Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): a rationale and study protocol.

BACKGROUND: Patients on haemodialysis (HD) exhibit increased cardiovascular mortality associated with accelerated vascular calcification (VC). VC is influenced by inhibitors such as matrix Gla protein (MGP), a protein activated in the presence of vitamin K. HD patients exhibit marked vitamin K deficiency, and supplementation with vitamin K reduces inactive MGP levels in these patients. The VitaVasK trial analyses whether vitamin K1 supplementation affects the progression of coronary and aortic calcification in HD patients. METHODS: VitaVasK is a prospective, randomized, parallel group, multicentre trial (EudraCT No.: 2010-021264-14) that will include 348 HD patients in an open-label, two-arm design. After baseline multi-slice computed tomography (MSCT) of the heart and thoracic aorta, patients with a coronary calcification volume score of at least 100 will be randomized to continue on standard care or to receive additional supplementation with 5 mg vitamin K1 orally thrice weekly. Treatment duration will be 18 months, and MSCT scans will be repeated after 12 and 18 months. Primary end points are the progression of thoracic aortic and coronary artery calcification (calculated as absolute changes in the volume scores at the 18-month MSCT versus the baseline MSCT). Secondary end points comprise changes in Agatston score, mitral and aortic valve calcification as well as major adverse cardiovascular events (MACE) and all-cause mortality. VitaVask also aims to record MACE and all-cause mortality in the follow-up period at 3 and 5 years after treatment initiation. This trial may lead to the identification of an inexpensive and safe treatment or prophylaxis of VC in HD patients.

High-dose cholecalciferol to correct vitamin D deficiency in haemodialysis patients.

BACKGROUND: Vitamin D has emerged as an important survival factor in patients with chronic kidney disease. Non-activated vitamin D may also have beneficial effects on bone, cardiovascular and immune functions. Cholecalciferol is the prevalent non-activated vitamin D in Europe, but there is no valid prospective data available about its use in haemodialysis patients. Thus, we initiated a prospective study to evaluate dosing, safety and tolerability of cholecalciferol supplementation in haemodialysis patients. METHODS: The prospective study included 64 haemodialysis patients. During replenishment phase patients received 20 000 IU cholecalciferol/week for 9 months. In the open maintenance phase (15 months), patients were randomized to a treated group (20 000 IU cholecalciferol/month) and an untreated group, which did not receive cholecalciferol. RESULTS: Calcidiol [25(OH)D] deficiency (<37.5 nmol/l; <15 microg/l) was detected in 61/64 patients (95%). During the replenishment phase, calcidiol increased significantly from 16.65 +/- 9.6 to 79.48 +/- 27.15 nmol/l (6.66 +/- 3.84 microug/l to 31.79 +/- 10.86 microg/l) (P < 0.001). Recommended levels (>75 nmol/l; >30 microg/l; K/DOQI) were achieved in 57% of patients. Calcium increased from 2.28 +/- 0.17 to 2.37 +/- 0.19 mmol/l (9.1 +/- 0.69 mg/dl to 9.49 +/- 0.75 mg/dl) (P<0.01). Phosphorus, calcium-phosphorus product and parathyroid hormone showed no significant changes. Fifty-nine patients progressed to the maintenance phase. Analysis per protocol showed a significant drop of calcidiol in the treated [83.98 +/- 31.73 versus 78.5 +/- 38.75 nmol/l (33.59 +/- 12.69 versus 31.4 +/- 15.5 microg/l) (P < 0.001)] and untreated groups [86.35 +/- 40.75 versus 53.4 +/- 26.2 nmol/l (34.54 +/- 16.3 versus 21.36 +/- 10.48 microg/l) (P < 0.001)]. The comparison of the treated and the untreated groups showed no significant differences at the beginning of the maintenance phase: 83.98 +/- 31.73 versus 86.35 +/- 40.75 nmol/l (33.59 +/- 12.69 versus 34.54 +/- 16.3 microg/l). At the end they differed significantly: 78.5 +/- 38.75 versus 53.4 +/- 26.2 nmol/l (31.4 +/- 15.5 versus 21.36 +/- 10.48 microg/l) (P < 0.001). CONCLUSION: Vitamin D deficiency is present in a majority of haemodialysis patients. Supplementation with cholecalciferol is safe, well tolerated and reasonable to replenish vitamin D stores in haemodialysis patients. However, only 57% of patients achieved recommended calcidiol levels, thus favouring additional dose-finding studies.

Moxonidine treatment of hypertensive patients with advanced renal failure.

OBJECTIVES: To compare safety and tolerability of moxonidine versus nitrendipine in hypertensive patients with renal failure. A secondary endpoint was to test whether the sympatholytic drug moxonidine slows decline of renal function when added to standard therapy with an angiotensin-converting enzyme inhibitor or AT(1) receptor antagonist plus loop diuretic. DESIGN: This prospective, randomized, double-blind, multicenter study recruited 177 patients with advanced renal failure receiving antihypertensive standard therapy at outpatient clinics in Germany and Hungary. Following a 2 week run-in, patients were randomized to 24 weeks of add-on treatment with 0.3 mg/day moxonidine or 20 mg/day nitrendipine. RESULTS: The incidence of pre-defined specific adverse events was 42% in the moxonidine (37/89 patients) and 46% in the nitrendipine group (38/82 patients) in intention-to-treat analysis. Intensity and multiplicity were comparable. The dropout rate due to adverse events was 12.4% in the moxonidine and 9.8% in the nitrendipine group. Creatinine clearance according to Cockcroft and Gault decreased by 0.5 +/- 4.3 ml/min (mean +/- standard deviation) in the moxonidine group and 2.3 +/- 4.0 ml/min in the nitrendipine group. Serum creatinine increased by 12.7 +/- 49.2 micromol/l in the moxonidine group and by 43.4 +/- 71.3 micromol/l in the nitrendipine group. These differences were statistically significant (P < 0.05). CONCLUSION: Add-on treatment with 0.3 mg/day moxonidine in hypertensive patients with renal failure is well tolerated and not inferior to 20 mg/day nitrendipine with respect to the incidence of specific adverse events. The idea of a sympatholytic drug to be renoprotective is appealing but needs further evaluation.