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Cisplatin is a chemotherapeutic agent highly excreted in urine and known to cause acute kidney injury (AKI). As AKI diagnosis by serum creatinine (SCr) is usually delayed, endeavors for finding early AKI biomarkers continue. This study aims to determine if urine platinum (UP) concentration 24 hours after cisplatin infusion is associated with AKI, and to evaluate the association between urine platinum and tubular damage biomarkers: neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Children treated with cisplatin in 12 Canadian centers (April 2013 to December 2017) were included. Urine from the morning after the first cisplatin infusion of the first or second cisplatin cycle was measured for urine platinum, NGAL, and KIM-1. SCr and serum electrolytes were used to detect AKI by either SCr elevation or urinary electrolyte wasting (potassium, magnesium, phosphate). The associations of urine platinum with AKI, NGAL, and KIM-1 were assessed. A total of 115 participants (54% boys, median age, 8.5 years; interquartile range, 4.0-13.4) were included, of which 29 (25%) and 105 (91%) developed AKI defined by SCr and electrolyte criteria, respectively. Higher urine platinum was associated with higher cisplatin dose (Spearman rho, 0.21) and with younger age (Spearman rho, -0.33). Urine platinum was not associated with postinfusion AKIor KIM-1, but was weakly associated with NGAL, particularly in participants without SCr AKI (Pearson's r, 0.22). Urine platinum may be a marker of mild tubular injury but is not likely to be a useful biomarker of clinically evident AKI.

Reduced exercise capacity can predispose solid organ transplant (SOT) recipients to higher risk of diabetes, cardiovascular complications, and mortality and impact their quality of life. This systematic review and meta-analysis investigated the effects of exercise training (versus no training) in adult SOT recipients. We conducted an electronic search of randomized controlled trials reporting on exercise interventions in SOT recipients. Primary outcomes were exercise capacity, quadriceps muscle strength, and health-related quality of life (HRQoL). Twenty-nine articles met the inclusion criteria. In 24 studies, there were either high risk of bias or some concerns about the potential risk of bias. There was an increase in exercise capacity (VO2 peak) (SMD: 0.40; 95%CI 0.22-0.57; P = 0.0) and quadriceps muscle strength (SMD: 0.38; 95%CI 0.16-0.60; P = 0.001) in the exercise vs control groups. There were also improvements in several domains of the SF-36. Diastolic blood pressure improved in the exercise group compared to controls (SMD: -0.22; 95%CI -0.41-0.03; P = 0.02). Despite the considerable variation in exercise training characteristics and high risk of bias in the included studies, exercise training improved maximal exercise capacity, quadriceps muscle strength, HRQoL, and diastolic blood pressure and should be an essential part of the post-transplant care.

BACKGROUND There are challenges in achieving and maintaining therapeutic tacrolimus levels after solid organ transplantation (SOT). The purpose of this genome-wide association study (GWAS) was to generate an integrated clinical and genetic prediction model for tacrolimus levels in pediatric SOT. METHODS In a multicenter prospective observational cohort study (2015-18), children

Screening studies have shown that 0.7-4.5% of generally healthy children have isolated diastolic high BP. We therefore studied the characteristics of children with diastolic BP in the elevated and hypertensive ranges according to current guidelines in US children from the National Health and Nutrition Examination Survey (NHANES, 1999-2016).We studied 17,362 children (8-18 years) with BP measured by sphygmomanometry. High BP was categorized as isolated systolic (iSH), isolated diastolic (iDH), or Mixed.Overall, 86.0% (95% CI = 85.0-87.0) of the population had normal BP, 8.7% (8.0-9.3) elevated BP, 4.9% (4.4-5.5) Stage 1, and 0.4% (0.4-0.6) Stage 2. Moreover, 11.1% (10.3-12.0) had iSH, 1.9% (1.5-2.2) iDH, and 1.0% (0.8-1.2) Mixed. Children with iDH were more likely to be female, younger, white, and leaner than those with iSH, with lower rates of overweight/obesity. iDH was generally between normals and iSH. Resting heart rate was significantly higher in iDH even after adjustment for known covariates.Children with iDH may have a distinct clinical picture. A leaner habitus and higher resting heart rate may reflect differences in underlying pathophysiology. Longitudinal follow-up studies are needed to better define the pathogenesis, progression, and long-term prognosis in iDH.Using gold-standard auscultation and 2017 guidelines, isolated diastolic high BP (iDH) is found in 1.9% (95% CI 1.5-2.2) of American children; these children are younger, leaner, more female, and have fewer cardiometabolic risks. Resting heart rate is significantly higher in iDH compared to both normals and iSH even after adjustments for known covariates. Autonomic hyperactivity in iDH may speak to both etiology and therapeutic approaches. iDH appears to be a distinct clinical phenotype characterized by differences in anthropometric measures, sex, age, and resting heart rate. Follow-up studies are clearly needed to clarify its pathogenesis, progression, and prognosis.

Introduction The reclassification of membranoproliferative glomerulonephritis (MPGN) into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) has provided insights into 2 distinct diseases. Although outcomes in adults are poor in both diseases, the pediatric literature is scarce and limited to small, single-center cohorts. Methods We conducted a retrospective analysis of 165 pediatric patients across 17 hospitals to compare outcomes between children with IC-MPGN and C3G. Results Forty-two percent of patients initially diagnosed with MPGN were reclassified as C3G after a review of renal biopsy reports. There was a trend toward higher serum creatinine levels in patients with C3G compared with IC-MPGN both at diagnosis (mean 168.9 [range 45.4–292.4] vs. 93.7 [range 70.7–116.6] μmol/l, P = 0.25) and after a mean follow-up time of 4 years (mean 145.0 (range −8.1 to 298.1) vs 99.1 (range 46.3–151.9) μmol/l, P = 0.47), although the estimated glomerular filtration rate (eGFR) was not significantly different. Steroid treatment was associated with a significant improvement in eGFR versus no steroids in C3G (mean +43.0 (range 12.9–73.0) vs. −3.0 (range −23.1 to 17.2) ml/min per 1.73 m2, P = 0.02) but not in IC-MPGN. Overall kidney function was preserved in both groups although hypertension remained prevalent in 42.5% of the cohort at the last follow-up, and the urine protein/creatinine ratio remained elevated (mean 253.8 [range 91.9–415.7] mg/mmol). Conclusion This large pediatric IC-MPGN/C3G cohort revealed nearly half of the patients were misclassified, and there may be a trend toward worse renal prognosis in C3G although they may have greater steroid responsiveness. The overall prognosis appears to be more favorable than in adults; however, persistent hypertension and proteinuria suggest suboptimal disease control., Graphical abstract

Prognostic biomarkers of T cell–mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA‐DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P, Alloimmune risk categorization using HLA‐DR/DQ molecular mismatch risk correlates with the severity, frequency, and persistence of T cell–mediated rejection and with graft survival, independent of de novo DSA.

BACKGROUND: Few studies have described associations between the AKI biomarkers urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) with AKI in cisplatin-treated children. We aimed to describe excretion patterns of urine NGAL and KIM-1 and associations with AKI in children receiving cisplatin. METHODS: Participants (n=159) were enrolled between 2013 and 2017 in a prospective cohort study conducted in 12 Canadian pediatric hospitals. Participants were evaluated at early cisplatin infusions (at first or second cisplatin cycle) and late cisplatin infusions (last or second-to-last cycle). Urine NGAL and KIM-1 were measured (1) pre-cisplatin infusion, (2) post-infusion (morning after), and (3) at hospital discharge at early and late cisplatin infusions. Primary outcome: AKI defined by serum creatinine rise within 10 days post-cisplatin, on the basis of Kidney Disease Improving Global Outcomes guidelines criteria (stage 1 or higher). RESULTS: Of 159 children, 156 (median [interquartile range (IQR)] age: 5.8 [2.4–12.0] years; 78 [50%] female) had biomarker data available at early cisplatin infusions and 127 had data at late infusions. Forty six of the 156 (29%) and 22 of the 127 (17%) children developed AKI within 10 days of cisplatin administration after early and late infusions, respectively. Urine NGAL and KIM-1 concentrations were significantly higher in patients with versus without AKI (near hospital discharge of late cisplatin infusion, median [IQR] NGAL levels were 76.1 [10.0–232.7] versus 14.9 [5.4–29.7] ng/mg creatinine; KIM-1 levels were 4415 [2083–9077] versus 1049 [358–3326] pg/mg creatinine; P

Background. Lack of noninvasive diagnostic and prognostic biomarkers to reliably detect early allograft injury poses a major hindrance to long-term allograft survival in pediatric kidney transplant recipients. Methods. Validating Injury to the Renal Transplant Using Urinary Signatures Children’s Study, a North American multicenter prospective cohort study of pediatric kidney transplant recipients, aims to validate urinary cell mRNA and metabolite profiles that were diagnostic and prognostic of acute cellular rejection (ACR) and BK virus nephropathy (BKVN) in adult kidney transplant recipients in Clinical Trials in Organ Transplantation-4. Specifically, we are investigating: (1) whether a urinary cell mRNA 3-gene signature (18S-normalized CD3ε, CXCL10 mRNA, and 18S ribosomal RNA) discriminates biopsies with versus without ACR, (2) whether a combined metabolite profile with the 3-gene signature increases sensitivity and specificity of diagnosis and prognostication of ACR, and (3) whether BKV-VP1 mRNA levels in urinary cells are diagnostic of BKVN and prognostic for allograft failure. Results. To date, 204 subjects are enrolled, with 1405 urine samples, including 144 biopsy-associated samples. Among 424 urine samples processed for mRNA, the median A260:280 ratio (RNA purity) was 1.91, comparable with Clinical Trials in Organ Transplantation-4 (median 1.82). The quality control failure rate was 10%. Preliminary results from urine supernatant showed that our metabolomics platform successfully captured a broad array of metabolites. Clustering of pool samples and overlay of samples from various batches demonstrated platform robustness. No study site effect was noted. Conclusions. Multicenter efforts to ascertain urinary biomarkers in pediatric kidney transplant recipients are feasible with high-quality control. Further study will inform whether these signatures are discriminatory and predictive for rejection and infection.

Background Neuroblastoma is a common solid tumor of childhood and is often associated with hypertension. Potential etiologies contributing to hypertension include renal compression, pain, volume overload, and catecholamine secretion. Cases We completed a single center retrospective review of children with neuroblastoma and ≥stage II hypertension (per Hypertension Canada guidelines) over a 2-year period. All patients (n = 10) had elevated urine normetanephrine levels and eight had intra-abdominal tumors. Four patients had refractory hypertension requiring > three agents, of which three required alpha/beta blockade. Conclusion Although multifactorial, hypertension in neuroblastoma often has a neuroendocrine component. Excess normetanephrine production in neuroblastoma may be a more common hypertensive mechanism than previously appreciated. Urinary normetanephrine elevation could suggest potential neuroendocrine-mediated hypertension.

Male sex is a risk factor for progression of diabetic kidney disease, but the reasons for this predilection are unclear. Here, we demonstrate that cell sex and sex hormones alter the metabolic phenotype of human proximal tubular epithelial cells (PTECs). Male PTECs displayed increased glycolysis, mitochondrial respiration, oxidative stress, apoptosis, and high glucose-induced injury, compared to female PTECs. This phenotype was enhanced by dihydrotestosterone (DHT) and linked to increased mitochondrial utilization of glucose and glutamine. Studies in vivo pointed towards increased glutamine anaplerosis in diabetic male kidneys. Male sex was linked to increased levels of glutamate, TCA cycle, and glutathione cycle metabolites, in PTECs and in the blood metabolome of healthy youth and youth with type 2 diabetes. Conversely, female PTECs displayed increased levels of pyruvate, glutamyl-cysteine, cysteinylglycine, and a higher GSH/GSSG ratio than male PTECs, indicative of enhanced redox homeostasis. Finally, we identified transcriptional mechanisms that control kidney metabolism in a sex-specific fashion. While X-linked demethylase KDM6A facilitated metabolic homeostasis in female PTECs, transcription factor HNF4A mediated the deleterious effects of DHT in male PTECs. This work uncovers the role of sex in glucose/glutamine metabolism, that may explain the roots of sex dimorphism in the healthy and diabetic kidney.

BACKGROUND The role of antiviral prophylaxis to prevent Epstein-Barr virus (EBV) viremia or posttransplant lymphoproliferative disorder in pediatric solid organ transplant recipients is controversial. We examined whether valganciclovir (VAL) prophylaxis for cytomegalovirus infection was associated with EBV viremia following transplantation in EBV-naive children. METHODS A single-center, retrospective study was conducted of EBV-naive pediatric heart and renal transplant recipients with an EBV-positive donor from January 1996 to April 2017. VAL was tested for association with EBV viremia-free survival in the first 6 months posttransplantation when immunosuppressant exposure is the highest. Survival models evaluated VAL duration, with adjustment for other baseline confounders. RESULTS Among the cohort (n = 44), 3 (6.8%) were heart transplants, 25 (56.8%) received VAL, and 22 (50%) developed EBV viremia in the first-year posttransplantation. Mean time-to-viremia was 143 vs. 90 days for the VAL and no-VAL groups, respectively (p = 0.008), in the first 6 months. Only two patients developed viremia while on VAL. Each additional day of VAL was associated with 1.4% increase in viremia-free survival (p

Rationale & Objective: Chronic kidney disease (CKD) has wide-ranging and long-term consequences for young people and their families. The omission of outcomes that are important to young people with CKD and their caregivers limits knowledge to guide shared decision making. We aimed to identify the outcomes that are important to young people with CKD and their caregivers. Study Design: We used the nominal group technique whereby participants identified and ranked outcomes and explained their priorities. Settings & Participants: Young people with CKD (stages 1-5, dialysis, or transplantation) and their caregivers were purposively sampled from 6 centers across Australia, the United States, and Canada. Analytical Approach: Importance scores were calculated (scale of 0-1), and qualitative data were analyzed thematically. Results: 34 patients (aged 8-21 years) and 62 caregivers participated in 16 groups and identified 48 outcomes. The 5 highest ranked outcomes for patients were survival (importance score, 0.25), physical activity (0.24), fatigue (0.20), lifestyle restrictions (0.20), and growth (0.20); and for caregivers, kidney function (0.53), survival (0.28), infection (0.22), anemia (0.20), and growth (0.17). 12 themes were identified reflecting their immediate and current priorities (wanting to feel normal, strengthening resilience, minimizing intrusion into daily life, imminent threats to life, devastating family burdens, and seeking control over health) and considerations regarding future impacts (protecting health/development, remaining hopeful, concern for limited opportunities, prognostic uncertainty, dreading painful and invasive procedures, and managing expectations). Limitations: Only English-speaking participants were recruited. Conclusions: Kidney function, infection, survival, and growth were the highest priorities for patients with CKD and their caregivers. Young people with CKD also prioritized highly the outcomes that directly affected their lifestyle and sense of normality, while caregiver's highest priorities concerned the long-term health of their child, current health problems, and the financial and family burdens of caring for a child with CKD.

Recent reassessment of the use of race in estimated glomerular filtration rate (eGFR) in adults has instigated questions about the role of race in eGFR expressions for children. Little research has examined the associations of self-reported race with measured GFR (mGFR) adjusting for serum creatinine or cystatin C in children and young adults with chronic kidney disease (CKD). This study examined these associations and evaluated the performance of the previously published "U25" (under the age of 25 years) eGFR equations in a large cohort of children and young adults with CKD.Observational cohort study.Participants in the Chronic Kidney Disease in Children (CKiD) study including 190 Black and 675 non-Black participants contributing 473 and 1,897 annual person-visits, respectively.Self- or parental-reported race (Black, non-Black). Adjustment for serum creatinine or cystatin C, body size, and socioeconomic status.mGFR based on iohexol clearance.Linear regression with generalized estimating equations, stratified by age (6, 6-12, 12-18, and ≥18 years) incorporating serum creatinine or serum cystatin C. Contrasting performance in different self-reported racial groups of the U25 eGFR equations.Self-reported Black race was significantly associated with 12.8% higher mGFR among children in regression models including serum creatinine. Self-reported Black race was significantly associated with 3.5% lower mGFR after adjustment for cystatin C overall but was not significant for those over 12 years. The results were similar after adjustment for body size and socioeconomic factors. The average of creatinine- and cystatin C-based U25 equations was unbiased by self-reported race groups.Small number of children 6 years; lean body mass was estimated.Differences in the creatinine-mGFR relationship by self-reported race were observed in children and young adults with CKD and were consistent with findings in adults. Smaller and opposite differences were observed for the cystatin C-mGFR relationship, especially in the younger age group. We recommend inclusion of children for future investigations of biomarkers to estimate GFR. Importantly, for GFR estimation among those under 25 years of age, the average of the new U25 creatinine and cystatin C equations without race coefficients yields unbiased estimates of mGFR.

Background: posttransplant diabetes mellitus (PTDM) is a serious complication in kidney transplant recipients (KTRs) due to its negative impact on graft and patient survival. Although reported in 3% to 20% of pediatric KTRs, it has not been as well characterized in adults. In this study we describe incidence and risk factors associated with development of PTDM in pediatric KTRs.Methods: this work is a retrospective cohort study of nondiabetic pediatric patients, aged 6 months to 19 years, who underwent a first kidney transplant during 1995 to 2016. We estimated the cumulative incidence rate and used multivariable logistic regression to identify the diabetogenic risk factors for PTDM.Results: a total of 142 KTRs were included in this study. The cumulative incidence of PTDM was 31% and 14.1% in the first and second year posttransplant, respectively. Significant risk factors for PTDM in the first year after transplant included: dysglycemia in the first 8 to 30 days posttransplant (adjusted odds ratio [aOR], 3.02; 95% confidence interval [CI], 1.21 to 7.53; p=0.018) and use of sirolimus in the first 30 days posttransplant (aOR, 5.33; 95% CI, 1.16 to 24.35; p=0.031). No significant association was found with typical diabetogenic factors.Conclusions: the incidence of PTDM is high among pediatric KTRs. Independent risk factors associated with PTDM included meeting the criteria for dysglycemia or diabetes and sirolimus use in the first month posttransplant. Typical diabetogenic risk factors for type 2 diabetes were not associated with increased risk. This study provides valuable information for posttransplant medical care and future research.

Cisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented.Describe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults.Observational prospective cohort study.Six Canadian oncology centers (3 pediatric, 1 adult and 2 both).Three hundred adults and 300 children planned to receive cisplatin therapy.During two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort.Patients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival.It may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge.ACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices.Le cisplatine, un agent utilisé en chimiothérapie pour traiter les tumeurs solides, entraîne de l’insuffisance rénale aiguë (IRA); un facteur de risque connu de néphropathie chronique et de mortalité. Le diagnostic de l’IRA repose sur des biomarqueurs qui ne sont mesurables qu’après l’apparition d’une lésion rénale et d’une déficience fonctionnelle; ce qui empêche le diagnostic et le traitement précoce de la maladie. La métabolomique s’efforce d’établir le profil des métabolites impliqués dans le métabolisme des tissus cellulaires en relation avec des facteurs liés à la maladie ou au patient. Une étude canadienne portant sur la métabolomique et la néphrotoxicité du cisplatine (ACCENT) s’est amorcée, elle explore la puissance de la métabolomique dans l’identification de nouveaux biomarqueurs permettant de prédire le risque de néphrotoxicité du cisplatine et d’en distinguer la présence. L’objectif étant de mettre en œuvre des stratégies d’intervention précoce, dès l’apparition de l’IRA, et de limiter la gravité de la maladie.Décrire la conception et la méthodologie de l’étude ACCENT. Cette étude vise à établir et à valider des profils métabolomiques, dans l’urine et le sérum, associés au risque de néphrotoxicité médiée par le cisplatine chez les enfants et les adultes.Étude de cohorte prospective.Six centres canadiens d’oncologie (trois centres pédiatriques, un centre pour adultes et deux centres mixtes).L’étude porte sur 300 adultes et 300 enfants pour qui un traitement par cisplatine est prévu.L’IRA sera confirmée par mesure de la créatinine et des électrolytes dans le sérum et l’urine au cours de deux cycles de perfusion de cisplatine. De nombreuses variables relatives au patient et à la maladie seront recueillies prospectivement avant et pendant le traitement. Les analyses métabolomiques des échantillons de sérum et d’urine seront effectuées par spectrométrie de masse. Une approche métabolomique non ciblée sera utilisée pour analyser les échantillons avant et après les perfusions de cisplatine pour identifier les biomarqueurs candidats d’une IRA découlant du traitement par cisplatine. Les métabolites candidats seront validés dans une cohorte indépendante.Les patients seront recrutés avant le premier cycle de cisplatine. Le sang et l’urine seront recueillis à des moments précis, soit avant et pendant le traitement; plus précisément lors de la première perfusion, puis d’une perfusion subséquente au cours du traitement contre le cancer. Le principal critère d’évaluation est la présence d’IRA, laquelle sera établie selon la définition classique fondée sur la mesure de la créatinine sérique et d’une autre définition fondée sur les anomalies électrolytiques. Un examen des dossiers trois mois après la fin du traitement par cisplatine sera effectué afin de documenter la santé rénale et la survie des patients.Il pourrait être impossible de corriger tous les facteurs confusionnels mesurés et non mesurés lors de l’évaluation de la prédiction de l’IRA à l’aide de profils de métabolites. La collecte de données sur plusieurs sites sera un défi.ACCENT est la plus vaste étude portant sur des enfants et des adultes traités avec le cisplatine; cette étude tente de revoir le modèle actuel en utilisant la métabolomique pour diagnostiquer l’IRA. L’identification de biomarqueurs permettant de prédire et de détecter l’IRA chez les enfants et les adultes traités par cisplatine pourrait grandement éclairer les futures études et pratiques cliniques.ClinicalTrials.gov, insuffisance rénale induite par le cisplatine, NCT04442516.

Purpose Patient-reported outcome measures (PROMs) are standardized instruments used to collect data about the subjective assessment of medical care from the patient perspective. Implementing PROMs within pediatric clinical settings has gained increasing importance as health services prioritize patient-centred pediatric care. This study explores the perspectives of pediatric solid organ transplant patients, caregivers, and healthcare practitioners (HCPs) on implementing PROMs into clinical practice. Methods Qualitative description methods were used to elicit stakeholder perspectives. Semi-structured interviews were conducted across five Canadian transplant centres. Purposive sampling was used to obtain maximum variation across age, gender, and transplant program for all participants, as well as discipline for HCPs. Results The study included a total of 63 participants [patients (n = 20), caregivers (n = 22) and HCPs (n = 21)]. Nearly all participants endorsed the implementation of PROMs to enhance pediatric transplant clinical care. Three primary roles for PROMs emerged: (1) to bring a transplant patient’s overall well-being into the clinical care conversation; (2) to improve patient communication and engagement; and, (3) to inform the practice of clinical pediatric transplant care. Insights for effective implementation included completing electronic PROMs remotely and prior to clinical appointments by patients who are eight to 10 years of age or older. Conclusions This study contributes to current research that supports the use of PROMs in clinical pediatric care and guides their effective implementation into practice. Future directions include the development, usability testing, and evaluation of a proposed electronic PROM platform that will inform future research initiatives.

Introduction: Mental health comorbidities are common in persons with type 2 diabetes (T2D). The magnitude of mental health comorbidities in youth with T2D and possible protective factors against comorbidities, remain unclear, as previous studies have not compared outcomes with population-based samples or included measures of resilience. Methods: We performed a cross-sectional analysis of 178 Indigenous youth (15 yrs IQR: 13-17 yrs) with T2D from the iCARE cohort study and 270 randomly sampled population-based controls (15-24 yrs), from the Canadian Community Health Survey - Mental Health Component. Overall positive mental health and flourishing were assessed with the Mental Health Continuum-Short Form. Depression, anxiety and severe mental illness (SMI) were assessed with the Kessler Distress Scale. Measures of resilience were assessed in youth with T2D using the 64-question Resiliency Scales for Children and Adolescents. Results: Youth with T2D, were more likely to be female (65 vs. 49%), Indigenous (96 vs. 29%), live remotely (70 vs. 26%) and within a low income neighbourhood (p Conclusion: Youth with T2D live with a profound degree of mental health comorbidities relative to the general population of in Manitoba, Canada. Future studies are required to address the specific mental health needs youth with T2D and determined best clinical care practices. Disclosure J. Mcgavock: None. B. Wicklow: None. E. Sellers: None. K. Kroeker: None. T. Blydt-Hansen: None. A. Dart: None. Funding Canadian Institutes of Health Research; Diabetes Canada; Research Manitoba

Background: Youth living with type 2 diabetes (T2D) are characterized by an increased cardiovascular disease (CVD) risk profile. It is unclear if regular vigorous intensity physical activity (PA) modifies this CVD risk. Methods: Using a cross-sectional design, we compared cardiometabolic risk factors among 164 youth with T2D from the The Improving renal Complications in Adolescents with T2D through REsearch (iCARE) cohort, stratified according to participation in vigorous intensity organized sport. Outcomes of interest were HbA1c, ambulatory blood pressure (BP) parameters from 24 hr monitoring, hypertension according to 2017 American Academy of Pediatrics criteria and albuminuria determined from first morning urine samples. The main exposure, regular (≥ 3 days/week) participation in vigorous intensity organized sport was determined from a validated questionnaire (Adolescent Physical Activity Questionnaire). Results: Youth were 15 ± 3 yrs, 78% lived in a rural town, 68% were girls, mean BMI Z score was 2.4 ± 1.1 and mean HbA1c was 9.6 ± 2.6%. Youth that participated in regular vigorous intensity organized sport (40%; n=67) achieved nearly twice the dose of PA than less active peers (176 vs. 108 MET-HR/week; p=0.001). After adjusting for duration of diabetes, BMI Z score, sex and current smoking status, youth with T2D who engaged in regular vigorous intensity organized sport displayed lower HbA1c (9.1%, vs. 9.9% p = 0.052), diastolic BP (70 vs. 73 mmHg, p = 0.002) and diastolic load (20 vs. 26%, p = 0.023). Compared to youth that did not participate in regular vigorous intensity organized sport, those who did displayed a lower odds of albuminuria (OR: 0.40 95% CI: 0.19-0.84) and hypertension (OR: 0.39 95% CI: 0.16-0.95). Conclusions: Among youth living with T2D, self-reported frequent participation in vigorous organized sport is associated with lower CVD risk. These data need to be confirmed with prospective observational and experimental data. Disclosure J.L. Slaght: None. A. Dart: None. T. Blydt-Hansen: None. E. Sellers: None. B. Wicklow: None. J. Mcgavock: None. Funding Diabetes Canada (OG-3-11-3354-AD); Heart and Stroke Foundation of Canada; Canadian Institutes of Health Research (MOP-142309)

This cohort study examines the rate of and risk factors associated with acute kidney injury in children treatment who receive cisplatin infusions., Key Points Question What are the characteristics and risk factors associated with acute kidney injury among children receiving cisplatin infusions? Findings In this cohort study of 159 cisplatin-treated children, 16% to 30% developed acute kidney injury during earlier (first or second cycle) and later (second to last or last cycle) cisplatin infusion treatment and 70% developed electrolyte disturbances. Cancer type and preinfusion kidney function were significantly associated with acute kidney injury risk at earlier and later infusions, and cisplatin dose was associated with acute kidney injury risk at later infusions. Meaning The findings suggest that acute kidney injury is common during cisplatin infusions and that rate and risk factors differ at earlier vs later infusions., Importance Few multicenter pediatric studies have comprehensively described the epidemiologic characteristics of cisplatin-associated acute kidney injury using standardized definitions. Objective To examine the rate of and risk factors associated with acute kidney injury among children receiving cisplatin infusions. Design, Setting, and Participants This prospective cohort study examined children (aged

RATIONALE & OBJECTIVE: The KDIGO (Kidney Disease: Improving Global Outcomes) guideline on CKD presented an international classification system that ranks patients' risk for CKD progression. Few data on children informed guideline development STUDY DESIGN: Observational cohort study SETTINGS AND PARTICIPANTS: Children aged 1-18 years enrolled in the North American Chronic Kidney Disease in Children (CKiD) cohort study and the European Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) trial. PREDICTOR: Level of estimated glomerular filtration rate (eGFR) and proteinuria (urine protein-creatinine ratio (mg/mg)) at study entry OUTCOME: A composite event of renal replacement therapy, 50% reduction of estimated GFR (eGFR), or eGFR 2.0 at study entry. Six ordered stages with varying combinations of eGFR categories (60-89, 45-59, 30-44 and 15-29 ml/min/1.73m(2)) and UPCR categories (2.0) described the risk continuum. Median times to event ranged from >10 years for eGFR 45-90 and UPCR 2. Children with glomerular disease were estimated to have a 43% shorter time to event than children with nonglomerular disease. Cross-validation demonstrated risk patterns that were consistent across the ten subsample validation models. LIMITATIONS: Observational study, utilized cross validation rather than external validation CONCLUSION: CKD staged by level of eGFR and proteinuria characterizes the timeline of progression and can guide management strategies in children.

BACKGROUND: Indigenous populations are disproportionately affected by kidney failure at younger ages than other ethnic groups in Canada. As symptoms do not occur until disease is advanced, early kidney disease risk is often unrecognized. OBJECTIVES: We sought to evaluate the yield of community-based screening for early risk factors for kidney disease in youth from rural Indigenous communities in Canada. METHODS: The FINISHED project screened 11 rural First Nations communities in Manitoba, Canada after community and school engagement. The results for the 10- to 17-year olds are reported here. Body mass index (BMI), blood pressure, estimated glomerular filtration rate (eGFR), hemoglobin A1c’s (HbA1c) and urine albumin-to-creatinine ratios (ACR) were assessed. All children were triaged and referred to either primary or tertiary care, depending on risk. RESULTS: A total of 353 were screened (estimated 22.4% of population). The median age was 12 years (IQR 10 to 13), 55% were female and 55% were overweight or obese. Overall, 21.8% of children had at least one abnormality. Hypertension was identified in 5.4% and 11.9% had prehypertension. None of the children had an eGFR < 60 ml/min/1.73 m(2) however 10.5% had an ACR > 3 mg/mmol and 6.2% had an eGFR < 90 ml/min/1.73 m(2) suggestive of early kidney disease. Diabetes was identified in 1.4%, and 1.4% had HbA1c’s between 6.1% and 6.49%. CONCLUSIONS: Risk factors for chronic kidney disease are highly prevalent in rural Indigenous children. More research is required to confirm the persistence of these findings, and to evaluate the efficacy of screening children to prevent or delay progression to kidney failure.

OBJECTIVE The aim of this study was to determine whether the readiness for adopting healthy lifestyle behaviors was associated with mental health and comorbid conditions in youth with T2D. METHODS A cross-sectional comparison of various measures of mental health (distress, stress, resilience) and comorbid conditions (glycated hemoglobin, adiposity, hypertension) was conducted within a cohort of indigenous youth with T2D living in Canada, stratified according to their readiness to adopt healthy lifestyle behaviors based on Prochaska's transtheoretical model. RESULTS Within the entire cohort (n = 162), only 14% were considered ready to adopt all healthy lifestyle behaviors. The readiness to adopt all lifestyle behaviors was associated with higher positive mental health (47 vs. 39 units; P

Background and objectives The role of albuminuria as an indicator of progression has not been investigated in children with CKD in the absence of diabetes. Design, setting, participants, & measurements Children were enrolled from 49 centers of the CKD in Children study between January of 2005 and March of 2014. Cross-sectional multivariable linear regression (n=647) was used to examine the relationship between urine protein-to-creatinine (UP/C [milligrams per milligram]) and albumin-to-creatinine (ACR [milligrams per gram]) with eGFR (milliliters per minute per 1.73 m2). Parametric time-to-event analysis (n=751) was used to assess the association of UP/C, ACR, and urine nonalbumin-to-creatinine (Unon-alb/cr [milligrams per gram]) on the time to the composite endpoint of initiation of RRT or 50% decline in eGFR. Results The median follow-up time was 3.4 years and 202 individuals experienced the event. Participants with a UP/C≥0.2 mg/mg and ACR≥30 mg/g had a mean eGFR that was 16 ml/min per 1.73 m2 lower than those with a UP/C 2.0 mg/mg], RT=0.09 for ACR [>1333 mg/g], RT=0.07 for Unon-alb/cr [>715 mg/g]) levels to the lowest levels. A similar trend was seen when categories were created on the basis of clinically meaningful cutoff values of ACR ( 300 mg/g). Conclusions In children with CKD without diabetes, the utility of an initial UP/C, ACR, and Unon-alb/cr for characterizing progression is similar. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_05_30_Schwartz.mp3

De novo donor-specific antibodies (dnDSAs) that develop after renal transplantation are independent predictors of allograft loss. However, it is unknown if dnDSA C1q status or titer at the time of first detection can independently predict allograft loss. In a consecutive cohort of 508 renal transplant recipients, 70 developed dnDSAs. Histologic and clinical outcomes were correlated with the C1q assay or dnDSA titer. C1q positivity correlated with dnDSA titer (p < 0.01) and mean fluorescence intensity (p < 0.01) and was more common in class II versus class I dnDSAs (p < 0.01). C1q status correlated with tubulitis (p = 0.02) and C4d status (p = 0.03) in biopsies at the time of dnDSA development, but not T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR). De novo DSA titer correlated with Banff g, i, t, ptc, C4d scores, TCMR (p < 0.01) and ABMR (p < 0.01). Post-dnDSA graft loss was observed more frequently in recipients with C1q-positve dnDSA (p < 0.01) or dnDSA titer ≥ 1:1024 (p ≤ 0.01). However, after adjustment for clinical phenotype and nonadherence in multivariate models, neither C1q status nor dnDSA titer were independently associated with allograft loss, questioning the utility of these assays at the time of dnDSA development.

Purpose of the program: To provide guidance on the management of pediatric kidney transplant patients during the COVID-19 pandemic. Sources of information: Program-specific documents, preexisting, and related to COVID-19; documents from provincial, national, and international kidney transplant societies/agencies and organ procurement agencies; national and international webinars, including webinars that we hosted for input and feedback; with additional information from formal and informal review of published academic literature. Methods: Challenges in the care of pediatric kidney transplant patients during the COVID-19 pandemic were highlighted within the Canadian Society of Transplantation (CST) Pediatric Group. It identified pediatric kidney transplant nephrologists (including a pediatric nephrologist ethicist) across the country and formed a workgroup. The initial guidance document was drafted and members of the workgroup reviewed and discussed all suggestions in detail via e-mail and virtual meetings. Disagreements were resolved by consensus. The document was reviewed by the CST Kidney Transplant Working Group, by the Canadian Society of Nephrology (CSN) COVID-19 Rapid Response Team (RRT), and an infectious disease expert. The suggestions were presented at an interactive webinar sponsored by CSN in collaboration with the CST and Canadian Association of Pediatric Nephrologists (CAPN), and attended by pediatric kidney health care professionals for further peer input. Final revisions were made based on feedback received. CJKHD editors reviewed the parallel process peer review and edited the manuscript for clarity. Key findings: We identified 8 key areas of pediatric kidney transplant care that may be affected by the COVID-19 pandemic: (1) transplant activity, (2) outpatient clinic activity, (3) monitoring, (4) multidisciplinary care, (5) medications (immunosuppression and others), (6) patient/family education/support, (7) school and employment, and (8) management of pediatric kidney transplant patients who are COVID-19 positive. We make specific suggestions for each of these areas. Limitations: A full systematic review of available literature was not undertaken for the sake of expediency in development of this guideline. There is a paucity of literature to support evidence-based recommendations at this time. Instead, these guidelines were formulated based on expert opinion derived from available knowledge/experience and are subject to the biases associated with this level of evidence. The parallel review process that was created to expedite the publication of this work may not be as robust as standard arms’ length peer review processes. Implications: These recommendations are meant to serve as a guide to pediatric kidney transplant directors, clinicians, and administrators for providing the best patient care in the context of limited resources while protecting patients and health care providers wherever possible by limiting exposure to COVID-19. We recognize that recommendations may not be applicable to all provincial/local health authority practices and that they may not be delivered to all patients given the time and resource constraints affecting the individual provincial/local health jurisdiction.

Background. Despite age-related differences in biology, physiology, and behavior, transplant immunosuppression is not tailored by age. This likely contributes to high graft failure and posttransplant complications. We present the aims, design, and methods of the Pediatric Outcomes in Transplant: PersOnaliSing Immunosuppression To ImproVe Efficacy Study aimed at personalizing posttransplant immunosuppression in children and young adults. Methods. In this prospective observational cohort study, we recruited pediatric and young adult solid organ transplant, pediatric allogeneic hematopoietic stem cell transplant recipients, and matched living and deceased organ donors from 14 transplant centers across Canada. Clinical data, questionnaires, biospecimens, and pharmacy records were collected at serial time points: (1) to identify genetic and host immune factors that influence immunosuppression dose requirements across different ages and transplant types, (2) to identify viral-host interactions that increase susceptibility to Epstein-Barr virus infection, and (3) to define care processes and structures associated with medication adherence in adolescents and young adults. Results. From 2015 to 2018, 1662 new and prevalent transplant recipients were screened, 1166 were recruited for the various aims, including 370 liver, 445 kidney, 277 heart, 19 lung, 19 multiple, and 36 hematopoietic stem cell transplant transplants. Twelve percent were younger than 2 years, 30% were 2 to 10 years, 42% were 10 to 18 years, and 16% were 18 to 24 years at enrollment. Nine hundred thirty-one consented to participation in aims 1 and 2 (90% consent rate), 287 to aim 3 (82% consent rate). Biospecimens collected included 898 for DNA, 276 for immunoassays, and 717 for biomarker studies. Seventy percent participants have completed follow-up; 30% are pending study completion. Conclusions. The design of this national multicenter cross-organ network helped maximize recruitment of a large patient cohort for studying age and organ-related differences in immunosuppression needs that would not otherwise be feasible. Leveraging the unique clinical, biological, environmental, and behavioral characteristics of this cohort will help develop precision medicine strategies for individualizing posttransplant immunosuppression.

Background & Objectives Effective communication and shared decision making improve quality of care and patient outcomes but can be particularly challenging in pediatric chronic disease because children depend on their parents and clinicians to manage complex health care and developmental needs. We aimed to describe the perspectives of children with chronic kidney disease (CKD) and their parents with regard to communication and decision making. Study Design Qualitative study. Setting & Participants Children with CKD (n=34) and parents (n=62) from 6 centers across 6 cities in Australia, Canada, and the United States participated in 16 focus groups. Analytical Approach Transcripts were analyzed thematically. Results We identified 4 themes: (1) disempowered by knowledge imbalance (unprepared and ill-informed, suspicion of censorship, and inadequacy as technicians), (2) recognizing own expertise (intuition and instinct unique to parental bond, emerging wisdom and confidence, identifying opportunities for control and inclusion, and empowering participation in children), (3) striving to assert own priorities (negotiating broader life impacts, choosing to defer decisional burden, overprotected and overruled, and struggling to voice own preferences), and (4) managing child's involvement (respecting child's expertise, attributing "risky" behaviors to rebellion, and protecting children from illness burden). Limitations Only English-speaking participants were recruited, which may limit the transferability of the findings. We collected data from child and parent perspectives; however, clinician perspectives may provide further understanding of the difficulties of communication and decision making in pediatrics. Conclusions Parents value partnership with clinicians and consider long-term and quality-of-life implications of their child's illness. Children with CKD want more involvement in treatment decision making but are limited by vulnerability, fear, and uncertainty. There is a need to support the child to better enable him or her to become a partner in decision making and prepare him or her for adulthood. Collaborative and informed decision making that addresses the priorities and concerns of both children and parents is needed.

Understanding rates and determinants of clinical pathologic progression for recipients with de novo donor-specific antibody (dnDSA), especially subclinical dnDSA, may identify surrogate endpoints and inform clinical trial design. A consecutive cohort of 508 renal transplant recipients (n = 64 with dnDSA) was studied. Recipients (n = 388) without dnDSA or dysfunction had an eGFR decline of -0.65 mL/min/1.73 m(2) /year. In recipients with dnDSA, the rate eGFR decline was significantly increased prior to dnDSA onset (-2.89 vs. -0.65 mL/min/1.73 m(2) /year, p

Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II de novo donor-specific antibody (dnDSA) development correlates with tacrolimus trough levels and the recipient’s individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds 6 months before dnDSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developing dnDSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of dnDSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels

The goal of this study was to evaluate the utility of urinary metabolomics for noninvasive diagnosis of T cell–mediated rejection (TCMR) in pediatric kidney transplant recipients. Urine samples (n = 277) from 57 patients with surveillance or indication kidney biopsies were assayed for 134 unique metabolites by quantitative mass spectrometry. Samples without TCMR (n = 183) were compared to borderline tubulitis (n = 54) and TCMR (n = 30). Partial least squares discriminant analysis identified distinct classifiers for TCMR (area under receiver operating characteristic curve [AUC] = 0.892; 95% confidence interval [CI] 0.827–0.957) and borderline tubulitis (AUC = 0.836; 95% CI 0.781–0.892), respectively. Application of the TCMR classifier to borderline tubulitis samples yielded a discriminant score (−0.47 ± 0.33) mid-way between TCMR (−0.20 ± 0.34) and No TCMR (−0.80 ± 0.32) (p

Indigenous youth with type 2 diabetes (T2D) are disproportionately affected by early onset albuminuria and are at high risk of kidney failure in early adulthood. Traditional biological approaches have failed to fully explain the renal morbidity seen in this population. TheThe objective of this study was to evaluate the iCARE analytic framework which evaluates relationships between biological factors, mental health, inflammation, and albuminuria utilizing a structural equation modeling (SEM) approach.The first 187 youth with T2D (10-25 years) from the Manitoba iCARE cohort are presented here to evaluate our theoretical and analytic framework. An SEM was chosen to evaluate the statistical significance of proposed associations. The primary outcome was a nonorthostatic urine albumin:creatinine ratio ≥2 mg/mmol. Main exposures (ie, latent factors) included psychological health (distress, perceived stress, positive mental health and resilience), hypertension (24 hour monitored), and inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], fibrinogen). Hemoglobin A1c (HbA1c) and duration of diabetes were covariates.Within the initial cohort (median age = 15 years, duration of diabetes = 2.3 years, 66.8% female), 30.5% (n = 57) had nonorthostatic albuminuria (ALB), and the majority of ALB was persistent (confirmed in 2/3 samples over a 6-month period; n = 47). Youth with ALB had higher HbA1c (10.9% vs 8.9%;Albuminuria is highly prevalent in Indigenous youth with T2D. This preliminary analysis supports a theoretical framework linking glycemic control, hypertension, and inflammation, potentially mediated by psychological factors with albuminuria. These data support the need for more holistic models of evaluation and care for youth with T2D and multifactorial interventions to prevent complications.L’albuminurie à déclenchement précoce affecte de façon disproportionnelle les jeunes autochtones atteints de diabète de type 2 (T2D). Ces derniers présentent également un risque plus élevé d’insuffisance rénale au début de l’âge adulte. Les approches biologiques traditionnelles n’ont pas été en mesure d’expliquer entièrement la morbidité rénale observée dans cette population. Ainsi, l’étude de cohorte iCARE (Évaluer le cadre d’analyse iCARE qui examine les liens entre les facteurs biologiques, la santé mentale, l’inflammation et l’albuminurie à l’aide d’une approche de modélisation par équation structurelle (SEM).Les 187 premiers jeunes autochtones atteints de T2D (âgés de 10 à 25 ans) de la cohorte manitobaine iCARE sont présentés ici pour évaluer notre cadre théorique et analytique. Une SEM a été choisie pour évaluer la pertinence statistique des associations suggérées. Le résultat principal était un rapport urinaire albumine/créatinine non orthostatique d’au moins 2 mg/mmol. Les principaux risques (c.-à-d. les facteurs latents) comprenaient la santé mentale (détresse, stress perçu, bien-être mental et résilience), l’hypertension (suivie sur 24 heures) et les taux de marqueurs inflammatoires (CRP, ESR, fibrinogène). L’hémoglobine A1c (HbA1c) et la période depuis l’apparition du diabète constituaient les covariables.Les sujets retenus (66,8 % de sujets féminins) avaient 15 ans d’âge médian et étaient diabétiques depuis 2,3 ans. Dans cette cohorte, 30,5 % (n = 57) présentaient une albuminurie non orthostatique (confirmée dans 2/3 des échantillons sur une période de six mois) qui s’est avérée persistante dans la majorité des cas (n = 47). Les jeunes souffrant d’albuminurie présentaient des taux plus élevés d’HbA1c (10,9 c. 8,9 %;L’albuminurie est très répandue chez les jeunes autochtones atteints de T2D. Cette analyze préliminaire vient étayer un cadre théorique qui établit un lien entre l’albuminurie et le contrôle de la glycémie, l’hypertension et l’inflammation; lien potentiellement médié par des facteurs psychologiques. Ces données appuient la nécessité d’avoir des modèles plus holistiques d’évaluation et de prise en charge des jeunes atteints de T2D, et des interventions multifactorielles visant à prévenir les complications.

De novo donor-specific antibody (dnDSA) develops in 15-25% of renal transplant recipients within 5 years of transplantation and is associated with 40% lower graft survival at 10 years. HLA epitope matching is a novel strategy that may minimize dnDSA development. HLAMatchmaker software was used to characterize epitope mismatches at 395 potential HLA-DR/DQ/DP conformational epitopes for 286 donor-recipient pairs. Epitope specificities were assigned using single antigen HLA bead analysis and correlated with known monoclonal alloantibody epitope targets. Locus-specific epitope mismatches were more numerous in patients who developed HLA-DR dnDSA alone (21.4 vs. 13.2, p < 0.02) or HLA-DQ dnDSA alone (27.5 vs. 17.3, p < 0.001). An optimal threshold for epitope mismatches (10 for HLA-DR, 17 for HLA-DQ) was defined that was associated with minimal development of Class II dnDSA. Applying these thresholds, zero and 2.7% of patients developed dnDSA against HLA-DR and HLA-DQ, respectively, after a median of 6.9 years. Epitope specificity analysis revealed that 3 HLA-DR and 3 HLA-DQ epitopes were independent multivariate predictors of Class II dnDSA. HLA-DR and DQ epitope matching outperforms traditional low-resolution antigen-based matching and has the potential to minimize the risk of de novo Class II DSA development, thereby improving long-term graft outcome.

Background Among adults, lower socioeconomic status (SES) is a risk factor for chronic kidney disease (CKD), progression to end-stage renal disease, and poor health outcomes; but its impact on young people with CKD is not established. Study Design Prospective cohort study. Settings & Participants 572 children and adolescents aged 1-16 years with mild to moderate CKD residing in the United States and Canada who were enrolled in the Chronic Kidney Disease in Children (CKiD) Study. Predictor Self-reported annual household income category as a proxy measure for SES: ≥$75,000 (high income), $30,000 to Outcomes & Measurements Clinical characteristics and CKD severity at baseline (glomerular filtration rate [GFR] and comorbid conditions related to disease severity and management) and longitudinally (GFR decline and changes in blood pressure z scores and height z scores per year). Results At baseline, low and middle household incomes, compared to high income, were associated with minority race (39% and 20% vs 7%), lower maternal education (28% and 5% vs 1%), abnormal birth history (34% and 32% vs 21%), and having at least one clinical comorbid condition (66% and 64% vs 55%). Baseline median GFRs were similar across income categories (43-45 mL/min/1.73 m 2 ). After adjusting for baseline differences, average GFR declines per year for the low-, middle-, and high-income categories were −2.3%, −2.7%, and −1.9%, respectively, and were not statistically significantly different among groups. Blood pressure control tended to improve in all groups ( z score, −0.10 to −0.04) but higher income was associated with a faster improvement. Each group showed similar deficits in height at baseline. Height deficits diminished over time for participants from high-income families, but not among those from low-income families (z scores for height per year, 0.05 and −0.004, respectively; P = 0.03 for comparison of high and low income). Limitations Income is an imperfect measure for SES; CKiD participants are not representative of children and adolescents with CKD who are uninsured or not receiving care; statistical power to detect associations by income level is limited. Conclusions GFR decline was similar across income groups but better improvement in BP was observed among those with high income. Children and adolescents with CKD from lower income households are at higher risk of impaired growth.

Analysis of oxylipins derived from fatty acids may provide insight into the biological effects of dietary lipids beyond their effects on tissue fatty acid profiles. We have previously observed that diets with higher amounts of α-linolenic acid (ALA; 18:3n3) are associated with reduced obesity-related glomerulopathy (ORG). Therefore, to examine the renal oxylipin profile, the effects of dietary linoleic acid (LA; 18:2n6) and ALA on oxylipins and renal phospholipid fatty acid composition, and the relationship between oxylipins and ORG, diet-induced obese rats displaying ORG were fed 8 different diets for 8 wk as follows (oil/oil = combination of two oils) [shown as ALA/LA (in g) per 100 g oil]: canola/flax (20/18), canola (8/18), soy (9/53), high-oleic canola/canola (5/16), high-oleic canola (2/15), lard/soy (1/8), and safflower (0.2/73). Targeted lipidomic analysis by HPLC-tandem mass spectrometry revealed that LA and ALA oxylipins comprised 60% of the total renal oxylipin profile examined. Of the >60 oxylipins screened, only those derived either directly or indirectly from ALA were associated with less glomerulomegaly, indicative of reduced ORG progression. Both the amount and ratio of dietary LA and ALA influenced renal polyunsaturated fatty acids (PUFAs); in contrast, only fatty acid amount altered oxylipins derived from these fatty acids, but there was no apparent competition by LA or ALA on their formation. Dietary LA incorporation into renal phospholipids was higher than for ALA, but ALA oxylipin:ALA ratios were higher than the analogous LA ratios for select lipoxygenase reactions. This indicates that the effect of dietary ALA on renal oxylipins exceeded what was reflected in renal PUFA composition. In conclusion, dietary LA and ALA have differential effects on renal oxylipins and PUFAs, and ALA-derived oxylipins are associated with renoprotection in this model of ORG.

Summary: Eighty children with nephrotic syndrome underwent lumbar spine densitometry and vertebral morphometry soon after glucocorticoid initiation. We found an inverse relationship between glucocorticoid exposure and spine areal bone mineral density (BMD) Z-score and a low rate of vertebral deformities (8%). Introduction: Vertebral fractures are an under-recognized complication of childhood glucocorticoid-treated illnesses. Our goal was to study the relationships among glucocorticoid exposure, lumbar spine areal BMD (LS BMD), and vertebral shape in glucocorticoid-treated children with new-onset nephrotic syndrome. Methods: Lateral thoracolumbar spine radiography and LS BMD were performed in 80 children with nephrotic syndrome (median age 4.4 years; 46 boys) within the first 37 days of glucocorticoid therapy. Genant semiquantitative grading was used as the primary method for vertebral morphometry; the algorithm-based qualitative (ABQ) method was used for secondary vertebral deformity analysis. Results: Six of the 78 children with usable radiographs (8%; 95% confidence interval 4 to 16%) manifested a single Genant grade 1 deformity each. All deformities were mild anterior wedging (two at each of T6, T7, and T8). Four of the 78 children (5%; 95% confidence interval 2 to 13%) showed one ABQ sign of fracture each (loss of endplate parallelism; two children at T6 and two at T8). Two of the children with ABQ signs also had a Genant grade 1 deformity in the same vertebral body. None of the children with a Genant or ABQ deformity reported back pain. An inverse relationship was identified between LS BMD Z-score and glucocorticoid exposure. Conclusions: Although we identified an inverse relationship between steroid exposure and LS BMD soon after glucocorticoid initiation for childhood nephrotic syndrome, there was only a low rate of vertebral deformities. The clinical significance of these findings requires further study. © 2011 International Osteoporosis Foundation and National Osteoporosis Foundation.

Heme oxygenase-1 (HO-1) overexpression using gene transfer protects rat livers against ischemia/reperfusion (I/R) injury. This study evaluates the effects of Ad-HO-1 gene transfer in a rat renal isograft model. Donor LEW kidneys were perfused with Ad-HO-1, Ad-beta-gal, or PBS, stored at 4 degrees C for 24 h, and transplanted orthotopically into LEW recipients, followed by contralateral native nephrectomy. Serum creatinine, urine protein/creatinine ratios, severity of histologic changes, HO-1 mRNA/protein expression, and HO enzymatic activity were analyzed. Ad-HO-1 gene transfer conferred a survival advantage when compared with PBS- and Ad-beta-gal-treated controls, with median survival of 100, 7, and 7 d, respectively (P0.01). Serum creatinine levels were elevated at day 7 in all groups (range, 2.2 to 5.8 mg/dl) but recovered to 1.0 mg/dl by day 14 (P0.01) in Ad-HO-1 group, which was sustained thereafter. Urine protein/creatinine ratio at day 7 was elevated in both PBS and Ad-beta-gal, as compared with the Ad-HO-1 group (12.0 and 9.8 versus 5.0; P0.005); histologically, ATN and glomerulosclerosis was more severe in Ad-beta-gal group at all time points. Reverse transcriptase-PCR-based HO-1 gene expression was significantly increased before reperfusion (P0.001) and remained increased in the Ad-HO-1-treated group for 3 d after transplantation. Concomitantly, HO enzymatic activity was increased at transplantation and at 3 d posttransplant in the Ad-HO-1 group, compared with Ad-beta-gal controls (P0.05); tubular HO-1 expression was discernible early posttransplant in the Ad-HO-1 group alone. These findings are consistent with protective effects of HO-1 overexpression using a gene transfer approach against severe renal I/R injury, with reduced mortality and attenuation of tissue injury.

Background:Childhood cancer survivors experience adverse drug events leading to lifelong health issues. The Applying Biomarkers to Minimize Long-Term Effects of Childhood/Adolescent Cancer Treatmen...

Objective: To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus. Design: Systematic review and meta-analysis of individual patient data. Data sources: Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013. Eligibility: Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival. Results: The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls. Conclusions: Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.

To define glomerular filtration rate (GFR) decline, hypertension (HTN), and proteinuria in subjects with autosomal recessive polycystic kidney disease (ARPKD) and compare with 2 congenital kidney disease control groups in the Chronic Kidney Disease in Children cohort.GFR decline (iohexol clearance), rates of HTN (ambulatory/casual blood pressures), antihypertensive medication usage, left ventricular hypertrophy, and proteinuria were analyzed in subjects with ARPKD (n = 22) and 2 control groups: aplastic/hypoplastic/dysplastic disorders (n = 44) and obstructive uropathies (n = 44). Differences between study groups were examined with the Wilcoxon rank sum test.Annualized GFR change in subjects with ARPKD was -1.4 mL/min/1.73 m(2) (-6%), with greater decline in subjects age ≥ 10 years (-11.5%). However, overall rates of GFR decline did not differ significantly in subjects with ARPKD vs controls. There were no significant differences in rates of HTN or left ventricular hypertrophy, but subjects with ARPKD had a greater percent on ≥ 3 blood pressure medications (32% vs 0%, P.0001), more angiotensin-converting enzyme inhibitor use (82% vs 27% vs 36%, P.0005), and less proteinuria (urine protein: creatinine = 0.1 vs 0.6, P.005).This study reports rates of GFR decline, HTN, and proteinuria in a small but well-phenotyped ARPKD cohort. The relatively slow rate of GFR decline in subjects with ARPKD and absence of significant proteinuria suggest that these standard clinical measures may have limited utility in assessing therapeutic interventions and highlight the need for other ARPKD kidney disease progression biomarkers.

To assess depression in children with chronic kidney disease and to determine associations with patient characteristics, intellectual and educational levels, and health-related quality of life (HRQoL).Subjects aged 6-17 years from the Chronic Kidney Disease in Children cohort study completed the Children's Depression Inventory (CDI), Wechsler Abbreviated Scales of Intelligence, Wechsler Individual Achievement Test-II-Abbreviated, and the Pediatric Inventory of Quality of Life Core Scales 4.0. Regression analyses determined associations of CDI score and depression status with subject characteristics, intellectual and educational levels, and HRQoL. A joint linear mixed model and Weibull model were used to determine the effects of CDI score on longitudinal changes in glomerular filtration rate and time to renal replacement therapy.A total of 344 subjects completed the CDI. Eighteen (5%) had elevated depressive symptoms, and another 7 (2%) were being treated for depression. In adjusted analyses, maternal education beyond high school was associated with 5% lower CDI scores (estimate, 0.95; 95% CI, 0.92-0.99). Depression status was associated with lower IQ (99 vs 88; P = .053), lower achievement (95 vs 77.5; P.05), and lower HRQoL by parent and child reports (effect estimates, -15.48; 95% CI, -28.71 to -2.24 and -18.39; 95% CI, -27.81 to -8.96, respectively). CDI score was not related to change in glomerular filtration rate.Children with depression had lower psychoeducational skills and worse HRQoL. Identifying and treating depression should be evaluated as a means of improving the academic performance and HRQoL of children with chronic kidney disease.

The NAPRTCS transplant registry has collected clinical information on children undergoing kidney transplantation since 1987 and now includes information on 11 603 kidney transplants in 10 632 patients. Since the first data analysis in 1989, NAPRTCS reports have documented marked improvements in outcome after kidney transplantation in addition to identifying factors associated with both favorable and poor outcomes. Patient demographics have changed over the course of the registry with a decrease in the percentage of white recipients from a high of 72% in 1987 to less than 43% in 2007. The percentage of living donors decreased to its lowest point in 2007 at 37%. Acute rejection rates continue to decline with improvements in short- and long-term graft survival. Recently, NAPRTCS data have been used as a source of benchmark data for pediatric kidney transplant centers.