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.

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.

Real-world evidence on the dosing and safety of C.E.R.A. in pediatric dialysis patients: findings from the International Pediatric Dialysis Network registries.

BACKGROUND: This retrospective real-world study used data from two registries, International Pediatric Peritoneal Dialysis Network (IPPN) and International Pediatric Hemodialysis Network (IPHN), to characterize the efficacy and safety of continuous erythropoietin receptor activator (C.E.R.A.) in pediatric patients with chronic kidney disease (CKD) on peritoneal dialysis (PD) or hemodialysis (HD). METHODS: IPPN and IPHN collect prospective data (baseline and every 6 months) from pediatric PD and HD centers worldwide. Demographics, clinical characteristics, dialysis information, treatment, laboratory parameters, number and causes of hospitalization events, and deaths were extracted for patients on C.E.R.A. treatment (IPPN: 2007-2021; IPHN: 2013-2021). RESULTS: We analyzed 177 patients on PD (median age 10.6 years) and 52 patients on HD (median age 14.1 years) who had ≥ 1 observation while being treated with C.E.R.A. The median (interquartile range [IQR]) observation time under C.E.R.A. exposure was 6 (0-12.5) and 12 (0-18) months, respectively. Hemoglobin concentrations were stable over time; respective means (standard deviation) at last observation were 10.9 (1.7) g/dL and 10.4 (1.7) g/dL. Respective median (IQR) monthly C.E.R.A. doses at last observation were 3.5 (2.3-5.1) µg/kg, or 95 (62-145) µg/m2 and 2.1 (1.2-3.4) µg/kg, or 63 (40-98) µg/m2. Non-elective hospitalizations occurred in 102 (58%) PD and 32 (62%) HD patients. Seven deaths occurred (19.8 deaths per 1000 observation years). CONCLUSIONS: C.E.R.A. was associated with efficient maintenance of hemoglobin concentrations in pediatric patients with CKD on dialysis, and appeared to have a favorable safety profile. The current analysis revealed no safety signals.

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.

Calcimimetic AMG-416 induced short-term changes in calcium concentrations and calcium isotope ratios in rats.

Calcium (Ca) isotopes (δ44/42Ca) in serum and urine have been suggested as novel sensitive markers of bone calcification. The response of δ44/42Ca to acute changes in Ca homeostasis, has not yet been demonstrated. We measured serum Ca and δ44/42Ca in rats maintained on a standard and a 50% Ca reduced diet for 4 weeks, and after injection of 1 mg/kg of the calcimimetic AMG-416, 24 h prior to sacrifice. AMG-416 decreased serum Ca by a maximum of 0.38 ± 0.10 and 0.53 ± 0.35 mmol/l after 12 and 6 h, respectively, in the standard and low-Ca diet groups (p = 0.0006/0.02), while serum δ44/42Ca did not change over 24 h in both groups. Urinary Ca concentrations were higher 24 h after AMG-416 injection in both groups (p = 0.03/0.06), urine δ44/42Ca was not different compared to the untreated control groups. Our data does not show acute changes in δ44/42Ca in response to a single dose of AMG-416 within 24 h after injection, possibly due to a lack of bone calcification.

Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis.

[Figure: see text].

Peritoneal transformation shortly after kidney transplantation in pediatric patients with preceding chronic peritoneal dialysis.

BACKGROUND: The unphysiological composition of peritoneal dialysis (PD) fluids induces progressive peritoneal fibrosis, hypervascularization and vasculopathy. Information on these alterations after kidney transplantation (KTx) is scant. METHODS: Parietal peritoneal tissues were obtained from 81 pediatric patients with chronic kidney disease stage 5 (CKD5), 72 children on PD with low glucose degradation product (GDP) PD fluids, and from 20 children 4-8 weeks after KTx and preceding low-GDP PD. Tissues were analyzed by digital histomorphometry and quantitative immunohistochemistry. RESULTS: While chronic PD was associated with peritoneal hypervascularization, after KTx vascularization was comparable to CKD5 level. Submesothelial CD45 counts were 40% lower compared with PD, and in multivariable analyses independently associated with microvessel density. In contrast, peritoneal mesothelial denudation, submesothelial thickness and fibrin abundance, number of activated, submesothelial fibroblasts and of mesothelial-mesenchymal transitioned cells were similar after KTx. Diffuse peritoneal podoplanin positivity was present in 40% of the transplanted patients. In subgroups matched for age, PD vintage, dialytic glucose exposure and peritonitis incidence, submesothelial hypoxia-inducible factor 1-alpha abundance and angiopoietin 1/2 ratio were lower after KTx, reflecting vessel maturation, while arteriolar and microvessel p16 and cleaved Casp3 were higher. Submesothelial mast cell count and interleukin-6 were lower, whereas transforming growth factor-beta induced pSMAD2/3 was similar as compared with children on PD. CONCLUSIONS: Peritoneal membrane damage induced with chronic administration of low-GDP PD fluids was less severe after KTx. While peritoneal microvessel density, primarily defining PD transport and ultrafiltration capacity, was normal after KTx and peritoneal inflammation less pronounced, diffuse podoplanin positivity and profibrotic activity were prevalent.

Sodium handling in pediatric patients on maintenance dialysis.

The risk of cardiovascular disease remains exceedingly high in pediatric patients with chronic kidney disease stage 5 on dialysis (CKD 5D). Sodium (Na+) overload is a major cardiovascular risk factor in this population, both through volume-dependent and volume-independent toxicity. Given that compliance with a Na+-restricted diet is generally limited and urinary Na+ excretion impaired in CKD 5D, dialytic Na+ removal is critical to reduce Na+ overload. On the other hand, an excessive or too fast intradialytic Na+ removal may lead to volume depletion, hypotension, and organ hypoperfusion. This review presents current knowledge on intradialytic Na+ handling and possible strategies to optimize dialytic Na+ removal in pediatric patients on hemodialysis (HD) and peritoneal dialysis (PD). There is increasing evidence supporting the prescription of lower dialysate Na+ in salt-overloaded children on HD, while improved Na+ removal may be achieved in children on PD with an individual adaptation of dwell time and volume and with icodextrin use during the long dwell.

Missing trial results: analysis of the current publication rate of studies in pediatric dialysis from 2003 to 2020.

BACKGROUND: Decision-making in the field of pediatric dialysis requires evidence from clinical trials, but, similar to other fields of pediatric medicine, might be affected by a low trial publication rate. METHODS: We analyzed the current publication rate, the time to publication, and factors that might be associated with both rate of and time to publication in pediatric dialysis studies registered as completed on ClinicalTrials.gov from 2003 until November 2020. RESULTS: Fifty-three respective studies were identified. These enrolled 7287 patients in total. 28 of 53 studies (52.8%) had results available. We identified a median time to publication of 20.5 months (range, 3-67). Studies published after the FDA Amendments Act establishment in 2007 were published faster (P = 0.025). There was no trend toward a higher publication rate of studies completed more recently (P = 0.431). 26 of 53 studies (49.1%) focused on medication and control of secondary complications of kidney failure. 12 of 53 studies (22.6%) enrolled only children, were published faster (P = 0.029) and had a higher 5-year publication rate (P = 0.038) than studies enrolling both children and adults. 25 of 53 studies (47.1%) were co-funded by industry. These were published faster (P = 0.025). CONCLUSIONS: Currently, only 52.8% of all investigated studies in pediatric dialysis have available results, and the overall median time to publication did not meet FDA requirements. This might introduce a publication bias into the field, and it might negatively impact clinical decision-making in this critical subspecialty of pediatric medicine. A higher resolution version of the Graphical abstract is available as Supplementary information.

Diagnosis and management of mineral and bone disorders in infants with CKD: clinical practice points from the ESPN CKD-MBD and Dialysis working groups and the Pediatric Renal Nutrition Taskforce.

BACKGROUND: Infants with chronic kidney disease (CKD) form a vulnerable population who are highly prone to mineral and bone disorders (MBD) including biochemical abnormalities, growth retardation, bone deformities, and fractures. We present a position paper on the diagnosis and management of CKD-MBD in infants based on available evidence and the opinion of experts from the European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis working groups and the Pediatric Renal Nutrition Taskforce. METHODS: PICO (Patient, Intervention, Comparator, Outcomes) questions were generated, and relevant literature searches performed covering a population of infants below 2 years of age with CKD stages 2-5 or on dialysis. Clinical practice points (CPPs) were developed and leveled using the American Academy of Pediatrics grading matrix. A Delphi consensus approach was followed. RESULTS: We present 34 CPPs for diagnosis and management of CKD-MBD in infants, including dietary control of calcium and phosphate, and medications to prevent and treat CKD-MBD (native and active vitamin D, calcium supplementation, phosphate binders). CONCLUSION: As there are few high-quality studies in this field, the strength of most statements is weak to moderate, and may need to be adapted to individual patient needs by the treating physician. Research recommendations to study key outcome measures in this unique population are suggested. A higher resolution version of the Graphical abstract is available as Supplementary information.

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.

The effects of hospital and dialysis unit characteristics on hospitalizations for access-related complications among children on maintenance dialysis: a European, multicenter, observational, cross-sectional study.

BACKGROUND: Previous studies investigating hospitalizations in dialysis patients have focused primarily on patient-centered factors. We analyzed the impact of hospital and dialysis unit characteristics on pediatric dialysis patients' hospitalizations for access-related complications (ARCs). METHODS: This cross-sectional study involved 102 hemodialysis (HD) and 163 peritoneal dialysis (PD) patients. Data between July 2017 and July 2018 were analyzed. RESULTS: Children's hospitals (CHs) had more pediatric nephrologists and longer PD experience (years) than general hospitals (GHs) (p = 0.026 and p = 0.023, respectively). A total of 53% of automated PD (APD) and 6% of continuous ambulatory PD (CAPD) patients were in CHs (p < 0.001). Ninety-three percent of APD and 69% of CAPD patients were treated in pediatric-specific PD units (p = 0.001). CHs had a higher prevalence in providing hemodiafiltration (HDF) than GHs (83% vs. 30%). Ninety-seven percent of HDF vs. 66% for conventional HD (cHD) patients, and 94% of patients with arteriovenous fistula (AVF) vs. 70% of those with central venous catheters (CVC), were dialyzed in pediatric-specific HD units (p = 0.001 and p = 0.016, respectively). Eighty patients (51 PD and 29 HD) had 135 (84 PD, 51 HD) hospitalizations. CAPD was an independent risk factor for hospitalizations for infectious ARCs (I-ARCs) (p = 0.009), and a health center's PD experience negatively correlated with CAPD patient hospitalizations for I-ARCs (p = 0.041). cHD and dialyzing in combined HD units significantly increased hospitalization risk for non-infectious (NI-)ARCs (p = 0.044 and p = 0.017, respectively). CONCLUSIONS: CHs and pediatric-specific dialysis units have higher prevalence of APD and HDF use. Hospitalizations for I-ARCs in CAPD are lower in centers with longer PD experience, and pediatric HD units are associated with fewer hospitalizations due to NI-ARCs. A higher resolution version of the Graphical abstract is available as Supplementary information.

Sodium intake and urinary losses in children on dialysis: a European multicenter prospective study.

BACKGROUND: Sodium (Na) balance is unexplored in dialyzed children. We assessed a simplified sodium balance (sNaB) and its correlates in pediatric patients receiving maintenance dialysis. METHODS: Patients < 18 years old on hemodialysis (HD) or peritoneal dialysis (PD) in six European Pediatric Dialysis Working Group centers were recruited. sNaB was calculated from enteral Na, obtained by a 3-day diet diary, Na intake from medications, and 24-h urinary Na (uNa). Primary outcomes were systolic blood pressure and diastolic blood pressure standard deviation scores (SBP and DBP SDS), obtained by 24-h ambulatory blood pressure monitoring or office BP according to age, and interdialytic weight gain (IDWG). RESULTS: Forty-one patients (31 HD), with a median age of 13.3 (IQR 5.2) years, were enrolled. Twelve patients (29.3%) received Na-containing drugs, accounting for 0.6 (0.7) mEq/kg/day. Median total Na intake was 1.5 (1.1) mEq/kg/day, corresponding to 60.6% of the maximum recommended daily intake for healthy children. Median uNa and sNaB were 0.6 (1.8) mEq/kg/day and 0.9 (1.7) mEq/kg/day, respectively. The strongest independent predictor of sNaB in the cohort was urine output. In patients receiving HD, sNaB correlated with IDWG, pre-HD DBP, and first-hour refill index, a volume index based on blood volume monitoring. sNaB was the strongest predictor of IDWG in multiple regression analysis (ß = 0.63; p = 0.005). Neither SBP SDS nor DBP SDS correlated with sNaB. CONCLUSIONS: Na intake is higher than uNa in children on dialysis, and medications may be an important source of Na. sNaB is best predicted by urine output in the population, and it is a significant independent predictor of IDWG in children on HD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Impact of Cinacalcet and Etelcalcetide on Bone Mineral and Cardiovascular Disease in Dialysis Patients.

PURPOSES OF REVIEW: With chronic kidney disease (CKD) progression, secondary hyperparathyroidism (sHPT) and mineral and bone metabolism disease (MBD) almost inevitably develop and result in renal osteodystrophy and cardiovascular disease (CVD). Together with active vitamin D, calcimimetics are the main therapy for sHPT in CKD. This review provides an overview of the therapeutic effects of oral cinacalcet and intravenous etelcalcetide on CKD-MBD and vascular disease, with a focus on pediatric dialysis patients. RECENT FINDINGS: Randomized controlled trials in adults and children demonstrate efficient lowering of parathyroid hormone (PTH) by the calcimimetics together with a reduction in serum calcium and phosphate when combined with low-dose active vitamin D, while therapy with active vitamin D analogs alone increases serum calcium and phosphate. Cinacalcet and etelcalcetide both improve bone formation and correct adynamic bone, i.e., have a direct bone anabolic effect. They decrease serum calciprotein particles, which are involved in endothelial dysfunction, atherogenesis, and vascular calcification. Clinical trials in adults suggest a modest slowing of the progression of cardiovascular calcification with cinacalcet. Calcimimetic agents represent a major pharmacological tool for improved control of CKD-MBD, by efficiently counteracting sHPT and allowing for better control of calcium/phosphate and bone homeostasis. Albeit definite evidence is lacking, the beneficial effects of calcimimetics on CVD are promising. Routine use of cinacalcet has been suggested in children.

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.

Mouse Models of Mineral Bone Disorders Associated with Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) inevitably develop mineral and bone disorders (CKD-MBD), which negatively impact their survival and quality of life. For a better understanding of underlying pathophysiology and identification of novel therapeutic approaches, mouse models are essential. CKD can be induced by surgical reduction of a functional kidney mass, by nephrotoxic compounds and by genetic engineering specifically interfering with kidney development. These models develop a large range of bone diseases, recapitulating different types of human CKD-MBD and associated sequelae, including vascular calcifications. Bones are usually studied by quantitative histomorphometry, immunohistochemistry and micro-CT, but alternative strategies have emerged, such as longitudinal in vivo osteoblast activity quantification by tracer scintigraphy. The results gained from the CKD-MBD mouse models are consistent with clinical observations and have provided significant knowledge on specific pathomechanisms, bone properties and potential novel therapeutic strategies. This review discusses available mouse models to study bone disease in CKD.

Naturally occurring stable calcium isotope ratios are a novel biomarker of bone calcium balance in chronic kidney disease.

Dysregulated calcium homeostasis is common in chronic kidney disease and causally associated with disorders of bone mineralization. However, radiological measures and biomarkers do not allow accurate evaluation of bone calcium balance. Non-radioactive calcium isotopes, 42Ca and 44Ca, are present in our diet and sequestered into body compartments following principles of kinetic isotope fractionation. Isotopically light 42Ca is preferentially incorporated into bone, while heavier 44Ca is excreted. The ratio (44/42Caserum) increases when bone formation exceeds resorption and vice versa, reflecting bone calcium balance. We measured these calcium isotopes by inductively coupled plasma mass-spectrometry in blood, urine and feces of 42 children with chronic kidney disease and 92 receiving dialysis therapy. We compared the isotope ratios with bone biomarkers and determined total bone mineral content by dual-energy x-ray absorptiometry and peripheral quantitative CT expressed as age-adjusted z-scores. The 44/42Caserum ratio positively correlated with serum calcium, 25-hydroxyvitamin D and alkaline phosphatases and inversely with serum parathyroid hormone and other bone resorption markers. The 44/42Caserum ratio positively correlated with age-adjusted z-scores of tibial trabecular bone mineral density and total bone mineral content measured by peripheral quantitative CT, and hip bone mineral density measured by dual-energy X-ray absorptiometry. Significant and independent predictors of total bone mineral content, measured by, were the 44/42Caserum ratio and parathyroid hormone. The 44/42Caserum ratio, repeated after four weeks, highly correlated with baseline values. When adjusted for calcium-containing medications and kidney impairment, the 44/42Caserum ratio in patients receiving dialysis was 157% lower than that of age-matched children and 29% lower than levels in elderly women with osteoporosis, implying significantly lower bone mineral content. Thus, calcium isotope ratios may provide a novel, sensitive and non-invasive method of assessing bone calcium balance in chronic kidney disease.

The calcium-sensing receptor stabilizes podocyte function in proteinuric humans and mice.

Calcimimetic agents allosterically increase the calcium ion sensitivity of the calcium-sensing receptor (CaSR), which is expressed in the tubular system and to a lesser extent in podocytes. Activation of this receptor can reduce glomerular proteinuria and structural damage in proteinuric animal models. However, the precise role of the podocyte CaSR remains unclear. Here, a CaSR knockdown in cultured murine podocytes and a podocyte-specific CaSR knockout in BALB/c mice were generated to study its role in proteinuria and kidney function. Podocyte CaSR knockdown abolished the calcimimetic R-568 mediated calcium ion-influx, disrupted the actin cytoskeleton, and reduced cellular attachment and migration velocity. Adriamycin-induced proteinuria enhanced glomerular CaSR expression in wild-type mice. Albuminuria, podocyte foot process effacement, podocyte loss and glomerular sclerosis were significantly more pronounced in adriamycin-treated podocyte-specific CaSR knockout mice compared to wild-type littermates. Co-treatment of wild-type mice with adriamycin and the calcimimetic cinacalcet reduced proteinuria in wild-type, but not in podocyte-specific CaSR knockout mice. Additionally, four children with nephrotic syndrome, whose parents objected to glucocorticoid therapy, were treated with cinacalcet for one to 33 days. Proteinuria declined transiently by up to 96%, serum albumin increased, and edema resolved. Thus, activation of podocyte CaSR regulates key podocyte functions in vitro and reduced toxin-induced proteinuria and glomerular damage in mice. Hence, our findings suggest a potential novel role of CaSR signaling in control of glomerular disease.

Acute paediatric kidney replacement therapies in Europe: demographic results from the EurAKId Registry.

BACKGROUND: Acute kidney injury (AKI), particularly that requiring dialysis, is a severe complication in hospitalized children that is associated with high morbidity and mortality. A prospective European AKI registry (EurAKId registry, NCT02960867) was created to describe the epidemiology and outcomes of paediatric patients treated with acute dialysis. METHODS: Children were recruited who were between 0 and 18 years of age and were treated both in and outside the paediatric intensive care unit (PICU) with peritoneal dialysis (PD), haemodialysis (HD) or continuous kidney replacement therapy (CKRT) for AKI or metabolic derangement, fluid overload (FO), sepsis or respiratory distress. Five age groups and 12 categories of primary diseases were defined. RESULTS: Data on 340 patients were analysed, of whom 86% received dialysis for AKI and 14% for reasons other than AKI. Boys accounted for 60% of the patients. Illness severity was greater in children with cardiac and haematologic diseases than those with kidney diseases. Most patients received dialysis in the PICU (84%). The most frequently used dialysis modality was CKRT (64%), followed by PD (14%) and HD (14%). The overall survival rate was 65%. Survival was significantly lower in children with three comorbidities than in children with no comorbidities (41% and 83%; P < 0.001). CONCLUSIONS: The EurAKId registry is the first prospective registry considering paediatric acute kidney replacement therapies (KRTs) in both critical and non-critical care settings, focusing on the three dialysis modalities in Europe. The clinical indications for KRT have expanded; our population was characterized by critically ill patients, primarily boys, who frequently received dialysis in the PICU with CKRT.

Hemodiafiltration in the pediatric population.

Hemodiafiltration (HDF) is increasingly adopted as a safe and effective treatment compared to conventional hemodialysis (HD) in children. We describe the outcomes of prospective observational studies in children on HDF versus HD showing that HDF was associated with an attenuation of the cardiovascular risk profile, improved blood pressure control, reduced inflammation, improved bone health and growth, and most importantly, an improved health-related quality of life.