A Prospective, Randomized, Open-Label Trial Investigating the Effect of 1 Alpha Hydroxy Vitamin D2 on the Development of Coronary Calcification in New ESRD Patients Using the 1-84/7-84 PTH Ratio to Determine Dosing

Patients with chronic renal failure are at increased risk for vascular calcification and cardiovascular complications. For example, data from the USRDS database demonstrates that 42% of all deaths among chronic dialysis patients are cardiovascular in origin with 22% of those deaths due to arrhythmias or overt acute myocardial infarction. While numerous factors including hypertension, hyperlipidemia and diabetes contribute to both renal failure and coronary disease, recent studies find that patients with CKD experience an accelerated rate of coronary calcification. Medial calcification reduces compliance of medium to large elastic arteries such as the aorta and common carotids. The resulting loss of elasticity is thought to contribute to the high prevalence of systolic hypertension and left ventricular hypertrophy (LVH) among patients with ESRD 15.

The type of vascular calcification associated with diabetes and ESRD is histologically distinct from that found in atherosclerotic plaques. In patients with CKD or diabetes calcium deposits are concentric and uniformly distributed within the medial layer of the vessel wall. The deposition of calcium does not require the presence of atherosclerotic lesions and occurs in the absence of intimal hyperplasia. Infiltration of the adventia by T cells and activated macrophages leads to expression of bone morphogenetic protein 2 (BMP-2) and osteopontin (OPN) by pericytic myofibroblasts. In diabetics, BMP-2 expression is enhanced by the simultaneous upregulation of two BMP-2 associated transcription factors Msx1 and Msx2 3. The resulting transcription of BMP-2 genes leads to mineralization of non-endochondrial matrix. The expression of OPN is a consistent feature of medial calcification 4. Osteopontin or "bone bridge" is a highly phosphorylated glycoprotein that binds calcium and integrin receptors. The expression of osteopontin can be stimulated by vitamin D and increased circulating levels of phosphate.

Moreover, physiologic concentrations of 1, 25, dihydroxyvitamin D increases calcium deposition in cultured vascular smooth muscle cells and is associated with reduced expression of PTH related peptide (1-34 PTH) suggesting that amino PTH fragments are not only involved in regulating bone turnover, but also function to prevent dystrophic vascular calcification. Indeed, these observations raise the question of whether carboxy PTH fragments can accelerate vascular calcification.

Because second generation PTH assays detect both 1-84 and 7-84 PTH fragments, the use of vitamin D analogues to treat secondary hyperparathyroidism could lead to excessive suppression of 1-84 and a preponderance of carboxy PTH fragments. As observed by Jono et.al accumulation of 7-84 could contribute to excessive vascular calcification. We hypothesize that limiting the accumulation of 7-84 PTH fragments by maintaining a 1-84/7-84 ratio above 1.6 will reduce the amount of vitamin D analogues administered and ultimately reduce the development of coronary calcification. To investigate this hypothesis, we propose to prospectively treat 50 patients with 1, 25 dihydroxyvitamin D2 where doses are determined by maintaining a 1-84/7-84 ration > 1.6 or by maintaining intact PTH levels between 150-350 pg/ml using existing second generation PTH assays.

4.0 Hypothesis & Objectives