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Bone alkaline phosphatase isoforms in CKD patients on hemodialysis with low and high bone turnover
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology. Department of Nephrology, Karolinska University Hospital, Stockholm, Sweden.
Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, USA.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry. Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, USA.
2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Renal osteodystrophy encompasses the bone histologic abnormalities seen in patients with chronic kidney disease (CKD). The bone-specific alkaline phosphatase (BALP) isoform B1x is exclusively found in serum of some CKD patients.

Study Design: The aim of this cross-sectional diagnostic test study was to examine the relationship between serum BALP isoform activities and histomorphometric parameters of bone in patients with CKD on chronic hemodialysis.

Setting & Participants: Anterior iliac crest bone biopsy samples from 40 CKD patients were selected on the basis of bone turnover for histomorphometric analysis. There were samples from 20 patients with low and 20 with non-low bone turnover.

Index Test: In serum, BALP, BALP isoforms (B/I, B1x, B1 and B2), and parathyroid hormone (PTH) were measured.

Reference Test or Outcome: Indices of osteoblastic activity and number.

Other Measurements: Parathyroid hormone

Results: B1x was found in 21 patients (53%) who had lower median levels of BALP, 18.6 versus 46.9 U/L; B/I, 0.10 versus 0.22 μkat/L; B1, 0.40 versus 0.88 μkat/L; B2, 1.21 versus 2.66 μkat/L; and PTH, 49 versus 287 pg/mL, compared to patients without B1x (p<0.001). B1x correlated inversely with osteoblast number and activity. ROC curves showed that B1x (AUC 0.83) can be used for diagnosis of low osteoblastic activity, while BALP (AUC 0.78) and PTH (AUC 0.77) are useful for diagnosis of high osteoblast number seen with high bone turnover.

Limitations: Small number of study participants.

Conclusions: The presence of B1x in serum may be a sign of perturbed osteoblast activity and it may be useful as a diagnostic parameter for low bone turnover rate.

Place, publisher, year, edition, pages
2014.
Keyword [en]
Bone-specific alkaline phosphatase; isoforms; renal osteodystrophy; osteoblast activity; low bone turnover
National Category
Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-111868OAI: oai:DiVA.org:liu-111868DiVA: diva2:761377
Available from: 2014-11-06 Created: 2014-11-06 Last updated: 2015-03-31Bibliographically approved
In thesis
1. Bone alkaline phosphatase isoforms in chronic kidney disease: mineral and bone disorder
Open this publication in new window or tab >>Bone alkaline phosphatase isoforms in chronic kidney disease: mineral and bone disorder
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic kidney disease (CKD) is associated with increased mortality and cardiovascular complications. Disturbances in mineral metabolism occur early <luring the course of CKD and several components of the CKD-mineral and bone disorder (CKD-MBD) are independent predictors of mortality. Alkaline phosphatase (ALP) is necessary for skeletal mineralization and is also involved in the process of vascular calcification. In recent years, ALP has evolved as a strong predictor of mortality in the CKD population. The significant role of ALP in the mineralization process renders it a putative target for the treatment and prevention of vascular calcification. Three circulating isoforms of bone ALP (BALP) have been identified (B/I, B 1, and B2). A fourth isoform, Blx, has been identified exclusively in serum from patients with CKD. The aim of the present thesis was to further elucidate the role ofthe BALP isoforms in CKD with respect to bone abnormalities and vascular calcification.

In study I we identified the novel BALP isoform Blx in 20% of patients with mild to moderate CKD. Blx was associated with lower glomerular filtration rate and higher serum phosphate and calcium x phosphate product, which are risk factors for cardiovascular mortality in CKD. We also identified the BALP isoforms B/I, Bl and B2 as predictors of total hip bone mineral density.

Study II was an experimental study, investigating the role of the BALP isoforms in phosphate induced calcification of human aortic smooth muscle cells (HASMCs). We found that the ALP expressed in HASMCs is exclusively BALP. Phosphate induced calcification of HASMCs was associated with increased BALP isoforms B/I, Blx, and B2 activities, which implies functional differences between the BALP isoforms in HASMC calcification.

In study III we investigated the association of BALP isoforms in serum and histomorphometric parameters of bone in patients on chronic hemodialysis. W e identified the BALP isoform Blx as a novel marker for reduced osteoblastic activity.

Study IV was a prospective cohort study of the association of serum BALP isoforms with aortic calcification and vascular stiffness in prevalent chronic dialysis patients. Blx was associated with baseline and time varying vascular stiffness, determined by pulse wave velocity, but not with calcification of the abdominal aorta. We also found an association of Blx with better event-free survival.

In conclusion, these studies demonstrate that the BALP isoforms, especially isoform Blx, are involved in different aspects of CKD-MBD. This opens up for further research to identify the BALP isoforms as diagnostic markers and possible treatment targets in CKD-MBD.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 89 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1427
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-111870 (URN)10.3384/diss.diva-111870 (DOI)978-91-7519-204-8 (ISBN)
Public defence
2014-11-21, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2014-11-06 Created: 2014-11-06 Last updated: 2015-06-08Bibliographically approved

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Haarhaus, MathiasMagnusson, Per

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