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(Circulation. 2008;118:1748-1757.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Dialysis Accelerates Medial Vascular Calcification in Part by Triggering Smooth Muscle Cell Apoptosis

Rukshana C. Shroff, MRCPCH; Rosamund McNair; Nichola Figg; Jeremy N. Skepper, PhD; Leon Schurgers, PhD; Ashmeet Gupta, MRCPCH; Melanie Hiorns, FRCR; Ann E. Donald, PhD; John Deanfield, FRCP; Lesley Rees, FRCPCH; Catherine M. Shanahan, PhD

From the Nephrology (R.C.S., A.G., L.R.), Radiology (M.H.), and Vascular Physiology (A.E.D., J.D.) Units, Great Ormond Street Hospital and University College London Institute of Child Health; BHF Centre, Cardiovascular Division, King’s College London (R.C.S., C.M.S.), London; Department of Medicine, Addenbrooke’s Hospital (R.M., N.F.); Multi-Imaging Centre, Department of Anatomy (J.N.S.), Cambridge, United Kingdom; and CARIM and VitaK (L.S.), University of Maastricht, Maastricht, The Netherlands.

Correspondence to Catherine Shanahan, PhD, BHF Centre, BHF Senior Fellow and Professor of Cellular Signalling, Cardiovascular Division, 125 Coldharbour Lane, King’s College London, London SE5 9NU. E-mail cathy.shanahan{at}kcl.ac.uk

Received April 3, 2008; accepted August 14, 2008.

Background— Vascular calcification is associated with increased morbidity and mortality in stage V chronic kidney disease, yet its early pathogenesis and initiating mechanisms in vivo remain poorly understood. To address this, we quantified the calcium (Ca) load in arteries from children (10 predialysis, 24 dialysis) and correlated it with clinical, biochemical, and vascular measures.

Methods and Results— Vessel Ca load was significantly elevated in both predialysis and dialysis and was correlated with the patients’ mean serum Caxphosphate product. However, only dialysis patients showed increased carotid intima-media thickness and increased aortic stiffness, and calcification on computed tomography was present in only the 2 patients with the highest Ca loads. Importantly, predialysis vessels appeared histologically intact, whereas dialysis vessels exhibited evidence of extensive vascular smooth muscle cell (VSMC) loss owing to apoptosis. Dialysis vessels also showed increased alkaline phosphatase activity and Runx2 and osterix expression, indicative of VSMC osteogenic transformation. Deposition of the vesicle membrane marker annexin VI and vesicle component mineralization inhibitors fetuin-A and matrix Gla-protein increased in dialysis vessels and preceded von Kossa positive overt calcification. Electron microscopy showed hydroxyapatite nanocrystals within vesicles released from damaged/dead VSMCs, indicative of their role in initiating calcification.

Conclusions— Taken together, this study shows that Ca accumulation begins predialysis, but it is the induction of VSMC apoptosis in dialysis that is the key event in disabling VSMC defense mechanisms and leading to overt calcification, eventually with clinically detectable vascular damage. Thus the identification of factors that lead to VSMC death in dialysis will be of prime importance in preventing vascular calcification.

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CLINICAL PERSPECTIVE

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Clinical Summaries
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