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Bone alkaline phosphatase isoforms in chronic kidney disease: mineral and bone disorder
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.
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: urn:nbn:se:liu:diva-111870DOI: 10.3384/diss.diva-111870ISBN: 978-91-7519-204-8 (print)OAI: oai:DiVA.org:liu-111870DiVA: diva2:761401
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
List of papers
1. Clinical significance of bone alkaline phosphatase isoforms, including the novel B1x isoform, in mild to moderate chronic kidney disease
Open this publication in new window or tab >>Clinical significance of bone alkaline phosphatase isoforms, including the novel B1x isoform, in mild to moderate chronic kidney disease
2009 (English)In: NEPHROLOGY DIALYSIS TRANSPLANTATION, ISSN 0931-0509, Vol. 24, no 11, 3382-3389 p.Article in journal (Refereed) Published
Abstract [en]

Background. Mineral bone disorder (MBD) is a common complication of chronic kidney disease (CKD) even during the early stages. Bone alkaline phosphatase (BALP) is a marker of bone fort-nation and plays a pivotal role in the mineralization process. Three BALP isoforms (B/I, B1 and B2) have been identified in healthy individuals and a fourth isoform (B1x) has been discovered in serum from dialysis patients. We investigated these BALP isoforms, type I procollagen intact amino-terminal propeptide (PINP), carboxy-terminal telopeptide of type I collagen (CTX) and tartrate-resistant acid phosphatase isoform 5b (TRACP5b), as well as bone mineral density (BMD) in predialysis CKD patients. Methods. PINP, CTX, TRACP5b and BALP isoforms were analysed in serum from 46 patients within CKD stages 3-5. BMD was determined by dual-energy x-ray absorptiometry. Results. PINP, TRACP5b and the BALP isoforms, B/I, B1 and B2, were independent predictors of total hip BMD in all patients. Furthermore, B/I predicted osteopaenia in the hip and in the distal 1/3 of the radius in CKD stage 3. The B1x isoform was detected in nine patients (20%), who had lower GFR, higher phosphate and calcium x phosphate product. Conclusion. We found an association of BALP isoforms and other markers of bone turnover with total hip BMD, which predominantly comprises trabecular bone. The association of the new BALP isoform B1x with risk factors for vascular calcification leads us to hypothesize a possible role for B1x in this process. The significance of the BALP isoforms in CKD remains to be further explored in experimental and clinical settings in conjunction with bone histomorphometry.

Keyword
alkaline phosphatase, bone mineral density, bone turnover, mineral bone disorder, predialysis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-52373 (URN)10.1093/ndt/gfp300 (DOI)
Available from: 2009-12-18 Created: 2009-12-18 Last updated: 2014-11-06
2. Calcifying Human Aortic Smooth Muscle Cells Express Different Bone Alkaline Phosphatase Isoforms, Including the Novel B1x Isoform
Open this publication in new window or tab >>Calcifying Human Aortic Smooth Muscle Cells Express Different Bone Alkaline Phosphatase Isoforms, Including the Novel B1x Isoform
2013 (English)In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 50, no 2, 167-174 p.Article in journal (Refereed) Published
Abstract [en]

Background: Vascular calcification, causing cardiovascular morbidity and mortality, is associated with hyperphosphatemia in chronic kidney disease (CKD). In vitro, phosphate induces transdifferentiation of vascular smooth muscle cells to osteoblast-like cells that express alkaline phosphatase (ALP). In vivo, raised serum ALP activities are associated with increased mortality. A new bone ALP isoform (B1x) has been identified in serum from CKD patients. The present study investigated the different ALP isoforms in calcifying human aortic smooth muscle cells (HAoSMCs). Methods: HAoSMCs were cultured for 30 days in medium containing 5 or 10 mmol/l beta-glycerophosphate in the presence or absence of the ALP-specific inhibitor tetramisole. Results: All known bone-specific ALP (BALP) isoforms (B/I, B1x, B1 and B2) were identified in HAoSMCs. beta-Glycerophosphate stimulated calcification of HAoSMCs, which was associated with increased BALP isoforms B/I, B1x and B2. Tetramisole inhibited the beta-glycerophosphate-induced HAoSMC calcification, which was paralleled by the inhibition of the B1x and B/I, but not the other isoforms. Conclusions: HAoSMCs express the four known BALP isoforms. B/I, B1x and B2 could be essential for soft tissue calcification. B/I and B1x were more affected by tetramisole than the other isoforms, which suggests different biological functions during calcification of HAoSMCs.

Place, publisher, year, edition, pages
S. Karger, 2013
Keyword
Bone-specific alkaline phosphatase, Chronic kidney disease, Human aortic smooth muscle cells, Isoforms, Phosphate, Vascular calcification
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90089 (URN)10.1159/000346161 (DOI)000314995500008 ()
Note

Funding Agencies|Ingrid Asps Foundation for Nephrology Research at Linkoping University||County Council of Ostergotland||Swedish Association for Kidney Patients||

Available from: 2013-03-21 Created: 2013-03-19 Last updated: 2017-12-06
3. Bone alkaline phosphatase isoforms in CKD patients on hemodialysis with low and high bone turnover
Open this publication in new window or tab >>Bone alkaline phosphatase isoforms in CKD patients on hemodialysis with low and high bone turnover
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.

Keyword
Bone-specific alkaline phosphatase; isoforms; renal osteodystrophy; osteoblast activity; low bone turnover
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-111868 (URN)
Available from: 2014-11-06 Created: 2014-11-06 Last updated: 2015-03-31Bibliographically approved
4. A multicenter prospective study of bone alkaline phosphatase isoforms and arterial calcification in chronic kidney disease patients on dialysis
Open this publication in new window or tab >>A multicenter prospective study of bone alkaline phosphatase isoforms and arterial calcification in chronic kidney disease patients on dialysis
2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Chronic kidney disease – mineral and bone disorder (CKD-MBD) is associated with high morbidity and mortality due to frequent cardiovascular (CV) complications. Accelerated arterial stiffening and calcification are associated with serum alkaline phosphatase (ALP) in advanced CKD. We have previously described three bone ALP (BALP) isoforms in healthy individuals and detected a novel isoform, B1x, exclusively in serum from some CKD patients, in bone and in calcifying vascular smooth muscle cells. We investigated the association of these BALP isoforms, abdominal aortic calcification (AAC) score and carotid – femoral pulse wave velocity (PWV), with outcome in a 2-year prospective multicenter study of 68 prevalent dialysis patients participating in the Calcification Outcome in Renal Disease (CORD) study. Twenty-one patients experienced a combined event of all-cause mortality or a first nonfatal CV event during follow-up. PWV (hazard ratio 1.067, P = 0.03) was independently associated with the combined event. B1x was detected in 53 patients and was associated with baseline PWV (Kendall's tau 0.23, P = 0.007) and with variation of PWV over time (estimate 14.14, P = 0.03). Patients with B1x had lower levels of PTH and total ALP, indicating a possible association with low bone turnover. We found no association of BALP isoforms with AAC score. Cox regression revealed B1x as a positive predictor of event free survival (hazard ratio 0.98, P = 0.01). In conclusion, B1x is associated with vascular stiffness in CKD 5D. This finding is contrasted by the ability of B1x to predict longer event free survival in the current study.

Keyword
Chronic kidney disease – mineral and bone disorder, dialysis, bone alkaline phosphatase, mortality, cardiovascular disease
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-111869 (URN)
Available from: 2014-11-06 Created: 2014-11-06 Last updated: 2015-03-31Bibliographically approved

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