Role of Kidney Proximal Tubular Secretion in Critical Illness

项目摘要 2019冠状病毒病（COVID-19）是由严重急性呼吸系统综合征引起的全球大流行病 冠状病毒2型（SARS-CoV-2）。SARS-CoV-2已在肾脏的多种细胞类型中被鉴定， 包括肾小管上皮细胞、内皮细胞和足细胞，提示病理作用。早期临床 数据表明，COVID-19患者的急性肾损伤（阿基）发生率和严重程度更高; 然而，现有的研究缺乏与未患COVID-19的类似患者的比较， SARS-CoV-2对肾损伤和功能的因果影响的可靠评估。 阿基的大多数潜在原因涉及对肾小管上皮细胞及其微环境的损伤。然而 阿基中肾功能的流行临床评估基于血清肌酐的增量变化 假设肾小球滤过和肾小管功能在体内紧密耦合， 单个.为了挑战这一假设，我们的母公司NIDDK资助了“肾脏近端肾小管的作用”项目， 危重病患者的分泌物”（R 01 DK 124063，PI Kestenbaum）正在招募一个前瞻性的危重病患者队列， 没有COVID-19的成年人，使用我们开发的一种新的测定方法定量肾小管分泌清除， 并确定这种内在肾功能对预后和肾脏药物给药的影响。 在这份补充文件中，我们建议扩大家长补助金的独特工具，以界定SARS的影响- 肾小管上的CoV-2。为了实现这一目标，我们将全面表征肾小管 在新冠病毒宿主反应和结局（Chrome）研究中发挥作用，这是一项正在进行的前瞻性研究， 患有COVID-19的危重患者，包括未患有COVID-19的类似患者的对照组。 在我们现有的肾小管分泌清除率测量中，我们将增加肾小管合成、远端 肾小管活力和肾小管损伤。我们将测试COVID-19是否与这些管状结构的变化相关， 在住院治疗过程中，在30天随访时出现持续性肾功能不全。

PROJECT ABSTRACT Coronavirus disease 2019 (COVID-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 has been identified within multiple cell types of the kidneys, including tubular epithelial cells, endothelial cells, and podocytes, suggesting pathologic effects. Early clinical data suggest a greater incidence and severity of acute kidney injury (AKI) in persons who have COVID-19; however, existing studies lack comparisons with similarly ill persons who do not have COVID-19, preventing reliable assessment of the causal impact of SARS-CoV-2 on kidney injury and function. Most underlying causes of AKI involve injury to tubular epithelial cells and their microenvironment. Yet, the prevailing clinical assessment of kidney function in AKI is based on incremental changes in serum creatinine concentrations under the assumption that glomerular filtration and tubular functions are tightly coupled within an individual. To challenge this assumption, our parent NIDDK funded grant, “Role of Kidney Proximal Tubular Secretion in Critical Illness” (R01DK124063, PI Kestenbaum) is recruiting a prospective cohort of critically ill adults without COVID-19, quantifying tubular secretory clearance using a novel assay that we have developed, and determining the impact of this intrinsic kidney function on prognosis and kidney drug dosing. In this supplement, we propose to expand the unique tools of the parent grant to delineate the impact of SARS- CoV-2 on the kidney tubules. To accomplish this goal, we will comprehensively characterize kidney tubular functions in the Covid-19 Host Response and Outcomes (CHROME) study, an ongoing prospective study of critically ill persons with COVID-19 that includes a comparison group of similarly ill persons without COVID-19. To our existing measurements of tubular secretory clearance, we will add markers of tubular synthesis, distal tubular viability, and tubular injury. We will test whether COVID-19 is associated with changes in these tubular processes over the course of hospitalization and with persistent kidney dysfunction at 30-day follow-up.