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Background: The presence of vascular dysfunction is a well-recognized feature in youth with type 1 diabetes (T1D), accentuating their lifetime risk of cardiovascular events. Therapeutic strategies to mitigate vascular dysfunction are a high clinical priority. In the bromocriptine quick release T1D study (BCQR-T1D), we tested the hypothesis that BCQR would improve vascular health in youth with T1D. Methods: BCQR-T1D was a placebo-controlled, random-order, double-blinded, cross-over study investigating the cardiovascular and metabolic impact of BCQR in T1D. Adolescents in the BCQR-T1D study were randomized 1:1 to phase-1: 4 weeks of BCQR or placebo after which blood pressure and central aortic stiffness measurements by pulse wave velocity, relative area change, and distensibility from phase-contrast magnetic resonance imaging were performed. Following a 4-week washout period, phase 2 was performed in identical fashion with the alternate treatment. Results: Thirty-four adolescents (mean age 15.9±2.6 years, hemoglobin A1c 8.6±1.1%, body mass index percentile 71.4±26.1, median T1D duration 5.8 years) with T1D were enrolled and had magnetic resonance imaging data available. Compared with placebo, BCQR therapy decreased systolic (∆=−5 mmHg [95% CI, −3 to −7]; P P =0.039). BCQR reduced ascending aortic pulse wave velocity (∆=−0.4 m/s; P =0.018) and increased relative area change (∆=−2.6%, P =0.083) and distensibility (∆=0.08%/mmHg; P =0.017). In the thoraco-abdominal aorta, BCQR decreased pulse wave velocity (∆=−0.2 m/s; P =0.007) and increased distensibility (∆=0.05 %/mmHg; P =0.013). Conclusions: BCQR improved blood pressure and central and peripheral aortic stiffness and pressure hemodynamics in adolescents with T1D over 4 weeks versus placebo. BCQR may improve aortic stiffness in youth with T1D, supporting future longer-term studies.

ImportanceThere is limited evidence for therapeutic options for pediatric COVID-19 outside of multisystem inflammatory syndrome in children (MIS-C).ObjectiveTo determine whether the use of steroids within 2 days of admission for non–MIS-C COVID-19 in children is associated with hospital length of stay (LOS). The secondary objective was to determine their association with intensive care unit (ICU) LOS, inflammation, and fever defervescence.Design, Setting, and ParticipantsThis cohort study analyzed data retrospectively for children (ExposureAdministration of steroids within 2 days of admission.Main Outcomes and MeasuresLength of stay in the hospital and ICU. Adjustment for confounders was done by mixed linear regression and propensity score matching.ResultsA total of 1163 patients met inclusion criteria and had a median (IQR) age of 7 years (0.9-14.3). Almost half of all patients (601/1163, 51.7%) were male, 33.8% (392/1163) were non-Hispanic White, and 27.9% (324/1163) were Hispanic. Of the study population, 184 patients (15.8%) received steroids within 2 days of admission, and 979 (84.2%) did not receive steroids within the first 2 days. Among 1163 patients, 658 (56.5%) required respiratory support during hospitalization. Overall, patients in the steroids group were older and had greater severity of illness, and a larger proportion required respiratory and vasoactive support. On multivariable linear regression, after controlling for treatment with remdesivir within 2 days, country, race and ethnicity, obesity and comorbidity, number of abnormal inflammatory mediators, age, bacterial or viral coinfection, and disease severity according to ICU admission within first 2 days or World Health Organization ordinal scale of 4 or higher on admission, with a random intercept for the site, early steroid treatment was not significantly associated with hospital LOS (exponentiated coefficient, 0.94; 95% CI, 0.81-1.09; P = .42). Separate analyses for patients with an LOS of 2 days or longer (n = 729), those receiving respiratory support at admission (n = 286), and propensity score–matched patients also showed no significant association between steroids and LOS. Early steroid treatment was not associated with ICU LOS, fever defervescence by day 3, or normalization of inflammatory mediators.Conclusions and RelevanceSteroid treatment within 2 days of hospital admission in a heterogeneous cohort of pediatric patients hospitalized for COVID-19 without MIS-C did not have a statistically significant association with hospital LOS.

Type 2 diabetes (T2D) is a global health pandemic with significant humanitarian, economic, and societal implications, particularly for youth and young adults who are experiencing an exponential rise in incident disease. Youth-onset T2D has a more aggressive phenotype than adult-onset T2D, and this translates to important differences in rates of progression of diabetic kidney disease (DKD). We hypothesize that youth-onset DKD due to T2D may exhibit morphometric, metabolic, and molecular characteristics that are distinct from adult-onset T2D and develop secondary to inherent differences in renal energy expenditure and substrate metabolism, resulting in a central metabolic imbalance. Kidney structural changes that are evident at the onset of puberty also serve to exacerbate the organ’s baseline high rates of energy expenditure. Additionally, the physiologic state of insulin resistance seen during puberty increases the risk for kidney disease and is exacerbated by both concurrent diabetes and obesity. A metabolic mismatch in renal energetics may represent a novel target for pharmacologic intervention, both for prevention and treatment of DKD. Further investigation into the underlying molecular mechanisms resulting in DKD in youth-onset T2D using metabolomics and RNA sequencing of kidney tissue obtained at biopsy is necessary to expand our understanding of early DKD and potential targets for therapeutic intervention. Furthermore, large-scale clinical trials evaluating the duration of kidney protective effects of pharmacologic interventions that target a metabolic mismatch in kidney energy expenditure are needed to help mitigate the risk of DKD in youth-onset T2D.

The issues of fluid balance and fluid overload are currently considered crucial aspects of pediatric critically ill patients' care.This review describes current understanding of fluid management in critically ill children in terms of fluid balance and fluid overload and its effects on patients' outcomes. The review describes current evidence surrounding definitions, monitoring, and treatment of positive fluid balance. In particular, the review focuses on specific patient conditions, including perioperative cardiac surgery, severe acute respiratory failure, and extracorporeal membrane oxygenation therapy, as the ones at highest risk of developing fluid overload and poor clinical outcomes. Gaps in understanding include specific thresholds at which fluid overload occurs in all critically ill children or specific populations and optimal timing of decongestion of positive fluid balance.Current evidence on fluid balance in critically ill children is mainly based on retrospective and observational studies, and intense research should be recommended in this important field. In theory, active decongestion of patients with fluid overload could improve mortality and other clinical outcomes, but randomized trials or advanced pragmatic studies are needed to better understand the optimal timing, patient characteristics, and tools to achieve this.

Early diabetic kidney disease (DKD) is common in young persons with type 1 (T1D) and type 2 diabetes (T2D) and accentuates their lifetime risk of kidney failure, requiring dialysis or a kidney transplant. Although clinical manifestations of DKD are similar in T1D and T2D, the structural lesions may differ, and it remains unclear whether DKD in T1D and T2D represent distinct diseases. Accordingly, the objective of this study is to build machine learning (ML) models using clinical and kidney MRI data to classify diabetes status, as well as structural and functional kidney differences of individuals with T1D versus T2D. We hypothesize that a highly accurate multimodal neural network can be constructed that integrates clinical and functional kidney MRI images.Data were obtained from several studies at University of Colorado in youth with T1D (n=102), T2D (n=91) as well as non-diabetic controls (n=60). A total of 253 participants were included in the analyses. First, we applied to clinical data (CASPER, IMPROVE-T2D, CROCODILE, and RENAL-HEIR trials) logistic regression and 7 ML models: extreme gradient boosting machine (XGBoost), XGBoost with grid search, k-nearest neighbors (KNN), support vector machine (SVM), decision tree, random forest, and a 3-layer neural network (NN-EHR). When a small subset of the clinical data was used as features, the NN-EHR yielded the highest accuracy of 84%. Next, we considered the MRI images (27,000 images from the 253 individuals). We applied three convoluted NN to perform the classification: AlexNet, VGG16, and a 4-layer Neural Network for Diabetes Detection (NN4DD). Considering the images alone, VGG16 and NN4DD both achieved an accuracy of > 80%. Additionally, by integrating the clinical data and the MRI images, the fusion neural network achieved an accuracy of almost 100%. Finally, an interpretability analysis of NN4DD indicated notable differences in kidney structure and function among the three groups.Although the cost of MRI is prohibitive and thus impractical for diabetes diagnosis, these results provide a proof-of-concept that fused neural networks that integrate multimodal data can be a valuable diagnostic tool, and provide structural and functional insight on kidney differences between T1D and T2D. This research is sponsored in part by the Natural Sciences and Engineering Council (Canada) and the National Institutes of Health (USA). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Objective: Glomerular injury is a recognized complication of diabetic ketoacidosis (DKA), yet the tubular lesions are poorly understood. The aim of this prospective study was to evaluate the presence and reversibility of tubular injury during DKA in children with type 1 diabetes (T1D). Research Design and Methods: Blood and urine samples were collected from 40 children with DKA (52% boys, mean age 11 ± 4 years, venous pH7.2 ± 0.1, glucose 451 ± 163 mg/dL) at three timepoints: 0–8 and 12–24 h after starting insulin, and 3 months after discharge. Mixed-effects models evaluated the changes in tubular injury markers over time (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule 1 [KIM-1], and interleukin 18 [IL-18]). We also evaluated the relationships among the tubular injury biomarkers, copeptin, a vasopressin surrogate, and serum uric acid (SUA). Results: Serum NGAL, KIM-1, and IL-18 were highest at 0–8h (306.5 ± 45.9ng/mL, 128.9 ± 10.1pg/mL, and 564.3 ± 39.2pg/mL, respectively) and significantly decreased over 3 months (p=0.03, p=0.01, and p < 0.001, respectively). There were strong relationships among increases in copeptin and SUA and rises in tubular injury biomarkers. At 0–8h, participants with acute kidney injury (AKI) [17%] showed significantly higher concentrations of tubular injury markers, copeptin, and SUA. Conclusions: DKA was characterized by tubular injury, and the degree of injury associated with elevated copeptin and SUA. Tubular injury biomarkers, copeptin and SUA may be able to predict AKI in DKA.

BackgroundIt is well known that influenza and other respiratory viruses are wintertime-seasonal in temperate regions. However, respiratory disease seasonality in the tropics remains elusive. In this study, we aimed to characterize the seasonality of influenza-like illness (ILI) and influenza virus in Ho Chi Minh City (HCMC), Vietnam.MethodsWe monitored the daily number of ILI patients in 89 outpatient clinics from January 2010 to December 2019. We collected nasal swabs and tested for influenza from a subset of clinics from May 2012 to December 2019. We used spectral analysis to describe the periodicities in the system. We evaluated the contribution of these periodicities to predicting ILI and influenza patterns through lognormal and gamma hurdle models.FindingsDuring ten years of community surveillance, 66,799 ILI reports were collected covering 2.9 million patient visits; 2604 nasal swabs were collected 559 of which were PCR-positive for influenza virus. Both annual and nonannual cycles were detected in the ILI time series, with the annual cycle showing 8.9% lower ILI activity (95% CI: 8.8%-9.0%) from February 24 to May 15. Nonannual cycles had substantial explanatory power for ILI trends (ΔAIC = 183) compared to all annual covariates (ΔAIC = 263). Near-annual signals were observed for PCR-confirmed influenza but were not consistent along in time or across influenza (sub)types.InterpretationOur study reveals a unique pattern of respiratory disease dynamics in a tropical setting influenced by both annual and nonannual drivers. Timing of vaccination campaigns and hospital capacity planning may require a complex forecasting approach.FundingNational Institutes of Health, Wellcome Trust.

The labile β-lactam ring of penicillins and other β-lactam antibiotics is characterized by its pronounced susceptibility to various nucleophiles, acid-base reagents, oxidizing agents or even solvents like water and alcohol. However, the major pathways of β-lactams degradation are similar, leading to various breakdown products. The discovery of cephalosporin and demonstration of its improved stability in aqueous solution, as well as its enhanced in vitro activity against penicillin-resistant organisms, were major breakthroughs in the development of β-lactam antibiotics. Although cephalosporins are more stable with respect to hydrolytic degradation than penicillins, they still experience a variety of chemical and enzymatic transformations. The present study was designed to gain insight into the kinetics of cephalosporin degradation, more specifically, ceftriaxone degradation at its therapeutic concentration. As ceftriaxone is one of the most frequently used parenteral antibiotics in treating specific infections, understanding of its degradation mechanisms at the concentration administered parenterally is essential for development of formulations containing this API. Therefore, our study was focused on obtaining information on the rates and mechanisms of ceftriaxone degradation in aqueous environment at the therapeutic concentration of 20 mg/mL. The study was directed towards obtaining kinetic information on the rates and mechanisms of ceftriaxone degradation in water, a mixture of water and deuterium oxide, and deuterium oxide itself at the neutral pH (range of 6.7 to 7.6). Specific ceftriaxone degradation products were observed in aged samples prepared in the examined solvents using HPLC and MS. By comparing the degradation rates in H2O and D2O, the observation of a kinetic isotope effect (KIE) provided some valuable insight as to the nature of the initial ceftriaxone degradation. This result, in combination with an investigation of the reaction order for the degradation using the method of initial rates, highlighted the important contribution of the formation of a previously unreported dimer-type species. Computational analysis was utilized to get a molecular insight into chemical processes governing the ceftriaxone degradation and to rationalize the stabilizing effect of replacing H2O with D2O. For that purpose, molecular dynamics simulations in both explicit solvents were carried out, together with a range of mechanistic DFT calculations to obtain the underlying kinetic and thermodynamic parameters of the most prevailing reactions in solution. In doing so, focus was on two dominant processes, (i) the opening of the β-lactam ring following the hydrolytic cleavage of its C–N amide bond, and (ii) the breaking of the C–S bond linking the triazine moiety with the rest of the structure.

Objective: Type 2 diabetes (T2D) is a leading cause of end stage kidney disease (ESKD) worldwide. Recent studies suggest a more aggressive clinical course of diabetic kidney disease (DKD) in youth-onset than adult-onset T2D. We compared kidney structural lesions in youth- and adult-onset T2D to determine if youth-onset was associated with greater early tissue injury. Methods: Quantitative microscopy was performed on kidney tissue obtained from research kidney biopsies in 161 Pima Indians (117 women, 44 men) with T2D. Onset of T2D was established by serial oral glucose tolerance testing and participants were stratified as youth-onset ( Results: At biopsy, the 52 participants with youth-onset T2D were younger than the 109 with adult-onset T2D (39.1±9.9 vs. 51.4±10.2 years, pvs. 17.0±7.8 years, p=0.09). Median urine albumin-to-creatinine ratio was higher in the youth-onset group (58 [25th-75th percentile, 17-470] vs. 27 [13-73] mg/g, p=0.02). Youth-onset participants had greater glomerular basement membrane (GBM) width (552±128 nm vs. 490±114nm, p=0.002) and mesangial fractional volume (0.31±0.10 vs. 0.27±0.08, p=0.001) than adult-onset participants. Percentage glomerular sclerosis, glomerular volume, mesangial fractional volume, and GBM width were also inversely associated with age of diabetes onset as a continuous variable. Conclusion: Younger age of T2D onset strongly associates with more severe kidney structural lesions. Studies are underway to elucidate the pathways underlying these associations.

Gadolinium is a metal used in contrast agents for magnetic resonance imaging. Although gadolinium is widely used in clinical settings, many concerns regarding its toxicity and bioaccumulation after gadolinium-based contrast agent administration have been raised and published over the last decade. To date, most toxicological studies have focused on identifying acute effects following gadolinium exposure, rather than investigating associated toxicity mechanisms. In this study, we employ functional toxicogenomics to assess mechanistic interactions of gadolinium with

Background: Many low-resource settings have limited access to serum creatinine tests necessary for kidney disease identification. Among Malawian patients who are hospitalized after trauma, we evaluated the use of point-of-care saliva urea nitrogen (SUN) dipsticks to predict acute kidney injury (AKI). Methods: In a nested prospective cohort study, we enrolled hospitalized acute trauma patients aged ≥6 months to evaluate AKI (defined by KDIGO criteria) and the test characteristics of SUN to predict AKI.

Concomitant type 2 diabetes and chronic kidney disease increases the risk of heart failure. Recent studies demonstrate beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on chronic kidney disease progression and heart failure hospitalization in patients with and without diabetes. In addition to inhibiting glucose reabsorption, SGLT2 inhibitors decrease proximal tubular sodium reabsorption, possibly leading to transient natriuresis. We review the hypothesis that SGLT2 inhibitor’s natriuretic and osmotic diuretic effects mediate their cardioprotective effects. The degree to which these benefits are related to changes in sodium, independent of the kidney, is currently unknown. Aside from effects on osmotically active sodium, we explore the intriguing possibility that SGLT2 inhibitors could also modulate nonosmotic sodium storage. This alternative hypothesis is based on emerging literature that challenges the traditional 2-compartment model of sodium balance to provide support for a 3-compartment model that includes the binding of sodium to glycosaminoglycans, such as those in muscles and skin. This recent research on nonosmotic sodium storage, as well as direct cardiac effects of SGLT2 inhibitors, provides possibilities for other ways in which SGLT2 inhibitors might mitigate heart failure risk. Overall, we review the effects of SGLT2 inhibitors on sodium balance and sensitivity, cardiac tissue, interstitial fluid and plasma volume, and nonosmotic sodium storage., Lay summary SGLT2 inhibitors have cardiovascular benefits that include HF outcomes in patients with and without diabetes. Because the underlying mechanisms are only partly explained by improvements in BP, body weight, or glucose control, other mechanisms have been proposed. We focus here on a central role for effects on sodium as underlying the positive benefits of SGLT2 inhibitors in HF. We explore the new (although still unconfirmed) idea that SGLT2 inhibitors exert some of their positive effects by affecting nonosmotic sodium (ie, sodium bound to muscles and skin and not dissolved in the blood). SGLT2 inhibitors have emerged as a class of drugs, previously prescribed for patients with T2D, that have in more recent years been shown to have substantial heart and kidney clinical benefits in patients with and without T2D.The degree to which these benefits are related to kidney-independent changes in sodium homeostasis is currently unknown.A better understanding of the nonosmotic mechanisms underpinning the benefits of SGLT2 inhibition on HF (with reduced or preserved left ventricular ejection fraction) may allow researchers to assess the effects of SGLT2 inhibitors in combination with other treatments that affect sodium balance.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors lower risk of cardiovascular and kidney events in people with type 2 diabetes. In the empagliflozin in type 1 diabetes clinical program (Empagliflozin as Adjunctive to inSulin thErapy [EASE]), glycemic control, body weight, and BP improved with

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

Research indicates that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection can impact every organ, and the effects can range from asymptomatic to severe disease. Since it was first discovered in December 2019, our understanding has grown about its impact on kidney disease. In general, children have less severe disease than adults, and this tendency appears to extend to special pediatric kidney populations (e.g., chronic kidney disease and immunosuppressed patients with solid organ transplants or nephrotic syndrome). However, in a fraction of infected children, SARS-CoV2 causes an array of kidney manifestations, ranging from acute kidney injury to thrombotic microangiopathy, with potential implications for increased risk of morbidity and mortality. Additional considerations surround the propensity for clotting extracorporeal circuits in children with SARS-CoV2 infection that are receiving kidney replacement therapy. This review provides an update on our current understanding of SARS-CoV2 for pediatric nephrologists and highlights knowledge gaps to be addressed by future research during this ongoing pandemic, particularly the social disparities magnified during this period.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) and its complications are increasing worldwide. Youth-onset T2DM has been reported in all racial and ethnic groups, but Indigenous peoples and people of colour are disproportionately affected. People with youth-onset T2DM often have a more aggressive clinical course than those with adult-onset T2DM or those with type 1 diabetes mellitus. Moreover, the available treatment options for children and adolescents with T2DM are more limited than for adult patients. Intermediate complications of youth-onset T2DM, such as increased albuminuria, often develop in late childhood or early adulthood, and end-stage complications, including kidney failure, develop in mid-life. The increasing frequency, earlier onset and greater severity of childhood obesity in the past 50 years together with increasingly sedentary lifestyles and an increasing frequency of intrauterine exposure to diabetes are important drivers of the epidemic of youth-onset T2DM. The particularly high risk of the disease in historically disadvantaged populations suggests an important contribution of social and environmental factors, including limited access to high-quality health care, healthy food choices and opportunities for physical activity as well as exposure to stressors including systemic racism and environmental pollutants. Understanding the mechanisms that underlie the development and aggressive clinical course of youth-onset T2DM is key to identifying successful prevention and management strategies.

Some asymptomatic individuals carrying SARS-CoV-2 can transmit the virus and contribute to outbreaks of COVID-19. Here, we use detailed surveillance data gathered during COVID-19 resurgences in six cities of China at the beginning of 2021 to investigate the relationship between asymptomatic proportion and age. Epidemiological data obtained before mass vaccination provide valuable insights into the nature of pathogenicity of SARS-CoV-2. The data were collected by multiple rounds of city-wide PCR testing with contact tracing, where each patient was monitored for symptoms through the whole course of infection. The clinical endpoint (asymptomatic or symptomatic) for each patient was recorded (the pre-symptomatic patients were classified as symptomatic). We find that the proportion of infections that are asymptomatic declines with age (coefficient = −0.006, 95% CI: −0.008 to −0.003,p< 0.01), falling from 42% (95% CI: 6–78%) in age group 0–9 years to 11% (95% CI: 0–25%) in age group greater than 60 years. Using an age-stratified compartment model, we show that this age-dependent asymptomatic pattern, together with the distribution of cases by age, can explain most of the reported variation in asymptomatic proportions among cities. Our analysis suggests that SARS-CoV-2 surveillance strategies should take account of the variation in asymptomatic proportion with age.

ImportanceIncreasing evidence indicates that acute kidney injury (AKI) occurs frequently in children and young adults and is associated with poor short-term and long-term outcomes. Guidance is required to focus efforts related to expansion of pediatric AKI knowledge.ObjectiveTo develop expert-driven pediatric specific recommendations on needed AKI research, education, practice, and advocacy.Evidence ReviewAt the 26th Acute Disease Quality Initiative meeting conducted in November 2021 by 47 multiprofessional international experts in general pediatrics, nephrology, and critical care, the panel focused on 6 areas: (1) epidemiology; (2) diagnostics; (3) fluid overload; (4) kidney support therapies; (5) biology, pharmacology, and nutrition; and (6) education and advocacy. An objective scientific review and distillation of literature through September 2021 was performed of (1) epidemiology, (2) risk assessment and diagnosis, (3) fluid assessment, (4) kidney support and extracorporeal therapies, (5) pathobiology, nutrition, and pharmacology, and (6) education and advocacy. Using an established modified Delphi process based on existing data, workgroups derived consensus statements with recommendations.FindingsThe meeting developed 12 consensus statements and 29 research recommendations. Principal suggestions were to address gaps of knowledge by including data from varying socioeconomic groups, broadening definition of AKI phenotypes, adjudicating fluid balance by disease severity, integrating biopathology of child growth and development, and partnering with families and communities in AKI advocacy.Conclusions and RelevanceExisting evidence across observational study supports further efforts to increase knowledge related to AKI in childhood. Significant gaps of knowledge may be addressed by focused efforts.

As of early 2021, there have been over 3.5 million pediatric cases of SARS-CoV-2, including 292 pediatric deaths in the United States. Although most pediatric patients present with mild disease, they are still at risk for developing significant morbidity requiring hospitalization and intensive care unit (ICU) level of care. This study was performed to evaluate if the presence of concurrent respiratory viral infections in pediatric patients admitted to the hospital with SARS-CoV-2 was associated with an increased rate of ICU level of care.A multicenter, international, noninterventional, cross-sectional study using data provided through The Society of Critical Care Medicine Discovery Network Viral Infection and Respiratory Illness Universal Study database.The medical ward and ICU of 67 participating hospitals.Pediatric patients younger than 18 years hospitalized with SARS-CoV-2.None.A total of 922 patients were included. Among these patients, 391 required ICU level care and 31 had concurrent non-SARS-CoV-2 viral coinfection. In a multivariate analysis, after accounting for age, positive blood culture, positive sputum culture, preexisting chronic medical conditions, the presence of a viral respiratory coinfection was associated with need for ICU care (odds ratio, 3.6; 95% confidence interval, 1.6-9.4; P0.01).This study demonstrates an association between concurrent SARS-CoV-2 infection with viral respiratory coinfection and the need for ICU care. Further research is needed to identify other risk factors that can be used to derive and validate a risk-stratification tool for disease severity in pediatric patients with SARS-CoV-2.

The association between increased serum urate and hypertension has been a subject of intense controversy. Extracellular uric acid drives uric acid deposition in gout, kidney stones, and possibly vascular calcification. Mendelian randomization studies, however, indicate that serum urate is likely not the causal factor in hypertension although it does increase the risk for sudden cardiac death and diabetic vascular disease. Nevertheless, experimental evidence strongly suggests that an increase in intracellular urate is a key factor in the pathogenesis of primary hypertension. Pilot clinical trials show beneficial effect of lowering serum urate in hyperuricemic individuals who are young, hypertensive, and have preserved kidney function. Some evidence suggest that activation of the renin–angiotensin system (RAS) occurs in hyperuricemia and blocking the RAS may mimic the effects of xanthine oxidase inhibitors. A reduction in intracellular urate may be achieved by lowering serum urate concentration or by suppressing intracellular urate production with dietary measures that include reducing sugar, fructose, and salt intake. We suggest that these elements in the western diet may play a major role in the pathogenesis of primary hypertension. Studies are necessary to better define the interrelation between uric acid concentrations inside and outside the cell. In addition, large-scale clinical trials are needed to determine if extracellular and intracellular urate reduction can provide benefit hypertension and cardiometabolic disease.

The worldwide prevalence of type 2 diabetes (T2D) is steadily increasing, and it remains a challenging public health problem for populations in both developing and developed countries around the world. Despite the recent advances in novel anti-diabetic agents, diabetic kidney disease (DKD) and cardiovascular disease (CVD) remain the leading causes of morbidity and mortality in T2D. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), incretin hormones that stimulate post-prandial insulin secretion, serve as a promising avenue for treatment of T2D as they result in a variety of anti-hyperglycemic effects including increased endogenous insulin secretion, decreased gluconeogenesis, inhibition of pancreatic α-cell glucagon production, decreased pancreatic β-cell apoptosis, and increased β-cell proliferation. GLP-1RAs have also been found to delay gastric emptying, promote weight loss, increase satiety, decrease hypertension, improve dyslipidemia, reduce inflammation, improve albuminuria, induce natriuresis, improve cardiovascular function, and prevent thrombogenesis. In this review, we will present risk factors for the development of cardiac and kidney disease in individuals with T2D and discuss possible mechanisms for the cardiorenal protective effects seen with GLP-1RAs. We will also present the possibility of dual and tri-receptor agonist therapies with GLP-1, gastric inhibitory peptide, and glucagon RAs as an area of possible mechanistic synergy in the treatment of T2D and the prevention of cardiorenal complications.

Objective To develop an ethically, legally, and clinically appropriate ventilator allocation policy for AdventHealth Tampa and AdventHealth Carrollwood in Tampa, Florida, which could be enacted swiftly during the Covid-19 pandemic. Methods During Spring 2020, a subcommittee of the Medical Ethics Committee established consensus on the fundamental principles of the policy, then built on existing ethical, legal, and clinical guidance. Results The plan was finalized in May 2020. The plan triages patients based on exclusion criteria (imminent mortality), prognosis and expected benefit of ventilation (using the Sequential Organ Failure Assessment), and change in prognosis over time. Decisions are made by committee in order to minimize moral distress among individual patient care providers. Conclusions Due to international concerns about healthcare resource shortages during the Covid-19 pandemic, hospitals need allocation policies informed by the crisis standard of care, the hospital’s ethical duty to plan for an emergency, and federal civil rights laws Policy Implications: This type of policy can serve as a model for other institutions to develop crisis standards of care resource allocation policies, which are a necessary component of disaster planning.

Glomerular filtration rate (GFR) is a key measure of kidney function but often inaccurately ascertained by serum creatinine and cystatin C in pediatrics. In this pilot trial, we evaluated the relationship between GFR calculated by using phase-contrast MRI (PC-MRI) biomarkers and GFR byA total of twenty-one pediatric BMT candidates (8-21 years of age) were recruited for a research kidney PC-MRI. After completion ofThe GFR-MRI variables selected by elastic net included average heart rate during imaging (bpm), peak aorta flow below the kidney artery take-offs (ml/s), average kidney artery blood flow, average peak kidney vein blood flow, and average kidney vein blood flow (ml/s). The GFR-MRI model demonstrated strong agreement with GFR byIn this pilot study, noninvasive GFR-MRI showed strong agreement with gold standard GFR in youth scheduled for BMT. Further work is needed to evaluate whether non-contrast GFR-MRI holds promise to become a superior alternative to eGFR and GFR by clearance techniques. A higher resolution version of the Graphical abstract is available as Supplementary information.

The molecular mechanisms of SGLT2 inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometrics data were collected from research kidney biopsies donated by participants with youth onset type 2 diabetes (T2D), aged 12-21 years of age, and healthy controls (HC) to study the effects of SGLT2i on kidney transcriptomics. Participants with T2D were more obese, had higher glomerular filtration rate, mesangial and glomerular volumes than HC. There were no clinically significant differences between participants prescribed SGLT2i (T2Di(+), n=10) and other T2D (T2Di(-), n=6). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster. Transcriptional alterations in T2Di(+) compared to T2Di(-) were seen across most nephron segments, most prominently in the distal nephron. SGLT2i treatment was associated with suppression of genes in the glycolysis, gluconeogenesis, tricarboxylic acid cycle pathways in PT, but enhanced expression in thick ascending limb. The energy sensitive mTOR signaling pathway transcripts were suppressed towards HC level in all nephron segments in T2Di(+). These transcriptional changes were confirmed in a diabetes mouse model treated with SGLT2i. Therefore, the beneficial effects of SGLT2i treatment to the kidneys might be from mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling across nephron segments, including those not expressing SGLT2.

TG concentrations across lipoprotein subclasses associate with diabetic kidney disease (DKD) in adults with T1D, but little is known about this relationship in youth with T1D. We evaluated cross-sectional relationships among TG concentrations across lipoprotein subclasses, intraglomerular hemodynamics, and renal oxygen availability (RO2) in youth with T1D. Glomerular filtration rate (GFR) , RO2, renal plasma flow (RPF) , afferent arteriolar resistance (RA) , efferent arteriolar resistance (RE) , intraglomerular pressure (PGLO) , and urine albumin-to-creatinine ratio (UACR) were assessed. Concentrations of lipid constituents from lipoprotein subclasses were quantified via targeted nuclear magnetic resonance spectroscopy (Nightingale Health Ltd., Helsinki, Finland) . Particle sizes for VLDL, LDL, intermediate-density lipoprotein, and HDL were measured. Fifty youth with T1D (age 16.0 ± 3.0 years, 50% female, HbA1c 8.7 ± 1.3%, T1D duration 5.7 ± 2.6 years) and 20 without T1D were included. VLDL-TG concentrations and small LDL-TG correlated with intraglomerular hemodynamic function parameters and RO2. To conclude, strong relationships were found among renal function markers and TG concentrations across lipoprotein subclasses in adolescents with T1D. Disclosure M.E.Pauley: None. K.L.Tommerdahl: None. C.Vinovskis: None. L.Pyle: None. R.Wadwa: Advisory Panel; Dompé, Consultant; Beta Bionics, Inc., Other Relationship; Tandem Diabetes Care, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care, Inc. R.G.Nelson: None. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company. Funding MEP supported by NIH (T32DK063687) ; KLT supported by NIH (K23 HL159292) , Children’s Hospital Colorado Research Institute Research Scholar Award, University of Colorado Diabetes Research Center (P30 DK116073) , Ludeman Family Center for Women’s Health Research at the University of Colorado, and Dept of Pediatrics, Section of Endocrinology at University of Colorado School of Medicine; PB supported by NIDDK (RDK129211, R21 DK129720, K23 DK116720, UC DK114886, and P30 DK116073) , JDRF (2-SRA-2019-845-S-B, 3-SRA-2017-424-M-B, 3-SRA-2022-1097-M-B) , Boettcher Foundation, American Heart Association (20IPA35260142) , Ludeman Family Center for Women’s Health Research at the University of Colorado, Department of Pediatrics, Section of Endocrinology and Barbara Davis Center for Diabetes at University of Colorado School of Medicine

Standardization of GFR by BSA can underestimate kidney function in overweight individuals. Standardization of GFR by ECV, rather than BSA, may be a way to avoid measurement bias. Our aim was to compare the distribution and agreement of GFR measures in people with type 1 diabetes at risk of kidney disease, and to determine associations with clinical hemodynamic measures. In this exploratory analysis of the PERL clinical trial of allopurinol, the distribution and agreement of 4 measurements for GFR were compared in 542 participants with eligible data. GFR was measured using gold-standard iohexol plasma clearance procedures, and ECV was calculated using the Jødal-Bröchner-Mortensen method, which estimates ECV using results from clearance studies. GFR was standardized using ECV corrected for 14 L of fluid volume rather than 1.73 m2 of BSA. Agreement between measurements was assessed by Bland-Altman and Spearman correlation analyses. The trial primary outcome was re-analyzed using ECV-adjusted GFR. Mean age and BMI were 51±years and 29.5±6.0 kg/m2. The distribution of normalized GFR measures overlapped and agreement was strong; GFR/ECV overestimated GFR/BSA by 2.9 numerical units (mean 70.5 ml/min/14 L vs. 67.6 ml/min/1.73 m2) . Heart rate was associated with unstandardized GFR (r=-0.10, p=0.023) . Associations between diastolic blood pressure and all measures of GFR were observed (r ranged from 0.17-0.18; p-values Disclosure L.Lovblom: None. R.Pop-busui: Advisory Panel; Averitas Pharma, Inc., Boehringer Ingelheim International GmbH, Nevro Corp., Novo Nordisk, Reata Pharmaceuticals, Inc., Regenacy Pharmaceuticals, Inc. S.Polsky: Advisory Panel; Medtronic, Other Relationship; diaTribe, Research Support; Dexcom, Inc., Eli Lilly and Company, Leona M. and Harry B. Helmsley Charitable Trust, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Sanofi-Aventis U.S. A.B.Karger: Consultant; Roche Diagnostics, Research Support; Kyowa Kirin Co., Ltd., Siemens. A.Galecki: None. B.A.Perkins: Advisory Panel; Abbott Diabetes, Insulet Corporation, Sanofi, Board Member; Novo Nordisk, Other Relationship; Abbott Diabetes, Insulet Corporation, Medtronic, Novo Nordisk, Research Support; BMO Bank of Montreal, Novo Nordisk. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. S.O.Lanctot: Employee; Medtronic. D.M.Maahs: Advisory Panel; Abbott Diabetes, Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Consultant; Aditx Therapeutics, Inc., Biospex. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company. M.Mauer: None. L.Caramori: Advisory Panel; Bayer AG, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Research Support; Bayer AG, Novartis AG. S.Rosas: Advisory Panel; AstraZeneca, Teladoc Health, Other Relationship; Bayer AG, Research Support; AstraZeneca, Bayer AG. P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. K.R.Tuttle: Advisory Panel; Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Consultant; AstraZeneca, Eli Lilly and Company, Research Support; Bayer AG, Goldfinch Bio, Inc., Novo Nordisk, Travere. Funding Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171

Our objective was to compare renal hemodynamic function between obese youth with and without type 2 diabetes (T2D) and relate these measures to adipose insulin resistance (IR) . We assessed insulin sensitivity and kidney function in obese youth with (n=31, 15.8 ± 1.8 years, BMI 35.6 ± 6.6 kg/m2) , and without (n=20, 15.3 ± 2.1 years, BMI 38.2 ± 7.4 kg/m2) T2D. A hyperglycemic clamp was performed with 20% dextrose to maintain mild hyperglycemia for 240 minutes. Free fatty acids (FFA) were measured at baseline and every minutes during the steady state. FFA suppression (baseline FFA subtracted from steady state FFA) was used to estimate adipose IR. Iohexol and p-aminohippurate clearances were used to measure GFR and renal plasma flow, respectively. Renal hemodynamic parameters were calculated using Gomez equations. FFA suppression was attenuated in youth with T2D compared to obese controls (55.6% vs. 92.1%, p Youth with T2D had impaired FFA suppression compared to obese controls, indicating adipose IR. Impaired FFA suppression was associated with perturbed renal hemodynamics, indicating a potential role for adipose IR in the development of early diabetic kidney disease. Disclosure C.Platnick: None. P.V.Prasad: None. L.Li: None. L.Pyle: None. R.G.Nelson: None. D.Van raalte: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Sanofi, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Sanofi. K.J.Nadeau: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company.

There is a limited published literature reporting dose-dependent data for in vivo tumorigenesis prevalence in different organs of various rodent models after exposure to low, single doses of charged particle beams. The goal of this study is to reduce uncertainties in estimating particle-radiation-induced risk of lung tumorigenesis for manned travel into deep space by improving our understanding of the high-LET-dependent dose-response from exposure to individual ion beams after low particle doses (0.03–0.80 Gy). Female CB6F1 mice were irradiated with low single doses of either oxygen, silicon, titanium, or iron ions at various energies to cover a range of dose-averaged LET values from 0.2–193 keV/µm, using 137Cs γ-rays as the reference radiation. Sham-treated controls were included in each individual experiment totally 398 animals across the 5 studies reported. Based on power calculations, between 40–156 mice were included in each of the treatment groups. Tumor prevalence at 16 months after radiation exposure was determined and compared to the age-matched, sham-treated animals. Results indicate that lung tumor prevalence is non-linear as a function of dose with suggestions of threshold doses depending on the LET of the beams. Histopathological evaluations of the tumors showed that the majority of tumors were benign bronchioloalveolar adenomas with occasional carcinomas or lymphosarcomas which may have resulted from metastases from other sites.

Background: Global vascular dysfunction is well-recognized in youth with type 1 diabetes (T1D) , accentuating lifetime cardiovascular event risk and making therapeutic strategies to mitigate vascular dysfunction a high priority. In the BCQR-T1D study, we tested the hypothesis that BCQR, a medication used in obese adults with type 2 diabetes, would improve vascular health in T1D youth. Methods: BCQR-T1D was a placebo-controlled, random-order, double-blinded, cross-over study investigating cardiovascular and metabolic impacts of BCQR in T1D. Youth were randomized 1:1 to phase-1: 4-weeks of BCQR or placebo after which blood pressure (BP) , peripheral vascular stiffness by brachial artery distensibility (BrachD) , and central aortic stiffness by pulse wave velocity (PWV) , relative area change (RAC) and distensibility from phase-contrast MRI, were performed. Following a 4-week washout period, phase 2 was performed in identical fashion with the alternate treatment. Results: Forty-two adolescents (mean age 15.9 years, HbA1c 8.6%, BMI %ile 71.4, T1D duration 5.8 years) with T1D were enrolled. Compared to placebo, BCQR therapy decreased systolic (∆ = -5 mmHg, p Conclusions: BCQR improved BP, central and peripheral aortic stiffness and pressure hemodynamics in T1D adolescents over 4 weeks vs. placebo, even if normal weight, supporting future longer-term studies. Disclosure M.Schäfer: None. I.E.Schauer: None. K.J.Nadeau: None. L.Browne: None. U.Truong: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company. J.K.Snell-bergeon: Stock/Shareholder; GlaxoSmithKline plc. A.Baumgartner: None. K.S.Hunter: None. J.Reusch: Advisory Panel; Medtronic. A.J.Barker: None. Funding JDRF BROM QR THERP3-SRA-2015-125-M-R

Background: Describe the incidence and associated outcomes of gastrointestinal (GI) manifestations of acute coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in hospitalized children (MIS-C). Methods: Retrospective review of the Viral Infection and Respiratory Illness Universal Study registry, a prospective observational, multicenter international cohort study of hospitalized children with acute COVID-19 or MIS-C from March 2020 to November 2020. The primary outcome measure was critical COVID-19 illness. Multivariable models were performed to assess for associations of GI involvement with the primary composite outcome in the entire cohort and a subpopulation of patients with MIS-C. Secondary outcomes included prolonged hospital length of stay defined as being >75th percentile and mortality. Results: Of the 789 patients, GI involvement was present in 500 (63.3%). Critical illness occurred in 392 (49.6%), and 18 (2.3%) died. Those with GI involvement were older (median age of 8 yr), and 18.2% had an underlying GI comorbidity. GI symptoms and liver derangements were more common among patients with MIS-C. In the adjusted multivariable models, acute COVID-19 was no associated with the primary or secondary outcomes. Similarly, despite the preponderance of GI involvement in patients with MIS-C, it was also not associated with the primary or secondary outcomes. Conclusions: GI involvement is common in hospitalized children with acute COVID-19 and MIS- C. GI involvement is not associated with critical illness, hospital length of stay or mortality in acute COVID-19 or MIS-C.

BACKGROUND AND AIMS Approximately 40% of people with type 2 diabetes (T2D) develop chronic kidney disease (CKD) and, despite current treatment, T2D is the most common cause of progression to kidney failure. This situation underscores the need for additional pharmacotherapeutic options. Analyses of cardiovascular outcomes trials suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, lower albuminuria and attenuate estimated glomerular filtration rate (eGFR) decline in people with T2D. Previous analyses suggest that GLP-1RAs reduce hypoxia and inflammation and, thereby, have a mode of action on the kidneys that is distinct from other treatments, such as sodium-glucose cotransporter-2 (SGCT-2) inhibitors and renin–angiotensin–aldosterone system (RAAS) blockers. Furthermore, the primary benefit of semaglutide appears to be in people with an eGFR < 60 mL/min/1.73 m2, a group in which there is a significant residual risk of progression and a consequent unmet need for effective treatment. To gain further insights on the kidney-protective mechanism of action of semaglutide, the REMODEL trial is integrating investigative functional kidney magnetic resonance imaging (MRI) and kidney biopsies; recent developments in these techniques permit elucidation of the mechanisms underlying kidney protection with current therapies. Mechanistic findings of the REMODEL trial will complement those of the ongoing FLOW clinical trial, which is designed to evaluate clinical outcomes in people with T2D and CKD treated with once-weekly (OW) subcutaneous semaglutide. METHOD REMODEL (NCT04865770) is a 52-week, multicentre, international clinical trial (Figure 1). Primary endpoints are MRI-based and include change from baseline to week 52 in kidney oxygenation (measured with BOLD MRI R2*), global kidney perfusion (phase-contrast MRI) and kidney inflammation (T1 Mapping MRI). Secondary endpoints evaluated from kidney biopsies in a nested cohort (n ∼ 45) include change from baseline to week 52 in intrarenal mRNA expression, assessed by single-nucleus transcriptomics and glomerular basement membrane width, assessed by morphometry. Other secondary endpoints include the apparent diffusion coefficient (estimating renal fibrosis; evaluated with diffusion-weighted MRI), natriuresis, albumin excretion rate and creatinine clearance. MRI outcomes will also be evaluated at week 4 to identify potential early effects of semaglutide in the kidney. Examples of MRI and kidney biopsy single-cell gene expression profile data from participants with CKD are shown in Figure 2 (data not from REMODEL). Safety will be assessed throughout the trial. RESULTS REMODEL was initiated in April 2021 and is being conducted in Canada, France, Italy, Poland, South Africa, Spain and USA. CONCLUSION REMODEL will investigate the effect of the GLP-1RA semaglutide on inflammatory and hypoxia-related pathways in the kidney. The combination of MRI and tissue-level interrogation with biopsies will complement standard laboratory findings, enabling the identification of cells and pathways involved in kidney disease and protection. The trial will provide valuable mechanistic insights on the use of OW semaglutide in people with T2D and CKD and may stimulate the development of a precision medicine approach to the management of such individuals. In addition, REMODEL will complement the findings of the FLOW trial.

OBJECTIVES/GOALS: The goal of this study is to investigate the potential independent relationship between epicardial adipose tissue (EAT) and cardiometabolic health in youth-onset type 2 diabetes (T2D) and explore changes in EAT as a potential mediator of changes in cardiometabolic health in response to vertical sleeve gastrectomy (VSG). METHODS/STUDY POPULATION: We will assess glycemic control, insulin sensitivity and secretion in youth with T2D before and 3 months after VSG. Fasting labs, anthropometrics, and a 4-hour, frequently sampled liquid mixed meal tolerance test (45g carbohydrates, 14g fat, and 14g protein) were performed. Calculations included glucose, insulin, and GLP-1 area under the curve (AUC), Matsuda Index, HOMA-IR, and oral disposition index (DI). These cardiometabolic outcomes will then be assessed for associations between total EAT volume, measured from cardiac MRI. RESULTS/ANTICIPATED RESULTS: Previous studies have shown that individuals with obesity have higher EAT than lean controls, and adults with T2D have even higher EAT than obese controls. Therefore, we anticipate that our participants will have higher volume of EAT than what has been reported in the literature and that they will have worsening cardiometabolic outcomes without MBS. Our anticipated results will include: Weight and BMI, hemoglobin A1c, diabetes medications, Matsuda Index, HOMA-IR, DI, and glucose and insulin AUC during an MMTT. Cardiac MRI's are being analyzed and will give total EAT volume and will be analyzed for correlations with the cardiometabolic outcomes of body composition, aortic stiffness, blood pressure, cardiac structure and function, as well as lipid panel and insulin sensitivity. DISCUSSION/SIGNIFICANCE: This study is the first to specifically assess EAT in adolescents with T2D. The assessment of EAT will be done with gold-standard MRI and correlated with cardiometabolic health assessed by gold-standard methods. Together, the results will give insight into EAT as a potential independent cardiometabolic risk factor in adolescents undergoing VSG.

OBJECTIVE Insulin resistance and obesity are independently associated with type 1 diabetes (T1D) and are known risk factors for cardiovascular and kidney diseases, the leading causes of death in T1D. We evaluated the effect of BMI on cardiovascular and kidney outcomes in youth with T1D versus control youth with normal weight or obesity and youth with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Pubertal youth (n = 284) aged 12–21 years underwent assessments of resting heart rate (RHR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), leptin, hs-CRP, adiponectin, ratio of urine albumin to creatinine, and estimated glomerular filtration rate. Participants with T1D underwent bicycle ergometry for VO2peak, monitoring for peripheral brachial artery distensibility (BAD), endothelial function testing for reactive hyperemic index, and aortic MRI for central arterial stiffness or shear. RESULTS In adolescents with T1D, RHR, SBP, DBP, mean arterial pressure, leptin, hs-CRP, and hypertension prevalence were significantly higher, and BAD, descending aorta pulse wave velocity, and VO2peak lower with an obese versus normal BMI. Although hypertension prevalence and RHR were highest in obese adolescents with T1D and adiponectin lowest in youth with T2D, other measures were similar between obese adolescents with T1D and those with T2D. CONCLUSIONS Obesity, now increasingly prevalent in people with T1D, correlates with a less favorable cardiovascular and kidney risk profile, nearly approximating the phenotype of youth with T2D. Focused lifestyle management in youth-onset T1D is critically needed to reduce cardiovascular risk.