Skip to main content
Top
Published in: Pediatric Nephrology 7/2011

01-07-2011 | Original Article

Serum osteoprotegerin, RANKL and fibroblast growth factor-23 in children with chronic kidney disease

Authors: Ekaterini Siomou, Anna Challa, Nikoleta Printza, Vasileios Giapros, Fotini Petropoulou, Andromachi Mitsioni, Fotios Papachristou, Constantinos J. Stefanidis

Published in: Pediatric Nephrology | Issue 7/2011

Login to get access

Abstract

Osteoprotegerin (OPG), receptor activator of the nuclear factor κB ligand (RANKL) and fibroblast growth factor-23 (FGF-23) play a central role in renal osteodystrophy. We evaluated OPG/RANKL and FGF-23 levels in 51 children with chronic kidney disease (CKD) [n = 26 stage 3 or 4 (CKD3–4) and n = 25 stage 5 (CKD5)] and 61 controls. Any possible association with intact parathyroid hormone (iPTH) and bone turnover markers was also investigated. The OPG levels were lower in the CKD3–4 group (p < 0.001) and higher in the CKD5 group (p < 0.01) than in the controls, while RANKL levels did not differ. The FGF-23 levels were higher in both patient groups (p < 0.0001), while the levels of phosphate and iPTH were higher only in the CKD5 group (p < 0.0001). There were independent positive correlations between OPG and RANKL (β = 0.297, p < 0.01) and FGF-23 (β = 0.352, p < 0.05) and a negative correlation with the bone resorption marker TRAP5b (β = −0.519, p < 0.001). OPG was positively correlated with iPTH (R = 0.391, p < 0.01). An independent positive correlation between FGF-23 and phosphate (β = 0.368, p < 0.05) or iPTH (β = 0.812, p < 0.0001) was noted. In conclusion, we found that higher OPG levels in patients with CKD stage 5 correlated with the levels of RANKL, FGF-23, iPTH, and TRAP5b. These findings may reflect a compensatory mechanism to the negative balance of bone turnover. High FGF-23 levels in early CKD stages may indicate the need for intervention to manage serum phosphate (Pi) levels.
Literature
1.
go back to reference Moe S, Drüeke T, Cunningham J, Goodman W, Martin K, Olgaard K, Ott S, Sprague S, Lameire N, Eknoyan G (2006) Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 69:1945–1953CrossRefPubMed Moe S, Drüeke T, Cunningham J, Goodman W, Martin K, Olgaard K, Ott S, Sprague S, Lameire N, Eknoyan G (2006) Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 69:1945–1953CrossRefPubMed
2.
go back to reference Salusky IB, Coburn JW, Brill J, Foley J, Slatopolsky E, Fine RN, Goodman WG (1988) Bone disease in pediatric patients undergoing dialysis with CAPD or CCPD. Kidney Int 33:975–982CrossRefPubMed Salusky IB, Coburn JW, Brill J, Foley J, Slatopolsky E, Fine RN, Goodman WG (1988) Bone disease in pediatric patients undergoing dialysis with CAPD or CCPD. Kidney Int 33:975–982CrossRefPubMed
3.
go back to reference Salusky IB, Ramirez JA, Oppenheim W, Gales B, Segre GV, Goodman WG (1994) Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD. Kidney Int 45:253–258CrossRefPubMed Salusky IB, Ramirez JA, Oppenheim W, Gales B, Segre GV, Goodman WG (1994) Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD. Kidney Int 45:253–258CrossRefPubMed
4.
go back to reference Ziólkowska H, Pańczyk-Tomaszewska M, Dębiński A, Polowiec Z, Sawicki A, Sieniawska M (2000) Bone biopsy results and serum bone turnover parameters in uremic children. Acta Paediatr 89:666–671CrossRefPubMed Ziólkowska H, Pańczyk-Tomaszewska M, Dębiński A, Polowiec Z, Sawicki A, Sieniawska M (2000) Bone biopsy results and serum bone turnover parameters in uremic children. Acta Paediatr 89:666–671CrossRefPubMed
5.
go back to reference Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Jüppner H, Wolf M (2005) Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16:2205–2215CrossRefPubMed Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Jüppner H, Wolf M (2005) Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16:2205–2215CrossRefPubMed
6.
go back to reference Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319CrossRefPubMed Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319CrossRefPubMed
7.
go back to reference Min H, Morony S, Sarosi I, Dunstan CR, Capparelli C, Scully S, Van G, Kaufman S, Kostenuik PJ, Lacey DL, Boyle WJ, Simonet WS (2000) Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med 192:463–474CrossRefPubMedPubMedCentral Min H, Morony S, Sarosi I, Dunstan CR, Capparelli C, Scully S, Van G, Kaufman S, Kostenuik PJ, Lacey DL, Boyle WJ, Simonet WS (2000) Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med 192:463–474CrossRefPubMedPubMedCentral
8.
go back to reference Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a lignad for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANE/RANKL. Proc Natl Acad Sci USA 95:3597–3602CrossRefPubMedPubMedCentral Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a lignad for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANE/RANKL. Proc Natl Acad Sci USA 95:3597–3602CrossRefPubMedPubMedCentral
9.
go back to reference Li X, Ominsky MS, Stolina M, Warmington KS, Geng Z, Niu QT, Asuncion FJ, Tan HL, Grisanti M, Dwyer D, Adamu S, Ke HZ, Simonet WS, Kostenuik PJ (2009) Increased RANK ligand in bone marrow of orchiectomized rats and prevention of their bone loss by the RANK ligand inhibitor ostoprotegerin. Bone 45:669–676CrossRefPubMed Li X, Ominsky MS, Stolina M, Warmington KS, Geng Z, Niu QT, Asuncion FJ, Tan HL, Grisanti M, Dwyer D, Adamu S, Ke HZ, Simonet WS, Kostenuik PJ (2009) Increased RANK ligand in bone marrow of orchiectomized rats and prevention of their bone loss by the RANK ligand inhibitor ostoprotegerin. Bone 45:669–676CrossRefPubMed
10.
go back to reference Huang JC, Sakata T, Pfieger LL, Bencsik M, Halloran BP, Bikle DD, Nissenson RA (2004) PTH differentially regulates expression of RANKL and OPG. J Bone Miner Res 19:235–244CrossRefPubMed Huang JC, Sakata T, Pfieger LL, Bencsik M, Halloran BP, Bikle DD, Nissenson RA (2004) PTH differentially regulates expression of RANKL and OPG. J Bone Miner Res 19:235–244CrossRefPubMed
11.
go back to reference Coen G, Ballanti P, Balducci A, Calabria S, Fischer MS, Jankovic L, Manni M, Morosetti M, Moscaritolo E, Sardella D, Bonucci E (2002) Serum osteoprotegerin and renal osteodystrophy. Nephrol Dial Transplant 17:233–238CrossRefPubMed Coen G, Ballanti P, Balducci A, Calabria S, Fischer MS, Jankovic L, Manni M, Morosetti M, Moscaritolo E, Sardella D, Bonucci E (2002) Serum osteoprotegerin and renal osteodystrophy. Nephrol Dial Transplant 17:233–238CrossRefPubMed
12.
go back to reference Shaarawy M, Fathy SA, Mehany NL, Hindy OW (2007) Circulating levels of osteoprotegerin and receptor activator of NF-kappaB ligand in patients with chronic renal failure. Clin Chem Lab Med 45:1498–1503CrossRefPubMed Shaarawy M, Fathy SA, Mehany NL, Hindy OW (2007) Circulating levels of osteoprotegerin and receptor activator of NF-kappaB ligand in patients with chronic renal failure. Clin Chem Lab Med 45:1498–1503CrossRefPubMed
13.
go back to reference Ziólkowska H, Roszkowska-Blaim M (2006) Osteoprotegerin and calcium-phosphorus metabolism parameters in children with chronic renal failure. Przegl Lek 63[Suppl 3]:68–71PubMed Ziólkowska H, Roszkowska-Blaim M (2006) Osteoprotegerin and calcium-phosphorus metabolism parameters in children with chronic renal failure. Przegl Lek 63[Suppl 3]:68–71PubMed
14.
go back to reference Swolin-Eide D, Hansson S, Larsson L, Magnusson P (2006) The novel bone alkaline phosphatase B1x isoform in children with kidney disease. Pediatr Nephrol 21:1723–1729CrossRefPubMed Swolin-Eide D, Hansson S, Larsson L, Magnusson P (2006) The novel bone alkaline phosphatase B1x isoform in children with kidney disease. Pediatr Nephrol 21:1723–1729CrossRefPubMed
15.
go back to reference Swolin-Eide D, Magnusson P, Hansson S (2007) Bone mass, biochemical markers and growth in children with chronic kidney disease: a 1-year prospective study. Acta Paediatr 96:720–725CrossRefPubMed Swolin-Eide D, Magnusson P, Hansson S (2007) Bone mass, biochemical markers and growth in children with chronic kidney disease: a 1-year prospective study. Acta Paediatr 96:720–725CrossRefPubMed
16.
go back to reference Swolin-Eide D, Hansson S, Magnusson P (2009) Children with chronic kidney disease: a 3-year prospective study of growth, bone mass and bone turnover. Acta Paediatr 98:367–373CrossRefPubMed Swolin-Eide D, Hansson S, Magnusson P (2009) Children with chronic kidney disease: a 3-year prospective study of growth, bone mass and bone turnover. Acta Paediatr 98:367–373CrossRefPubMed
17.
go back to reference Shroff RC, Shah V, Hiorns MP, Schoppet M, Hofbauer LC, Hawa G, Schurgers LJ, Singhal A, Merryweather I, Brogan P, Shanahan C, Deanfield J, Rees L (2008) The circulating calcification inhibitors, fetuin-A and osteoprotegerin, but not Matrix Gla protein, are associated with vascular stiffness and calcification in children on dialysis. Nephrol Dial Transplant 23:3263–3271CrossRefPubMed Shroff RC, Shah V, Hiorns MP, Schoppet M, Hofbauer LC, Hawa G, Schurgers LJ, Singhal A, Merryweather I, Brogan P, Shanahan C, Deanfield J, Rees L (2008) The circulating calcification inhibitors, fetuin-A and osteoprotegerin, but not Matrix Gla protein, are associated with vascular stiffness and calcification in children on dialysis. Nephrol Dial Transplant 23:3263–3271CrossRefPubMed
18.
go back to reference Ozkaya O, Buyan N, Bideci A, Gonen S, Ortac E, Fidan K, Cinaz P, Söylemezoğlu O (2007) Osteoprotegerin and RANKL serum levels and their relationship with serum ghrelin in children with chronic renal failure and on dialysis. Nephron Clin Pract 105:c153–c158CrossRefPubMed Ozkaya O, Buyan N, Bideci A, Gonen S, Ortac E, Fidan K, Cinaz P, Söylemezoğlu O (2007) Osteoprotegerin and RANKL serum levels and their relationship with serum ghrelin in children with chronic renal failure and on dialysis. Nephron Clin Pract 105:c153–c158CrossRefPubMed
19.
go back to reference Kagami S, Ohkido I, Yokoyama K, Shigematsu T, Hosoya T (2008) Osteoprotegerin affects the responsiveness of fibroblast growth factor-23 to high oral phosphate intake. Clin Nephrol 70:306–311CrossRefPubMed Kagami S, Ohkido I, Yokoyama K, Shigematsu T, Hosoya T (2008) Osteoprotegerin affects the responsiveness of fibroblast growth factor-23 to high oral phosphate intake. Clin Nephrol 70:306–311CrossRefPubMed
20.
go back to reference Kidney Disease Outcomes Quality Initiative, National Kidney Foundation (2005) K/DOQI clinical practice guidelines for bone metabolism and disease in children with chronic kidney disease. Am J Kidney Dis 46[4 Suppl 1]:S1–S121 Kidney Disease Outcomes Quality Initiative, National Kidney Foundation (2005) K/DOQI clinical practice guidelines for bone metabolism and disease in children with chronic kidney disease. Am J Kidney Dis 46[4 Suppl 1]:S1–S121
21.
go back to reference Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637CrossRefPubMedPubMedCentral Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637CrossRefPubMedPubMedCentral
22.
go back to reference Klaus G, Watson A, Edefonti A, Fischbach M, Rönnholm K, Schaefer F, Simkova E, Stefanidis CJ, Strazdins V, Vande Walle J, Schröder C, Zurowska A, Ekim M, European Pediatric Dialysis Working Group (EPDWG) (2006) Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. Pediatr Nephrol 21:151–159CrossRefPubMed Klaus G, Watson A, Edefonti A, Fischbach M, Rönnholm K, Schaefer F, Simkova E, Stefanidis CJ, Strazdins V, Vande Walle J, Schröder C, Zurowska A, Ekim M, European Pediatric Dialysis Working Group (EPDWG) (2006) Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. Pediatr Nephrol 21:151–159CrossRefPubMed
24.
go back to reference Kazama JJ, Kato H, Sato T, Shigematsu T, Fukagawa M, Iwasaki Y, Gejyo F (2002) Circulating osteoprotegerin is not removed through haemodialysis membrane. Nephrol Dial Transplant 17:1860–1861CrossRefPubMed Kazama JJ, Kato H, Sato T, Shigematsu T, Fukagawa M, Iwasaki Y, Gejyo F (2002) Circulating osteoprotegerin is not removed through haemodialysis membrane. Nephrol Dial Transplant 17:1860–1861CrossRefPubMed
25.
go back to reference Wittersheim E, Mesquita M, Demulder A, Guns M, Louis O, Melot C, Dratwa M, Bergmann P (2006) OPG, RANK-L, bone metabolism, and BMD in patients on peritoneal dialysis and hemodialysis. Clin Biochem 39:617–622CrossRefPubMed Wittersheim E, Mesquita M, Demulder A, Guns M, Louis O, Melot C, Dratwa M, Bergmann P (2006) OPG, RANK-L, bone metabolism, and BMD in patients on peritoneal dialysis and hemodialysis. Clin Biochem 39:617–622CrossRefPubMed
26.
go back to reference Wesseling K, Bakkalogly S, Salusky I (2008) Chronic kidney disease mineral and bone disorder in children. Pediatr Nephrol 23:195–207CrossRefPubMed Wesseling K, Bakkalogly S, Salusky I (2008) Chronic kidney disease mineral and bone disorder in children. Pediatr Nephrol 23:195–207CrossRefPubMed
27.
go back to reference Rogers A, Eastell R (2005) Review: Circulating osteoprotegerin and receptor activator for nuclear factor κB ligand: Clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab 90:6323–6331CrossRefPubMed Rogers A, Eastell R (2005) Review: Circulating osteoprotegerin and receptor activator for nuclear factor κB ligand: Clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab 90:6323–6331CrossRefPubMed
29.
go back to reference Gattineni J, Baum M (2010) Regulation of phosphate transport by fibroblast growth factor 23 (FGF23): implications for disorders of phosphate metabolism. Pediatr Nephrol 25:591–601CrossRefPubMed Gattineni J, Baum M (2010) Regulation of phosphate transport by fibroblast growth factor 23 (FGF23): implications for disorders of phosphate metabolism. Pediatr Nephrol 25:591–601CrossRefPubMed
30.
go back to reference Krajisnik T, Björklund P, Marsell R, Ljunggren O, Akerström G, Jonsson KB, Westin G, Larsson TE (2007) Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195:125–131CrossRefPubMed Krajisnik T, Björklund P, Marsell R, Ljunggren O, Akerström G, Jonsson KB, Westin G, Larsson TE (2007) Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195:125–131CrossRefPubMed
31.
go back to reference Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J (2007) The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117:4003–4008PubMedPubMedCentral Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J (2007) The parathyroid is a target organ for FGF23 in rats. J Clin Invest 117:4003–4008PubMedPubMedCentral
32.
go back to reference Hasegawa H, Nagano N, Urakawa I, Yamazaki Y, Iijima K, Fujita T, Yamashita T, Fukumoto S, Shimada T (2010) 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 78:975–980CrossRefPubMed Hasegawa H, Nagano N, Urakawa I, Yamazaki Y, Iijima K, Fujita T, Yamashita T, Fukumoto S, Shimada T (2010) 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 78:975–980CrossRefPubMed
33.
go back to reference Magnusson P, Hansson S, Swolin-Eide D (2010) A prospective study of fibroblast growth factor-23 in children with chronic kidney disease. Scand J Clin Lab Invest 70:15–20CrossRefPubMed Magnusson P, Hansson S, Swolin-Eide D (2010) A prospective study of fibroblast growth factor-23 in children with chronic kidney disease. Scand J Clin Lab Invest 70:15–20CrossRefPubMed
34.
go back to reference Wesseling-Perry K, Pereira RC, Wang H, Elashoff RM, Sahney S, Gales B, Jüppner H, Salusky IB (2009) Relationship between plasma fibroblast growth factor-23 concentration and bone mineralization in children with renal failure on peritoneal dialysis. J Clin Endocrinol Metab 94:511–517CrossRefPubMed Wesseling-Perry K, Pereira RC, Wang H, Elashoff RM, Sahney S, Gales B, Jüppner H, Salusky IB (2009) Relationship between plasma fibroblast growth factor-23 concentration and bone mineralization in children with renal failure on peritoneal dialysis. J Clin Endocrinol Metab 94:511–517CrossRefPubMed
35.
go back to reference Ureña P, De Vernejoul MC (1999) Circulating biochemical markers of bone remodeling in uremic patients. Kidney Int 55:2141–2156CrossRefPubMed Ureña P, De Vernejoul MC (1999) Circulating biochemical markers of bone remodeling in uremic patients. Kidney Int 55:2141–2156CrossRefPubMed
36.
go back to reference Shidara K, Inaba M, Okuno S, Yamada S, Kumeda Y, Imanishi Y, Yamakawa T, Ishimura E, Nishizawa Y (2008) Serum levels of TRAP5b, a new bone resorption marker unaffected by renal dysfunction, as a useful marker of cortical bone loss in hemodialysis patients. Calcif Tissue Int 82:278–287CrossRefPubMed Shidara K, Inaba M, Okuno S, Yamada S, Kumeda Y, Imanishi Y, Yamakawa T, Ishimura E, Nishizawa Y (2008) Serum levels of TRAP5b, a new bone resorption marker unaffected by renal dysfunction, as a useful marker of cortical bone loss in hemodialysis patients. Calcif Tissue Int 82:278–287CrossRefPubMed
37.
go back to reference Seiler S, Heine GH, Fliser D (2009) Clinical relevance of FGF-23 in chronic kidney disease. Kidney Int 76[Suppl 114]:S34–S42CrossRef Seiler S, Heine GH, Fliser D (2009) Clinical relevance of FGF-23 in chronic kidney disease. Kidney Int 76[Suppl 114]:S34–S42CrossRef
Metadata
Title
Serum osteoprotegerin, RANKL and fibroblast growth factor-23 in children with chronic kidney disease
Authors
Ekaterini Siomou
Anna Challa
Nikoleta Printza
Vasileios Giapros
Fotini Petropoulou
Andromachi Mitsioni
Fotios Papachristou
Constantinos J. Stefanidis
Publication date
01-07-2011
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Nephrology / Issue 7/2011
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-011-1870-5

Other articles of this Issue 7/2011

Pediatric Nephrology 7/2011 Go to the issue