Vitamin D is derived from dietary sources and sunlight-induced cutaneous synthesis, and is converted to 25-hydroxyvitamin D (25D) in the liver.  Circulating 25D is converted to its biologically active form, 1,25-dihydroxyvitamin D (1,25D), in the kidneys, immune cells, and other tissues by the cytochrome P450 enzyme, 1-α hydroxylase (CYP27B1).  The conversion of 25D to 1,25D by CYP27B1 is tightly regulated by two opposing hormones: parathyroid hormone (PTH), which stimulates CYP27B1, and fibroblast growth factor 23 (FGF23), which inhibits CYP27B1.  1,25D is essential for maintaining normal calcium and phosphate homeostasis, but also has a variety of “non-classical” effects.  These effects are mediated through 1,25D binding to the intracellular vitamin D receptor (VDR), which is expressed nearly ubiquitously.  The 1,25D-VDR complex translocates into the nucleus, where it binds to DNA vitamin D response elements (VDREs), ultimately influencing the expression of over 200 target genes.  These genes affect a variety of critical inflammatory/immunomodulatory pathways relevant to acute kidney injury (AKI).

We established that patients with acute kidney injury (AKI) have elevated blood levels of fibroblast growth factor 23 (FGF23), an osteocyte-derived phosphaturic hormone that inhibits vitamin D synthesis.  Further, we found that higher circulating levels of FGF23 and decreased levels of vitamin D metabolites are early indicators of AKI and death in a variety of clinical settings, including in hospitalized patients, in critically ill patients, and in patients undergoing cardiac surgery.

In a randomized, double-blind, placebo-controlled trial conducted in critically ill patients with severe sepsis, we found that treatment with the activated form of vitamin D (1,25-dihydroxyvitamin D) increases leukocyte mRNA expression of hCAP18, an important antimicrobial peptide, and IL-10, a key anti-inflammatory cytokine.  We are currently conducting a follow-up study, ACTIVATE-AKI: Activated Vitamin D for the Prevention and Treatment of Acute Kidney Injury.  ACTIVATE-AKI is a phase II, randomized, double-blinded, placebo-controlled trial testing whether vitamin D metabolites are effective in preventing or attenuating AKI in critically ill patients.


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Leaf DE, Wolf M, Waikar SS, Chase H, Christov M, Cremers S, Stern L. FGF-23 Levels in Patients with AKI and Risk of Adverse Outcomes. Clin J Am Soc Nephrol 2012;7(8):1217-23.  PubMed