Factors influencing circuit lifetime in paediatric continuous kidney replacement therapies - results from the EurAKId registry.

BACKGROUND: Continuous kidney replacement therapy (CKRT) has recently become the preferred kidney replacement modality for children with acute kidney injury (AKI). We hypothesise that CKRT technical parameters and treatment settings in addition to the clinical characteristics of patients may influence the circuit lifetime in children. METHODS: The study involved children included in the EurAKId registry (NCT02960867), who underwent CKRT treatment. We analysed patient characteristics and CKRT parameters. The primary end point was mean circuit lifetime (MCL). Secondary end points were number of elective circuit changes and occurrence of dialysis-related complications. RESULTS: The analysis was composed of 247 children who underwent 37,562 h of CKRT (median 78, IQR 37-165 h per patient). A total of 1357 circuits were utilised (3, IQR 2-6 per patient). MCL was longer in regional citrate anticoagulation (RCA), compared to heparin (HA) and no anticoagulation (NA) (42, IQR 32-58 h; 24, IQR 14-34 h; 18, IQR 12-24 h, respectively, p < 0.001). RCA was associated with longer MCL regardless of the patient's age or dialyser surface. In multivariate analysis, MCL correlated with dialyser surface area (beta = 0.14, p = 0.016), left internal jugular vein vascular access site (beta = -0.37, p = 0.027), and the use of HA (beta = -0.14, p = 0.038) or NA (beta = -0.37, p < 0.001) vs. RCA. RCA was associated with the highest ratio of elective circuit changes and the lowest incidence of complications. CONCLUSION: Anticoagulation modality, dialyser surface, and vascular access site influence MCL. RCA should be considered when choosing first-line anticoagulation for CKRT in children. Further efforts should focus on developing guidelines and clinical practice recommendations for paediatric CKRT.

Safety and Efficacy of Cinacalcet in Children Aged Under 3 Years on Maintenance Dialysis.

Introduction: Secondary hyperparathyroidism (sHPT) is particularly severe in rapidly growing infants in dialysis. Although cinacalcet is effective and licensed in dialysis in children aged >3 years, its efficacy and safety for children aged <3 years is unknown. Methods: We identified 26 children aged <3 years who were on dialysis and treated with cinacalcet between 2009 and 2021 in 8 European pediatric centers. Results: Median (interquartile range) age at the start of cinacalcet was 18 (interquartile range: 11-27) months, serum parathyroid hormone (PTH) was 792 (411-1397) pg/ml, corresponding to 11.6 (5.9-19.8) times the upper limit of normal (ULN). Serum calcium was 2.56 (2.43-2.75) mmol/l, and serum phosphate 1.47 (1.16-1.71) mmol/l. Serum 25-OH vitamin D (25-OHD) was 70 (60-89) nmol/l, 3 children were vitamin D deficient (<50 nmol/l). The initial cinacalcet dose was 0.4 (0.2-0.8) mg/kg/d and the maximum dose was 1.1 (0.6-1.2) mg/kg/d. The median follow-up under cinacalcet was 1.2 (0.7-2.0) years. PTH decreased to 4.3 (2.2-7.8) times the ULN after 6 months, to 2.0 (1.0-5.3) times ULN after 12 months, and to 1.6 (0.5-3.4) times thereafter (P = 0.017/0.003/<0.0001, log-transformed PTH). Seven of the 26 infants developed 10 hypocalcemic episodes <2.10 mmol/l. Oral calcium intake was 84% (66%-117%) of recommended nutrient intake at start, 100% (64%-142%) at 3 months and declined to 78% (65%-102%) at 12 months of therapy. Three children developed clinical signs of precocious puberty. Conclusion: Cinacalcet efficiently controlled severe sHPT in children aged <3 years and was associated with hypocalcemic episodes (similar to what is observed in older children) and precious puberty, thereby mandating meticulous control of calcium (considering nutrition, supplementation, and dialysate) and endocrine changes.

Changes in the cardiovascular risk profile in children approaching kidney replacement therapy.

Background: Despite significant cardiovascular (CV) morbidity in children on dialysis and after kidney transplantation, data on the evolution of CV damage in children with chronic kidney disease (CKD) approaching kidney replacement therapy (KRT) is unknown. Methods: The burden, progression, and predictors of CV damage before KRT onset were explored in two prospective multicenter cohorts from Europe and Canada: Cardiovascular Comorbidity in Children with CKD (4C) and Haemodiafiltration, Heart and Height (3H) studies, conducted from 2009-19 and 2013-16, respectively. CV damage and risk factors were evaluated (i) cross sectionally at KRT-start (n = 248), and (ii) longitudinally over the 2-years preceding KRT start (n = 157; 331 patient-visits). Longitudinal analyses with mixed-effects models estimated associations of modifiable CV risk factors with change in carotid intima-media thickness (cIMT) standard deviation score (SDS), pulse wave velocity (PWV-SDS), left ventricular (LV) mass and systolic dysfunction. Findings: 248 patients, age 14.3 (12.2, 16.2) years were evaluated at median 35 (28-114) days before KRT start. Elevated cIMT-SDS and PWV-SDS were present in 43% and 25%, and LV hypertrophy and systolic dysfunction in 49% and 33%. Aortic stiffness and LV hypertrophy significantly increased, especially in the year before KRT start (adjusted odds ratio, OR 0.33, P = 0.002 and OR 0.54, P = 0.01, respectively). 79% of children had >3 modifiable CV risk factors at KRT onset. Diastolic BP and BMI were strongly associated with a linear increase in all CV measures. After controlling for CV risk factors, the time to KRT onset no longer predicted the burden of CV damage. Interpretation: This comprehensive CV evaluation shows the progressive accrual of modifiable risk factors and a high burden of CV damage in the years preceding KRT onset. CV damage in the pre-KRT period is preventable. Funding: Supported by EU4Health Programme (101085068) and Kidney Research UK (RP39/2013).

Prospective Study of Modifiable Risk Factors of Arterial Hypertension and Left Ventricular Hypertrophy in Pediatric Patients on Hemodialysis.

Introduction: Fluid and salt overload in patients on dialysis result in high blood pressure (BP), left ventricular hypertrophy (LVH) and hemodynamic instability, resulting in cardiovascular morbidity. Methods: Analysis of 910 pediatric patients on maintenance hemodialysis/hemodiafiltration (HD/HDF), prospectively followed-up with 2758 observations recorded every 6-months in the International Pediatric Hemodialysis Network (IPHN). Results: Uncontrolled hypertension was present in 55% of observations, with 27% of patients exhibiting persistently elevated predialysis BP. Systolic and diastolic age- and height-standardized BP (BP-SDS) were independently associated with the number of antihypertensive medications (odds ratio [OR] = 1.47, 95% confidence interval 1.39-1.56, 1.36 [1.23-1.36]) and interdialytic weight gain (IDWG; 1.19 [1.14-1.22], 1.09 [1.06-1.11]; all P < 0.0001). IDWG was related to urine output (OR = 0.27 [0.23-0.32]) and dialysate sodium (dNa; 1.06 [1.01-1.10]; all P < 0.0001). The prevalence of masked hypertension was 24%, and HD versus HDF use was an independent risk factor of elevated age- and height-standardized mean arterial pressure (MAP-SDS) (OR = 2.28 [1.18-4.41], P = 0.01). Of the 1135 echocardiograms, 51% demonstrated LVH. Modifiable risk factors included predialysis systolic BP-SDS (OR = 1.06 [1.04-1.09], P < 0.0001), blood hemoglobin (0.97 [0.95-0.99], P = 0.004), HD versus HDF modality (1.09 [1.02-1.18], P = 0.01), and IDWG (1.02 [1.02-1.03], P = 0.04). In addition, HD modality increased the risk of LVH progression (OR = 1.23 [1.03-1.48], P = 0.02). Intradialytic hypotension (IDH) was prevalent in patients progressing to LVH and independently associated with predialysis BP-SDS below 25th percentile, lower number of antihypertensives, HD versus HDF modality, ultrafiltration (UF) rate, and urine output, but not with dNa. Conclusion: Uncontrolled hypertension and LVH are common in pediatric HD, despite intense pharmacologic therapy. The outcome may improve with use of HDF, and superior anemia and IDWG control; the latter via lowering dNa, without increasing the risk of IDH.

Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolaemia: An expert consensus statement from ERKNet and ESPN.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

Knock-out of dipeptidase CN2 in human proximal tubular cells disrupts dipeptide and amino acid homeostasis and para- and transcellular solute transport.

AIM: Although of potential biomedical relevance, dipeptide metabolism has hardly been studied. We found the dipeptidase carnosinase-2 (CN2) to be abundant in human proximal tubules, which regulate water and solute homeostasis. We therefore hypothesized, that CN2 has a key metabolic role, impacting proximal tubular transport function. METHODS: A knockout of the CN2 gene (CNDP2-KO) was generated in human proximal tubule cells and characterized by metabolomics, RNA-seq analysis, paracellular permeability analysis and ion transport. RESULTS: CNDP2-KO in human proximal tubule cells resulted in the accumulation of cellular dipeptides, reduction of amino acids and imbalance of related metabolic pathways, and of energy supply. RNA-seq analyses indicated altered protein metabolism and ion transport. Detailed functional studies demonstrated lower CNDP2-KO cell viability and proliferation, and altered ion and macromolecule transport via trans- and paracellular pathways. Regulatory and transport protein abundance was disturbed, either as a consequence of the metabolic imbalance or the resulting functional disequilibrium. CONCLUSION: CN2 function has a major impact on intracellular amino acid and dipeptide metabolism and is essential for key metabolic and regulatory functions of proximal tubular cells. These findings deserve in vivo analysis of the relevance of CN2 for nephron function and regulation of body homeostasis.

Multicenter Long-Term Real World Data on Treatment With Lumasiran in Patients With Primary Hyperoxaluria Type 1.

Introduction: The RNA interference (RNAi) medication lumasiran reduces hepatic oxalate production in primary hyperoxaluria type 1 (PH1). Data outside clinical trials are scarce. Methods: We report on retrospectively and observationally obtained data in 33 patients with PH1 (20 with preserved kidney function, 13 on dialysis) treated with lumasiran for a median of 18 months. Results: Among those with preserved kidney function, mean urine oxalate (Uox) decreased from 1.88 (baseline) to 0.73 mmol/1.73 m2 per 24h after 3 months, to 0.72 at 12 months, and to 0.65 at 18 months, but differed according to vitamin B6 (VB6) medication. The highest response was at month 4 (0.55, -70.8%). Plasma oxalate (Pox) remained stable over time. Glomerular filtration rate increased significantly by 10.5% at month 18. Nephrolithiasis continued active in 6 patients, nephrocalcinosis ameliorated or progressed in 1 patient each. At last follow-up, Uox remained above 1.5 upper limit of normal (>0.75 mmol/1.73 m2 per 24h) in 6 patients. Urinary glycolate (Uglyc) and plasma glycolate (Pglyc) significantly increased in all, urine citrate decreased, and alkali medication needed adaptation. Among those on dialysis, mean Pox and Pglyc significantly decreased and increased, respectively after monthly dosing (Pox: 78-37.2, Pglyc: 216.4-337.4 µmol/l). At quarterly dosing, neither Pox nor Pglyc were significantly different from baseline levels. An acid state was buffered by an increased dialysis regimen. Systemic oxalosis remained unchanged. Conclusion: Lumasiran treatment is safe and efficient. Dosage (interval) adjustment necessities need clarification. In dialysis, lack of Pox reduction may relate to dissolving systemic oxalate deposits. Pglyc increment may be a considerable acid load requiring careful consideration, which definitively needs further investigation.

Hemodiafiltration for children with stage 5 chronic kidney disease: technical aspects and outcomes.

Despite significant medical and technical improvements in the field of dialysis, the morbidity and mortality among patients with chronic kidney disease (CKD) stage 5 on dialysis remains extremely high. Hemodiafiltration (HDF), a dialysis method that combines the two main principles of hemodialysis (HD) and hemofiltration-diffusion and convection-has had a positive impact on survival when delivered with a high convective dose. Improved outcomes with HDF have been attributed to the following factors: HDF removes middle molecular weight uremic toxins including inflammatory cytokines, increases hemodynamic stability, and reduces inflammation and oxidative stress compared to conventional HD. Two randomized trials in adults have shown improved survival with HDF compared to high-flux HD. A large prospective cohort study in children has shown that HDF attenuated the progression of cardiovascular disease, improved bone turnover and growth, reduced inflammation, and improved blood pressure control compared to conventional HD. Importantly, children on HDF reported fewer headaches, dizziness, and cramps; had increased physical activity; and improved school attendance compared to those on HD. In this educational review, we discuss the technical aspects of HDF and results from pediatric studies, comparing outcomes on HDF vs. conventional HD. Convective volume, the cornerstone of treatment with HDF and a key determinant of outcomes in adult randomized trials, is discussed in detail, including the practical aspects of achieving an optimal convective volume.

Comparative analysis of hospitalizations among patients treated with hemodialysis and peritoneal dialysis in European pediatric nephrology centers: results from a prospective EPDWG/ESPN Dialysis Working Group study.

Background and hypothesis: Hospital admissions in pediatric dialysis patients need to be better studied, and most existing studies are retrospective and based on registry data. This study aimed to analyse and compare hospital admission rates, causes, length of stay (LOS), and outcomes in children treated with peritoneal dialysis (PD) and hemodialysis (HD). Methods: Data from 236 maintenance PD and 138 HD patients across 16 European dialysis centers were collected between 1 July 2017 and 30 June 2018. A total of 178 hospitalized patients (103 PD, 75 HD) were included for further analyses. Results: There were 465 hospitalization events (268 PD, 197 HD) with a rate of 0.39 admissions per 100 patient-days at risk (PDAR) and 2.4 hospital days per 100 PDAR. The admission rates were not significantly different between HD and PD patients. The most common causes of hospitalization were access-related infections (ARI) (17%), non-infectious complications of access (NIAC) (14%), and infections unrelated to access (12%). ARI was the leading cause in PD patients (24%), while NIAC was more common in HD patients (19%). PD patients had more ARIs, diagnostic procedures, and treatment adjustments (P < .05), while HD patients had more NIACs, infections unrelated to access, access placement procedures, and interventional/surgical procedures (P < .001). LOS was longer with acute admissions than non-acute admissions (P < .001). Overall LOS and LOS in the intensive care unit were similar between HD and PD patients. High serum uric acid and low albumin levels were significant predictors of longer LOS (P = .022 and P = .045, respectively). Young age, more significant height deficit, and older age at the start of dialysis were predictors of longer cumulative hospital days (P = .002, P = .001, and P = .031, respectively). Conclusion: Access-related complications are the main drivers of hospitalization in pediatric dialysis patients, and growth and nutrition parameters are significant predictors of more extended hospital stays.

Differential effects of biocompatible peritoneal dialysis fluids on human mesothelial and endothelial cells in 2D and 3D phenotypes.

INTRODUCTION: Peritoneal dialysis (PD) is a life maintaining treatment in patients with end-stage renal disease. Its chronic application leads to peritoneal mesothelial layer denudation and fibrotic transformation along with vascular activation of inflammatory pathways. The impact of different PD fluids (PDF) on mesothelial and endothelial cell function and repair mechanisms are not comprehensively described. MATERIALS AND METHODS: Mesothelial (MeT-5A) and endothelial cells (EA.hy926) were cultured in 1:1 ratio with cell medium and different PDF (icodextrin-based, amino acid-based, and glucose-based). Cell adhesion, cell migration, and cell proliferation in 2D and spheroid formation and collagen gel contraction assays in 3D cell cultures were performed. RESULTS: Cell proliferation and cell-mediated gel contraction were both significantly decreased in all conditions. 3D spheroid formation was significantly reduced with icodextrin and amino acid PDF, but unchanged with glucose PDF. Adhesion was significantly increased by amino acid PDF in mesothelial cells and decreased by icodextrin and amino acid PDF in endothelial cells. Migration capacity was significantly decreased in mesothelial cells by all three PDF, while endothelial cells remained unaffected. CONCLUSIONS: In 3D phenotypes the effects of PDF are more uniform in both mesothelial and endothelial cells, mitigating spheroid formation and gel contraction. On the contrary, effects on 2D phenotypes are more uniform in the icodextrin and amino acid PDF as opposed to glucose ones and affect mesothelial cells more variably. 2D and 3D comparative assessments of PDF effects on the main peritoneal membrane cell barriers, the mesothelial and endothelial, could provide useful translational information for PD studies.

Cardiac, possible cardiac, and likely non-cardiac origin of chest pain : A hitherto underestimated parameter in German chest pain units.

BACKGROUND: Current guidelines emphasize the diagnostic value of non-cardiac or possibly cardiac chest pain. The goal of this analysis was to determine whether German chest pain units (CPUs) adequately address conditions with "atypical" chest pain in existing diagnostic structures. METHOD: A total of 11,734 patients from the German CPU registry were included. The analyses included mode of admission, critical time intervals, diagnostic steps, and differential diagnoses. RESULTS: Patients with unspecified chest pain were younger, more often female, were less likely to have classic cardiovascular risk factors and tended to present more often as self-referrals. Patients with acute coronary syndrome (ACS) mostly had prehospital medical contact. Overall, there was no difference between these two groups regarding the time from the onset of first symptoms to arrival at the CPU. In the CPU, the usual basic diagnostic measures were performed irrespective of ACS as the primary working diagnosis. In the non-ACS group, further ischemia-specific diagnostics were rarely performed. Extra-cardiac differential diagnoses were not specified. CONCLUSION: The establishment of broader awareness programs and opening CPUs for low-threshold evaluation of self-referring patients should be discussed. Regarding the rigid focus on the clarification of cardiac causes of chest pain, a stronger interdisciplinary approach should be promoted.

2-Deoxy-glucose ameliorates the peritoneal mesothelial and endothelial barrier function perturbation occurring due to Peritoneal Dialysis fluids exposure.

Peritoneal dialysis (PD) and prolonged exposure to PD fluids (PDF) induce peritoneal membrane (PM) fibrosis and hypervascularity, leading to functional PM degeneration. 2-deoxy-glucose (2-DG) has shown potential as PM antifibrotic by inhibiting hyper-glycolysis induced mesothelial-to-mesenchymal transition (MMT). We investigated whether administration of 2-DG with several PDF affects the permeability of mesothelial and endothelial barrier of the PM. The antifibrotic effect of 2-DG was confirmed by the gel contraction assay with embedded mesothelial (MeT-5A) or endothelial (EA.hy926) cells cultured in Dianeal® 2.5 % (CPDF), BicaVera® 2.3 % (BPDF), Balance® 2.3 % (LPDF) with/without 2-DG addition (0.2 mM), and qPCR for αSMA, CDH2 genes. Moreover, 2-DG effect was tested on the permeability of monolayers of mesothelial and endothelial cells by monitoring the transmembrane resistance (RTM), FITC-dextran (10, 70 kDa) diffusion and mRNA expression levels of CLDN-1 to -5, ZO1, SGLT1, and SGLT2 genes. Contractility of MeT-5A cells in CPDF/2-DG was decreased, accompanied by αSMA (0.17 ± 0.03) and CDH2 (2.92 ± 0.29) gene expression fold changes. Changes in αSMA, CDH2 were found in EA.hy926 cells, though αSMA also decreased under LPDF/2-DG incubation (0.42 ± 0.02). Overall, 2-DG mitigated the PDF-induced alterations in mesothelial and endothelial barrier function as shown by RTM, dextran transport and expression levels of the CLDN-1 to -5, ZO1, and SGLT2. Thus, supplementation of PDF with 2-DG not only reduces MMT but also improves functional permeability characteristics of the PM mesothelial and endothelial barrier.

Technical requirements and devices available for long-term hemodialysis in children-mind the gap!

Children requiring long-term kidney replacement therapy are a "rare disease" cohort. While the basic technical requirements for hemodialysis (HD) are similar in children and adults, key aspects of the child's cardiovascular anatomy and hemodynamic specifications must be considered. In this article, we describe the technical requirements for long-term HD therapy for children and the devices that are currently available around the world. We highlight the characteristics and major technical shortcomings of permanent central venous catheters, dialyzers, dialysis machines, and software available to clinicians who care for children. We show that currently available HD machines are not equipped with appropriately small circuits and sensitive control mechanisms to perform safe and effective HD in the youngest patients. Manufacturers limit their liability, and health regulatory agencies permit the use of devices, only in children according to the manufacturers' pre-specified weight limitations. Although registries show that 6-23% of children starting long-term HD weigh less than 15 kg, currently, there is only one long-term HD device that is cleared for use in children weighing 10 to 15 kg and none is available and labelled for use in children weighing less than 10 kg anywhere in the world. Thus, many children are being treated "off-label" and are subject to interventions delivered by medical devices that lack pediatric safety and efficacy data. Moreover, recent improvements in dialysis technology offered to adult patients are denied to most children. We, in turn, advocate for concerted action by pediatric nephrologists, industry, and health regulatory agencies to increase the development of dedicated HD machines and equipment for children.

Vascular access in children requiring maintenance haemodialysis: a consensus document by the European Society for Paediatric Nephrology Dialysis Working Group

There are three principle forms of vascular access available for the treatment of children with end stage kidney disease (ESKD) by haemodialysis: tunnelled catheters placed in a central vein (central venous lines, CVLs), arteriovenous fistulas (AVF), and arteriovenous grafts (AVG) using prosthetic orbiological material. Compared with the adult literature, there are few studies in children to provide evidence based guidelines for optimal vascular access type or its management and outcomes in children with ESKD.