nefrНефрологияNephrology (Saint-Petersburg)1561-62742541-9439Pavlov First Saint-Petersburg State Medical Universitynefr-168Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИ КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯORIGINAL ARTICLES CLINICAL STUDIESРоль фактора роста фибробластов-23 в патогенезе нарушений обмена фосфора при нефропатиях у детейThe role of fibroblast growth factor-23 in aberration of phosphate metabolism pathogenesis in children with nephropathiesАнаньинПетр ВладимировичAnaninPetr V.ananin.pv@gmail.comКомароваОльга ВикторовнаKomarovaOlga V.komarova@nczd.ruВашуринаТатьяна ВалерьевнаVashurinaTatiana V.tvv@mail.ruЗробокОльга ИсофатовнаZrobokOlga I.zrobok@nczd.ruЗубковаИрина ВалентиновнаZubkovaIrina V.ananin.pv@gmail.comБржозовскаяЕкатерина АнатольевнаBrzhozovskaiaEkaterina A.ananin.pv@gmail.comПанкратенкоТатьяна ЕвгеньевнаPankratenkoTatiana E.tatiana2103@inbox.ruМузуровАлександр ЛьвовичMuzurovAlexandr L.al_muz@mail.ruЗверевДмитрий ВладимировичZverevDmiriy V.al_muz@mail.ruЦыгинАлексей НиколаевичTsyginAlexey N.tsygin@nczd.ruФедеральное государственное бюджетное учреждение «Научный Центр Здоровья детей» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre of Children’s HealthRussian FederationМосковский областной научно-исследовательский клинический институт им. М.Ф. ВладимирскогоРоссияMoscow Regional Research and Clinical InstituteRussian FederationЦентр гравитационной хирургии крови и гемодиализа ДГКБ св. ВладимираРоссияSt. Vladimir clinical childrens hospitalRussian Federation2016010320162025967Copyright © Ананьин П.В., Комарова О.В., Вашурина Т.В., Зробок О.И., Зубкова И.В., Бржозовская Е.А., Панкратенко Т.Е., Музуров А.Л., Зверев Д.В., Цыгин А.Н., 20162016Ананьин П.В., Комарова О.В., Вашурина Т.В., Зробок О.И., Зубкова И.В., Бржозовская Е.А., Панкратенко Т.Е., Музуров А.Л., Зверев Д.В., Цыгин А.Н.Ananin P.V., Komarova O.V., Vashurina T.V., Zrobok O.I., Zubkova I.V., Brzhozovskaia E.A., Pankratenko T.E., Muzurov A.L., Zverev D.V., Tsygin A.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nephrolog.ru/jour/article/view/168

ВВЕДЕНИЕ. Фактор роста фибробластов 23 (FGF-23) - фосфатурический гормон, синтезируемый остеоцитами и играющий важную роль в патогенезе некоторых гипофосфатемических состояний. ЦЕЛЬЮ ИССЛЕДОВАНИЯ было изучение влияния FGF-23 на состояние минерального обмена при отдельных нефропатиях у детей. ПАЦИЕНТЫ И МЕТОДЫ. В исследование включено 87 детей от 7 мес до 17 лет 10 мес. Уровень интактного FGF-23 был измерен методом иммуноферментного анализа (ELISA) у детей с гипофосфатемическим рахитом (n=15), синдромом Фанкони (n=9), хронической болезнью почек 3-5 стадии (n=35), стероидным остеопорозом (n=10) и у детей, не имеющих нефропатий (n=18). У детей с нефропатиями измерены биохимические показатели фосфорного обмена в крови и моче. РЕЗУЛЬТАТЫ. В группе сравнения уровень FGF-23 составил 22,92 пг/мл (5,91-54,37), 5 детей исключены из анализа в связи с уровнем FGF-23 ниже границы определения (<5 пг/мл). У детей во всех группах получен достоверно повышенный уровень FGF-23 относительно группы сравнения: при гипофосфатемическом рахите 73,11 пг/ мл (40,08-125,71), p<0,01, при синдроме Фанкони - 141,56 пг/мл (34,27-302,64), p<0,01, при хронической болезни почек 613,71 (20,15-6230,77), p<0,01, при остеопорозе - 106,65 (61,64-147,74), p<0,01. У детей с ХБП 3-5 стадии выявлена достоверная корреляция FGF-23 с СКФ (по формуле Шварца), r=-0,678, p<0,01. У детей с синдромом Фанкони на фоне терапии фосфатами и витамином D выявлены высокий уровень FGF-23 и его корреляция с сывороточным фосфором при сохраняющейся гипофосфатемии r=0,843, p<0,05. ВЫВОДЫ. Результаты свидетельствуют о вовлечении FGF-23 в патогенез минеральных нарушений при различных нефропатиях. У детей, как и у взрослых, FGF-23 повышается по мере прогрессирования ХБП, достигая максимума при ХБП 5 стадии.

INTRODUCTION: Fibroblast growth factor-23 (FGF-23) is a phosphaturic hormone, synthesized by osteocytes and involved in the pathogenesis of several hypophosphatemic diseases. THE AIM OF STUDYwas to evaluate influence of intact (iFGF-23) on mineral metabolism in children with different nephropathies. PATIENTS AND METHODS: 87 children, age from 7 months to 17 years 10 months were included in the study. Level of intact FGF-23 was measured (with ELISA) in children with hypophosphatemic rickets (n=15), Fanconi syndrome (n=9), chronic kidney disease stage 3-5 (n=35), steroid osteoporosis (n=10) and in children without nephropathies (n=18). Routine biochemistry markers of phosphate metabolism were measured in children with kidney diseases. RESULTS: FGF-23 level in comparison group was 22,92 pg/ml (5,91-54,37), 5 children were excluded because of undetectable level (<5 pg/ml). All children with kidney diseases had significantly elevated FGF-23 level (in comparison with healthy children): in children with hypophosphatemic rickets FGF-23 level was 73,11 pg/ml (40,08-125,71), p<0,01, in Fanconi syndrome patients - 141,56 pg/ml (34,27-302,64), p<0,01, CKD 3-5 stage patients - 613,71 pg/ml (20,15-6230,77), p<0,01, osteoporosis patients - 106,65 pg/ml (61,64-147,74), p<0,01. Correlation between FGF-23 level and eGFR (using Schwartz formula) in CKD 3-5 stage was found, r= -0,678, p<0,01. Children with Fanconi syndrome on phosphate and vitamin D supplementation had elevated FGF-23 level and we found the strong correlation between FGF-23 level and serum phosphate level (r=0,843, p<0,05) despite of hypophosphatemia. CONCLUSIONS: Our results suggest that FGF-23 is involved in pathogenesis of mineral disorders in different nephropathies. Besides, FGF-23 is rising with the progression of CKD, reaching maximum level in 5-th stage of CKD in pediatric patients as in adult ones.

фактор роста фибробластов 23гипофосфатемичесий рахитсиндром Фанкониостеопорозхроническая болезнь почекдетиFGF-23fibroblast growth factor 23FGF-23hypophosphatemic ricketsFanconi syndromeosteoporosischronic kidney diseasechildrenReferencesLanzano L., Lei T., Okamura K et al. Differential modulation of the molecular dynamics of the type IIa and IIc sodium phosphate cotransporters by parathyroid hormone. Am J Physiol Cell Physiol 2011;850-861Lanzano L., Lei T., Okamura K et al. Differential modulation of the molecular dynamics of the type IIa and IIc sodium phosphate cotransporters by parathyroid hormone. Am J Physiol Cell Physiol 2011;850-861Brenner & Rector’s the kidney / [edited by] Maarten W. Taal [et al.]. - 9th ed. Taal., 239-246Brenner & Rector’s the kidney / [edited by] Maarten W. Taal [et al.]. - 9th ed. Taal., 239-246Neuman W. Bone material and calcification mechanisms. Fundamental and Clinical Bone Physiology 1980; 83-107Neuman W. Bone material and calcification mechanisms. Fundamental and Clinical Bone Physiology 1980; 83-107Quarles L.D. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 2008 Dec;118(12):3820-3828 doi: 10.1172/JCI36479. Epub 2008 Dec 1Quarles L.D. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 2008 Dec;118(12):3820-3828 doi: 10.1172/JCI36479. Epub 2008 Dec 1Penido M.G., Alon U.S. Phosphate homeostasis and its role in bone health. Pediatr Nephro. 2012 Nov;27(11):2039-2048Penido M.G., Alon U.S. Phosphate homeostasis and its role in bone health. Pediatr Nephro. 2012 Nov;27(11):2039-2048Kocelak P., Olszanecka-Glinianowicz M., Chudek J. Fibroblast growth factor 23 - structure., function and role in kidney diseases. Adv Clin Exp Med 2012; 21(3): 391-401Kocelak P., Olszanecka-Glinianowicz M., Chudek J. Fibroblast growth factor 23 - structure., function and role in kidney diseases. Adv Clin Exp Med 2012; 21(3): 391-401Rowe P.S. Regulation of bone-renal mineral and energy metabolism: the PHEX., FGF-23., DMP1., MEPE ASARM pathway. Crit RevEukaryot Gene Expr 2012; 22(1):61-86Rowe P.S. Regulation of bone-renal mineral and energy metabolism: the PHEX., FGF-23., DMP1., MEPE ASARM pathway. Crit RevEukaryot Gene Expr 2012; 22(1):61-86Amatschek S., Haller M., Oberbauer R. Renal phosphate handling in human - what can we learn from hereditary hypophos-phataemias? Eur J Clin Invest 2010 40(6): 552-560Amatschek S., Haller M., Oberbauer R. Renal phosphate handling in human - what can we learn from hereditary hypophos-phataemias? Eur J Clin Invest 2010 40(6): 552-560Saito T., Fukumoto S. Fibroblast Growth Factor 23 (FGF-23) and Disorders of Phosphate Metabolism. Int J Pediatr Endocrinol 2009;2009:496514Saito T., Fukumoto S. Fibroblast Growth Factor 23 (FGF-23) and Disorders of Phosphate Metabolism. Int J Pediatr Endocrinol 2009;2009:496514Weber TJ et al. Serum FGF-23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res 2003; 18(7): 1227-1234Weber TJ et al. Serum FGF-23 levels in normal and disordered phosphorus homeostasis. J Bone Miner Res 2003; 18(7): 1227-1234Добронравов В.А. Современный взгляд на патофизиологию вторичного гиперпаратиреоза: роль фактора роста фибробластов 23 и Klotho. Нефрология 2011; 15 (4): 11-20Добронравов В.А. Современный взгляд на патофизиологию вторичного гиперпаратиреоза: роль фактора роста фибробластов 23 и Klotho. Нефрология 2011; 15 (4): 11-20Shimada T., Hasegawa H., Yamazaki Y. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004 Mar;19(3):429-435. Epub 2003 Dec 29Shimada T., Hasegawa H., Yamazaki Y. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004 Mar;19(3):429-435. Epub 2003 Dec 29Wolf M. Update on fibroblast growth factor 23 in chronic kidney disease. Kidney Int 2012; 82: 737-747Wolf M. Update on fibroblast growth factor 23 in chronic kidney disease. Kidney Int 2012; 82: 737-747Gattineni J., Baum M. Regulation of phosphate transport by fibroblast growth factor 23 (FGF-23): implications for disorders of phosphate metabolism. Pediatr Nephrol 2010 Apr; 25(4):591-601Gattineni J., Baum M. Regulation of phosphate transport by fibroblast growth factor 23 (FGF-23): implications for disorders of phosphate metabolism. Pediatr Nephrol 2010 Apr; 25(4):591-601Tilman B Drüeke., Klotho., FGF-23., and FGF receptors in chronic kidney disease: a yin-yang situation? Kidney Int 2010; 78: 1057-1060Tilman B Drüeke., Klotho., FGF-23., and FGF receptors in chronic kidney disease: a yin-yang situation? Kidney Int 2010; 78: 1057-1060Lee HS., Kim SY, Kwak MJ et al. A novel de novo mutation within PHEX gene in a young girl with hypophosphatemic rickets and review of literature. Ann Pediatr Endocrinol Metab 2014 Mar; 19(1):36-41Lee HS., Kim SY, Kwak MJ et al. A novel de novo mutation within PHEX gene in a young girl with hypophosphatemic rickets and review of literature. Ann Pediatr Endocrinol Metab 2014 Mar; 19(1):36-41Shimada T., Muto T., Urakawa I et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 2002;143:3179-3182Shimada T., Muto T., Urakawa I et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 2002;143:3179-3182Levy-Litan V., Hershkovitz E., Avizov L et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet 2010; 86(2):273-278Levy-Litan V., Hershkovitz E., Avizov L et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet 2010; 86(2):273-278Feng 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; 38:1310-1315Feng 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; 38:1310-1315Feng JQ., Clinkenbeardb EL., Yuanc B et al. Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone 2013 June; 54(2): 213-221Feng JQ., Clinkenbeardb EL., Yuanc B et al. Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone 2013 June; 54(2): 213-221Mackenzie NC., Zhu D., Milne EM et al. Altered bone development and an increase in FGF-23 expression in Enpp1(-/-) mice. PLoS One 2012; 7(2):e32177Mackenzie NC., Zhu D., Milne EM et al. Altered bone development and an increase in FGF-23 expression in Enpp1(-/-) mice. PLoS One 2012; 7(2):e32177Wang X., Wang S., Li C et al. Inactivation of a novel FGF-23 regulator., FAM20C., leads to hypophosphatemic rickets in mice. PLoS Genet 2012; 8(5):e1002708Wang X., Wang S., Li C et al. Inactivation of a novel FGF-23 regulator., FAM20C., leads to hypophosphatemic rickets in mice. PLoS Genet 2012; 8(5):e1002708Sahay M., Sahay R. Renal rickets-practical approach. Indian J Endocrinol Metab 2013 Oct; 17(Suppl1): S35-S44Sahay M., Sahay R. Renal rickets-practical approach. Indian J Endocrinol Metab 2013 Oct; 17(Suppl1): S35-S44Carpenter TO., Imel YA., Holm IA et al. A Clinician’s guide to x-linked hypophosphatemia. J Bone Miner Res 2011 July; 26(7): 1381-1388Carpenter TO., Imel YA., Holm IA et al. A Clinician’s guide to x-linked hypophosphatemia. J Bone Miner Res 2011 July; 26(7): 1381-1388Liang G., Katz LD., Insogna KL et al. Survey of the enthe-sopathy of Xlinked hypophosphatemia and its characterization in Hyp mice. Calcif Tiss Int 2009; 85:235-246Liang G., Katz LD., Insogna KL et al. Survey of the enthe-sopathy of Xlinked hypophosphatemia and its characterization in Hyp mice. Calcif Tiss Int 2009; 85:235-246Паян К.А., Савенкова Н.Д., Левиашвили Ж.Г., Левиашвили Н.Г. Окуло-церебро-ренальный синдром Лоу у детей. Росс вестн перинатол и педиатрии 1998; (4):39-43Паян К.А., Савенкова Н.Д., Левиашвили Ж.Г., Левиашвили Н.Г. Окуло-церебро-ренальный синдром Лоу у детей. Росс вестн перинатол и педиатрии 1998; (4):39-43Лойманн Э., Цыгин А.Н., Саркисян А.А. Детская нефрология: практическое руководство, ЛитТера, 2011; 220-236Лойманн Э., Цыгин А.Н., Саркисян А.А. Детская нефрология: практическое руководство, ЛитТера, 2011; 220-236Bastepe M, Jüppner H. Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation. RevEndocr Metab Disord 2008 Jun; 9(2):171-180Bastepe M, Jüppner H. Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation. RevEndocr Metab Disord 2008 Jun; 9(2):171-180White KE, Hum JM, Econs MJ. Hypophosphatemic rickets: revealing novel control points for phosphate homeostasis. Curr Osteoporos Rep 2014 Sep;12(3):252-262White KE, Hum JM, Econs MJ. Hypophosphatemic rickets: revealing novel control points for phosphate homeostasis. Curr Osteoporos Rep 2014 Sep;12(3):252-262Amanzadeh J, Reilly RF Jr. Hypophosphatemia: an evidence-based approach to its clinical consequences and management. Nat Clin Pract Nephrol 2006 Mar;2(3):136-148Amanzadeh J, Reilly RF Jr. Hypophosphatemia: an evidence-based approach to its clinical consequences and management. Nat Clin Pract Nephrol 2006 Mar;2(3):136-148Verge CF, Lam A, Simpson JM et al. Effects of therapy in X-linked hypophosphatemic rickets. N Engl J Med 1991; 325:1843-1848Verge CF, Lam A, Simpson JM et al. Effects of therapy in X-linked hypophosphatemic rickets. N Engl J Med 1991; 325:1843-1848Novais E, Stevens PM. Hypophosphatemic rickets: the role of hemiepiphsiodesis. J Pediatr Orthop 2006;26:238-244Novais E, Stevens PM. Hypophosphatemic rickets: the role of hemiepiphsiodesis. J Pediatr Orthop 2006;26:238-244Gutierrez O, Isakova T, Rhee E et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005 Jul; 16(7):2205-2215Gutierrez O, Isakova T, Rhee E et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005 Jul; 16(7):2205-2215Pereira RC, Juppner H, Azucena-Serrano CE et al. Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease, Bone 2009; Dec; 45(6): 1161-1168Pereira RC, Juppner H, Azucena-Serrano CE et al. Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease, Bone 2009; Dec; 45(6): 1161-1168Brossard JH, Lepage R, Cardinal H et al. Influence of glomerular filtration rate on non-(1-84) parathyroid hormone detected by intact PTH assays. Clin Chem 2000; 46: 697-703Brossard JH, Lepage R, Cardinal H et al. Influence of glomerular filtration rate on non-(1-84) parathyroid hormone detected by intact PTH assays. Clin Chem 2000; 46: 697-703Siomou E, Stefanidis CJ. FGF-23 in children with CKD: a new player in the development of CKD-mineral and bone disorder. Nephrol Dial Transplant 2012; 27: 4259-4262Siomou E, Stefanidis CJ. FGF-23 in children with CKD: a new player in the development of CKD-mineral and bone disorder. Nephrol Dial Transplant 2012; 27: 4259-4262Sinha MD, Turner C, Dalton RN et al. Investigating FGF-23 concentrations and its relationship with declining renal function in paediatric patients with pre-dialysis CKD Stages 3-5. Nephrol Dial Transplant 2012 Dec; 27(12):4361-4368Sinha MD, Turner C, Dalton RN et al. Investigating FGF-23 concentrations and its relationship with declining renal function in paediatric patients with pre-dialysis CKD Stages 3-5. Nephrol Dial Transplant 2012 Dec; 27(12):4361-4368van Husen M, Fischer AK, Lehnhardt A et al. Fibroblast growth factor 23 and bone metabolism in children with chronic kidney disease. Kidney Int 2010; 78: 200-206van Husen M, Fischer AK, Lehnhardt A et al. Fibroblast growth factor 23 and bone metabolism in children with chronic kidney disease. Kidney Int 2010; 78: 200-206Endo I, Fukumoto S, Ozono K et al. Clinical usefulness of measurement of fibroblast growth factor 23 (FGF-23) in hypophosphatemic patients: proposal of diagnostic criteria using FGF-23 measurement. Bone 2008 Jun;42(6):1235-1239Endo I, Fukumoto S, Ozono K et al. Clinical usefulness of measurement of fibroblast growth factor 23 (FGF-23) in hypophosphatemic patients: proposal of diagnostic criteria using FGF-23 measurement. Bone 2008 Jun;42(6):1235-1239

The authors declare that there are no conflicts of interest present.