Vitamin D in chronic kidney disease: more questions than answers.

DIETARY VITAMIN D SUPPLEMENTATION IS ADVOCATED throughout the world, and in recent years it has received substantial public interest. Vitamin D metabolism is complex. The active metabolite 1,25hydroxyvitamin D is involved in calcium and phosphorus homeostasisandthevitaminDreceptorisexpressedinmanytissues, such as skeletal muscle, brain, prostate, breast, colon, and immune cells. Vitamin D status is usually assessed by measurementof the inactivemetabolite25-hydroxyvitaminDinserum, but no consensus exists on optimal serum levels. Unlike other vitamins, an oral supply of vitamin D is not essential for humans provided they are exposed to sufficient amounts of sunlight. UV-B radiation enters the skin and converts 7-dehydrocholesterol to previtamin D3, 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-/fungusderived 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. 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 m, the renal reserve of the enzyme 1 -hydroxylase becomes inadequate. 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 m. Secondary hyperparathyroidism ensues in such circumstances. In turn, reduced activation of the vitamin D receptor has been associated with developmentof arterialhypertension, left ventricularhypertrophy, heart failure, and vascular calcification. Several cell types such as vascular smooth muscle cells, osteoblasts, and endothelial cells also express 1 -hydroxylase to form 1,25-hydroxyvitamin D locally. 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. 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 (19nor-1,25-dihydroxyvitamin D2) and 22-oxacalcitriol (22-oxa1,25-dihydroxyvitamin D3). A third compound, doxecalciferol (1 -hydroxyvitamin D2) represents a prodrug that requires enzymatic activation. Although such therapy seems a logical consequence from a pathophysiological standpoint, a metaanalysis of 76 randomized controlled trials of vitamin D compounds including 3667 patients with CKD demonstrated that vitamin D compounds were not associated with reduced risk of death, bone pain, vascular calcification, or parathyroidectomy but were associated with increased risk of hypercalcemia and hyperphosphatemia. No consistent reduction in parathyroid hormone was observed. The report of the PRIMO (Paricalcitol Capsule Benefits in Renal Failure–Induced Cardiac Morbidity) trial by Thadhani et al in this issue of JAMA adds to the overall evidence of the lack of effectiveness of active vitamin D compounds. The fact thatvitaminDreceptorsarealsoexpressed in themyocardium has generated interest in the potential cardiac effects of vitamin D, including inhibition of myocyte proliferation and hypertrophyandeffectsonatrialnatriureticpeptidesynthesisand secretionsuppression. Thadhani et alhypothesized thatdaily administration of paricalcitol for 48 weeks would reduce left ventricular mass index as assessed by cardiac magnetic resonanceimaging.Atotalof227patientswereenrolledinthedoubleblind,randomizedplacebo-controlledPRIMOtrial,allofwhom had mild left ventricular hypertrophy and an estimated GFR of 15 to 60 mL/min/1.73 m.