Rapidly Progressive Severe Vascular Calcification Sparing the Kidney Allograft Following Warfarin Initiation

Abstract

We describe a case of rapid onset of vascular calcification coincident with the initiation of warfarin therapy in a kidney transplant patient. Calcification developed within the media of the blood vessel wall, with relative intimal sparing. Medium and small sized arteries were affected, but the aorta was mostly free of calcifications, suggesting a differential response to warfarin between the intima and media as well as between different vascular beds. In addition, unlike the highly calcified native kidney's vessels, the kidney allograft was not calcified, suggesting local, genetically determined, mechanisms in preventing vascular calcification. Distal subcutaneous necrosis ultimately lead to the patient's demise. Index wordsvascular calcification; warfarin; hemodialysis; MGP Vascular calcification is a major contributor to the morbidity and mortality of end-stage renal disease (ESRD) patients. Whereas atherosclerosis typically involves the vessel intima, ESRD patients are particularly susceptible to a form of vascular calcification involving the media and elastic lamina of large and medium sized arteries. Recently, vitamin K dependent proteins have gained recognition as important components in this process. 1 MGP (matrix Gla protein) acts as a potent vascular calcification inhibitor, and Gas6 (growth arrestspecific 6) controls vascular smooth muscle cell death and calcification. Both are produced by vascular smooth muscle cells, and undergo post-translational carboxylation in order to become biologically active, a process requiring sufficient levels of reduced vitamin K, as well as several important enzymes, including vitamin K epoxide reductase and gammaglutamylcarboxylase. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Financial Disclosure: The authors declare that they have no relevant financial interests. NIH Public Access Author ManuscriptAm J Kidney Dis. Author manuscript; available in PMC 2011 December 1. Warfarin, widely used as an anticoagulant, interferes with the post-translational modification of vitamin K dependent proteins, rendering them inactive. Although its anticoagulant effect has gained widespread therapeutic use, less is known about its potential side effect on vitamin K dependent proteins within the vasculature. In animal models, warfarin administration, albeit at supraphysiological doses, induces widespread medial vascular calcification 2 . Its clinical use has been associated with the development of calciphylaxis 3 , a form of metastatic small vessel calcification, aortic valve and coronary calcification 4 , and stroke 5 .We describe a cas...

The Role of Vitamin K in Soft-Tissue Calcification

“…Koos et al (21) demonstrated that subjects taking anticoagulants had a significantly higher degree of arterial and aortic valve calcification than control subjects. In a case report, Hristova et al (22) described a kidney transplant recipient exhibiting massive arterial calcification after the initiation of warfarin therapy. Distal subcutaneous necrosis ultimately led to the patient's death.…”

CKD-MBD after kidney transplantation

“…In the majority of adult patients, the rate of vascular calcification slows considerably post-transplantation; however, despite normalization of serum calcium and phosphorus levels, these lesions often do not regress [ 80 , 81 ] (Fig. 1 ), and, in some patients, particularly those treated with warfarin therapy, an accelerated progression of vascular calcifications may even be observed [ 82 ]. EBCT is not used to evaluate vascular calcification in children; however, EBCT data from young adults who developed renal failure as children, as well as autopsy and biopsy data indicate that vascular calcification is present in children with late stages of CKD [ 83 ] and those treated with maintenance dialysis [ 64 , 80 , 84 , 85 ], particularly those treated with high doses of calcium-containing phosphate binders [ 64 ].…”

Vitamin K in Chronic Kidney Disease

“…The first study [35] demonstrating strongly increased calcification of the aortic valves in patients taking oral anticoagulants—including warfarin and acenocoumarol—has been confirmed by many other researchers: Koos et al demonstrated that subjects taking vitamin K antagonist anticoagulants had a significantly higher degree of arterial and aortic valve calcification than control subjects [36]. In a case report, Hristova et al described a kidney transplant recipient exhibiting massive arterial calcification after the initiation of warfarin therapy [37]. Distal subcutaneous necrosis ultimately led to the patient’s death.…”