comparative effectiveness kidney stone research that focused on individualized care, shared decision-making, and improvement of patient-reported experiences. This process provided actionable recommendations for future patient-centered clinical trials within kidney stone disease.

Ureteral Stent Placement Prior to Definitive Stone Treatment Is Associated With Higher Postoperative Emergency Department Visits and Opioid Prescriptions for Youth Having Ureteroscopy or Shock Wave Lithotripsy.

PURPOSE: Little is known about the impact of ureteral stents on youth having stone surgery. We evaluated the association of ureteral stent placement before or concurrent with ureteroscopy and shock wave lithotripsy with emergency department visits and opioid prescriptions among pediatric patients. MATERIALS AND METHODS: We conducted a retrospective cohort study of individuals aged 0-24 years who underwent ureteroscopy or shock wave lithotripsy from 2009-2021 at 6 hospitals in PEDSnet, a research network that aggregates electronic health record data from children's health systems in the United States. The exposure, primary ureteral stent placement, was defined as a stent placed concurrent with or within 60 days before ureteroscopy or shock wave lithotripsy. Associations between primary stent placement and stone-related ED visits and opioid prescriptions within 120 days of the index procedure were evaluated with mixed-effects Poisson regression. RESULTS: Two-thousand ninety-three patients (60% female; median age 15 years, IQR 11-17) had 2,477 surgical episodes; 2,144 were ureteroscopy and 333 were shock wave lithotripsy. Primary stents were placed in 1,698 (79%) ureteroscopy episodes and 33 (10%) shock wave lithotripsy episodes. Ureteral stents were associated with a 33% higher rate of emergency department visits (IRR 1.33; 95% CI 1.02-1.73) and a 30% higher rate of opioid prescriptions (IRR 1.30; 95% CI 1.10-1.53). The magnitudes of both associations were greater for shock wave lithotripsy. Results were similar for age <18 and were lost when restricted to concurrent stent placement. CONCLUSIONS: Primary ureteral stent placement was associated with more frequent emergency department visits and opioid prescriptions, driven by pre-stenting. These results support elucidating situations where stents are not necessary for youth with nephrolithiasis.

Genetic testing in children with nephrolithiasis and nephrocalcinosis.

BACKGROUND: Diagnosing genetic kidney disease has become more accessible with low-cost, rapid genetic testing. The study objectives were to determine genetic testing diagnostic yield and examine predictors of genetic diagnosis in children with nephrolithiasis/nephrocalcinosis (NL/NC). METHODS: This retrospective multicenter cross-sectional study was conducted on children ≤ 21 years old with NL/NC from pediatric nephrology/urology centers that underwent the Invitae Nephrolithiasis Panel 1/1/2019-9/30/2021. The diagnostic yield of the genetic panel was calculated. Bivariate and multiple logistic regression were performed to assess for predictors of positive genetic testing. RESULTS: One hundred and thirteen children (83 NL, 30 NC) from 7 centers were included. Genetic testing was positive in 32% overall (29% NL, 40% NC) with definite diagnoses (had pathogenic variants alone) made in 11.5%, probable diagnoses (carried a combination of pathogenic variants and variants of uncertain significance (VUS) in the same gene) made in 5.4%, and possible diagnoses (had VUS alone) made in 15.0%. Variants were found in 28 genes (most commonly HOGA1 in NL, SLC34A3 in NC) and 20 different conditions were identified. Compared to NL, those with NC were younger and had a higher proportion with developmental delay, hypercalcemia, low serum bicarbonate, hypophosphatemia, and chronic kidney disease. In multivariate analysis, low serum bicarbonate was associated with increased odds of genetic diagnosis (ß 2.2, OR 8.7, 95% CI 1.4-54.7, p = 0.02). CONCLUSIONS: Genetic testing was high-yield with definite, probable, or possible explanatory variants found in up to one-third of children with NL/NC and shows promise to improve clinical practice. A higher resolution version of the Graphical abstract is available as Supplementary information.

Antireflux Surgery at National Surgical Quality Improvement Program-Pediatric Hospitals.

PURPOSE: This study aims to examine contemporary practice patterns and compare short-term outcomes for vesicoureteral reflux procedures (ureteral reimplant/endoscopic injection) using National Surgical Quality Improvement Program-Pediatric data. MATERIALS AND METHODS: Procedure-specific variables for antireflux surgery were developed to capture data not typically collected in National Surgical Quality Improvement Program-Pediatric (eg vesicoureteral reflux grade, urine cultures, 31-60-day followup). Descriptive statistics were performed, and logistic regression assessed associations between patient/procedural factors and outcomes (urinary tract infection, readmissions, unplanned procedures). RESULTS: In total, 2,842 patients (median age 4 years; 76% female; 68% open reimplant, 6% minimally invasive reimplant, 25% endoscopic injection) had procedure-specific variables collected from July 2016 through June 2018. Among 88 hospitals, a median of 24.5 procedures/study period were performed (range 1-148); 95% performed ≥1 open reimplant, 30% ≥1 minimally invasive reimplant, and 70% ≥1 endoscopic injection, with variability by hospital. Two-thirds of patients had urine cultures sent preoperatively, and 76% were discharged on antibiotics. Outcomes at 30 days included emergency department visits (10%), readmissions (4%), urinary tract infections (3%), and unplanned procedures (2%). Over half of patients (55%) had optional 31-60-day followup, with additional outcomes (particularly urinary tract infections) noted. Patients undergoing reimplant were younger, had higher reflux grades, and more postoperative occurrences than patients undergoing endoscopic injections. CONCLUSIONS: Contemporary data indicate that open reimplant is still the most common antireflux procedure, but procedure distribution varies by hospital. Emergency department visits are common, but unplanned procedures are rare, particularly for endoscopic injection. These data provide basis for comparing short-term complications and developing standardized perioperative pathways for antireflux surgery.

Postoperative Imaging Patterns of Pediatric Nephrolithiasis: Opportunities for Improvement.

PURPOSE: Imaging following surgical intervention for nephrolithiasis is important to define operative success and ensure the absence of silent obstruction. We assessed nationwide postoperative imaging patterns in children undergoing ureteroscopy and shock wave lithotripsy. MATERIALS AND METHODS: We reviewed the MarketScan® Commercial Claims and Encounters database from 2007 to 2013 for patients 1 to 18 years old undergoing ureteroscopy or shock wave lithotripsy. We assessed imaging exposure following index procedure within 90 days as a primary analysis and 180 days as a secondary analysis of the index procedure. Univariate and multivariate statistical analyses were performed to assess factors associated with undergoing postoperative imaging. RESULTS: A total of 4,251 children met inclusion criteria, of whom 1,647 had undergone shock wave lithotripsy and 2,604 had undergone ureteroscopy. Postoperative imaging was performed in 57.5% of the cohort, with a higher proportion of children undergong imaging following shock wave lithotripsy compared to ureteroscopy (73% vs 47.8%, p <0.001). Noncomputerized tomographic imaging modalities were most common following ureteroscopy (70.8%) and shock wave lithotripsy (84.6%). Younger children and those with complex medical conditions or complicated postoperative courses were more likely to undergo followup imaging. Computerized tomography was more commonly used in older children and females. At 180-day followup 63% of the cohort had undergone any imaging, again more frequently following shock wave lithotripsy (77.0%) vs ureteroscopy (45.0%). CONCLUSIONS: A large percentage of children with nephrolithiasis do not undergo followup imaging after shock wave lithotripsy, and even fewer undergo imaging after ureteroscopy. Most followup imaging is done within 90 days of surgery. Further work is needed to define appropriate postoperative imaging practices in this population.

Laparoscopic heminephrectomy for duplex system: observed difference in outcomes between upper and lower pole resections.

INTRODUCTION: Renal duplication is a relatively common congenital abnormality of the urinary tract, but symptomatic duplex kidney is a rare presentation in adults. Traditionally, the treatment of choice for poorly functioning moiety has been heminephrectomy. There is extensive literature detailing the outcomes of minimally invasive upper pole heminephrectomy, but comparatively little published regarding lower pole resection, especially in adult patients. We present a series of 13 patients who underwent minimally invasive heminephrectomy for duplex kidney. MATERIALS AND METHODS: Over a 6 year period (2011-2017) 13 patients at a single center underwent laparoscopic heminephrectomy for symptomatic duplex kidney with a poorly functioning moiety. A retrospective review of case notes and imaging was undertaken. RESULTS: Eight and 5 patients underwent upper and lower pole heminephrectomies, respectively. Laparoscopic transperitoneal approach was utilized in all cases. Median length of stay was 2 days (range 1 to 16 days). In the upper pole cohort, one patient had a postoperative infection requiring IV antibiotics. In the lower pole cohort by contrast, there were three major complications (60%). Conversion to complete nephrectomy was necessary in one case; one patient had urinary leakage requiring selective embolization and one patient required a second operation to resect remnant calyces. Furthermore, two patients (40%) developed late recurrence of symptoms. CONCLUSIONS: Symptomatic duplex kidney is a rare presentation in adults. In our experience, heminephrectomy for non-functioning renal unit is safe and reproducible in experienced hands with no major complications and resolution of symptoms in the majority of patients. We have, however, observed a higher complication rate in those undergoing resection of a lower pole moiety. Alternative management such as uretero-ureterostomy should be considered in these cases.

Multi-Institutional Review of Outcomes and Complications of Robot-Assisted Laparoscopic Extravesical Ureteral Reimplantation for Treatment of Primary Vesicoureteral Reflux in Children.

PURPOSE: Robot-assisted laparoscopic extravesical ureteral reimplantation has been proposed as a minimally invasive alternative to open ureteral reimplantation for correcting primary vesicoureteral reflux in children. However, in the current literature there are conflicting data regarding the safety and efficacy of this approach. Amid ongoing debate we analyzed outcomes and complications from this procedure in a large multi-institutional cohort. MATERIALS AND METHODS: We reviewed the records of children who underwent robot-assisted laparoscopic extravesical ureteral reimplantation at 9 academic centers from 2005 to 2014. Radiographic failure was defined as persistent vesicoureteral reflux on postoperative voiding cystourethrogram or radionuclide cystogram. Complications were graded using the Clavien-Dindo scale. RESULTS: A total of 260 patients (363 ureters) underwent robot-assisted laparoscopic extravesical ureteral reimplantation for primary vesicoureteral reflux during the study period. The cohort included 90 patients with either duplex ureter (42), failed endoscopic treatment (40) or concomitant diverticulectomy (8). Of the 280 ureters with postoperative voiding cystourethrogram or radionuclide cystogram available radiographic resolution was seen in 246 (87.9%). There were 25 complications overall (9.6%), with 7 grade 3 complications (2.7%) and no grade 4 or 5 complications. Four patients (3.9%) had transient urinary retention following bilateral reimplantation. CONCLUSIONS: Robot-assisted laparoscopic extravesical ureteral reimplantation has a low complication rate consistent with published series of open ureteral reimplantation. Radiographic success rates are approaching those of the open procedure but continue to fall short of the gold standard approach. These findings necessitate critical thinking regarding potential technique improvements and further prospective investigation into the efficacy of this procedure.

The intestinal microbiome of children with initial and recurrent nephrolithiasis: A pilot study and exploratory analysis.

INTRODUCTION: Kidney stone disease in children is rising disproportionate to the general population, representing a disease population with a distinct biological mechanism as compared to adults. Factors influencing recurrent kidney stone disease in children are poorly characterized and the associations of the intestinal microbiome within sub-populations of kidney stone formers, however, are not well described. We evaluated a pilot cohort of children with nephrolithiasis comparing patients based on recurrent kidney stone episodes and abnormal 24-h urinary parameters, with dual aims to compare the microbiome signal in children with initial and recurrent nephrolithiasis and to explore additional associations in microbiome composition and diversity within this population. METHODS: Children aged 6-18 with a history of nephrolithiasis, without an active ureteral calculus or antibiotic exposure within 30 days of study entry were eligible to participate. All participants had a 24-h urine study within 6 months of study entry and provided a fecal sample. Microbiome samples were analyzed using 16S ribosomal DNA sequencing techniques for alpha and beta diversity comparing initial and recurrent stone formers as well as microbiome multivariate association (MaAsLin2) to determine differentially abundant taxa. Shotgun sequencing reads were aligned to custom oxidase degradation and butyrate production gene databases (5 databases total). Comparisons for MaAsLin2 and shotgun metagenomics, normalized to sequencing depth, were based on stone recurrence, sex, hypercalcuria (≤4 mg/kg/day), hyperoxaluria (≥45 mg/1.73 m2), and hypocitraturia (<310 mg/1.73 m2 [females] or < 365 mg/1.73 m2 [males]). RESULTS: A total of 16 enrolled children provided samples sufficient for analyses, including 9 girls and 7 boys, of whom 5 had experienced recurrent kidney stone events. Three participants had hypercalcuria, 2 had hyperoxaluria, and 4 had hypocitraturia. Comparisons of Formyl-CoA transferase between index and recurrent urinary stone disease revealed a trend towards higher mean abundance of the gene in initial stone formers (0.166% vs 0.0343%, p = 0.2847) (Summary Figure), while trends toward lower biodiversity were also noted in the recurrent stone cohort on both Faith (p = 0.06) and Shannon (p = 0.05) indices. Exploratory analyses found Eubacterium siraeum to be significantly greater in relative abundance in children with documented hypercalciuria (p = 0.001). DISCUSSION: Our pilot study demonstrates possible signals in both microbial diversity and oxalate gene expression, both of which are lower in recurrent pediatric kidney stone patients. These findings warrant further investigation as a potential diagnostic marker for future kidney stone events.

Use of Low-Dose Computed Tomography in Children With Nephrolithiasis: An Analysis From 2 Tertiary Pediatric Centers.

INTRODUCTION: Although ultrasound (US) is the preferred first-line imaging for pediatric nephrolithiasis, CT may be necessary in cases of a nondiagnostic US or when US in not available. Utilization of dose reduction strategies in children undergoing CT for nephrolithiasis is not well described. We compared use of low-dose CT (LDCT) in children presenting to 2 pediatric centers. METHODS: We performed a retrospective chart review of children ≤ 17 years of age presenting with suspected nephrolithiasis to 2 tertiary children's hospitals, inclusive of those referred to these centers from nonpediatric facilities between 2013 and 2019. Children were included with an index CT scan from either the pediatric or referring center while those who had prior documented CT for nephrolithiasis within the study period or missing radiation dose assessment were excluded. The primary outcome was LDCT as defined as radiation dose < 3 mGy. The primary comparator was pediatric vs outside referral center. Exploratory analysis evaluated other factors associated with LDCT, including radiation dosage as a continuous variable. RESULTS: A total of 155 individuals met inclusion criteria, with 126 (81.3%) receiving standard dose and 29 (18.7%) receiving LDCT. Pediatric facilities were more likely to utilize LDCT as compared to referral centers (P < .05). Older age and higher BMI were also found to be associated with increased radiation dose exposure. CONCLUSIONS: Pediatric facilities utilized LDCT more frequently, although age and BMI may also influence imaging choices. An understanding of the factors associated with dose reduction in CT will impact future efforts to explore optimum imaging stewardship in pediatric nephrolithiasis.

A Systematic Scoping Review of Comparative Effectiveness Studies in Kidney Stone Disease.

OBJECTIVE: To review the status of comparative effectiveness studies for kidney stone disease with focus on study outcome, type, population, time trends, and patient-centered approaches. METHODS: A systematic scoping review was performed for articles published between January 1, 2005, and March 30, 2021, using keywords relevant to kidney stone disease. Studies published in English that compared two or more alternative methods for prevention, diagnosis, treatment, monitoring, or care delivery were included. Two reviewers independently reviewed abstracts and an arbitrator resolved discrepancies. Nine reviewers abstracted information from full-length studies. Descriptive statistics were summarized, and linear regression was performed to evaluate temporal trends of study characteristics. RESULTS: We reviewed 1773 abstracts and 707 full-length manuscripts focused on surgical intervention (440); medical expulsive therapy (MET) (152); analgesic control (80); and homeopathic, diagnostics, and/or prophylaxis (84). Randomized controlled trials were common across all outcome categories, including surgery (41.6%), MET (60.2%), analgesic control (81.3%), homeopathic (41.2%), diagnostic (47.6%), and prophylaxis (49.1%). Patient-reported outcomes were utilized in 71.7% and 95% of MET and analgesic control studies, respectively, but in the minority of all other study themes. Over time, meta-analyses and multicenter studies increased [P < .001]. CONCLUSION: Surgical and MET themes dominate published comparative literature in kidney stone disease. There is substantial variation in use of patient-reported outcomes across surgical themes. Multicentered studies and those generating higher level evidence have increased over time but opportunities exist to improve collaborative, high-quality, and patient-centered research in kidney stone disease.

Interfacility Transfer of Children With Time-Sensitive Surgical Conditions, 2002-2017.

Importance: Surgical care for children in the United States has become increasingly regionalized among fewer centers over time. The degree to which regionalization may be associated with access to urgent surgical care for time-sensitive conditions is not clear. Objective: To investigate whether transfers and travel distance have increased for 4 surgical conditions, and whether changes in transfers and travel distance have been more pronounced for rural vs urban children. Design, Setting, and Participants: This retrospective cross-sectional study analyzed data from 9 State Inpatient Databases from 2002 to 2017. Participants included children aged younger than 18 years undergoing urgent or emergent procedures for malrotation with volvulus, esophageal foreign body, and ovarian and testicular torsion. Exposure: Residential and hospital zip codes were categorized as rural or urban. Hospitals were categorized as pediatric hospitals, adult hospitals with pediatric services, and adult hospitals without pediatric services. Main Outcomes and Measures: Primary outcomes were transfer for care and travel distance between patients' home residences and the hospitals where care was provided. Transfer and travel distance were analyzed using multivariable regression models. Results: Among the 5865 children younger than 18 years undergoing procedures for malrotation with volvulus, esophageal foreign body, ovarian torsion, or testicular torsion, 461 (7.9%) resided in a rural area; 1097 (20.5%) were Hispanic, 1334 (24.9%) were non-Hispanic Black, and 2255 (42.0%) were non-Hispanic White; 2763 (47.1%) were covered by private insurance and 2535 (43.2%) were covered by Medicaid; and the median (IQR) age was 9 (2-14) years. Most care was provided at adult hospitals (73.4% with and 16.9% without pediatric services); the number of hospitals providing this care decreased from 493 to 292 hospitals (2002 vs 2017). Transfer was associated with rural residence (adjusted odds ratio [aRR], 2.3 [95% CI, 1.8-3.0]; P < .001) and increased over time (2017 vs 2002: aOR, 2.8 [95% CI, 2.0-3.8]; P < .001). Similarly, travel distance was associated with rural residence (adjusted risk ratio [aRR], 4.4 [95% CI, 3.9-4.8]; P < .001) and increased over time (2017 vs 2002: aRR, 1.3 [95% CI, 1.2-1.4]; P < .001). Rural children were more frequently transferred (2017 vs 2002) for esophageal foreign body (48.0% [12 of 25] vs 7.3% [4 of 55]; P < .001), ovarian torsion (26.7% [4 of 15] vs 0% [0 of 18]; P = .01), and testicular torsion (18.2% [2 of 11] vs 0% [0 of 16]; P = .04). Travel distance for rural children increased the most for torsions, from a median (IQR) of 19.1 (2.3-35.4) to 43.0 (21.6-98.8) miles (P = .03) for ovarian torsion and from 7.3 (0.4-23.7) to 44.5 (33.1-48.8) miles (P < .001) for testicular torsion. Conclusions and Relevance: In this cross-sectional study of children with time-sensitive surgical conditions, the number of hospitals providing urgent surgical care to children decreased over time. Transfers of care, especially among rural children, and travel distance, especially for those with ovarian and testicular torsion, increased over time.

The development of surgical ability during pediatric urology fellowship and its evolution in the early years of practice.

BACKGROUND: North American Pediatric Urology fellowship programs underwent a structural change in 2021 that allows more flexibility in training. Given this opportunity as well as widespread concern about the development of contemporary surgical trainees, it is prudent to understand in detail the current state of preparedness of pediatric urology fellowship graduates for independent practice. OBJECTIVE: The study aimed to determine recent pediatric urology graduates' reported levels of comfort both at graduation and following the start of clinical practice in performing select index procedures. We also queried the aspects of training and clinical practice perceived to be the most valuable for the development of surgical confidence. STUDY DESIGN: Graduates of ACGME approved pediatric urology fellowships from 2016 to 2021 were surveyed. Index procedures were described via brief case vignettes. Respondents were asked to indicate their comfort level with each index procedure following fellowship graduation and at the current time point. Comfort levels were defined by the degree of support that respondents would seek from senior colleagues in preparation for case booking. Respondents were also asked about the most helpful operative settings during training and factors contributing to high and low comfort. RESULTS: Fifty-three pediatric urologists (49%) completed the survey out of 109 invited. Most respondents practiced at an academic center. Perceived comfort was very high for low complexity procedures. The responses varied more widely for procedures of moderate and significant complexity (Figure). Across the cohort, there was a substantial increase in comfort between graduation and the current time point for all procedures queried. The most highly valued operative settings in fellowship were those offering real or simulated independence. Respondents most often attributed high comfort to robust case volumes and overall surgical skill gained in fellowship. DISCUSSION: New pediatric urology faculty differ widely in surgical confidence, particularly for more complex procedures. There is meaningful growth in the confidence and self-perceived independence of pediatric urologists during their initial years of practice. The early years are a critical time of continuing maturation and development that should be supported with structured systems of mentorship. Future challenges include low case volumes for rare conditions and the centralization of complex care. CONCLUSION: These findings will provide valuable context for pediatric urology fellowship directors as they evaluate and redesign their programs under the new, more flexible structure. There are opportunities to formalize early practice mentorship to support the growth of new faculty.