Long-Term Cardiovascular Outcomes in Children and Adolescents With Hypertension.

Importance: Hypertension affects 6% of all children, and its prevalence is increasing. Childhood hypertension tracks into adulthood and is associated with subclinical cardiovascular disease; however, there is a lack of evidence linking childhood hypertension to cardiovascular outcomes, which may contribute to underdiagnosis and undertreatment. Objective: To determine the long-term associated risk of major adverse cardiac events (MACE) among children diagnosed with hypertension. Design, Setting, and Participants: This was a population-based, retrospective, matched cohort study conducted from 1996 to 2022. The study included all children (aged 3-18 years) alive in Ontario, Canada, from 1996 to 2021, who were identified using provincial administrative health databases. Children with prior kidney replacement therapy were excluded. Exposure: Incident hypertension diagnosis, identified by validated case definitions using diagnostic and physician billing claims. Each case was matched with 5 controls without hypertension by age, sex, birth weight, maternal gestational hypertension, prior comorbidities (chronic kidney disease, diabetes, cardiovascular surgery), and a propensity score for hypertension. Main Outcomes and Measures: The primary outcome was MACE (a composite of cardiovascular death, stroke, hospitalization for myocardial infarction or unstable angina, or coronary intervention). Time to MACE was evaluated using the Kaplan-Meier method and Cox proportional hazards regression. Results: A total of 25 605 children (median [IQR] age, 15 [11-17] years; 14 743 male [57.6%]) with hypertension were matched to 128 025 controls without hypertension. Baseline covariates were balanced after propensity score matching, and prior comorbidities were uncommon (hypertension vs control cohort: malignancy, 1451 [5.7%] vs 7908 [6.2%]; congenital heart disease, 1089 [4.3%] vs 5408 [4.2%]; diabetes, 482 [1.9%] vs 2410 [1.9%]). During a median (IQR) of 13.6 (7.8-19.5) years of follow-up, incidence of MACE was 4.6 per 1000 person-years in children with hypertension vs 2.2 per 1000 person-years in controls (hazard ratio, 2.1; 95% CI, 1.9-2.2). Children with hypertension were at higher associated risk of stroke, hospitalization for myocardial infarction or unstable angina, coronary intervention, and congestive heart failure, but not cardiovascular death, compared with nonhypertensive controls. Conclusions and Relevance: Children diagnosed with hypertension had a higher associated long-term risk of MACE compared with controls without hypertension. Improved detection, follow-up, and control of pediatric hypertension may reduce the risk of adult cardiovascular disease.

Impact of childhood nephrotic syndrome on obesity and growth: a prospective cohort study.

BACKGROUND: Children with nephrotic syndrome are at risk of obesity and growth impairment from repeated steroid treatment. However, incidence and risk factors for obesity and short stature remain uncertain, which is a barrier to preventative care. Our aim was to determine risk, timing, and predictors of obesity and short stature among children with nephrotic syndrome. METHODS: We evaluated obesity and longitudinal growth among children (1-18 years) enrolled in Insight into Nephrotic Syndrome: Investigating Genes, Health, and Therapeutics. We included children with nephrotic syndrome diagnosed between 1996-2019 from the Greater Toronto Area, Canada, excluding congenital or secondary nephrotic syndrome. Primary outcomes were obesity (body mass index Z-score ≥ + 2) and short stature (height Z-score ≤ -2). We evaluated prevalence of obesity and short stature at enrolment (< 1-year from diagnosis) and incidence during follow-up. Cox proportional hazards models determined the association between nephrotic syndrome classification and new-onset obesity and short stature. RESULTS: We included 531 children with nephrotic syndrome (30% frequently relapsing by 1-year). At enrolment, obesity prevalence was 23.5%, 51.8% were overweight, and 4.9% had short stature. Cumulative incidence of new-onset obesity and short stature over median 4.1-year follow-up was 17.7% and 3.3% respectively. Children with frequently relapsing or steroid dependent nephrotic syndrome within 1-year of diagnosis were at increased risk of new-onset short stature (unadjusted hazard ratio 3.99, 95%CI 1.26-12.62) but not obesity (adjusted hazard ratio 1.56, 95%CI 0.95-2.56). Children with ≥ 7 and ≥ 15 total relapses were more likely to develop obesity and short stature, respectively. CONCLUSIONS: Obesity is common among children with nephrotic syndrome early after diagnosis. Although short stature was uncommon overall, children with frequently relapsing or steroid dependent disease are at increased risk of developing short stature. Effective relapse prevention may reduce steroid toxicity and the risk of developing obesity or short stature.

Renal Implications of Long-Term Systemic Bevacizumab for Recurrent Respiratory Papillomatosis.

BACKGROUND: Bevacizumab is a vascular endothelial growth factor (VEGF) inhibitor that is used off-label for select cases of recurrent respiratory papillomatosis (RRP) that are severe, involve the distal airway or lung parenchyma, and refractory to other forms of adjuvant therapy. However, there is limited safety data for the use of bevacizumab in children and VEGF inhibitors are reported to have a range of adverse renal effects, including hypertension, proteinuria, and thrombotic microangiopathy (TMA). CASE-DIAGNOSIS/TREATMENT: This report describes a case of severe juvenile-onset RRP that had an exceptionally high operative burden that was refractory to several adjuvant treatment strategies (including intralesional cidofovir and subcutaneous pegylated interferon). Bevacizumab treatment resulted in a dramatic and sustained improvement in disease control over a 5-year period. However, after 3 years of treatment, the patient developed hypertension and proteinuria and was found to have evidence of a glomerular TMA on kidney biopsy. These complications were successfully managed with a reduction in bevacizumab frequency and angiotensin-converting enzyme inhibitor initiation. CONCLUSIONS: Clinicians caring for children treated with VEGF inhibitors should be aware of the potential renal complications and their management.

Early recognition and prevention of acute kidney injury in hospitalised children.

Acute kidney injury is common in hospitalised children and is associated with poor patient outcomes. Once acute kidney injury occurs, effective therapies to improve patient outcomes or kidney recovery are scarce. Early identification of children at risk of acute kidney injury or at an early injury stage is essential to prevent progression and mitigate complications. Paediatric acute kidney injury is under-recognised by clinicians, which is a barrier to optimisation of inpatient care and follow-up. Acute kidney injury definitions rely on functional biomarkers (ie, serum creatinine and urine output) that are inadequate, since they do not account for biological variability, analytical issues, or physiological responses to volume depletion. Improved predictive tools and diagnostic biomarkers of kidney injury are needed for earlier detection. Novel strategies, including biomarker-guided care algorithms, machine-learning methods, and electronic alerts tied to clinical decision support tools, could improve paediatric acute kidney injury care. Clinical prediction models should be studied in different paediatric populations and acute kidney injury phenotypes. Research is needed to develop and test prevention strategies for acute kidney injury in hospitalised children, including care bundles and therapeutics.

Risk of Target Organ Damage in Children With Primary Ambulatory Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: Target organ damage (TOD) such as left ventricular hypertrophy (LVH), abnormal pulse wave velocity, and elevated carotid intima-media thickness are common among adults with hypertension and are associated with overt cardiovascular events. The risk of TOD among children and adolescents with hypertension confirmed by ambulatory blood pressure monitoring is poorly understood. In this systematic review, we compare the risks of TOD among children and adolescents with ambulatory hypertension to normotensive individuals. METHODS: A literature search was conducted to include all relevant English-language publications from January 1974 to March 2021. Studies were included if patients underwent 24-hour ambulatory blood pressure monitoring and ≥1 TOD was reported. Ambulatory hypertension was defined by society guidelines. Primary outcome was the risk of TOD, including LVH, left ventricular mass index, pulse wave velocity, and carotid intima-media thickness among children with ambulatory hypertension compared with those with ambulatory normotension. Meta-regression calculated the effect of body mass index on TOD. RESULTS: Of 12 252 studies, 38 (n=3609 individuals) were included for analysis. Children with ambulatory hypertension had an increased risk of LVH (odds ratio, 4.69 [95% CI, 2.69-8.19]), elevated left ventricular mass index (pooled difference, 5.13 g/m2.7; [95% CI, 3.78-6.49]), elevated pulse wave velocity (pooled difference, 0.39 m/s [95% CI, 0.20-0.58]), and elevated carotid intima-media thickness (pooled difference, 0.04 mm [95% CI, 0.02-0.05]), compared with normotensive children. Meta-regression showed a significant positive effect of body mass index on left ventricular mass index and carotid intima-media thickness. CONCLUSIONS: Children with ambulatory hypertension have adverse TOD profiles, which may increase their risk for future cardiovascular disease. This review highlights the importance of optimizing blood pressure control and screening for TOD in children with ambulatory hypertension. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42020189359.

Long-term Health Care Utilization and Associated Costs After Dialysis-Treated Acute Kidney Injury in Children.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) is common among hospitalized children and is associated with increased hospital length of stay and costs. However, there are limited data on postdischarge health care utilization after AKI hospitalization. Our objectives were to evaluate health care utilization and physician follow-up patterns after dialysis-treated AKI in a pediatric population. STUDY DESIGN: Retrospective cohort study, using provincial health administrative databases. SETTING & PARTICIPANTS: All children (0-18 years) hospitalized between 1996 and 2017 in Ontario, Canada. Excluded individuals comprised non-Ontario residents; those with metabolic disorders or poisoning; and those who received dialysis or kidney transplant before admission, a kidney transplant by 104 days after discharge, or were receiving dialysis 76-104 days from dialysis start date. EXPOSURE: Episodes of dialysis-treated AKI, identified using validated health administrative codes. AKI survivors were matched to 4 hospitalized controls without dialysis-treated AKI by age, sex, and admission year. OUTCOME: Our primary outcome was postdischarge hospitalizations, emergency department visits, and outpatient physician visits. Secondary outcomes included outpatient visits by physician type and composite health care costs. ANALYTICAL APPROACH: Proportions with≥1 event and rates (per 1,000 person-years). Total and median composite health care costs. Adjusted rate ratios using negative binomial regression models. RESULTS: We included 1,688 pediatric dialysis-treated AKI survivors and 6,752 matched controls. Dialysis-treated AKI survivors had higher rehospitalization and emergency department visit rates during the analyzed follow-up periods (0-1, 0-5, and 0-10 years postdischarge, and throughout follow-up), and higher outpatient visit rates in the 0-1-year follow-up period. The overall adjusted rate ratio for rehospitalization was 1.46 (95% CI, 1.25-1.69; P<0.0001) and for outpatient visits was 1.16 (95% CI, 1.09-1.23; P=0.01). Dialysis-treated AKI survivors also had higher health care costs. Nephrologist follow-up was infrequent among dialysis-treated AKI survivors (18.6% by 1 year postdischarge). LIMITATIONS: Potential miscoding of study exposures or outcomes. Residual uncontrolled confounding. Data for health care costs and emergency department visits was unavailable before 2006 and 2001, respectively. CONCLUSIONS: Dialysis-treated AKI survivors had greater postdischarge health care utilization and costs versus hospitalized controls. Strategies are needed to improve follow-up care for children after dialysis-treated AKI to prevent long-term complications.

High Blood Pressure in Children and Adolescents: Current Perspectives and Strategies to Improve Future Kidney and Cardiovascular Health.

Hypertension is one of the most common causes of preventable death worldwide. The prevalence of pediatric hypertension has increased significantly in recent decades. The cause of this is likely multifactorial, related to increasing childhood obesity, high dietary sodium intake, sedentary lifestyles, perinatal factors, familial aggregation, socioeconomic factors, and ethnic blood pressure (BP) differences. Pediatric hypertension represents a major public health threat. Uncontrolled pediatric hypertension is associated with subclinical cardiovascular disease and adult-onset hypertension. In children with chronic kidney disease (CKD), hypertension is also a strong risk factor for progression to kidney failure. Despite these risks, current rates of pediatric BP screening, hypertension detection, treatment, and control remain suboptimal. Contributing to these shortcomings are the challenges of accurately measuring pediatric BP, limited access to validated pediatric equipment and hypertension specialists, complex interpretation of pediatric BP measurements, problematic normative BP data, and conflicting society guidelines for pediatric hypertension. To date, limited pediatric hypertension research has been conducted to help address these challenges. However, there are several promising signs in the field of pediatric hypertension. There is greater attention being drawn on the cardiovascular risks of pediatric hypertension, more emphasis on the need for childhood BP screening and management, new public health initiatives being implemented, and increasing research interest and funding. This article summarizes what is currently known about pediatric hypertension, the existing knowledge-practice gaps, and ongoing research aimed at improving future kidney and cardiovascular health.

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

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

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

Long-Term Kidney Outcomes Following Dialysis-Treated Childhood Acute Kidney Injury: A Population-Based Cohort Study.

BACKGROUND: AKI is common during pediatric hospitalizations and associated with adverse short-term outcomes. However, long-term outcomes among survivors of pediatric AKI who received dialysis remain uncertain. METHODS: To determine the long-term risk of kidney failure (defined as receipt of chronic dialysis or kidney transplant) or death over a 22-year period for pediatric survivors of dialysis-treated AKI, we used province-wide health administrative databases to perform a retrospective cohort study of all neonates and children (aged 0-18 years) hospitalized in Ontario, Canada, from April 1, 1996, to March 31, 2017, who survived a dialysis-treated AKI episode. Each AKI survivor was matched to four hospitalized pediatric comparators without dialysis-treated AKI, on the basis of age, sex, and admission year. We reported the incidence of each outcome and performed Cox proportional hazards regression analyses, adjusting for relevant covariates. RESULTS: We identified 1688 pediatric dialysis-treated AKI survivors (median age 5 years) and 6752 matched comparators. Among AKI survivors, 53.7% underwent mechanical ventilation and 33.6% had cardiac surgery. During a median 9.6-year follow-up, AKI survivors were at significantly increased risk of a composite outcome of kidney failure or death versus comparators. Death occurred in 113 (6.7%) AKI survivors, 44 (2.6%) developed kidney failure, 174 (12.1%) developed hypertension, 213 (13.1%) developed CKD, and 237 (14.0%) had subsequent AKI. AKI survivors had significantly higher risks of developing CKD and hypertension versus comparators. Risks were greatest in the first year after discharge and gradually decreased over time. CONCLUSIONS: Survivors of pediatric dialysis-treated AKI are at higher long-term risks of kidney failure, death, CKD, and hypertension, compared with a matched hospitalized cohort.

Post-transplant malignancies in pediatric organ transplant recipients.

The majority of cancer diagnoses in pediatric solid organ transplant recipients (SOTRs) are post-transplantation lymphoproliferative disorders (PTLD) or skin cancers. However, pediatric SOTRs are also at significantly elevated risk for multiple other solid and hematological cancers. The risks of specific cancers vary by transplanted organ, underlying disease, and immunosuppression factors. More than one-quarter of pediatric SOTRs develop cancer within 30 years of transplantation and their risk of solid cancer is 14 times greater than the general population. Pediatric SOTRs are at significantly higher risk of cancer-associated death. Improving patient survival among pediatric SOTRs puts them at risk of adult epithelial cancers associated with environmental carcinogenic exposures. Vaccination against oncogenic viruses and avoidance of excessive immunosuppression may reduce the risk of solid cancers following transplantation. Patient and family education regarding photoprotection is an essential component of skin cancer prevention. There is significant variability in cancer screening recommendations for SOTRs and general population approaches are typically not validated for transplant populations. An individualized approach to cancer screening should be developed based on estimated cancer risk, patient life expectancy, and screening test performance.