Evaluation of Genetic Associations with Clinical Phenotypes of Kidney Stone Disease.

Background and objective: Previous studies have reported a strong genetic contribution to kidney stone risk. This study aims to identify genetic associations of kidney stone disease within a large-scale electronic health record system. Methods: We performed genome-wide association studies (GWASs) for nephrolithiasis from genotyped samples of 5571 cases and 83 692 controls. This analysis included a primary GWAS focused on nephrolithiasis and subsequent subgroup GWASs stratified by stone composition types. For significant risk variants, we performed association analyses with stone composition and first-time 24-h urine parameters. To assess disease severity, we investigated the associations with age at first stone diagnosis, age at first stone-related procedure, and time between first and second stone-related procedures. Key findings and limitations: The primary GWAS analysis identified ten significant loci, all located on chromosome 16 within coding regions of the UMOD gene. The strongest signal was rs28544423 (odds ratio 1.17, 95% confidence interval 1.11-1.23, p = 2.7 × 10-9). In subgroup GWASs stratified by six kidney stone composition subtypes, 19 significant loci were identified including two loci in coding regions (brushite; NXPH1, rs79970906 and rs4725104). The UMOD single nucleotide polymorphism rs28544423 was associated with differences in 24-h excretion of urinary analytes, and the minor allele was positively associated with calcium oxalate dihydrate stone composition (p < 0.05). No associations were found between UMOD variants and disease severity. Limitations include an omitted variable bias and a misclassification bias. Conclusions and clinical implications: We replicated germline variants associated with kidney stone disease risk at UMOD and reported novel variants associated with stone composition. Genetic variants of UMOD are associated with differences in 24-h urine parameters and stone composition, but not disease severity. Patient summary: We identify genetic variants linked to kidney stone disease within an electronic health record (EHR) system. These findings suggest a role for the EHR to enable a precision-medicine approach for stone disease.

PheMIME: an interactive web app and knowledge base for phenome-wide, multi-institutional multimorbidity analysis.

OBJECTIVES: To address the need for interactive visualization tools and databases in characterizing multimorbidity patterns across different populations, we developed the Phenome-wide Multi-Institutional Multimorbidity Explorer (PheMIME). This tool leverages three large-scale EHR systems to facilitate efficient analysis and visualization of disease multimorbidity, aiming to reveal both robust and novel disease associations that are consistent across different systems and to provide insight for enhancing personalized healthcare strategies. MATERIALS AND METHODS: PheMIME integrates summary statistics from phenome-wide analyses of disease multimorbidities, utilizing data from Vanderbilt University Medical Center, Mass General Brigham, and the UK Biobank. It offers interactive and multifaceted visualizations for exploring multimorbidity. Incorporating an enhanced version of associationSubgraphs, PheMIME also enables dynamic analysis and inference of disease clusters, promoting the discovery of complex multimorbidity patterns. A case study on schizophrenia demonstrates its capability for generating interactive visualizations of multimorbidity networks within and across multiple systems. Additionally, PheMIME supports diverse multimorbidity-based discoveries, detailed further in online case studies. RESULTS: The PheMIME is accessible at https://prod.tbilab.org/PheMIME/. A comprehensive tutorial and multiple case studies for demonstration are available at https://prod.tbilab.org/PheMIME_supplementary_materials/. The source code can be downloaded from https://github.com/tbilab/PheMIME. DISCUSSION: PheMIME represents a significant advancement in medical informatics, offering an efficient solution for accessing, analyzing, and interpreting the complex and noisy real-world patient data in electronic health records. CONCLUSION: PheMIME provides an extensive multimorbidity knowledge base that consolidates data from three EHR systems, and it is a novel interactive tool designed to analyze and visualize multimorbidities across multiple EHR datasets. It stands out as the first of its kind to offer extensive multimorbidity knowledge integration with substantial support for efficient online analysis and interactive visualization.

Diversity, Equity, and Inclusion in Urolithiasis Clinical Trials: Representative Enrollment by Race, Ethnicity, and Sex.

INTRODUCTION: We sought to assess whether participant enrollment is appropriately representative of the overall urolithiasis population in published urolithiasis clinical trials. METHODS: PubMed was queried for urolithiasis US clinical trials published from 2000 to 2022. Trials were evaluated for reporting patient race/ethnicity and sex data. These were then compared to the stone prevalence reported by the National Health and Nutrition Examination Survey from 2015 to 2018. We calculated a representation quotient (RQ) to describe enrollment of patients and then stratified by geographic location, study type, and funding source. RESULTS: Of the 180 urolithiasis trials performed in the US, we identified 40 trials (22%) reporting race or ethnicity and 104 trials (58%) reporting sex. Male and female participants are well represented (RQ 0.97 and 1.02, respectively). Overall, the RQ of Black, Asian American and Pacific Islander, White, Hispanic, and mixed/other participants is 1.84, 1.06, 1.04, 0.46, and 0.34, respectively. Trials completed in the Western Section and multi-institutional trials have the most proportional enrollment, while trials in the South Central and Southeastern Sections have underrepresentation of mixed/other and Hispanic patients. Enrollment was similar among all trial subtypes. Government- and industry-funded trials had more diverse enrollment than academic-funded trials. CONCLUSIONS: Only 1 in 4 published US urolithiasis trials report race or ethnicity enrollment. Mixed race and Hispanic participants are consistently underrepresented, while Black participants are overrepresented. Government- and industry-sponsored multi-institutional trials have the most proportional representation. Investigators should prioritize inclusive recruitment and improve reporting practices to accurately reflect the diversity of the urolithiasis population.

Interoperability of phenome-wide multimorbidity patterns: a comparative study of two large-scale EHR systems.

Background: Electronic health records (EHR) are increasingly used for studying multimorbidities. However, concerns about accuracy, completeness, and EHRs being primarily designed for billing and administrative purposes raise questions about the consistency and reproducibility of EHR-based multimorbidity research. Methods: Utilizing phecodes to represent the disease phenome, we analyzed pairwise comorbidity strengths using a dual logistic regression approach and constructed multimorbidity as an undirected weighted graph. We assessed the consistency of the multimorbidity networks within and between two major EHR systems at local (nodes and edges), meso (neighboring patterns), and global (network statistics) scales. We present case studies to identify disease clusters and uncover clinically interpretable disease relationships. We provide an interactive web tool and a knowledge base combining data from multiple sources for online multimorbidity analysis. Findings: Analyzing data from 500,000 patients across Vanderbilt University Medical Center and Mass General Brigham health systems, we observed a strong correlation in disease frequencies (Kendall's τ = 0.643) and comorbidity strengths (Pearson ρ = 0.79). Consistent network statistics across EHRs suggest similar structures of multimorbidity networks at various scales. Comorbidity strengths and similarities of multimorbidity connection patterns align with the disease genetic correlations. Graph-theoretic analyses revealed a consistent core-periphery structure, implying efficient network clustering through threshold graph construction. Using hydronephrosis as a case study, we demonstrated the network's ability to uncover clinically relevant disease relationships and provide novel insights. Interpretation: Our findings demonstrate the robustness of large-scale EHR data for studying phenome-wide multimorbidities. The alignment of multimorbidity patterns with genetic data suggests the potential utility for uncovering shared biology of diseases. The consistent core-periphery structure offers analytical insights to discover complex disease interactions. This work also sets the stage for advanced disease modeling, with implications for precision medicine. Funding: VUMC Biostatistics Development Award, the National Institutes of Health, and the VA CSRD.

Real-World Effectiveness of Preventive Pharmacological Therapy in Patients With Urolithiasis: A Retrospective Cohort Study.

RATIONALE & OBJECTIVE: Data supporting the efficacy of preventive pharmacological therapy (PPT) to reduce urolithiasis recurrence are based on clinical trials with composite outcomes that incorporate imaging findings and have uncertain clinical significance. This study evaluated whether the use of PPT leads to fewer symptomatic stone events. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Medicare enrollees with urolithiasis who completed 24-hour urine collections that revealed hypercalciuria, hypocitraturia, low urine pH, or hyperuricosuria. EXPOSURE: PPT (thiazide diuretics for hypercalciuria, alkali for hypocitraturia or low urine pH, or uric acid lowering drugs for hyperuricosuria) categorized as (1) adherent to guideline-concordant PPT, (2) nonadherent to guideline-concordant PPT, or (3) untreated. OUTCOME: Symptomatic stone event occurrence (emergency department [ED] visit or hospitalization for urolithiasis or stone-directed surgery). ANALYTICAL APPROACH: Cox proportional hazards regression. RESULTS: Among 13,942 patients, 31.0% were prescribed PPT. Compared with no treatment, concordant/adherent PPT use was associated with a significantly lower hazard of symptomatic stone events for patients with hypercalciuria (HR, 0.736 [95% CI, 0.593-0.915]) and low urine pH (HR, 0.804 [95% CI, 0.650-0.996]) but not for patients with hypocitraturia or hyperuricosuria. These associations were largely driven by significantly lower rates of ED visits after initiating PPT among the concordant/adherent group versus untreated patients. Patients with hypercalciuria had adjusted 2-year predicted probabilities of a visit of 3.8% [95% CI, 2.5%-5.2%%] and 6.9% [95% CI, 6.0%-7.7%] for the concordant/adherent PPT and no-treatment groups, respectively. Among patients with low urine pH, these probabilities were 4.3% (95% CI, 2.9%-5.7%) and 7.3% (95% CI, 6.5%-8.0%) for the concordant/adherent PPT and no-treatment groups, respectively. LIMITATIONS: Potential bias from the possibility that patients prescribed PPT had more severe disease than untreated patients. CONCLUSIONS: Patients with urolithiasis and hypercalciuria who were adherent to treatment with thiazide diuretics as well as those with low urine pH adherent to prescribed alkali therapy had fewer symptomatic stone events than untreated patients. PLAIN-LANGUAGE SUMMARY: Despite multiple clinical trials demonstrating the efficacy of thiazide diuretics and alkali for secondary prevention of kidney stones, they are infrequently prescribed due in part to a lack of data about their effectiveness in real-world settings. We analyzed medical claims from older adults with kidney stones for whom urine chemistry data were available. We found that patients who took prescribed thiazide diuretics for elevated urine calcium levels or alkali for low urinary pH were less likely to experience symptomatic stone recurrences than untreated patients. This benefit was expressed as lower rates of emergency department visits after initiating therapy. Our findings should inform the prescription of and adherence to treatment with thiazide diuretics and alkali for the prevention of recurrent kidney stones.

Surgeon, and Institution Characteristics Associated Surgical Preferences in the Pediatric KIDney Stone Care Improvement Network.

OBJECTIVE: To reveal barriers and opportunities to implement evidence for the management of pediatric kidney stone disease, we determined surgeon and institutional factors associated with preferences for the type of surgical intervention for kidney and ureteral stones. METHODS: We conducted a cross-sectional study of urologists participating in the Pediatric KIDney Stone Care Improvement Network (PKIDS) trial. Questionnaires ascertained strengths of urologists' preferences for types of surgery as well as characteristics of participating urologists and institutions. The outcome was the strength of preferences for ureteroscopy, shockwave lithotripsy, and percutaneous nephrolithotomy for four scenarios for which two alternative procedures are recommended by the AUA guidelines: (1) 2 cm kidney stone, (2) 9 mm proximal ureteral stone, (3) 1.5 cm lower pole kidney stone, (4) 1 cm nonlower pole kidney stone. Principal component analysis was performed to identify unique clusters of factors that explain surgical preferences. RESULTS: One hundred forty-eight urologists at 29 sites completed surveys. Stated preferences were highly skewed except for the choice between ureteroscopy and percutaneous nephrolithotomy for a 1.5 cm kidney stone. Shockwave lithotripsy ownership and local practice patterns most frequently associated with the strength of surgeons' preferences for the type of surgery. Principal component analysis revealed that three clusters of stone, patient, and heterogenous characteristics explained 30% of the variance in preferences. CONCLUSION: There is wide variation in the strengths of preferences for surgical interventions supported by current guidelines that are partially explained by surgeon and institutional characteristics. These results reveal opportunities to develop strategies for guidelines that consider real-world drivers of care.

Preventive Pharmacological Therapy and Risk of Recurrent Urinary Stone Disease.

BACKGROUND: Urinary stone disease is a prevalent condition associated with a high recurrence risk. Preventive pharmacological therapy has been proposed to reduce recurrent stone episodes. However, limited evidence exists regarding its effectiveness, contributing to its underutilization by physicians. This study aimed to evaluate the association between preventive pharmacological therapy (thiazide diuretics, alkali therapy, and uric acid-lowering medications) and clinically significant urinary stone disease recurrence. METHODS: Using data from the Veterans Health Administration, adults with an index episode of urinary stone disease from 2012 through 2019 and at least one urinary abnormality (hypercalciuria, hypocitraturia, or hyperuricosuria) on 24-hour urine collection were included. The primary outcome was a composite variable representing recurrent stone events that resulted in emergency department visits, hospitalizations, or surgery for urinary stone disease. Cox proportional hazards regression was performed to estimate the association between preventive pharmacological therapy use and recurrent urinary stone disease while adjusting for relevant baseline patient characteristics. RESULTS: Among the cohort of patients with urinary abnormalities ( n =5637), treatment with preventive pharmacological therapy was associated with a significant 19% lower risk of recurrent urinary stone disease during the 12-36-month period after the initial urine collection (hazard ratio, 0.81; 95% confidence interval, 0.65 to 1.00; P = 0.0496). However, the effectiveness of preventive pharmacological therapy diminished over longer follow-up periods (12-48 and 12-60 months after the urine collection) and did not reach statistical significance. When examining specific urinary abnormalities, only alkali therapy for hypocitraturia was associated with a significant 26% lower recurrence risk within the 12-36-month timeframe (hazard ratio, 0.74; 95% confidence interval, 0.56 to 0.97; P = 0.03). CONCLUSIONS: When considering all urinary abnormalities together, this study demonstrates that the use of preventive pharmacological therapy is associated with a lower risk of clinically significant recurrent episodes of urinary stone disease in the 12-36 month timeframe after urine collection, although only the association with the use of alkali therapy for hypocitraturia was significant when individual abnormalities were examined.

Evaluation of genetic associations with clinical phenotypes of kidney stone disease.

Introduction and Objective: We sought to replicate and discover genetic associations of kidney stone disease within a large-scale electronic health record (EHR) system. Methods: We performed genome-wide association studies (GWASs) for nephrolithiasis from genotyped samples of 5,571 cases and 83,692 controls. Among the significant risk variants, we performed association analyses of stone composition and first-time 24-hour urine parameters. To assess disease severity, we investigated the associations of risk variants with age at first stone diagnosis, age at first procedure, and time from first to second procedure. Results: The main GWAS analysis identified 10 significant loci, each located on chromosome 16 within coding regions of the UMOD gene, which codes for uromodulin, a urine protein with inhibitory activity for calcium crystallization. The strongest signal was from SNP 16:20359633-C-T (odds ratio [OR] 1.17, 95% CI 1.11-1.23), with the remaining significant SNPs having similar effect sizes. In subgroup GWASs by stone composition, 19 significant loci were identified, of which two loci were located in coding regions (brushite; NXPH1 , rs79970906 and rs4725104). The UMOD SNP 16:20359633-C-T was associated with differences in 24-hour excretion of urinary calcium, uric acid, phosphorus, sulfate; and the minor allele was positively associated with calcium oxalate dihydrate stone composition (p<0.05). No associations were found between UMOD variants and disease severity. Conclusions: We replicated germline variants associated with kidney stone disease risk at UMOD and reported novel variants associated with stone composition. Genetic variants of UMOD are associated with differences in 24-hour urine parameters and stone composition, but not disease severity.

Comparison of Class-Specific Side Effects Across Preventative Pharmacologic Therapies for Kidney Stone Disease.

INTRODUCTION: Clinical guidelines recommend monitoring for metabolic derangements while on preventive pharmacologic therapy for kidney stone disease. The study objective was to compare the frequency of side effects among patients receiving alkali citrate, thiazides, and allopurinol. METHODS: Using claims data from working-age adults with kidney stone disease (2008-2019), we identified those with a new prescription for alkali citrate, thiazide, or allopurinol within 12 months after their index stone-related diagnosis or procedure. We fit multivariable logistic regression models, adjusting for cohort characteristics like comorbid illness and medication adherence, to estimate 2-year measured frequencies of claims-based outcomes of acute kidney injury, falls/hip fracture, gastritis, abnormal liver function tests/hepatitis, hypercalcemia, hyperglycemia/diabetes, hyperkalemia, hypokalemia, hyponatremia, and hypotension. RESULTS: Our cohort consisted of 1776 (34%), 2767 (53%), and 677 (13%) patients prescribed alkali citrate, thiazides, or allopurinol, respectively. Comparing unadjusted rates of incident diagnoses, thiazides compared to alkali citrate and allopurinol were associated with the highest rates of hypercalcemia (2.3% vs 1.5% and 1.0%, respectively, P = .04), hypokalemia (6% vs 3% and 2%, respectively, P < .01), and hyperglycemia/diabetes (17% vs 11% and 16%, respectively, P < .01). No other differences with the other outcomes were significant. In adjusted analyses, compared to alkali citrate, thiazides were associated with a higher odds of hypokalemia (OR=2.01, 95% CI 1.44-2.81) and hyperglycemia/diabetes (OR=1.52, 95% CI 1.26-1.83), while allopurinol was associated with a higher odds of hyperglycemia/diabetes (OR=1.34, 95% CI 1.02-1.75). CONCLUSIONS: These data provide evidence to support clinical guidelines that recommend periodic serum testing to assess for adverse effects from preventive pharmacologic therapy.

Prospective Multicenter Evaluation of Pain Before and After Removal of Nonobstructing Renal Calculi: A CoRE Initiative.

PURPOSE: Flank pain associated with stone disease is typically caused by a stone that obstructs urine flow. However, it is plausible that nonobstructing kidney stones may still cause pain. We performed a multicenter, observational trial to evaluate whether treatment of small nonobstructing calyceal stones improves pain and kidney stone-specific health-related quality of life. MATERIALS AND METHODS: Patients aged 18 years or older with nonobstructing renal stone(s) up to 10 mm in longest diameter and moderate to severe pain were recruited. All participants completed 3 questionnaires: the Brief Pain Inventory (BPI), the Patient-Reported Outcomes Measurement Information System pain interference form 6a, and the Wisconsin Stone Quality of Life questionnaire. Thereafter, all participants underwent ureteroscopy for renal stone treatment. All 3 questionnaires were repeated at 2, 6 to 8, and at 12 weeks postprocedure. The primary outcomes were change in preoperative to 12-week postoperative mean BPI score and worst BPI pain score. RESULTS: A total of 43 patients with nonobstructing kidney stones and associated flank pain were recruited. All stones were removed. Preoperatively, BPI scores for mean pain and worst pain were 5.5 and 7.2, respectively which decreased to 1.8 and 2.8 respectively at 12 weeks postoperatively. Wisconsin Stone Quality of Life questionnaire mean score increased from 70.4 to 115.3 at 12 weeks postoperatively. A total of 86% and 69% of patients had at least a 20% and 50% reduction in their mean pain scores, respectively. CONCLUSIONS: This study determined that patients benefit significantly from the removal of calyceal nonobstructing kidney stones for at least 12 weeks with a reduction in pain and an increase in quality of life. Therefore, surgical removal of these stones in this patient population should be offered as a treatment option.