NDT Advance Access originally published online on March 26, 2007
Nephrology Dialysis Transplantation 2007 22(6):1537-1546; doi:10.1093/ndt/gfm094
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Fetuin-A (AHSG) prevents extraosseous calcification induced by uraemia and phosphate challenge in mice
1Department of Nephrology and Clinical Immunology, 2Interdisciplinary Center for Clinical Research on Biomaterials and Material-Implant Interactions ‘IZKF-BioMAT’ and 3Department of Biomedical Engineering, RWTH Aachen University Hospital, Aachen, Germany
Correspondence and offprint requests to: Ralf Westenfeld, MD, Department of Nephrology and Clinical Immunology, University Hospital Aachen, Pauwelsstr, 30 D-52057 Aachen, Germany. Email: ralf.westenfeld{at}rwth-aachen.de
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Abstract |
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Background. Chronic kidney disease (CKD) is associated with vascular and tissue calcification. The extent of vascular calcification has been identified as an independent risk factor of cardiovascular death in patients on haemodialysis.
Methods. We studied the role of fetuin-A in CKD-associated calcification using a mouse model of graded renal insufficiency generated by nephrectomy and high phosphate diet. We used wild-type and fetuin-A-deficient mice on the calcification resistant genetic background C57BL/6 to study the influence on calcification of CKD, dietary phosphate and fetuin deficiency. Hyperphosphataemia, elevated BUN, hyperparathyroidism and von Kossa histochemistry served as indicators of calcification disease. The expression of osteopontin, a marker of osteoblast-like cell differentiation was analyzed by realtime PCR and immunohistechemistry.
Results. We detected tissue and genotype-specific susceptibility for calcification. Fetuin-A-deficient mice with CKD and high phosphate diet had only a moderately elevated serum calcium phosphate product (6.9 ± 1.4 mmol2/l2), but suffered severe calcification of kidney, heart and lung. In contrast, wild-type mice under the same conditions developed renal calcinosis only despite an elevated serum calcium phosphate product (9.6 ± 0.9 mmol2/l2). Calcification was preceded by the local induction of osteopontin, a marker for osteoblast-like cell differentiation.
Conclusion. Fetuin-A deficiency, CKD and high phosphate diet act synergistically in the pathogenesis of extraosseous calcification.
Keywords: calcification; calcium; chronic kidney disease; osteopontin; phosphate
Received for publication: 5. 7.06
Accepted in revised form: 1. 2.07
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