Allopurinol hypersensitivity syndrome: Raising awareness of an uncommon but potentially serious adverse event among kidney stone patients.

Allopurinol is a commonly prescribed agent in the urologic population for the prevention of urinary stones. Although generally well-tolerated, several serious potential side effects can occur with its use. Allopurinol hypersensitivity syndrome (AHS), in particular, is a relatively rare but potentially life-threatening complication. With the observed increase in urinary stone disease, especially those of uric acid composition, it is likely that the use of allopurinol will increase. Urologists play an important role in the assessment and medical management of patients with urinary stones, thus a greater awareness of the potential adverse events associated with allopurinol use, especially AHS, is important, as well as strategies that can minimize such risks. In this report we review the potential adverse effects of allopurinol. In addition, the results of a comprehensive review of the current literature on AHS will be presented, highlighting those patients at highest risk, reviewing the genetic susceptibility testing currently available, and providing guidance on best practices when allopurinol therapy is being considered.

Predictive modelling of urinary stone composition using machine learning and clinical data: implications for treatment strategies and pathophysiological insights.

PURPOSE: Preventative strategies and surgical treatment for urolithiasis depend on stone composition. However, stone composition is often unknown until the stone is passed or surgically managed. Given that stone composition likely reflects the physiological parameters during its formation, we used clinical data from stone formers to predict stone composition. MATERIAL AND METHODS: Stone composition, 24-hour urine, serum biochemistry, patient demographic and medical history were prospectively collected from 777 kidney stone patients. Data were used to train gradient boosted machine and logistic regression models to distinguish calcium vs non-calcium, calcium oxalate monohydrate vs dihydrate, and calcium oxalate vs calcium phosphate vs uric acid stone types. Model performance was evaluated using kappa score and the influence of each predictor variable was assessed. RESULTS: The calcium vs non-calcium model successfully differentiated stone types with a kappa of 0.5231. The most influential predictors were 24-hour urine calcium, blood urate and phosphate. The calcium oxalate monohydrate vs dihydrate model is the first of its kind and could discriminate stone types with a kappa of 0.2042. The key predictors were 24-hour urine urea, calcium, and oxalate. The multiclass model had a kappa of 0.3023 and the top predictors were age, and 24-hour urine calcium and creatinine. CONCLUSIONS: Clinical data can be leveraged with machine learning algorithms to predict stone composition, which may help urologists determine stone type and guide their management plan before stone treatment. Investigating the most influential predictors of each classifier may improve the understanding of key clinical features of urolithiasis and shed light on the pathophysiology.

Multi-site microbiota alteration is a hallmark of kidney stone formation.

BACKGROUND: Inquiry of microbiota involvement in kidney stone disease (KSD) has largely focussed on potential oxalate handling abilities by gut bacteria and the increased association with antibiotic exposure. By systematically comparing the gut, urinary, and oral microbiota of 83 stone formers (SF) and 30 healthy controls (HC), we provide a unified assessment of the bacterial contribution to KSD. RESULTS: Amplicon and shotgun metagenomic sequencing approaches were consistent in identifying multi-site microbiota disturbances in SF relative to HC. Biomarker taxa, reduced taxonomic and functional diversity, functional replacement of core bioenergetic pathways with virulence-associated gene markers, and community network collapse defined SF, but differences between cohorts did not extend to oxalate metabolism. CONCLUSIONS: We conclude that multi-site microbiota alteration is a hallmark of SF, and KSD treatment should consider microbial functional restoration and the avoidance of aberrant modulators such as poor diet and antibiotics where applicable to prevent stone recurrence. Video Abstract.

In focus: perplexing increase of urinary stone disease in children, adolescent and young adult women and its economic impact.

Background: Urinary stone disease (USD) historically has affected older men, but studies suggest recent increases in women, leading to a near identical sex incidence ratio. USD incidence has doubled every 10 years, with disproportionate increases amongst children, adolescent, and young adult (AYA) women. USD stone composition in women is frequently apatite (calcium phosphate), which forms in a higher urine pH, low urinary citrate, and an abundance of urinary uric acid, while men produce more calcium oxalate stones. The reasons for this epidemiological trend are unknown. Methods: This perspective presents the extent of USD with data from a Canadian Province and a North American institution, explanations for these findings and offers potential solutions to decrease this trend. We describe the economic impact of USD. Findings: There was a significant increase of 46% in overall surgical interventions for USD in Ontario. The incidence rose from 47.0/100,000 in 2002 to 68.7/100,000 population in 2016. In a single United States institution, the overall USD annual unique patient count rose from 10,612 to 17,706 from 2015 to 2019, and the proportion of women with USD was much higher than expected. In the 10-17-year-old patients, 50.1% were girls; with 57.5% in the 18-34 age group and 53.6% in the 35-44 age group. The roles of obesity, diet, hormones, environmental factors, infections, and antibiotics, as well as the economic impact, are discussed. Interpretation: We confirm the significant increase in USD among women. We offer potential explanations for this sex disparity, including microbiological and pathophysiological aspects. We also outline innovative solutions - that may require steps beyond typical preventive and treatment recommendations.

A population-based retrospective cohort study of surgical trends and outcomes of pediatric urolithiasis in Ontario, Canada (2002-2019).

INTRODUCTION: The worldwide incidence of pediatric urinary stone disease (PUSD) is increasing. However, there is no commensurate data on whether this translates to an increasing need for surgical intervention for PUSD, given the role of conservative management. OBJECTIVE: We aimed to evaluate the trends and outcomes of clinically significant PUSD, using administrative databases to identify patients surgically treated for PUSD. STUDY DESIGN: This retrospective population-based cohort study assessed the incidence and trends of surgically treated PUSD and outcomes in Ontario, Canada in patients <18 years of age who underwent their first PUSD procedure between 2002 and 2019 utilizing administrative databases held at the Institute of Clinical Evaluative Sciences (ICES). We assessed the incidence of surgically treated PUSD, demographics, initial surgical treatment and imaging modality, and risk factors for repeat intervention within 5 years. Statistical analyses summarized demographics, surgical trends, and logistic regression was used to identify risk factors for repeat surgical intervention. RESULTS: We identified 1149 patients (mean age 11.3 years), with 59.6% older than 12 years. There was a decrease in the number of PUSD procedures performed per year that was close to statistical significance (p = 0.059) and a trend towards increased utilization of ureteroscopy (URS) compared with Shockwave Lithotripsy (SWL). In addition, there was a significant increase in the proportion of females surgically treated with PUSD (p = 0.001). In the 706 patients followed for 5 years, 17.7% underwent a repeat procedure within 6 months, while 20.4% underwent a repeat procedure from 6-months to 5 years. Renal stone location (OR 2.79, 95% confidence interval (CI) 1.62-4.80, p = 0.0002) and index SWL (OR 1.66, 95% CI 1.20-2.31, p = 0.0025) were risk factors for repeat surgical intervention within the first 6-months. There was an increasing utilization of ultrasound (US) compared to computerized tomography (CT) (p = 0.0008). DISCUSSION: Despite the literature reporting increasing PUSD incidence, we observed a non-significant decrease in the number of surgical PUSD procedures performed. Exclusion of those treated conservatively may explain our results. The increase in the proportion of females treated reflects the narrowing gender gap in stone disease. A trend towards increased URS utilization was observed and re-intervention rates were similar to previous studies. CONCLUSION: The overall rate of surgically treated PUSD did not show an increasing trend in Ontario, Canada from 2002 to 2019. URS was the most common surgical treatment modality, with a corresponding decline in SWL rates. PUSD was associated with a high surgical re-intervention rate within 6 months.

Corrigendum: New perspectives on an old grouping: the genomic and phenotypic variability of Oxalobacter formigenes and the implications for calcium oxalate stone prevention.

[This corrects the article DOI: 10.3389/fmicb.2022.1011102.].

Vitamins as regulators of calcium-containing kidney stones - new perspectives on the role of the gut microbiome.

Calcium-based kidney stone disease is a highly prevalent and morbid condition, with an often complicated and multifactorial aetiology. An abundance of research on the role of specific vitamins (B6, C and D) in stone formation exists, but no consensus has been reached on how these vitamins influence stone disease. As a consequence of emerging research on the role of the gut microbiota in urolithiasis, previous notions on the contribution of these vitamins to urolithiasis are being reconsidered in the field, and investigation into previously overlooked vitamins (A, E and K) was expanded. Understanding how the microbiota influences host vitamin regulation could help to determine the role of vitamins in stone disease.

The Role of Urinary Modulators in the Development of Infectious Kidney Stones.

Introduction: The pathogenesis of infectious kidney stones is poorly understood. Bacteria have been implicated in promoting infectious stones via urease production; however, there is mounting evidence indicating the relationship is more complex. The aim of our study was to characterize suspected biotic and abiotic extrinsic factors that may modulate the formation of infectious stones. Materials and Methods: A high-throughput experimental model with Griffith's artificial urine was used to test a wide variety of urinary modulators and cytoplasmic enzymes present in crude cell-free extracts (CFEs) from bacterial strains to investigate how they impact struvite and calcium (Ca) phosphate crystal production. Crystal formation was evaluated with spectrophotometry and growth curve analysis. Light microscopy and scanning electron microscopy/X-ray diffraction was used for crystal structure and composition identification. Results: The acidic urinary modulators used in this study prevented crystal formation, whereas osteopontin had a significant inhibitory effect. Addition of CFEs from Proteus mirabilis 175A and 177A resulted in Ca phosphate and struvite crystals. Of interest, Klebsiella pneumoniae and Klebsiella oxytoca produced crystals including Ca phosphate and Ca oxalate, respectively. Pseudomonas aeruginosa had no urease production detected and produced Ca phosphate crystals. Discussion: Urinary modulators can have a wide variety of effects on infectious stone formation and the role of pH is important but does not guarantee robust crystal formation. Bacterial strains can produce Ca oxalate, Ca phosphate, and struvite stones with and without urease activity. Conclusion: Various urinary modulators appear to influence the process and are worthy of further evaluation as a potential therapeutic strategy to prevent infection-related urinary stone formation. Stones formed from urinary tract infections may be a result of multiple encoded metabolic pathways and discovering these would improve our understanding of the stone-bacterial relationship.

Osteopontin phosphopeptide mitigates calcium oxalate stone formation in a Drosophila melanogaster model.

Kidney stone disease affects nearly one in ten individuals and places a significant economic strain on global healthcare systems. Despite the high frequency of stones within the population, effective preventative strategies are lacking and disease prevalence continues to rise. Osteopontin (OPN) is a urinary protein that can inhibit the formation of renal calculi in vitro. However, the efficacy of OPN in vivo has yet to be determined. Using an established Drosophila melanogaster model of calcium oxalate urolithiasis, we demonstrated that a 16-residue synthetic OPN phosphopeptide effectively reduced stone burden in vivo. Oral supplementation with this peptide altered crystal morphology of calcium oxalate monohydrate (COM) in a similar manner to previous in vitro studies, and the presence of the OPN phosphopeptide during COM formation and adhesion significantly reduced crystal attachment to mammalian kidney cells. Altogether, this study is the first to show that an OPN phosphopeptide can directly mitigate calcium oxalate urolithiasis formation in vivo by modulating crystal morphology. These findings suggest that OPN supplementation is a promising therapeutic approach and may be clinically useful in the management of urolithiasis in humans.

Portable Endoscopic Simulator for Urologic Training: A Face/Content and Construct Validity Study.

Mastering a surgical skill requires experience and repetition, yet opportunities for surgical trainees to gain real experience are variable and limited by case load. Surgical simulators have emerged in an attempt to overcome these limitations. However, the few currently available skills simulators for flexible endoscopy are costly, have limited accessibility and versatility, lack portability, and require dedicated time for practice. The use of a portable skills simulator to teach flexible endoscopy may provide a feasible alternative. This study introduces a novel, low-cost, portable, endoscopic simulation system for training basic endoscopic skills. Using custom software, the simulator presents a virtual environment featuring 3D models of anatomy, endoscopes, and endoscopic tools. The virtual endoscope and its tools are directly controlled in the simulation by motion input from a custom-manufactured portable endoscopic controller that communicates data via a Bluetooth interface. This two-part study presents proof of concept and initial pilot data examining the face/content validity and preliminary construct validity of the portable endoscopic simulator. In part 1, experts (n = 2) and novices (n = 6) provided ratings of fidelity and utility as a training tool. In part 2, experts (n = 4) and novices (n = 4) completed 10 simulated sequential basic endoscopic tasks, and time to completion was assessed. Findings indicate that the simulator has good utility as a training tool, but some features require modification to be more realistic. Furthermore, both novices and experts improved on the task with repeated measurements (p < 0.001), but there were no significant differences between experts and novices in time to completion. Although more robust validation is required, this simulator appears promising as a feasible and cost-effective tool for providing simulation training on basic endoscopic skills.

The Interactive Relationship Between Instructor Perceptions and Learner Personality on Surgical Skills Performance.

OBJECTIVE: The objective of this study was to examine the association between learner personality and capacity to be trained (i.e., performance improvement) on a surgical task, and how instructor perceptions of the learners' capacity to be trained interact with learner personality and performance during training and feedback. There is meaningful heterogeneity in the degree of learner surgical skills acquisition despite receiving the same amount of training. While learner personality may independently contribute to skill acquisition, the instructor-learner feedback process is also important to consider. To better understand this interpersonal relationship, it is necessary to also consider instructor factors (i.e., perceptions), and how this may contribute to learner variability in skills training. DESIGN: This exploratory study employed a prospective two-phase design. Medical and non-medical undergraduate students (N = 62) completed measures of personality and participated in two 20-minute training sessions with expert feedback 2 weeks apart, performing an end-to-side anastomosis on a low-fidelity model. Learner performance and instructors' perceptions of a learner's capacity to be trained were assessed. PARTICIPANTS: Sixty-two medical and non-medical undergraduate students. RESULTS: There was a significant interaction between learner Extraversion and instructor's perceptions of learner capacity to be trained. Higher learner Extraversion was only associated with an increase in performance improvement for those who were considered trainable (OR = 4.83, p = 0.017). Post hoc analysis revealed a significant difference in the amount of feedback provided to participants who were considered trainable (M = 9.45) versus not trainable (M = 16.48). CONCLUSIONS: This study highlights the importance of both individual learner factors and instructor perceptions on surgical skill acquisition.

Simple prostatectomy using the open and robotic approaches for lower urinary tract symptoms: A retrospective, case-control series.

INTRODUCTION: We aimed to assess the outcome of our series of simple prostatectomy at our institution using the open simple prostatectomy (OSP) and robotic-assisted simple prostatectomy (RASP) approaches. METHODS: We conducted a retrospective chart review of men who underwent OSP and RASP at Western University, in London, ON. Preoperative, intraoperative, and postoperative data were collected and analyzed. RESULTS: From 2012-2020, 29 men underwent a simple prostatectomy at our institution. Eight patients underwent an OSP and 21 patients underwent a RASP. The median age was 69 years. Preoperative median prostate volume was 153 cm³ (range 80-432). The surgical indications were failed medical treatment, urinary retention, hydronephrosis, cystolithiasis, and recurrent hematuria. The median operative time was 137.5 minutes in OSP and 185 minutes in RASP (p=0.04). Median estimated blood loss was 2300 ml (range 600-4000) and 100 ml (range 50-400) in the open and robotic procedures, respectively (p=0.4). The mean length of hospital stay was shorter in the RASP group, one day vs. three days (z=4.152, p&lt;0.005). Perioperative complication rates were significantly lower in the group undergoing RASP, with no complications recorded in this group (p=0.004). Both groups demonstrated excellent functional results, with most patients reporting complete urinary continence (p=0.8). CONCLUSIONS: We report very good perioperative outcomes, with a minimal risk profile and excellent functional results, leading to marked improvement in patients' symptoms at followup after both the OSP and RASP approaches. RASP was associated with a shorter length of hospital stay, decreased blood loss, and a lower complication rate.

A population-based, retrospective cohort study analyzing contemporary trends in the surgical management of urinary stone disease in adults.

INTRODUCTION: We aimed to review the trends and incidence of surgical intervention for adults with upper urinary tract stones in Ontario, Canada, and to hypothesize potential causes for the observed changes. METHODS: We carried out a retrospective, population-based cohort study using administrative databases held at the Institute of Clinical Evaluative Sciences (ICES) to identify all adults (≥18 years) who underwent surgical treatment for urolithiasis, defined by records using a combination of both hospital and physician billing from 2002-2019. Descriptive statistics were used to summarize baseline patient demographics, and surgical trends were analyzed using the Cochrane-Armitage test for trend. RESULTS: From 2002-2019, 140 263 patients were treated surgically for urolithiasis. During this time period, the total number of surgically treated stone disease increased by 80.5%. By type of procedure, percutaneous nephrolithotomy (PCNL) increased by 187% and ureteroscopy (URS) increased by 158%, while the number of shockwave lithotripsy (SWL) declined by 31.4%. The adult population in Ontario in the years evaluated grew by 24.4%. The number of surgical procedures per 100 000 people over this time grew by 45.3%. For every 1% increase in the population, there was a 2.6% rise in stone-related surgical procedures. CONCLUSIONS: The number of stone-related surgical procedures performed rose significantly and cannot be accounted for by population growth alone. This rise was proportionally larger in the female population, further supporting a narrowing of the gender gap in urinary stone disease. The reasons for the increase are likely multifactorial and may imply an increasing incidence of surgically treated stone disease. The change in the proportion of URS and SWL performed may demonstrate a continued shift in surgical preference or may be reflective of resource limitations and availability. The increase in PCNL volumes may also suggest a greater complexity of cases. These findings should be considered for future resource planning and require further study.

High-Throughput in vitro Gel-Based Plate Assay to Screen for Calcium Oxalate Stone Inhibitors.

OBJECTIVE: Kidney stones are a common medical condition that is increasing in prevalence worldwide. Approximately, ∼80% of urinary calculi are composed of calcium oxalate (CaOx). There is a growing interest toward identifying therapeutic compounds that can inhibit the formation of CaOx crystals. However, some chemicals (e.g., antibiotics and bacterial metabolites) may directly promote crystallization. Current knowledge is limited regarding crystal promoters and inhibitors. Thus, we have developed an in vitro gel-based diffusion model to screen for substances that directly influence CaOx crystal formation. MATERIALS AND METHODS: We used double diffusion of sodium oxalate and calcium chloride-loaded paper disks along an agar medium to facilitate the controlled formation of monohydrate and dihydrate CaOx crystals. A third disk was used for the perpendicular diffusion of a test substance to assess its influence on CaOx crystal formation. RESULTS: We confirmed that citrates and magnesium are effective inhibitors of CaOx crystals. We also demonstrated that 2 strains of uropathogenic Escherichia coli are able to promote crystal formation. While the other tested uropathogens and most antibiotics did not change crystal formation, ampicillin was able to reduce crystallization. CONCLUSION: We have developed an inexpensive and high-throughput model to evaluate substances that influence CaOx crystallization.

New perspectives on an old grouping: The genomic and phenotypic variability of Oxalobacter formigenes and the implications for calcium oxalate stone prevention.

Oxalobacter formigenes is a unique bacterium with the ability to metabolize oxalate as a primary carbon source. Most kidney stones in humans are composed of calcium and oxalate. Therefore, supplementation with an oxalate-degrading bacterium may reduce stone burden in patients suffering from recurrent calcium oxalate-based urolithiasis. Strains of O. formigenes are divided into two groups: group I and group II. However, the differences between strains from each group remain unclear and elucidating these distinctions will provide a better understanding of their physiology and potential clinical applications. Here, genomes from multiple O. formigenes strains underwent whole genome sequencing followed by phylogenetic and functional analyses. Genetic differences suggest that the O. formigenes taxon should be divided into an additional three species: Oxalobacter aliiformigenes sp. nov, Oxalobacter paeniformigenes sp. nov, and Oxalobacter paraformigenes sp. nov. Despite the similarities in the oxalyl-CoA gene (oxc), which is essential for oxalate degradation, these strains have multiple unique genetic features that may be potential exploited for clinical use. Further investigation into the growth of these strains in a simulated fecal environment revealed that O. aliiformigenes strains are capable of thriving within the human gut microbiota. O. aliiformigenes may be a better therapeutic candidate than current group I strains (retaining the name O. formigenes), which have been previously tested and shown to be ineffective as an oral supplement to mitigate stone disease. By performing genomic analyses and identifying these novel characteristics, Oxalobacter strains better suited to mitigation of calcium oxalate-based urolithiasis may be identified in the future.

Postoperative outcomes of ureteroscopy for pediatric urolithiasis: A secondary analysis of the National Surgical Quality Improvement Program Pediatric.

INTRODUCTION: Incidence of pediatric urinary stone disease (PUSD) has increased over recent decades. Innovations in ureteroscopic technology has expanded the role of endourologic stone management in children. However, there is currently no consensus on the optimal use of ureteroscopy (URS) within the heterogenous PUSD population. OBJECTIVE: The primary objective was to investigate the rate of 30-day unplanned readmissions in pediatric patients after URS. The secondary objective was to examine the influence of demographic, perioperative, postoperative, and reoperation variables as predictors of an increased risk of unplanned readmission in this sample. STUDY DESIGN: A secondary analysis was performed on retrospectively collected data from the National Surgical Quality Improvement Program Pediatric between 2015 and 2018. Pediatric patients diagnosed with PUSD and treated with URS were identified. Patients undergoing concurrent or additional surgeries during the URS procedure were excluded. Data on demographic, perioperative, postoperative, and unplanned reoperation variables were examined for their possible influence on 30-day unplanned readmissions. Descriptive statistics were used to characterize the study cohort. Continuous and categorical variables were analyzed using independent samples t-test, one-way ANOVA with Tukey post-hoc test, and Chi-square Tests or Fisher's Exact Test, respectfully. Multivariate analysis was performed using stepwise logistic regression. RESULTS: A total of 2510 patients were identified within the study period. The majority of children undergoing URS were between 12 and 18 years of age (66.1%), female (56.9%), and had renal calculi (45.2%). Of these, 162 (6.5%) experienced a 30-day unplanned readmission related to the URS procedure. The most common reasons for an unplanned readmission was urinary tract infection (31.4%), new/unresolved stone (28.3%), and postoperative pain (8.2%). Multivariate modelling showed that females (Relative Risk [RR]: 2.03; 95% Confidence Interval [95%CI]: 1.34-3.07), patients with renal stones (RR: 1.77; 95%CI: 1.10-2.83), and inpatients at the time of surgery (RR: 1.61; 95%CI: 1.03-2.51) were more at risk of an unplanned readmission within 30-days of an URS procedure. CONCLUSION: This study reports on short-term unplanned readmission rates in pediatric patients who underwent an URS procedure. Further it highlights possible predictors of unplanned readmission rates within a sampling of patients from NSQIP affiliated institutions. The findings from this study can be used to guide future studies around the safe use of URS in pediatric patients.