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Mechanisms and treatment of extraosseous calcification in chronic kidney disease

Nature Reviews Nephrology volume 7, pages 509–516 (2011)Cite this article

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Abstract

Strong and unidirectional associations exist between the severity of cardiovascular calcifications and mortality in patients with advanced chronic kidney disease. In the past 10 years, a wealth of experimental and clinical information has been published on the key pathophysiological events that contribute to the development and progression of vascular and soft-tissue calcifications. These processes involve a sensitive balance of calcification inhibition, induction and removal. The traditional view of regarding secondary hyperparathyroidism and elevated calcium × phosphate product as the pivotal risk factors for calcification has been challenged by data demonstrating a role for other, more subtle and complex pathomechanisms. These mechanisms include the loss of endogenous calcification inhibitors, deficient clearance of calcified debris, effects of vitamin K and vitamin D, and the action of calcification inducers as in osteogenic transdifferentiation. In this Review, we describe our current knowledge of the factors involved in the passive and active regulation of extraosseous calcification processes, with an assessment of their importance as targets for future diagnostic and therapeutic interventions.

Key Points

  • Extraosseous calcification is highly prevalent in patients with chronic kidney disease and may contribute to impaired outcomes

  • Defective clearance mechanisms of calcified debris, such as fetuin-A-dependent calciprotein particles, may contribute to increased calcification and serve as a future therapeutic target

  • Both phosphate and calcium contribute to osteogenic transdifferentiation in the vessel wall and serum levels of these elements should thus be closely controlled in patients with chronic kidney disease

  • Vitamin D and vitamin K have been linked to the regulation of calcification mechanisms, and controlled supplementation of these vitamins may be required in patients with chronic kidney disease

  • Drugs with anticalcific therapeutic potential include sodium thiosulfate, bisphosphonates and calcimimetics, which intervene with extraosseous calcification processes through various molecular mechanisms

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Figure 1: Microcalcifications from a uremic iliac artery visualized by transmission electron microscopy.
Figure 2: Centrifugation procedure of FMC purification from human blood.
Figure 3: The two forms of vitamin K, vitamin K1 (phylloquinone, mainly derived from vegetables) and vitamin K2 (menaquinone, mainly derived from fermented food such as cheese), are differentially distributed in the body.

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Authors and Affiliations

  1. Department of Medicine III, Division of Nephrology, Klinikum Coburg GmbH, Ketschendorfer Straβe 33, Coburg, 96450, Germany

    Markus Ketteler, Hansjörg Rothe & Patrick H. Biggar

  2. Department of Medicine II, Division of Nephrology and Clinical Immunology, University Hospital of the RWTH Aachen, Pauwelsstraβe 30, Aachen, 52074, Germany

    Thilo Krüger & Georg Schlieper

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M. Ketteler, P. H. Biggar and G. Schlieper wrote the article. All the authors contributed equally to researching data for the article, substantial contribution to discussion of the content, and reviewing and editing of the manuscript before submission.

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M. Ketteler has worked as a consultant for and received speakers bureau honoraria from Abbott, Amgen, Fresenius Medical Care, Genzyme and Shire, and received grant/research support from Abbott and Amgen. P. H. Biggar has received speakers bureau honoraria from Abbott, Amgen and Genzyme. G. Schlieper has received speakers bureau honoraria from Amgen, Gambro and Genzyme and received grant/research support from Genzmye. H. Rothe and T. Krüger declare no competing interests.

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Ketteler, M., Rothe, H., Krüger, T. et al. Mechanisms and treatment of extraosseous calcification in chronic kidney disease. Nat Rev Nephrol 7, 509–516 (2011). https://doi.org/10.1038/nrneph.2011.91

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