Dysregulated Mineral Metabolism in Acute Kidney Injury

描述（由申请方提供）：矿物质代谢失调是晚期慢性肾病（CKD）的普遍特征，与心血管疾病负担增加密切相关。相反，在急性肾损伤（阿基）中，对矿物质代谢的了解相对较少。我们的初步数据表明，在CKD中观察到的许多矿物质代谢异常，如低钙血症、高磷酸盐血症、高甲状旁腺激素、成纤维细胞生长因子-23（FGF 23）升高和维生素D缺乏症，也在阿基中观察到。这些矿物质代谢紊乱是否与阿基的不良结局相关，就像它们在CKD中一样，以及干预它们是否可能影响临床结局，尚未进行严格的研究。我们建议研究两组阿基患者的矿物质代谢紊乱：脓毒症引起的阿基和心脏手术后发生的阿基。 在脓毒症和阿基患者中，维生素D缺乏很常见，与不良结局密切相关。维生素D对免疫和炎症有重要作用。我们提出了一项初步研究，评估活化维生素D对伴有或不伴有阿基的脓毒症危重患者的免疫、炎症和肾损伤生物标志物的影响。我们将入组60例患者，并将其按1：1随机分配接受骨化三醇2 mcg IV与安慰剂单次给药。阿基受试者将以相同数量分为两组。我们将在研究药物给药后0、6、24和48小时采集血浆和尿液。我们将检验以下假设：与安慰剂相比，骨化三醇给药将对先天免疫和炎症标志物产生有利影响，通过血浆cathelicidin增加和血浆IL-6水平降低来确定，并将保护免受阿基，通过尿KIM-1水平降低来确定。 FGF 23水平升高与CKD和ESRD的死亡率增加相关，但尚未在阿基中进行详细研究。我们建议研究FGF 23作为心脏手术相关阿基不良结局的生物标志物。我们将使用病例队列研究设计，比较病例（心脏手术后发生阿基的患者）与非病例之间的FGF 23水平。我们将检验以下假设：血浆FGF 23水平升高是心脏手术后90天死亡或持续性肾损伤的复合临床结局的独立预测因子。

DESCRIPTION (provided by applicant): 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.