Influence of parathyroid mass on the regulation of PTH secretion
2006; Elsevier BV; Volume: 70; Linguagem: Inglês
10.1038/sj.ki.5001597
ISSN1523-1755
Autores Tópico(s)Magnesium in Health and Disease
ResumoIn advanced uremia, parathyroid hormone (PTH) levels should be controlled at a moderately elevated level in order to promote normal bone turnover. As such, a certain degree of parathyroid gland (PG) hyperplasia has to be accepted. No convincing evidence of apoptosis or of involution of PG hyperplasia exists. However, even considerable parathyroid hyperplasia can be controlled when the functional demand for increased PTH levels is abolished. When 20 isogenic PG were implanted into one parathyroidectomized (PTX) rat normalization of Ca2+ and PTH levels and normal suppressibility of PTH secretion by high Ca2+ was obtained. Similarly, normal levels of Ca2+ and PTH and suppressibility of PTH secretion were obtained when Eight isogenic PG from uremic rats were implanted into normal rats or when long-term uremia and severe secondary hyperparathyroidism (sec. HPT) was reversed by an isogenic kidney transplantation. Normalization of PTH levels after experimental kidney transplantation took place despite a persistent decrease of vitamin D receptor (VDR) mRNA and calcium sensing receptor (CaR) mRNA in PG. Thus, in experimental models PTH levels are determined by the functional demand and not by parathyroid mass, per se. When non-suppressible sec. HPT is present in patients referred to PTX, nodular hyperplasia with differences in gene expression between different nodules has been observed in most cases. An altered expression of some autocrine/paracrine factors has been demonstrated in the nodules. Enhanced expression of PTH-related peptide (PTHrP) has been demonstrated in PG from patients with severe secondary HPT. PTHrP has been shown to stimulate PTH secretion in vivo and in vitro. PTH/PTHrP receptor was demonstrated in the parathyroids. The low Ca2+ stimulated PTH secretion was enhanced by 300% by PTHrP 1–40. The altered quality of the parathyroid mass and not only the increased parathyroid mass, per se, might be responsible for non-controllable hyperparathyroidism in uremia and after kidney transplantation. In advanced uremia, parathyroid hormone (PTH) levels should be controlled at a moderately elevated level in order to promote normal bone turnover. As such, a certain degree of parathyroid gland (PG) hyperplasia has to be accepted. No convincing evidence of apoptosis or of involution of PG hyperplasia exists. However, even considerable parathyroid hyperplasia can be controlled when the functional demand for increased PTH levels is abolished. When 20 isogenic PG were implanted into one parathyroidectomized (PTX) rat normalization of Ca2+ and PTH levels and normal suppressibility of PTH secretion by high Ca2+ was obtained. Similarly, normal levels of Ca2+ and PTH and suppressibility of PTH secretion were obtained when Eight isogenic PG from uremic rats were implanted into normal rats or when long-term uremia and severe secondary hyperparathyroidism (sec. HPT) was reversed by an isogenic kidney transplantation. Normalization of PTH levels after experimental kidney transplantation took place despite a persistent decrease of vitamin D receptor (VDR) mRNA and calcium sensing receptor (CaR) mRNA in PG. Thus, in experimental models PTH levels are determined by the functional demand and not by parathyroid mass, per se. When non-suppressible sec. HPT is present in patients referred to PTX, nodular hyperplasia with differences in gene expression between different nodules has been observed in most cases. An altered expression of some autocrine/paracrine factors has been demonstrated in the nodules. Enhanced expression of PTH-related peptide (PTHrP) has been demonstrated in PG from patients with severe secondary HPT. PTHrP has been shown to stimulate PTH secretion in vivo and in vitro. PTH/PTHrP receptor was demonstrated in the parathyroids. The low Ca2+ stimulated PTH secretion was enhanced by 300% by PTHrP 1–40. The altered quality of the parathyroid mass and not only the increased parathyroid mass, per se, might be responsible for non-controllable hyperparathyroidism in uremia and after kidney transplantation. Parathyroid tissue is a discontinuous replicator tissue, which is characterized by a low cell turnover, a low rate of mitosis, and no separate stem cells.1.Drueke T.B. Cell biology of parathyroid gland hyperplasia in chronic renal failure.J Am Soc Nephrol. 2000; 11: 1141-1152PubMed Google Scholar, 2.Parfitt A.M. The hyperparathyroidism of chronic renal failure: a disorder of growth.Kidney Int. 1997; 52: 3-9Abstract Full Text PDF PubMed Scopus (180) Google Scholar As estimated by Parfitt the mean life span of normal parathyroid cells is 20 years in humans and 2 years in rats.2.Parfitt A.M. The hyperparathyroidism of chronic renal failure: a disorder of growth.Kidney Int. 1997; 52: 3-9Abstract Full Text PDF PubMed Scopus (180) Google Scholar, 3.Wang Q. Palnitkar S. Parfitt A.M. Parathyroid cell proliferation in the rat: effect of age and of phosphate administration and recovery.Endocrinology. 1996; 137: 4558-4562Crossref PubMed Scopus (64) Google Scholar Mitosis can be stimulated by functional demand.4.Tominaga Y. Takagi H. Molecular genetics of hyperparathyroid disease.Curr Opin Nephrol Hypertens. 1996; 5: 336-341Crossref PubMed Scopus (66) Google Scholar In human subjects parathyroid growth progresses in response to chronic renal failure through several stages from diffuse hyperplasia to nodular hyperplasia and to formation of adenomas. Hyperplasia is initiated by hypocalcemia and phosphorus (P) retention and becomes more severe as the result of calcitriol deficiency.5.Rodriguez M. Canalejo A. Garfia B. et al.Pathogenesis of refractory secondary hyperparathyroidism.Kidney Int. 2002; 61: 155-160Abstract Full Text Full Text PDF Scopus (61) Google Scholar Similarity exists in the gene expression between the cells in each nodule, while differences in gene expressions may be found between nodules.6.Valimaki S. Farnebo F. Forsberg L. et al.Heterogeneous expression of receptor mRNAs in parathyroid glands of secondary hyperparathyroidism.Kidney Int. 2001; 60: 1666-1675Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 7.Matsushita H. Hara M. Endo Y. et al.Proliferation of parathyroid cells negatively correlates with expression of parathyroid hormone-related protein in secondary parathyroid hyperplasia.Kidney Int. 1999; 55: 130-138Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Monoclonal growth of the parathyroid cells has been found in a majority of the uremic patients with refractory hyperparathyroidism.8.Arnold A. Brown M.F. Urena P. et al.Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia.J Clin Invest. 1995; 95: 2047-2053Crossref PubMed Scopus (374) Google Scholar The genes responsible for monoclonality have not been identified. Apparently, somatic mutations confer a growth advantage to clones of parathyroid cells, that are causing monoclonal growth and nodular parathyroid hyperplasia, although these two phenomena are not strictly linked. It seems that at the initial stages, development of parathyroid hyperplasia is a regulatory phenomenon, but that during the progression it escapes from normal growth control. The main factors responsible for parathyroid hyperplasia appear to be the same as those responsible for the enhanced parathyroid hormone (PTH) biosynthesis and secretion. The precise molecular mechanisms involved in parathyroid hyperplasia are sparsely clarified. The potential role of transforming growth factor-α, known to promote cell growth, in the parathyroid hyperplasia has been addressed.9.Dusso A.S. Pavlopoulos T. Naumovich L. et al.p21(WAF1) and transforming growth factor-alpha mediate dietary phosphate regulation of parathyroid cell growth.Kidney Int. 2001; 59: 855-865Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 10.Cozzolino M. Lu Y. Finch J. et al.p21WAF1 and TGF-alpha mediate parathyroid growth arrest by vitamin D and high calcium.Kidney Int. 2001; 60: 2109-2117Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 11.Cozzolino M. Brancaccio D. Gallieni M. et al.Pathogenesis of parathyroid hyperplasia in renal failure.J Nephrol. 2005; 18: 5-8PubMed Google Scholar, 12.Cozzolino M. Lu Y. Sato T. et al.A Critical role for enhanced-TGF{alpha} and EGFR Expression in the initiation of parathyroid hyperplasia in experimental kidney disease.Am J Physiol Renal Physiol. 2005; 289: F1096-F1102Crossref PubMed Scopus (69) Google Scholar Enhanced expression of transforming growth factor-α and its receptor, the epidermal growth factor receptor, occurs early after the onset of uremia in rats and is aggravated by high P or low calcium diets.12.Cozzolino M. Lu Y. Sato T. et al.A Critical role for enhanced-TGF{alpha} and EGFR Expression in the initiation of parathyroid hyperplasia in experimental kidney disease.Am J Physiol Renal Physiol. 2005; 289: F1096-F1102Crossref PubMed Scopus (69) Google Scholar Furthermore, there is enhanced transforming growth factor-α expression in human hyperplastic parathyroid tissue.13.Gogusev J. Duchambon P. Stoermann-Chopard C. et al.De novo expression of transforming growth factor-alpha in parathyroid gland tissue of patients with primary or secondary uraemic hyperparathyroidism.Nephrol Dial Transplant. 1996; 11: 2155-2162Crossref PubMed Scopus (68) Google Scholar Conversely, high dietary calcium, P restriction, and vitamin D therapy of uremic rats prevent the increase in transforming growth factor-α and induce expression of the cyclin-dependent kinase inhibitor, p21.9.Dusso A.S. Pavlopoulos T. Naumovich L. et al.p21(WAF1) and transforming growth factor-alpha mediate dietary phosphate regulation of parathyroid cell growth.Kidney Int. 2001; 59: 855-865Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 10.Cozzolino M. Lu Y. Finch J. et al.p21WAF1 and TGF-alpha mediate parathyroid growth arrest by vitamin D and high calcium.Kidney Int. 2001; 60: 2109-2117Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar Finally, female gender may favor parathyroid cell proliferation.14.Almaden Y. Felsenfeld A.J. Rodriguez M. et al.Proliferation in hyperplastic human and normal rat parathyroid glands: role of phosphate, calcitriol, and gender.Kidney Int. 2003; 64: 2311-2317Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar An important question is whether regression of parathyroid hyperplasia can be induced. Can the increased glandular mass seen in uremia be reduced? Such a reduction would call for massive apoptosis to take place in the parathyroids. This question has not yet been resolved. Examination for apoptosis in the parathyroids is not an easy task.1.Drueke T.B. Cell biology of parathyroid gland hyperplasia in chronic renal failure.J Am Soc Nephrol. 2000; 11: 1141-1152PubMed Google Scholar The parathyroids have an extremely low cell turnover, and, probably, a poorly developed program for cell deletion. The number of apoptotic cells in normal human parathyroids is very low, 1/10,000 parathyroid cells.15.Zhang P. Duchambon P. Gogusev J. et al.Apoptosis in parathyroid hyperplasia of patients with primary or secondary uremic hyperparathyroidism.Kidney Int. 2000; 57: 437-445Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar In rat models, several research groups have been unable to find evidence for programmed parathyroid cell death in normal or in hyperplastic parathyroid tissue.3.Wang Q. Palnitkar S. Parfitt A.M. Parathyroid cell proliferation in the rat: effect of age and of phosphate administration and recovery.Endocrinology. 1996; 137: 4558-4562Crossref PubMed Scopus (64) Google Scholar, 16.Naveh-Many T. Rahamimov R. Livni N. Silver J. Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D.J Clin Invest. 1995; 96: 1786-1793Crossref PubMed Scopus (364) Google Scholar, 17.Wada M. Furuya Y. Sakiyama Ji et al.The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor.J Clin Invest. 1997; 100: 2977-2983Crossref PubMed Scopus (237) Google Scholar Experimental studies documented that parathyroid hyperplasia is easily prevented, but poorly reversible.18.Szabo A. Merke J. Beier E. et al.1,25(OH)2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia.Kidney Int. 1989; 35: 1049-1056Abstract Full Text PDF PubMed Scopus (242) Google Scholar, 19.Yi H. Fukagawa M. Yamato H. et al.Prevention of enhanced parathyroid hormone secretion, synthesis and hyperplasia by mild dietary phosphorus restriction in early chronic renal failure in rats: possible direct role of phosphorus.Nephron. 1995; 70: 242-248Crossref PubMed Scopus (72) Google Scholar, 20.Colloton M. Shatzen E. Miller G. et al.Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism.Kidney Int. 2005; 67: 467-476Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar If reversal by apoptosis takes place at all, it is probably an extremely slow process.3.Wang Q. Palnitkar S. Parfitt A.M. Parathyroid cell proliferation in the rat: effect of age and of phosphate administration and recovery.Endocrinology. 1996; 137: 4558-4562Crossref PubMed Scopus (64) Google Scholar There are no known stimuli for apoptosis in the parathyroid cell,1.Drueke T.B. Cell biology of parathyroid gland hyperplasia in chronic renal failure.J Am Soc Nephrol. 2000; 11: 1141-1152PubMed Google Scholar although an effect of vitamin D is a possibility has not been completely excluded as such a stimulus.21.Henry H.L. Taylor A.N. Norman A.W. Response of chick parathyroid glands to the vitamin D metabolites, 1,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol.J Nutr. 1977; 107: 1918-1926PubMed Google Scholar, 22.Fukagawa M. Okazaki R. Takano K. et al.Regression of parathyroid hyperplasia by calcitriol-pulse therapy in patients on long-term dialysis.N Engl J Med. 1990; 323: 421-422Crossref PubMed Scopus (135) Google Scholar, 23.Fukagawa M. Kitaoka M. Yi H. et al.Serial evaluation of parathyroid size by ultrasonography is another useful marker for the long-term prognosis of calcitriol pulse therapy in chronic dialysis patients.Nephron. 1994; 68: 221-228Crossref PubMed Scopus (155) Google Scholar In human studies, in general as well as in daily clinical practice evaluating parathyroid growth and glandular hyperplasia is not possible nor is it possible to obtain a biopsy of the parathyroid glands. Histological, immunohistochemical and molecular examination of parathyroid tissues from uremic patients is only available in the relatively rare situations, in which parathyroidectomy is performed. These are usually cases where hyperparathyroidism, resistant to treatment, is present in patients after years on dialysis treatment. Attempts to estimate the glandular size and nodularity, using ultrasonography, scintigraphy, and positron emission tomography scans, are also usually limited to this minority of the uremic population, in which severly increased glandular mass is present. Thus, the different stages in the development of parathyroid growth from normal glands to severe hyperplasia are not available for direct studies. We, therefore, depend upon knowledge obtained from experimental studies. In experimental models of uremia parathyroid glands are easily available and manipulation of the different factors of relevance for parathyroid growth is possible, either by dietary or pharmacological means. However, the degree of experimental uremia is usually relatively mild since more severe uremia is relatively short lasting as the rats will not survive. Nodular parathyroid hyperplasia has never been induced in animal uremic models. As such, parathyroid glands in experimental uremic animals represent diffuse chief cell hyperplasia with the exception of in a single study, where a heterogenous pattern of proliferation and expression of CaR was observed in female uremic rats kept on a high P diet.24.Brown A.J. Ritter C.S. Finch J.L. Slatopolsky E.A. Decreased calcium-sensing receptor expression in hyperplastic parathyroid glands of uremic rats: role of dietary phosphate.Kidney Int. 1999; 55: 1284-1292Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar This means that there is a huge gap between our ability to evaluate parathyroid hyperplasia in experimental studies and the human clinical situation. We might assume that the experimental models represent an early phase in the development of parathyroid hyperplasia in uremia, while parathyroid tissue from parathyroidectomized (PTX) patients represents the very late stage of parathyroid hyperplasia. Accepting this assumption, experimental data might provide us with important information. Parathyroid hyperplasia can be prevented by phosphate restriction, early initiation of treatment with active vitamin D analogs, or calcimimetics.11.Cozzolino M. Brancaccio D. Gallieni M. et al.Pathogenesis of parathyroid hyperplasia in renal failure.J Nephrol. 2005; 18: 5-8PubMed Google Scholar, 12.Cozzolino M. Lu Y. Sato T. et al.A Critical role for enhanced-TGF{alpha} and EGFR Expression in the initiation of parathyroid hyperplasia in experimental kidney disease.Am J Physiol Renal Physiol. 2005; 289: F1096-F1102Crossref PubMed Scopus (69) Google Scholar, 18.Szabo A. Merke J. Beier E. et al.1,25(OH)2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia.Kidney Int. 1989; 35: 1049-1056Abstract Full Text PDF PubMed Scopus (242) Google Scholar, 20.Colloton M. Shatzen E. Miller G. et al.Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism.Kidney Int. 2005; 67: 467-476Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 25.Wada M. Nagano N. Furuya Y. et al.Calcimimetic NPS R-568 prevents parathyroid hyperplasia in rats with severe secondary hyperparathyroidism.Kidney Int. 2000; 57: 50-58Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Established parathyroid hyperplasia can be arrested by similar initiatives,11.Cozzolino M. Brancaccio D. Gallieni M. et al.Pathogenesis of parathyroid hyperplasia in renal failure.J Nephrol. 2005; 18: 5-8PubMed Google Scholar, 12.Cozzolino M. Lu Y. Sato T. et al.A Critical role for enhanced-TGF{alpha} and EGFR Expression in the initiation of parathyroid hyperplasia in experimental kidney disease.Am J Physiol Renal Physiol. 2005; 289: F1096-F1102Crossref PubMed Scopus (69) Google Scholar, 18.Szabo A. Merke J. Beier E. et al.1,25(OH)2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia.Kidney Int. 1989; 35: 1049-1056Abstract Full Text PDF PubMed Scopus (242) Google Scholar, 20.Colloton M. Shatzen E. Miller G. et al.Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism.Kidney Int. 2005; 67: 467-476Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 25.Wada M. Nagano N. Furuya Y. et al.Calcimimetic NPS R-568 prevents parathyroid hyperplasia in rats with severe secondary hyperparathyroidism.Kidney Int. 2000; 57: 50-58Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar and it can also be controlled by reversal of uremia.26.Lewin E. Garfia B. Recio F.L. et al.Persistent downregulation of calcium-sensing receptor mRNA in rat parathyroids when severe secondary hyperparathyroidism is reversed by an isogenic kidney transplantation.J Am Soc Nephrol. 2002; 13: 2110-2116Crossref PubMed Scopus (54) Google Scholar, 27.Lewin E. Wang W. Olgaard K. Reversibility of experimental secondary hyperparathyroidism.Kidney Int. 1997; 52: 1232-1241Abstract Full Text PDF PubMed Scopus (49) Google Scholar Clinical experience has largely confirmed this assumption. Today, secondary hyperparathyroidism (sec. HPT) can be controlled in patients with long-term uremia in whom considerable parathyroid hyperplasia is to be expected. Several clinical studies have documented that PTH levels can be suppressed in most uremic patients and this suppression can be maintained by continuous treatment with phosphate binders, vitamin D analogs or calcimimetics.28.Chertow G.M. Dillon M. Burke S.K. et al.A randomized trial of sevelamer hydrochloride (RenaGel) with and without supplemental calcium. Strategies for the control of hyperphosphatemia and hyperparathyroidism in hemodialysis patients.Clin Nephrol. 1999; 51: 18-26PubMed Google Scholar, 29.Slatopolsky E.A. Burke S.K. Dillon M.A. RenaGel, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. The RenaGel Study Group.Kidney Int. 1999; 55: 299-307Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar, 30.Brandi L. Daugaard H. Tvedegaard E. et al.Effect of intravenous 1-alpha-hydroxyvitamin D3 on secondary hyperparathyroidism in chronic uremic patients on maintenance hemodialysis.Nephron. 1989; 53: 194-200Crossref PubMed Google Scholar, 31.Martin K.J. Gonzalez E.A. Gellens M. et al.19-Nor-1-alpha-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis.J Am Soc Nephrol. 1998; 9: 1427-1432PubMed Google Scholar, 32.Akizawa T. Suzuki M. Akiba T. et al.Clinical effects of maxacalcitol on secondary hyperparathyroidism of uremic patients.Am J Kidney Dis. 2001; 38: S147-S151Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 33.Akiba T. Marumo F. Owada A. et al.Controlled trial of falecalcitriol versus alfacalcidol in suppression of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism.Am J Kidney Dis. 1998; 32: 238-246Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 34.Hamdy N.A. Kanis J.A. Beneton M.N. et al.Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure.BMJ. 1995; 310: 358-363Crossref PubMed Scopus (302) Google Scholar, 35.Rapoport J. Mostoslavski M. 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Martin K.J. de Francisco A.L. et al.Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.N Engl J Med. 2004; 350: 1516-1525Crossref PubMed Scopus (948) Google Scholar PTH levels return, however, to pre-treatment values when the treatment is stopped.28.Chertow G.M. Dillon M. Burke S.K. et al.A randomized trial of sevelamer hydrochloride (RenaGel) with and without supplemental calcium. Strategies for the control of hyperphosphatemia and hyperparathyroidism in hemodialysis patients.Clin Nephrol. 1999; 51: 18-26PubMed Google Scholar, 29.Slatopolsky E.A. Burke S.K. Dillon M.A. RenaGel, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. The RenaGel Study Group.Kidney Int. 1999; 55: 299-307Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar, 33.Akiba T. Marumo F. Owada A. et al.Controlled trial of falecalcitriol versus alfacalcidol in suppression of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism.Am J Kidney Dis. 1998; 32: 238-246Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar This rebound of PTH levels suggest that even with good control of parathyroid function under maintainance treatment, no involution of hyperplastic glands takes place. Nevertheless, even severe HPT can be controlled in patients that previously needed PTX.38.Block G.A. Martin K.J. de Francisco A.L. et al.Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.N Engl J Med. 2004; 350: 1516-1525Crossref PubMed Scopus (948) Google Scholar However, some patients remain unresponsive to treatment.23.Fukagawa M. Kitaoka M. Yi H. et al.Serial evaluation of parathyroid size by ultrasonography is another useful marker for the long-term prognosis of calcitriol pulse therapy in chronic dialysis patients.Nephron. 1994; 68: 221-228Crossref PubMed Scopus (155) Google Scholar, 39.Gallieni M. Brancaccio D. Padovese P. et al.Low-dose intravenous calcitriol treatment of secondary hyperparathyroidism in hemodialysis patients. Italian Group for the Study of Intravenous Calcitriol.Kidney Int. 1992; 42: 1191-1198Abstract Full Text PDF PubMed Scopus (96) Google Scholar, 40.Schindler S. Mannstadt M. Urena P. et al.PTH secretion in patients with chronic renal failure assessed by a modified CiCa clamp method: effects of 1-year calcitriol therapy.Clin Nephrol. 2004; 61: 253-260Crossref PubMed Scopus (6) Google Scholar The long-term response to calcitriol has been reported to depend upon the size of the largest parathyroid gland.23.Fukagawa M. Kitaoka M. Yi H. et al.Serial evaluation of parathyroid size by ultrasonography is another useful marker for the long-term prognosis of calcitriol pulse therapy in chronic dialysis patients.Nephron. 1994; 68: 221-228Crossref PubMed Scopus (155) Google Scholar This, however, does not prove that the amount of parathyroid mass by itself is decisive for the response to treatment. The quality of the increased mass might still be of significant importance for whether it is controllable by calcitriol treatment or not. Following kidney transplantation, plasma PTH will fall in most patients with sec. HPT despite previous long-term uremia. Part of this fall might be due to clearance of C-terminal PTH fragments as a result of the improvement in glomerular filtration rate (GFR), as most assays which have been used until recently co-measure some long C-terminal PTH fragments.41.Brossard J.H. Cloutier M. Roy L. et al.Accumulation of a non-(1–84) molecular form of parathyroid hormone (PTH) detected by intact PTH assay in renal failure: importance in the interpretation of PTH values.J Clin Endocrinol Metab. 1996; 81: 3923-3929Crossref PubMed Scopus (281) Google Scholar, 42.Nguyen-Yamamoto L. Rousseau L. Brossard J.H. et al.Origin of parathyroid hormone (PTH) fragments detected by intact-PTH assays.Eur.J Endocrinol. 2002; 147: 123-131Crossref PubMed Scopus (62) Google Scholar, 43.Lepage R. Roy L. Brossard J.H. et al.A non-(1–84) circulating parathyroid hormone (PTH) fragment interferes significantly with intact PTH commercial assay measurements in uremic samples.Clin Chem. 1998; 44: 805-809PubMed Google Scholar In most cases plasma PTH returns to near normal over time, although not all studies are confirmative.44.Dumoulin G. Hory B. Nguyen N.U. et al.No trend toward a spontaneous improvement of hyperparathyroidism and high bone turnover in normocalcemic long-term renal transplant recipients.Am J Kidney Dis. 1997; 29: 746-753Abstract Full Text PDF PubMed Scopus (79) Google Scholar The normalization of GFR seems, however, to be decisive for the normalization of the PTH levels.45.Reinhardt W. Bartelworth H. Jockenhovel F. et al.Sequential changes of biochemical bone parameters after kidney transplantation.Nephrol Dial Transplant. 1998; 13: 434-440Crossref Google Scholar, 46.Botha J.F. Botha J.R. Parathyroid function after successful renal transplantation.S Afr J Surg. 1997; 35: 113-116PubMed Google Scholar, 47.Claesson K. Hellman P. Frodin L. Rastad J. Prospective study of calcium homeostasis after renal transplantation.World J Surg. 1998; 22: 635-641Crossref PubMed Scopus (19) Google Scholar, 48.Uchida K. Tominaga Y. Tanaka Y. Takagi H. 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