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Renal Osteodystrophy with Special Emphasis on Secondary Hyperparathyroidism

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Renal Osteodystrophy with Special Emphasis on Secondary Hyperparathyroidism ArtigoRENAL OSTEODYSTROPHY Original WITH SPECIAL EMPHASIS ON SECONDARY HYPERPARATHYROIDISM Rev Port Nefrol Hipert 2005; 19 (Suppl 1): 9-18 Renal osteodystrophy with special emphasis on secondary hyperparathyroidism Ewa Lewin, Jinxing Huan, Klaus Olgaard Nephrological Department B, the Copenhagen County Hospital in Herlev, and Nephrological Department P, Rigshospitalet, Copenhagen, Denmark. ABSTRACT ventive and/or therapeutic effect on HPT and the accompanying ROD in chronic uraemia include Chronic uraemia is associated with severe phosphate restriction, phosphate binders, low disturbances in the calcium, phosphorus and calcium dialysate, vitamin D analogs and vitamin D homeostasis, leading to the develop- calcimimetics. ment of secondary hyperparathyroidism (HPT) with increased biosynthesis and secretion of parathyroid hormone (PTH) and hyperplasia of SECONDARY HYPERPARATHYROIDISM IN the parathyroid glands. Renal osteodystrophy URAEMIA (ROD) is a frequent and serious complication in chronic uraemic patients, which in a majority Secondary hyperparathyroidism (sec. HPT) of patients is secondary to the severe distur- develops early in renal insufficiency and may bances in parathyroid homeostasis with high affect the function of several organs1-3. The PTH levels leading to a high turnover bone dis- stimuli for the development of sec. HPT of re- ease, osteitis fibrosa, and with low PTH levels levance to renal failure are hypocalcaemia, leading to a low turnover bone disease, the ady- hyperphosphatemia and low levels of 4-8 namic bone disease. 1,25(OH)2D . Hypocalcaemia increases the Therapeutic strategies with a beneficial pre- PTH gene expression per parathyroid cell, in- Revista Portuguesa de Nefrologia e Hipertensão 9 Ewa Lewin, Jinxing Huan, Klaus Olgaard creases the secretion of mature PTH from the are selectively decreased in uraemia27. Other parathyroid cells, and increases the number of factors that are regulating the secretion of PTH parathyroid cells4,5,9. The effect of low calcium include some of autocrine or paracrine na- on PTH gene expression is posttrans- ture13,29. Such an autocrine/paracrine regulation criptional10,11. The extra cellular Ca2+ depending might be involved in the induction of sec. HPT13. suppression of PTH secretion is mediated via In addition to increased levels of intact PTH, pro- the calcium-sensing receptor (CaR) that is lo- duced by the parathyroid glands, an accumula- cated on the surface of the parathyroid cells12. tion of C-terminal PTH fragments takes place in Expression of the CaR mRNA and protein is di- uraemia. A specific effect of some of these frag- minished in human parathyroid glands of ad- ment has been proposed, possibly via a unique vanced uraemia and in rat parathyroids of 5/6 receptor30, but the biologically significance of nephrectomized rats, indicating an impaired sen- such a receptor remains unknown. The expres- sitivity to extra cellular calcium in uraemia13-16. sion of all these factors may be influenced by In addition to reducing the plasma Ca2+ concen- the chronic uraemia31,32. As such, hyperpa- tration hyperphosphatemia has a calcium inde- rathyroi-dism associated with chronic uraemia pendent direct effect on the regulation of PTH results from a combination of functional and secretion, as demonstrated in in vitro models in structural changes in the parathyroid glands, as rat, bovine and human parathyroid glands8,17-19. shown in Figure 1. The mechanism is posttranscriptional11. The cel- lular target for phosphate is still unknown5. 1,25(OH)2D3 (Calcitriol) is an important regula- HYPERPLASIA OF THE PARATHYROID tor of the PTH gene and may play a specific role GLANDS in the control of the glandular mass20-22. Phar- macological doses of calcitriol decrease PTH Parathyroid tissue is a discontinuous repli- gene expression at the transcriptional level by cator tissue, which is characterized by a low binding the 1,25(OH)2D3 receptor (VDR) to a vi- cell turnover, a low rate of mitosis, and no sepa- tamin D-responsive element on the PTH gene rate stem cells9,33. As estimated by Parfitt the promoter23,24. The levels of calcitriol in mild and mean life span of normal parathyroid cell is 20 moderate uraemia are maintained within the years in humans and 2 years in rats33,34. Mitosis normal range at the expense of elevated PTH can be stimulated by functional demand. In hu- levels. In uraemia low levels of VDR have been man subjects parathyroid growth progresses in demonstrated in the parathyroid cells6,13,25, to- response to chronic renal failure through sev- gether with an impaired affinity of vitamin D to eral stages from diffuse hyperplasia to nodular its receptor, resulting in a reduced activity of hyperplasia and to formation of adenomas. Dif- calcitriol26. Furthermore, uraemia per se en- fuse hyperplasia is initiated by hypocalcaemia hances the stability of PTH mRNA by a and phosphorus retention and becomes more posttranscriptional mechanism that decreases severe as the result of calcitriol deficiency35. The the degradation of RNA, independent of changes next stage is that hyperplasia becomes nodular in circulating levels of calcium and phosphate27. and the glandular enlargement asymmetrical. The factors that are responsible for the degra- The nodules consist of cells that are more dation of PTH in the parathyroid cell are prob- closely packed with large nuclei, an increased ably cytosolic endonucleases11,28. Such factors prevalence of mitosis and depletion of VDR and 10 Revista Portuguesa de Nefrologia e Hipertensão RENAL OSTEODYSTROPHY WITH SPECIAL EMPHASIS ON SECONDARY HYPERPARATHYROIDISM CaR16,36,37. Detailed histochemical and immu- nochemical studies indicate similarity in gene expression between the cells in each nodule, but differences between nodules36,38. Monoclonal growth of the parathyroid cells has been found in a majority of the uraemic patients with refrac- tory hyperparathyroidism39. The genes respon- sible for monoclonality have not been identified. Apparently, somatic mutations confer a growth advantage to clones of parathyroid cells, which causes monoclonal growth and nodular parathy- roid hyperplasia, although these two phenom- ena are not strictly linked. The next stage is Figure 1. A schematic presentation of some of the many factors emergence of an adenoma in one or occasion- involved in the development of secondary hyperparathyroidism ally more than one of the nodules, as an expres- in chronic uraemia. sion of a mutation in one of the cells that are undergoing the most rapid proliferation. In some cases there is a loss of a tumor suppressor gene on chromosome 11, a molecular defect with the athyroid cell proliferation even further. This was potential for disrupting the control of the cell cy- proven indirectly by the observation that admin- 40 cle . The final and least common stage is ma- istration of a calcium-sensing receptor agonist, lignant transformation leading to parathyroid NPS-R568, or calcitriol led to the suppression carcinoma, an event reported in 5 patients on of parathyroid cell proliferation in uraemic 41 long term haemodialysis . It seems that at the rats44,45. initial stages development of parathyroid hyper- The role of phosphorus accumulation in pa- plasia is a regulatory phenomenon, but that dur- rathyroid cell growth is documented in several ing the progression it escapes from normal studies in uraemic rats4,7,42. Conversely, an early growth control. dietary phosphate restriction prevented parathy- The precise role of the disturbances in cal- roid cell proliferation and over secretion of PTH cium, phosphorus and calcitriol levels for the in uraemic rats8,46,47. Furthermore, it has been development of abnormal parathyroid growth in found in uraemic rats that hyperphosphatemia uraemia, as well as the precise role of these induced parathyroid cell hyperplasia, even when factors in the regulation of normal parathyroid changes in plasma calcium and calcitriol were growth have not been well established. Calcium carefully avoided, pointing towards a direct ef- deficiency together with calcitriol deficiency are fect of phosphorus on cell proliferation4. probably the most important stimuli for parathy- Thus, in uraemia severe disturbances exist roid hyperplasia, as it has been shown in vivo in in the many parameters related to calcium 4 uraemic rats by Naveh-Many et al. A concomi- homeostasis, resulting in severe disturbances tant decrease in the expressions of CaR and in the important target organ - the skeleton. VDR as described in the parathyroid glands of uraemic rats13,42 and chronic dialysis pa- tients13,16,43 should theoretically enhance par- Revista Portuguesa de Nefrologia e Hipertensão 11 Ewa Lewin, Jinxing Huan, Klaus Olgaard RENAL OSTEODYSTROPHY tion or might be seen as a special form of bone disease, the adynamic or aplastic bone disease Renal osteodystrophy (ROD) is a disabling 52. Osteomalacia is characterized by an in- skeletal disease in uraemic patients consisting creased amount of unmineralized osteoid bone. of either a high turnover bone disease, a low Mineralization of bone matrix depends upon the turnover bone disease or a mixture of both. The presence of adequate supply of vitamin D in the type of bone lesion is correlated to increased form of its active metabolite, 1,25(OH)2D3, but production or to over suppression of PTH le- also of calcium, and phosphorus and of the pre- vels48-50. sence of a normal pH. The precise role of vita- The high turnover bone disease, osteitis fi- min D in the mineralization process is not clear, brosa (cystica) is related to the severity of the just as the exact mechanism involved in the sec. HPT. PTH in concert with locally produced development of uraemic osteomalacia is not cytokines and factors (some produced by bone clear. In uraemia all factors necessary for the marrow cells and some by osteoblast precur- appropriate mineralization process might be dis- sors), IL-1, TNF and later IL-6, IL-11, GM-CSF, turbed. Today, adequate correction of acidosis M-CSF induce recruitment and differentiation of and sufficient supplementation with calcium, vi- osteoclast precursors resulting in stimulation of tamin D and protein has made overt osteoma- bone reabsorption51.
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