Acute kidney injury (AKI) is a devastating complication of critical illness. No pharmacologic therapies reliably prevent or treat AKI. Novel therapeutic targets for clinical intervention are therefore needed. Vitamin D metabolites have important and potentially beneficial antiinflammatory effects which prevent AKI in animal models. Since vitamin D metabolites are often decreased in critical illness, we propose that deficiencies in the vitamin D axis may be risk factors for incident AKI, and that exogenous vitamin D metabolites may be novel therapeutic agents for AKI prevention. Our preliminary data support these hypotheses. We showed that patients with established AKI have decreased levels of 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) in association with elevated fibroblast growth factor 23 (FGF23) levels; the latter is known to suppress both renal and extra-renal conversion of 25D to 1,25D. In further preliminary data, we recently published the results of a pilot RCT demonstrating that administration of a single 2 g IV dose of 1,25D to critically il patients increases leukocyte mRNA expression of interleukin-10 (IL-10) and heme oxygenase-1 (HO-1). These important antiinflammatory proteins prevent AKI in animal models.
In Aim 1 of this proposal, we will leverage an established ICU cohort to perform the first comprehensive, prospective study to investigate whether 25D, 1,25D, and FGF23 are independent risk factors for adverse renal outcomes among 200 critically ill patients with a high AKI event rate. Primary outcomes will include: incident AKI, assessed by serum creatinine; renal tubular injury, assessed by urinary NGAL and KIM- 1; and need for renal replacement therapy or death.
In Aim 2 we will enroll 150 critically ill patients at risk of AKI into a three-arm, double-blind, randomied study of 25D, 1,25D, or placebo to test the effects of repeated doses of vitamin D metabolites on renal and immunomodulatory endpoints. We will test whether 25D and/or 1,25D attenuate incident kidney injury, assessed by time averaged levels of both serum creatinine and urinary NGAL and KIM-1. Further, we will test whether 25D and/or 1,25D increase monocyte mRNA expression of antiinflammatory targets IL-10, HO-1, HIF1a, and thrombomodulin, decrease monocyte mRNA expression of proinflammatory targets ICAM-1 and IL-6, and increase T regulatory (Treg) %, all of which attenuate kidney injury in animal models. Additionally, we will evaluate physiologic endpoints including plasma levels of FGF23 and monocyte mRNA expression of 1-a hydroxylase and 24-hydroxylase to elucidate whether peripheral conversion of 25D to 1,25D is impaired in critical illness. By unifying a comprehensive, prospective clinical outcomes study and an innovative trial under one thematic umbrella, we will generate novel, clinically relevant insights into the emerging role of vitamin D metabolites in critical illness an AKI that could have important diagnostic and therapeutic implications.
Acute kidney injury is a devastating complication of critical illness. Vitamin D metabolites have important and potentially beneficial antiinflammatory effects, and vitamin D levels are often decreased in critical illness. Thus, we propose that deficiencies in the vitamin D axis may be risk factors for the development of acute kidney injury, and that administration of vitamin D metabolites may be novel therapeutic agents to prevent acute kidney injury among critically ill patients.
| Poyan Mehr, Ali; Tran, Mei T; Ralto, Kenneth M et al. (2018) De novo NAD+ biosynthetic impairment in acute kidney injury in humans. Nat Med 24:1351-1359 |
| Neyra, Javier A; Leaf, David E (2018) Risk Prediction Models for Acute Kidney Injury in Critically Ill Patients: Opus in Progressu. Nephron 140:99-104 |
| Leaf, David E; Siew, Edward D; Eisenga, Michele F et al. (2018) Fibroblast Growth Factor 23 Associates with Death in Critically Ill Patients. Clin J Am Soc Nephrol 13:531-541 |
| Rabadi, Seham; Udo, Ikemesit; Leaf, David E et al. (2018) Acute blood loss stimulates fibroblast growth factor 23 production. Am J Physiol Renal Physiol 314:F132-F139 |
| Leaf, David E; Waikar, Sushrut S (2017) End Points for Clinical Trials in Acute Kidney Injury. Am J Kidney Dis 69:108-116 |
| Eisenga, Michele F; van Londen, Marco; Leaf, David E et al. (2017) C-Terminal Fibroblast Growth Factor 23, Iron Deficiency, and Mortality in Renal Transplant Recipients. J Am Soc Nephrol 28:3639-3646 |
| Leaf, David E; Jacob, Kirolos A; Srivastava, Anand et al. (2017) Fibroblast Growth Factor 23 Levels Associate with AKI and Death in Critical Illness. J Am Soc Nephrol 28:1877-1885 |
| Kota, Satya K; Pernicone, Elizabeth; Leaf, David E et al. (2017) BPI Fold-Containing Family A Member 2/Parotid Secretory Protein Is an Early Biomarker of AKI. J Am Soc Nephrol 28:3473-3478 |
| Leaf, David E; Swinkels, Dorine W (2016) Catalytic iron and acute kidney injury. Am J Physiol Renal Physiol 311:F871-F876 |
| Leaf, David E; Cheng, Xingxing S; Sanders, Jason L et al. (2016) An electronic alert to decrease Kayexalate ordering. Ren Fail 38:1752-1754 |
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