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  • 1.
    Haarhaus, Mathias
    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.
    Bone alkaline phosphatase isoforms in chronic kidney disease: mineral and bone disorder2014Doctoral 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.

    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, p. 3382-3389Article 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.

    Keywords
    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, p. 167-174Article 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
    Keywords
    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.

    Keywords
    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.

    Keywords
    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
  • 2.
    Haarhaus, Mathias
    et al.
    Linköping University, Department of Medical and Health Sciences, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology.
    Magnusson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
    Calcifying Human Aortic Smooth Muscle Cells Express Different Bone Alkaline Phosphatase Isoforms, Including the Novel B1x Isoform2013In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 50, no 2, p. 167-174Article in journal (Refereed)
    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.

  • 3.
    Haarhaus, Mathias
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nephrology. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology UHL.
    Fernström, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nephrology. Östergötlands Läns Landsting, Reconstruction Centre, Department of Neurosurgery UHL.
    Larsson, Lasse
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Magnusson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Magnusson, Martin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nephrology.
    Evaluation of bio-intact (1-84) parathyroid hormone, vitamin D status and bond mineral density in patients with predialysis chronic renal failure2004In: ASN Renal Week,2004, 2004Conference paper (Other academic)
  • 4.
    Haarhaus, Mathias
    et al.
    Linköping University, Department of Medicine and Care, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Nephrology.
    Fernström, Anders
    Linköping University, Department of Medicine and Care, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology UHL.
    Magnusson, Martin
    Linköping University, Department of Medicine and Care, Nephrology. Linköping University, Faculty of Health Sciences.
    Magnusson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Clinical significance of bone alkaline phosphatase isoforms, including the novel B1x isoform, in mild to moderate chronic kidney disease2009In: NEPHROLOGY DIALYSIS TRANSPLANTATION, ISSN 0931-0509, Vol. 24, no 11, p. 3382-3389Article in journal (Refereed)
    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.

  • 5.
    Haarhaus, Mathias
    et al.
    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.
    Fernström, Anders
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology. Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, USA.
    Magnusson, Per
    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.
    A multicenter prospective study of bone alkaline phosphatase isoforms and arterial calcification in chronic kidney disease patients on dialysis2014Manuscript (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.

  • 6.
    Haarhaus, Mathias
    et al.
    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.
    Monier-Faugere, Marie-Claude
    Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Albert B. Chandler Medical Center, USA.
    Magnusson, Per
    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.
    Malluche, Hartmut H.
    Bone alkaline phosphatase isoforms in CKD patients on hemodialysis with low and high bone turnover2014Manuscript (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.

  • 7.
    Haarhaus, Mathias
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Karolinska University Hospital, Sweden.
    Monier-Faugere, Marie-Claude
    University of Kentucky, KY 40536 USA.
    Magnusson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Malluche, Hartmut H.
    University of Kentucky, KY 40536 USA.
    Bone Alkaline Phosphatase Isoforms in Hemodialysis Patients With Low Versus Non-Low Bone Turnover: A Diagnostic Test Study2015In: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 66, no 1, p. 99-105Article in journal (Refereed)
    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 patients with CKD. Study Design: The aim of this cross-sectional diagnostic test study was to examine the relationship between serum bALP isoform activity and histomorphometric parameters of bone in patients with CKD receiving maintenance hemodialysis. Settings and Participants: Anterior iliac crest bone biopsy samples from 40 patients with CKD 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: Low bone turnover was defined by mineral apposition rate, 0.36 mu m/d. Non-low bone turnover was defined by mineral apposition rate greater than= 0.36 mu m/d. Other Measurements: PTH. 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 mu kat/L; B1, 0.40 versus 0.88 mu kat/L; B2, 1.21 versus 2.66 mu kat/L; and PTH, 49 versus 287 pg/mL, compared with patients without B1x (P less than 0.001). 13 patients (65%) with low bone turnover and 8 patients (40%) with non-low bone turnover (P less than 0.2) had detectable B1x. B1x correlated inversely with histomorphometric parameters of bone turnover. Receiver operating characteristic curves showed that B1x can be used for the diagnosis of low bone turnover (area under the curve [AUC], 0.83), whereas bALP (AUC, 0.89) and PTH (AUC, 0.85) are useful for the diagnosis of non-low bone turnover. Limitations: Small number of study participants. Requirement of high-performance liquid chromatography methods for measurement of B1x. Conclusions: B1x, PTH, and bALP have similar diagnostic accuracy in distinguishing low from non-low bone turnover. The presence of B1x is diagnostic of low bone turnover, whereas elevated bALP and PTH levels are useful for the diagnosis of non-low bone turnover.

  • 8.
    Hadimeri, Henrik
    et al.
    Kärnsjukhuset, Skövde, Sweden.
    Frisenette-Fich, Carsten
    Ryhov, Jönköping, Sweden.
    Deurell, Sven-Ingemar
    Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Svensson, Lars
    Höglandssjukhuset, Eksjö, Sweden.
    Carlsson-Bjering, Lena
    Höglandssjukhuset, Eksjö, Sweden.
    Fernström, Anders
    Linköping University, Department of Medical and Health Sciences, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Almroth, Gabriel
    Linköping University, Department of Medicine and Care, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Melander, Stefan
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Haarhaus, Mathias
    Linköping University, Department of Medicine and Care, Nephrology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Andersson, Per-Olof
    Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Cassel, Agneta
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Mauritz, Nils-Johan
    Ryhov, Jönköping, Sweden.
    Ståhl-Nilsson, Agneta
    Ryhov, Jönköping, Sweden.
    Wilske, Jan
    Värnamo Sjukhus, Sweden .
    Nordström, Kataryna
    Värnamo Sjukhus, Sweden .
    Oruda, Pavel
    Värnamo Sjukhus, Sweden .
    Eriksson, Marie
    Umeå University, Sweden .
    Inghilesi Larsson, Annelie
    Umeå University, Sweden .
    Stegmayr, Bernd
    Umeå University, Sweden .
    A fixed protocol for outpatient clinic routines in the care of patients with severe renal failure2013In: Renal failure, ISSN 0886-022X, E-ISSN 1525-6049, Vol. 35, no 6, p. 845-854Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The primary aim of this study was to assess whether a fixed protocol, using a specially trained team, for intermediate follow-up to fulfillment of guideline targets is non-inferior to conventional follow-up in the care of uraemic patients. A secondary aim was to investigate possible impact on patient outcome.

    METHODS:

    The cohort comprised 424 patients from seven centers. Inclusion criteria were either serum creatinine exceeding 200 µmol/l or calculated clearance below 30 ml/min, representing CKD 4 or 5a. Six centers followed a standardized protocol (group 1). One center provided controls (group 2). The study design was prospective and interventional. The variables measured were blood hemoglobin, bicarbonate, calcium, phosphate, intact parathyroid hormone, albumin, renal function variables, blood pressure and RAAS blockade. The number of patients achieving the set goals was analyzed as a time trend to determine if the intervention resulted in an improvement.

    RESULTS:

    At baseline, group 1 had significantly lower GFR and higher serum creatinine, calcium, phosphate, calcium × phosphate product and bicarbonate, lower mean arterial pressure (MAP), systolic blood pressures and less use of RAAS. During the intervention, group 1 improved in the direction of guidelines for blood hemoglobin, albumin, bicarbonate and MAP. Outcome of secondary endpoints gave a risk of death of 30% in both groups, while the risk of renal replacement therapy was higher in group 1.

    CONCLUSIONS:

    However, the time to renal replacement therapy was significantly shorter in the intervention group, indicating that other variables than guideline achievements are important for the patient.

  • 9.
    Ljungdahl, Nina
    et al.
    Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Linköping University, Faculty of Health Sciences.
    Haarhaus, Mathias
    Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Linköping University, Faculty of Health Sciences.
    Linder, Cecilia
    Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Magnusson, Per
    Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Comparison of 3 Third-Generation Assays for Bio-intact Parathyroid Hormone2006In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 52, no 5, p. 903-904Article in journal (Refereed)
  • 10. Söderlund, Gustav
    et al.
    Haarhaus, Mathias
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Nephrology. Östergötlands Läns Landsting, Centre for Medicine, Department of Nephrology UHL.
    Chisalita, Ioana Simona
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Arnqvist, Hans
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Inhibition of puromycin-induced apoptosis in breast cancer cells by IGF-I occurs simultaneously with increased protein synthesis2004In: Neoplasma (Bratislava), ISSN 0028-2685, E-ISSN 1338-4317, Vol. 51, no 1Article in journal (Refereed)
    Abstract [en]

    The objective of the following work was to study the apoptosis inducing effect of puromycin in MCF-7 breast cancer cells and compare this effect with cycloheximide and emetine, 2 other inhibitors of protein synthesis. We also wished to investigate if the apoptosis modulating effect of insulin-like growth factor-1 (IGF-I) was similar for the 3 inhibitors. An immunological assay, quantifying mono- and oligonucleosome fragments and morphological criteria after nuclear staining, were used to study apoptosis. Protein synthesis was measured by incorporation of 3H-leucine in the cells, and solution hybridization and Western blot were performed to estimate IGF-I receptor m-RNA and IGF-I receptor protein respectively. Puromycin at 0.5 μg/ml induced a high level of apoptosis in MCF-7 breast cancer cells, although there was still a non-negligible amount of synthesized protein. In the case of cycloheximide and emetine, apoptosis occured when protein synthesis was almost completely blocked. IGF-I at a concentration of 10 ng/ml significantly reduced the level of apoptosis induced by puromycin, emetine, or cycloheximide. We also noticed a parallel increase in 3H-leucine incorporation when apoptosis induced by puromycin was lowered as an effect of IGF-I, in contrast to cycloheximide and emetine where IGF-I reduced the apoptosis level without increasing the 3H-leucine incorporation. At a higher concentration of puromycin (5. 7 μg/ml), which blocked protein synthesis, IGF-I at 10 ng/ml did not reduce apoptosis. The level of IGF-I receptor m-RNA was not influenced by the use of a concentration of puromycin (0.5 μg/ml) inducing a high degree of apoptosis. These results suggest, that reduction of puromycin-induced apoptosis by IGF-I occurs simultaneously with increased protein synthesis, in contrast to emetine and cycloheximide. Furthermore it would appear that puromycin-induced apoptosis is not caused by reduced levels of IGF-I receptors.

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