title: Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD.
abstract: Patients with CKD often progress to ESRD and develop cardiovascular disease (CVD), yet available therapies only modestly improve clinical outcomes. Observational studies report independent associations between elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels and risks of ESRD, CVD, and death. Phosphate excess induces arterial calcification, and although elevated FGF23 helps maintain serum phosphate levels in the normal range in CKD, it may contribute mechanistically to left ventricular hypertrophy (LVH). Consistent epidemiologic and experimental findings suggest the need to test therapeutic approaches that lower phosphate and FGF23 in CKD. Dietary phosphate absorption is one modifiable determinant of serum phosphate and FGF23 levels. Limited data from pilot studies in patients with CKD stages 3-4 suggest that phosphate binders, low phosphate diets, or vitamin B3 derivatives, such as niacin or nicotinamide, may reduce dietary phosphate absorption and serum phosphate and FGF23 levels. This review summarizes current knowledge regarding the deleterious systemic effects of phosphate and FGF23 excess, identifies questions that must be addressed before advancing to a full-scale clinical outcomes trial, and presents a novel therapeutic approach to lower serum phosphate and FGF23 levels that will be tested in the COMBINE Study: The CKD Optimal Management With BInders and NicotinamidE study.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; tamara.isakova@northwestern.edu.
authors.forename: Tamara
authors.initials: T
authors.lastname: Isakova
authors.affiliation: Nephrology Section, Veterans Affairs San Diego Healthcare System and Division of Nephrology and Preventive Medicine, University of California, San Diego, San Diego, California;
authors.forename: Joachim H
authors.initials: JH
authors.lastname: Ix
authors.affiliation: NorthShore University Health System-University of Chicago, Pritzker School of Medicine, Evanston, Illinois;
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Sprague
authors.affiliation: Salt Lake City Veterans Affairs Healthcare System and Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah;
authors.forename: Kalani L
authors.initials: KL
authors.lastname: Raphael
authors.affiliation: Renal Section, VA Pittsburgh Healthcare System, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Linda
authors.initials: L
authors.lastname: Fried
authors.affiliation: Department of Biostatistics and Epidemiology, Cleveland Clinic Foundation, Cleveland, Ohio;
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Gassman
authors.affiliation: Division of Renal Diseases and Hypertension, the George Washington University, Washington DC;
authors.forename: Dominic
authors.initials: D
authors.lastname: Raj
authors.affiliation: Salt Lake City Veterans Affairs Healthcare System and Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah;
authors.forename: Alfred K
authors.initials: AK
authors.lastname: Cheung
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and.
authors.forename: John W
authors.initials: JW
authors.lastname: Kusek
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Flessner
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: Myles
authors.initials: M
authors.lastname: Wolf
authors.affiliation: Denver Nephrology, Denver, Colorado.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Block
mesh_terms: D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D010710:Phosphates / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000378:metabolism*
chemical_list: C000717427:FGF23 protein, human; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23
keywords: chronic kidney disease; phosphate binders; phosphate uptake