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.

Family functioning and quality of life among children with nephrotic syndrome during the first pandemic wave.

BACKGROUND: During the SARS-CoV-2 global pandemic, one of the longest lockdowns worldwide occurred in Ontario, Canada, during the first wave. For parents and children managing care at home and at risk for COVID-19, the impact on their psychosocial functioning is unknown. METHODS: A total of 122 families of children aged 2-18 years were enrolled as part of the prospective cohort of childhood nephrotic syndrome and completed a survey during the first wave of the pandemic (August 21-December 10), 2020. In a subset, 107 families had data available pre-pandemic to assess change. Validated measures included the McMaster Family Assessment Device (FAD) for parents and children ≥ 12 years for family functioning, the Patient Health Questionnaire for Depression and Anxiety (PHQ-4) for both parent and child, and Pediatric Quality of Life Inventory (PEDSQL™-V4) for children only. Scores were compared using Student's t-test or the Mann-Whitney U test, as appropriate. RESULTS: Among the 107 children, 71% were male with a mean age of 9 years old at the time of questionnaire completion, and the mean age of parents was 41 years old. Parents and children reported that family functioning improved during COVID (parent: p < 0.01; child: p = 0.05). Children's overall HRQOL declined (p = 0.04), specifically increased sleep disruption (p = 0.01). Increasing child age was associated with a greater sleep disruption (ß = - 1.6 [IQR: - 2.6, - 0.67]) and a related decrease in QOL (ß = - 1.0 [IQR: - 1.7, - 0.2]), adjusted for sex. CONCLUSIONS: Despite the positive effects of family dynamics during the first wave, there were negative effects of sleep disruptions and reduced quality of life in children, especially among older children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Incidence of cardiovascular disease and mortality in childhood solid organ transplant recipients: a population-based study.

BACKGROUND: With improved survival among children after transplantation, our understanding of the risk for developing other comorbidities is improving, yet little is known about the long-term risk of cardiovascular events and mortality after solid organ transplantation. METHODS: In a cohort study using health administrative data, we compared cardiovascular events in children (n = 615) with liver, lung, kidney, small bowel, or multi-organ transplant at the Hospital for Sick Children, Toronto, Canada, with asthmatic children (n = 481,697) between 1996 and 2014. Outcomes included non-fatal cardiovascular events, cardiovascular death, all-cause mortality, and a composite of non-fatal and fatal cardiovascular events. Time-stratified Cox proportional hazards models were used. RESULTS: Among 615 children, 317 (52%) were recipients of kidneys, 253 (41%) of livers, and the remaining 45 (7%) had lung, small bowel, or multi-organ transplants. Median follow-up was 12.1 [7.2, 16.7] years. Non-fatal incident cardiovascular events were 34 times higher among solid organ transplant recipients than non-transplanted children (incidence rate ratio (IRR) 34.4, 95% CI: 25.5, 46.4). Among transplant recipients, the cumulative incidence of non-fatal and fatal cardiovascular events was 2.3% and 13.0%, 5 and 15 years after transplantation, respectively. CONCLUSIONS: Increased rate of cardiovascular events in children after transplantation highlights the need for surveillance during transition into adulthood and beyond. A higher resolution version of the Graphical abstract is available as Supplementary information.

Impact of steroids and steroid-sparing agents on quality of life in children with nephrotic syndrome.

BACKGROUND: Steroids and/or steroid-sparing medications are commonly used for nephrotic syndrome treatment; however, the impact of these medications on health-related quality of life over time is not well described. METHODS: Longitudinal cohort is up to 5 years where children were assessed with baseline and annual Pediatric Quality of Life Inventory questionnaire. A mixed-effects linear regression determined differences in scores among children receiving steroids and/or steroid-sparing agents for at least 30 days compared with those not on medication at 1, 3, 6, and 12 months prior to assessment. RESULTS: Among 295 children, 64% were male, with a median age of 3.7 (interquartile range [IQR], 2.7, 5.9) years at diagnosis, and comprised 25% Europeans, 40% South Asians, and 8% East/Southeast Asians. Adjusted HRQOL scores were reduced among children taking steroids and steroid-sparing agents among 705 HRQOL measures (median 2 [IQR, 1, 3] per child). Compared to children without medication, steroid and steroid-sparing agent use up to 12 months prior to assessment were associated with an overall HRQOL drop of 3.17 (95% confidence interval [CI], - 5.25, - 1.08) and 3.18 (95% CI, - 5.24, - 1.12), respectively, after adjustment. Functioning domain scores were reduced by 4.41 points (95% CI, - 6.57, - 2.25) in children on steroids, whereas fatigue domain scores were reduced by 5.47 points (95% CI, - 9.28, - 1.67) in children on steroid-sparing agents after adjustment. CONCLUSIONS: HRQOL is consistently decreased in children receiving steroids and steroid-sparing agents, with differential effects on functioning and fatigue. Counseling families on possible effects of prolonged treatment periods is important in the management of childhood nephrotic syndrome.

Prevalence of Asthma and Allergies and Risk of Relapse in Childhood Nephrotic Syndrome: Insight into Nephrotic Syndrome Cohort.

OBJECTIVE: To determine the lifetime prevalence of allergies in childhood nephrotic syndrome, the seasonality of presentation and relapses, and the impact of allergies on subsequent relapses. STUDY DESIGN: In a longitudinal cohort of children with nephrotic syndrome (ages 1-18 years), assessment for allergic diseases was conducted using the validated and modified version of the International Study of Asthma and Allergies in Childhood questionnaire at enrollment. Outcomes included frequently relapsing nephrotic syndrome, relapse rates, and the relapse-free duration after initial steroid therapy. RESULTS: Among 277 participants, the majority were male (65%) with a median age of 3.7 years (IQR 2.8-5.8) at presentation. A total of 64% reported lifetime allergies with 20% having asthma, 33% wheezing, 27% eczema, and 24% rhinitis. Over 3.3 years of follow-up, presence of asthma and allergies was not associated with frequently relapsing nephrotic syndrome (OR 1.20; 95% CI 0.60, 2.40), higher relapse rates (relative risk 0.95; 95% CI 0.71, 1.27), or risk of first relapse (hazard ratio 1.10; 95% CI 0.83, 1.47) compared with those with no history of allergic diseases. There was also no seasonal variation evident at initial presentation or frequency of relapses. CONCLUSIONS: Two-thirds of children with nephrotic syndrome at presentation have allergic symptoms and asthma; however, neither are associated with an increased frequency of relapses.

Incidence of new-onset diabetes mellitus and association with mortality in childhood solid organ transplant recipients: a population-based study.

BACKGROUND: Precise estimates of the long-term risk of new-onset diabetes and its impact on mortality among transplanted children are not known. METHODS: We conducted a cohort study comparing children undergoing solid organ (kidney, heart, liver, lung and multiple organ) transplant (n = 1020) between 1991 and 2014 with healthy non-transplanted children (n = 7 134 067) using Ontario health administrative data. Outcomes included incidence of diabetes among transplanted and non-transplanted children, the relative hazard of diabetes among solid organ transplant recipients, overall and at specific intervals posttransplant, and mortality among diabetic transplant recipients. RESULTS: During 56 019 824 person-years of follow-up, the incidence rate of diabetes was 17.8 [95% confidence interval (CI) 15-21] and 2.5 (95% CI 2.5-2.5) per 1000 person-years among transplanted and non-transplanted children, respectively. The transplant cohort had a 9-fold [hazard ratio (HR) 8.9; 95% CI 7.5-10.5] higher hazard of diabetes compared with those not transplanted. Risk was highest within the first year after transplant (HR 20.7; 95% CI 15.9-27.1), and remained elevated even at 5 and 10 years of follow-up. Lung and multiple organ recipients had a 5-fold (HR 5.4; 95% CI 3.0-9.8) higher hazard of developing diabetes compared with kidney transplant recipients. Transplant recipients with diabetes had a three times higher hazard of death compared with those who did not develop diabetes (HR 3.3; 95% CI 2.3-4.8). CONCLUSIONS: The elevated risk of diabetes in transplant recipients persists even after a decade, highlighting the importance of ongoing surveillance. Diabetes after transplantation increases the risk of mortality among childhood transplant recipients.

Association of low birth weight and prematurity with clinical outcomes of childhood nephrotic syndrome: a prospective cohort study.

BACKGROUND: Low birth weight (LBW)/prematurity have been proposed as risk factors for the development of kidney disease in adulthood. Whether there is an association between LBW/prematurity and poor renal outcomes in childhood onset nephrotic syndrome remains unknown. METHODS: Children with nephrotic syndrome diagnosed between 1 and 18 years of age were followed prospectively from 1996 to 2016 at The Hospital for Sick Children (N = 377). LBW/prematurity was defined as birth weight < 2500 g or gestational age < 36 weeks. Normal birth weight (NBW) was defined as birth weight ≥ 2500 g. Measures evaluating clinical course of nephrotic syndrome include initial steroid-resistant nephrotic syndrome (SRNS), time to first relapse, and frequently relapsing nephrotic syndrome. Kaplan-Meier survival analysis, logistic regression, and Cox proportional hazards regression were used to determine the association of LBW/prematurity with clinical outcomes. RESULTS: Median birth weights in LBW/premature (n = 46) and NBW (n = 331) children were 2098 g (interquartile range [IQR] 1700-2325 g) and 3317 g (IQR 2977-3685 g), respectively. Odds of having SRNS were 3.78 (95% confidence interval [CI] 1.28-11.21) times higher among LBW/premature children than NBW children. An 8% decrease in odds of developing SRNS was observed for every 100 g increase in birth weight (adjusted odds ratio [OR] 0.92; 95% CI 0.86-0.98). Median time to first relapse did not differ (hazard ratio [HR] 0.89; 95% CI 0.53-1.16). CONCLUSIONS: LBW/premature children were more likely to develop SRNS but did not have a difference in time to first relapse with NBW children. Understanding the impact and mechanism of birth weight and steroid-resistant disease needs further study.

Incidence of hyperglycemia and diabetes and association with electrolyte abnormalities in pediatric solid organ transplant recipients.

BACKGROUND: Posttransplant hyperglycemia is an important predictor of new-onset diabetes after transplantation, and both are associated with significant morbidity and mortality. Precise estimates of posttransplant hyperglycemia and diabetes in children are unknown. Low magnesium and potassium levels may also lead to diabetes after transplantation, with limited evidence in children. METHODS: We conducted a cohort study of 451 pediatric solid organ transplant recipients to determine the incidence of hyperglycemia and diabetes, and the association of cations with both endpoints. Hyperglycemia was defined as random blood glucose levels ≥11.1 mmol/L on two occasions after 14 days of transplant not requiring further treatment. Diabetes was defined using the American Diabetes Association Criteria. For magnesium and potassium, time-fixed, time-varying and rolling average Cox proportional hazards models were fitted to evaluate the association with hyperglycemia and diabetes. RESULTS: Among 451 children, 67 (14.8%) developed hyperglycemia and 27 (6%) progressed to diabetes at a median of 52 days (interquartile range 22-422) from transplant. Multi-organ recipients had a 9-fold [hazard ratio (HR) 8.9; 95% confidence interval (CI) 3.2-25.2] and lung recipients had a 4.5-fold (HR 4.5; 95% CI 1.8-11.1) higher risk for hyperglycemia and diabetes, respectively, compared with kidney transplant recipients. Both magnesium and potassium had modest or no association with the development of hyperglycemia and diabetes. CONCLUSIONS: Hyperglycemia and diabetes occur in 15 and 6% children, respectively, and develop early posttransplant with lung or multi-organ transplant recipients at the highest risk. Hypomagnesemia and hypokalemia do not confer significantly greater risk for hyperglycemia or diabetes in children.

Incidence and risk factors of early surgical complications in young renal transplant recipients: A persistent challenge.

There is a paucity of data on the rate of urological and vascular complications in very young children after kidney transplant. We conducted a study on the incidence and risk factors for early post-transplant surgical complications in young recipients (<5 years) over three decades. The primary outcome was any urological or vascular complication within 30 days of transplant, and the secondary outcome was incidence rate of graft failure reported as per 1000 person-years. Risk factors associated with surgical complications were analyzed by logistic regression. There were 22 (26.5%) complications in 21 children with vascular thrombosis being the most common complication. There was no significant difference in the number of complications in period 1 (1985-1994) and period 2 (1995-2014) (P=.1). The incidence rate of graft failure was higher in period 1 (IR 70.8, 95% CI 41.1, 121.9) compared to period 2 (IR 20.7, 95% CI 9.3, 46.0). Cumulative incidence of graft survival at 1, 3, and 5 years' post-transplant was 96.5%, 92.6%, and 90%, respectively, in those without compared to 71%, 65.1%, and 58.6%, respectively, in children with complications. In conclusion, early surgical, especially vascular, complications are quite common in young renal transplant recipients and lead to significantly reduced graft survival.

Prognostic factors in metastatic gastric cancer: results of a population-based, retrospective cohort study in Ontario.

BACKGROUND: Stage IV gastric cancer is lethal, and little population-based research on prognostic factors has been performed in low-incidence countries. Therefore, we investigated the consistency of the associations of patient, disease and healthcare system factors identified in previous population-based research to understand their generalizability to other low-incidence populations. METHODS: A population-based, retrospective cohort study of patients diagnosed with Stage IV gastric cancer in Ontario between 1 April 2005 and 31 March 2008 was performed. Kaplan-Meier methodology and the log-rank test were used for bivariate analysis. Multivariate Cox proportional hazard regression was performed. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. RESULTS: On multivariate analysis, patient, disease and healthcare system factors were independent predictors of survival. Increasing age per 10 years (HR 1.07; 95% CI 1.02-1.10), a tumor located in the gastroesophageal junction (HR 1.09; 95% CI 0.94-1.27) or middle of the stomach (HR 1.14; 95% CI 0.97-1.35), presence of carcinomatosis (HR 1.61; 95% CI 1.42-1.83) and a larger burden of metastatic disease (2-3 sites of metastatic disease: HR 1.17; 95% CI 1.03-1.32; ≥ 4 sites: HR 1.69; 95% CI 1.30-2.20) were associated with worse prognosis. Female gender, receipt of surgery, chemotherapy and radiotherapy and treatment from a high-volume, gastric cancer specialist were all associated with significantly better prognosis. In addition, there was evidence of significant geographic variation in survival. CONCLUSION: This study provides supporting evidence for patient, disease and healthcare system prognostic factors in metastatic gastric cancer. Future work investigating the role of emerging molecular and biologic information will need to take these established prognostic factors into consideration.

Location, size, and distance: criteria for quality in esophagogastroduodenos copy reporting for pre-operative gastric cancer evaluation.

BACKGROUND: There is a lack of existing literature regarding the quality of esophagogastroduodenoscopy (EGD) reporting for gastric cancer evaluation. This study aims to determine criteria for quality endoscopic evaluation of gastric cancer in North America by identifying important features of the EGD report for pre-operative evaluation of gastric cancer and assessing inclusion of these features in existing reports. METHODS: Semi-structured interviews were conducted with experienced endoscopists from community and academic hospitals affiliated with the University of Toronto to identify essential elements for an EGD report. Then, 225 EGD reports from 2005 to 2008 were evaluated by two trained reviewers for inclusion of recommended EGD report elements and global assessment of report quality and adequacy for surgical planning. RESULTS: Essential elements recommended by interviewed endoscopists include tumor size, location, and distance from gastroesophageal junction (GEJ). Approximately 95 % of all reports documented the location of lesions, <5 % documented distance from the GEJ, and <15 % documented tumor size. Overall report quality was rated as excellent for 4-5 % of reports; 20-42 % of all reports were deemed to be adequate for surgical planning. All surgeons interviewed as part of the endoscopist panel indicated that they would repeat the EGD before consulting with patients regarding surgical planning. CONCLUSIONS: For pre-operative evaluation of gastric cancer, tumor size, location, and distance from key anatomical landmarks were proposed as essential elements of a quality EGD report. Most of the reviewed reports did not document these elements. Report quality is perceived to be poor and may lead to repeat endoscopy. Developing a standardized EGD reporting format based on inclusion of individual parameters can improve the quality of gastric cancer management.

The rationale and design of Insight into Nephrotic Syndrome: Investigating Genes, Health and Therapeutics (INSIGHT): a prospective cohort study of childhood nephrotic syndrome.

BACKGROUND: Nephrotic syndrome is one of the most commonly diagnosed kidney diseases in childhood and its progressive forms can lead to chronic kidney disease (CKD) and/or end-stage renal disease (ESRD). There have been few longitudinal studies among a multi-ethnic cohort to determine potential risk factors influencing disease susceptibility, treatment response, and progression of nephrotic syndrome. Temporal relationships cannot be studied through cross-sectional study design. Understanding the interaction between various factors is critical to developing new strategies for treating children with kidney disease. We present the rationale and the study design of a longitudinal cohort study of children with nephrotic syndrome, the Insight into Nephrotic Syndrome: Investigating Genes, Health and Therapeutics (INSIGHT) study. The specific aims are to determine: 1) socio-demographic, environmental, and genetic factors that influence disease susceptibility; 2) rates of steroid treatment resistance and steroid treatment dependence, and identify factors that may modify treatment response; 3) clinical and genetic factors that influence disease susceptibility and progression to CKD and ESRD; and 4) the interaction between the course of illness and socio-demographic, environmental, and clinical risk factors. METHODS/DESIGN: INSIGHT is a disease-based observational longitudinal cohort study of children with nephrotic syndrome. At baseline, participants complete questionnaires and provide biological specimen samples (blood, urine, and toenail clippings). Follow-up questionnaires and repeat biological specimen collections are performed annually for up to five years. DISCUSSION: The proposed cohort will provide the structure to test various risk factors predicting or influencing disease susceptibility, treatment response, and progression to CKD among children with nephrotic syndrome. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01605266.

Longitudinal Changes in Cardiac Structure and Function in Pediatric Kidney Transplant Recipients.

BACKGROUND: Cardiovascular disease results in increased morbidity and mortality in pediatric kidney transplant recipients. Longitudinal changes in cardiac structure and function and the association with blood pressure control over time in pediatric kidney transplant recipients are unknown. METHODS: To determine the influence of blood pressure control on cardiac changes following pediatric kidney transplant, we conducted a retrospective cohort study of children who received their first kidney transplant at the Hospital for Sick Children from 2004 to 2015. Children were followed until transfer to adult care or censoring in July 2018. Cardiac structure and function parameters were collected from clinical echocardiograms and assessed using standardized scores. Blood pressure control was determined by systolic blood pressure Z scores (above or below the 90th percentile) in combination with antihypertensive medications. A segmented mixed-effects model assessed Z scores of interventricular septum thickness, left ventricular end-diastolic dimension, and left ventricular posterior wall dimension. RESULTS: Of 142 children included, 58% were men, mean age at transplant was 11 (±4.5) years, and average follow-up time was 4 (±3) years. All cardiac structural Z scores improved during follow-up. Interventricular septum thickness normalized at 4.0 years post-transplant. Left ventricular end-diastolic dimension normalized at 1.5 years post-transplant. Left ventricular posterior wall dimension normalized at 6.3 years post-transplant. Left ventricular mass index showed sustained improvement up to 12 years post-transplant. Individuals with uncontrolled blood pressure had increased left ventricular mass (ß=2.97 [95% CI, 0.77-5.16]). CONCLUSIONS: Cardiac structural abnormalities improve following kidney transplantation and normalize within 7 years, especially with controlled blood pressure. Strict blood pressure control is critical after pediatric kidney transplantation.

Trends in the epidemiology of childhood nephrotic syndrome in Africa: A systematic review.

Background: Childhood nephrotic syndrome, if left untreated, leads to progressive kidney disease or death. We quantified the prevalence of steroid-sensitive nephrotic syndrome, steroid-resistant nephrotic syndrome, and histological types as the epidemiology of nephrotic syndrome in Africa remains unknown, yet impacts outcomes. Methods: We searched MEDLINE, Embase, African Journals Online, and WHO Global Health Library for articles in any language reporting on childhood nephrotic syndrome in Africa from January 1, 1946 to July 1, 2020. Primary outcomes included steroid response, biopsy defined minimal change disease, and focal segmental glomerulosclerosis (FSGS) by both pooled and individual proportions across regions and overall. Findings: There were 81 papers from 17 countries included. Majority of 8131 children were steroid-sensitive (64% [95% CI: 63-66%]) and the remaining were steroid-resistant (34% [95% CI: 33-35%]). Of children biopsied, pathological findings were 38% [95% CI: 36-40%] minimal change, 24% [95% CI: 22-25%] FSGS, and 38% [95% CI: 36-40%] secondary causes of nephrotic syndrome. Interpretation: Few African countries reported on the prevalence of childhood nephrotic syndrome. Steroid-sensitive disease is more common than steroid-resistant disease although prevalence of steroid-resistant nephrotic syndrome is higher than reported globally. Pathology findings suggest minimal change and secondary causes are common. Scarcity of data in Africa prevents appropriate healthcare resource allocation to diagnose and treat this treatable childhood kidney disease to prevent poor health outcomes. Funding: Funding was provided by the Canadian Institute for Health Research (CIHR) and the National Institute of Health (NIH) for the H3 Africa Kidney Disease Research Network. This research was undertaken, in part, from the Canada Research Chairs program.

Evidence-based performance indicators of primary care for asthma: a modified RAND Appropriateness Method.

PURPOSE: To develop evidence-based performance indicators that measure the quality of primary care for asthma. DATA SOURCES: Cochrane Database of Systematic Reviews, MEDLINE, EMBASE and CINAHL for peer-reviewed articles published in 1998-2008 and five national/global asthma management guidelines. STUDY SELECTION: Articles with a focus on current asthma performance indicators recognized or used in community and primary care settings. Data extraction Modified RAND Appropriateness METHOD: was used. The work described herein was conducted in Canada in 2008. Five clinician experts conducted the systematic literature review. Asthma-specific performance indicators were developed and the strength of supporting evidence summarized. A survey was created and mailed to 17 expert panellists of various disciplines, asking them to rate each indicator using a 9-point Likert scale. Percentage distribution of the Likert scores were generated and given to the panellists before a face-to-face meeting, which was held to assess consensus. At the meeting, they ranked all indicators based on their reliability, validity, availability and feasibility. RESULTS: Literature search yielded 1228 articles, of which 135 were used to generate 45 performance indicators in five domains: access to care, clinical effectiveness, patient centeredness, system integration and coordination and patient safety. The top five ranked indicators were: Asthma Education from Certified Asthma Educator, Pulmonary Function Monitoring, Asthma Control Monitoring, Controller Medication Use and Asthma Control. CONCLUSION: The top 15 ranked indicators are recommended for implementation in primary care to measure asthma care delivery, respiratory health outcomes and establish benchmarks for optimal health service delivery over time and across populations.

Incidence and Risk Factors of Obesity in Childhood Solid-Organ Transplant Recipients.

BACKGROUND: Obesity is a significant public health concern; however, the incidence post solid-organ transplantation is not well reported. METHODS: This study determined the incidence and risk factors of obesity among pediatric solid-organ transplant recipients (heart, lung, liver, kidney, multiorgan) at The Hospital for Sick Children (2002-2011), excluding prevalent obesity. Follow-up occurred from transplantation until development of obesity, last follow-up, or end of study. Incidence of obesity was determined overall, by baseline body mass index, and organ group. Risk factors were assessed using Cox proportional-hazards regression. RESULTS: Among 410 (55% male) children, median transplant age was 8.9 (interquartile range [IQR]: 1.0-14.5) years. Median follow-up time was 3.6 (IQR: 1.5-6.4) years. Incidence of obesity was 65.2 (95% confidence interval [CI]: 52.7-80.4) per 1000 person-years. Overweight recipients had a higher incidence, 190.4 (95% CI: 114.8-315.8) per 1000 person-years, than nonoverweight recipients, 56.1 (95% CI: 44.3-71.1). Cumulative incidence of obesity 5-years posttransplant was 24.1%. Kidney relative to heart recipients had the highest risk (3.13 adjusted hazard ratio [aHR]; 95% CI: 1.53-6.40) for obesity. Lung and liver recipients had similar rates to heart recipients. Those with higher baseline body mass index (z-score; 1.72 aHR; 95% CI: 1.39-2.14), overweight status (2.63 HR; 95% CI: 1.71-4.04), and younger transplant age (y; 1.18 aHR; 95% CI: 1.12-1.25) were at highest risk of obesity. Higher cumulative steroid dosage (per 10 mg/kg) was associated with increased risk of obesity after adjustment. CONCLUSIONS: Among all transplanted children at The Hospital for Sick Children, 25% developed obesity within 5-years posttransplant. Kidney recipients, younger children, those overweight at transplant, and those with higher cumulative steroid use (per 10 mg/kg) were at greatest risk. Early screening and intervention for obesity are important preventative strategies.

Elevated Risk of Cancer After Solid Organ Transplant in Childhood: A Population-based Cohort Study.

BACKGROUND: Cancer risk is elevated among adult transplant recipients, but there is limited data regarding long-term cancer risk and mortality in pediatric recipients. METHODS: We conducted a population-based retrospective cohort study in Ontario, Canada. We included pediatric recipients of solid organ transplants at the Hospital for Sick Children, Toronto, from 1991 to 2014, and compared rates of new cancers and cancer-specific mortality to nontransplanted Ontario children born in the same year. We constructed standard and time-dependent Cox proportional hazards models accounting for competing risk of death. RESULTS: A total of 951 recipients (kidney, n = 400; liver, n = 283; heart, n = 218; lung, n = 36; multiorgan/small bowel, n = 14) were compared with 5.3 million general population children. Mean (SD) age was 8.2 (6.4) years; 50% were male. Over a mean (SD) follow-up of 10.8 (7.1) years, cumulative incidence of cancer was 20% in recipients and 1.2% in the general population (incidence rate ratio, 32.9; 95% confidence interval [CI], 26.6-40.8). Risk was highest in the first year posttransplant (adjusted hazard ratio [aHR],176; 95% CI, 117-264), but remained elevated beyond 10 years (aHR, 10.8; 95% CI, 6.3-18.6). Lymphoproliferative disorders were predominant (77%); however, solid cancers (renal, sarcomas, genital, thyroid) were seen. Recipients of lung or multiorgan transplants were at highest risk. Cancer-specific mortality was also higher among recipients (HR, 93.1; 95% CI, 59.6-145.2). CONCLUSIONS: Childhood transplant recipients have a 30 times greater cancer incidence versus the general population. Further investigation is needed to guide screening strategies in this at-risk population.

Incidence of Cytomegalovirus DNAemia in Pediatric Kidney Transplant Recipients After Cessation of Antiviral Prophylaxis.

BACKGROUND: Late cytomegalovirus (CMV) infection can occur after cessation of viral prophylaxis in kidney transplant recipients, yet, timing of infection is unclear and longer duration of prophylaxis may be warranted. METHODS: We conducted a retrospective cohort study of 86 children (35 CMV donor seropositive, recipient seronegative [D + R-] and 51 CMV recipient seropositive [R+]) younger than 18 years who received a kidney transplant between January 2002 and June 2014 and were treated with antiviral prophylaxis for 3 months after transplantation. Incidence of CMV DNAemia and CMV disease was determined using Kaplan-Meier analyses and risk factors were assessed using Poisson regression. RESULTS: Of the 86 children, 61.6% were male and median age at transplant was 13.4 years (interquartile range [IQR], 8.9-15.6) with a median follow-up of 35.2 months (IQR, 18.0-54.5). Incidence of CMV DNAemia within the first 3 months after prophylaxis cessation in CMV D + R- and CMV R+ children was 22.9% and 23.5% and incidence of CMV disease was 11.4% and 0%, respectively. Cumulative incidence of CMV DNAemia in both groups was similar (31.4%). Children who received antithymocyte globulin were more likely to develop CMV DNAemia compared with those who received anti-IL-2 (IRR, 2.98; 95% confidence interval, 1.41-6.30) after controlling for age, sex, Epstein-Barr Virus serostatus and rejection. CONCLUSIONS: This study demonstrates a high incidence of CMV infection after cessation of antiviral prophylaxis. These results support extension of antiviral prophylaxis beyond 3 months and/or intensive viral load monitoring to reduce risk of CMV infection in D + R- and R+ children, especially those receiving antithymocyte globulin.

Evaluating TNM stage prognostic ability in a population-based cohort of gastric adenocarcinoma patients in a low-incidence country.

OBJECTIVES: TNM stage is the preeminent cancer staging system and a fundamental determinant of disease prognosis. Our goal was to evaluate the predictive power of TNM stage for gastric adenocarcinoma (GAC), in a low-incidence country. METHODS: A province-wide chart review of GAC patients diagnosed from April 1, 2005 to March 31, 2008 was conducted in Ontario and linked to routinely collected vital status data with a follow-up on March 31, 2012. TNM staging was classified using the sixth and seventh Union International for Cancer Control/American Joint Committee on Cancer editions. Kaplan-Meier and log-rank tests compared stage-stratified survival estimates. Discrimination was evaluated using Harrell's C statistic. RESULTS: The cohort included 2366 patients. One- and 5-year survival was 43% and 17%. Using the sixth edition, 9% of patients had stage I disease, 5.4% stage II, 7.3% stage III, and 64% stage IV; 15% were not staged. Using the seventh edition, 9% were stage I, 7.7% stage II, 16% stage III, and 54% stage IV; 14% were not staged. Stage-stratified 5-year survival ranged from 68% to 7% with the sixth edition and from 70% to 4% with the seventh edition. Harrell's C statistic was 0.64 (0.63-0.65) for the broad sixth edition staging categories and 0.68 (0.67-0.69) for the broad seventh edition. Discriminative power was similar for the refined stage categories and across multiple subgroup analyses; it was best in non-metastatic patients. CONCLUSION: Existing staging systems for GAC used in North America predict individualized prognosis poorly. The creation of a more complex prediction tool is necessary to provide accurate and precise prognostication information to oncologists, patients, and their families.

Parental Health Literacy and Outcomes of Childhood Nephrotic Syndrome.

OBJECTIVE: Determine the association of parental health literacy with treatment response among children with nephrotic syndrome. METHODS: This was a cohort study of children aged 1-18 with nephrotic syndrome and their parent. Health literacy was measured using the validated Short Test of Functional Health Literacy in Adults assessing reading comprehension and numeracy. Outcomes included initial relapse-free period, frequently relapsing disease, relapse rate, second-line medication use, and complete remission after therapy. RESULTS: Of 190 parents, 80% had adequate health literacy (score >67 of 100), and higher scores were not correlated with higher education. Almost all achieved perfect numeracy scores (>86%); numeracy was not associated with outcomes. After adjusting for immigration, education, and income, higher reading comprehension scores (tertile 3) compared with lower scores (tertile 1) were significantly associated with lower risk of first relapse (hazard ratio 0.67, 95% confidence interval [CI] 0.48-0.94, P trend = .02), lower odds of frequently relapsing disease (odds ratio [OR] 0.38, 95% CI 0.21-0.70, P trend = .002), lower relapse rate (rate ratio 0.77, 95% CI 0.73-0.80, P trend < .001), and higher odds of complete remission after both initial steroids and cyclophosphamide (OR 2.07, 95% CI 1.36-3.16, P trend = .003; OR 5.97, 95% CI 2.42-14.7, P trend < .001). CONCLUSIONS: Lower parental health literacy, specifically reading comprehension, is associated with higher relapse rates among children with nephrotic syndrome and fewer achieving complete remission. This underscores the importance of assessing and targeting health literacy for chronic management of childhood-onset diseases.