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Objective: To evaluate renal outcomes and survival in youth with type 2 diabetes (T2DM) versus type 1 diabetes (T1DM) versus nondiabetic control subjects.Research Design and Methods: In total, 342 prevalent youth (aged 1-18 years) with T2DM, 1,011 youth with T1DM, and 1,710 control subjects identified from 1986 to 2007 were anonymously linked to health care records housed at the Manitoba Centre for Health Policy to assess long-term outcomes using ICD codes.Results: Youth with T2DM were found to have a fourfold increased risk of renal failure versus youth with T1DM. Risk factors associated with renal failure were renin angiotensin aldosterone system inhibitor use and albuminuria in adolescence. Compared with control subjects (age, sex, and postal code matched), youth with T2DM had a 23-fold increased risk of renal failure and a 39-fold increased risk of dialysis. Kaplan-Meier survival at 10 years was 91.4% in the type 2 diabetic group versus 99.5% in the type 1 diabetic group (P < 0.0001). Renal survival was 100% at 10 years in both groups. It decreased to 92.0% at 15 years and 55.0% at 20 years in the type 2 diabetic group but remained stable in the type 1 diabetic group (P < 0.0001).Conclusions: Youth with T2DM are at high risk of adverse renal outcomes and death. Albuminuria and angiotensin aldosterone system inhibitor use, which may be a marker of severity of disease, are associated with poor outcomes in early adulthood. [ABSTRACT FROM AUTHOR]

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., (© 2024. The Author(s).)

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.

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; (R 2  = 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., Competing Interests: Declaration of competing interest All authors have no potential conflicts of interest to report., (Copyright © 2023. Published by Elsevier Inc.)

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 > 90 th 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., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Agarwal, Wicklow, Dart, Hizon, Sellers, McGavock, Talbot, Fonseca, Xu, Davie, Jones, Acharjee and Dolinsky.)

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., (© 2021. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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., (Copyright © 2021 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

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/m 2 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., Competing Interests: A-L. Lapeyraque reports advisory board attendances for Alexion Inc. All remaining authors have nothing to disclose. The funding agencies had no role in the design of study, collection, analysis, or interpretation of data., (Copyright © 2021 by the American Society of Nephrology.)

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 [HbA 1c ], 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 HbA 1c , 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., Competing Interests: Competing interests: Paul Komenda reports support from the Canadian Institutes of Health Research, outside the submitted work. Allison Dart reports funding from the Canadian Institutes of Health Research, the Children’s Hospital Research Institute of Manitoba and Research Manitoba, outside the submitted work. No other competing interests were declared., (© 2021 CMA Joule Inc. or its licensors.)

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., (Copyright © 2021 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests: JLS, JMM, ABD, EACS, MG, and MC have no financial conflicts to disclose. BAW has received funding from CIHR, Diabetes Canada, the Children’s Hospital Research Institute of Manitoba (CHRIM), and the Lawson Foundation for unrelated investigator‐led studies. She is currently the site PI for a Boehringer Ingelheim study unrelated to the current study content. She has not received monetary support personally from pharmaceutical companies. EACS has received funding from Diabetes Canada, CHRIM, and the Public Health Agency of Canada for unrelated investigator‐led studies. ABD currently has research funding from CIHR, Research Manitoba, and CHRIM. JMM, EACS, BAW, and ABD were also supported by a Research Manitoba grant to the DEVOTION research cluster. None of the cited agencies was involved in the design, conduct, or approval of this manuscript. JMM holds grants from the CIHR, Diabetes Canada, Children’s Hospital Foundation of Manitoba, the Heart and Stroke Foundation of Canada (HSFC), the Cosmopolitan Foundation, and the Lawson Foundation., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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/m 3 ) 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.

Aims/hypothesis: The release of podocyte-derived microparticles into the urine may reflect early kidney injury in diabetes. We measured the urinary excretion of podocyte-derived microparticles in youth with type 1 and type 2 diabetes, and related the values to blood pressure, renal function and blood glucose levels., Methods: Cross-sectional, exploratory analysis of urine samples and clinical data from youth with type 1 (n = 53) and type 2 (n = 50) diabetes was carried out. Urinary podocyte-derived microparticle numbers, measured by flow cytometry, were assessed in relation to measures of blood glucose levels and renal function., Results: Podocyte-derived microparticle excretion (MPE) normalised to urinary creatinine (MP/UCr) was higher in type 1 vs type 2 diabetes (median [IQR] MP/UCr: 7.88 [8.97] vs 1.84 [8.62]; p < 0.0001), despite the type 2 diabetes group having higher blood pressure (systolic blood pressure, median [range]: 124 [110-154] vs 114 [94-143] mmHg) and higher proportions of microalbuminuria (44.0% vs 13.2%), but shorter time since diabetes diagnosis (median [range]: 1.2 [0.0-7.0] vs 6.4 [2.0-13.9] years), than the type 1 diabetes cohort. MPE in youth with type 1 diabetes was associated with blood glucose (p = 0.01) and eGFR (p = 0.03) but not HbA 1c , systolic or diastolic blood pressure or urine albumin/creatinine ratio. After adjustment for age at baseline, duration of diabetes, sex and BMI, the association with eGFR remained significant (p = 0.04). No associations were found between MPE and these clinical variables in youth with type 2 diabetes., Conclusions/interpretation: Significant associations between podocyte MPE, blood glucose levels and eGFR were observed in youth with type 1 diabetes but not in those with type 2 diabetes, notwithstanding increased renal pathology in the type 2 diabetes cohort. These findings suggest that podocyte injury differs in the two diabetes cohorts. Graphical abstract.

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., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Background: The validity of pediatric estimated glomerular filtration rate equations (eGFRs) in early stages of CKD including hyperfiltration is unknown. The purpose of this study was to develop an eGFR equation for adolescents with obesity and type 2 diabetes (T2D)., Methods: eGFRs were developed from iohexol-derived GFRs (iGFRs) in 26 overweight/obese (BMI > 85th percentile) youth and 100 with T2D from the iCARE (Improving renal Complications in Adolescents with T2D through REsearch) cohort. Twenty percent of the cohort was withheld as a validation dataset. Linear regression analyses were used to develop the best formula based on body size, sex, creatinine, urea, ± cystatin C. Comparable validity of commonly used eGFR equations was assessed., Results: Mean age 15.4 + 2.4 years, BMI Z-score 2.5 + 1.2, 61% female, and mean iGFR 129.0 + 27.7 ml/min/ 1.73 m 2 . The best adjusted eGFR formula (ml/min/1.73 m 2 ) was 50.7 × BSA 0.816  × (height (cm)/creatinine) 0.405  × 0.8994 if sex = female | 1 otherwise. It resulted in 53.8% of eGFRs within 10% of measured iGFR and 96.2% within 30%. Bland-Altman 95% limits of agreement in the external dataset were - 37.6 to 45.5 ml/min/1.73m 2 (bias = 3.96), and the correlation was 0.62. This equation performed better than all previously published creatinine-based eGFRs. cystatin C did not significantly improve results; however, some other cystatin C formulas also performed well., Conclusions: The iCARE equation provides a more accurate creatinine-based eGFR in obese youth with and without T2D. Further studies are warranted to evaluate within-subject variability and applicability to lower GFRs and other populations.

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 i mproving renal C omplications in A dolescents with type 2 diabetes through RE search 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., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

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.

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 m 2 (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 m 2 . Overall, 29 % of the patients started dialysis with an eGFR of ≥10.5 ml/min/1.73 m 2 . 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 m 2 , 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.

Objective: Type 2 diabetes is increasing in children worldwide, with Canadian First Nations (FN) children disproportionally affected. The prevalence of gestational diabetes mellitus (GDM) also is increasing. The objective of this study was to evaluate the impact of GDM exposure in utero and FN status on the subsequent risk of type 2 diabetes in offspring in the first 30 years of life., Research Design and Methods: In this population-based historical prospective cohort study, we used administrative databases linked to a clinical database to explore the independent association and interaction between GDM and FN status on the subsequent development of type 2 diabetes in offspring., Results: Among 321,008 births with a median follow-up of 15.1 years, both maternal GDM and FN status were independently associated with subsequent risk of type 2 diabetes in offspring in the first 30 years of life (hazard ratio 3.03 [95% CI 2.44-3.76; P < 0.0001] vs. 4.86 [95% CI 4.08-5.79; P < 0.0001], respectively). No interaction between GDM and FN status on type 2 diabetes risk was observed. FN status had a stronger impact on the development of type 2 diabetes in offspring than GDM., Conclusions: GDM is an important modifiable risk factor for type 2 diabetes, and its prevention may reduce the prevalence of subsequent type 2 diabetes in offspring. This study adds unique and rigorous evidence to the global public health debate about the impact of GDM on the long-term health of offspring., (© 2016 by the American Diabetes Association.)

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.

Background: Over the past 30 years, the prevalence of diabetes has steadily increased among Canadians, and is particularly evident among First Nations (FN) women. The interplay between FN ancestry, gestational diabetes and the development of subsequent diabetes among mothers remains unclear., Methods: After excluding known pre-existing diabetes, we explored whether FN ancestry may modify the association between gestational diabetes and post-partum diabetes among women in Manitoba (1981-2011) via a historical prospective cohort database study. We analysed administrative data in the Population Health Research Data Repository using Kaplan-Meier survival analysis and Cox proportional hazards regression., Results: Gestational diabetes was diagnosed in 11 906 of 404 736 deliveries (2.9%), 6.7% of FN and 2.2% of non-FN pregnant women (P < 0.0001). Post-partum diabetes during ≤ 30 years follow-up was more than three times higher among FN women than among non-FN women (P < 0.0001). Diabetes developed in 76.0% of FN and 56.2% of non-FN women with gestational diabetes within the follow-up period. The hazard ratio of gestational diabetes for post-partum diabetes was 10.6 among non-FN women and 5.4 among FN women. Other factors associated with a higher risk of diabetes included lower family income among FN and non-FN women and rural/remote residences among FN women. Among non-FN women, urban residence was associated with a higher risk of diabetes., Conclusion: Gestational diabetes increases post-partum diabetes in FN and non-FN women. FN women had substantially more gestational diabetes or post-partum diabetes than non-FN women, partially due to socio-economic and environmental barriers. Reductions in gestational diabetes and socio-economic inequalities are required to prevent diabetes in women, particularly in FN population., (© 2015 Diabetes UK.)

Background: Significant practice variation exists in Canada with respect to timing of dialysis initiation in children. In the absence of evidence to guide practice, physicians' perceptions may significantly influence decision-making., Objective: The objectives of this study are to (1) evaluate Canadian pediatric nephrologists' perceptions regarding dialysis initiation in children with chronic kidney disease (CKD) and (2) determine the factors guiding practice that may contribute to practice variation across Canada., Design: This study was a cross-sectional online survey., Setting: This study was done in academic pediatric nephrology centers in Canada., Participants: The participants of this study are pediatric nephrologists., Measurements and Methods: An anonymous web-based survey was administered to pediatric nephrologists in Canada to evaluate perspectives and practice patterns regarding timing of dialysis initiation. We also explored the importance of estimated glomerular filtration rate (eGFR) vs. symptoms and the role of patient and provider factors influencing decisions., Results: Thirty-five nephrologists (59 %) completed the survey. Most respondents care for advanced CKD patients in a multidisciplinary clinic (86 %) and no centers have a formal policy on timing of dialysis initiation. Seventy-five percent of centers follow <20 stage 4-5 CKD patients, and 9 % follow >30 patients. Discussions about dialysis initiation are generally informal (75 %) and the decision to start is made by the nephrologist (37 %) or a team (57 %). Fifty percent agreed GFR was important when deciding when to initiate dialysis, 41 % were neutral, and 9 % disagreed. Variability exists in the threshold that nephrologists considered early (vs. late) dialysis initiation: >20 (21 %), >15 (38 %), >12 (26 %), and >10 ml/min/1.73 m(2) (12 %). Practitioners however typically start dialysis in asymptomatic patients at eGFRs of 7-9 (9 %), 10-11 (41 %), 12-14 (38 %), and 15-19 (6 %) ml/min/1.73 m(2). Patient factors important in the decision to start dialysis for >90 % of nephrologists were fatigue, >10 % weight loss, nausea, increasing missed school, and awaiting a pre-emptive transplant. Age was only a factor for 56 %., Limitations: This study has a 59 % response rate., Conclusions: Variability exists in Canada regarding the importance and threshold of eGFR guiding the decision as to when to start dialysis in children, whereas patient symptoms are almost universally important to pediatric nephrologists' decision-making. Additional studies evaluating outcomes of children starting dialysis earlier vs. later are needed to standardize decision-making and care for children with kidney failure.

Objective: To determine the prevalence and the clinical features associated with persistent albuminuria in Canadian children aged <18 years with type 2 diabetes., Study Design: This national prospective surveillance study involved a network of pediatricians and pediatric endocrinologists. Cases of persistent albuminuria in children with type 2 diabetes were reported during a 24-month period from 2010 to 2012. Persistent albuminuria was defined as an elevated albumin-to-creatinine ratio in a minimum of 2 out of 3 urine samples obtained at least 1 month apart over 3-6 months and confirmed with a first morning sample. Descriptive statistics were used to illustrate demographic and clinical features of the population. The prevalence of persistent albumuria was estimated using data from a previous national surveillence study of type 2 diabetes in children., Results: Fifty cases were reported over the 24-month study period. The estimated prevalence of persistent albuminuria in children with type 2 diabetes in Canada was 5.1%. The median duration of diabetes at the time of diagnosis of albuminuria was 21 days (IQR, 0-241 days). Almost two-thirds (64%) were female, 80% were of Canadian First Nations heritage, and 76% were from Manitoba. Exposure to gestational or pregestational diabetes in utero occurred in 65%, and 48% had a family history of diabetes-related renal disease. Structural anomalies of the kidney were found in 37%., Conclusion: Persistent albuminuria occurs in youths with type 2 diabetes in the first year after diagnosis, demonstrates regional variation, and is associated with First Nations heritage and exposure to maternal diabetes during pregnancy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are the primary cause of chronic kidney disease in children. The relevance of timing of diabetes mellitus (DM) exposure on risk of CAKUT in exposed children is unknown., Study Design: Population-based nested case-control study., Setting & Participants: Infants born between fiscal years 1996/1997 and 2009/2010 in Manitoba, Canada, identified using administrative data housed at the Manitoba Centre for Health Policy., Predictors: Pregestational (including first 20 weeks' gestation) and gestational (>20 weeks) DM and relevant confounders (maternal age; renin-angiotensin-aldosterone system inhibitor use; low socioeconomic status; alcohol, illicit drug, and smoking use during pregnancy; region of residence; and size for gestational age [surrogate of glycemic control])., Outcome: CAKUT identified by International Classification of Diseases codes., Results: 945 case patients with CAKUT and 4,725 controls (matched for gestational age, sex, and birth year) were identified. Maternal pregestational DM occurred in 39 (4.1%) of the CAKUT group and 111 (2.3%) controls (P = 0.002), whereas gestational DM occurred in 40 (4.2%) of the CAKUT group and 157 (3.3%) controls (P = 0.2). In the conditional multivariable logistic regression model, pregestational DM was associated with CAKUT (OR, 1.67; 95% CI, 1.14-2.46), whereas gestational DM was not (OR, 1.29; 95% CI, 0.90-1.85). Both large (LGA) and small for gestational age (SGA) also were associated significantly with CAKUT (LGA: OR, 1.34 [95% CI, 1.11-1.63]; SGA: OR, 1.59 [95% CI, 1.26-2.01])., Limitations: Lack of data for maternal glycemic control and body mass index., Conclusions: This study suggests that DM in the first 20 weeks of pregnancy is associated with CAKUT in exposed infants. The association between CAKUT and LGA suggests that poor glycemic control increases risk. Screening and intervention studies in women of childbearing age with DM are warranted to determine whether the risk of chronic kidney disease in children can be modified., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Youth-onset type 2 diabetes is associated with a high burden of renal complications, culminating with end stage kidney disease in early adulthood. The establishment of relevant bioclinical determinants of albuminuria and ultimately progression of chronic kidney disease in youth is critically important to facilitate patient risk stratification and aid in the development of treatment targets and tailored prevention strategies. In response to the important gaps in knowledge, we created a prospective cohort study of youth with type 2 diabetes titled the Improving Renal Complications in Adolescents with Type 2 Diabetes through the REsearch (iCARE) Study., Methods: iCARE is a prospective observational cohort study of individuals with type 2 diabetes diagnosed prior to 18 years of age; the recruitment target was 400 patients. Phase 1 entailed a detailed phenotypic assessment of youth, including anthropometrics, biochemistry, 24-hour ambulatory blood pressure monitoring, overnight urine collections for albumin excretion, renal ultrasound and iohexol-derived glomerular filtration rate. Phase 2 of the study is an evaluation of psychological factors, including hair-derived cortisol; validated questionnaires for perceived stress, distress and resiliency; and a detailed evaluation of systemic and urine inflammatory biomarkers. Annual follow up is planned to assess temporal associations between clinical risk factors and renal outcomes, including progression of albuminuria., Conclusion: This study will provide novel insight into the risk factors for albuminuria and progression of chronic kidney disease in youth with type 2 diabetes. New knowledge generated by this study will inform clinical care, and the infrastructure developed will provide a framework for future intervention studies., (Copyright © 2014 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the risk of complications in youth with type 2 diabetes., Research Design and Methods: Population-based cohorts of 342 youth (1-18 years of age) with prevalent type 2 diabetes, 1,011 youth with type 1 diabetes, and 1,710 nondiabetic control youth were identified between 1986 and 2007 from a clinical registry and linked to health care records to assess long-term outcomes using ICD-9CM and ICD-10CA codes., Results: Youth with type 2 diabetes had an increased risk of any complication (hazard ratio 1.47 [95% CI 1.02-2.12]). Significant adverse clinical factors included age at diagnosis (1.08 [1.02-2.12]), HbA1c (1.06 [1.01-1.12]), and, surprisingly, renin-angiotensin-aldosterone system (RAAS) inhibitor use (1.75 [1.27-2.41]). HNF-1α G319S polymorphism was protective in the type 2 diabetes cohort (0.58 [0.34-0.99]). Kaplan-Meier statistics revealed an earlier diagnosis of renal and neurologic complications in the type 2 diabetes cohort, manifesting within 5 years of diagnosis. No difference in retinopathy was seen. Cardiovascular and cerebrovascular diseases were rare; however, major complications (dialysis, blindness, or amputation) started to manifest 10 years after diagnosis in the type 2 diabetes cohort. Youth with type 2 diabetes had higher rates of all outcomes than nondiabetic control youth and an overall 6.15-fold increased risk of any vascular disease., Conclusions: Youth with type 2 diabetes exhibit complications sooner than youth with type 1 diabetes. Younger age at diagnosis is potentially protective, and glycemic control is an important modifiable risk factor. The unexpected adverse association between RAAS inhibitor use and outcome is likely a confounder by indication; however, further evaluation in young people is warranted.

Background: Practice variation is common for nephrotic syndrome (NS) treatment., Methods: A cross-sectional, web-based survey on NS treatment was administered to 58 Canadian pediatric nephrologists with the aim to document existing practice variation and compare practice with the recommendations of the Kidney Disease Improving Global Outcomes Clinical Practice Guideline for NS., Results: Of the 58 nephrologists asked to participate in the survey, 40 (69 %) responded. Among these, 62 % prescribed initial daily glucocorticoid (GC) therapy for 6 weeks, 26 % for 4 weeks by 26 %, and 10 % prescribed 'other'. Alternate-day GC was continued for 6 weeks by 63 % of respondents and for >6 and <6 weeks by 32 and 6 %, respectively. For biopsy-confirmed minimal change disease, 65 and 46 % of respondents chose oral cyclophosphamide for frequently relapsing and steroid-dependent phenotypes, respectively; calcineurin inhibitors or mycophenolate were the second most popular choices. Kidney biopsy was 'always' performed by 16, 39, and 97 % of respondents for frequently relapsing, steroid-dependent, and steroid-resistant patients, respectively. Rituximab had been administered by 60 % of respondents; 22, 56, and 72 % reported that they would consider rituximab for frequently relapsing, steroid-dependent, and steroid-resistant patients, respectively. Most notable differences between practice and Guideline recommendations were first presentation GC duration, GC-sparing agent choices in frequently relapsing and steroid-dependent patients, and biopsy practices., Conclusions: There is substantial Canadian practice variation in NS treatment. Assessment of factors driving variation and strategies to implement Guideline recommendations are needed.

Background: Hydroxyethyl starches (HES) are synthetic colloids commonly used for fluid resuscitation to replace intravascular volume, yet they have been increasingly associated with adverse effects on kidney function. This is an update of a Cochrane review first published in 2010., Objectives: To examine the effects of HES on kidney function compared to other fluid resuscitation therapies in different patient populations., Search Methods: We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library), MEDLINE, EMBASE, MetaRegister and reference lists of articles. The most recent search was completed on November 19, 2012., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs in which HES was compared to an alternate fluid therapy for the prevention or treatment of effective intravascular volume depletion. Primary outcomes were renal replacement therapy (RRT), author-defined kidney failure and acute kidney injury (AKI) as defined by the RIFLE criteria., Data Collection and Analysis: Screening, selection, data extraction and quality assessments for each retrieved article were carried out by two authors using standardised forms. All outcomes were analysed using relative risk (RR) and 95% confidence intervals (95% CI). Authors were contacted when published data were incomplete. Preplanned sensitivity and subgroup analyses were performed after data were analysed with a random-effects model., Main Results: This review included 42 studies (11,399 patients) including 19 studies from the original review (2010), as well as 23 new studies. Fifteen studies were excluded from the original review (nine retracted from publication due to concerns about integrity of data and six lacking individual patient creatinine data for the calculation of RIFLE criteria). Overall, there was a significant increase in the need for RRT in the HES treated individuals compared to individuals treated with other fluid therapies (RR 1.31, 95% CI 1.16 to 1.49; 19 studies, 9857 patients) and the number with author-defined kidney failure (RR 1.59, 95% CI 1.26 to 2.00; 15 studies, 1361 patients). The RR of AKI based on RIFLE-F (failure) criteria also showed an increased risk of AKI in individuals treated with HES products (RR 1.14, 95% CI 1.01 to 1.30; 15 studies, 8402 participants). The risk of meeting urine output and creatinine based RIFLE-R (risk) criteria for AKI was in contrast in favour of HES therapies (RR 0.95, 95% CI 0.91 to 0.99; 20 studies, 8769 patients). However, when RIFLE-R urine output based outcomes were excluded as per study protocol, the direction of AKI risk again favoured the other fluid type, with a non-significant RR of AKI in HES treated patients (RR 1.05, 95% CI 0.97 to 1.14; 8445 patients). A more robust effect was seen for the RIFLE-I (injury) outcome, with a RR of AKI of 1.22 (95% CI 1.08 to 1.37; 8338 patients). No differences between subgroups for the RRT and RIFLE-F based outcomes were seen between sepsis versus non-sepsis patients, high molecular weight (MW) and degree of substitution (DS) versus low MW and DS (≥ 200 kDa and > 0.4 DS versus 130 kDa and 0.4 DS) HES solutions, or high versus low dose treatments (i.e. ≥ 2 L versus < 2 L). There were differences identified between sepsis versus non-sepsis subgroups for the RIFLE-R and RIFLE-I based outcomes only, which may reflect the differing renal response to fluid resuscitation in pre-renal versus sepsis-associated AKI. Overall, methodological quality of the studies was good., Authors' Conclusions: The current evidence suggests that all HES products increase the risk in AKI and RRT in all patient populations and a safe volume of any HES solution has yet to be determined. In most clinical situations it is likely that these risks outweigh any benefits, and alternate volume replacement therapies should be used in place of HES products.

Youth onset type 2 diabetes (T2DM) continues to increase worldwide, concomitant with the rising obesity epidemic. There is evidence to suggest that youth with T2DM are affected by the same comorbidities and complications as adults diagnosed with T2DM. This review highlights specifically the kidney disease associated with youth onset T2DM, which is highly prevalent and associated with a high risk of end-stage kidney disease in early adulthood. A general understanding of this complex disease by primary care providers is critical, so that at-risk individuals are identified and managed early in the course of their disease, such that progression can be modified in this high-risk group of children and adolescents. A review of the pediatric literature will include a focus on the epidemiology, risk factors, pathology, screening, and treatment of kidney disease in youth onset T2DM.

Objective: To validate a case definition for diabetes in the pediatric age-group using administrative health data., Research Design and Methods: Population-based administrative data from Manitoba, Canada for the years 2004-2006 were anonymously linked to a clinical registry to evaluate the validity of algorithms based on a combination of hospital claim, outpatient physician visit, and drug use data over 1-3 years in youth 1-18 years of age. Agreement between data sources, sensitivity, specificity, negative (NPV) and positive predictive value (PPV) were evaluated for each algorithm. In addition, ascertainment rate of each data source, prevalence, and differences between subtypes of diabetes were evaluated., Results: Agreement between data sources was very good. The diabetes definition including one or more hospitalizations or two or more outpatient claims over 2 years provided a sensitivity of 94.2%, specificity of 99.9%, PPV of 81.6% and NPV of 99.9%. The addition of one or more prescription claims to the same definition over 1 year provided similar results. Case ascertainment rates of both sources were very good to excellent and the ascertainment-corrected prevalence for youth-onset diabetes for the year 2006 was 2.4 per 1,000. It was not possible to distinguish between subtypes of diabetes within the administrative database; however, this limitation could be overcome with an anonymous linkage to the clinical registry., Conclusions: Administrative data are a valid source for the determination of pediatric diabetes prevalence that can provide important information for health care planning and evaluation.

Background: In pediatric recipients, the pathophysiology of chronic renal allograft injury is poorly understood., Methods: We studied the evolution and determinants of tubulointerstitial, vascular, and glomerular injury in 240 pediatric protocol renal allograft biopsies during the first 5 years posttransplant., Results: Chronic tubulointerstitial injury (ci, ct) developed predominantly during the first 12 months posttransplant, whereas chronic vascular damage (cv, and arteriolar hyalinosis [ah]) and global glomerulosclerosis (gs) became increasingly prevalent at 25 to 36 months and beyond. Chronic interstitial lesions were associated with acute rejection and borderline histology (odds ratio [OR] 2.3, P<0.04), recipient body surface area less than 1.0 m2 (OR 3.6, P<0.05), and obesity (OR 2.0, P<0.03). Determinants of ct were acute rejection (OR 2.6, P=0.02) and acute tubular necrosis (OR 2.8, P<0.04). Vascular fibrous intimal thickening and ah were associated with donor hypertension (OR 3.6, P=0.001) and recipient body surface area less than 1.0 m (OR 2.6, P=0.02), respectively. The severity of ah correlated with the incidence of gs (r=0.32, P<0.0001), with 7.8% gs for ah0, 14.3% gs for ah1, 60.0% gs for ah2, and 95.5% gs for ah3 (median values). Antibody induction conferred protection from ci (OR 0.31, P=0.008), ct (OR 0.33, P=0.002), and ah (OR 0.12, P<0.001) progression., Conclusions: By 5 years posttransplant, pediatric renal allografts manifest a substantial burden of tubulointerstitial and microvascular injury. These lesions are associated with donor hypertension, acute inflammation, renal hypoperfusion, obesity, and calcineurin inhibitor toxicity. The pervasiveness and rapid progression of microvascular lesions at 25 to 36 months suggest that attempts at reducing calcineurin inhibitor exposure should be made before two years posttransplant.

Background: Hydroxyethyl starches (HES) are synthetic colloids commonly used for fluid resuscitation, yet controversy exists about their impact on kidney function., Objectives: To examine the effects of HES on kidney function compared to other fluid resuscitation therapies in different patient populations., Search Strategy: We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library), MEDLINE, EMBASE, MetaRegister and reference lists of articles., Selection Criteria: Randomised controlled trials (RCTs) and quasi-RCTs in which HES was compared to an alternate fluid therapy for the prevention or treatment of effective intravascular volume depletion. Primary outcomes were renal replacement therapy (RRT), author-defined kidney failure and acute kidney injury (AKI) as defined by the RIFLE criteria. Secondary outcomes included serum creatinine and creatinine clearance., Data Collection and Analysis: Screening, selection, data extraction and quality assessments for each retrieved article were carried out by two authors using standardised forms. Authors were contacted when published data were incomplete. Preplanned sensitivity and subgroup analyses were performed after data were analysed with a random effects model., Main Results: The review included 34 studies (2607 patients). Overall, the RR of author-defined kidney failure was 1.50 (95% CI 1.20 to 1.87; n = 1199) and 1.38 for requiring RRT (95% CI 0.89 to 2.16; n = 1236) in HES treated individuals compared with other fluid therapies. Subgroup analyses suggested increased risk in septic patients compared to non-septic (surgical/trauma) patients. Non-septic patient studies were smaller and had lower event rates, so subgroup differences may have been due to lack of statistical power in these studies. Only limited data was obtained for analysis of kidney outcomes by the RIFLE criteria. Overall, methodological quality of studies was good but subjective outcomes were potentially biased because most studies were unblinded., Authors' Conclusions: Potential for increased risk of AKI should be considered when weighing the risks and benefits of HES for volume resuscitation, particularly in septic patients. Large studies with adequate follow-up are required to evaluate the renal safety of HES products in non-septic patient populations. RIFLE criteria should be applied to evaluate kidney function in future studies of HES and, where data is available, to re-analyse those studies already published. There is inadequate clinical data to address the claim that safety differences exist between different HES products.

In 1999, our center implemented a policy of outpatient protocol biopsies as standard practice for the clinical management of pediatric renal allograft recipients. In order to determine the safety of this procedure, we conducted a retrospective chart audit of all outpatient renal allograft biopsies performed at our center. Biopsies were performed under conscious (midazolam) or procedural (propofol/fentanyl) sedation. Localization of the lower pole of the renal allograft was achieved with renal ultrasound. Using a Biopty gun with a 16-gauge needle, two cores were obtained. Patients were discharged four h post-biopsy. Patient demographics, hospital length of stay (LOS), specimen adequacy (per Banff criteria) and major and minor adverse events were recorded in a central database. Data were expressed as mean +/- SD. From June 1999 to July 2004, we performed 162 biopsies in 43 pediatric renal allograft recipients. Most patients underwent extraperitoneal transplantation (42/43, 97.7%) and were greater than five yr of age at biopsy (129/131 biopsies, 98.5%). The majority of these procedures (131/162, 80.9%) were conducted in the outpatient department, with 113 of 131 (86.3%) being obtained for protocol (n = 89) and one-month follow-up acute rejection therapy (n = 24) indications. Patients underwent 3.7 +/- 2.7 biopsies (range = 1-11). Specimen adequacy was achieved in 119 of 124 (96.0%) of documented cases. The overall incidence of adverse events was 12 of 131 (9.2%) biopsies, all of which were minor in severity. Macroscopic hematuria was the most common minor adverse event, occurring after 11 of 131 (8.4%) biopsies. While macroscopic hematuria prolonged LOS (adverse events vs. no adverse events: 23.0 +/- 26.0 vs. 8.6 +/- 4.1 h, p = 0), none of these episodes required major surgical or radiographic interventions. We conclude that in patients greater than five yr of age with extraperitoneal renal allografts, outpatient protocol biopsies using a 16-gauge needle are sufficiently safe to justify their inclusion in the routine clinical management of pediatric renal allograft recipients and in pediatric clinical trials.