Vitamin D receptor and analogs.
In chronic kidney disease (CKD), high circulating levels of parathyroid hormone (PTH) cause osteitis fibrosa, bone loss, and cardiovascular complications that increase morbidity and mortality. Impaired production of 1,25-dihydroxyvitamin D (calcitriol), the hormonal form of vitamin D, is a major contributor to the generation and maintenance of parathyroid hyperplasia and increased synthesis and secretion of PTH. Calcitriol inhibits PTH gene transcription and ameliorates parathyroid hyperplasia by suppressing the expression of and growth signals from the autocrine transforming growth factor alpha (TGFalpha)/epidermal growth factor receptor (EGFR)-growth loop, a main determinant of parathyroid cell proliferation. Calcitriol reduction of parathyroid hyperplasia and serum PTH levels demands a functional vitamin D receptor (VDR). Although VDR is normal in CKD, parathyroid VDR content is reduced markedly. Furthermore, VDR function, as a transcriptional regulator of vitamin D responsive genes, is impaired by several factors including hypocalcemia, hyperphosphatemia, accumulation of uremic toxins, and reduction in cellular levels of the VDR partner, retinoid X receptor. Therapy with calcitriol analogs can overcome the antagonism on calcitriol-VDR actions induced by CKD. Although not all analog formulations are equally effective, they offer a wider therapeutic window in counteracting vitamin D resistance and survival advantage over exclusive calcitriol therapy.
Dusso
Adriana S
AS
Renal Division, Washington University School of Medicine, St Louis, MO 63110, USA. adusso@im.wustl.edu
Thadhani
Ravi
R
Slatopolsky
Eduardo
E
D002117:Calcitriol / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D002120:Calcium Channel Agonists / Q000627:therapeutic use*; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D010280:Parathyroid Glands / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D002120:Calcium Channel Agonists; D018167:Receptors, Calcitriol; D002117:Calcitriol