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.

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.

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.

Parental attitudes to genetic testing differ by ethnicity and immigration in childhood nephrotic syndrome: a cross-sectional study.

BACKGROUND: Studies in the USA report differences in opinion among parents of different ethnic groups toward genetic testing for their child; however, there are no studies that address this issue in the diverse ethnic and immigrant population in Canada. OBJECTIVE: This study aims to determine whether ethnicity and immigration status influences parental interest in clinical genetic testing for a potentially progressive kidney disease. DESIGN: This is a cross-sectional study. SETTING: Participants were recruited from the Greater Toronto Area, Canada. PARTICIPANTS: The study included 320 parents of children ages 1-18 years with nephrotic syndrome enrolled in the Insight into Nephrotic Syndrome: Investigating Genes, Health and Therapeutics (INSIGHT) observational cohort study. MEASUREMENTS: Demographic, ethnicity, immigration, and child specific factors as well as interest in genetic testing were collected through self-reported questionnaires administered at baseline study visit. METHODS: Logistic regression models were used to examine association of ethnicity and immigration status with interest in genetic testing. RESULTS: The majority of parents (85 %) were interested in genetic testing for their child. South Asian and East/Southeast Asian parents had 74 and 76 % lower odds of agreeing to genetic testing when compared to Europeans (odds ratio (OR) 0.26, 95 % confidence interval (CI) 0.10-0.68; OR 0.24, 95 % CI 0.07-0.79, respectively) after controlling for age and sex of child, age and education level of parent, initial steroid resistance, and duration of time in Canada. Immigrants to Canada also had significantly lower odds (OR 0.29, 95 % CI 0.12-0.72) of agreeing to genetic testing after similar adjustment. Higher education level was not associated with greater interest in genetic testing (OR 1.24, 95 % CI 0.64-2.42). LIMITATIONS: Participants have already agreed to aggregate genetic testing for research purposes as part of enrolment in INSIGHT study. CONCLUSION: While majority of parents were interested in genetic testing for their child, immigrants, particularly South Asians and East/Southeast Asians, were more likely to decline genetic testing. Genetic counseling needs to be tailored to address specific concerns in these parental groups to maximize informed decision-making in the clinical setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01605266.

MISE EN CONTEXTE: Des études aux États-Unis font état de différences d'opinions parmi les parents provenant de différentes origines ethniques quant à la possibilité de procéder à des tests de dépistage génétique sur leurs enfants. Toutefois il n'existe aucune étude qui traite de cette question au sein des différents groupes ethniques au Canada. OBJECTIFS DE L'ÉTUDE: L'étude avait pour but de vérifier si l'origine ethnique ou le statut d'immigrant des parents influençait leur façon d'aborder la question du dépistage génétique pour la détection d'une néphropathie potentiellement évolutive chez leur enfant. CADRE ET TYPE D'ÉTUDE: Cette étude transversale s'est tenue dans la grande région de Toronto au Canada. PARTICIPANTS: Il s'agit de 320 parents d'enfants âgés de 1 à 18 ans atteints d'un syndrome néphrotique qui participaient à l'étude de cohorte observationnelle INSIGHT (Insight into Nephrotic Syndrome: Investigating Genes Health and Therapeutics). MESURES: Les données soit la répartition démographique l'origine ethnique ou le statut d'immigrant des parents, les éléments propres à l'enfant ainsi que le niveau d'intérêt des parents à l'égard des tests de dépistage génétique, ont été colligées à partir d'un questionnaire remis aux parents lors de la première visite. MÉTHODOLOGIE: Des modèles de régression logistique ont été utilisés pour établir un parallèle entre l'origine ethnique ou le statut d'immigrant d'un parent et son intérêt à soumettre son enfant à un dépistage génétique. RÉSULTATS: La majorité des participants à l'étude (85 %) démontrait un intérêt envers la possibilité de soumettre leur enfant à un test de dépistage génétique. Toutefois dans le cas précis des gens originaires de l'Asie du Sud et de ceux provenant de l'Extrême-Orient ou de l'Asie du Sud-Est, les probabilités de consentir à un tel test étaient respectivement de 74 % et de 76 % plus faibles que pour les gens d'origine européenne. (Risque relatif [RR] : 0,26 à 95 % d'intervalle de confiance [IC] : 0.10-0.68; RR : 0,24 à 95 % IC : 0.07-0.79 respectivement). Ces résultats ont été obtenus après l'exclusion d'indicateurs relatifs à l'âge et au sexe de l'enfant, au sexe et au niveau d'éducation des parents, à la résistance de l'enfant au traitement initial par les stéroïdes et à la durée du séjour au Canada. Cette observation s'est également confirmée chez les immigrants reçus, pour qui la probabilité de consentir à un tel test pour leur enfant s'est aussi avérée significativement moins élevée après l'application des mêmes correctifs (RR : 0,29, à 95 % IC : 0.12-0.72). Aucune corrélation n'a pu être établie entre le niveau d'éducation élevé des parents et un intérêt accru à soumettre leur enfant à un test de dépistage génétique (RR : 1,24 à 95 % IC : 0.64-2.42). LIMITES DE L'ÉTUDE: Les résultats sont limités du fait que les participants avaient consenti à soumettre leur enfant à un test de dépistage génétique fà des fins de recherche dans le cadre de leur inclusion à l'étude INSIGHT. CONCLUSIONS: Alors que la majorité des parents ayant participé à l'étude voyait d'un bon œil la possibilité de soumettre leur enfant à un test de dépistage génétique les immigrants reçus ainsi que les participants originaires de l'Asie du Sud, de l'Extrême-Orient et de l'Asie du Sud-Est se sont avérés plus susceptibles de décliner l'offre. Par conséquent, le processus de consultation en génétique doit être adapté pour mieux répondre aux inquiétudes et aux préoccupations de ces groupes de parents; ceci afin de tirer le meilleur parti d'une prise de décision éclairée dans un contexte clinique.

Ethnic Differences in Incidence and Outcomes of Childhood Nephrotic Syndrome.

BACKGROUND AND OBJECTIVES: Ethnic differences in outcomes among children with nephrotic syndrome are unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a longitudinal study at a single regional pediatric center comparing ethnic differences in incidence from 2001 to 2011 census data and longitudinal outcomes, including relapse rates, time to first relapse, frequently relapsing disease, and use of cyclophosphamide. Among 711 children, 24% were European, 33% were South Asian, 10% were East/Southeast Asian, and 33% were of other origins. RESULTS: Over 10 years, the overall incidence increased from 1.99/100,000 to 4.71/100,000 among children ages 1-18 years old. In 2011, South Asians had a higher incidence rate ratio of 6.61 (95% confidence interval, 3.16 to 15.1) compared with Europeans. East/Southeast Asians had a similar incidence rate ratio (0.76; 95% confidence interval, 0.13 to 2.94) to Europeans. We determined outcomes in 455 children from the three largest ethnic groups with steroid-sensitive disease over a median of 4 years. South Asian and East/Southeast Asian children had significantly lower odds of frequently relapsing disease at 12 months (South Asian: adjusted odds ratio; 0.55; 95% confidence interval, 0.39 to 0.77; East/Southeast Asian: adjusted odds ratio; 0.42; 95% confidence interval, 0.34 to 0.51), fewer subsequent relapses (South Asian: adjusted odds ratio; 0.64; 95% confidence interval, 0.50 to 0.81; East/Southeast Asian: adjusted odds ratio; 0.47; 95% confidence interval, 0.24 to 0.91), lower risk of a first relapse (South Asian: adjusted hazard ratio, 0.74; 95% confidence interval, 0.67 to 0.83; East/Southeast Asian: adjusted hazard ratio, 0.65; 95% CI, 0.63 to 0.68), and lower use of cyclophosphamide (South Asian: adjusted hazard ratio, 0.82; 95% confidence interval, 0.53 to 1.28; East/Southeast Asian: adjusted hazard ratio, 0.54; 95% confidence interval, 0.41 to 0.71) compared with European children. CONCLUSIONS: Despite the higher incidence among South Asians, South and East/Southeast Asian children have significantly less complicated clinical outcomes compared with Europeans.