Effects of Dietary Phosphorus Bioaccessibility and Calcitriol onPhosphorus and Calcium Whole-Body Balance and Kinetics in Moderate CKD

PROJECT SUMMARY/ABSTRACT Chronic kidney disease (CKD) is highly prevalent, affecting approximately 37 million U.S. adults. CKD- mineral and bone disorder (CKD-MBD) is a common comorbidity of CKD that results in increased risk of cardiovascular and bone disease and associated morbidity and mortality. Abnormal phosphorus (P) metabolism

is central to the development of CKD-MBD and is intimately linked with calcium (Ca) metabolism. Incomplete understanding of the underlying physiology of Ca and P in CKD and in response to treatments is a major knowledge gap that hinders research and clinical progress in CKD-MBD. P and Ca physiology is complex and

involves interacting effects of three regulatory hormones, calcitriol, parathyroid hormone, and fibroblast growth factor-23, on a multi-tissue axis of intestine, kidney, and bone. Despite the complexity, most human research has relied on serum and urine Ca and P measures to infer aspects of whole-body physiology. Yet, prior work

has shown that serum and urine Ca and P are not reliable markers of whole-body balance or intestinal absorption in CKD. Formal metabolic balance studies combined with isotope tracers can reveal the underlying whole-body Ca and P physiology and, notably, can distinguish intestinal absorption from bone resorption and formation. This

project seeks to fill this knowledge gap through two specific aims. Aim 1 will determine the effects of dietary P restriction on P and Ca intestinal absorption, whole-body balance, and kinetics in adults with moderate CKD. Aim 2 will determine the effects of calcitriol, a key P and Ca regulatory hormone, on P and Ca intestinal

absorption, whole-body balance, and kinetics in adults with moderate CKD. Each aim will be addressed in a clinical study using a two-phase randomized cross-over design with controlled feeding and metabolic balance and kinetics methods in adults with moderate-stage CKD. In Study 1 (Aim 1), subjects will be randomly assigned

to a cross-over order of low and high diet P, achieved through manipulation of P source based on current understanding that inorganic P sources have much higher bioaccessibility compared with P found naturally in plant and animal foods, as recommended by current guidelines. In the second study (Aim 2), subjects will be

randomly assigned to a cross-over order of calcitriol and identical placebo. Each study will consist of a 1-week run-in period on the controlled diet/intervention, 1-week full metabolic balance period with complete urine and stool collections and oral and intravenous administration of P and Ca isotopes for kinetic modeling to determine

components of P and Ca metabolism including: intestinal absorption, renal clearance, and movement to and from bone, with kinetic measures continuing during a third week. After a washout period, subjects will cross-over to the second intervention period. The long-term objective of this project is to advance foundational knowledge

of whole-body P and Ca physiology in CKD that will contribute to progress in translational and clinical research with the goal of reducing morbidity and mortality associated with CKD-MBD. This relates to the mission of the NIDDK to support research aimed at improving the health and quality of life of patients with kidney disease.