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.

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.

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.

Perspectives of Clinicians on Shared Decision Making in Pediatric CKD: A Qualitative Study.

RATIONALE & OBJECTIVE: Clinical decision-making priorities may differ among children, their parents, and their clinicians. This study describes clinicians' perspectives on shared decision making in pediatric chronic kidney disease (CKD) and identifies opportunities to improve shared decision making and care for children with CKD and their families. STUDY DESIGN: Semistructured interviews. SETTING & PARTICIPANTS: Fifty clinicians participated, including pediatric nephrologists, nurses, social workers, surgeons, dietitians, and psychologists involved in providing care to children with CKD. They worked at 18 hospitals and 4 university research departments across 11 countries (United States of America, Canada, Australia, People's Republic of China, United Kingdom, Germany, France, Italy, Lithuania, New Zealand, and Singapore). ANALYTICAL APPROACH: Interview transcripts were analyzed thematically. RESULTS: We identified 4 themes: (1) striving to blend priorities (minimizing treatment burden, emphasizing clinical long-term risks, achieving common goals), (2) focusing on medical responsibilities (carrying decisional burden and pressure of expectations, working within system constraints, ensuring safety is foremost concern), (3) collaborating to achieve better long-term outcomes (individualizing care, creating partnerships, encouraging ownership and participation in shared decision making, sensitive to parental distress), and (4) forming cumulative knowledge (balancing reassurance and realistic expectations, building understanding around treatment, harnessing motivation for long-term goals). LIMITATIONS: Most clinicians were from high-income countries, so the transferability of the findings to other settings is uncertain. CONCLUSIONS: Clinicians reported striving to minimize treatment burden and working with children and their families to manage their expectations and support their decision making. However, they are challenged with system constraints and sometimes felt the pressure of being responsible for the child's long-term outcomes. Further studies are needed to test whether support for shared decision making would promote strategies to establish and improve the quality of care for children with CKD.

Patient and caregiver perspectives on blood pressure in children with chronic kidney disease.

BACKGROUND: More than 50% of children with chronic kidney disease (CKD) have uncontrolled hypertension, increasing their long-term risk of cardiovascular disease and progression to kidney failure. Children receiving medications or dialysis may also experience acute blood pressure fluctuations accompanied by debilitating symptoms. We aimed to describe the perspectives of children with CKD and their parental caregivers on blood pressure to inform patient-centered care. METHODS: Secondary thematic analysis was conducted on qualitative data from the Standardized Outcomes in Nephrology-Children and Adolescents initiative, encompassing 16 focus groups, an international Delphi survey and two consensus workshops. We analyzed responses from children with CKD (ages 8-21 years) and caregivers (of children ages 0-21 years) pertaining to blood pressure. RESULTS: Overall, 120 patients and 250 caregivers from 22 countries participated. We identified five themes: invisibility and normalization (reassured by apparent normotension, absence of symptoms and expected links with CKD), confused by ambiguity (hypertension indistinguishable from cardiovascular disease, questioning the need for prophylactic intervention, frustrated by inconsistent messages and struggling with technical skills in measurement), enabling monitoring and maintaining health (gaging well-being and preventing vascular complications), debilitating and constraining daily living (provoking anxiety and agitation, helpless and powerless and limiting life activities) and burden of medications (overwhelmed by the quantity of tablets and distress from unexpected side effects). CONCLUSIONS: For children with CKD and their caregivers, blood pressure was an important heath indicator, but uncertainty around its implications and treatment hampered management. Providing educational resources to track blood pressure and minimizing symptoms and treatment burden may improve outcomes in children with CKD.

Sociodemographic determinants of chronic kidney disease in Indigenous children.

Rates of chronic kidney disease (CKD) are disproportionately increased in Indigenous peoples. The focus has traditionally been on adults, as they experience the highest rates of kidney failure requiring kidney replacement therapy. The impacts of colonization, systemic racism, and sociodemographic marginalization however impact the health of Indigenous peoples across the lifespan. This review presents the social context within which Indigenous children develop and the impact relevant to kidney health across the developmental stages. In utero exposures impact nephron endowment which can manifest in glomerular hyperfiltration and sclerosis as well as an increased risk of congenital anomalies of the kidney and urinary tract. Young children are at increased risk of autoimmune conditions, secondary to infectious and environmental exposures, and are also exposed to the impacts of a Western lifestyle manifesting early onset overweight/obesity. Adolescents begin to manifest more severe metabolic complications such as type 2 diabetes. The impacts of early onset diabetes are associated with aggressive kidney complications and high rates of kidney failure in young adulthood. Finally, the key elements of successful prevention and treatment strategies are discussed including the importance of screening for asymptomatic, modifiable early disease, linked with clinical primary and tertiary care follow-up, and culturally relevant and safe care.

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

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

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.

Maternal body mass index, offspring body mass index, and blood pressure at 18 years: a causal mediation analysis.

OBJECTIVE: Understanding the natural history of hypertension is key to identifying prevention strategies. Previous work suggests that in utero exposures and offspring anthropometrics may play a role. This study examined the relationship between maternal pre-pregnancy body mass index (BMI) and the mediating role of childhood and adolescent BMI on offspring blood pressure at 18 years. METHODS: We performed multivariable regression and causal mediation analyses within 3217 mother - offspring pairs from the Avon Longitudinal Study of Parents and Children prospective birth cohort. The main exposure was maternal pre-pregnancy BMI, and the outcome was offspring blood pressure at 18 years of age categorized as normal or elevated. Latent trajectory analysis was used to quantify the mediator, offspring BMI trajectories, derived from multiple measurements throughout childhood and adolescence. Mediation analyses were repeated using current offspring BMI at 18 years as a continuous variable. RESULTS: Multivariable logistic regression revealed that for every 1 unit increase in maternal BMI, the risk of elevated blood pressure at 18 years of age increased by 5% (aOR: 1.05, 95% CI: 1.03-1.07; p < 0.001). The strength of this association was reduced after adjusting for offspring BMI trajectory (aOR: 1.03, 95% CI: 1.00-1.05; p = 0.017) and eliminated after adjusting for offspring BMI at 18 years (aOR: 1.00; 95% CI: 0.98-1.03; p = 0.70). Causal mediation analysis confirmed offspring BMI at 18 years as a mediator, where BMI trajectory accounted for 46% of the total effect of maternal BMI on elevated offspring blood pressure and current BMI account for nearly the entire effect. CONCLUSIONS: Maternal pre-pregnancy BMI is associated with an increased risk of elevated blood pressure in offspring at 18 years of age although it appears to be entirely mediated by offspring BMI.

Experiences of First Nations adolescents living with type 2 diabetes: a focus group study.

BACKGROUND: Despite prevention efforts, type 2 diabetes mellitus continues to increase in incidence among First Nations children and is associated with early and aggressive complications. We aimed to determine the experiences of adolescents living with type 2 diabetes and the barriers to living well with type 2 diabetes that adolescents perceived. METHODS: We recruited adolescents with type 2 diabetes mellitus from the pediatric diabetes clinic in Winnipeg, Manitoba, to participate in a day-long facilitated focus group discussion. Group discussions were recorded and transcribed verbatim. We used interpretive description methodology to inform the thematic analysis of the transcripts. RESULTS: Eight adolescents with a mean age of 15 years participated. Five adolescents identified as female; most were Indigenous (7/8). The mean duration since diagnosis of diabetes was 2.5 years. Adolescents reported struggling with acceptance of their diagnosis, with the stigma and shame associated with the diagnosis and with daily self-management tasks. Three themes were developed from the focus group discussions: bearing witness, the "weight" of diabetes and support (lack of support). INTERPRETATION: Adolescents with diagnoses of type 2 diabetes experience associated stigma and shame, which are substantial barriers to self-care. A broader understanding of their lived experience, including the socioecological and emotional context, could help to improve health care provision and intervention strategies for this population.

Impact of point-of-care screening for hypertension, diabetes and progression of chronic kidney disease in rural Manitoba Indigenous communities.

BACKGROUND: In 2013-2015, we conducted point-of-care screening for hypertension, diabetes and chronic kidney disease in rural and remote Indigenous communities in Manitoba, Canada. In this study, we aimed to determine whether optimal follow-up care was provided, defined as proportion of individuals with appropriate kidney disease laboratory testing, medication prescriptions and physician visits. METHODS: We linked screening data from participants to provincial administrative data sets to evaluate whether frequencies of laboratory testing, prescriptions of disease-modifying medications, and primary care and nephrology visits differed in the 18 months before and after screening. We also conducted a propensity score matching analysis to compare outcomes between screened and unscreened adults. RESULTS: Of 1353 adults who received the screening intervention and who had complete administrative data available, 44% were at risk of kidney failure at screening. Among these individuals, frequencies of comprehensive laboratory testing (estimated glomerular filtration rate and urine albumin to creatinine ratio) improved by 17.0% (95% confidence interval [CI] 11.5 to 22.5), anti-hyperglycemic medications improved by 4.4% (95% CI 1.0 to 7.8), and nephrology visits for participants meeting referral criteria improved by 5.9% (95% CI 3.4 to 8.5). We observed significant improvements in laboratory testing, antihyperglycemic medications and nephrology visits in the screened group compared with the 1:1 matched comparison group. INTERPRETATION: Point-of-care screening programs in rural and remote Indigenous communities are adaptable methods for increasing awareness, monitoring risk and treating chronic diseases. Interventions such as the development of a national screening program could improve chronic disease care in high-risk populations.

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

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

Youth perceptions and experiences of type 2 diabetes: Protocol for a collaborative knowledge translation approach and qualitative study.

AIMS: The aim of this study is to generate an in-depth understanding of youth perceptions and experiences of living with type 2 diabetes to inform knowledge translation, research and intervention development. DESIGN: Interpretive descriptive qualitative study. METHODS: Twenty to 25 youth aged 10-18 years with a diagnosis of type 2 diabetes will be purposively recruited through the Diabetes Education Resource for Children and Adolescents in Winnipeg, Manitoba, and through the Improving Renal Complications in Adolescents With Type 2 Diabetes Through the REsearch [iCARE] cohort. Socio-demographic information will be collected. Semi-structured interviews will occur iteratively with inductive thematic analysis. Data will be professionally transcribed and managed using NVivo 1.0 software. The University Ethics Committee approved this study (May 2020). DISCUSSION: There is a critical gap in understanding youth experiences of type 2 diabetes. Research involving youth with type 2 diabetes is predominantly quantitative in nature, largely reflecting risk factors, underlying mechanisms and treatment outcomes associated with diabetes management. In-depth qualitative research on youth experiences can help identify youth priorities, provide insight into critical misalignments between stakeholder perspectives, and drive forward a more consolidated youth-centred research agenda. IMPACT: Understanding and applying knowledge of youth experiences is critical as the prevalence of, and challenges associated with, youth onset type 2 diabetes continues to increase worldwide. This research will generate a robust interpretive description of youth lived experiences and perceptions of type 2 diabetes where such research is lacking, to inform basic and applied research within an interdisciplinary investigative and clinical research team with relevance to other jurisdictions. In response to calls for youth-oriented research in type 2 diabetes, this work will catalyse collaborative knowledge translation using creative and youth-directed initiatives.

Establishing core outcome domains in pediatric kidney disease: report of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-KIDS) consensus workshops.

Trials in children with chronic kidney disease do not consistently report outcomes that are critically important to patients and caregivers. This can diminish the relevance and reliability of evidence for decision making, limiting the implementation of results into practice and policy. As part of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-Kids) initiative, we convened 2 consensus workshops in San Diego, California (7 patients, 24 caregivers, 43 health professionals) and Melbourne, Australia (7 patients, 23 caregivers, 49 health professionals). This report summarizes the discussions on the identification and implementation of the SONG-Kids core outcomes set. Four themes were identified; survival and life participation are common high priority goals, capturing the whole child and family, ensuring broad relevance across the patient journey, and requiring feasible and valid measures. Stakeholders supported the inclusion of mortality, infection, life participation, and kidney function as the core outcomes domains for children with chronic kidney disease.

Developing Consensus-Based Outcome Domains for Trials in Children and Adolescents With CKD: An International Delphi Survey.

RATIONALE & OBJECTIVE: The inconsistency in outcomes reported and lack of patient-reported outcomes across trials in children with chronic kidney disease (CKD) limits shared decision making. As part of the Standardized Outcomes in Nephrology (SONG)-Kids initiative, we aimed to generate a consensus-based prioritized list of critically important outcomes to be reported in all trials in children with CKD. STUDY DESIGN: An online 2-round Delphi survey in English, French, and Hindi languages. SETTINGS & PARTICIPANTS: Patients (aged 8-21 years), caregivers/family, and health care professionals (HCPs) rated the importance of outcomes using a 9-point Likert scale (7-9 indicating critical importance) and completed a Best-Worst Scale. ANALYTICAL APPROACH: We assessed the absolute and relative importance of outcomes. Comments were analyzed thematically. RESULTS: 557 participants (72 [13%] patients, 132 [24%] caregivers, and 353 [63%] HCPs) from 48 countries completed round 1 and 312 (56%) participants (28 [40%] patients, 64 [46%] caregivers, and 220 [56%] HCPs) completed round 2. Five outcomes were common in the top 10 for each group: mortality, kidney function, life participation, blood pressure, and infection. Caregivers and HCPs rated cardiovascular disease higher than patients. Patients gave lower ratings to all outcomes compared with caregivers/HCPs except they rated life participation (round 2 mean difference, 0.1), academic performance (0.1), mobility (0.4), and ability to travel (0.4) higher than caregivers and rated ability to travel (0.4) higher than HCPs. We identified 3 themes: alleviating disease and treatment burden, focusing on the whole child, and resolving fluctuating and conflicting goals. LIMITATIONS: Most participants completed the survey in English. CONCLUSIONS: Mortality, life participation, kidney function, and blood pressure were consistently highly prioritized by patients, caregivers, and HCPs. Patients gave higher priority to some lifestyle-related outcomes compared with caregivers/HCPs. Establishing critically important outcomes for all trials in children with CKD may improve consistent reporting of survival, kidney health, and clinical and life impact outcomes that are meaningful for decision making.

Evaluation of administrative case definitions for chronic kidney disease in children.

INTRODUCTION: Administrative data is increasingly used for chronic disease surveillance; however, its validity to define cases of chronic kidney disease (CKD) in children is unknown. We sought to evaluate the performance of case definitions for CKD in children. METHODS: We utilized population-based administrative data from the Manitoba Center for Health Policy to evaluate the validity of algorithms based on a combination of hospital claims, outpatient physician visits, and pharmaceutical use over 1-3 years in children <18 years of age. Algorithms were compared with a laboratory-based definition (estimated glomerular filtration rate < 90 ml/min/1.73 m2 and/or presence of proteinuria). RESULTS: All algorithms evaluated had very low sensitivity (0.20-0.39) and moderate positive predictive value (0.52-0.68). Algorithms had excellent specificity (0.98-0.99) and negative predictive value (0.96-0.97). Receiver operating characteristic (ROC) curves indicate fair accuracy (0.60-0.68). Sensitivity improved with increasing years of data. One or more physician claims and one or more prescriptions over 3 years had the highest sensitivity and ROC. CONCLUSIONS: The sensitivity of administrative data algorithms for CKD is unacceptably low for a screening test. Specificity is excellent; therefore, children without CKD are correctly identified. Alternate data sources are required for population-based surveillance of this important chronic disease.

Intrauterine exposure to diabetes and risk of cardiovascular disease in adolescence and early adulthood: a population-based birth cohort study.

BACKGROUND: It is unclear whether intrauterine exposure to maternal diabetes is associated with risk factors for cardiovascular disease and related end points in adulthood. We examined this potential association in a population-based birth cohort followed up to age 35 years. METHODS: We performed a cohort study of offspring born between 1979 and 2005 (n = 293 546) and followed until March 2015 in Manitoba, Canada, using registry-based administrative data. The primary exposures were intrauterine exposure to gestational diabetes and type 2 diabetes mellitus. The primary outcome was a composite measure of incident cardiovascular disease events, and the secondary outcome was a composite of risk factors for cardiovascular disease in offspring followed up to age 35 years. RESULTS: The cohort provided 3 628 576 person-years of data (mean age at latest follow-up 20.5 [standard deviation 6.4] years, 49.3% female); 2765 (0.9%) of the offspring experienced a cardiovascular disease end point, and 12 673 (4.3%) experienced a cardiovascular disease risk factor. After propensity score matching, the hazard for cardiovascular disease end points was elevated in offspring exposed to gestational diabetes (adjusted hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.12-1.79) but not type 2 diabetes (adjusted HR 1.40, 95% CI 0.98-2.01). A similar association was observed for cardiovascular disease risk factors (gestational diabetes: adjusted HR 1.92, 95% CI 1.75-2.11; type 2 diabetes: adjusted HR 3.40, 95% CI 3.00-3.85). INTERPRETATION: Intrauterine exposure to maternal diabetes was associated with higher morbidity and risk related to cardiovascular disease among offspring up to 35 years of age.

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

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

Cardiac structure and function in youth with type 2 diabetes in the iCARE cohort study: Cross-sectional associations with prenatal exposure to diabetes and metabolomic profiles.

OBJECTIVE: This study aimed to determine the degree of left ventricular (LV) dysfunction and its determinants in adolescents with type 2 diabetes (T2D). We hypothesized that adolescents with T2D would display impaired LV diastolic function and that these cardiovascular complications would be exacerbated in youth exposed to maternal diabetes in utero. METHODS: Left ventricular structure and function, carotid artery intima media thickness and strain, and serum metabolomic profiles were compared between adolescents with T2D (n = 121) and controls (n = 34). Sub-group analyses examined the role of exposure to maternal diabetes as a determinant of LV or carotid artery structure and function among adolescents with T2D. RESULTS: Adolescents with T2D were 15.1 ± 2.5 years old, (65% female, 99% Indigenous), had lived with diabetes for 2.7 ± 2.2 years, had suboptimal glycemic control (HbA1c = 9.4 ± 2.6%) and 58% (n = 69) were exposed to diabetes in utero. Compared to controls, adolescents with T2D displayed lower LV diastolic filling (early diastole/atrial filling rate ratio [E/A] = 1.9 ± 0.6 vs 2.2 ± 0.6, P = 0.012), lower LV relaxation and carotid strain (0.12 ± 0.05 vs 0.17 ± 0.05, P = .03) and elevated levels of leucine, isoleucine and valine. Among adolescents with T2D, exposure to diabetes in utero was not associated with differences in LV diastolic filling, LV relaxation, carotid strain or branched chain amino acids. CONCLUSIONS: Adolescents with T2D display LV diastolic dysfunction, carotid artery stiffness, and elevated levels of select branch chain amino acids; differences were not associated with exposure to maternal diabetes in utero.

Widening the lens to childhood: relevance and lifetime risk of kidney failure.

PURPOSE OF REVIEW: Lifetime risk of outcomes is emerging as a highly relevant health indicator, even in the context of low absolute risk of disease progression in short time frames. Evidence to support this concept for kidney failure is increasing, with growing emphasis on the long-term impact of risk factors occurring early in life. RECENT FINDINGS: Proteinuria and stage of chronic kidney disease (CKD) are now established predictors of CKD progression in children, and youth with type 2 diabetes are emerging as a group at significant risk. Recent population-based studies have also examined the lifetime risk of end-stage renal disease in individuals with any childhood CKD. A recent study found that even in the absence of biomarkers of renal injury, childhood CKD can increase the lifetime risk of end-stage renal disease four-fold, and up to 10-fold in adults less than 40 years of age. SUMMARY: Children with CKD are at high lifetime risk of kidney failure and require follow-up. Identifying children at highest lifetime risk through the use of biomarkers and risk equations, and determining the optimal duration and intensity of follow-up requires further research.