Search

Rationale & objective To identify differences in socioeconomic factors (SES) and subclinical CVD markers by race among CKiD participants and determine whether differences in CVD markers persist after adjusting for SES. Study design Analysis of 3103 visits with repeated measures from 628 children (497 Caucasian; 131 African American) enrolled in the CKiD study. Setting & participants Children with mild-moderate CKD with at least 1 CV parameter (ambulatory blood pressure, left ventricular mass index [LVMI], or lipid profile) measured. Exposures African American race OUTCOMES: Ambulatory hypertension, LVMI, triglycerides, high-density lipoprotein-cholesterol. Analytical approach Due to increased CV risks of glomerular disease, the analysis was stratified by CKD etiology. Inverse probability weighting was used to adjust for SES (health insurance, household income, maternal education, food insecurity, abnormal birth history). Linear and logistic regression were used to evaluate association of race with CV markers. Results African American children were disproportionately affected by adverse SES. African Americans with non-glomerular CKD had more ambulatory hypertension and higher LVMI, but more favorable lipid profile; after adjustment for SES, age, and sex, the magnitude of differences in these CV markers attenuated but remained statistically significant. Only LVMI differed by race in the glomerular CKD group, despite adjustment for SES. Limitations Study design limits causal inference. Conclusion African American children with CKD are disproportionately affected by socioeconomic disadvantages compared with Caucasians. The degree to which CV markers differ by race is influenced by disease etiology. African Americans with non-glomerular CKD have increased LVMI, more ambulatory hypertension and favorable lipid profile, but a trend towards attenuation in magnitude after adjustment for SES was observed. African Americans with glomerular CKD have increased LVMI, which persisted after SES adjustment. As many social determinants of health were not captured, future research should examine effects of systemic racism on CV health in this population.

Children with kidney failure have increased risk for cardiovascular morbidities before and after transplantation. Ejection fraction is often preserved, masking cardiac dysfunction until severe. Data on longitudinal changes in diastolic function and cardiac geometry are limited.A prospective study was conducted to investigate longitudinal changes in diastolic function and structure pre- and post-kidney transplant compared with healthy peers. Transplant recipients (n = 41) had echocardiograms pre-transplant, 1, 18, 30, and 42 months post-transplant. The controls (n = 26) underwent one echocardiogram. Diastolic function and cardiac geometry were assessed by E/e' lateral, E/A, interventricular septal end diastole diameter, left ventricular internal end diastole diameter, left ventricular posterior wall end diastole diameter, and left atrial dimension.E/e' of patients remained worse than controls until 30 months post-transplant, and E/A was impaired at all time points compared to the controls. Left ventricular geometry was abnormal in 46% pre-transplant and remained altered in 44.7%, 32.3%, 30.7%, and 27.2% at 1, 18, 30, and 42 months post-transplant. Determinants of diastolic dysfunction included hemodialysis, uncontrolled hypertension, steroid exposure, and metabolic syndrome; abnormal geometry was associated with glomerular diagnosis, dialysis duration, obesity, steroids, and metabolic syndrome. Abnormal diastolic function and structure were associated with left ventricular hypertrophy.Diastolic dysfunction and geometry partially improve after transplant but remain abnormal in a subset of patients compared to healthy peers. Traditional indicators of systolic function are preserved. Modifiable risk factors include dialysis modality and duration, uncontrolled hypertension, corticosteroids, obesity, and metabolic syndrome. Attention to diastolic changes provides opportunity for early intervention. A higher resolution version of the Graphical abstract is available as Supplementary information.

Accurate detection of hypertension is crucial for clinical management of pediatric chronic kidney disease (CKD). The 2017 American Academy of Pediatrics childhood hypertension guidelines included new normative blood pressure (BP) values and revised definitions of BP categories. In this study, we examined the effect of applying these changes to the Chronic Kidney Disease in Children (CKiD) cohort compared to use of the 2004 Fourth Report normative data and definitions.Observational cohort study.Children and adolescents in the CKiD cohort.Clinic blood pressure measurements.Blood pressure percentiles and hypertension stages calculated using the 2017 and 2004 guidelines.Agreement analysis compared the estimated percentile and prevalence of high blood pressure based on the 2017 and 2004 guidelines to clinic and combined ambulatory blood pressure readings.The proportion of children classified as having normal clinic blood pressure was similar using the 2017 and 2004 guidelines, but the use of the 2017 normative data classified more participants as having hypertensive-range blood pressure (22% vs. 11%) with marginal reproducibility (kappa= 0.569, 95%CI: 0.538, 0.599). Those identified as hypertensive by the 2017 guidelines had higher levels of proteinuria compared to those identified using the 2004 guidelines. There were substantially more participants with white coat and ambulatory hypertension when using the 2017 guidelines (3.5% vs. 1.5%; and 15.5% vs. 7.9%, respectively). The proportion with masked hypertension was lower using the 2017 guidelines (40.2% vs. 47.8%, respectively) with good reproducibility (kappa= 0.799, 95%CI: 0.778, 0.819), and the percentage of participants with normal ambulatory blood pressure was similar (40.9% vs. 42.9%, respectively), LIMITATIONS: Relationship with long-term progression and target organ damage was not assessed.A greater percentage of children with CKD were identified as hypertensive based on both clinic and ambulatory blood pressure when using the 2017 vs. the 2004 guidelines, and the 2017 guidelines better discriminated those with higher levels of proteinuria. The substantial differences in the classification of hypertension when using the 2004 vs. 2017 guidelines should inform clinical care.

Introduction Rabbit antithymocyte globulin (rATG) dosing strategies for induction in pediatric kidney transplantation vary between centers. It is not known whether a lower rATG induction dose provides safe and effective immunosuppression compared with a “standard” higher dose. Methods We performed a retrospective multicenter study of all isolated first-time kidney transplant recipients 4.5 mg/kg) exposure groups. Outcomes examined included 12 months posttransplant graft function (estimated glomerular filtration rate [eGFR]); the occurrence of acute rejection, donor-specific antibody (DSA), neutropenia, and viral infection (cytomegalovirus [CMV], Epstein-Barr virus [EBV], and BK virus); and 24-month outcomes of posttransplant lymphoproliferative disorder (PTLD) occurrence and patient and graft survival. Results Two hundred thirty-five patients were included. Baseline features of the low and standard rATG dose groups were similar. By 12 months, the rATG dose group had no significant impact on the occurrence of neutropenia, positive DSA, or viral polymerase chain reaction (PCR). Graft function was similar. Acute rejection rates were similar at 17% (low dose) versus 19% (standard dose) (P = 0.13). By 24 months, graft survival (96.4% vs. 94.6%) and patient survival (100% vs. 99.3%) were similar between the low- and standard-dose groups (P = 0.54 and 0.46), whereas the occurrence of PTLD trended higher in the standard-dose group (0% vs. 2.6%, P = 0.07). Conclusion A low rATG induction dose ≤ 4.5 mg/kg provided safe and effective outcomes in this multicenter low immunologic risk pediatric cohort. Prospective studies are warranted to define the optimal rATG induction dose in pediatric kidney transplantation., Graphical abstract

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.

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: Frailty is a condition of decreased physiologic reserve and increased vulnerability to stressors. Frailty in combination with inflammation has been associated with increased mortality risk in adults with advanced chronic kidney disease (CKD). This study aimed to investigate prevalence and outcomes associated with a frailty-inflammation phenotype, or “fragility,” in children with CKD. DESIGN/METHODS: We analyzed 557 children (age 6-19 years, eGFR 30-90ml/min/1.73m(2)) from the Chronic Kidney Disease in Children (CKiD) study. Based on adult models, the CKiD fragility model included four indicators: (1) Suboptimal growth/weight gain (BMI3 mg/L). Logistic regression was used to evaluate association of fragility indicators with three adverse outcomes: frequent infection (>1 per year/3 years), hospitalization (any), and rapid CKD progression (decline in eGFR>30% or initiation of renal replacement therapy within 3 years). RESULTS: Prevalence of fragility indicators one year after study entry were 39% (suboptimal growth/weight gain), 62% (low muscle mass), 29% (fatigue), and 18% (inflammation). Prevalence of adverse outcomes during subsequent 3 years were 13% (frequent infection), 22% (hospitalization) and 17% (rapid CKD progression). Children with ≥3 fragility indicators had 3.16-fold odds of frequent infection and 2.81-fold odds of hospitalization, but didn’t have rapid CKD progression. CONCLUSIONS: A fragility phenotype, characterized by the presence of ≥3 indicators, is associated with adverse outcomes, including infection and hospitalization in children with CKD.

Belatacept is an intravenously infused selective T cell costimulation blocker approved for preventing organ rejection in renal transplant recipients aged ≥18 years. This phase I trial examined the pharmacokinetics and pharmacodynamics (percentage CD86 receptor occupancy [%CD86RO]) of a single dose of belatacept (7.5 mg/kg) administered to kidney transplant recipients aged 12‐17 years receiving a stable calcineurin inhibitor–based immunosuppressive regimen. Nine adolescents (mean age 15.1 years) who were seropositive for Epstein‐Barr virus were enrolled; all completed the 6‐month study. Pharmacokinetics suggested relatively low variability of exposure (coefficients of variation for maximum observed serum concentration [C max] and area under the serum concentration‐time curve from time zero extrapolated to infinity [AUC 0‐ INF] were 20% and 25%, respectively). Mean half‐life (T 1/2) occurred 7.2 days postinfusion. Belatacept total body clearance was 0.48 mL/h/kg, and volume of distribution at steady‐state (V ss) was low at 0.09 L/kg. Compared with historical data from healthy adult volunteers administered a single dose of belatacept 10 mg/kg and adult kidney transplant recipients administered multiple doses of belatacept 5 mg/kg, pharmacokinetic values for adolescents were similar, indicating consistency across adolescent and adult populations. Mean %CD86RO increased with increasing belatacept concentration, indicating a direct relationship between pharmacokinetics and pharmacodynamics. Four patients reported 7 serious adverse events; none was considered related to belatacept. These data will inform belatacept dose selection in future studies of adolescent kidney transplant recipients., Results from a phase I study of adolescent renal transplant recipients administered a single intravenous infusion of belatacept at 7.5 mg/kg show comparable pharmacokinetic and pharmacodynamic values to those obtained historically from healthy adult volunteers given a single dose of belatacept (10 mg/kg) and adult kidney transplant recipients administered multiple doses of belatacept (5mg/kg/dose).

INTRODUCTION There are no guidelines regarding management of failed pediatric renal transplants. MATERIALS & METHODS We performed a first of its kind multicenter study assessing prevalence of transplant nephrectomy, patient characteristics, and outcomes in pediatric renal transplant recipients with graft failure from January 1, 2006, to December 31, 2016. RESULTS Fourteen centers contributed data on 186 pediatric recipients with failed transplants. The 76 recipients that underwent transplant nephrectomy were not significantly different from the 110 without nephrectomy in donor or recipient demographics. Fifty-three percent of graft nephrectomies were within a year of transplant. Graft tenderness prompted transplant nephrectomy in 91% (P

Maintenance of adequate health and well-being of pediatric transplant recipients both prior to and after transplant takes a concerted effort among different members of a multidisciplinary team that includes a pediatric nephrologist, nutritionist, social worker, psychologist, and many other providers depending upon the unique circumstances of a child. The aim of this chapter is to cover important domains that include timely vaccinations to prevent vaccine-preventable diseases, to optimize nutrition, growth, bone health, and physical and psychosocial development and well-being prior to and after transplant. While it is ideal for children to receive transplantation before they ever enter dialysis to provide them with a chance at best long-term outcomes, it is not always feasible. This chapter will also briefly highlight the importance of proper chronic kidney disease (CKD) and dialysis management for optimal outcomes.

This chapter describes the physiology and selected disorders related to urinary tract, kidneys, blood pressure, fluids, and electrolytes.

Carnitine plays a key role in energy production in the myocardium and is efficiently removed by continuous kidney replacement therapy (CKRT). Effects of levocarnitine supplementation on myocardial function in children receiving CKRT have not been investigated. This controlled pilot cohort study of 48 children investigated effects of levocarnitine supplementation on myocardial strain in children receiving CKRT for acute kidney injury (AKI). Children (n = 9) with AKI had total (TC) and free plasma carnitine (FC) measurements and echocardiogram for longitudinal and circumferential strain at baseline (prior to CKRT) and follow-up (on CKRT for > 1 week with intravenous levocarnitine supplementation, 20 mg/kg/day). Intervention group was compared with three controls: (1) CKRT controls (n = 10) received CKRT > 1 week (+AKI, no levocarnitine), (2) ICU controls (n = 9) were parenteral nutrition-dependent for > 1 week (no AKI, no levocarnitine), and (3) healthy controls (n = 20). In the Intervention group, TC and FC increased from 36.0 and 18 μmol/L to 93.5 and 74.5 μmol/L after supplementation. TC and FC of unsupplemented CKRT controls declined from 27.2 and 18.6 μmol/L to 12.4 and 6.6 μmol/L, which was lower vs. ICU controls (TC 32.0, FC 26.0 μmol/L), p < 0.05. Longitudinal and circumferential strain of the Intervention group improved from − 18.5% and − 18.3% to − 21.1% and − 27.6% after levocarnitine supplementation; strain of CKRT controls (-14.4%, -20%) remained impaired and was lower vs. Intervention and Healthy Control groups at follow-up, p < 0.05. Levocarnitine supplementation is associated with repletion of plasma carnitine and improvement in myocardial strain and may benefit pediatric patients undergoing prolonged CKRT.

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (P(meta)=6.71E-28, OR=1.88) and TNFSF15 (P(meta)=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).

Introduction Limited information is available describing the current prevalence of proteinuria and HIV-associated CKDs (HIV-CKDs) in children and adolescents living with HIV and receiving antiretroviral therapy in the United States. Methods To address this issue, we performed a retrospective study of children and adolescents living with HIV who received medical care at Children’s National Hospital in Washington, DC, between January 2012 and July 2019. Demographic data, clinical parameters (mode of HIV transmission, viral loads, CD4 cell counts, serum creatinine, glomerular filtration rate [GFR], plasma lipid levels, proteinuria, blood pressure, renal biopsies), and medical treatments, all done as a standard of clinical care, were collected and analyzed. Results The majority of the 192 patients enrolled were of African descent (88%) and acquired HIV through vertical transmission (97%). The prevalence of all HIV-CKDs was 6%. Of these patients, 39% had intermittent or persistent proteinuria, and 7% percent had proteinuria with a mild decline in GFR (60–80 ml/min per 1.73 m2), and 6% had a mild decline in GFR without proteinuria. Documented hypertension was present in 6% of the patients, mainly in association with HIV-CKD. Patients with persistent proteinuria (3%) and biopsy-proven HIV-CKD had a slow but constant progression of their renal diseases. Conclusions The prevalence of persistent proteinuria and HIV-CKD was lower than that reported in previous studies conducted in the United States. However, intermittent proteinuria, mild reductions in GFR, and progression of established HIV-CKD were common findings in this group of patients with predominantly vertically acquired HIV who were receiving antiretroviral therapy., Graphical abstract

The NAPRTCS has collected clinical information on children undergoing renal transplantation since 1987 and now includes information on 12 920 renal transplants in 11 870 patients. Since the first data analysis in 1989, NAPRTCS reports have documented marked improvements in patient and allograft outcomes after pediatric renal transplantation in addition to identifying factors associated with both favorable and poor outcomes. The registry has served to document and influence practice patterns, clinical outcomes, and changing trends in renal transplantation and also provides historical perspective. This report highlights current practices in an era of major changes in DD kidney allocation and continuing steroid minimization. This report presents outcomes of the patients in the NAPRTCS transplant registry up to end of 2017. In particular, an increase in the cumulative incidence of late first AR has occurred in the most recent cohort, while all prior cohorts had a lower cumulative incidence of late first AR.

Children are at increased risk of developing metabolic syndrome (MS) after kidney transplantation, which contributes to long-term cardiovascular (CV) morbidities and decline in allograft function. While MS in the general population occurs due to excess caloric intake and physical inactivity, additional chronic kidney disease and transplant-related factors contribute to the development of MS in transplant recipients. Despite its significant health consequences, the interplay of the individual components in CV morbidity in pediatric transplant recipients is not well understood. Additionally, the optimal methods to detect early CV dysfunction are not well defined in this unique population. The quest to establish clear guidelines for diagnosis is further complicated by genetic differences among ethnic groups that necessitate the development of race-specific criteria, particularly with regard to individuals of African descent who carry the apolipoprotein L1 variant. In children, since major CV events are rare and traditional echocardiographic measures of systolic function, such as ejection fraction, are typically well preserved, the presence of CV disease often goes undetected in the early stages. Recently, new noninvasive imaging techniques have become available that offer the opportunity for early detection. Carotid intima-media thickness and impaired myocardial strain detected by speckle tracking echocardiography or cardiac magnetic resonance are emerging as early and sensitive markers of subclinical CV dysfunction. These highly sensitive tools may offer the opportunity to elucidate subtle CV effects of MS in children after transplantation. Current knowledge and future directions are explored in this review.

Renal transplantation is the treatment of choice for children with end-stage renal disease (ESRD) since it decreases morbidity and mortality and improves quality of life. Potent immunosuppressive medications have significantly improved the short and medium-term outcomes while long-term outcomes continue to remain a challenge. This article reviews the current practices involved in the care of pediatric renal transplant recipients and challenges faced by them. Here, we provide a brief overview of various aspects of care for pediatric renal transplant recipients that include indications and contraindications, immunologic workup, pre-transplant evaluation, currently used immunosuppressive therapies, long-term complications and graft survival.

RATIONALE & OBJECTIVE: Traditional and nontraditional cardiovascular disease (CVD) risk factors are highly prevalent in children with chronic kidney disease (CKD). We examined the longitudinal association of adiposity with cardiac damage among children with CKD and explored whether this association was modified by sex. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study at 49 pediatric nephrology centers across North America. EXPOSURE: Age- and sex-specific body mass index (BMI) z-score. OUTCOME: Age- and sex-specific left ventricular mass index (LVMI) z-score and left ventricular hypertrophy (LVH). ANALYTICAL APPROACH: Longitudinal analyses using mixed effects models to estimate sex-specific associations of BMI z-scores with LVMI z-score and with LVH, accounting for repeated measurements over time. RESULTS: Among 725 children with 2829 person-years of follow-up, median age was 11.0 years and median estimated glomerular filtration rate was 52.6 ml/min/1.73m(2). Nearly one-third of both boys and girls were overweight or obese, median LVMI z-score was 0.18 (IQR: −0.67, 1.08), and 11% had LVH. Greater BMI z-scores were independently associated with greater LVMI z-scores and greater odds of LVH. For each 1-unit higher BMI z-score, LVMI z-score was 0.24 (95% CI: 0.17, 0.31) SD higher in boys and 0.38 (95% CI: 0.29, 0.47) SD higher in girls [p(interaction)=0.01]. For each 1-unit higher BMI z-score, the odds of LVH was 1.5-fold (95% CI: 1.1, 2.1) higher in boys and 3.1-fold (95% CI: 1.8, 4.4) higher in girls [p(interaction)= 0.005]. LIMITATIONS: Not all children had repeated measurements. LVH is a surrogate and not a hard cardiac outcome. The observational design limits causal inference. CONCLUSIONS: In children, adiposity is independently associated with the markers of cardiac damage, LVMI z-score, and LVH. This association is stronger among girls than boys. Pediatric overweight and obesity may therefore have a substantial impact on CV risk among children with CKD.

Background: The presence of circulating de novo donor specific anti-HLA antibodies (dnDSA) has been implicated in an immune-mediated form of accelerated systemic arteriosclerosis in adult heart and kidney transplant recipients, however this has not been previously investigated in pediatric kidney transplant recipients. Carotid intima-media thickness (CIMT) is a reliable method for detection of arteriosclerosis. We hypothesized that children who develop dnDSA after kidney transplant would have increased CIMT compared with those who remain dnDSA negative. Methods: A prospective, controlled pilot cohort study of 38 transplant patients and 20 healthy controls was conducted to investigate the association between CIMT and development of dnDSA after kidney transplant. CIMT, anthropometrics, blood pressure and lipid panel were measured at 1, 18, and 30 months post-transplant. DSA was checked at 6, 12, 18, 24 and 30 months post-transplant. CIMT of DSA positive transplant recipients was compared to DSA negative and controls. Results: Of the 38 transplant recipients, 7 patients developed dnDSA by 18–30 months post-transplant. Among 5 dnDSA positive patients who did not receive treatment for DSA prior to CIMT measurement (n=6 observations), the median CIMT was 0.505 mm (95% CI 0.454–0.560 mm) at 18–30 months post-transplant, compared to 0.455 mm (95% CI 0.440–0.470) in DSA negative transplant recipients (n = 54 observations of 30 patients) and 0.450 mm (95% CI 0.436–0.460) in the healthy controls (20 observations of 20 patients). Presence of dnDSA was independently associated with a 7.8% increase in CIMT compared to those without dnDSA (p=0.006), after adjusting for race, hypertension, dyslipidemia, and abdominal obesity. Conclusions: Development of dnDSA was associated with increased CIMT, an indicator of arteriosclerosis, in a cohort of dnDSA positive pediatric kidney transplant recipients. The association between dnDSA and CIMT was independent of traditional CV risk factors, including hypertension, dyslipidemia, and abdominal obesity.

Background Prior to transplantation, effects of advanced CKD contribute to malnutrition and impaired growth. After transplant, children are expected to thrive, however, in a subset of transplant recipients this does not occur. Factors associated with post-transplant FTT are poorly understood. Objective A retrospective cohort study was conducted to determine factors associated with FTT and association of FTT with infections and hospitalizations. Methods Records of 119 children transplanted between 2005 and 2016 were reviewed. FTT was defined by ≥2 of the following post-transplant criteria: (a) low BMI or deceleration in BMI z-score, (b) poor growth velocity, and (c) chronic hypoalbuminemia at 1 or 3 years post-transplant. Association of FTT with deceased donor transplant, de novo DSA, intolerance to MMF, anemia, vitamin D deficiency, and CIC was investigated by logistic regression. Poisson regression was used to identify outcomes associated with FTT. Results Low pre-transplant BMI and post-transplant CIC dependence were independently associated with FTT after transplant. Odds of FTT at 1 year post-transplant decreased by 0.5 for each 1 unit increase in pre-transplant BMI z-score. Requirement for CIC conferred 3.8 and 7.8 higher odds of FTT at 1 and 3 years. Patients with FTT had 2.7 and 2.6 times infections and hospitalizations during the first year, and 4.2 and 4.3 times infections and hospitalizations over 3 years post-transplant. Conclusions Children with low BMI prior to transplant and those requiring CIC after transplant are at increased risk for post-transplant FTT. FTT is associated with adverse outcomes, evidenced by increased infections and hospitalizations.

Background Kidney transplant recipients are at high risk for CV morbidity. However, the measure of obesity that best predicts CV risk has not been established. Objective A prospective, controlled study was conducted to compare the ability of BMI, WC, and WHr to identify CV risk in pediatric kidney transplant recipients. Methods Transplant recipients, aged 3-20 years, had echocardiogram, CIMT, BMI, WC, WHr, blood pressure, lipids, and leptin measured. Receiver operating characteristic analysis was used to compare the ability of BMI, WC, and WHr to detect a composite adverse CV outcome. Presence of the composite outcome was defined by ≥3 of the following five criteria: (a) LVH, (b) high CIMT, (c) impaired myocardial strain, (d) dyslipidemia, and/or (e) hypertension. Multivariate analysis was conducted by generalized estimating equation regression. Results We analyzed 108 visits of 42 transplant recipients. Prevalence of obesity by WHr (43.5%) was higher than BMI (24.1%) and WC (12.0%). Proportion of WHr-obese who met criteria for the adverse CV outcome was higher (62.2%) than BMI (34.6%) and WC-obese (33.3%). Leptin levels were higher in children with obesity. Area under the ROC curve for WHr-obese (0.77) was higher compared to BMI (0.47) and WC (0.48) to detect the CV outcome, P = 0.0006. WHr-obesity was associated with 5.72 increased odds of having the adverse CV outcome, P = 0.0001, while BMI and WC were not significant. Conclusion WHr is more sensitive than BMI or WC to detect subclinical CV risk and should be included in screening of pediatric kidney transplant recipients.

Cardiovascular (CV) risk is high in children with chronic kidney disease (CKD), and further compounded in those who are overweight. Children with CKD have a unique body habitus not accurately assessed by body mass index (BMI). Waist-to-height ratio (WHr), a better predictor of CV risk in populations with short stature, has not been investigated in children with CKD.Analysis of 1723 visits of 593 participants enrolled in the Chronic Kidney Disease in Children (CKiD) study was conducted. CKiD participants had BMI and WHr measured and classified as follows: (1) lean (WHr ≤ 0.49, BMI 85th percentile); (2) WHr-overweight (WHr 0.49, BMI 85th percentile); (3) BMI-overweight (WHr ≤ 0.49, BMI ≥ 85th percentile); or (4) overweight by both BMI and WHr. Left ventricular mass index (LVMI), fasting lipids, fibroblast growth factor 23 (FGF23), blood pressure, and glucose were measured as markers of CV risk. Linear mixed-effects regression was used to evaluate differences in CV markers between overweight and lean groups.Participants were 12.2 years old, 60% male, and 17% African-American. Approximately 15% were overweight by WHr but not by BMI. Overweight status by WHr-only or both WHr and BMI was associated with lower high-density lipoprotein (HDL) and higher LVMI, triglycerides, and non-HDL cholesterol compared to lean. CV markers of participants overweight by BMI-only were similar to those of lean children.WHr-adiposity is associated with an adverse CV risk profile in children with CKD. A significant proportion of children with central adiposity are missed by BMI. WHr should be utilized as a screening tool for CV risk in this population.

The development of dnDSA anti-HLA antibodies has been shown to be a significant risk factor for graft failure. In 2008, we instituted a routine protocol of standardized monitoring and treatment of dnDSA in pediatric kidney transplant recipients. Of 67 first-time pediatric kidney transplant recipients, 26 (38%) developed dnDSA after 1.36 (IQ 1-2.14) years. Coefficient of variance of tacrolimus, a surrogate marker of non-adherence, was found to be the single most important risk factor for dnDSA development. Overall, there was a significant reduction in dnDSA with treatment in 19 (76%) children. No difference in graft survival and estimated glomerular filtration rate was noted between dnDSA negative and those treated for dnDSA. There was an increased risk of hospitalization in those treated for dnDSA. This study suggests that early detection and treatment of dnDSA can help to prevent graft failure and preserve graft function in the short term. Future studies and longer follow-up are needed to fully elucidate the effect of early detection and treatment of dnDSA in pediatric kidney transplant recipients.

Carnitine deficiency is known to occur in chronic hemodialysis; however, the effect of continuous renal replacement therapy (CRRT) on carnitine homeostasis has not been studied. We hypothesized that children receiving CRRT are at risk for deficiency because of continuous removal, absent intake, decreased production, and comorbidities related to critical illness. Records of patients with acute kidney injury receiving CRRT at Children's National Health System between 2011 and 2014 were reviewed for total carnitine (TC), free carnitine (FC), feeding modality, severity of illness, and survival outcome. The proportion of carnitine-deficient patients at baseline, 1, 2, and ≥3 weeks on CRRT were compared by chi-square, and relationships with other variables assessed by Pearson's correlation and logistic regression. The study group included 42 CRRT patients, age 7.9 + 1.1 years. At baseline, 30.7% and 35.7% of patients were TC and FC deficient. Within 1 week, 64.5% (P = 0.03) and 70% (P = 0.03) were TC and FC deficient, and prevalence of deficiency increased to 80% (P = 0.01) and 90% (P = 0.008) by 2 weeks; 100% of patients were TC and FC deficient after being on CRRT for ≥3 weeks (P = 0.005 and P = 0.01, respectively, vs. baseline). TC and FC levels negatively correlated with days on CRRT (r = -0.39, P = 0.001 and r = -0.35, P = 0.005). Patients with TC and FC deficiency had 5.9 and 4.9 greater odds of death than those with normal levels (P = 0.02 and P = 0.03). Carnitine is significantly and rapidly depleted with longer time on CRRT, and carnitine deficiency is associated with increased mortality. Consequences of deficiency and benefits of supplementation in the pediatric CRRT population should be investigated.

Background: Many pediatric transplant (TX) centers routinely monitor Epstein-Barr (EB) viral load (VL) by real time quantitative PCR and intervene to prevent post-transplant lymphoproliferative disorder (PTLD). Some children develop asymptomatic persistent VL (PVL). Outcome of different interventions in preventing PTLD and other undesired effects on acute rejection (AR), graft failure (GF) and function amongst children with asymptomatic PVL is not known. Methods: NAPRTCS centers invited to enter data on children with asymptomatic PVL (≥ 6 months) into the EB VL registry. Comparison group included children into the NAPRTCS TX arm during the same period without PVL or VL monitoring. EB VL were arbitrarily divided into low (1-10), medium (>10-100) and high (>100times detection limit for the center) ratio. Results: Of 645 children (18 centers), 85 (13.2%) developed onset of PVL at a mean of 6.4 ± 6.3 months post-TX. PVL children were more likely to be younger (< 5 years) at TX and less likely to be African-American and majority (75.3%) was mismatched for EBV (donor EBV IgG positive and recipient negative). Thymoglobulin induction was used in 29.4% children with PVL versus 37% in controls (p=ns). PTLD developed in 7/85 (8.2%) children with PVL versus 5/560 (0.9%) controls (p < 0.0001). EB VL ratios were not different in those with and without PTLD. EB PVL as time varying covariate did not affect patient survival, GF and AR (HR, 0.85, 0.53 and 0.99). The change in GFR overtime in children with PVL was comparable to controls. Conclusion: Children with PVL (actual load not predictive) are at increased risk for PTLD, but not for AR, death, GF or loss of graft function.

Central venous catheter is commonly utilized as a hemodialysis access in the pediatric population. Long-standing central venous catheters can be complicated by superior vena cava (SVC) stenosis and thrombosis that can rarely present as pleural effusions. We report a case of a 5-year-old boy on chronic hemodialysis who presented with combined pleural and pericardial effusions, which was secondary to catheter induced SVC stenosis. Both the pleural effusion and the pericardial effusion in this patient subsequently improved with the relief of SVC stenosis. This case report highlights the serious complications of SVC stenosis associated with long-standing central venous catheters which is an under-recognized problem in the pediatric population.

Obesity and metabolic syndrome (MS) are common after kidney transplantation, but their contribution to adverse cardiovascular (CV) outcomes in children are not well known. A prospective, controlled, longitudinal cohort study was conducted to investigate the effects of obesity and MS on left ventricular hypertrophy (LVH) and myocardial strain in pediatric kidney transplant recipients.Transplant recipients (n = 42) had anthropometrics [body mass index (BMI), waist circumference, waist-to-height ratio], biochemical parameters (fasting glucose, lipid panel, HbA1c%), and echocardiogram with speckle tracking analysis for strain measured at 1, 18, and 30 months post-transplant. Additionally, 35 pre-transplant echocardiograms were analyzed retrospectively. Healthy children (n = 24) served as controls.Waist-to-height ratio detected abdominal obesity in 46% of transplant patients, whereas only 8.1% were identified as obese by waist circumference. Ejection fraction and fractional shortening of the transplant group were normal. Prevalence of LVH was 35.2%, 17.1%, and 35.5% at 1, 18, and 30 months respectively. The longitudinal strain of transplant group was worse than controls at all time points (p 0.001). Hemodialysis was independently associated with 21% worse longitudinal strain during the pre-transplant period (p = 0.04). After transplantation, obesity, MS, and systolic hypertension predicted increased odds of LVH (p 0.04). Worse longitudinal strain was independently associated with obesity, MS, hypertension, and the combination of MS with elevated low density lipoprotein (LDL) cholesterol (p 0.04), whereas higher estimated glomerular filtration rate (eGFR) conferred a protective effect (p 0.001).Obesity and MS adversely affect CV outcomes after transplantation. Further studies are needed to investigate speckle tracking echocardiography as a tool for early detection of subclinical myocardial dysfunction in this population.

Organ TX recipients are at an increased risk of developing cancers of the lower genital tract related to HPV. The quadrivalent HPV vaccine has high efficacy in preventing these diseases, but response to many vaccines is suboptimal after organ transplantation. Liver and kidney TX recipients received quadrivalent HPV vaccine. Serum samples were tested for anti-HPV levels. Of 20 renal transplant recipients screened, 14 received vaccine. Of these, seven completed the vaccine series and seven had incomplete vaccination. Of five liver TX children, three received vaccines (two complete and one incomplete). All eight kidney and liver TX children with complete vaccination and available results were seronegative at baseline and had seroconversion at month 7 for all four HPV types. Six of 14 (42.8%) kidney TX recipients developed AR. During the same time period, eight of 28 (28.5%) non-vaccine renal transplant recipients developed AR (p = ns). Transplant adolescents developed 100% seroconversion to all four HPV serotypes with HPV vaccine with serologic titers similar to historic controls. A non-significant increased incidence of AR was noted among kidney transplant vaccine recipients. A much larger study would be needed to evaluate whether HPV vaccination increases AR in transplant adolescents.

Carnitine plays a key role in energy production in the myocardium. Carnitine deficiency commonly occurs in patients on chronic hemodialysis (HD) and may contribute to cardiomyopathy.Carnitine levels and cardiac function of nine children on HD were assessed before and after 6 months of intravenous levocarnitine supplementation. Standard echocardiographic (ECHO) measures of left ventricular (LV) function as well as strain and strain rate analysis using novel speckle-tracking echocardiography were performed and the results compared to those of a control group of children on chronic HD.Following carnitine supplementation, total (49.0 ± 1.67 vs. 298.0 ± 31.8 μmol/L) and free carnitine (29.0 ± 1.20 vs. 180.4 ± 19.2 μmol/L) increased (p 0.0001), and the acyl:free (A:F) carnitine ratio improved (0.73 ± 0.04 vs. 0.65 ± 0.05; p = 0.02). There were no changes in standard ECHO measures of LV function, including end diastolic dimension, mass index, ejection fraction, and fractional shortening. There was significant (p = 0.017) improvement in the longitudinal strain rate (-1.48 ± 0.11 vs -1.91 ± 0.12) after carnitine supplementation in the study group. No improvements in LV function, strain, or strain rate occurred in controls.Levocarnitine supplementation improved carnitine levels, the A:F ratio, and longitudinal strain rate in children on HD.

Safety and efficacy of alemtuzumab in the treatment of AR in children after renal transplantation is unknown. Five episodes of refractory late AR in three children (three episodes in patient 1 and a single episode in patients 2 and 3 occurring after 7-23 months of transplantation) were treated with one dose of alemtuzumab as a rescue therapy. Four episodes (Banff IA-IB) in patients 1 and 2 reversed fully or partially with alemtuzumab, whereas patient 3 with Banff IB-IIA AR failed to respond. Patient 1 had recurrent AR 5, 13, and 15 months later; first two episodes responded to retreatment with alemtuzumab, and the last episode was not treated causing allograft failure. Patient 2 had steroid-responsive AR after two months and had a functioning allograft 25 months later. A transient reduction in all lymphocyte subsets except natural killer cells occurred in all patients. Patient 3 (treated with steroids, Thymoglobulin(R) , intravenous immunoglobulin, and rituximab prior to alemtuzumab) suffered many bacterial infections during one-yr period after therapy. However, symptomatic viral infections were not observed in any of the children. Treatment with alemtuzumab may prolong allograft survival in multidrug-resistant AR but may not prevent recurrent AR in non-adherent children.

Sgambat K, Tuchman S, Ryan L, Wood R, Moudgil A. Low bone mineral density and nutritional vitamin D deficiency in pediatric renal transplant recipients: Assessment of risk factors and response to oral vitamin D therapy. Pediatr Transplantation 2011: 15: 790–797. © 2011 John Wiley & Sons A/S. Abstract: VitD deficiency and bone disease are common after Tx. Prevalence and risk factors for low VitD and BMD and response to VitD therapy were investigated in pediatric renal Tx recipients. 25-hydroxy VitD levels of 71 Tx were compared to 54 healthy AA children. DXA of 44 Tx were compared to 47 AA controls. Of Tx, 59% were AA. Majority (59.1%) of Tx were VitD deficient (23.9%) or insufficient (35.2%). Prevalence of low VitD levels was double in AA (73.9%) vs. non-AA Tx (37.7%), (p = 0.003). Low VitD among Tx was associated with AA ethnicity (p

Background and objectives: The treatment of idiopathic nephrotic syndrome is often complicated by a refractory and relapsing course, with risk of drug toxicity and progressive renal failure. We report the efficacy and safety of rituximab in patients with steroid-resistant (SRNS) and steroid-dependent nephrotic syndrome (SDNS) refractory to standard therapy. Design, setting, participants, & measurements: This was a cohort study in academic, tertiary care centers in India and the United States. Patients with SRNS or SDNS, not responding to medications or showing calcineurin inhibitor toxicity, treated with two to four doses of intravenous rituximab, and followed ≥12 months were included. Remission was termed as complete, partial, or no response. Results: Thirty-three patients with SRNS (24 initial, 9 late resistance) and 24 with SDNS, with mean ages of 12.7 ± 9.1 and 11.7 ± 2.9 years, respectively, were included. Six months after rituximab therapy, 9 (27.2%) patients with SRNS showed complete remission, 7 (21.2%) had partial remission, and 17 (51.5%) had no response. At 21.5 ± 11.5 months, remission was sustained in 15 (complete: 7, partial: 8) patients. Of 24 patients with SDNS, remission was sustained in 20 (83.3%) at 12 months and in 17 (71%) at follow-up of 16.8 ± 5.9 months. The mean difference in relapses before and 12 months after treatment with rituximab was 3.9 episodes/patient per year. Conclusions: Therapy with rituximab was safe and effective in inducing and maintaining remission in a significant proportion of patients with difficult SRNS and SDNS.

As originally published, this article contained errors owing to oversights in typesetting. The article has now been amended accordingly.