Development and progression of secondary hyperparathyroidism in chronic kidney disease: lessons from molecular genetics
2007; Elsevier BV; Volume: 74; Issue: 3 Linguagem: Inglês
10.1038/sj.ki.5002287
ISSN1523-1755
AutoresWilliam G. Goodman, L. Darryl Quarles,
Tópico(s)Magnesium in Health and Disease
ResumoThe identification of the calcium-sensing receptor (CaSR) and the clarification of its role as the major regulator of parathyroid gland function have important implications for understanding the pathogenesis and evolution of secondary hyperthyroidism in chronic kidney disease (CKD). Signaling through the CaSR has direct effects on three discrete components of parathyroid gland function, which include parathyroid hormone (PTH) secretion, PTH synthesis, and parathyroid gland hyperplasia. Disturbances in calcium and vitamin D metabolism that arise owing to CKD diminish the level of activation of the CaSR, leading to increases in PTH secretion, PTH synthesis, and parathyroid gland hyperplasia. Each represents a physiological adaptive response by the parathyroid glands to maintain plasma calcium homeostasis. Studies of genetically modified mice indicate that signal transduction via the CaSR is a key determinant of parathyroid cell proliferation and parathyroid gland hyperplasia. Because enlargement of the parathyroid glands has important implications for disease progression and disease severity, it is possible that clinical management strategies that maintain adequate calcium-dependent signaling through the CaSR will ultimately prove useful in diminishing parathyroid gland hyperplasia and in modifying disease progression. The identification of the calcium-sensing receptor (CaSR) and the clarification of its role as the major regulator of parathyroid gland function have important implications for understanding the pathogenesis and evolution of secondary hyperthyroidism in chronic kidney disease (CKD). Signaling through the CaSR has direct effects on three discrete components of parathyroid gland function, which include parathyroid hormone (PTH) secretion, PTH synthesis, and parathyroid gland hyperplasia. Disturbances in calcium and vitamin D metabolism that arise owing to CKD diminish the level of activation of the CaSR, leading to increases in PTH secretion, PTH synthesis, and parathyroid gland hyperplasia. Each represents a physiological adaptive response by the parathyroid glands to maintain plasma calcium homeostasis. Studies of genetically modified mice indicate that signal transduction via the CaSR is a key determinant of parathyroid cell proliferation and parathyroid gland hyperplasia. Because enlargement of the parathyroid glands has important implications for disease progression and disease severity, it is possible that clinical management strategies that maintain adequate calcium-dependent signaling through the CaSR will ultimately prove useful in diminishing parathyroid gland hyperplasia and in modifying disease progression. Secondary hyperparathyroidism (SHPT) is a common consequence of chronic kidney disease (CKD).1.Sherrard D.J. Hercz G. 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Recent developments in the management of secondary hyperparathyroidism.Kidney Int. 2001; 59: 1187-1201Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar The current review focuses more narrowly, however, on the key determinants of parathyroid gland function in CKD and the factors that influence the development and progression of SHPT. Recent scientific advances provide a much better understanding of the molecular mechanisms and signal transduction pathways involved in the pathogenesis of SHPT due to CKD and in the regulation of PTH synthesis and secretion in this important clinical disorder. The natural history of SHPT is characterized by indolent progression as the duration and severity of CKD increase.6.Parfitt A.M. The hyperparathyroidism of chronic renal failure: a disorder of growth.Kidney Int. 1997; 52: 3-9Abstract Full Text PDF PubMed Google Scholar,7.Martinez I. Saracho R. Montenegro J. Llach F. 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Dillon M.A. et al.Hyperparathyroidism and dialysis vintage.Clin Nephrol. 2000; 54: 295-300PubMed Google Scholar It may progress ultimately to an advanced stage that is refractory to medical treatment requiring surgical management by parathyroidectomy. Several abnormalities in parathyroid gland function contribute to the persistent elevations in serum or plasma PTH levels that characterize patients with SHPT. These include increases in PTH secretion by individual parathyroid cells, increases in PTH production per cell owing to enhanced gene expression and cellular enlargement or hypertrophy, and increases in the total number of parathyroid cells because of tissue hyperplasia.6.Parfitt A.M. The hyperparathyroidism of chronic renal failure: a disorder of growth.Kidney Int. 1997; 52: 3-9Abstract Full Text PDF PubMed Google Scholar,13.Brown E.M. Wilson R.E. 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Namii Y. et al.Clonal analysis of nodular parathyroid hyperplasia in renal hyperparathyroidism.World J Surg. 1996; 20: 744-750Crossref PubMed Scopus (137) Google Scholar,18.Tominaga Y. Takagi H. Molecular genetics of hyperparathyroid disease.Curr Opin Nephrol Hypertens. 1996; 5: 336-341Crossref PubMed Scopus (52) Google Scholar,19.Chen R.A. Goodman W.G. The role of the calcium-sensing receptor in parathyroid gland physiology.Am J Physiol Renal Physiol. 2004; 286: F1005-F1011Crossref PubMed Scopus (80) Google Scholar Abnormally high plasma PTH levels have important adverse consequences on bone metabolism. Reductions in bone mass, which affect cortical bone primarily, are a characteristic feature of SHPT.20.Rix M. Andreassen H. Eskildsen P. et al.Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure.Kidney Int. 1999; 56: 1084-1093Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar,21.Rix M. Eskildsen P. 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Eskildsen P. et al.Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure.Kidney Int. 1999; 56: 1084-1093Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar,24.Alem A.M. Sherrard D.J. Gillen D.L. et al.Increased risk of hip fracture among patients with end-stage renal disease.Kidney Int. 2000; 58: 396-399Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar SHPT can also aggravate hyperphosphatemia, a frequent and serious biochemical abnormality among patients managed with conventional dialysis regimens.25.Goodman W.G. Frazao J.M. Goodkin D.A. et al.A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism.Kidney Int. 2000; 58: 436-445Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar,26.Lindberg J.S. Moe S.M. Goodman W.G. et al.The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus product levels in hemodialysis patients with secondary hyperparathyroidism.Kidney Int. 2003; 63: 248-254Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar The clinical management of SHPT is problematic because current therapies do not fully correct the abnormalities leading to its development and progression. Several reports have documented that the need for surgical intervention to definitively control SHPT increases as a function of the number of years of treatment with dialysis.10.Malberti F. Marcelli D. Conte F. et al.Parathyroidectomy in patients on renal replacement therapy: an epidemiologic study.J Am Soc Nephrol. 2001; 12: 1242-1248PubMed Google Scholar Indeed, despite a modest decline during the mid-1990s, the annual rate of parathyroidectomy in 2002 among patients undergoing dialysis in the United States was no different than that observed in 1992.27.Foley R.N. Li S. Liu J. et al.The fall and rise of parathyroidectomy in U.S. hemodialysis patients, 1992 to 2002.J Am Soc Nephrol. 2005; 16: 210-218Crossref PubMed Scopus (71) Google Scholar Such findings suggest that conventional approaches to the medical management of SHPT in patients with CKD, which often include the use of large intravenous doses of vitamin D sterols, do not effectively target one or more key factors that account for disease progression. In this regard, factors that regulate the cell cycle in general and the growth and proliferation of parathyroid cells in particular may prove ultimately to be extremely important determinants of parathyroid gland hyperplasia, an integral component of SHPT among patients with CKD that contributes substantially to disease severity.28.Goodman W.G. Calcimimetics: a remedy for all problems of excess parathyroid hormone activity in chronic kidney disease?.Curr Opin Nephrol Hypertens. 2005; 14: 355-360Crossref PubMed Google Scholar Information about the physiology of the parathyroid glands and the pathophysiology of parathyroid gland function in various clinical disorders has increased markedly in recent years. The calcium-sensing receptor (CaSR) and the vitamin D receptor (VDR) together with recently identified phosphate-regulating hormones represent the major determinants of parathyroid gland function in CKD. The CaSR, which was discovered by Brown, Hebert, and co-workers in 1993, plays a dominant role through G-protein-coupled signal transduction pathways that modulate PTH secretion directly.29.Brown E.M. Gamba G. Riccardi D. et al.Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid.Nature. 1993; 366: 575-580Crossref PubMed Google Scholar,30.Brown E.M. MacLeod R.J. Extracellular calcium sensing and extracellular calcium signaling.Physiol Rev. 2001; 81: 239-297Crossref PubMed Google Scholar Signaling via the CaSR also affects other components of parathyroid gland function that are relevant to understanding the pathogenesis and progression of SHPT among those with CKD. These include effects on pre-pro-PTH gene transcription, PTH mRNA expression, and parathyroid gland hyperplasia (Figure 1).19.Chen R.A. Goodman W.G. The role of the calcium-sensing receptor in parathyroid gland physiology.Am J Physiol Renal Physiol. 2004; 286: F1005-F1011Crossref PubMed Scopus (80) Google Scholar,30.Brown E.M. MacLeod R.J. Extracellular calcium sensing and extracellular calcium signaling.Physiol Rev. 2001; 81: 239-297Crossref PubMed Google Scholar Vitamin D analogues, acting through vitamin D nuclear receptors, regulate PTH mRNA expression, but they do not influence PTH secretion directly.31.Okazaki T. Igarashi T. Kronenberg H.M. 5'-flanking region of the parathyroid hormone gene mediates negative regulation by 1,25-(OH)2 vitamin D3.J Biol Chem. 1988; 263: 2203-2208Abstract Full Text PDF PubMed Google Scholar,32.Demay M.B. Kiernan M.S. DeLuca H.F. Kronenberg H.M. Sequences in the human parathyroid hormone gene that bind the 1, 25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-dihydroxyvitamin D3.Proc Natl Acad Sci U S A. 1992; 89: 8097-8101Crossref PubMed Google Scholar Hyperphosphatemia contributes to the development and severity of hyperparathyroidism in CKD, but the factors that mediate these effects, either directly or indirectly in parathyroid tissue, remain to be determined.33.Denda M. Finch J. Slatopolsky E. Phosphorus accelerates the development of parathyroid hyperplasia and secondary hyperparathyroidism in rats with renal failure.Am J Kidney Dis. 1996; 28: 596-602Abstract Full Text PDF PubMed Google Scholar The respective roles of calcium and vitamin D as discrete modifiers of parathyroid gland function have been clarified further by studies of genetically modified mice. Apart from being a major component of bone, calcium ions serve crucial and diverse physiological functions. They act both as first and second messengers in signal transduction in a variety of cells, mediate synaptic function in neural tissue and contractility in myocardial cells, and traverse cell membranes through ion-specific channels.30.Brown E.M. MacLeod R.J. Extracellular calcium sensing and extracellular calcium signaling.Physiol Rev. 2001; 81: 239-297Crossref PubMed Google Scholar Because alterations in the concentration of ionized calcium in extracellular fluid can adversely affect many physiological processes, the level of ionized calcium in blood is maintained normally within a very narrow range. PTH is the principal calcium-regulating hormone in man. Parathyroid tissue evolved originally to allow animals to adapt to life in the relatively calcium-deficient surroundings of terrestrial compared with marine aquatic environments. The parathyroid glands secrete PTH in a pulsatile manner that is regulated by a calcium-sensing G-protein-coupled receptor, or the CaSR, located on the surface of parathyroid cells.34.Kitamura N. Shigeno C. Shiomi K. et al.Episodic fluctuation in serum intact parathyroid hormone concentration in men.J Clin Endocrinol Metab. 1990; 70: 252-263Crossref PubMed Google Scholar,35.Schmitt C.P. Schaefer F. Huber D. et al.1,25(OH)2-vitamin D3 reduces spontaneous and hypocalcemic-stimulated pulsatile component of parathyroid hormone secretion.J Am Soc Nephrol. 1998; 9: 54-62PubMed Google Scholar,36.Schmitt C.P. Huber D. Mehls O. et al.Altered instantaneous and calcium-modulated oscillatory PTH secretion patterns in patients with secondary hyperparathyroidism.J Am Soc Nephrol. 1998; 9: 1832-1844PubMed Google Scholar The actions of PTH to regulate serum calcium concentrations are mediated both directly and indirectly. Minute-to-minute changes in PTH release into the circulation affect serum calcium levels directly by modifying calcium transport in the distal nephron and by affecting the exchange of calcium between plasma and a rapidly exchangeable pool in bone (Figure 2).34.Kitamura N. Shigeno C. Shiomi K. et al.Episodic fluctuation in serum intact parathyroid hormone concentration in men.J Clin Endocrinol Metab. 1990; 70: 252-263Crossref PubMed Google Scholar,35.Schmitt C.P. Schaefer F. Huber D. et al.1,25(OH)2-vitamin D3 reduces spontaneous and hypocalcemic-stimulated pulsatile component of parathyroid hormone secretion.J Am Soc Nephrol. 1998; 9: 54-62PubMed Google Scholar,37.Goodman W.G. Mitch W.E. Klahr S. Calcium, Phosphorus and Vitamin D. 5th edn. Lippincott Williams & Wilkins, Philadelphia2005: 47-70Google Scholar,38.Goodman W.G. Calcium and phosphorus metabolism in patients who have chronic kidney disease.Med Clin North Am. 2005; 89: 631-647Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The actions of PTH on calcium transport in the distal nephron and on the miscible calcium pool in bone occur within minutes to hours.39.Parfitt A.M. The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease. I. Mechanisms of calcium transfer between blood and bone and their cellular basis: morphologic and kinetic approaches to bone turnover.Metabolism. 1976; 25: 809-844Abstract Full Text PDF PubMed Scopus (83) Google Scholar,40.Parfitt A.M. The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease. II. PTH and bone cells: bone turnover and plasma calcium regulation.Metabolism. 1976; 25: 909-955Abstract Full Text PDF PubMed Google Scholar Moreover, the very steep slope of the inverse sigmoidal curve that describes the relationship between blood-ionized calcium and plasma PTH levels assures that small variations in ionized calcium concentration elicit large reciprocal changes in PTH secretion to modulate these fluxes appropriately.41.Mayer G.P. Habener J.F. Potts Jr, J.T. Parathyroid hormone secretion in vivo. Demonstration of a calcium-independent nonsuppressible component of secretion.J Clin Invest. 1976; 57: 678-683Crossref PubMed Google Scholar Ongoing short-term variations in PTH secretion that are mediated by the CaSR thus provide a robust mechanism for maintaining a constant level of ionized calcium in blood by regulating continuously the amounts of calcium that enter or leave the plasma compartment via the kidney and bone (Figure 3).37.Goodman W.G. Mitch W.E. Klahr S. Calcium, Phosphorus and Vitamin D. 5th edn. Lippincott Williams & Wilkins, Philadelphia2005: 47-70Google Scholar,38.Goodman W.G. Calcium and phosphorus metabolism in patients who have chronic kidney disease.Med Clin North Am. 2005; 89: 631-647Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,39.Parfitt A.M. The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease. I. Mechanisms of calcium transfer between blood and bone and their cellular basis: morphologic and kinetic approaches to bone turnover.Metabolism. 1976; 25: 809-844Abstract Full Text PDF PubMed Scopus (83) Google Scholar,40.Parfitt A.M. The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease. II. PTH and bone cells: bone turnover and plasma calcium regulation.Metabolism. 1976; 25: 909-955Abstract Full Text PDF PubMed Google ScholarFigure 3Plasma PTH levels (triangles, dashed line, left y-axis) and blood-ionized calcium concentrations (right y-axis) at 1-min intervals in a volunteer with normal renal and parathyroid gland function. Note that plasma PTH levels fluctuate over time, consistent with pulsatile PTH release that is regulated by the CaSR. In contrast, blood-ionized calcium levels remain constant (Goodman, unpublished observations).View Large Image Figure ViewerDownload (PPT) When short-term variations in calcium-regulated PTH secretion are insufficient to fully maintain blood-ionized calcium concentrations, additional compensatory responses are invoked to restore baseline values. The case of hypocalcemia will be discussed in some detail because it is most relevant to understanding the pathogenesis of SHPT due to CKD. As mentioned previously, only minor changes in blood-ionized calcium concentration increase PTH secretion promptly and markedly.41.Mayer G.P. Habener J.F. Potts Jr, J.T. Parathyroid hormone secretion in vivo. Demonstration of a calcium-independent nonsuppressible component of secretion.J Clin Invest. 1976; 57: 678-683Crossref PubMed Google Scholar,42.Goodman W.G. Veldhuis J.D. 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Gornbein J. et al.Direct in vivo comparison of calcium-regulated parathyroid hormone secretion in normal volunteers and patients with secondary hyperparathyroidism.J Clin Endocrinol Metab. 1993; 76: 1489-1494Crossref PubMed Scopus (91) Google Scholar Indeed, PTH levels increase substantially before a measurable reduction in blood-ionized calcium can be detected, results that demonstrate the exquisite sensitivity of the CaSR in modulating PTH secretion. As blood-ionized calcium levels decline progressively, plasma PTH levels reach maximum values that are approximately four- to fivefold higher than baseline after 20–30 min (Figure 4).43.Ramirez J.A. Goodman W.G. Gornbein J. et al.Direct in vivo comparison of calcium-regulated parathyroid hormone secretion in normal volunteers and patients with secondary hyperparathyroidism.J Clin Endocrinol Metab. 1993; 76: 1489-1494Crossref PubMed Scopus (91) Google Scholar They do not rise further, however, when sustained reductions in blood-ionized calcium are induced experimentally by continued infusions of sodium citrate that are sufficient to overcome the immediate corrective responses mediated by the kidney and bone as summarized previously. A four- to fivefold increase in the concentration of PTH in plasma thus represents the maximal secretory response of the parathyroids to acute hypocalcemia in human volunteers with normal renal and parathyroid gland function.43.Ramirez J.A. Goodman W.G. Gornbein J. et al.Direct in vivo comparison of calcium-regulated parathyroid hormone secretion in normal volunteers and patients with secondary hyperparathyroidism.J Clin Endocrinol Metab. 1993; 76: 1489-1494Crossref PubMed Scopus (91) Google Scholar,45.Messa P. Vallone C. Mioni G. et al.Direct in vivo assessment of parathyroid hormone-calcium relationship curve in renal patients.Kidney Int. 1994; 46: 1713-1720Abstract Full Text PDF PubMed Google Scholar,46.Cardinal J. Brossard J.H. Roy L. et al.The set point of parathyroid hormone stimulation by calcium is normal in progressive renal failure.J Clin Endocrinol Metab. 1998; 83: 3839-3844Crossref PubMed Google Scholar If very short-term increases in PTH secretion are insufficient to prevent a decline in blood-ionized calcium concentration and restore basal levels of the CaSR activation, additional PTH is made available for secretion by upregulating pre-pro-PTH gene transcription and PTH synthesis. The factors responsible for enhancing PTH gene expression during hypocalcemia have yet to be clarified fully, but both transcriptional and post-transcriptional mechanisms are probably involved. First, a CRE that negatively regulates pre-pro-PTH gene transcription has been identified approximately 3.6 kb upstream from the transcriptional start site (Figure 5).47.Okazaki T. Ando K. Igarashi T. et al.Conserved mechanism of negative gene regulation by extracellular calcium. Parathyroid hormone gene versus atrial natriuretic polypeptide gene.J Clin Invest. 1992; 89: 1268-1273Crossref PubMed Google Scholar,48.Okazaki T. Zajac J.D. Igarashi T. et al.Negative regulatory elements in the human parathyroid hormone gene.J Biol Chem. 1991; 266: 21903-21910Abstract Full Text PDF PubMed Google Scholar To the extent that decreases in blood-ionized calcium concentration lower cytosolic free-calcium levels and/or diminish calcium-mediated signaling in parathyroid cells, a reduction in calcium-response element-dependent inhibition of pre-pro-PTH gene transcription would be expected to enhance PTH mRNA abundance as reported previously.14.Russell J. Silver J. Sherwood L.M. The effects of calcium and vitamin D metabolites on cytoplasmic mRNA coding for pre-proparathyroid hormone in isolated parathyroid cells.Trans Assoc Am Physicians. 1984; 97: 296-303PubMed Google Scholar,49.Sherwood L.M. Mayer G.P. Ramberg Jr, C.F. et al.Regulation of parathyroid hormone secretion: proportional control by calcium, lack of effect of phosphate.Endocrinology. 1968; 83: 1043-1051Crossref PubMed Google Scholar Other mechanisms such as changes in the frequency and/or the amplitude of oscillations in cytosolic free-calcium concentrations may also contribute.19.Chen R.A. Goodman W.G. The role of the calcium-sensing receptor in parathyroid gland physiology.Am J Physiol Renal Physiol. 2004; 286: F1005-F1011Crossref PubMed Scopus (80) Google Scholar Because transcriptional mechanisms are involved, the time course of these adaptive responses in parathyroid tissue is substantially greater than that described previously for calcium-regulated PTH secretion. Many hours are required for them to affect calcium metabolism systemically. Second, hypocalcemia has been reported to stabilize the mRNA for PTH and prolong its half-life.50.Naveh-Many T. Silver J. Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia and vitamin D in the rat.J Clin Invest. 1990; 86: 1313-1319Crossref PubMed Google Scholar,51.Moallem E. Kilav R. Silver J. Naveh-Many T. RNA-protein binding and post-transcriptional regulation of parathyroid hormone gene expression by calcium and phosphate.J Biol Chem. 1998; 273: 5253-5259Crossref PubMed Scopus (203) Google Scholar The effect appears to be mediated by cytosolic proteins that bind to PTH mRNA and interfere with its degradation by endopeptidases within parathyroid cells. Increases in PTH mRNA stability thus promote message translation at the ribosomal level, increase the amount of PTH produced by each parathyroid cell, and provide more of the hormone that can be stored in secretory granules for subsequent release into the circulation by calcium-regulated secre
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