Rationale and Approaches to Phosphate and Fibroblast Growth ... : Journal of the American Society of Nephrology (original) (raw)

Up Front Matters

Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD

Isakova, Tamara*; Ix, Joachim H.†; Sprague, Stuart M.‡; Raphael, Kalani L.§; Fried, Linda‖; Gassman, Jennifer J.¶; Raj, Dominic**; Cheung, Alfred K.§; Kusek, John W.††; Flessner, Michael F.††; Wolf, Myles*; Block, Geoffrey A.‡‡

*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;

†Nephrology Section, Veterans Affairs San Diego Healthcare System and Division of Nephrology and Preventive Medicine, University of California, San Diego, San Diego, California;

‡NorthShore University Health System-University of Chicago, Pritzker School of Medicine, Evanston, Illinois;

§Salt Lake City Veterans Affairs Healthcare System and Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah;

‖Renal Section, VA Pittsburgh Healthcare System, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;

¶Department of Biostatistics and Epidemiology, Cleveland Clinic Foundation, Cleveland, Ohio;

**Division of Renal Diseases and Hypertension, the George Washington University, Washington DC;

††National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and

‡‡Denver Nephrology, Denver, Colorado

Correspondence: Dr. Tamara Isakova, 633 N. St. Clair St., Suite 18-083, Chicago, IL 60611. Email: [email protected]

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.