Mineral metabolism abnormalities and vitamin D receptor activation in cardiorenal syndromes

Over the last decade, it has become increasingly clear that the cardiovascular and renal systems are interdependent. Primary disorders of either system have been shown to disturb the other system. As a result, a class of cardiorenal syndromes (CRS) has been identified wherein a vicious cycle is established as an acute/chronic dysfunction of either the kidney or the heart exacerbates the loss of function in the other organ. Progressive loss of kidney function observed in patients with CRS (mostly types 2 and 4) leads to reduced production of calcitriol (active vitamin D) and an imbalance in calcium and phosphorus levels, which are correlated with increased rates of cardiovascular events and mortality. In addition, hypocalcemia can lead to prolonged and excessive secretion of parathyroid hormone (PTH), eventually leading to development of secondary hyperparathyroidism. Therefore, based on this important mechanism of organ damage, one of the major goals of therapy for patients with CRS is to restore regulatory control of PTH. Although administration of calcitriol increases serum calcium levels and reduces PTH levels, it is also associated with elevated serum levels of calcium-phosphorus product. Therefore, compounds that selectively activate vitamin D receptors, potentially reducing calcium x phosphate toxicity, are likely to enhance cardiorenal protection and provide significant clinical benefit.