Nuclear Magnetic Resonance Metabolomic Profiling and Urine Chemistries in Incident Kidney Stone Formers Compared with Controls
The results demonstrated that FUS mutations underlie a specific subtype of ALS and enable a careful stratification of newly diagnosed FUS-ALS cases for clinical course and potential therapeutic windows.
KEY FINDINGS: Although NMR-quantified metabolites did not improve discrimination, several urine metabolic profiles were identified that may improve understanding of kidney stone pathogenesis.
BACKGROUND: The urine metabolites and chemistries that contribute to kidney stone formation are not fully understood. This study examined differences between the urine metabolic and chemistries profiles of first-time stone formers and controls.
DETAILS: High-resolution 1H-nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was performed in 24-hour urine samples from a prospective cohort of 418 first-time symptomatic kidney stone formers and 440 controls. In total, 48 NMR-quantified metabolites in addition to 12 standard urine chemistries were assayed. Analysis of covariance was used to determine the association of stone former status with urine metabolites or chemistries after adjusting for age and sex and correcting for the false discovery rate. Gradient-boosted machine methods with nested cross-validation were applied to predict stone former status. Among the standard urine chemistries, stone formers had lower urine oxalate and potassium and higher urine calcium, phosphate, and creatinine. Among NMR urine metabolites, stone formers had lower hippuric acid, trigonelline, 2-furoylglycine, imidazole, and citrate and higher creatine and alanine. A cross-validated model using urine chemistries, age, and sex yielded a mean AUC of 0.76 (95% CI, 0.73 to 0.79). A cross-validated model using urine chemistries, NMR-quantified metabolites, age, and sex did not meaningfully improve the discrimination (mean AUC, 0.78; 95% CI, 0.75 to 0.81). In this combined model, among the top ten discriminating features, four were urine chemistries and six NMR-quantified metabolites.
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Source: Thongprayoon, C., Vuckovic, I., Vuckovic, L. E., et al. (2022). Nuclear Magnetic Resonance Metabolomic Profiling and Urine Chemistries in Incident Kidney Stone Formers Compared with Controls. JASN. 2022, 33(11): 2071-2086. Published: November, 2022. DOI: 10.1681/ASN.2022040416.
Relationship Between Time-Varying Achieved HbA1c and Risk of Coronary Artery Disease Events Among Common Haptoglobin Phenotype Groups with Type 2 Diabetes
The present ADVANCE analysis suggests that not having HbA1c equal to or above 8.0%, rather than achieving HbA1c less than 7.0%, was found to be particularly important for CAD prevention among people with type 2 diabetes and the common Hp2-2 phenotype. While the subgroup analyses were likely underpowered, their inclusion is hypothesis generating and can be used in future meta-analyses to improve power and generalizability.
KEY FINDINGS: The present ADVANCE analysis suggests that not having HbA1c >=8.0%, rather than achieving HbA1c <7.0%, was found to be particularly important for CAD prevention among people with type 2 diabetes and the common Hp2-2 phenotype. While the subgroup analyses were likely underpowered, their inclusion is hypothesis generating and can be used in future meta-analyses to improve power and generalizability.
BACKGROUND: This study sought to determine whether the association between attaining specific glycated hemoglobin (HbA1c) targets (<7.0% (<53 mmol/mol) and >=8.0% (>=64 mmol/mol) compared with 7.0%-7.9%) over time and risk of incident coronary artery disease (CAD) was dependent on haptoglobin (Hp) phenotype in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study.
DETAILS: Prospectively collected HbA1c data from the ADVANCE biomarker case-cohort study, updated at 6 months and every 12 months thereafter over a median of 5.0 (IQR 4.5-5.3) years, were analyzed in relation to incident CAD in the Hp2-2 (n=1323) and non-Hp2-2 (n=2069) phenotypes separately using weighted multivariable-adjusted Cox regression models. Additional a priori stratifications by sex, race, previous cardiovascular disease (CVD), and type 2 diabetes duration were performed. Mean HbA1c was similar in each phenotype group throughout the study. Compared with HbA1c of 7.0%-7.9%, HbA1c <7.0% was not associated with CAD risk for any phenotype group or subgroup. HbA1c >=8.0% compared with 7.0%-7.9% over time was associated with higher CAD risk for the Hp2-2 phenotype only (HR 1.53, 95% CI 1.01 to 2.32; no significant association in the non-Hp2-2 type: 1.26, 0.89 to 1.77, p-interaction=0.71); this was pronounced when those with previous CVD at baseline were excluded (Hp2-2: 2.80, 1.41 to 5.53, p-interaction=0.03). Compared with HbA1c of <8.0%, having HbA1c >=8.0% was associated with a 59% higher CAD risk among participants with the Hp2-2 phenotype (1.59, 1.12 to 2.26) and a 39% higher CAD risk among participants without the Hp2-2 phenotype (1.39, 1.03 to 1.88, p-interaction=0.97).
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Copyright © BMJ Publishing Group Ltd. All rights reserved.
Source: Cahill, L. E., Warren, R. A., Lavallée, S. K., et al. Relationship Between Time-Varying Achieved HbA1c and Risk of Coronary Artery Disease Events Among Common Haptoglobin Phenotype Groups With Type 2 Diabetes: The ADVANCE Study. BMJ Open Diabetes Research & Care. 2025; 13(3): e004713. Published: May 6, 2025. DOI: 10.1136/bmjdrc-2024-004713.
Continuous Glucose Monitoring with Geriatric Principles in Older Adults with Type 1 Diabetes and Hypoglycemia
In older adults with T1D and high risk of hypoglycemia, CGM use enhanced by geriatric principles can lower hypoglycemia without worsening glycemic control in a cost-effective fashion.
KEY FINDINGS: In older adults with T1D and high risk of hypoglycemia, CGM use enhanced by geriatric principles can lower hypoglycemia without worsening glycemic control in a cost-effective fashion.
BACKGROUND: Continuous glucose monitoring (CGM) use in older adults with type 1 diabetes (T1D) has shown benefits. However, the impact of CGM use, coupled with simplified treatment regimens and personalized glycemic goals that are better suited for older patients with multiple comorbidities and hypoglycemia, is not known.
DETAILS: Older adults (>=65 years) with T1D with hypoglycemia (two or more episodes of hypoglycemia [blood glucose <70 mg/dL for >=20 min over 2 weeks]) who were CGM naive or CGM users were randomized to intervention and control groups. The intervention consisted of the combined use of CGM with geriatric principles (i.e., adjusting goals based on overall health, and simplification of regimens based on CGM patterns and clinical characteristics) over 6 months. The control group received usual care by their endocrinologist. The primary end point was change in time when blood glucose was <70 mg/dL from baseline to 6 months. Cost-effectiveness was calculated using a health care sector perspective. Authors randomized 131 participants (aged 71 ± 5 years; 21% >=75 years old) to the intervention (n = 68; CGM users = 33) or the control (n = 63; CGM users = 40) group. The median change in hypoglycemia from baseline to 6 months was -2.6% in the intervention group and -0.3% in the control group (median difference, -2.3% [95% CI -3.7%, -1.3%]; P < 0.001). This improvement was seen in both CGM naive (-2.8%; 95% CI -5.6%, -0.8%) and CGM users (-1.2%; 95% CI -2.7%, -0.1%). The HbA1c did not differ between the groups (7.5% vs. 7.3%). The intervention was cost-effective (incremental cost-effectiveness ratio $71,623 per quality adjusted life-year).
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Source: Munshi, M., N., Slyne, C., Adam, A., et al. Continuous Glucose Monitoring with Geriatric Principles in Older Adults with Type 1 Diabetes and Hypoglycemia: A Randomized Controlled Trial. Diabetes Care. 2025; 48(5):694-702. Published: May, 2025. DOI: 10.2337/dc24-1069.
Interdisciplinary Care for Geriatric Syndromes in CKD
Implementing an interdisciplinary model of care that addresses geriatric syndromes in CKD is possible but will require overcoming policy-related, financial, cultural, and structural barriers. Such a model of care may ultimately benefit patients and nephrologists.
KEY FINDINGS: Implementing an interdisciplinary model of care that addresses geriatric syndromes in CKD is possible but will require overcoming policy-related, financial, cultural, and structural barriers. Such a model of care may ultimately benefit patients and nephrologists.
BACKGROUND: Despite their prevalence, prognostic significance, and prioritization by patients, key geriatric syndromes, such as cognitive impairment, frailty, and depression, are not routinely addressed in CKD care in the United States (US). In an interdisciplinary care model, health professionals with diverse expertise collaborate to address all symptoms and functional impairments occurring alongside a patient's chronic disease. Thus, routinely addressing geriatric syndromes in CKD may require implementing this evidence-based model of care and adapting it to the needs of patients with CKD. In a formative step to understanding how health systems could implement an interdisciplinary model of care to address geriatric syndromes in CKD, we interviewed health professionals around the world with relevant expertise.
DETAILS: Authors conducted a qualitative study informed by the Consolidated Framework for Implementation Research. Authors interviewed nephrologists, administrators, geriatricians, palliative medicine specialists, subspecialists, and allied health professionals working in other interdisciplinary clinics from the United States, United Kingdom, India, and Canada. Authors analyzed results using an inductive-deductive approach. Thematic saturation occurred at 42 experts. Three major domains emerged: barriers to implementation, strategies to mitigate barriers, and benefits of implementation. Barriers were categorized into overarching themes related to (1) aging-friendly policy and workforce availability, (2) organizational culture and structure, and (3) nephrologist and patient perceptions. Strategies to mitigate barriers were categorized into themes related to (1) demonstrating viability, (2) facilitating effective health communication, (3) soliciting support from administrators and clinicians, and (4) expanding the base for patient information and treatment evidence. Proposed benefits of implementation included improved shared decision making and reduced nephrologist burnout.
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Source: Subash, A.,Levinson, M., Bonnet, K., et al. (20245). Interdisciplinary Care for Geriatric Syndromes in CKD: A Qualitative Study. Clinical Journal of the American Society of Nephrology. 2025; 20(5): 652-664. Published: May, 2025. DOI: 10.2215/CJN.0000000658.
Adverse Pregnancy Outcomes and Long-Term Risk of Heart Failure in Women
In this large national cohort, women who experienced any of 5 major adverse pregnancy outcomes had increased risk for HF up to 46 years later. Women with adverse pregnancy outcomes need early preventive actions and long-term clinical care to reduce the risk of HF.
KEY FINDINGS: In this large national cohort, women who experienced any of 5 major adverse pregnancy outcomes had increased risk for HF up to 46 years later. Women with adverse pregnancy outcomes need early preventive actions and long-term clinical care to reduce the risk of HF.
BACKGROUND: Adverse pregnancy outcomes, such as preterm delivery and hypertensive disorders of pregnancy, may be associated with higher future risks of heart failure (HF). However, the comparative effects of different adverse pregnancy outcomes on long-term risk of HF, and their potential causality, are unclear. The authors sought to examine 5 major adverse pregnancy outcomes in relation to long-term risk of HF in a large population-based cohort.
DETAILS: A national cohort study was conducted of all 2,201,638 women with a singleton delivery in Sweden in 1973-2015, followed up for HF identified from nationwide outpatient and inpatient diagnoses through 2018. Cox regression was used to compute HRs for HF associated with preterm delivery, small for gestational age, preeclampsia, other hypertensive disorders of pregnancy, and gestational diabetes, while adjusting for other adverse pregnancy outcomes and maternal factors. Co-sibling analyses assessed for potential confounding by shared familial (genetic or environmental) factors. In 48 million person-years of follow-up, 667,774 women (30%) experienced an adverse pregnancy outcome, and 19,922 women (0.9%) were diagnosed with HF (median age, 61 years). All 5 adverse pregnancy outcomes were independently associated with long-term increased risk of HF. With up to 46 years of follow-up after delivery, adjusted HRs for HF associated with specific adverse pregnancy outcomes were: gestational diabetes, 2.19 (95% CI: 1.95-2.45); preterm delivery, 1.68 (95% CI: 1.61-1.75); other hypertensive disorders, 1.68 (95% CI: 1.48-1.90); preeclampsia, 1.59 (95% CI: 1.53-1.66); and small for gestational age, 1.35 (95% CI: 1.31-1.40). All HRs remained significantly elevated (1.3- to 3.0-fold) even 30 to 46 years after delivery. These findings were only partially explained by shared familial factors. Women with multiple adverse pregnancy outcomes had further increases in risk (eg, up to 46 years after delivery, adjusted HRs associated with 1, 2, or ≥3 adverse pregnancy outcomes were 1.51 [95% CI: 1.47-1.56], 2.31 [95% CI: 2.19-2.45], and 3.18 [95% CI: 2.85-3.56], respectively).
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Source: Crump, C., Crump, J., and Crump, K. (20245). Adverse Pregnancy Outcomes and Long-Term Risk of Heart Failure in Women: National Cohort and Co-Sibling Study. J Am Coll Cardiol HF.. 2025; 3(4): 589–598. Published: April, 2025. DOI: 10.1016/j.jchf.2024.11.004.
Strong Association of Autoantibodies Targeting Deamidated Extracellular Epitopes of Insulinoma Antigen-2 With Clinical Onset of Type 1 Diabetes
CD4+ T cells from patients with type 1 diabetes (T1D) have a significant response to post-translationally modified (PTM) deamidated IA-2 peptides; autoantibodies to these PTM neoepitopes remain to be identified in T1D.
KEY FINDINGS: Study results indicate that PTM and unmodified IA-2ecA are predominantly present at late stages of T1D development in patients with clinical new-onset T1D.
BACKGROUND: Increasing evidence shows that pathogenic T cells in type 1 diabetes (T1D) that may have evaded negative selection recognize post-translationally modified (PTM) epitopes of self-antigens.
DETAILS: Authors have investigated the profiles of autoantibodies specifically targeting the deamidated epitopes of insulinoma antigen-2 extracellular domain (IA-2ec) to explore their relationship with T1D development. Authors compared the characteristics of autoantibodies targeting the IA-2ec Q > E epitopes (PTM IA-2ecA) as well as those targeting the IA-2ec unmodified epitopes (IA-2ecA) in participants across different stages of T1D development and in individuals with other types of diabetes and other kinds of autoimmunity. In patients with new-onset T1D, the prevalence of PTM IA-2ecA (26.1%) was significantly higher than that of IA-2ecA (19.5%; P < 0.0001). In a longitudinal newborn cohort, both IA-2ecAs were present, but they were rare in preclinical stage 1 T1D, and with much lower positivity in individuals with stage 3 T1D who had been closely followed from birth in a clinical study compared with patients diagnosed in routine clinical settings with overt symptoms. In participants with latent autoimmune diabetes in adults, type 2 diabetes, and celiac disease autoimmunity, authors did not observe significant positivity of either IA-2ecAs.
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Source: Jia, X., Wenzlau, J. M., Zhang, C., al. (2025). Strong Association of Autoantibodies Targeting Deamidated Extracellular Epitopes of Insulinoma Antigen-2 With Clinical Onset of Type 1 Diabetes. Diabetes. 2025; 74(4): 544-553. Published: March 20, 2025. DOI: 10.2337/db24-0571.
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