Nonclassical aspects of differential vitamin D receptor activation: implications for survival in patients with chronic kidney disease

Abstract

The 'classical' effects of vitamin D receptor activator or agonist (VDRA) therapy for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease primarily involves suppressive effects on the parathyroid gland, and regulation of calcium and phosphorus absorption in the intestine and mobilisation in bone. Observational studies in haemodialysis patients report improved cardiovascular and all-cause survival among those receiving VDRA therapy compared with those not on VDRA therapy. Among VDRAs, the selective VDRA paricalcitol has been associated with greater survival than nonselective VDRAs, such as calcitriol (1,25-dihydroxyvitamin D(3)). The survival benefits of paricalcitol appear to be linked, at least in part, to 'nonclassical' actions of VDRAs, possibly through VDRA-mediated modulation of gene expression. In cardiovascular tissues, VDRAs are reported to have beneficial effects such as anti-inflammatory and antithrombotic effects, inhibition of vascular smooth muscle cell proliferation, inhibition of vascular calcification and stiffening, and regression of left ventricular hypertrophy. VDRAs are also reported to negatively regulate the renin-angiotensin system, which plays a key role in hypertension, myocardial infarction and stroke. The selective VDRAs, paricalcitol and maxacalcitol, are associated with direct protective effects on glomerular architecture and antiproteinuric effects in response to renal damage. Paricalcitol regulates several cardiovascular and renal parameters more favourably than nonselective VDRAs. Complex nonclassical effects, which are not clearly understood, possibly contribute to the improved survival seen with VDRAs, especially paricalcitol.