DNA methylation signatures of youth-onset type 2 diabetes and exposure to maternal diabetes.

OBJECTIVE: Youth-onset type 2 diabetes (T2D) is physiologically distinct from adult-onset, but it is not clear how the two diseases differ at a molecular level. In utero exposure to maternal type 2 diabetes (T2D) is known to be a specific risk factor for youth-onset T2D. DNA methylation (DNAm) changes associated with T2D but which differ between youth- and adult-onset might delineate the impacts of T2D development at different ages and could also determine the contribution of exposure to in utero diabetes. METHODS: We performed an epigenome-wide analysis of DNAm on whole blood from 218 youth with T2D and 77 normoglycemic controls from the iCARE (improving renal Complications in Adolescents with type 2 diabetes through REsearch) cohort. Associations were tested using multiple linear regression models while adjusting for maternal diabetes, sex, age, BMI, smoking status, second-hand smoking exposure, cell-type proportions and genetic ancestry. RESULTS: We identified 3830 differentially methylated sites associated with youth T2D onset, of which 3794 were moderately (adjusted p-value < 0.05 and effect size estimate > 0.01) associated and 36 were strongly (adjusted p-value < 0.05 and effect size estimate > 0.05) associated. A total of 3725 of these sites were not previously reported in the EWAS Atlas as associated with T2D, adult obesity or youth obesity. Moreover, three CpGs associated with youth-onset T2D in the PFKFB3 gene were also associated with maternal T2D exposure (FDR < 0.05 and effect size > 0.01). This is the first study to link PFKFB3 and T2D in youth. CONCLUSION: Our findings support that T2D in youth has different impacts on DNAm than adult-onset, and suggests that changes in DNAm could provide an important link between in utero exposure to maternal diabetes and the onset of T2D.

Sex differences in kidney metabolism may reflect sex-dependent outcomes in human diabetic kidney disease.

Diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and progresses faster in males than in females. We identify sex-based differences in kidney metabolism and in the blood metabolome of male and female individuals with diabetes. Primary human proximal tubular epithelial cells (PTECs) from healthy males displayed increased mitochondrial respiration, oxidative stress, apoptosis, and greater injury when exposed to high glucose compared with PTECs from healthy females. Male human PTECs showed increased glucose and glutamine fluxes to the TCA cycle, whereas female human PTECs showed increased pyruvate content. The male human PTEC phenotype was enhanced by dihydrotestosterone and mediated by the transcription factor HNF4A and histone demethylase KDM6A. In mice where sex chromosomes either matched or did not match gonadal sex, male gonadal sex contributed to the kidney metabolism differences between males and females. A blood metabolomics analysis in a cohort of adolescents with or without diabetes showed increased TCA cycle metabolites in males. In a second cohort of adults with diabetes, females without DKD had higher serum pyruvate concentrations than did males with or without DKD. Serum pyruvate concentrations positively correlated with the estimated glomerular filtration rate, a measure of kidney function, and negatively correlated with all-cause mortality in this cohort. In a third cohort of adults with CKD, male sex and diabetes were associated with increased plasma TCA cycle metabolites, which correlated with all-cause mortality. These findings suggest that differences in male and female kidney metabolism may contribute to sex-dependent outcomes in DKD.

24-h ambulatory blood pressure readings and associations with albuminuria in youth with type 2 diabetes: A cross sectional analysis from the iCARE cohort.

AIMS: To evaluate associations between 24-h ambulatory blood pressure monitor (ABPM) data vs. single casual blood pressure (BP) and albuminuria in youth with type 2 diabetes. METHODS: A cross-sectional analysis of youth with type 2 diabetes 10-<18 yrs. from the iCARE cohort. MAIN EXPOSURES: daytime HTN (+/- nocturnal), isolated nocturnal HTN and single casual BP. MAIN OUTCOME: non-orthostatic urine albumin: creatinine ratio (ACR) ≥ 3 mg/mmol and log-transformed urine ACR. Regressions evaluated associations between 1. HTN status based on ABPM and log-transformed urine ACR (continuous) and 2. ABPM-derived BP z-scores and casual BPcentiles and albuminuria status (categorical). RESULTS: Of 281 youth included, 19.6 % had daytime HTN (+/- nocturnal), and 28.5 % isolated nocturnal HTN on 24-h ABPM. In multivariate linear regression, HTN (ABPM) (ß = 0.553; p = 0.001), duration of diabetes (ß = 0.857; p = 0.02), HbA1c (ß = 1.172; p ≤0.0001) and ACEI/ARB use (ß = 3.94; p < 0.0001) were positively associated with log-transformed ACR; (R2 = 0.184). In logistic regression analysis, all ABPM LMS z-scores were positively associated with albuminuria; casual BPcentile was not significant. CONCLUSIONS: Youth with type 2 diabetes have high rates of HTN based on 24-ABPM data. ABPM-derived measures of BP are associated with albuminuria. These data support the routine use of ABPM devices to diagnose hypertension in youth with type 2 diabetes.

An analysis of sex differences and socioeconomic deprivation among Canadian children with high blood pressure: a retrospective, cross-sectional study.

BACKGROUND: Understanding which children are at highest risk for high blood pressure (HBP) can inform surveillance and treatment. This study evaluated sex differences in childhood HBP and its associations with socioeconomic status. METHODS: This retrospective cross-sectional study assessed 74,233 children with data from a national primary care electronic medical record database. Differences between sex and material and social deprivation scores for children with and without HBP were examined. Covariates included age, BMI z-score, diabetes, hyperlipidemia, and depression. HBP was defined as > 90th percentile for < 13-year-olds, and ≥ 120/80 for age ≥ 13 years on 2 separate occasions between 2010 and 2017. RESULTS: The prevalence of HBP was 10.2% in males and 7.6% in females (p < 0.0001). Children with HBP had higher BMI z-scores (0.66 vs. 0.18, p < 0.0001), and higher rates of diabetes (1.31 vs. 0.54%, p < 0.0001), depression (9.89 vs. 7.11%, p < 0.0001), and hyperlipidemia (2.82 vs. 0.86%, p < 0.0001). In univariate regression analyses, boys in the most materially deprived quintile had increased odds of HBP (OR 1.24 (95% CI 1.08-1.43)), whereas females did not (OR 1.11 (95% CI 0.95-1.29)). In multivariate regression, male sex was associated with HBP with adjusted OR of 1.39 (95% CI 1.24-1.55). After statistical adjustment, material deprivation was no longer significant (aOR 1.05, 95% CI 0.94-1.17). CONCLUSIONS: Male sex is associated with HBP in Canadian children. This study also suggests a possible association between material deprivation and HBP, particularly in boys. Further study is required to better understand this relationship. A higher resolution version of the Graphical abstract is available as Supplementary information.

Youth-onset type 2 diabetes mellitus: an urgent challenge.

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.

Integrative analysis reveals novel associations between DNA methylation and the serum metabolome of adolescents with type 2 diabetes: A cross-sectional study.

Objective: Rates of type 2 diabetes (T2D) among adolescents are on the rise. Epigenetic changes could be associated with the metabolic alterations in adolescents with T2D. Methods: We performed a cross sectional integrated analysis of DNA methylation data from peripheral blood mononuclear cells with serum metabolomic data from First Nation adolescents with T2D and controls participating in the Improving Renal Complications in Adolescents with type 2 diabetes through Research (iCARE) cohort study, to explore the molecular changes in adolescents with T2D. Results: Our analysis showed that 43 serum metabolites and 36 differentially methylated regions (DMR) were associated with T2D. Several DMRs were located near the transcriptional start site of genes with established roles in metabolic disease and associated with altered serum metabolites (e.g. glucose, leucine, and gamma-glutamylisoleucine). These included the free fatty acid receptor-1 (FFAR1), upstream transcription factor-2 (USF2), and tumor necrosis factor-related protein-9 (C1QTNF9), among others. Conclusions: We identified DMRs and metabolites that merit further investigation to determine their significance in controlling gene expression and metabolism which could define T2D risk in adolescents.

Poor Sleep, Increased Stress and Metabolic Comorbidity in Adolescents and Youth With Type 2 Diabetes.

OBJECTIVES: The impacts of stress and disrupted sleep on type 2 diabetes management and related comorbidities in adolescents and youth remain unknown. In this study, we examine sleep in adolescents and youth living with type 2 diabetes and matched controls and its association with stress, glycemic management, albuminuria and hypertension. METHODS: A cross-sectional analysis was conducted to assess the relationship between sleep quality (Pittsburgh Sleep Quality Index [PSQI]) and stress (Perceived Stress Scale-14 [PSS-14] and Kessler Psychological Distress Scale [K6]) with metabolic control within a cohort of male and female adolescents and youth (10 to 23 years old) with type 2 diabetes and weight- and ethnicity-matched controls. RESULTS: One hundred eighty-one adolescents and youth with type 2 diabetes (15.0±2.44 years of age, body mass index z score [BMIz] 1.85±0.60, 62.5% female) and 52 controls (16±2.9 years, BMIz 1.99±0.58, 61.5% female) were included in the investigation. Participants slept for an average of 8.38 hours per night, and 49% of individuals with type 2 diabetes and 46% of controls rated their sleep quality as "poor." No sex differences were seen for sleep scores (p=0.13), but females reported higher stress (p=0.001) and distress (p=0.03). No differences in glycated hemoglobin (p=0.11), BMIz (p=0.28), hypertension (p=0.24) or albuminuria (p=0.79) were seen in individuals reporting good vs poor sleep. Regression analysis showed that poor sleep was associated with higher glycated hemoglobin (p=0.029). CONCLUSIONS: Many adolescents and youth reported poor sleep, which was associated with stress, distress and worse glycemic management. Differences were observed between sexes. The long-term effects of poor sleep and psychological distress warrant further study.

Development of a patient-reported outcome measure for the assessment of symptom burden in pediatric chronic kidney disease (PRO-Kid).

BACKGROUND: Chronic kidney disease (CKD) and kidney failure in childhood are associated with significant and life-altering morbidities and lower quality of life. Emerging evidence suggests that management should be guided in part by symptom burden; however, there is currently no standardized assessment tool for quantifying symptom burden in this pediatric population. This study aimed to develop and refine a patient-reported symptom assessment tool for children with CKD/kidney failure (PRO-Kid), to evaluate the frequency and impact of symptoms. METHODS: This was a prospective observational study of children and caregivers of children with CKD/kidney failure at two Canadian pediatric care centers. Building on previously published patient-reported outcome measures (PROs) for the assessment of symptom burden in other populations, we drafted a 13-item questionnaire. Cognitive interviews were performed with children and caregivers of children with CKD/kidney failure to iteratively refine the questionnaire. RESULTS: Twenty-four participants completed cognitive interviewing (11 children, 13 caregivers). The most common symptoms endorsed were feeling left out, feeling sad/depressed, inability to focus, tiredness, nausea, vomiting, not wanting to eat, and changes in the taste of food. Feeling left out was added to the questionnaire as almost all participants voiced this as a frequent and impactful symptom, resulting in a 14-item questionnaire. CONCLUSIONS: PRO-Kid is the first pediatric CKD/kidney failure-specific PRO tool to assess symptom burden. Future work should validate this tool in a larger cohort so that it may be used to improve the care of children living with CKD/kidney failure. A higher resolution version of the Graphical abstract is available as Supplementary information.

Impact of a screen, triage and treat program for identifying chronic disease risk in Indigenous children.

BACKGROUND: The First Nations Community Based Screening to Improve Kidney Health and Prevent Dialysis project was a point-of-care screening program in rural and remote First Nations communities in Manitoba that aimed to identify and treat hypertension, diabetes and chronic kidney disease. The program identified chronic disease in 20% of children screened. We aimed to characterize clinical screening practices before and after intervention in children aged 10-17 years old and compare outcomes with those who did not receive the intervention. METHODS: This observational, prospective cohort study started with community engagement and followed the principles of ownership, control, access and possession (OCAP). We linked participant data to administrative data at the Manitoba Centre for Health Policy to assess rates of primary care and nephrology visits, disease-modifying medication prescriptions and laboratory testing (i.e., glycosylated hemoglobin [HbA1c], estimated glomerural filtration rate [eGFR] and urine albumin- or protein-to-creatinine ratio). We analyzed the differences in proportions in the 18 months before and after the intervention. We also conducted a 1:2 propensity score matching analysis to compare outcomes of children who were screened with those who were not. RESULTS: We included 324 of 353 children from the screening program (43.8% male; median age 12.3 yr) in this study. After the intervention, laboratory testing increased by 5.8% (95% confidence interval [CI] 1.1% to 10.1%) for HbA1c, by 9.9% (95% CI 4.2% to 15.5%) for eGFR and by 6.2% (95% CI 2.3% to 10.0%) for the urine albumin- or protein-to-creatinine ratio. We observed significant improvements in laboratory testing in screened patients in the group who were part of the program, compared with matched controls. INTERPRETATION: Chronic disease surveillance and care increased significantly in children after the implementation of a point-of-care screening program in rural and remote First Nation communities. Interventions such as active surveillance programs have the potential to improve the chronic disease care being provided to First Nations children.

Cardiovascular Comorbidity Associated With Albuminuria in Youth-Onset Type 2 Diabetes: Analyses From the iCARE Study.

OBJECTIVES: Little is known about the relationship between albuminuria in youth with type 2 diabetes (T2D) and cardiovascular risk. We aimed to determine whether youth with T2D and albuminuria have evidence of increased cardiovascular risk and/or early cardiovascular dysfunction compared with youth with T2D without albuminuria. METHODS: Youth with T2D were stratified by albuminuria status. Cardiovascular risk factors, including body mass index (BMI), 24-hour blood pressure, lipid profile, smoking and smoking exposure, habitual physical activity and screen time, were compared between groups. Left ventricular structure and function and carotid intima-media thickness (cIMT) were evaluated in participants who underwent cardiac imaging. RESULTS: Two hundred sixty-five youth participated, 83 (31.3%) of whom had albuminuria. Ethnicity, sex, BMI z score, age at diagnosis, duration of diabetes and hepatocyte nuclear factor-1alpha status did not differ between youth stratified by albuminuria. Smoking, exposure to second-hand smoke and low physical activity levels did not differ between groups. Youth with albuminuria were more likely to have hypertension, dyslipidemia and poor glycemic control. Left ventricular structure and carotid cIMT did not differ between groups, but youth with albuminuria had evidence of early left ventricular diastolic dysfunction. CONCLUSIONS: We found evidence of increased cardiovascular disease risk factors and left ventricular diastolic dysfunction in youth with T2D and albuminuria compared with those without albuminuria, despite a relatively short duration of disease. Thus, albuminuria may serve as a marker of early cardiovascular disease risk in youth with T2D.

Physical activity and cardiometabolic health in adolescents with type 2 diabetes: a cross-sectional study.

INTRODUCTION: Youth living with type 2 diabetes display increased risk of cardiovascular disease (CVD). It is unclear if regular physical activity (PA) modifies this risk. RESEARCH DESIGN AND METHODS: We compared CVD risk factors in a cross-sectional study of 164 youth with type 2 diabetes stratified according to weekly vigorous-intensity PA. Outcomes were hemoglobin A1c (HbA1c), ambulatory blood pressure (BP; ambulatory 24-hour readings), plasma lipoproteins, and albuminuria. The main exposure, vigorous-intensity PA, was quantified with the Adolescent Physical Activity Recall Questionnaire. RESULTS: Youth were 15±3 years, and 78% lived rurally and 68% were female, with a mean body mass index (BMI) Z-score of 2.4±1.1 and a mean HbA1c of 9.6% ±2.6%. Youth who participated in regular vigorous-intensity PA (40%; n=67) achieved nearly twice the dose of PA than peers who did not (62 vs 34 metabolic equivalent score-hour/week, p=0.001). After adjusting for duration of diabetes, BMI Z-score, sex, and smoking, youth who engaged in vigorous-intensity PA displayed lower HbA1c (9.1% vs 9.9%, p=0.052), diastolic BP (70 mm Hg vs 73 mm Hg, p=0.002), diastolic load (20% vs 26%, p=0.023), and mean arterial pressure (87.3 mm Hg vs 90.3 mm Hg, p<0.01), compared with youth who did not. Compared with youth who did not participate in regular vigorous-intensity PA, those who did also displayed lower odds of albuminuria after adjusting for duration of diabetes, sex, smoking, rural residence, and BMI Z-score (adjusted OR: 0.40, 95% CI 0.19 to 0.84). CONCLUSIONS: Among youth with type 2 diabetes, participation in vigorous-intensity PA is associated with lower CVD risk.

The Tri-ponderal Mass Index is associated with adiposity in adolescent type 2 diabetes mellitus: a cross-sectional analysis.

Pediatric type 2 diabetes mellitus (T2DM) patients are often overweight or obese, yet there are no validated clinical measures of adiposity to stratify cardiometabolic risk in this population. The tri-ponderal mass index (TMI, kg/m3) has recently been reported as a measure of adiposity in children, but there has been no validation of the association of TMI with adiposity in pediatric T2DM. We hypothesized that in children with T2DM, the TMI can serve as a more accurate measure of adiposity when compared to BMI z-score, and that it is associated with components of the metabolic syndrome. This is a cross-sectional secondary data analysis from the Improving Renal Complications in Adolescents with Type 2 Diabetes Through REsearch (iCARE) study (n = 116, age 10.20-17.90 years). Spearman's correlations and multivariable regression were used in the analyses. When compared to DXA, TMI demonstrated significant correlation with total adiposity versus BMI z-score (TMI r = 0.74, p-value < 0.0001; BMI z-score r = - 0.08, p-value 0.403). In regression analyses, TMI was associated with WHtR (B = 35.54, 95% CI 28.81, 42.27, p-value < 0.0001), MAP dipping (B = 1.73, 95% CI 0.12, 3.33, p-value = 0.035), and HDL (B = - 5.83, 95% CI - 10.13, - 1.54, p-value = 0.008). In conclusion, TMI is associated with adiposity and components of the metabolic syndrome in pediatric T2DM patients.

Characteristics Associated with Variation in Corticosteroid Exposure in Children with Steroid-Sensitive Nephrotic Syndrome: Results from a Canadian Longitudinal Study.

Background: Variation in dose and duration of corticosteroids for childhood-onset steroid-sensitive nephrotic syndrome occurs worldwide, likely reflecting the evolving evidence on optimal dosing and variable severity of the disease observed between patients. We conducted a study to determine the associations between site, physician, and patient factors, and average daily corticosteroid dose and duration of therapy. Methods: Data were derived from the Canadian Childhood Nephrotic Syndrome (CHILDNEPH) Project, an observational longitudinal study from 2013 to 2019 of children with nephrotic syndrome involving pediatric nephrologists in 11 sites across Canada. The primary outcome was average daily corticosteroid dose prescribed per episode of proteinuria, reported as mg/m2 prednisone equivalents. Secondary outcome was duration of treatment for each episode of proteinuria in days. Exposure variables were categorized into site-, physician-, and patient-level variables. Results: In total, 328 children, median age at enrollment of 4.3 years old (interquartile range [IQR], 3.6), participated and were followed for a median time of 2.62 years (IQR, 2.6). The observed variability in average daily corticosteroid dose and in duration of therapy was mostly attributed to the site where the patient was treated. Accounting for between patient, physician, and site differences, average daily corticosteroid dose decreased with increasing age (beta coefficient, -0.07; 95% confidence interval [95% CI], -0.09 to -0.05], P<0.001). African and Indigenous ethnicity was associated with longer treatment duration compared with White patients (beta coefficient: African, 42.29, 95% CI, 7.85 to 76.73, P=0.02; Indigenous, 29.65, 95% CI, 2.79 to 56.52, P=0.03). Conclusions: We found practice variation with respect to corticosteroid prescriptions across 11 Canadian sites, and that variation is mostly explained at the site level. Age and ethnicity are important factors to be considered, because they are significantly associated with the average corticosteroid dose and duration of therapy.

An evaluation of renin-angiotensin system markers in youth with type 2 diabetes and associations with renal outcomes.

AIMS/HYPOTHESIS: Youth with type 2 diabetes (T2D) have high rates of obesity, hypertension and suboptimal glycemic control. We hypothesized that renin-angiotensin system (RAS) activation is present in youth with T2D and associated with poor glycemic control and renal outcomes. METHODS: Cross-sectional analysis of 183 youth with T2D and 100 controls from the Improving renal Complications in Adolescents with T2D through REsearch cohort. Diabetes youth stratified by urine albumin:creatinine ratio (ACR) < or ≥2 mg/mmol. RAS levels measured with enzyme-linked immunosorbent assay (ELISA) and enzyme activities by synthetic substrates. In T2D, levels log transformed and Tobit linear regressions evaluated for associations with hemoglobin A1c (HbA1c), mean arterial pressure (MAP), estimated glomerular filtration rate (eGFR), ACR. RESULTS: Youth were 14 to 15 years, with diabetes duration 1.7 to 1.8 years; 21.3% albuminuria. Serum: differences in plasma renin activity (<0.0001), and angiotensin converting enzyme (ACE) activity (P = .003) in T2D vs controls. Urine: higher ACE activity and ACE2 protein/activity (all P < .0001) in T2D, higher levels in T2D with albuminuria. Multivariable regressions: higher serum ACE activity (ß = 0.03, SE 0.01;P < .01), urine ACE activity (ß = 0.44, SE 0.18;P < .01), ACE2 (ß = 0.51, SE 0.19;P < .01) positively associated with HbA1c; urine angiotensinogen (AGT) negatively associated (ß = -0.28 [SE 0.06;P < .01]). Higher serum aldosterone (ß = 0.11 [SE 0.04;P < .01]) and urine AGT (ß = 0.32 [SE 0.07;P < .01]) significantly associated with ACR and urine ACE2 (ß = 0.21 [SE 0.13;P < .03]). No associations between RAS markers and eGFR/MAP. CONCLUSIONS/INTERPRETATION: RAS activation present in youth with T2D and associated with higher HbA1c. Higher serum aldosterone and urine AGT associated with albuminuria. The prognostic significance of the combined effect of glycemia and RAS activation on renal outcomes requires additional investigation.

A Holistic Approach to Risk for Early Kidney Injury in Indigenous Youth With Type 2 Diabetes: A Proof of Concept Paper From the iCARE Cohort.

BACKGROUND: Indigenous youth with type 2 diabetes (T2D) are disproportionately affected by early onset albuminuria and are at high risk of kidney failure in early adulthood. Traditional biological approaches have failed to fully explain the renal morbidity seen in this population. The improving renal Complications in Adolescents with type 2 diabetes through REsearch cohort (iCARE) study was therefore designed in collaboration with patients, to more holistically evaluate risk factors for renal morbidity. We hypothesize that both biological factors and mental health influence renal outcomes, mediated via inflammatory pathways. OBJECTIVE: The objective of this study was to evaluate the iCARE analytic framework which evaluates relationships between biological factors, mental health, inflammation, and albuminuria utilizing a structural equation modeling (SEM) approach. METHODS: The first 187 youth with T2D (10-25 years) from the Manitoba iCARE cohort are presented here to evaluate our theoretical and analytic framework. An SEM was chosen to evaluate the statistical significance of proposed associations. The primary outcome was a nonorthostatic urine albumin:creatinine ratio ≥2 mg/mmol. Main exposures (ie, latent factors) included psychological health (distress, perceived stress, positive mental health and resilience), hypertension (24 hour monitored), and inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], fibrinogen). Hemoglobin A1c (HbA1c) and duration of diabetes were covariates. RESULTS: Within the initial cohort (median age = 15 years, duration of diabetes = 2.3 years, 66.8% female), 30.5% (n = 57) had nonorthostatic albuminuria (ALB), and the majority of ALB was persistent (confirmed in 2/3 samples over a 6-month period; n = 47). Youth with ALB had higher HbA1c (10.9% vs 8.9%; P < .001), more hypertension (94.2% vs 78·2%; P = .02), longer duration of diabetes (3.4 vs 2.4 years; P = .01), higher distress (9.2 vs 7.3; P = .02), and stress scores (28.7 vs 26.4; P = .03), and elevated inflammatory markers (CRP: 4.9 vs 3.1 mg/L; P = .01, fibrinogen: 3.7 vs 3.3 µmol/L; P = .02). Factors directly associated with ALB in the SEM were hypertension (0.28; P = .001), inflammation (0.41; P < .001), and HbA1c (0.50; P < .001). Psychological health was independently associated with inflammation (-0.20; P < .001) but not directly associated with ALB. CONCLUSIONS: Albuminuria is highly prevalent in Indigenous youth with T2D. This preliminary analysis supports a theoretical framework linking glycemic control, hypertension, and inflammation, potentially mediated by psychological factors with albuminuria. These data support the need for more holistic models of evaluation and care for youth with T2D and multifactorial interventions to prevent complications.

CONTEXTE: L'albuminurie à déclenchement précoce affecte de façon disproportionnelle les jeunes autochtones atteints de diabète de type 2 (T2D). Ces derniers présentent également un risque plus élevé d'insuffisance rénale au début de l'âge adulte. Les approches biologiques traditionnelles n'ont pas été en mesure d'expliquer entièrement la morbidité rénale observée dans cette population. Ainsi, l'étude de cohorte iCARE (improving renal Complications in Adolescents with type 2 diabetes through REsearch) a été conçue en collaboration avec les patients pour évaluer de façon plus globale les facteurs de risque de morbidité rénale. Nous posons l'hypothèse que les résultats rénaux sont influencés à la fois par la santé mentale du patient et des facteurs biologiques, avec médiation par les voies inflammatoires. OBJECTIF: Évaluer le cadre d'analyse iCARE qui examine les liens entre les facteurs biologiques, la santé mentale, l'inflammation et l'albuminurie à l'aide d'une approche de modélisation par équation structurelle (SEM). MÉTHODOLOGIE: Les 187 premiers jeunes autochtones atteints de T2D (âgés de 10 à 25 ans) de la cohorte manitobaine iCARE sont présentés ici pour évaluer notre cadre théorique et analytique. Une SEM a été choisie pour évaluer la pertinence statistique des associations suggérées. Le résultat principal était un rapport urinaire albumine/créatinine non orthostatique d'au moins 2 mg/mmol. Les principaux risques (c.-à-d. les facteurs latents) comprenaient la santé mentale (détresse, stress perçu, bien-être mental et résilience), l'hypertension (suivie sur 24 heures) et les taux de marqueurs inflammatoires (CRP, ESR, fibrinogène). L'hémoglobine A1c (HbA1c) et la période depuis l'apparition du diabète constituaient les covariables. RÉSULTATS: Les sujets retenus (66,8 % de sujets féminins) avaient 15 ans d'âge médian et étaient diabétiques depuis 2,3 ans. Dans cette cohorte, 30,5 % (n = 57) présentaient une albuminurie non orthostatique (confirmée dans 2/3 des échantillons sur une période de six mois) qui s'est avérée persistante dans la majorité des cas (n = 47). Les jeunes souffrant d'albuminurie présentaient des taux plus élevés d'HbA1c (10,9 c. 8,9 %; P < ,001), davantage d'hypertension (94,2 c. 78,2 %; P = ,02), étaient diabétiques depuis plus longtemps (3,4 c. 2,4 ans; P = ,01), vivaient davantage de détresse (9,2 c. 7,3; P = ,02), et présentaient des scores pour le stress (28,7 c. 26,4; P = ,03) et des taux de marqueurs inflammatoires plus élevés (CRP : 4,9 c. 3,1 mg/L; P = ,01, fibrinogène : 3,7 c. 3,3 µmol/L; P = ,02). Avec la SEM, les facteurs directement associés à l'albuminurie étaient l'hypertension (0,28; P = ,001), l'inflammation (0,41; P < ,001) et l'HbA1c (0,50; P < ,001). La santé psychologique a été associée à l'inflammation de manière indépendante (−0,20; P < ,001), mais n'a pas été directement associée à l'albuminurie. CONCLUSION: L'albuminurie est très répandue chez les jeunes autochtones atteints de T2D. Cette analyze préliminaire vient étayer un cadre théorique qui établit un lien entre l'albuminurie et le contrôle de la glycémie, l'hypertension et l'inflammation; lien potentiellement médié par des facteurs psychologiques. Ces données appuient la nécessité d'avoir des modèles plus holistiques d'évaluation et de prise en charge des jeunes atteints de T2D, et des interventions multifactorielles visant à prévenir les complications.

Biomarkers for Early Acute Kidney Injury Diagnosis and Severity Prediction: A Pilot Multicenter Canadian Study of Children Admitted to the ICU.

OBJECTIVE: Acute kidney injury occurs early in PICU admission and increases risks for poor outcomes. We evaluated the feasibility of a multicenter acute kidney injury biomarker urine collection protocol and measured diagnostic characteristics of urine neutrophil gelatinase-associated lipocalin, interleukin-18, and liver fatty acid binding protein to predict acute kidney injury and prolonged acute kidney injury. DESIGN: Prospective observational pilot cohort study. SETTING: Four Canadian tertiary healthcare PICUs. PATIENTS: Eighty-one children 1 month to 18 years old. Exclusion criteria were as follows: cardiac surgery, baseline severe kidney disease, and inadequate urine or serum for PICU days 1-3. INTERVENTIONS: PICUs performed standardized urine collection protocol to obtain early PICU admission urine samples, with deferred consent. MEASUREMENTS AND MAIN RESULTS: Study barriers and facilitators were recorded. Acute kidney injury was defined based on Kidney Disease: Improving Global Outcomes serum creatinine criteria (acute kidney injuryserum creatinine) and by serum creatinine and urine output criteria (acute kidney injuryserum creatinine+urine output) Prolonged acute kidney injury was defined as acute kidney injury duration of 48 hours or more. PICU days 1-3 neutrophil gelatinase-associated lipocalin, interleukin-18, and liver fatty acid binding protein were evaluated for acute kidney injury prediction (area under the curve). Biomarkers on the first day of acute kidney injury attainment (day 1 acute kidney injury) were evaluated for predicting prolonged acute kidney injury. Eighty-two to 95% of subjects had urine collected from PICU days 1-3. Acute kidney injuryserum creatinine developed in 16 subjects (20%); acute kidney injuryserum creatinine+urine output developed in 38 (47%). On PICU day 1, interleukin-18 predicted acute kidney injuryserum creatinine with area under the curve=0.82, but neutrophil gelatinase-associated lipocalin and liver fatty acid binding protein predicted acute kidney injuryserum creatinine with area under the curve of less than or equal to 0.69; on PICU day 2, area under the curve was higher (not shown). Interleukin-18 and liver fatty acid binding protein on day 1 acute kidney injury predicted prolonged acute kidney injuryserum creatinine (area under the curve=0.74 and 0.83, respectively). When acute kidney injuryserum creatinine+urine output was used to define acute kidney injury, biomarker area under the curves were globally lower. CONCLUSIONS: Protocol urine collection to procure early admission samples is feasible. Individual biomarker acute kidney injury prediction performance is highly variable and modest. Larger studies should evaluate utility and cost effectiveness of using early acute kidney injury biomarkers.

Screening for chronic kidney disease in Canadian indigenous peoples is cost-effective.

Canadian indigenous (First Nations) have rates of kidney failure that are 2- to 4-fold higher than the non-indigenous general Canadian population. As such, a strategy of targeted screening and treatment for CKD may be cost-effective in this population. Our objective was to assess the cost utility of screening and subsequent treatment for CKD in rural Canadian indigenous adults by both estimated glomerular filtration rate and the urine albumin-to-creatinine ratio. A decision analytic Markov model was constructed comparing the screening and treatment strategy to usual care. Primary outcomes were presented as incremental cost-effectiveness ratios (ICERs) presented as a cost per quality-adjusted life-year (QALY). Screening for CKD was associated with an ICER of $23,700/QALY in comparison to usual care. Restricting the model to screening in communities accessed only by air travel (CKD prevalence 34.4%), this ratio fell to $7,790/QALY. In road accessible communities (CKD prevalence 17.6%) the ICER was $52,480/QALY. The model was robust to changes in influential variables when tested in univariate sensitivity analyses. Probabilistic sensitivity analysis found 72% of simulations to be cost-effective at a $50,000/QALY threshold and 93% of simulations to be cost-effective at a $100,000/QALY threshold. Thus, targeted screening and treatment for CKD using point-of-care testing equipment in rural Canadian indigenous populations is cost-effective, particularly in remote air access-only communities with the highest risk of CKD and kidney failure. Evaluation of targeted screening initiatives with cluster randomized controlled trials and integration of screening into routine clinical visits in communities with the highest risk is recommended.

Variation in estimated glomerular filtration rate at dialysis initiation in children.

BACKGROUND: Data guiding the timing of dialysis initiation in children are limited. We sought to determine current practice and secular trends in Canada with respect to the timing of dialysis initiation in children based on estimated glomerular filtration rate (eGFR). METHODS: This observational study included incident chronic dialysis patients aged ≤21 years identified from the Canadian Organ Replacement Register who started dialysis in Canada between January 2001 and December 2010 at any of the nine participating Canadian centers (n = 583). Youth were categorized utilizing CKiD Schwartz eGFR into ≥10.5 (higher) or <10.5 ml/min/1.73 m2 (lower) eGFR groups. Differences at dialysis initiation by facility and region were examined, and secular trends were determined. RESULTS: Median eGFR at dialysis initiation was 8.1 (interquartile range 5.4-11.0) ml/min/1.73 m2. Overall, 29 % of the patients started dialysis with an eGFR of ≥10.5 ml/min/1.73 m2. The proportion of children starting with higher eGFR increased from 27.3 % in 2001 to 35.4 % in 2010 (p = 0.04) and differed by treatment facility (12-70 %; p = 0.0001). Factors associated with higher eGFR at dialysis initiation in the adjusted regression model were female sex [odds ratio (OR) 1.48; 95 % confidence interval (CI) 1.02-2.14], genetic cause of end-stage kidney disease (OR 2.77; 95 % CI 1.37-5.58) and living ≥50 km from treatment facility (OR 1.47; 95 % CI 1.01-2.14). CONCLUSIONS: One-third of the children were found to have initiated dialysis with an eGFR ≥10.5 ml/min/1.73 m2, however significant practice variation exists with respect to timing of dialysis initiation by treatment facility. More data is required to evaluate the clinical implications of this practice variation.

Breastfeeding Initiation Associated With Reduced Incidence of Diabetes in Mothers and Offspring.

OBJECTIVE: To examine associations between breastfeeding initiation and subsequent diabetes among First Nations (indigenous people in Canada who are not Métis or Inuit) and non-First Nations mothers and their offspring with and without gestational diabetes mellitus (GDM). METHODS: This retrospective database study included 334,553 deliveries (1987-2011) in Manitoba with up to 24 years of follow-up for diabetes using population-based databases. Information of breastfeeding initiation before hospital discharge was obtained from hospital abstracts recorded by nurses in postpartum wards. Cox proportional hazard models were applied to examine the association between breastfeeding initiation and risk of diabetes in mothers and their offspring. RESULTS: Breastfeeding initiation was recorded in 83% of non-First Nations mothers and 56% of First Nations mothers (P<.001). Breastfeeding initiation was associated with a reduced risk of incident (later developed) diabetes in non-First Nations mothers without GDM (hazard ratio [HR] 0.73 [or -27% of risk], 95% confidence interval [CI] 0.68-0.79), non-First Nations mothers with GDM (HR 0.78 or -22% of risk, CI 0.69-0.89), First Nations mothers without GDM (HR 0.89 or -11% of risk, CI 0.81-0.98), and First Nations mothers with GDM (HR 0.82 or -18% of risk, CI 0.73-0.92) with 24 years of follow-up or less. With 24 years of follow-up or less, breastfeeding initiation was associated with a 17% lower risk of youth-onset type 2 diabetes in offspring (HR 0.83, CI 0.69-0.99, P=.038). The association between breastfeeding initiation and subsequent diabetes in mothers and offspring was independent of family income, rural residence, First Nations status, GDM, parity, gestational hypertension, and age of the mother. CONCLUSION: Breastfeeding initiation is associated with a reduced risk of diabetes among women and their offspring in Manitoba. The results suggest that breastfeeding might be a potentially modifiable factor to reduce the risk of diabetes in both First Nations and non-First Nations women and children.