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.

Keywords: chronic kidney disease; phosphate binders; phosphate uptake.

Figure 1.

Multi-step development of phosphate and FGF23 reduction strategies in CKD. Schematic representation of the multi-step process for testing the utility of phosphate and FGF23 reduction strategies in CKD. The COMBINE (CKD Optimal Management with Binders and Nicotinamide) study and its objectives are represented by the boxes with dashed outlines.

Figure 2.

Biochemical phenotype of disordered mineral metabolism in CKD. The graph summarizes evolution of abnormal mineral metabolism along the spectrum of CKD. Depicted values are based on published literature. The x-axis represents glomerular filtration. The y-axis represents circulating levels of individual analytes with temporal changes in and normal ranges of FGF23 shown in red, 1,25 dihydroxyvitamin D (1,25D) shown in purple, parathyroid hormone (PTH) shown in green, and phosphate shown in blue. Elevated FGF23 is the earliest alteration in mineral metabolism in CKD (1). Elevations in FGF23 levels cause the early decline in 1,25D levels (2) that leads to secondary hyperparathyroidism (3). All of these changes occur prior to elevations in serum phosphate levels (4). This figure is reproduced from Wolf, with permission from the American Society of Nephrology. Copyright © [2010] the American Society of Nephrology. All rights reserved.

Figure 3.

Dietary phosphate absorption in the small intestine. Intestinal absorption of dietary phosphate may occur by passive paracellular diffusion via tight junctions and by active transcellular transport via NPT2b, the major sodium phosphate co-transporter in the small intestine. Low phosphate diets and phosphate binders reduce luminal phosphate concentration, which may upregulate NPT2b-dependent dietary phosphate absorption. Because nicotinamide reduces NPT2b expression, use of this agent in combination with low phosphate diets and phosphate binders may maximize reductions in dietary phosphate absorption.

Figure 4.

The COMBINE study schema. The COMBINE study is a randomized, double-blind, placebo-controlled, 12-month study of 200 CKD stages 3–4 patients that will test the hypothesis that nicotinamide and lanthanum carbonate will safely lower serum phosphate and FGF23 levels compared with placebo.