[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-462341-105":59,"doc-detail-462341-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","current-controversies-on-adequate-circulating-vitamin-d-levels-in-ckd-review","Current Controversies on Adequate Circulating Vitamin D Levels in CKD - review","","Management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) has evolved over five decades as understanding of the vitamin D endocrine system deepened. This review synthesizes key pathophysiological insights and clinical evidence behind three paradigm shifts: selective VDR activation beyond calcitriol replacement, the high prevalence and independent mortality risk of nutritional 25(OH)D deficiency, and the FGF23–Klotho axis that links toxicity, Klotho loss, and diagnostic measurement limits. It argues for nuanced, potentially combined therapeutic strategies and emphasizes overcoming assay constraints to guide personalized therapy.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/current-controversies-on-adequate-circulating-vitamin-d-levels-in-ckd-review/462341/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/current-controversies-on-adequate-circulating-vitamin-d-levels-in-ckd-review/462341.png","ImageObject",300,407,{"name":92,"@type":93},"Aria Callaghan","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-02","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",14,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What are the three main paradigm shifts discussed in the review?","Question",{"text":113,"@type":114},"The review highlights: (1) moving from simple calcitriol replacement to selective VDR activation, (2) recognizing nutritional 25(OH)D deficiency as highly prevalent with independent mortality risk, and (3) reframing therapy around the FGF23–Klotho axis and its competing effects.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Why is nutritional 25(OH)D deficiency considered clinically important in CKD?",{"text":118,"@type":114},"The review states that 25(OH)D deficiency is common in CKD and is associated with independent mortality risk, reflecting the kidney’s complex role in maintaining systemic vitamin D supply and the relevance of extrarenal vitamin D activation.",{"name":120,"@type":111,"acceptedAnswer":121},"What therapeutic dilemma arises from the FGF23–Klotho axis?",{"text":122,"@type":114},"VDR activators are said to induce protective Klotho but may worsen toxic FGF23, while calcimimetics do not increase FGF23 but provide no Klotho benefit, creating a competing risk–benefit balance.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},462341,1790821896,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":31,"preview_page_count":4},962084926284,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Review  \nCurrent Controversies on Adequate Circulating Vitamin D Levels in CKD  \nAdriana S. Dusso 1,*, Daniela J. Porta 1 and Carlos Bernal-Mizrachi 1,2  \nAcademic Editor: Ligia Petrica  \nReceived: 15 November 2025  \nRevised: 15 December 2025  \nAccepted: 19 December 2025  \nPublished: 22 December 2025  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \n1 Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA  \n2 Department of Medicine, VA Medical Center, St. Louis, MO 63106, USA  \n* Correspondence: [adusso@wustl.edu](adusso@wustl.edu)[ ](adusso@wustl.edu)Abstract  \nManagement of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) has evolved dramatically over the past five decades, driven by discoveries that have fundamentally reshaped our understanding of the vitamin D endocrine system and its role in disease progression. This review synthesizes the key pathophysiological insights and clinical evidence underlying three critical paradigm shifts. The first shift moved beyond simple calcitriol replacement with the development of selective vitamin D receptor activators (VDRAs) designed to minimize hypercalcemia while maximizing PTH suppression. Crucially, these analogs revealed unexpected survival benefits, suggesting protective VDR actions extending beyond mineral metabolism. The second shift recognized the profound prevalence and independent mortality risk associated with nutritional vitamin D (25(OH)D) deficiency in CKD. This highlighted the kidney’s complex role in maintaining systemic 25(OH)D supply and the importance of extrarenal vitamin D activation, although optimal assessment, targets, and supplementation strategies remain highly controversial due to CKD-specific pathophysiology (e.g., megalin loss, impaired uptake, obesity effects) and complex dosing paradoxes. The third, and most impactful, shift centers on the FGF23-Klotho axis. Pathologically high FGF23 is now established as a direct cardiovascular and skeletal toxin, acting via Klotho-independent pathways in CKD, while the profound deficiency of the protective, anti-aging hormone Klotho exacerbates systemic damage (inflammation, oxidative stress, impaired autophagy) . This creates a major therapeutic dilemma, as VDRAs induce protective Klotho but worsen toxic FGF23, while calcimimetics do not increase FGF23 but offer no Klotho benefit. Furthermore, this complex interplay is obscured by significant limitations in accurately measuring FGF23 isoforms, soluble Klotho, and true vitamin D status. These paradigm shifts reveal a complex pathophysiology far beyond simple PTH control, demanding a move towards nuanced, potentially combined therapeutic strategies that balance FGF23 burden with Klotho preservation. Overcoming the profound diagnostic limitations to accurately monitor this axis and guide personalized therapy represents the critical next frontier in improving outcomes for patients with CKD.  \nKeywords: vitamin D; calcidiol; calcitriol; FGF23; klotho; renal damage; cardiovascular damage  \n1. Introduction  \nChronic Kidney Disease (CKD), affecting over 11% of the global population, is characterized by accelerated multi-organ aging that escalates the risk of cardiovascular morbidity and mortality by 10-to 20-fold compared to the general population [1,2] .  \nThe secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD), characterized by elevated parathyroid hormone (PTH), parathyroid gland overgrowth, and disordered mineral metabolism, is a major contributor to the high rates of bone disease and cardiovascular mortality in CKD patients [3] .  \nFor over fifty years, since the discovery of the kidney’s role in synthesizing active vitamin D (1,25(OH) 2D) [4], the management of secondary hyperparathyroidism (SHPT) in chronic","cbCaibO38jF4tgmq","https://ap.wps.com/l/cbCaibO38jF4tgmq","pdf",1108927,"English","# Introduction\n## Paradigm Shift 1: From Simple 1,25(OH)2D Replacement to Selective VDR Activation\n### Pathophysiological Discoveries and Impact on CKD Progression\n#### Parathyroid Glands","[{\"question\":\"What are the three main paradigm shifts discussed in the review?\",\"answer\":\"The review highlights: (1) moving from simple calcitriol replacement to selective VDR activation, (2) recognizing nutritional 25(OH)D deficiency as highly prevalent with independent mortality risk, and (3) reframing therapy around the FGF23–Klotho axis and its competing effects.\"},{\"question\":\"Why is nutritional 25(OH)D deficiency considered clinically important in CKD?\",\"answer\":\"The review states that 25(OH)D deficiency is common in CKD and is associated with independent mortality risk, reflecting the kidney’s complex role in maintaining systemic vitamin D supply and the relevance of extrarenal vitamin D activation.\"},{\"question\":\"What therapeutic dilemma arises from the FGF23–Klotho axis?\",\"answer\":\"VDR activators are said to induce protective Klotho but may worsen toxic FGF23, while calcimimetics do not increase FGF23 but provide no Klotho benefit, creating a competing risk–benefit balance.\"}]","Current Controversies on Adequate Circulating Vitamin D Levels in CKD - review | PDF",1790763853]