The Pathophysiology of Early-Stage Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) and Response to Phosphate Binders in the Rat

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic disorder that describes the complex bone and mineral abnormalities that occur in CKD. To understand the pathophysiology of CKD-MBD and determine whether the early use of phosphate binders would alter this physiology, we used a naturally occurring, slowly progressive model of CKD-MBD, the Cy/+ rat. Male Cy/+ rats were compared with their normal littermates at 20 weeks of age after 1 week of no phosphate binder, calcium carbonate, or sevelamer carbonate. The Cy/+ rat had renal function that was 50% of that of normal littermates, elevated parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), decreased 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] levels, but normal calcium and phosphorus levels. There was a significant positive correlation of blood FGF23 and phosphorus levels and blood FGF23 and urine phosphorus levels. There was an inverse correlation between FGF23 and calcium levels. mRNA from the kidney demonstrated 50% reduction in klotho and Npt2a expression but no difference in CYP27B1. In the intestine, CKD animals had reduced active phosphate absorption in the jejunum using modified Ussing chambers and a reduction in Npt2b expression throughout the small intestine compared with normal littermates. In bone, mRNA expression of FGF23 was reduced (driven by lowering with phosphate binders), and TRAP expression was increased in CKD. By histology, there was increased osteoclast activity and number, and there were reductions in some measures of femoral neck mechanical strength. One week of phosphate binders reduced intestinal phosphate flux, serum phosphorus levels, and urinary phosphate excretion. These results demonstrate marked abnormalities in kidney, intestine, and bone in early CKD-MBD. While phosphate binders were effective in lowering urine phosphorus, they had little effect on end organs after 1 week of administration. (C) 2011 American Society for Bone and Mineral Research.