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Dialyse aktuell 2021; 25(10): 403-409
DOI: 10.1055/a-1559-6564
DOI: 10.1055/a-1559-6564
Schwerpunkt
Nephrologie
CKD-MBD und sekundärer Hyperparathyreoidismus (Teil 1)
Pathophysiologie der Homöostase von PTH, Vitamin D und Phosphat
ZUSAMMENFASSUNG
Der Begriff CKD-MBD (Chronic Kidney Disease – Mineral Bone Disorder) ist seit einigen Jahren für Störungen des Kalzium-Phosphat-Stoffwechsels und der damit verbundenen Risiken für das Mineral-Knochen- und Herz-Kreislauf-System bei chronischen Nierenerkrankungen bekannt. Die Bezeichnung entstand nach einem Paradigmenwechsel in der Pathophysiologie des sekundären Hyperparathyreoidismus und da neue Akteure wie FGF23 und Klotho gefunden wurden, die eine wichtige Rolle bei der Entstehung der Störungen spielen. Das wachsende Verständnis der Zusammenhänge zwischen den neuen Akteuren und Kalzium, Phosphat, Vitamin D und Vitamin K2 und der Verkalkung von Gefäßen und Weichteilen beeinflusste unweigerlich unsere Therapien. Dieser erste Teil des Beitrags verschafft einen Überblick über die neuesten Erkenntnisse zum Phosphat-Sensing, die Rolle von FGF23 und Klotho und die Besonderheiten des Vitamin-D- und Vitamin-K-Stoffwechsels bei Gesundheit und chronischer Nierenerkrankung.
Publication History
Article published online:
14 December 2021
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Literatur
- 1 Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009: S1-130 DOI: 10.1038/ki.2009.188
- 2 Takeyama K, Kato S. The Vitamin D 1-alpg Hydroxylase Gene and its Regulation by active Vitamin D3. Biosci Biotechnol Biochem 2011; 75: 208-213 DOI: 10.1271/bbb.100684.
- 3 Kim MS, Kondo T, Takada I. et al DNA demethylation in hormone-induced transcriptional derepression. Nature 2009; 461: 1007-1012 DOI: 10.1038/nature08456.
- 4 Zierold C, Mings JA. DeLuca. Regulation of 25-hydroxyvitamin D3-24-hydroxylase mRNA by 1,25-ihydroxyvitamin D3 and parathyroid hormone. J Cell Biochem 2003; 88: 234-237 DOI: 10.1002/jcb.
- 5 Jones G, Prosser DE, Kaufmann M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): Its important role in the degradation of vitamin D. Arch Biochem Biophys 2012; 523: 9-18 DOI: 10.1016/j.abb.2011.11.003.
- 6 Slatopolsky E, Caglar S, Pennell JP. et al On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest 1971; 50: 492-499 DOI: 10.1172/JCI106517.
- 7 Razzaque MS. The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol 2009; 5: 611-619 DOI: 10.1038/nrendo.2009.196.
- 8 Kuro-o M. Endocrine FGFs and Klothos: emerging concepts. Trends Endocrinol Metab 2008; 19: 239-245 DOI: 10.1016/j.tem.2008.06.002.
- 9 Berndt T, Thomas LF, Craig TA. et al Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption. PNAS 2007; 104: 11085-11090 DOI: 10.1073/pnas.0704446104.
- 10 Hebert SC, Cheng S, Geibel J. Functions and roles of the extracellular Ca2+-sensing receptor in the gastrointestinal tract. J Cell Calcium 2004; 35: 239-247 DOI: 10.1016/j.ceca.2003.10.015.
- 11 Cheng SX, Geibel JP, Hebert SC. Extracellular polyamines regulate fluid secretion in rat colonic crypts via the extracellular calcium-sensing receptor. Gastroenterology 2004; 126: 148-158 DOI: 10.1053/j.gastro.2003.10.064.
- 12 Chattopadhyay N, Cheng I, Rogers K. et al Identification and localization of extracellular Ca(2+)-sensing receptor in rat intestine. Am J Physiol 1998; 274: G122-G130 DOI: 10.1152/ajpgi.1998.274.1.G122.
- 13 Cheng SX, Okuda M, Hall AE. et al Expression of calcium-sensing receptor in rat colonic epithelium: evidence for modulation of fluid secretion. Am J Physiol Gastrointest Liver Physiol 2002; 283: G240-G250 DOI: 10.1152/ajpgi.00500.2001.
- 14 Conigrave AD, Brown EM. L-amino acid-sensing by calcium-sensing receptors: implications for GI physiology. Am J Physiol 2006; 291: G753-G761 DOI: 10.1016/j.ics.2006.08.017.
- 15 Centeno PP, Herberger A, Mun HC. et al Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion. Nat Comm 2019; 10: 4693 DOI: 10.1038/s41467-019-12399-9.
- 16 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 DOI: 10.1038/366575a0.
- 17 Drücke TB. Modulation and action of the calcium sensing receptor. Nephrol Dial Transplant 2004; 19: V20-V26
- 18 Geng Y, Mosyak L, Kurinov I. et al Structural mechanism of ligand activation in human calcium-sensing receptor. Elife 2016; 5: e13662 DOI: 10.7554/eLife.13662.
- 19 Akiyama K, Miura Y, Hayashi H. et al Calciprotein particles regulate fibroblast growth factor-23 expression in osteoblasts. Kidney Int 2020; 97: 702-712 DOI: 10.1016/j.kint.2019.10.019.
- 20 Nishida Y, Taketani Y, Yamanaka-Okomura H. et al Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney International 2006; 70: 2141-2147 DOI: 10.1038/sj.ki.5002000.
- 21 Isakova T, Wahl P, Vargas GS. et al Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 2011; 79: 1370-1378 DOI: 10.1038/ki.2011.47.
- 22 Hasegawa H, Nagano N, Urakawa I. et al Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease. Kidney Int 2010; 78: 975-980 DOI: 10.1038/ki.2010.313.
- 23 Feng JQ, Ward LM, Liu S. et al Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 2006; 38: 1310-1315 DOI: 10.1038/ng1905.
- 24 Liu S, Zhou J, Tang W. et al Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol metab 2006; 291: E38-E49 DOI: 10.1152/ajpendo.00008.2006.
- 25 Shimada T, Mizutani S, Muto T. et al Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci USA 2001; 98: 6500-6505 DOI: 10.1073/pnas.101545198.
- 26 Shimada T, Muto T, Urikawa I. et al Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 2002; 143: 3179-3182 DOI: 10.1210/endo.143.8.8795.
- 27 Frishberg Y, Ito N, Rinat C. et al Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23. J Bone Miner Res 2007; 22: 235-242 DOI: 10.1359/jbmr.061105.
- 28 Takashi Y, Kosako H, Sawatsubashi S. et al Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation. Proc Natl Acad Sci USA 2019; 116: 11418-11427 DOI: 10.1073/pnas.1815166116.
- 29 McKay MM, Morrisson DK.. Integrating signals from RTKs to ERK/MAPK. Oncogene 20077 26: 3113-3121 DOI: 10.1038/sj.onc.1210394.
- 30 Shimada T, Yamazaki Urakawa I. et al FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem Biophys Res Commun 2004; 314: 409-414 DOI: 10.1016/j.bbrc.2003.12.102.
- 31 Baum M, Schiavi S, Dwarakanath V. et al Effect of fibroblast growth factor-23 on phosphate transport in proximal tubules. Kidney Int 2005; 68: 1148-1153 DOI: 10.1111/j.1523-1755.2005.00506.x.
- 32 Gattineni J, Bates C, Twombley K. et al FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 2009; 297: F282-F291 DOI: 10.1152/ajprenal.90742.2008.
- 33 Kurosu H, Kuro-o M. The Klotho gene family as a regulator of endocrine fibroblast growth factors. Cell Endocrinol 2008; 299: 72-78 DOI: 10.1016/j.mce.2008.10.052.
- 34 Hu MC, Shi M, Zhang J. et al Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 2011; 22: 124-136 DOI: 10.1681/ASN.2009121311.
- 35 Lim K, Lu TS, Molostov G. et al Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23. Circulation 2012; 125: 2243-2255 DOI: 10.1161/CIRCULATIONAHA.111.053405.
- 36 Perwad F, Azam N, Zhang MYH. et al Dietary and Serum Phosphorus Regulate Fibroblast Growth Factor 23 Expression and 1,25-Dihydroxyvitamin D Metabolism in Mice. Endocrinology 2005; 146: 5358-5364 DOI: 10.1210/en.2005-0777.
- 37 Shimada T, Hasegawa H, Yamazaki Y. et al FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004; 19: 429-435 DOI: 10.1359/JBMR.0301264.
- 38 Baxter LA, DeLuca HF. Stimulation of 25-hydroxyvitamin D3-1alpha-hydroxylase by phosphate depletion. J Biol Chem 1976; 251: 3158-3161
- 39 Hughes MR. et al Regulation of serum 1alpha,25-dihydroxyvitamin D3 by calcium and phosphate in the rat. Science 1975; 190: 578-580 DOI: 10.1126/science.1188357.
- 40 Tanaka Y, Deluca HF. The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus. Arch Biochem Biophys 1973; 154: 566-574 DOI: 10.1210/endo.142.5.8119.
- 41 Yoshida T, Yoshida N, Monkawa T. et al Dietary phosphorus deprivation induces 25-hydroxyvitamin D(3) 1alpha-hydroxylase gene expression. Endocrinology 2001; 142: 1720-1726 DOI: 10.1210/endo.142.5.8119.
- 42 Galitzer H, Ben-Dov IZ, Silver J. et al Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int 2010; 77: 211-218 DOI: 10.1038/ki.2009.464.
- 43 Komaba H, Goto S, Fujii H. et al Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients. Kidney Int 2010; 77: 232-238 DOI: 10.1038/ki.2009.414.
- 44 Canalejo R, Canalejo A, Martinez-Monera JM. et al FGF23 fails to inhibit uremic parathyroid glands. J Am Soc Nephrol 2010; 21: 1125-1135 DOI: 10.1681/ASN.2009040427.
- 45 Cunningham J, Locatelli F, Rodriguez M. Secondary Hyperparathyroidism: Pathogenesis, Disease Progression, and Therapeutic Options. Clin J Am Soc Nephrol 2011; 6: 913-921 DOI: 10.2215/CJN.06040710.
- 46 Taal MW, Thurston V, McIntyre N. et al The impact of vitamin D status on the relativeincrease in fibroblast growth factor 23 andparathyroid hormone in chronic kidney disease. Kidney Int 2014; 86: 407-413 DOI: 10.1038/ki.2013.537.
- 47 Pavik I, Jaeger P, Ebner L. et al Secreted Klotho and FGF23 in chronic kidney disease Stage 1 to 5: a sequence suggested from a cross-sectional study. Nephrol Dial Transplant 2013; 28: 352-359 DOI: 10.1093/ndt/gfs460.
- 48 Shimamura Y, Hahada K. et al Serum levels of soluble secreted α-Klotho are decreased in the early stages of chronic kidney disease, making it a probable novel biomarker for early diagnosis. Clin Exp Nephrol 2012; 16: 722-729 DOI: 10.1007/s10157-012-0621-7.
- 49 Bikle D. Vitamin D: Production, Metabolism, and Mechanisms of Action. 2017 Aug 11. In: Feingold KR, Anawalt B, Boyce A, et al. (editors). Endotext South Darmouth, Im Internet. https://www.ncbi.nlm.nih.gov/books/NBK278935/ Stand: 21.10.2021
- 50 Henry HL. Regulation of vitamin D metabolism. Best Pract Res Clin Endocrinol Metab 2011; 25: 531-541 DOI: 10.1016/j.beem.2011.05.003.
- 51 Lopez I, Rodriguez-Ortiz ME, Almaden Y. et al Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo. Kidney Int 2011; 80: 475-482 DOI: 10.1038/ki.2011.107.
- 52 Fan Y, Ruyie BI, Densmore MJ. et al Parathyroid hormone 1 receptor is essential to induce FGF23 production and maintain systemic mineral ion homeostasis. FASEB J 2016; 30: 428-440 DOI: 10.1096/fj.15-278184.
- 53 Meir T, Durlacher K, Pan Z. et al Parathyroid hormone activates the orphan nuclearreceptor Nurr1 to induce FGF23 transcription. Kidney Int 2014; 86: 1106-1115 DOI: 10.1038/ki.2014.215.
- 54 Collins MT, Lindsay JR. et al Fibroblast growth Factor-23 is regulated by 1alpha,25-dihydroxyvitamin D. J Bone Miner Res 2005; 20: 1944-1950 DOI: 10.1359/JBMR.050718.
- 55 Saito H. et al Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem 2005; 280: 2543-2549 DOI: 10.1074/jbc.M408903200.
- 56 Kuro-o M. A potential link between phosphate and aging: lessons from Klotho-deficient mice. Mech Ageing Dev 2010; 131: 270-275 DOI: 10.1016/j.mad.2010.02.008.
- 57 Maiti A Beckman MJ. Extracellular calcium is a direct effecter of VDR levels in proximal tubule epithelial cells that counter-balances effects of PTH on renal vitamin D metabolism. J Steroid Biochem Mol Biol 2007; 103: 504-508 DOI: 10.1016/j.jsbmb.2006.11.012.
- 58 Goodman WG, Quarles LD. Development and progression of secondary hyperparathyroidism in chronic kidney disease: lessons from molecular genetics. Kidney Int 2008; 74: 276-288 DOI: 10.1038/sj.ki.5002287.
- 59 Uchiyama T, Okhido I, Nakashima A. et al Severe chronic kidney disease environment reduced calcium-sensing receptor expression in parathyroid glands of adenine-induced rats even without high phosphorus diet. BMC Nephrol 2020; 21: 21 DOI: 10.1186/s12882-020-01880-z.
- 60 Holick MF. Vitamin Deficiency. Engl J Med 2007; 357: 266-281 DOI: 10.1056/NEJMra070553.
- 61 Holick MF, Binkley NC, Bischoff-Ferrari HA. et al Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2011; 96: 1911-1930 DOI: 10.1210/jc.2011-0385.
- 62 National Kidney Foundation K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003; 42: S1-S201
- 63 Ross AC, Manson JAE, Abrams SA. et al The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011; 96: 53-58 DOI: 10.1210/jc.2010-2704.
- 64 Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004; 80 Suppl 1678S-1688S DOI: 10.1093/ajcn/80.6.1678S.
- 65 Pilz S, März W, Cashman KD. et al Rationale and Plan for Vitamin D Food Fortification: A Review and Guidance Paper. Front Endocrinol 2018; 8: 373 DOI: 10.3389/fendo.2018.00373.
- 66 Calvo M, Whiting SJ, Barton CN. Vitamin D fortification in the United States and Canada: current status and data needs. Am J Clin Nutr 2004; 80 Suppl 1710S-1716S DOI: 10.1093/ajcn/80.6.1710S.
- 67 Calvo M, Whiting SJ. Survey of current vitamin D food fortification practices in the United States and Canada. J Steroid Biochem Mol Biol 2013; 136: 211-213 DOI: 10.1016/j.jsbmb.2012.09.034.
- 68 Zhu J, DeLuca HF. Vitamin D 25-hydroxylase – Four decades of searching, are we there yet?. Arch Biochem Biophys 2012; 523: 30-36 DOI: 10.1016/j.abb.2012.01.013.
- 69 Cheng JB, Levine MA, Bell NH. et al Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci USA 2004; 101: 7711-7715 DOI: 10.1073/pnas.0402490101.
- 70 Nykjaer A, Fyfe JC, Kozyraki Ret al. Cubilin dysfunction causesabnormal metabolism of the steroid hormone 25(OH) vitaminD(3). Proc Natl Acad Sci USA 2001; 98: 13895-13900 DOI: 10.1073/pnas.241516998.
- 71 Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Ren Physiol 2005; 289: F8-F28 DOI: 10.1152/ajprenal.00336.2004.
- 72 Boullion R, Carmeliet G, Verlinden L. et al Vitamin D and Human Health: Lessons from Vitamin D Receptor Null Mice. Endocr Rev 2008; 29: 726-776 DOI: 10.1210/er.2008-0004.
- 73 Ritter CS, Armbrecht HJ, Slatopolsky E, Brown AJ. 25-Hydroxyvitamin D(3) suppresses PTH synthesis and secretion in bovine parathyroid cells. Kidney Int 2006; 70: 654-659 DOI: 10.1038/sj.ki.5000394.