A new role for vitamin D receptor activation in chronic kidney disease

Abstract

Valdivielso JM, Cannata-Andía J, Coll B, Fernández E. A new role for vitamin D receptor activation in chronic kidney disease. Am J Physiol Renal Physiol 297: F1502-F1509, 2009. First published July 22, 2009 doi:10.1152/ajprenal.00130.2009.-Vitamin D has proven to be much more than a simple "calcium hormone." The fact that the vitamin D receptor has been found in cells not related to mineral metabolism supports that statement. The interest of nephrologists in vitamin D and its effects beyond mineral metabolism has increased over the last few years, evidencing the importance of this so-called "sunshine hormone." In the present review, we highlight the most recent developments in the traditional use of vitamin D in chronic kidney disease (CKD) patients, namely, the control of secondary hyperparathyroidism (sHPT). Furthermore, we also explore the data available regarding the new possible therapeutic uses of vitamin D for the treatment of other complications present in CKD patients, such as vascular calcification, left ventricular hypertrophy, or proteinuria. Finally, some still scarce but very promising data regarding a possible role of vitamin D in kidney transplant patients also are reviewed. The available data point to a potential beneficial effect of vitamin D in CKD patients beyond the control of mineral metabolism.VITAMIN D IS A STEROID HORMONE that has long been known for its important role in regulating body levels of calcium (Ca) and phosphorus (P) and in mineralization of bone. However, there is an increasing amount of data proving that vitamin D exerts its effects beyond kidney, intestine, and bone (Fig. 1). The active form of vitamin D (calcitriol) mediates its biological effects by binding to the vitamin D receptor (VDR), which then translocates to the nuclei of target cells (for review, see Ref. 47). The VDR is a ligand-activated transcription factor that, after activation, recruits cofactor molecules and binds to specific DNA binding sites to modify the expression of target genes. Ligand-mediated conformational changes of the VDR contribute to specific mechanisms in its signaling cascade. Thus the structural chemical modification of active vitamin D is a powerful tool in discovering new compounds that show selective activation of the VDR. Over the last years, a number of new VDR activators (VDRAs), defined as compounds that can bind to VDR and induce its activation, have been synthesized and used in several diseases, including in patients with CKD. Their potential as new therapeutic agents has boosted this area of research. Moreover, new evidence suggests that VDR polymorphisms may influence the response to VDRAs (125). Present Use of VDRAs in Patients with CKDOne of the main complications in patients with CKD is the development of secondary hyperparathyroidism (sHPT). In the past, the increase in parathyroid gland (PTG) size and parathyroid hormone (PTH) synthesis were attributed to a decrease in circulating Ca. As a result, patients with sHPT were treated with oral vitamin D metabolites to correct ...

Calcitriol Treatment Increases Serum Levels of the Soluble Receptor of Advanced Glycation End Products in Hemodialysis Patients with Secondary Hyperparathyroidism

“…Vitamin D has been considered the firstline therapy to suppress PTH levels for ESRD patients with SHP (Bhan and Thadhani 2009;Patel and Singh 2009). Vitamin D has a wide range of beneficial effects besides PTH suppression, including modulating immune response and cell differentiation (Nagpal et al 2005;Valdivielso et al 2009). Because of these effects of vitamin D, it may offer new means to control the inflammatory state of ESRD patients, and vitamin D administration has been shown to improve mortality in HD patients (Teng et al 2003;Teng et al 2005).…”

The Multiple Roles of Vitamin D Besides Calcium-Phosphorus Metabolism

“…One of the most important reasons was that the reduction/absence of kidney α1-hydroxylase, which mediates the final hydroxylation step of 25(OH)D to 1,25-(OH) 2 D, could lead to the vitamin D deficiency in CKD patients. Vitamin D deficiency causes parathyroid hyperplasia and increased parathyroid hormone; the consequent hyperparathyroidism and hyper-phosphatemia are important risk factors for mortality in CKD patients [23,24]. Accordingly, vitamin D treatment is associated with a reduced rate of cardiovascular diseases (CVDs) and mortality [25].…”

“…Combination therapy with a RAS inhibitor and a vitamin D analog was found to markedly improve renal injuries in the diabetic vitamin D receptor null-mutant mice which developed more severe renal injuries because of more robust RAS activation [30]. Another study found that combined therapy with losartan and paricalcitol completely reduced proteinuria in a model of experimental diabetic nephropathy, suggesting that the combination of an ACE inhibitor or an ANG II receptor blocker plus a VDRA may be a good therapeutic option [23,24].…”

“…LVH is also a major risk factor for coronary ischemia, congestive heart failure, and cardiac arrhythmias [24].…”

“…Moreover, vitamin D is able to modulate contractility of cardiomyocytes in vitro by changing the distribution of the myosin chains and modulating Ca entry into cardiac muscle cells. In patients, the use of VDRA has been associated with improvements in left ventricular function and reductions in LVH [24].…”