Pediatric Nephrology

, Volume 21, Issue 11, pp 1723–1729 | Cite as

The novel bone alkaline phosphatase B1x isoform in children with kidney disease

  • Diana Swolin-Eide
  • Sverker Hansson
  • Lasse Larsson
  • Per MagnussonEmail author
Original Article


The bone alkaline phosphatase (BALP) B1x isoform has previously only been identified in some adults with chronic kidney disease on dialysis and in human bone tissue. Twenty-nine patients, 3–20 years of age, with reduced renal function due to a variety of kidney diseases were examined. We measured parathyroid hormone (PTH), biointact (whole 1–84) PTH, osteoprotegerin (OPG), CrossLaps (CTX), tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) type I procollagen intact amino-terminal propeptide (PINP), osteocalcin, total alkaline phosphatase (ALP), and BALP isoforms B/I, B1x, B1, and B2. Fifty percent higher levels were detected of PTH vs. biointact PTH, demonstrating non-(1–84) PTH fragments detected by the PTH assay. Increased activities were found in five, four, and three patients for total ALP, B1, and B2, respectively. Sixteen (55%) patients had increased B/I levels. B1x was identified in two (7%) patients, who had OPG levels in the higher range independently of age, glomerular filtration rate (GFR), and biointact PTH. B1x was identified prior to and after 9 days of growth hormone (GH) therapy in one patient but not after 1, 3, 6, and 12 months, however. In conclusion, our study demonstrates that the novel BALP B1x isoform is occasionally found to be present in children with kidney disease but to a lesser degree in comparison with adults with chronic kidney disease on dialysis. It is essential to perform bone histomorphometry for future investigations in order to elucidate the exact nature of circulating B1x in patients with kidney disease for accurate classification of type of renal bone disease.


Renal osteodystrophy Chronic kidney disease Parathyroid hormone Pediatric Growth hormone 



We are grateful to Cecilia Linder and Christina Linnér for excellent technical assistance. This study was supported by grants from the Swedish Research Council, the Swedish Society of Medicine, the County Council of Östergötland, the Magn. Bergvalls Foundation, the Åke Wiberg Foundation, the Sahlgrenska University Foundation, the R&D Council in Göteborg and Southern Bohuslän, the Swedish Association for Kidney Patients, and Första Majblommans Riksförbund.


  1. 1.
    Hruska K (2000) Pathophysiology of renal osteodystrophy. Pediatr Nephrol 333:166–174Google Scholar
  2. 2.
    Kuizon BD, Salusky IB (2003) Renal osteodystrophy: pathogenesis, diagnosis, and treatment. In: Glorieux FH, Pettifor JM, Jüppner H (Eds.) Pediatric bone. Biology and diseases. Academic Press, London, pp 679–701Google Scholar
  3. 3.
    Kuizon BD, Salusky IB (1999) Growth retardation in children with chronic renal failure. J Bone Miner Res 14:1680–1690PubMedGoogle Scholar
  4. 4.
    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 45:253–258PubMedGoogle Scholar
  5. 5.
    Ziolkowska H, Panczyk-Tomaszewska M, Debinski A, Polowiec Z, Sawicki A, Sieniawska M (2000) Bone biopsy results and serum bone turnover parameters in uremic children. Acta Paediatr 89:666–671PubMedGoogle Scholar
  6. 6.
    Ureña P, de Vernejoul M-C (1999) Circulating biochemical markers of bone remodeling in uremic patients. Kidney Int 55:2141–2156PubMedGoogle Scholar
  7. 7.
    Rix M, Andreassen H, Eskildsen P, Langdahl B, Olgaard K (1999) Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. Kidney Int 56:1084–1093PubMedGoogle Scholar
  8. 8.
    Bervoets ARJ, Spasovski GB, Behets GJ, Dams G, Polenakovic MH, Zafirovska K, Van Hoof VO, De Broe ME, D’Haese PC (2003) Useful biochemical markers for diagnosing renal osteodystrophy in predialysis endstage renal failure patients. Am J Kidney Dis 41:997–1007PubMedGoogle Scholar
  9. 9.
    Slatopolsky E, Finch J, Clay P, Martin D, Sicard G, Singer G, Gao P, Cantor T, Dusso A (2000) A novel mechanism for skeletal resistance in uremia. Kidney Int 58:753–761PubMedGoogle Scholar
  10. 10.
    Gao P, Scheibel S, D’Amour P, John MR, Rao SD, Schmidt-Gayk H, Cantor TL (2001) Development of a novel immunoradiometric assay exclusively for biologically active whole parathyroid hormone 1–84: implications for improvement of accurate assessment of parathyroid function. J Bone Miner Res 16:605–614PubMedGoogle Scholar
  11. 11.
    Inaba M, Nakatsuka K, Imanishi Y, Watanabe M, Mamiya Y, Ishimura E, Nishizawa Y (2004) Technical and clinical characterization of the bioPTH (1–84) immunochemiluminometric assay and comparison with a secondgeneration assay for parathyroid hormone. Clin Chem 50:385–390PubMedGoogle Scholar
  12. 12.
    Lee SK, Lorenzo JA (1999) Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endocrinology 140:3552–3561PubMedGoogle Scholar
  13. 13.
    Rogers A, Eastell R (2005) Circulating osteoprotegerin and receptor activator for nuclear factor kB ligand: clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab 90:6323–6331PubMedGoogle Scholar
  14. 14.
    Magnusson P, Degerblad M, Sääf M, Larsson L, Thorén M (1997) Different responses of bone alkaline phosphatase isoforms during recombinant insulin-like growth factor-I (IGF-I) and during growth hormone therapy in adults with growth hormone deficiency. J Bone Miner Res 12:210–220PubMedGoogle Scholar
  15. 15.
    Whyte MP (1994) Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev 15:439–461PubMedGoogle Scholar
  16. 16.
    Johnson KA, Hessle L, Vaingankar S, Wennberg C, Mauro S, Narisawa S, Goding JW, Sano K, Millán JL, Terkeltaub R (2000) Osteoblast tissue-nonspecific alkaline phosphatase antagonizes and regulates PC-1. Am J Physiol Regul Integr Comp Physiol 279:R1365–R1377PubMedGoogle Scholar
  17. 17.
    Magnusson P, Löfman O, Larsson L (1992) Determination of alkaline phosphatase isoenzymes in serum by high-performance liquid chromatography with postcolumn reaction detection. J Chromatogr 576:79–86PubMedGoogle Scholar
  18. 18.
    Magnusson P, Löfman O, Larsson L (1993) Methodological aspects on separation and reaction conditions of bone and liver alkaline phosphatase isoform analysis by high-performance liquid chromatography. Anal Biochem 211:156–163PubMedGoogle Scholar
  19. 19.
    Magnusson P, Ärlestig L, Paus E, Di Mauro S, Testa MP, Stigbrand T, Farley JR, Nustad K, Millán JL (2002) Monoclonal antibodies against tissue-nonspecific alkaline phosphatase. Report of the ISOBM TD9 workshop. Tumour Biol 23:228–248PubMedGoogle Scholar
  20. 20.
    Magnusson P, Farley JR (2002) Differences in sialic acid residues among bone alkaline phosphatase isoforms: a physical, biochemical, and immunological characterization. Calcif Tissue Int 71:508–518PubMedGoogle Scholar
  21. 21.
    Magnusson P, Häger A, Larsson L (1995) Serum osteocalcin and bone and liver alkaline phosphatase isoforms in healthy children and adolescents. Pediatr Res 38:955–961PubMedGoogle Scholar
  22. 22.
    Magnusson P, Sharp CA, Magnusson M, Risteli J, Davie MWJ, Larsson L (2001) Effect of chronic renal failure on bone turnover and bone alkaline phosphatase isoforms. Kidney Int 60:257–265PubMedGoogle Scholar
  23. 23.
    Magnusson P, Sharp CA, Farley JR (2002) Different distributions of human bone alkaline phosphatase isoforms in serum and bone tissue extracts. Clin Chim Acta 325:59–70PubMedGoogle Scholar
  24. 24.
    Levey AS, Eckardt K-U, Tsukamoto Y, Levin A, Coresh J, Rossert J, de Zeeuw D, Hostetter TH, Lameire N, Eknoyan G (2005) Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 67:2089–2100PubMedGoogle Scholar
  25. 25.
    Schwartz GJ, Haycock GB, Edelmann Jr CM, Spitzer A (1976) A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58:259–269PubMedGoogle Scholar
  26. 26.
    Nussbaum SR, Zahradnik RJ, Lavigne JR, Brennan GL, Nozawa-Ung K, Kim LY, Keutmann HT, Wang C-A, Potts Jr JT, Segre GV (1987) Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia. Clin Chem 33:1364–1367PubMedGoogle Scholar
  27. 27.
    Szulc P, Hofbauer LC, Heufelder AE, Roth S, Delmas PD (2001) Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status. J Clin Endocrinol Metab 86:3162–3165PubMedGoogle Scholar
  28. 28.
    Masters PW, Jones RG, Purves DA, Cooper EH, Cooney JM (1994) Commercial assays for serum osteocalcin give clinically discordant results. Clin Chem 40:358–363PubMedGoogle Scholar
  29. 29.
    Melkko J, Kauppila S, Niemi S, Risteli L, Haukipuro K, Jukkola A, Risteli J (1996) Immunoassay for intact amino-terminal propeptide of human type I procollagen. Clin Chem 42:947–954PubMedGoogle Scholar
  30. 30.
    Rosenquist C, Fledelius C, Christgau S, Pedersen BJ, Bonde M, Qvist P, Christiansen C (1998) Serum CrossLaps One Step ELISA. First application of monoclonal antibodies for measurement in serum of bonerelated degradation products from C-terminal telopeptides of type I collagen. Clin Chem 44:2281–2289PubMedGoogle Scholar
  31. 31.
    Sassi M-L, Eriksen H, Risteli L, Niemi S, Mansell J, Gowen M, Risteli J (2000) Immunochemical characterization of assay for carboxyterminal telopeptide of human type I collagen: loss of antigenicity by treatment with cathepsin K. Bone 26:367–373PubMedGoogle Scholar
  32. 32.
    Halleen JM, Alatalo SL, Suominen H, Cheng SL, Janckila AJ, Väänänen HK (2000) Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption. J Bone Miner Res 15:1337–1345PubMedGoogle Scholar
  33. 33.
    Cioffi M, Corradino M, Gazzerro P, Vietri MT, Di Macchia C, Contursi A, Colicigno R, Catalano T, Molinari AM (2000) Serum concentrations of intact parathyroid hormone in healthy children. Clin Chem 46:863–864PubMedGoogle Scholar
  34. 34.
    Buzi F, Maccarinelli G, Guaragni B, Ruggeri F, Radetti G, Meini A, Mazzolari E, Cocchi D (2004) Serum osteoprotegerin and receptor activator of nuclear factors kB (RANKL) concentrations in normal children and in children with pubertal precocity, Turner’s syndrome and rheumatoid arthritis. Clin Endocrinol 60:87–91Google Scholar
  35. 35.
    Tarallo P, Henny J, Fournier B, Siest G (1990) Plasma osteocalcin: biological variations and reference limits. Scand J Clin Lab Invest 50:649–655PubMedGoogle Scholar
  36. 36.
    van der Sluis IM, Hop WC, van Leeuwen JPTM, Pols HAP, de Muinck Keizer-Schrama SMPF (2002) A crosssectional study on biochemical parameters of bone turnover and vitamin D metabolites in healthy dutch children and young adults. Horm Res 57:170–179PubMedGoogle Scholar
  37. 37.
    Crofton PM, Evans N, Taylor MRH, Holland CV (2002) Serum CrossLaps: pediatric intervals from birth to 19 years of age. Clin Chem 48:671–673PubMedGoogle Scholar
  38. 38.
    Alatalo SL, Ivaska KK, Waguespack SG, Econs MJ, Väänänen HK, Halleen JM (2004) Osteoclast-derived serum tartrate-resistant acid phosphatase 5b in Albers-Schönberg disease (type II autosomal dominant osteopetrosis). Clin Chem 50:883–890PubMedGoogle Scholar
  39. 39.
    Magnusson P, Larsson L, Magnusson M, Davie MWJ, Sharp CA (1999) Isoforms of bone alkaline phosphatase: characterization and origin in human trabecular and cortical bone. J Bone Miner Res 14:1926–1933PubMedGoogle Scholar
  40. 40.
    Ohlsson C, Bengtsson B-Å, Isaksson OGP, Andreassen TT, Slootweg MC (1998) Growth hormone and bone. Endocr Rev 19:55–79Google Scholar
  41. 41.
    Haffner D, Schaefer F, Nissel R, Wühl E, Tönshoff B, Mehls O (2000) Effect of growth hormone treatment on the adult height of children with chronic renal failure. German study group for growth hormone treatment in chronic renal failure. N Engl J Med 343:923–930PubMedGoogle Scholar
  42. 42.
    Kaskel F (2003) Chronic renal disease: a growing problem. Kidney Int 64:1141–1151PubMedGoogle Scholar
  43. 43.
    Lepage R, Roy L, Brossard J-H, Rousseau L, Dorais C, Lazure C, D’Amour P (1998) A non-(1–84) circulating parathyroid hormone (PTH) fragment interferes significantly with intact PTH commercial assay measurements in uremic samples. Clin Chem 44:805–809PubMedGoogle Scholar
  44. 44.
    Friedman PA (2004) PTH revisited. Kidney Int 66(Suppl 91):S13–S19Google Scholar
  45. 45.
    Rogers A, Saleh G, Hannon RA, Greenfield D, Eastell R (2002) Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women. J Clin Endocrinol Metab 87:4470–4475PubMedGoogle Scholar
  46. 46.
    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 17:233–238PubMedGoogle Scholar
  47. 47.
    Kazama JJ, Shigematsu T, Yano K, Tsuda E, Miura M, Iwasaki Y, Kawaguchi Y, Gejyo F, Kurokawa K, Fukagawa M (2002) Increased circulating levels of osteoclastogenesis inhibitory factor (osteoprotegerin) in patients with chronic renal failure. Am J Kidney Dis 39:525–532PubMedGoogle Scholar
  48. 48.
    Kazama JJ (2004) Osteoprotegerin and bone mineral metabolism in renal failure. Curr Opin Nephrol Hypertens 13:411–415PubMedGoogle Scholar
  49. 49.
    Risteli J, Risteli L (1999) Products of bone collagen metabolism. In: Seibel MJ, Robins SP, Bilezikian JP (Eds.) Dynamics of bone and cartilage metabolism: principles and clinical applications. Academic Press, London, pp 275–287Google Scholar
  50. 50.
    Bruder SP, Horowitz MC, Mosca JD, Haynesworth SE (1997) Monoclonal antibodies reactive with human osteogenic cell surface antigens. Bone 21:225–235PubMedGoogle Scholar
  51. 51.
    Ivaska KK, Hentunen TA, Vääräniemi J, Ylipahkala H, Pettersson K, Väänänen HK (2004) Release of intact and fragmented osteocalcin molecules from bone matrix during bone resorption in vitro. J Biol Chem 279:18361–18369PubMedGoogle Scholar
  52. 52.
    Charhon SA, Delmas PD, Malaval L, Chavassieux PM, Arlot M, Chapuy M-C, Meunier PJ (1986) Serum bone Gla-protein in renal osteodystrophy: comparison with bone histomorphometry. J Clin Endocrinol Metab 63:892–897PubMedGoogle Scholar
  53. 53.
    Ureña P, Ferreira A, Kung VT, Morieux C, Simon P, Ang KS, Souberbielle JC, Segre GV, Drüeke TB, de Vernejoul MC (1995) Serum pyridinoline as a specific marker of collagen breakdown and bone metabolism in hemodialysis patients. J Bone Miner Res 10:932–939PubMedGoogle Scholar

Copyright information

© IPNA 2006

Authors and Affiliations

  • Diana Swolin-Eide
    • 1
  • Sverker Hansson
    • 1
  • Lasse Larsson
    • 2
  • Per Magnusson
    • 2
    • 3
    Email author
  1. 1.Department of PediatricsThe Queen Silvia Children’s Hospital, The Sahlgrenska Academy at Göteborg UniversityGöteborgSweden
  2. 2.Division of Clinical ChemistryLaboratory Medicine Center, Linköping University HospitalLinköpingSweden
  3. 3.Bone and Mineral Metabolic Unit, Division of Clinical Chemistry, Department of Biomedicine and SurgeryFaculty of Health SciencesLinköpingSweden

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