Dysregulated mineral metabolism is a universal feature of advanced chronic kidney disease (CKD) and is strongly associated with an increased burden of cardiovascular disease. In acute kidney injury (AKI), in contrast, relatively little is known about mineral metabolism. Our preliminary data indicate that many of the abnormalities in mineral metabolism that are observed in CKD, such as hypocalcemia, hyperphosphatemia, hyperparathyroidism, elevated Fibroblast Growth Factor-23 (FGF23), and vitamin D deficiency are also observed in AKI. Whether these derangements in mineral metabolism are associated with adverse outcomes in AKI, as they are in CKD, and whether intervening on them might impact clinical outcomes, has not been rigorously studied. We propose to study derangements in mineral metabolism in two groups of patients with AKI: AKI resulting from sepsis and AKI occurring after cardiac surgery. Among patients with sepsis and AKI, vitamin D deficiency is common and is strongly associated with adverse outcomes. Vitamin D has important effects on immunity and inflammation. We propose a pilot study evaluating the effects of activated vitamin D on immune, inflammatory, and renal injury biomarkers among critically-ill patients with sepsis with or without AKI. We will enroll 60 patients and randomly assign them 1:1 to receive a single administration of calcitriol 2mcg IV versus placebo. Participants with AKI will be stratified in equal numbers into the two groups. We will collect plasma and urine at 0, 6, 24, and 48 hours after study drug administration. We will test the hypotheses that calcitriol administration, compared to placebo, will result in favorable effects on markers of innate immunity and inflammation, identified by an increase in plasma cathelicidin and a decrease in plasma IL-6 levels, and will protect against AKI, identified by a decrease in urinary KIM-1 levels. Elevated FGF23 levels are associated with increased mortality in CKD and ESRD but have not been studied in detail in AKI. We propose to study FGF23 as a biomarker of adverse outcomes in cardiac surgery-associated AKI. We will use a case-cohort study design, comparing FGF23 levels among cases (those who develop AKI after cardiac surgery) to non- cases. We will test the hypothesis that elevated plasma FGF23 levels are an independent predictor of the composite clinical outcome of mortality or sustained kidney injury 90 days following cardiac surgery.

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Observational studies among critically-ill patients with infection have shown strong associations between vitamin D deficiency and mortality. Vitamin D has important effects on the immune system;however, it is unknown whether administration of vitamin D to critically-ill patients with infection can enhance their immune system and ultimately improve clinical outcomes. We propose to test the effects of vitamin D administration on immune/inflammatory markers in the blood of critically-ill patients with severe infection.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1-GRB-G (M1))
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Rankin, Tracy L
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Brigham and Women's Hospital
United States
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Leaf, David E; Christov, Marta; Jüppner, Harald et al. (2016) Fibroblast growth factor 23 levels are elevated and associated with severe acute kidney injury and death following cardiac surgery. Kidney Int 89:939-48
Leaf, David E; Rajapurkar, Mohan; Lele, Suhas S et al. (2015) Increased plasma catalytic iron in patients may mediate acute kidney injury and death following cardiac surgery. Kidney Int 87:1046-54
Leaf, David E; Croy, Heather E; Abrahams, Sara J et al. (2015) Cathelicidin antimicrobial protein, vitamin D, and risk of death in critically ill patients. Crit Care 19:80
Leaf, David E; Raed, Anas; Donnino, Michael W et al. (2014) Randomized controlled trial of calcitriol in severe sepsis. Am J Respir Crit Care Med 190:533-41