Evaluation of Vitamin K Supplementation for Calcific Uremic Arteriolopathy

Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a vascular
calcification disorder associated with 60-80% one-year mortality and significant morbidity.
CUA predominantly affects end-stage renal disease (ESRD) patients and presents with painful
skin lesions. Although rare (prevalence: 4% in dialysis patients), the incidence of CUA is on
the rise as shown by us and others. Mural calcification of dermal arterioles is the hallmark
histological finding of CUA. However, there are significant gaps in the understanding of the
pathophysiology and risk factors for CUA and there are no effective therapies.

In animal models, vitamin K prevents vascular calcification by serving as a co-factor for
Matrix Gla Protein (MGP) carboxylation, a process that converts decarboxylated-MGP (dc-MGP)
to carboxylated-MGP (c-MGP). By inhibiting pro-calcification Bone Morphogenic Protein (BMP)
ligands, c-MGP acts as a potent vascular calcification inhibitor. uc-MGP is inactive with no
vascular calcification inhibitory properties. However, the effects of vitamin K
administration on CUA remain unknown.

Aim: To conduct a pilot randomized controlled trial (RCT) of oral vitamin K in CUA.

The investigators will examine the following hypotheses:

Hypothesis 1: Vitamin K therapy, when compared to placebo, increases carboxylated Matrix Gla
Protein in chronic hemodialysis patients with CUA.

Hypothesis 2: Vitamin K therapy can be safely administered in chronic hemodialysis patients
with CUA.

Hypothesis 3: Vitamin K therapy leads to improvement in CUA pain and average lesion size when
compared to placebo in chronic hemodialysis patients.

Study population and procedures: Twenty patients will be enrolled in this pilot RCT over the
2-year study period.

Study Procedures: Patients meeting the eligibility criteria will be consented and randomized
to receive either vitamin K (phylloquinone) 10 mg orally three times a week for a total of 12
weeks or identical appearing placebo. Follow-up will occur every 4 weeks during which
information will be obtained regarding pain severity, number and size of CUA lesion (s), and
adverse events. Blood samples will be taken at baseline and at 12-week follow-up.

Sample processing and assays: Blood samples (plasma and serum, total 30 mL) will be taken at
baseline and at 12-week follow-up.

Inclusion Criteria:

- Calcific uremic arteriolopathy (a.k.a. calciphylaxis)

Exclusion Criteria:

- Warfarin discontinuation contra-indicated (e.g. mechanical heart valve)

- Prior allergic reaction to vitamin K

- Prior history of venous thromboembolism

- Pregnancy and lactation