Pathogenese des renalen sekundären Hyperparathyreoidismus

H. Reichel

doi:10.1055/s-0037-1619856

Osteologie, Table of Contents

Osteologie 2008; 17(03): 113-118
DOI: 10.1055/s-0037-1619856

Renale Osteopathie

Schattauer GmbH

Pathogenese des renalen sekundären Hyperparathyreoidismus

Pathogenesis of renal secondary hyperparathyroidism

Authors

H. Reichel

¹Nephrologisches Zentrum, Villingen-Schwenningen

Abstract

Zusammenfassung

Ein renaler sekundärer Hyperparathyreoidismus (sHPT) wird bei der Mehrzahl der Patienten mit chronischer Nierenerkrankung diagnostiziert. Neben ossären Beschwerden ist der ausgeprägte sHPT mit extraossären klinischen Komplikationen wie erhöhter kardiovaskulärer Morbidität und Mortalität assoziiert. Die Pathogenese des renalen sHPT ist komplex und umfasst mehrere Faktoren. Der Mangel des renal synthetisierten aktiven Vitamin-D-Hormons Calcitriol führt zu gesteigerter PTH-Synthese und Förderung der Parathyreoidea-Proliferation (d. h. Vergrößerung des Pools PTH-sezernierender Zellen). Durch direkte Effekte auf die Parathyreoideae und indirekte Effekte ist die Hyperphosphatämie durch Steigerung der PTH-Synthese und Parathyreoidea-Proliferation maßgeblich an der Entwicklung des sHPT beteiligt. Hypokalzämie und verminderte Aktivierung des Kalzium-Sensing-Rezeptors (CaR) resultieren in verminderter Kalziumsensitivität der Parathyreoideae, gesteigerter PTH-Synthese und gesteigerter Parathyreoidea-Proliferation. Eine mit zunehmender Dauer der Urämie progrediente noduläre Parathyreoidea-Hyperplasie begünstigt die Entwicklung eines autonomen HPT. Bei nodulärer Hyperplasie sind der Vitamin-D-Rezeptorbestand und der CaR-Bestand der Parathyreoideazelle vermindert; häufiger bestehen chromosomale Veränderungen, die monoklonales Wachstum induzieren. Weitere Faktoren, die an der Pathogenese des sHPT beteiligt sind, umfassen skelettäre PTH-Resistenz, Mangel an nativem Vitamin D, metabolische Azidose und möglicherweise ein Anstieg von zirkulierendem FGF-23.

Summary

The majority of patients with chronic renal disease will develop renal secondary hyperparathyroidism (sHPT). Pronounced sHPT is associated, besides osseous symptoms, with extraosseous complications, namely increased cardiovascular morbidity and mortality. Pathogenesis of renal sHPT is complex. Reduced renal synthesis of the active vitamin D hormone calcitriol results in increased PTH-synthesis and parathyroid proliferation (i. e. an increase in the pool of PTH-secreting cells). Hyperphosphatemia stimulates PTH-synthesis and parathyroid proliferation through direct effects on the parathyroids and through indirect effects. Hypocalcemia and reduced activation of the parathyroid calcium-sensing receptor (CaR) cause decreased calcium-sensitivity of parathyroid glands, enhanced PTH-synthesis and parathyroid proliferation. Nodular parathyroid hyperplasia which occurs more frequently with increasing duration of uremia favors development of autonomous HPT. Nodular hyperplasia is associated with reduced vitamin D receptor and CaR expression and with chromosomal alterations which favor monoclonal growth. Additional factors which are involved in pathogenesis of sHPT comprise skeletal PTH-resistance, deficiency of native vitamin D, metabolic acidosis and possibly increased circulating FGF-23.

Schlüsselwörter

Renaler sekundärer Hyperparathyreoidismus - Calcitriol - Parathormon - Hyperphosphatämie - Hypokalzämie

Keywords

Renal secondary hyperparathyroidism - calcitriol - parathyroid hormone - hyperphosphatemia - hypocalcemia

Full Text

References

Literatur
1 Almaden Y, Canalejo A, Hernandez A. et al. Direct effect of phosphorus on PTH secretion from whole rat parathyroid glands in vitro. J Bone Miner Res 1996; 11: 970-976.
2 Arnold A, Brown MF, Urena P. et al. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest 1995; 95: 2047-2054.
3 Bayard F, Bec P, Ton HThat, Louvet JP. Plasma 25-hydroxycholecalciferol in chronic renal failure. EuropJ Clin Invest 1973; 03: 447-450.
4 Block GA, Klassen PS, Lazarus JM. et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004; 15: 2208-2218.
5 Bricker NS, Slatopolsky E, Reiss E, Avioli LV. Calcium, phosphorus, and bone in renal disease and transplantation. Arch Int Med 1969; 123: 543-550.
6 Brown EM, Gamba G, Riccardi D. et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 1993; 366: 575-580.
7 Canalejo A, Almaden Y, Torregrosa V. et al.: The in vitro effect of calcitriol on parathyroid cell proliferation and apoptosis. J Am Soc Nephrol. 2000; 11: 1865-1872.
8 Chin J, Miller SC, Wada M. et al. Activation of the calcium receptor by a calcimimetic compound halts the progression of secondary hyperparathyroidism in uremic rats. J Am Soc Nephrol 2000; 11: 903-911.
9 Chudek J, Ritz E, Kovacs G. Genetic abnormalities in parathyroid nodules of uremic patients. Clin Cancer Res 1998; 04: 211-214.
10 Colloton D, Shatzen E, Miller G. et al. Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism. Kidney Int 2005; 67: 467-476.
11 Malberti F, Farina M, Imbasciati E. The PTH-calcium curve and the set point of calcium in primary and secondary hyperparathyroidism. Nephrol Dial Transplant 1999; 14: 2398-2406.
12 Demay MB, Kiernan MS, DeLuca HF, Kronenberg HM. Sequences in the human parathyroid hormone gene that bind the 1,25 dihydroxyvitamin D₃ receptor and mediate transcriptional repression in response to 1,25-dihyroxyvitamin D₃ . Proc Natl Acad Sci USA 1992; 89: 8097-8101.
13 Drüeke TB, Martin D, Rodriguez M. Can calcimimetics inhibit parathyroid hyperplasia? Evidence from preclinical studies. Nephrol Dial Transplant 2007; 22: 1828-1839.
14 Falchetti A, Bale AE, Amorosi A. et al. Progression of uremic hyperparathyroidism involves allelic loss on chromosome 11. J Clin Endocrinol Metab 1993; 76: 139-144.
15 Fernandez E, Fibla J, Betriu A. et al. Association between vitamin D receptor gene polymorphisms and relative hypoparathyroidism in patients with chronic renal failure. J Am Soc Nephrol 1997; 08: 1546-1552.
16 Fukagawa M, Kazama JJ. FGF 23: its role in renal bone disease. Pediatr Nephrol 2006; 21: 1802-1806.
17 Fukuda N, Tanaka H, Tominaga Y. et al. Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 1993; 92: 1436-1443.
18 Gogusev J, Duchambon P, Hory B. et al. Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 1997; 51: 328-336.
19 Hsu CH, Patel SR, Vanholder R. Mechanism of decreased intestinal calcitriol receptor concentration in renal failure. Am J Physiol 1993; 264: F662-F669.
20 Imanishi Y, Tahara H, Palanisamy N. et al. Clonal chromosomal defects in the molecular pathogenesis of refractory hyperparathyroidism of uremia. J Am Soc Nephrol 2002; 13: 490-498.
21 Inagaki C, Dousseau M, Pacher N. et al. Structural analysis of gene marker loci on chromosomes 10 and 11 in primary and secondary uraemic hyperparathyroidism. Nephrol Dial Transplant 1998; 13: 350-357.
22 Kilav R, Silver J, Naveh-Many T. Parathyroid hormone gene expression in hypophosphatemia J Clin Invest. 1995; 96: 327-333.
23 Kos CH, Karaplis AC, Peng JB. et al. The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone. J Clin Invest 2003; 111: 1021-1028.
24 Lefebvre A, de Vernejoul MC, Gueris J. et al. Optimal correction of acidosis changes progression of dialysis osteodystrophy. Kidney Int 1989; 36: 1112-1118.
25 Levi R, Ben-Dov IZ, Lavi-Moshayoff V. et al. Hyperparathyroidism of experimental uremia is reversed by calcimimetics: Correlation with postranslational modification of trans acting factor AUF1. J Am Soc Nephrol 2006; 17: 107-112.
26 Lopes-Hilker S, Dusso AS, Rapp NS. et al. Phosphorus restriction reverses hyperparathyroidism in uremia independent of changes in calcium and calcitriol. Am J Physiol 1990; 259: F432-F437.
27 Mendes V, Jorgetti V, Nemeth J. et al. Secondary hyperparathyroidism in chronic haemodialysis patients: A clinico-pathological study. Proc EDTA-ERA 1983; 20: 731-736.
28 Moallem E, Kilav R, Silver J, Naveh-Many T. RNA-Protein binding and posttranscriptional regulation of parathyroid hormone gene expression by calcium and phosphate. J Biol Chem 1998; 273: 5253-5259.
29 Picton ML, Moore PR, Mawer EB. et al. Down-regulation of human osteoblast PTH/PTHrP receptor mRNA in end-stage renal failure. Kidney Int 2000; 58: 1440-1449.
30 Portale AA, Boothe BE, Halloran BP, Morris Jr RC. Effect of dietary phosphorus on circulating concentrations of 1,25-dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 1984; 73: 1580-1589.
31 Reichel H, Deibert B, Schmidt-Gayk H, Ritz E. Calcium metabolism in early chronic renal failure. Implications for the pathogenesis of hyperparathyroidism. Nephrol Dial Transplant 1991; 06: 162-169.
32 Roussanne MC, Lieberherr M, Souberielle JC. et al. Human parathyroid cell proliferation in response to calcium, NPS R-467, calcitriol and phosphate. Eur J Clin Invest 2001; 31: 610-616.
33 Sela-Brown A, Silver J, Brewer G, Naveh-Many T. Identification of AUF1 as a parathyroid hormone mRNA 3’-untranslated region–binding protein that determines parathyroid hormone mRNA stability. J Biol Chem 2000; 275: 7424-7429.
34 Silver J, Naveh-Many T, Mayer H. et al. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest 1986; 78: 1296-1301.
35 Silver J. Molecular mechanisms of secondary hyperparathyroidism. Nephrol Dial Transplant 2000; 15 (Suppl. 05) S2-S7.
36 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: 1049-1056.
37 Tominaga Y, Kohara S, Namii Y. et al. Clonal analysis of nodular parathyroid hyperplasia in renal hyperparathyroidism. World J Surg 1996; 20: 744-752.
38 Tominaga Y, Tsuzuki T, Uchida K. et al.: Expression of PRAD1/cyclin D1, retinoblastoma gene products, and Ki67 in parathyroid hyperparathyroidism caused by chronic renal failure versus primary adenoma. Kidney Int. 1999; 55: 1375-1383.
39 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: 50-58.
40 Wallfeldt C, Gylfe E, Larsson R. et al. Relationship between external and cytoplasmic calcium concentrations, parathyroid hormone release and weight of parathyroid glands in human hyperparathyroidism. J Endocrinol 1988; 116: 457-464.
41 Young EW, Albert JM, Satayathum S. et al. Predictors and consequences of altered mineral metabolism: The Dialysis Outcomes and Practice Patterns Study. Kidney Int 2005; 67: 1179-1187.