Dyslipidemia in children with chronic kidney disease-findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study.

BACKGROUND: Dyslipidemia is an important and modifiable risk factor for CVD in children with CKD. METHODS: In a cross-sectional study of baseline serum lipid levels in a large prospective cohort study of children with stage 3-5 (predialysis) CKD, frequencies of abnormal lipid levels and types of dyslipidemia were analyzed in the entire cohort and in subpopulations defined by fasting status or by the presence of nephrotic range proteinuria. Associated clinical and laboratory characteristics were determined by multivariable linear regression analysis. RESULTS: A total of 681 patients aged 12.2 ± 3.3 years with a mean eGFR of 26.9 ± 11.6 ml/min/1.73 m2 were included. Kidney diagnosis was classified as CAKUT in 69%, glomerulopathy in 8.4%, and other disorders in 22.6% of patients. Nephrotic range proteinuria (defined by a urinary albumin/creatinine ratio > 1.1 g/g) was present in 26.9%. Dyslipidemia was found in 71.8%, and high triglyceride (TG) levels were the most common abnormality (54.7%). Fasting status (38.9%) had no effect on dyslipidemia status. Except for a significant increase in TG in more advanced CKD, lipid levels and frequencies of dyslipidemia were not significantly different between CKD stages. Hypertriglyceridemia was associated with younger age, lower eGFR, shorter duration of CKD, higher body mass index (BMI-SDS), lower serum albumin, and higher diastolic blood pressure. CONCLUSIONS: Dyslipidemia involving all lipid fractions, but mainly TG, is present in the majority of patients with CKD irrespective of CKD stage or fasting status and is significantly associated with other cardiovascular risk factors.

Kidney length normative values - new percentiles by age and body surface area in Central European children and adolescents.

BACKGROUND: Kidney size evaluation is an essential examination in pediatric nephrology. While body length/height is the best predictor of kidney length, age-based and body surface area (BSA)-based normative values may be useful in clinical practice or research. This study aimed to establish ultrasound-based kidney length lambda-mu-sigma (LMS) percentiles by age and BSA in healthy children. METHODS: In 1758 Polish and Lithuanian children (868 boys, 49%) aged 0-19 years, kidney length was measured using ultrasonography. In all participants, anthropometric measurements were taken and kidney function was evaluated based on serum creatinine concentration. Participants with chronic or kidney diseases, abnormal kidney function, or pathologies in sonographic examination were excluded from the analysis. RESULTS: Kidney length (median kidney length) increased progressively from infancy to the age of 18 years, from 60.1 to 114.2 mm in males, and from 57.3 to 105.2 mm in females. A gradual increase of kidney length (50th percentile) in relation to BSA (from 46.1 mm in infants with a BSA of 0-1.2 m2 to 118.3 mm in adolescents with a BSA of 2.6-2.8 m2) was also observed. LMS percentiles by age (stratified by sex) and BSA were determined and presented as graphs and tables of percentiles and LMS parameters by 1-year age intervals and 0.2 m2 of BSA, respectively. CONCLUSIONS: We present the first age- and BSA-based kidney length LMS normative values based on the largest pediatric cohort to date, which can be used in both clinical practice and research studies. A higher resolution version of the Graphical abstract is available as Supplementary information.

Shift from severe hypotension to salt-dependent hypertension in a child with autosomal recessive polycystic kidney disease after bilateral nephrectomies: a case report.

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a significant cause of morbidity and mortality in infants and children. In severe cases bilateral nephrectomies are considered but may be associated with significant neurological complications and life-threatening hypotension. CASE PRESENTATION: We describe a case of a 17 months old boy with genetically confirmed ARPKD who underwent sequential bilateral nephrectomies at the age of 4 and 10 months. Following the second nephrectomy the boy was started on continuous cycling peritoneal dialysis with blood pressure on the lower range. At the age of 12 months after a few days of poor feeding at home the boy experienced a severe episode of hypotension and coma of Glasgow Come Scale of three. Brain magnetic-resonance imaging (MRI) showed signs of hemorrhage, cytotoxic cerebral edema and diffuse cerebral atrophy. During the subsequent 72 h he developed seizures requiring anti-epileptic drug therapy, gradually regained consciousness but remained significantly hypotensive after discontinuation of vasopressors. Thus, he received high doses of sodium chloride orally and intraperitoneally as well as midodrine hydrochloride. His ultrafiltration (UF) was targeted to keep him in mild-to-moderate fluid overload. After two months of stable condition the patient started to develop hypertension requiring four antihypertensive medications. After optimizing peritoneal dialysis to avoid fluid overload and discontinuation of sodium chloride the antihypertensives were discontinued, but hyponatremia with hypotensive episodes reoccurred. Sodium chloride was reintroduced resulting in recurrent salt-dependent hypertension. CONCLUSIONS: Our case report illustrates an unusual course of blood pressure changes following bilateral nephrectomies in an infant with ARPKD and the particular importance of tight regulation of sodium chloride supplementation. The case adds to the scarce literature about clinical sequences of bilateral nephrectomies in infants, and as well highlights the challenge of managing blood pressure in these patients. Further research on the mechanisms and management of blood pressure control is clearly needed.

Nutritional and Anthropometric Indices in Children Receiving Haemodiafiltration vs Conventional Haemodialysis - The HDF, Heart and Height (3H) Study.

BACKGROUND: The "HDF-Heart-Height" study showed that haemodiafiltration (HDF) is associated with improved growth compared to conventional haemodialysis (HD). We report a post-hoc analysis of this study assessing the effect of extracorporeal dialysis therapies on nutritional indices. METHODS: 107 children were included in the baseline cross-sectional analysis, of whom 79 (43 HD, 36 HDF) completed the 12-month follow-up. Height (Ht), optimal 'dry' weight (Wt), and body mass index (BMI) standard deviations scores (SDS), waist-to-hip ratio, des-acyl ghrelin (DAG), adiponectin, leptin, insulin-like growth factor-1 (IGF-1)-SDS and insulin were measured. RESULTS: The levels of nutritional indices were comparable between HDF and HD patients at baseline and 12-month. On univariable analyses Wt-SDS positively correlated with leptin and IGF-1-SDS, and negatively with DAG, while Ht-SDS of the overall cohort positively correlated with IGF1-SDS and inversely with DAG and adiponectin. On multivariable analyses, higher 12-month Ht-SDS was inversely associated with baseline DAG (beta = -0.13 per 500 higher; 95%CI -0.22, -0.04; P = .004). Higher Wt-SDS at 12-month was positively associated with HDF modality (beta = 0.47 vs HD; 95%CI 0.12-0.83; P = .01) and inversely with baseline DAG (beta = -0.18 per 500 higher; 95%CI -0.32, -0.05; P = .006). Growth Hormone (GH) treated patients receiving HDF had higher annualized increase in Ht SDS compared to those on HD. CONCLUSIONS: In children on HD and HDF both Wt- and Ht-SDS independently correlated with lower baseline levels of the anorexygenic hormone DAG. HDF may attenuate the resistance to GH, but further studies are required to examine the mechanisms linking HDF to improved growth.

Findings from 4C-T Study demonstrate an increased cardiovascular burden in girls with end stage kidney disease and kidney transplantation.

Mortality in children with kidney failure is higher in girls than boys with cardiovascular complications representing the most common causes of death. Pulse wave velocity (PWV), a measure of vascular stiffness, predicts cardiovascular mortality in adults. Here, PWV in children with kidney failure undergoing kidney replacement therapy was investigated to determine sex differences and potential contributing factors. Two-hundred thirty-five children (80 girls; 34%) undergoing transplantation (150 pre-emptive, 85 with prior dialysis) having at least one PWV measurement pre- and/or post-transplantation from a prospective cohort were analyzed. Longitudinal analyses (median/maximum follow-up time of 6/9 years) were performed for PWV z-scores (PWVz) using linear mixed regression models and further stratified by the categories of time: pre-kidney replacement therapy and post-transplantation. PWVz significantly increased by 0.094 per year and was significantly higher in girls (PWVz +0.295) compared to boys, independent of the underlying kidney disease. During pre-kidney replacement therapy, an average estimated GFR decline of 4 ml/min/1.73 m2 per year was associated with a PWVz increase of 0.16 in girls only. Higher diastolic blood pressure and low density lipoprotein were independently associated with higher PWVz during pre-kidney replacement therapy in both sexes. In girls post-transplantation, an estimated GFR decline of 4ml/min/1.73m2 per year pre-kidney replacement therapy and a longer time (over 12 months) to transplantation were significantly associated with higher PWVz of 0.22 and of 0.57, respectively. PWVz increased further after transplantation and was positively associated with time on dialysis and diastolic blood pressure in both sexes. Thus, our findings demonstrate that girls with advanced chronic kidney disease are more susceptible to develop vascular stiffening compared to boys, this difference persist after transplantation and might contribute to higher mortality rates seen in girls with kidney failure.

Kidney length normative values in children aged 0-19 years - a multicenter study.

BACKGROUND: Currently used pediatric kidney length normative values are based on small single-center studies, do not include kidney function assessment, and focus mostly on newborns and infants. We aimed to develop ultrasound-based kidney length normative values derived from a large group of European Caucasian children with normal kidney function. METHODS: Out of 1,782 children aged 0-19 years, 1,758 individuals with no present or past kidney disease and normal estimated glomerular filtration rate had sonographic assessment of kidney length. The results were correlated with anthropometric parameters and estimated glomerular filtration rate. Kidney length was correlated with age, height, body surface area, and body mass index. Height-related kidney length curves and table were generated using the LMS method. Multivariate regression analysis with collinearity checks was used to evaluate kidney length predictors. RESULTS: There was no significant difference in kidney size in relation to height between boys and girls. We found significant (p < 0.001), but clinically unimportant (Cohen's D effect size = 0.04 and 0.06) differences between prone vs. supine position (mean paired difference = 0.64 mm, 95% CI = 0.49-0.77) and left vs. right kidneys (mean paired difference = 1.03 mm, 95% CI = 0.83-1.21), respectively. For kidney length prediction, the highest coefficient correlation was observed with height (adjusted R2 = 0.87, p < 0.0001). CONCLUSIONS: We present height-related LMS-percentile curves and tables of kidney length which may serve as normative values for kidney length in children from birth to 19 years of age. The most significant predictor of kidney length was statural height.

Interventions for minimal change disease in adults with nephrotic syndrome.

BACKGROUND: Steroids have been used widely since the early 1970s for the treatment of adult-onset minimal change disease (MCD). Recently, newer agents have been used in adult MCD aiming to reduce the risk of adverse effects. The response rates to immunosuppressive agents in adult MCD are more variable than in children. The optimal agent, dose, and duration of treatment for the first episode of nephrotic syndrome, or for disease relapse(s) have not been determined. This is an update of a review first published in 2008. OBJECTIVES: We aimed to 1) evaluate the benefits and harms of different agents, including both immunosuppressive and non-immunosuppressive agents, in adults with MCD causing the nephrotic syndrome; and 2) evaluate the efficacy of interventions on 'time-to-remission' of nephrotic syndrome, in adults with MCD causing the nephrotic syndrome. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 21 July 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of any intervention for MCD with nephrotic syndrome in adults over 18 years were included. Studies comparing different types, routes, frequencies, and duration of immunosuppressive agents and non-immunosuppressive agents were assessed. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random-effects model and results were expressed as a risk ratio (RR) for dichotomous outcomes, or mean difference (MD) for continuous data with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Fifteen RCTs (769 randomised participants) were identified; four studies evaluated different prednisolone regimens, eight studies evaluated the calcineurin inhibitors (CNIs) (tacrolimus or cyclosporin), two studies evaluated enteric-coated mycophenolate sodium (EC-MPS) and one study evaluated levamisole. In all but two studies of non-corticosteroid agents, reduced-dose prednisolone was given with the treatment agent and the comparator was high-dose prednisolone. In the risk of bias assessment, 11 and seven studies were at low risk of bias for sequence generation and allocation concealment, respectively. No studies were at low risk of performance bias and eight studies were at low risk of detection bias. Thirteen, 10 and six studies were at low risk of attrition bias, reporting bias and other bias, respectively. Compared with no specific treatment, it is uncertain whether prednisolone increases the number with complete remission (1 study, 28 participants: RR 1.44, 95% CI 0.95 to 2.19), complete or partial remission (1 study, 28 participants: RR 1.38, 95% CI 0.98 to 1.95), subsequent relapse (1 study, 28 participants: RR 0.75, 95% CI 0.48 to 1.17), or reduces the adverse effects because the certainty of the evidence is very low. Compared with oral prednisolone alone, it is uncertain whether intravenous methylprednisolone and prednisolone increase the number with complete remission (2 studies, 35 participants: RR 1.76, 95% CI 0.17 to 18.32; I² = 90%), relapse (two studies, 19 participants. RR 1.18, 95% CI 0.65 to 2.15; I² = 0%) or adverse events because the certainty of the evidence is very low. Compared with prednisolone alone, CNIs with reduced-dose prednisolone or without prednisolone probably make little or no difference to the number achieving complete remission (8 studies; 492 participants: RR 0.99, 95% CI 0.93 to 1.05; I² = 0%), complete or partial remission (4 studies, 269 participants: RR 1.01, 95% CI 0.96 to 1.05; I² = 0%), or relapse (7 studies; 422 participants: RR 0.73, 95% CI 0.51 to 1.03; I² = 0%) (moderate certainty evidence), may reduce the risk of obesity or Cushing's Syndrome (5 studies; 388 participants: RR 0.11, 95% CI 0.02 to 0.59; I² = 45%) and the risk of acne (4 studies; 270 participants: RR 0.15, 95% CI 0.03 to 0.67; I² = 0%) (low certainty evidence); and had uncertain effects on diabetes or hyperglycaemia, hypertension, and acute kidney injury (AKI) (low certainty evidence). Compared with prednisolone alone, EC-MPS with reduced-dose prednisolone probably make little or no difference to the number undergoing complete remission at 4 weeks (1 study, 114 participants: RR 1.12, 95% CI 0.84 to 1.50), and at 24 weeks probably make little or no difference to the number undergoing complete remission (2 studies, 134 participants: RR 1.12, 95% CI 0.84 to 1.38; I² = 0%) (moderate certainty evidence), complete or partial remission (2 studies 134 participants: RR 0.92, 95% CI 0.75 to 1.12; I² = 0%), relapse (2 studies, 83 participants: RR 0.50, 95% CI 0.07 to 3.74; I² = 56%) (low certainty evidence); or to the adverse events of new-onset glucose intolerance, death, or AKI (low certainty evidence). One study (24 participants) compared levamisole and prednisolone with prednisolone in patients with relapsing disease. The authors identified no differences in mean relapse rate or adverse effects but no standard deviations were provided. AUTHORS' CONCLUSIONS: This updated review has identified evidence for the efficacy and adverse effects of CNIs and EC-MPS with or without reduced-dose prednisolone compared with prednisolone alone for the induction of remission in adults with MCD and nephrotic syndrome with some reductions in steroid-associated adverse events. RCT data on the efficacy and adverse effects of rituximab in adults with MCD are awaited. Further, adequately powered RCTs are required to determine the relative efficacies of CNIs and EC-MPS and to evaluate these medications in patients with relapsing or steroid-resistant disease.

Active vitamin D is cardioprotective in experimental uraemia but not in children with CKD Stages 3-5.

BACKGROUND: Uraemic cardiac remodelling is associated with vitamin D and Klotho deficiency, elevated fibroblast growth factor 23 (FGF23) and activation of the renin-angiotensin system (RAS). The cardioprotective properties of active vitamin D analogues in this setting are unclear. METHODS: In rats with 5/6 nephrectomy (5/6Nx) treated with calcitriol, the cardiac phenotype and local RAS activation were investigated compared with controls. A nested case-control study was performed within the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study, including children with chronic kidney disease (CKD) Stages 3-5 [estimated glomerular filtration rate (eGFR) 25 mL/min/1.73 m2] treated with and without active vitamin D. Echocardiograms, plasma FGF23 and soluble Klotho (sKlotho) were assessed at baseline and after 9 months. RESULTS: In rats with 5/6Nx, left ventricular (LV) hypertrophy, LV fibrosis and upregulated cardiac RAS were dose-dependently attenuated by calcitriol. Calcitriol further stimulated FGF23 synthesis in bone but not in the heart, and normalized suppressed renal Klotho expression. In the 4C study cohort, treatment over a mean period of 9 months with active vitamin D was associated with increased FGF23 and phosphate and decreased sKlotho and eGFR compared with vitamin D naïve controls, whereas LV mass index did not differ between groups. CONCLUSIONS: Active vitamin D ameliorates cardiac remodelling and normalizes renal Klotho expression in 5/6Nx rats but does not improve the cardiac phenotype in children with CKD Stages 3-5. This discrepancy may be due to further enhancement of circulating FGF23 and faster progression of CKD associated with reduced sKlotho and higher serum phosphate in vitamin D-treated patients.

Pathophysiology and consequences of arterial stiffness in children with chronic kidney disease.

Changes in arterial structure and function are seen early in the course of chronic kidney disease (CKD) and have been causally associated with cardiovascular (CV) morbidity. Numerous potential injuries encompassing both traditional and uremia-specific CV risk factors can induce structural arterial changes and accelerate arterial stiffening. When the buffering capacity of the normally elastic arteries is reduced, damage to vulnerable microcirculatory beds can occur. Moreover, the resultant increase to cardiac afterload contributes to the development of left ventricular hypertrophy and cardiac dysfunction. Adult studies have linked arterial stiffness with increased risk of mortality, CV events, cognitive decline, and CKD progression. Pulse wave velocity (PWV) is currently the gold standard of arterial stiffness assessment but its measurement in children is challenging due to technical difficulties and physiologic aspects related to growth and poor standardization between algorithms for calculating PWV. Nevertheless, studies in pediatric CKD have reported increased arterial stiffness in children with advanced CKD, on dialysis, and after kidney transplantation. Development of arterial stiffness in children with CKD is closely related to mineral-bone disease and hypertension, but other factors may also play a significant role. The clinical relevance of accelerated arterial stiffness in childhood on cardiovascular outcomes in adult life remains unclear, and prospective studies are needed. In this review we discuss mechanisms leading to arterial stiffness in CKD and its clinical implications, along with issues surrounding the technical aspects of arterial stiffness assessment in children.

Hemodiafiltration maintains a sustained improvement in blood pressure compared to conventional hemodialysis in children-the HDF, heart and height (3H) study.

BACKGROUND: Hypertension is prevalent in children on dialysis and associated with cardiovascular disease. We studied the blood pressure (BP) trends and the evolution of BP over 1 year in children on conventional hemodialysis (HD) vs. hemodiafiltration (HDF). METHODS: This is a post hoc analysis of the "3H - HDF-Hearts-Height" dataset, a multicenter, parallel-arm observational study. Seventy-eight children on HD and 55 on HDF who had three 24-h ambulatory BP monitoring (ABPM) measures over 1 year were included. Mean arterial pressure (MAP) was calculated and hypertension defined as 24-h MAP standard deviation score (SDS) ≥95th percentile. RESULTS: Poor agreement between pre-dialysis systolic BP-SDS and 24-h MAP was found (mean difference - 0.6; 95% limits of agreement -4.9-3.8). At baseline, 82% on HD and 44% on HDF were hypertensive, with uncontrolled hypertension in 88% vs. 25% respectively; p < 0.001. At 12 months, children on HDF had consistently lower MAP-SDS compared to those on HD (p < 0.001). Over 1-year follow-up, the HD group had mean MAP-SDS increase of +0.98 (95%CI 0.77-1.20; p < 0.0001), whereas the HDF group had a non-significant increase of +0.15 (95%CI -0.10-0.40; p = 0.23). Significant predictors of MAP-SDS were dialysis modality (ß = +0.83 [95%CI +0.51 - +1.15] HD vs. HDF, p < 0.0001) and higher inter-dialytic-weight-gain (IDWG)% (ß = 0.13 [95%CI 0.06-0.19]; p = 0.0003). CONCLUSIONS: Children on HD had a significant and sustained increase in BP over 1 year compared to a stable BP in those on HDF, despite an equivalent dialysis dose. Higher IDWG% was associated with higher 24-h MAP-SDS in both groups.

Establishing core outcome domains in pediatric kidney disease: report of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-KIDS) consensus workshops.

Trials in children with chronic kidney disease do not consistently report outcomes that are critically important to patients and caregivers. This can diminish the relevance and reliability of evidence for decision making, limiting the implementation of results into practice and policy. As part of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-Kids) initiative, we convened 2 consensus workshops in San Diego, California (7 patients, 24 caregivers, 43 health professionals) and Melbourne, Australia (7 patients, 23 caregivers, 49 health professionals). This report summarizes the discussions on the identification and implementation of the SONG-Kids core outcomes set. Four themes were identified; survival and life participation are common high priority goals, capturing the whole child and family, ensuring broad relevance across the patient journey, and requiring feasible and valid measures. Stakeholders supported the inclusion of mortality, infection, life participation, and kidney function as the core outcomes domains for children with chronic kidney disease.

Haemodiafiltration does not lower protein-bound uraemic toxin levels compared with haemodialysis in a paediatric population.

BACKGROUND: Haemodiafiltration (HDF) is accepted to effectively lower plasma levels of middle molecules in the long term, while data are conflicting with respect to the additive effect of convection on lowering protein-bound uraemic toxins (PBUTs). Here we compared pre-dialysis ß2-microglobulin (ß2M) and PBUT levels and the percentage of protein binding (%PB) in children on post-dilution HDF versus conventional high- (hf) or low-flux (lf) haemodialysis (HD) over 12 months of treatment. METHODS: In a prospective multicentre, non-randomized parallel-arm intervention study, pre-dialysis levels of six PBUTs and ß2M were measured in children (5-20 years) on post-HDF (n = 37), hf-HD (n = 42) and lf-HD (n = 18) at baseline and after 12 months. Analysis of variance was used to compare levels and %PB in post-HDF versus conventional hf-HD and lf-HD cross-sectionally at 12 months and longitudinal from baseline to 12 months. RESULTS: For none of the PBUTs, no difference was found in either total and free plasma levels or %PB between post-HDF versus the hf-HD and lf-HD groups. Children treated with post-HDF had lower pre-dialysis ß2M levels [median 23.2 (21.5; 26.6) mg/dL] after 12 months versus children on hf-HD [P<0.01; 35.2 (29.3; 41.2) mg/dL] and children on lf-HD [P<0.001; 47.2 (34.3; 53.0) mg/dL]. While ß2M levels remained steady in the hf-HD and lf-HD group, a decrease in ß2M was demonstrated for children on post-HDF (P<0.01). CONCLUSIONS: While post-HDF successfully decreased ß2M, no additive effect on PBUT over 12 months of treatment was found. PBUT removal is complex and hampered by several factors. In children, these factors might be different from adults and should be explored in future research.

Effects of Hemodiafiltration versus Conventional Hemodialysis in Children with ESKD: The HDF, Heart and Height Study.

BACKGROUND: Hypertension and cardiovascular disease are common in children undergoing dialysis. Studies suggest that hemodiafiltration (HDF) may reduce cardiovascular mortality in adults, but data for children are scarce. METHODS: The HDF, Heart and Height study is a nonrandomized observational study comparing outcomes on conventional hemodialysis (HD) versus postdilution online HDF in children. Primary outcome measures were annualized changes in carotid intima-media thickness (cIMT) SD score and height SD score. RESULTS: We enrolled 190 children from 28 centers; 78 on HD and 55 on HDF completed 1-year follow-up. The groups were comparable for age, dialysis vintage, access type, dialysis frequency, blood flow, and residual renal function. At 1 year, cIMT SD score increased significantly in children on HD but remained static in the HDF cohort. On propensity score analysis, HD was associated with a +0.47 higher annualized cIMT SD score compared with HDF. Height SD score increased in HDF but remained static in HD. Mean arterial pressure SD score increased with HD only. Factors associated with higher cIMT and mean arterial pressure SD-scores were HD group, higher ultrafiltration rate, and higher ß2-microglobulin. The HDF cohort had lower ß2-microglobulin, parathyroid hormone, and high-sensitivity C-reactive protein at 1 year; fewer headaches, dizziness, or cramps; and shorter postdialysis recovery time. CONCLUSIONS: HDF is associated with a lack of progression in vascular measures versus progression with HD, as well as an increase in height not seen in the HD cohort. Patient-related outcomes improved among children on HDF correlating with improved BP control and clearances. Confirmation through randomized trials is required.

Low levels of urinary epidermal growth factor predict chronic kidney disease progression in children.

Urinary epidermal growth factor (uEGF) has recently been identified as a promising biomarker of chronic kidney disease (CKD) progression in adults with glomerular disease. Low levels of uEGF predict CKD progression and appear to reflect the extent of tubulointerstitial damage. We investigated the relevance of uEGF in pediatric CKD. We performed a post hoc analysis of the Cardiovascular Comorbidity in Children with CKD (4C) study, which prospectively follows children aged 6-17 years with baseline estimated glomerular filtration rate (eGFR) of 10-60 ml/min/1.73 m2. uEGF levels were measured in archived urine collected within 6 months of enrollment. Congenital abnormalities of the kidney and urinary tract were the most common cause of CKD, with glomerular diseases accounting for <10% of cases. Median eGFR at baseline was 28 ml/min/1.73 m2, and 288 of 623 participants (46.3%) reached the composite endpoint of CKD progression (50% eGFR loss, eGFR < 10 ml/min/1.73 m2, or initiation of renal replacement therapy). In a Cox proportional hazards model, higher uEGF/Cr was associated with a decreased risk of CKD progression (HR 0.76; 95% CI 0.69-0.84) independent of age, sex, baseline eGFR, primary kidney disease, proteinuria, and systolic blood pressure. The addition of uEGF/Cr to a model containing these variables resulted in a significant improvement in C-statistics, indicating better prediction of the 1-, 2- and 3-year risk of CKD progression. External validation in a prospective cohort of 222 children with CKD demonstrated comparable results. Thus, uEGF may be a useful biomarker to predict CKD progression in children with CKD.

Indoxyl sulfate associates with cardiovascular phenotype in children with chronic kidney disease.

BACKGROUND: Cardiovascular disease is the leading cause of death in children with chronic kidney disease (CKD). Serum levels of gut-derived uremic toxins increase with deterioration of kidney function and are associated with cardiac comorbidities in adult CKD patients. METHODS: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) were measured by high-performance liquid chromatography in serum of children participating in the Cardiovascular Comorbidity in Children with CKD (4C) Study. Results were correlated with measurements of the carotid intima-media thickness (cIMT), central pulse wave velocity (PWV), and left ventricular mass index (LVMI) in children aged 6-17 years with initial eGFR of 10-60 ml/min per 1.73 m2. RESULTS: The median serum levels of total IS and of pCS, measured in 609 patients, were 5.3 µmol/l (8.7) and 17.0 µmol/l (21.6), respectively. In a multivariable regression model, IS and pCS showed significant positive associations with urea and negative associations with eGFR and uric acid. Furthermore, positive associations of pCS with age, serum albumin, and non-Mediterranean residency and a negative association with glomerular disease were observed. By multivariable regression analysis, only IS was significantly associated with a higher cIMT SDS at baseline and progression of PWV SDS within 12 months, independent of other risk factors. CONCLUSIONS: Serum levels of gut-derived uremic toxins IS and pCS correlated inversely with eGFR in children. Only IS was significantly associated with surrogate markers of cardiovascular disease in this large pediatric CKD cohort.

Effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism in children with chronic kidney disease.

Background: We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD). Methods: In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated. Results: Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2. Conclusions: Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD.

Effect of haemodiafiltration vs conventional haemodialysis on growth and cardiovascular outcomes in children - the HDF, heart and height (3H) study.

BACKGROUND: Cardiovascular disease is prevalent in children on dialysis and accounts for almost 30% of all deaths. Randomised trials in adults suggest that haemodiafiltration (HDF) with high convection volumes is associated with reduced cardiovascular mortality compared to high-flux haemodialysis (HD); however paediatric data are scarce. We designed the haemodiafiltration, heart and height (3H) study to test the hypothesis that children on HDF have an improved cardiovascular risk profile, growth and nutritional status and quality of life, compared to those on conventional HD. We performed a non-randomised parallel-arm intervention study within the International Paediatric Haemodialysis Network Registry comparing children on HDF and conventional HD to determine annualised change in cardiovascular end-points and growth. Here we present the 3H study design and baseline characteristics of the study population. METHODS: 190 children were screened and 177 (106 on HD and 71 on HDF) recruited from 28 centres in 10 countries. There was no difference in age, underlying diagnosis, comorbidities, previous dialysis therapy, dialysis vintage, residual renal function, type of vascular access or blood flow between HD and HDF groups. High flux dialysers were used in 63% of HD patients and ultra-pure water was available in 52%. HDF patients achieved a median convection volume of 13.3 L/m2; this was associated with the blood flow rate only ((p = 0.0004, r = 0.42) and independent of access type (p = 0.38). DISCUSSION: This is the largest study on dialysis outcomes in children that involves deep phenotyping across a wide range of cardiovascular, anthropometric, nutritional and health-related quality of life measures, to test the hypothesis that HDF leads to improved cardiovascular and growth outcomes compared to conventional HD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02063776 . The trial was prospectively registered on the 14 Feb 2014.

The Phenotypic Spectrum of Nephropathies Associated with Mutations in Diacylglycerol Kinase ε.

The recent discovery of mutations in the gene encoding diacylglycerol kinase ε (DGKE) identified a novel pathophysiologic mechanism leading to HUS and/or MPGN. We report ten new patients from eight unrelated kindreds with DGKE nephropathy. We combined these cases with all previously published cases to characterize the phenotypic spectrum and outcomes of this new disease entity. Most patients presented with HUS accompanied by proteinuria, whereas a subset of patients exhibited clinical and histologic patterns of MPGN without TMA. We also report the first two patients with clinical and histologic HUS/MPGN overlap. DGKE-HUS typically manifested in the first year of life but was not exclusively limited to infancy, and viral triggers frequently preceded HUS episodes. We observed signs of complement activation in some patients with DGKE-HUS, but the role of complement activation remains unclear. Most patients developed a slowly progressive proteinuric nephropathy: 80% of patients did not have ESRD within 10 years of diagnosis. Many patients experienced HUS remission without specific treatment, and a few patients experienced HUS recurrence despite complete suppression of the complement pathway. Five patients received renal allografts, with no post-transplant recurrence reported. In conclusion, we did not observe a clear genotype-phenotype correlation in patients with DGKE nephropathy, suggesting additional factors mediating phenotypic heterogeneity. Furthermore, the benefits of anti-complement therapy are questionable but renal transplant may be a feasible option in the treatment of patients with this condition.

Metabolic acidosis is common and associates with disease progression in children with chronic kidney disease.

Recent studies in adult chronic kidney disease (CKD) suggest that metabolic acidosis is associated with faster decline in estimated glomerular filtration rate (eGFR). Alkali therapies improve the course of kidney disease. Here we investigated the prevalence and determinants of abnormal serum bicarbonate values and whether metabolic acidosis may be deleterious to children with CKD. Associations between follow-up serum bicarbonate levels categorized as under 18, 18 to under 22, and 22 or more mmol/l and CKD outcomes in 704 children in the Cardiovascular Comorbidity in Children with CKD Study, a prospective cohort of pediatric patients with CKD stages 3-5, were studied. The eGFR and serum bicarbonate were measured every six months. At baseline, the median eGFR was 27 ml/min/1.73m2 and median serum bicarbonate level 21 mmol/l. During a median follow-up of 3.3 years, the prevalence of metabolic acidosis (serum bicarbonate under 22 mmol/l) was 43%, 60%, and 45% in CKD stages 3, 4, and 5, respectively. In multivariable analysis, the presence of metabolic acidosis as a time-varying covariate was significantly associated with log serum parathyroid hormone through the entire follow-up, but no association with longitudinal growth was found. A total of 211 patients reached the composite endpoint (ESRD or 50% decline in eGFR). In a multivariable Cox model, children with time-varying serum bicarbonate under 18 mmol/l had a significantly higher risk of CKD progression compared to those with a serum bicarbonate of 22 or more mmol/l (adjusted hazard ratio 2.44; 95% confidence interval 1.43-4.15). Thus, metabolic acidosis is a common complication in pediatric patients with CKD and may be a risk factor for secondary hyperparathyroidism and kidney disease progression.