Comments by Ron C. are in bold italics...

Dietary vitamin D supplementation is advocated throughout the world ( in leiu of adequate sun exposure), and in recent years it has received substantial public interest.1

Vitamin D metabolism is complex. The active metabolite 1,25-hydroxyvitamin D is involved in calcium and phosphorus homeostasis and the vitamin D receptor is expressed in many tissues ( virtually every tissue ), such as skeletal muscle, brain, prostate, breast, colon, and immune cells.2

Vitamin D status is usually assessed by measurement of the inactive metabolite 25-hydroxyvitamin D in serum, but no consensus exists on optimal serum levels.2 ( Numerous studies reveal that a level of about 50 ng/ml of 25(OH)D is a common level in mammals in nature; and in humans, any level below ~ 45 ng/ml will prevent the mother from transferring vitamin D to the fetus, and prevent appearance in the maternal milk. This leads to birth defects and rickets, and destruction of families due to false diagnosis of "child abuse" according to Dr. John Cannell of the Vitamin D Council (http://www.vitamindcouncil.org))

Unlike other vitamins, an oral supply of vitamin D is not essential for humans provided they are exposed to sufficient amounts of sunlight. (IN THE ABSENCE OF SUN SCREEN, AND ONLY IF INTENSE ENOUGH, AS WHEN THE SUN CREATES A SHADOW SHORTER THAN THE PERSON IS TALL)

UV-B radiation enters the skin and converts 7-dehydrocholesterol to previtamin D3 (aka cholecalciferol), which is rapidly converted to vitamin D3, the only naturally occurring form of vitamin D in humans (Figure). Dietary supplements contain either vitamin D3 (cholecalciferol) or the yeast-/fungus-derived vitamin D2 (ergocalciferol), which cannot be made by humans. After ingestion, both vitamins D2 and D3 are converted by the liver's vitamin D-25-hydroxylase to 25-hydroxyvitamin D and then by the kidneys' 1?-hydroxylase to the active form 1,25-hydroxyvitamin D.2

The last step in the activation cascade ensures that the presence of chronic kidney disease (CKD) has an adverse effect on vitamin D metabolism. Indeed, once the glomerular filtration rate (GFR) has declined to less than 30 mL/min/1.73 m2, the renal reserve of the enzyme 1?-hydroxylase becomes inadequate.3

Several small studies suggest that vitamin D deficiency is common in patients with CKD, reaching 70% to 80% in patients with stage 3 to 5 disease; ie, all patients with a GFR of less than 60 mL/min/1.73 m2.3 Secondary hyperparathyroidism ensues in such circumstances. In turn, reduced activation of the vitamin D receptor has been associated with development of arterial hypertension, left ventricular hypertrophy, heart failure, and vascular calcification.4

Several cell types such as vascular smooth muscle cells, osteoblasts, and endothelial cells ( red blood cells, marrow as well ) also express 1?-hydroxylase to form 1,25-hydroxyvitamin D locally.3

This highlights the importance of activating the vitamin D receptor in several tissues, as only the 1,25-hydroxyvitamin D form is able to do, and its binding to the nuclear receptor has been implicated in suppression of the renin-angiotensin-aldosterone system, in regulation of apoptosis, and in regulation of an inflammatory response.3 ( This binding is completely blocked, antagonized, by vitamin A, thereby preventing calcium absorption, hence a warning label on many multivitamins "May cause osteoporosis" )

The pathophysiological changes observed in patients with CKD open a therapeutic window for the use of vitamin D compounds that directly activate the vitamin D receptor. The number of drugs in clinical use remains quite small, although each of them has been available for more than 10 years. Two direct activators of the receptor are available: paricalcitol (19-nor-1,25-dihydroxyvitamin D2) and 22-oxacalcitriol (22-oxa-1,25-dihydroxyvitamin D3). A third compound, doxecalciferol (1?-hydroxyvitamin D2) represents a prodrug that requires enzymatic activation.5 ( There is mounting evidence that these analogs are not as effective as naturally ocurring versions )

1. Park A. The truth about vitamin D. Time. December 20, 2011. http://healthland.time.com/2011/12/20/the-truth-about-vitamin-d/. Accessed January 17, 2012
2. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281 PubMedCrossRef
3. Chonchol M, Kendrick J, Targher G. Extra-skeletal effects of vitamin D deficiency in chronic kidney disease. Ann Med. 2011;43(4):273-282 PubMedCrossRef
4. Cozzolino M, Ronco C. The impact of paricalcitol on left ventricular hypertrophy. Contrib Nephrol. 2011;171161-165 PubMed
5. Cunningham J, Zehnder D. New vitamin D analogs and changing therapeutic paradigms. Kidney Int. 2011;79(7):702-707 PubMedCrossRef

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