Clinical practice recommendations for native vitamin D therapy in children with chronic kidney disease Stages 2-5 and on dialysis

Vitamin D deficiency is widely prevalent and often severe in children and adults with chronic kidney disease (CKD). Although native vitamin D {25-hydroxyvitamin D [25(OH)D]} is thought to have pleiotropic effects on many organ systems, its skeletal effects have been most widely studied. The 25(OH)D deficiency is causally linked with rickets and fractures in healthy children and those with CKD, contributing to the CKD–mineral and bone disorder (MBD) complex. There are few studies to provide evidence for vitamin D therapy or guidelines for its use in CKD. A core working group (WG) of the European Society for Paediatric Nephrology (ESPN) CKD–MBD and Dialysis WGs have developed recommendations for the evaluation, treatment and prevention of vitamin D deficiency in children with CKD. We present clinical practice recommendations for the use of ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) in children with CKD Stages 2–5 and on dialysis. A parallel document addresses treatment recommendations for active vitamin D analogue therapy. The WG has performed an extensive literature review to include meta-analyses and randomized controlled trials in healthy children as well as children and adults with CKD, and prospective observational studies in children with CKD. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system has been used to develop and grade the recommendations. In the absence of applicable study data, the opinion of experts from the ESPN CKD–MBD and Dialysis WGs is provided, but clearly GRADE-ed as such and must be carefully considered by the treating physician, and adapted to individual patient needs as appropriate

Clinical practice recommendations for treatment with active Vitamin D analogues in children with chronic kidney disease Stages 2-5 and on dialysis

PubMedID: 28873971In patients with chronic kidney disease (CKD), renal synthesis of active Vitamin D [1, 25-dihydroxyVitamin D (1, 25(OH)2D)] declines and is associated with hypocalcaemia, secondary hyperparathyroidism and the spectrum of CKD-mineral and bone disorder (MBD). In advanced CKD, active Vitamin D analogues, including alfacalcidol, calcitriol and paricalcitol, are routinely administered. There are few studies on the use of Vitamin D analogues in children with CKD and on dialysis. It is difficult to define bone-specific outcomes that can guide treatment with active Vitamin D analogues in children with CKD-MBD. A core working group (WG) of the European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis WGs has developed recommendations for the use of active Vitamin D therapy in children with CKD and on dialysis. A second document in parallel with this one covers treatment recommendations for native Vitamin D therapy. The WGs have performed an extensive literature review to include systematic reviews and randomized controlled trials in adults and children with CKD and prospective observational studies in children with CKD. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system was used to develop and grade the recommendations. In the absence of applicable study data, the opinion of experts from the ESPN CKD-MBD and Dialysis WGs is provided, but clearly GRADE-ed as such and must be carefully considered by the treating physician and adapted to individual patient needs as appropriate. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.National Institute for Health ResearchRS holds a fellowship with the National Institute for Health Research (NIHR). Members of the ESPN CKD-MBD Working Group: Belgium: A. Prytula, Ghent University, Utopaed. France: J. Bachetta., University Children’s Hospital, Lyon. Germany: D. Haffner., Hannover Medical School, Hannover. G. Klaus, University Children’s Hospital, Marburg. Hungary: G. Reusz, Semmelweis University, Budapest. Italy: E. Verrina, G. Gaslini Institute, Genoa. The Netherlands: J. Groothoff, Academic Medical Center, Amsterdam. Spain: M.A. Gamero, Reina Sofía Universitary Hospital, Córdoba. Russia: E. Petrosyan, Russian National Research Medical University, Moscow. Turkey: S. A. Bakkaloglu, Gazi University Hospital, Ankara; I. Dursun, Erciyes University Faculty of Medicine, Kayseri. United Kingdom: R. Shroff, Great Ormond Street Hospital, London. Members of the ESPN Dialysis Working Group: Austria: C. Aufricht, Medical University of Vienna, Vienna. Belgium: J. Vande Walle, University Hospital Ghent, Department of Pediatric Nephrology/Urology, Ghent. Czech Republic: K. Vondrak, University Hospital Motol, Charles University Prague, 2nd Faculty of Medicine, Prague. Finland: T. Holtta, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki. France: B. Ranchin, Centre de Référence des Maladies Rénales Héréditaires, Hospices Civils de Lyon and Université Lyon, Lyon. M. Fischbach, Hautepierre University Hospital, Strasbourg. Germany: Claus Peter Schmitt, University of Heidelberg, Heidelberg. Günter Klaus, University Children’s Hospital, Marburg. Greece: Constantinos J. Stefanidis, A. and P. Kyriakou Childrens Hospital, Athens; N. Printza, Aristotle University of Thessaloniki, Thessaloniki. Italy: Alberto Edefonti, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan; E. Verrina, Giannina Gaslini Children’s Hospital, Dialysis Unit, Genova; E. Vidal, University Hospital of Padova, Padova. Lithuania: A. Jankauskiene, Vilniu

Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity.

Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global/Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D