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.

Temporal Trends in Practice Patterns After Introduction of Pediatric Hypertension Guidelines in Canada.

Importance: In 2016 and 2017, respectively, new Canadian and US guidelines for diagnosis and management of pediatric hypertension (HTN) were published. Six years after their publication, it is unknown whether the recommendations have led to changes in primary care practice patterns. Objectives: To determine whether HTN guidelines are associated with changes in practice patterns among primary care clinicians. Design, Setting, and Participants: This retrospective, multicenter, population-based cohort study was conducted across 3 phases: January 1, 2011, to December 31, 2015 (era 1), January 1, 2016, to December 31, 2017 (washout period), and January 1, 2018, to December 31, 2019 (era 2). Data were collected from 7 Canadian provinces using the Canadian Primary Care Sentinel Surveillance Network Electronic Medical Record database. Eligible participants included children and adolescents (aged ≥3 to <18 years) with 1 or more encounters in the database. Data analysis was conducted from February 2022 to February 2023. Exposure: Implementation of the 2016 Hypertension Canada and 2017 American Academy of Pediatrics guidelines. Main Outcomes and Measures: The primary outcomes were annual BP screening documentation, high BP follow-up documentation at 6 months and 1-year, HTN prevalence, laboratory testing rates, and medication prescription rates. Interrupted time series analysis was used to assess the association of the introduction of the Canadian and US guidelines with outcomes. Results: The study included 343 191 children and adolescents (mean [SD] age at first encounter, 6.7 (4.6) years; 173 290 female [50.5%]; 169 901 male [49.5%]), including 235 094 patients in era 1 and 193 473 patients in era 2. In era 1, 55 550 patients (23.6%) had at least 1 BP measurement, and in era 2, 45 006 patients (23.3%) had at least 1 BP measurement. There was a significant increase in BP screening in era 2 from 26 876 of 148 554 screenings (18.1%) to 28 556 of 141 192 screenings (20.2%; ß = 0.202; 95% CI, 0.009 to 0.390; P = .04), and the increasing trend was sustained. There was a significant decrease in the trend of follow-up of high BP measurement at 6 months (1265 of 4941 patients with BP measurements [25.6%] to 1718 of 7321 patients with BP measurements [23.5%]; ß = -0.490; 95% CI, -0.758 to -0.223; P = .001) and 1 year (1974 of 4941 measurements [40.0%] to 2314 of 7321 measurements [31.6%]; ß = -1.392; 95% CI, -1.573 to -1.212; P < .001) in era 2. The proportion of patients meeting HTN criteria significantly increased from 2540 of 55 550 patients (4.6%) in era 1 to 5690 of 45 006 patients (12.6%) in era 2 (ß = 0.0210; 95% CI, 0.0021 to 0.0410; P = .03). There was no significant change in the trend of laboratory testing rates in era 2 (949 of 4941 patients tested [19.2%] to 1149 of 7321 patients tested [15.7%]; ß = -0.159; 95% CI, -0.364 to 0.046; P = .12). The trend in prescribing of medications to patients with HTN also decreased in era 2 (1305 of 4941 patients prescribed medication [26.4%] to 1415 of 7321 patients prescribed medication [19.3%]; ß = -0.605; 95% CI, -0.830 to -0.358; P < .001). Conclusions and Relevance: The findings of this cohort study within the Canadian primary care setting suggest that there was a significant increase in BP screening and HTN prevalence after the publication of national and international HTN guidelines; however, the follow-up of high BP was still suboptimal. Increasing rates of pediatric HTN emphasize the need for better adherence to pediatric HTN guidelines to improve care and outcomes.

Factors Affecting Quality of Life in Adolescents Living With Type 2 Diabetes: A Substudy of the Improving Renal Complications in Adolescents With Type 2 Diabetes Through REsearch (iCARE) Cohort.

OBJECTIVES: Type 2 diabetes (T2D) disproportionately impacts adolescents living in challenging socioeconomic conditions. However, the impacts of T2D on quality of life (QOL) in this context are unknown. Our aim in this study was to evaluate QOL and identify its biological, psychological, and social determinants among adolescents living with and without T2D from similar sociodemographic backgrounds. Relationships between glycemic stability, early complications, and treatments of T2D and QOL were also examined. METHODS: Ninety-two adolescents with T2D and 59 at-risk controls were included from the Improving Renal Complications in Adolescents With Type 2 Diabetes Through Research (iCARE) cohort. The main outcome was QOL (Pediatric QOL Inventory [PedsQL]). Biological covariates included age, sex, body mass index z score, glycated hemoglobin, estimated glomerular filtration rate, and urine albumin:creatinine ratio. Psychological factors included perceived stress (14-item Perceived Stress Scale) and mental distress (6-item Kessler scale). Social factors included food security (Household Food Security Survey Module) and income quintile. Multivariate linear regression analyses were used to identify factors associated with QOL between adolescents with and without T2D, and within the T2D cohort. RESULTS: Mean total QOL scores among adolescents with T2D were lower than in controls (67.0±14.8 vs 71.7±16.2, p=0.04). Age, sex, and percent Indigenous ethnicity were not significantly different between groups. Mean duration of T2D was 2.3±2.0 years. In the multivariate analysis, QOL was not associated with diabetes status, but negative associations were seen between mental distress (ß=-1.46, p<0.001) and food insecurity QOL (ß=-6.26, p=0.037). No differences were seen between biological factors and QOL in either analysis. CONCLUSIONS: Significant factors associated with decreased QOL in adolescents living with T2D include mental distress and food insecurity, indicating areas for targeted intervention.

Insulin Secretion, Sensitivity, and Kidney Function in Young Individuals With Type 2 Diabetes.

OBJECTIVE: ß-Cell dysfunction and insulin resistance magnify the risk of kidney injury in type 2 diabetes. The relationship between these factors and intraglomerular hemodynamics and kidney oxygen availability in youth with type 2 diabetes remains incompletely explored. RESEARCH DESIGN AND METHODS: Fifty youth with type 2 diabetes (mean age ± SD 16 ± 2 years; diabetes duration 2.3 ± 1.8 years; 60% female; median HbA1c 6.4% [25th, 75th percentiles 5.9, 7.6%]; BMI 36.4 ± 7.4 kg/m2; urine albumin-to-creatinine ratio [UACR] 10.3 [5.9, 58.0] mg/g) 21 control participants with obesity (OCs; age 16 ± 2 years; 29% female; BMI 37.6 ± 7.4 kg/m2), and 20 control participants in the normal weight category (NWCs; age 17 ± 3 years; 70% female; BMI 22.5 ± 3.6 kg/m2) underwent iohexol and p-aminohippurate clearance to assess glomerular filtration rate (GFR) and renal plasma flow, kidney MRI for oxygenation, hyperglycemic clamp for insulin secretion (acute C-peptide response to glucose [ACPRg]) and disposition index (DI; ×103 mg/kg lean/min), and DXA for body composition. RESULTS: Youth with type 2 diabetes exhibited lower DI (0.6 [0.0, 1.6] vs. 3.8 [2.4, 4.5] × 103 mg/kg lean/min; P < 0.0001) and ACPRg (0.6 [0.3, 1.4] vs. 5.3 [4.3, 6.9] nmol/L; P < 0.001) and higher UACR (10.3 [5.9, 58.0] vs. 5.3 [3.4, 14.3] mg/g; P = 0.003) and intraglomerular pressure (77.8 ± 11.5 vs. 64.8 ± 5.0 mmHg; P < 0.001) compared with OCs. Youth with type 2 diabetes and OCs had higher GFR and kidney oxygen availability (relative hyperoxia) than NWCs. DI was associated inversely with intraglomerular pressure and kidney hyperoxia. CONCLUSIONS: Youth with type 2 diabetes demonstrated severe ß-cell dysfunction that was associated with intraglomerular hypertension and kidney hyperoxia. Similar but attenuated findings were found in OCs.

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.

Perspectives of Pediatric Nephrologists, Intensivists and Nurses Regarding AKI Management and Expected Outcomes.

Background: Acute kidney injury (AKI) in critically ill children is associated with increased risk for short- and long-term adverse outcomes. Currently, there is no systematic follow-up for children who develop AKI in intensive care unit (ICU). Objective: This study aimed to assess variation regarding management, perceived importance, and follow-up of AKI in the ICU setting within and between healthcare professional (HCP) groups. Design: Anonymous, cross-sectional, web-based surveys were administered nationally to Canadian pediatric nephrologists, pediatric intensive care unit (PICU) physicians, and PICU nurses, via professional listservs. Setting: All Canadian pediatric nephrologists, PICU physicians, and nurses treating children in the ICU were eligible for the survey. Patients: N/A. Measurements: Surveys included multiple choice and Likert scale questions on current practice related to AKI management and long-term follow-up, including institutional and personal practice approaches, and perceived importance of AKI severity with different outcomes. Methods: Descriptive statistics were performed. Categorical responses were compared using Chi-square or Fisher's exact tests; Likert scale results were compared using Mann-Whitney and Kruskal-Wallis tests. Results: Surveys were completed by 34/64 (53%) pediatric nephrologists, 46/113 (41%) PICU physicians, and 82 PICU nurses (response rate unknown). Over 65% of providers reported hemodialysis to be prescribed by nephrology; a mix of nephrology, ICU, or a shared nephrology-ICU model was reported responsible for peritoneal dialysis and continuous renal replacement therapy (CRRT). Severe hyperkalemia was the most important renal replacement therapy (RRT) indication for both nephrologists and PICU physicians (Likert scale from 0 [not important] to 10 [most important]; median = 10, 10, respectively). Nephrologists reported a lower threshold of AKI for increased mortality risk; 38% believed stage 2 AKI was the minimum compared to 17% of PICU physicians and 14% of nurses. Nephrologists were more likely than PICU physicians and nurses to recommend long-term follow-up for patients who develop any AKI during ICU stay (Likert scale from 0 [none] to 10 [all patients]; mean=6.0, 3.8, 3.7, respectively) (P < .05). Limitations: Responses from all eligible HCPs in the country could not obtained. There may be differences in opinions between HCPs that completed the survey compared to those that did not. Additionally, the cross-sectional design of our study may not adequately reflect changes in guidelines and knowledge since survey completion, although no specific guidelines have been released in Canada since survey dissemination. Conclusions: Canadian HCP groups have variable perspectives on pediatric AKI management and follow-up. Understanding practice patterns and perspectives will help optimize pediatric AKI follow-up guideline implementation.

Contexte: L'insuffisance rénale aiguë (IRA) chez les enfants gravement malades est associée à un risque accru d'issues défavorables à court et à long terme. En ce moment, il n'existe aucun suivi systématique pour les enfants qui développent une IRA pendant un séjour à l'unité des soins intensifs (USI). Objectif: Cette étude visait à évaluer les variations dans la prise en charge de l'IRA, de son importance perçue et de son suivi, tant au sein des groupes de professionnels de la santé (PS) qu'entre les différents groupes de PS. Conception: Des sondages transversaux à remplir de façon anonyme en ligne ont été menés à l'échelle nationale auprès de néphrologues pédiatriques canadiens, de médecins des unités de soins intensifs pédiatriques (USIP) et de membres du personnel infirmier des USIP ayant été répertoriés à partir de listes professionnelles. Cadre: Tous les néphrologues pédiatriques canadiens, médecins et membres du personnel infirmier qui traitent des enfants en USI étaient admissibles à répondre au sondage. Patients: S/O. Mesures: Les sondages comportaient des questions à choix multiples et des questions de type échelle de Likert qui portaient sur les pratiques actuelles de la gestion et de suivi à long terme de l'IRA, notamment sur les approches institutionnelles et personnelles de pratique et sur l'importance perçue de la gravité de l'IRA avec différents résultats. Méthodologie: Des statistiques descriptives ont été réalisées. Les réponses catégorielles ont été comparées à l'aide du chi-carré ou de tests exacts de probabilité de Fisher; les résultats des échelles de Likert ont été comparés à l'aide de tests de Mann-Whitney et de Kruskal-Wallis. Résultats: Les sondages ont été complétés par 53 % des néphrologues pédiatriques (34/64), 41 % des médecins d'USIP (46/113) et par 82 membres du personnel infirmier d'USIP (taux de réponse inconnu). Plus de 65 % des prestataires de soins ont déclaré que l'hémodialyse était prescrite par le service de néphrologie, alors que la dialyze péritonéale et la thérapie de remplacement rénal continu (TRRC) étaient confiées à la fois à la néphrologie, à l'USI ou à un modèle partagé néphrologie-USI. L'hyperkaliémie grave était l'indication la plus importante de la TRR pour les néphrologues et les médecins en USIP (échelle de Likert de 0 [pas important] à 10 [le plus important]; médiane = 10, 10, respectivement). Les néphrologues ont signalé un seuil inférieur d'IRA pour l'augmentation du risque de mortalité; 38 % d'entre eux estimaient que l'IRA de stade 2 était le seuil minimum, contre 17 % des médecins en USI et 14 % du personnel infirmier. Les néphrologues étaient plus susceptibles que les médecins et le personnel infirmier des USIP de recommander un suivi à long terme pour les patients qui développent une IRA pendant leur séjour en USI (échelle Likert de 0 [aucun] à 10 [tous les patients]; moyennes respectives = 6,0; 3,8 et 3,7 [p < 0,05]). Limites: Il n'a pas été possible d'obtenir les réponses de tous les PS admissibles au pays. Des différences d'opinions sont possibles entre les PS qui ont répondu au sondage et ceux qui ne l'ont pas fait. De plus, la conception transversale de notre étude pourrait ne pas refléter adéquatement les changements apportés aux lignes directrices et aux connaissances depuis la fin de cette enquête, bien qu'aucune ligne directrice particulière n'ait été publiée au Canada depuis la diffusion du sondage. Conclusion: Les divers groupes de professionnels de la santé canadiens ont des points de vue différents en ce qui concerne la prise en charge et le suivi de l'IRA chez les enfants. La compréhension des modèles de pratique et des perspectives permettra d'optimiser la mise en œuvre de directives de suivi de l'IRA pédiatrique.

Evaluation of administrative case definitions for hypertension in Canadian children.

Hypertension is increasing in children and warrants disease surveillance. We therefore sought to evaluate the validity of case definitions to identify pediatric hypertension in administrative healthcare data. Cases of hypertension in children 3-18 years of age were identified utilizing blood pressures recorded in the Manitoba Primary Care Research Network (MaPCReN) electronic medical record from 2014 to 2016. Prevalence of hypertension and associated clinical characteristics were determined. We then evaluated the validity of 18 case definitions combining outpatient physician visits (ICD9CM codes), hospital claims (ICD9CM/ICD10 codes) and antihypertensive use within 1-3 years of data housed at the Manitoba Centre for Health Policy. The MaPCReN database identified 241 children with hypertension and 4090 without (prevalence = 5.6%). The sensitivity of algorithms ranged between 0.18 and 0.51 and the specificity between 0.98 and 1.00. Pharmaceutical use increased the sensitivity of algorithms significantly. The algorithms with the highest sensitivity and area under the ROC curve were 1 or more hospitalization OR 1 or more physician claim OR 1 or more pharmaceutical record. Evaluating 2 years of data is recommended. Administrative data alone reflects diagnosis of hypertension with high specificity, but underestimate the true prevalence of this disease. Alternative data sources are therefore required for disease surveillance.

Patient-Reported Outcomes Over 24 Months in Pediatric CKD: Findings From the MyKidneyHealth Cohort Study.

RATIONALE & OBJECTIVE: The lived experience of children with chronic kidney disease (CKD) is poorly characterized. We examined the associations between patient-reported outcome (PRO) scores measuring their fatigue, sleep health, psychological distress, family relationships, and global health with clinical outcomes over time in children, adolescents, and younger adults with CKD and investigated how the PRO scores of this group compare with those of other children, adolescents, and younger adults. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 212 children, adolescentss, and adults aged 8 to 21 years with CKD and their parents recruited from 16 nephrology programs across North America. PREDICTORS: CKD stage, disease etiology, and sociodemographic and clinical variables. OUTCOME: PRO scores over 2 years. ANALYTICAL APPROACH: We compared PRO scores in the CKD sample with a nationally representative general pediatric population (ages 8 to 17 years). Change of PROs over time and association of sociodemographic and clinical variables with PROs were assessed using multivariable regression models. RESULTS: For all time points, 84% of the parents and 77% of the children, adolescents, and younger adults completed PRO surveys . The baseline PRO scores for the participants with CKD revealed a higher burden of fatigue, sleep-related impairment, psychological distress, impaired global health, and poorer family relationships compared with the general pediatric population, with median score differences≥1 SD for fatigue and global health. The baseline PRO scores did not differ by CKD stage or glomerular versus nonglomerular etiology. Over 2 years, PROs were stable with a<1-point annual change on average on each measure and intraclass correlation coefficients ranging from 0.53 to 0.79, indicating high stability. Hospitalization and parent-reported sleep problems were associated with worse fatigue, psychological health, and global health scores (all P<0.04). LIMITATIONS: We were unable to assess responsiveness to change with dialysis or transplant. CONCLUSIONS: Children with CKD experience a high yet stable burden of impairment across numerous PRO measures, especially fatigue and global health, independent of disease severity. These findings underscore the importance of assessing PROs, including fatigue and sleep measures, in this vulnerable population. PLAIN-LANGUAGE SUMMARY: Children with chronic kidney disease (CKD) have many treatment demands and experience many systemic effects. How CKD impacts the daily life of a child is poorly understood. We surveyed 212 children, adolescents, and younger adults with CKD and their parents over 24 months to assess the participants' well-being over time. Among children, adolescents, and younger adults with CKD we found a very high and persistent burden of psychological distress that did not differ by degree of CKD or type of kidney disease. The participants with CKD endorsed greater impairment in fatigue and global health compared with healthy children, adolescents, and younger adults, and parent-reported sleep problems were associated with poorer patient-reported outcome (PRO) scores across all domains. These findings emphasize the importance of including PRO measures, including fatigue and sleep measures, into routine clinical care to optimize the lived experience of children with CKD.

Child and caregiver perspectives on access to psychosocial and educational support in pediatric chronic kidney disease: a focus group study.

BACKGROUND: Children with chronic kidney disease (CKD) generally have worse educational and psychosocial outcomes compared with their healthy peers. This can impair their ability to manage their treatment, which in turn can have long-term health consequences through to adulthood. We attempted to capture the experiences of children with CKD and to describe the perspectives of their parents and caregivers on access to educational and psychosocial support. METHODS: Children with CKD (n = 34) and their caregivers (n = 62) were sampled via focus groups from pediatric hospitals in Australia, Canada, and the USA. Sixteen focus groups were convened and the transcripts were analyzed thematically. RESULTS: We identified four themes: disruption to self-esteem and identity (emotional turmoil of adolescence, wrestling with the sick self, powerlessness to alleviate child's suffering, balancing normality and protection); disadvantaged by lack of empathy and acceptance (alienated by ignorance, bearing the burden alone); a hidden and inaccessible support system (excluded from formal psychological support, falling behind due to being denied special considerations); and building resilience (finding partners in the journey, moving towards acceptance of the illness, re-establishing childhood). CONCLUSIONS: Children with CKD and their caregivers encountered many barriers in accessing psychosocial and educational support and felt extremely disempowered and isolated as a consequence. Improved availability and access to psychosocial and educational interventions are needed to improve the wellbeing and educational advancement of children with CKD. 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.

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.

Walking in two worlds with type 2 diabetes: a scoping review of prevention and management practices incorporating traditional indigenous approaches.

Type 2 diabetes is a complex chronic disease rapidly increasing among young people and disproportionately impacting Indigenous youth. Treatment programs are often inadequate for this population as they lack cultural relevance. A scoping review was conducted to explore traditional Indigenous approaches for diabetes prevention and management, to inform a program aimed at supporting Indigenous youth and families with type 2 diabetes. We seek to answer the following question: "Which traditional medicines and practices have been incorporated into intervention or prevention strategies for Indigenous people living with diabetes?" Search was done June 2021 using Ovid Medline, ESBCO and ProQuest databases. Terms included wellbeing, intervention, diabetes, and traditional approaches. Of the 2138 titles screened, 34 met inclusion criteria. Three studies integrated traditional Indigenous approaches into Western-based intervention programming. Content included traditional food and nutrition programs, gardening programs, Elder knowledge sharing, story telling, talking circles, feasting, prayer, traditional dancing, hunting, and school-based wellness curricula. Many were wholistic, co-created with community, Indigenous-led and held in accessible community spaces. The heterogeneity in approaches reflects the diversity of Indigenous nations and communities. This review identifies important elements to include in culturally relevant programs to address diabetes-related wellness.

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.

Pediatric hypertension screening and recognition in primary care clinics in Canada.

Objectives: Screening for hypertension in children is recommended by pediatric consensus guidelines. However, current practice is unknown. We evaluated rates of blood pressure assessment and hypertension recognition in primary care. Methods: This retrospective cohort study evaluated electronic medical record data from the Canadian Primary Care Sentinel Surveillance Network between 2011 and 2017. Children aged 3 to <18 years with at least one clinical encounter were included. Screening, follow-up, and hypertension recognition rates were evaluated. Descriptive statistics and multivariate logistical regression were used to determine patient and provider characteristics associated with increased screening and recognition of pediatric hypertension. Results: Among 378,002 children, blood pressure was documented in 33.3% of all encounters, increasing from 26.7% in 2011 to 36.2% in 2017; P=0.007. Blood pressure was documented in 76.0% of well child visits. Follow-up visits occurred within 6 months for 26.4% of children with elevated blood pressure, 57.1% of children with hypertension, and within 1 month for 7.2% of children with hypertension. Patient factors associated with increased blood pressure screening include being overweight (OR 2.15, CI 2.09 to 2.22), having diabetes (OR 1.69, CI 1.37 to 2.08), chronic kidney disease (OR 7.51, CI 6.54 to 8.62), increased social deprivation (OR 1.10, CI 1.09 to 1.11), and urban residence (OR 1.27, CI 1.15 to 1.4). Overall prevalence of hypertension was 1.9% (n=715) and of those, 5.6% (n=40) had recognized hypertension. Factors associated with increased recognition include male sex, overweight, and hyperlipidemia. Conclusions: Rates of hypertension screening and recognition are low in primary care settings in Canada, suggesting pediatric hypertension should be a priority for implementation and dissemination of interventions.

Impact of COVID-19 Pandemic on Adolescents and Young Adults Living With Type 2 Diabetes.

OBJECTIVES: The aim of this study was to assess the impacts of the COVID-19 pandemic on adolescents and young adults living with type 2 diabetes (T2D) involved in the national Improving Renal Complications in Adolescents with T2D through REsearch (iCARE) study. METHODS: The Environmental influences on Child Health Outcomes (ECHO) COVID-19 Questionnaire developed by the National Institutes of Health ECHO COVID-19 Task Force was administered to participants (n=85) from the iCARE study between June 2020 and October 2020. Children 12 years old (via parent report) and adolescents and young adults ≥13 years old (via self-report) participated. The questionnaire assessed the impact of the pandemic on health-care appointments, lifestyle, internet use, social connections and mental health. RESULTS: Participants were 17.0±3.1 (range, 12 to 27) years of age and predominantly female (61.3%). During the pandemic, 69.4% were able to attend their health-care appointments by telephone or virtual platforms, 31.7% ate more, 45.1% slept more and 29.3% spent less time on physical activities. There was an increase in internet use for both educational (42.0%) and noneducational purposes (54.9%). Participants felt less socially connected (64.6%). Participants also felt sometimes (59.2%), often (19.7%) and very often (6.7%) satisfied with their lives. DISCUSSION: Our study revealed that the COVID-19 pandemic has had various impacts on the daily lives of adolescents and young adults living with T2D. Future research should include longitudinal studies of the health burden of the COVID-19 pandemic on this population, with a more in-depth evaluation of mental health outcomes and clinical outcomes.

Urinary interleukin-9 in youth with type 1 diabetes mellitus.

AIMS: Interleukin-9 (IL-9) attenuates podocyte injury in experimental kidney disease, but its role in diabetic nephropathy is unknown. We sought to relate urinary IL-9 levels to the release of podocyte-derived extracellular vesicles (EVs) in youth with type 1 diabetes. We related urinary IL-9 levels to clinical variables and studied interactions between urinary IL-9, vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) on urinary albumin/creatinine ratio (ACR) a functional measure of podocyte injury. METHODS: We performed an analysis of urine samples and clinical data from a cohort of youth with type 1 diabetes (n = 53). Cytokines were measured using a Luminex platform (Eve Technologies), and nanoscale flow cytometry was employed to quantify urinary podocyte-derived EVs. All urinary measures were normalized to urinary creatinine. RESULTS: Mean age was 14.7 ± 1.6 years, and the mean time from diagnosis was 6.7 ± 2.9 years. Mean HbA1c was 70.3 ± 13.9 mmol/mol, mean ACR was 1.3 ± 1.9 mg/mmol, and mean eGFR was 140.3 ± 32.6 ml/min/1.73 m2. IL-9 was inversely related to podocyte EVs (r = - 0.56, p = 0.003). IL-9 was also inversely related to blood glucose, HbA1C and eGFR (r = - 0.44, p = 0.002; r = - 0.41, p = 0.003; r = - 0.49, p < 0.001, respectively) and positively correlated with systolic BP (r = 0.30, p = 0.04). There was a significant interaction between IL-9, EVs and ACR (p = 0.0143), and the relationship between IL-9 and ACR depended on VEGF (p = 0.0083), TNFα (p = 0.0231) and IL-6 levels (p = 0.0178). CONCLUSIONS: IL-9 is associated with podocyte injury in early type 1 diabetes, and there are complex interactions between urinary IL-9, inflammatory cytokines and ACR.

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.

Deriving Normative Data on 24-Hour Ambulatory Blood Pressure Monitoring for South Asian Children (ASHA): A Clinical Research Protocol.

BACKGROUND: The global prevalence of hypertension in children and adolescents has increased over the past 2 decades and is the strongest predictor of adult hypertension. South Asians have an increased prevalence of metabolic syndrome associated risk factors including abdominal obesity, diabetes, and hypertension. All these factors contribute to their increased cardiovascular disease burden. Accurate and early identification of hypertension in South Asian children is a necessary aspect of cardiovascular disease prevention. Ambulatory blood pressure monitoring (ABPM) is considered the gold-standard for pediatric blood pressure (BP) measurement. However, its utilization is limited due to the lack of validated normative reference data in diverse, multiethnic pediatric populations. OBJECTIVE: The primary objective is to establish normative height-sex and age-sex-specific reference values for 24-h ABPM measurements among South Asian children and adolescents (aged 5-17 years) in Ontario and British Columbia, Canada. Secondary objectives are to evaluate differences in ABPM measurements by body mass index classification, to compare our normative data against pre-existing data from German and Hong Kong cohorts, and to evaluate relationships between habitual movement behaviors, diet quality, and ABPM measurements. DESIGN: Cross-sectional study, quasi-representative sample. SETTING: Participants will be recruited from schools, community centers, and places of worship in Southern Ontario (Greater Toronto and Hamilton area, including the Peel Region) and Greater Vancouver, British Columbia. PARTICIPANTS: We aim to recruit 2113 nonoverweight children (aged 5-17 years) for the primary objective. We aim to recruit an additional 633 overweight or obese children to address the secondary objectives. MEASUREMENTS: Ambulatory BP monitoring measurements will be obtained using Spacelabs 90217 ABPM devices, which are validated for pediatric use. The ActiGraph GT3X-BT accelerometer, which has also been validated for pediatric use, will be used to obtain movement behavior data. METHODS: Following recruitment, eligible children will be fitted with 24-h ABPM and physical activity monitors. Body anthropometrics and questionnaire data regarding medical and family history, medications, diet, physical activity, and substance use will be collected. Ambulatory BP monitoring data will be used to develop height-sex- and age-sex-specific normative reference values for South Asian children. Secondary objectives include evaluating differences in ABPM measures between normal weight, overweight and obese children; and comparing our South Asian ABPM data to existing German and Hong Kong data. We will also use compositional data analysis to evaluate associations between a child's habitual movement behaviors and ABPM measures. LIMITATIONS: Bloodwork will not be performed to facilitate recruitment. A non-South Asian comparator cohort will not be included due to feasibility concerns. Using a convenience sampling approach introduces the potential for selection bias. CONCLUSIONS: Ambulatory BP monitoring is a valuable tool for the identification and follow-up of pediatric hypertension and overcomes many of the limitations of office-based BP measurement. The development of normative ABPM data specific to South Asian children will increase the accuracy of BP measurement and hypertension identification in this at-risk population, providing an additional strategy for primary prevention of cardiovascular disease.

CONTEXTE: La prévalence mondiale de l'hypertension chez les enfants et les adolescents a augmenté au cours des deux dernières décennies et constitue le plus important facteur prédictif de l'hypertension chez les adultes. Le syndrome métabolique associé aux facteurs de risque que sont l'obésité abdominale, le diabète et l'hypertension est plus prévalent chez les personnes d'origine sud-asiatique. Tous ces facteurs contribuent à une charge de morbidité cardiovasculaire accrue pour ces personnes. Le dépistage précis et précoce de l'hypertension chez les enfants d'Asie du Sud est un aspect incontournable de la prévention des maladies cardiovasculaires. Le monitoring ambulatoire de la pression artérielle (MAPA) est considéré comme la norme pour la mesure de la pression artérielle chez les enfants. Son utilization est toutefois limitée en raison de l'absence de références normatives validées dans des populations pédiatriques diversifiées et multiethniques. OBJECTIFS: L'objectif principal est d'établir des valeurs de référence normatives taille-sexe et âge-sexe pour les mesures de MAPA sur 24 heures chez les enfants et les adolescents d'origine sud-asiatique (âgés de 5-17 ans) de l'Ontario et de Colombie-Britannique (Canada). Les objectifs secondaires sont : 1) d'évaluer les différences dans les mesures de MAPA selon une classification basée sur l'indice de masse corporelle; 2) de comparer nos données normatives aux données préexistantes tirées de cohortes d'Allemagne et de Hong Kong, et 3) d'évaluer les relations entre les comportements actifs habituels, la qualité de l'alimentation et les mesures de MAPA. TYPE D'ÉTUDE: Étude transversale avec échantillon quasi représentatif. CADRE: Les participants seront recrutés dans des écoles, des centers communautaires et des lieux de culte du sud de l'Ontario (région du Grand Toronto et de Hamilton, y compris la région de Peel) et du Grand Vancouver en Colombie-Britannique. SUJETS: Nous souhaitons recruter 2113 enfants (5 à 17 ans) ne présentant pas de surpoids pour l'objectif principal. Et 633 enfants en surpoids ou obèses pour les objectifs secondaires. MESURES: Les mesures de MAPA seront obtenues à l'aide d'appareils Spacelabs 90217 validés pour un usage pédiatrique. L'accéléromètre ActiGraph GT3X-BT, également validé pour un usage pédiatrique, sera utilisé pour colliger des données sur le comportement actif. MÉTHODOLOGIE: Après le recrutement, les enfants admissibles seront équipés d'un appareil de MAPA pour 24 heures et de moniteurs d'activité physique. Les caractéristiques anthropométriques et les données d'un questionnaire portant sur les antécédents médicaux et familiaux, la médication, l'alimentation, l'activité physique et la consommation de substances seront recueillies. Les données de MAPA seront utilisées pour établir des valeurs de référence normatives taille-sexe et âge-sexe pour les enfants d'Asie du Sud. Les objectifs secondaires comprennent l'évaluation des différences dans les mesures de MAPA selon que les enfants ont un poids normal, un surpoids ou sont obèses, et la comparaison de nos données de MAPA pour des enfants d'Asie du Sud avec les données existantes en Allemagne et à Hong Kong. Nous procèderons également à l'analyze de composition des données afin d'évaluer les relations entre les comportements actifs habituels de l'enfant et les mesures de MAPA. LIMITES: Pour faciliter le recrutement, les analyses sanguines ne seront pas effectuées. Aucune cohorte de comparaison constituée de sujets non originaires d'Asie du Sud ne sera incluse en raison de problèmes de faisabilité. L'emploi d'une approche d'échantillonnage de commodité introduit un possible biais de sélection. CONCLUSION: Le MAPA est un outil précieux pour le dépistage et le suivi de l'hypertension pédiatrique et elle permet de surmonter plusieurs des limites de la mesure de la PA en cabinet. L'établissement de références normatives de MAPA spécifiques aux enfants d'Asie du Sud permettra d'accroître la précision de la mesure de la PA et le dépistage de l'hypertension dans cette population à risque, fournissant ainsi une stratégie supplémentaire pour la prévention primaire des maladies cardiovasculaires.