Parathyroid Gland Hyperplasia in Renal Failure

Abstract

Introduction S econdary hyperparathyroidism, a frequent complication of chronic renal failure, is characterized by parathyroid hyperplasia and enhanced synthesis and secretion of parathyroid hormone (PTH). As summarized in Figure 1, high circulating PTH levels are not only a major contributor to osteitis fibrosa and bone loss, typical features of renal osteodystrophy, but also to a variety of systemic defects including cardiovascular complications which increase mortality in renal failure patients. A link between the mechanisms controlling proliferation and hormonal production also exists in normal parathyroid cells, which respond to the stimulus of chronic hypocalcemia not only by an increase in PTH release but with a secondary expansion in cell mass. The mechanisms responsible for this link, however, remain poorly understood. In renal failure, hypocalcemia, hyperphosphatemia and vitamin D deficiency are the three main direct causes of hyperparathyroidism. Hyperphosphatemia and 1,25-dihydroxyvitamin D (l,25(OH)2D3) deficiency also enhance parathyroid function indirectly by lowering serum calcium (Ca).^'^'^ The regulation of PTH synthesis by Ca, phosphate (P) and vitamin D has been extensively studied. PTH-gene transcription is tightly controlled by Ca and l,25(OH)2D3 through mechanisms that involve the calcium sensing receptor (CaSR) and the vitamin D receptor (VDR), respectively. ' As renal disease progresses, a reduction in parathyroid content of both proteins renders the parathyroid glands more resistant to suppression of PTH synthesis and secretion in response to Ca and l,25(OH)2D3.^'^^ Serum Ca and P levels also control PTH synthesis through post-transcriptional mechanisms that involve the binding of cytosolic proteins to the 3'-untranslated region of the PTH mRNA, thus regulating transcript stability and consequently, PTH translation rates. ' ' Changes in the levels of serum Ca, P, l,25(OH)2D3 and in the parathyroid content of the CaSR and the VDR also have a dramatic impact on parathyroid tissue growth. ' ' However, the lack of an appropriate parathyroid cell line has precluded a better understanding of the pathogenic mechanisms mediating the potent effects of the three main regidators on the rate of parathyroid cell proliferation already induced by uremia. This chapter summarizes the current understanding of parathyroid tissue growth and presents new insights, emerging from the 5/6 nephrectomized rat model, into the molecular mechanisms contributing to the regulation of parathyroid hyperplasia in early uremia by Ca, P and l,25(OH)2D3.