Chapter 45 - Clinical Skeletal Syndromes Associated with Parathyroid Disorders in Chronic Kidney Disease

Abstract

The highest serum parathyroid hormone (PTH) concentrations are seen in patients with chronic renal failure. Circulating PTH rises progressively throughout the course of chronic kidney disease (CKD) and may induce systemic biological effects with either beneficial and/or detrimental effects on multiple organ functions. The most apparent beneficial effect of rising PTH concentrations in CKD is mitigating hyperphosphatemia by increasing renal phosphate excretion. The skeleton is a primary site for biological actions of PTH, as PTH is the main systemic regulator of bone remodeling. PTH also has effects on bone remodeling mediated by both cellular and regulatory pathways. The mechanisms for the increase in PTH concentrations in CKD are multi-factorial: hyperphosphatemia, calcitriol (1,25 dihydroxyvitamin D) deficiency, hypocalcemia, and perhaps elevation of fibroblast growth factor 23 (FGF23). In the early phases of CKD, hyperphosphatemia is prevented by increased osteocytic production of FGF23, which acts as a phosphaturic peptide. As CKD progresses to late stage 4 disease, these homeostatic mechanisms to control the serum phosphate concentration fail and sustained hyperphosphatemia results. Hyperphosphatemia is one of the leading risk factors associated with vascular and soft tissue calcification in CKD. In addition, hyperphosphatemia may have a direct stimulatory effect on the parathyroid gland cell resulting in glandular growth and increased PTH secretion. Both PTH and FGF23-mediated reductions in tubular epithelial phosphate transport militate against hyperphosphatemia but ultimately cannot. In normal individuals and those with mild CKD, FGF23 reduces PTH secretion, but as CKD progresses there may be decreased parathyroid cell membrane expression of FGF23 receptors and its co-receptor, Klotho, so that even high levels of FGF23 are no longer effective as a regulator of PTH production.