Thiamine as a Renal Protective Agent in Septic Shock

硫胺素作为感染性休克的肾脏保护剂

• 批准号: 10369886
• 负责人: Ari Moskowitz
• 金额: $ 4.66万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369886
• 关键词: Thiamine; Renal; Protective; Agent; Septic

Project Summary/Abstract: Septic shock is a common and highly morbid clinical syndrome that affects over 200,000 patients in the United States annually and results in over 40,000 deaths. Kidney failure is a frequent complication of sepsis and septic shock that is associated with worse outcomes. To date, the understanding of kidney injury in sepsis and septic shock has traditionally focused on decreased blood pressure leading to kidney hypoperfusion. Recent studies have challenged this paradigm, however, illustrating that sepsis associated kidney injury often occurs even when perfusion is adequate. These findings suggest that alternative pathophysiologic mechanisms may have a role in sepsis related kidney injury. The mechanisms remain poorly understood and as yet there are no proven interventions aimed at mitigating sepsis-induced kidney injury. Thiamine (vitamin B1), a key cofactor of pyruvate dehydrogenase, is a critical component of oxidative phosphorylation (i.e. aerobic mitochondrial respiration). In the absence of thiamine, mitochondrial metabolism shifts towards anaerobic energy production, which is inefficient and results in lactate production. Thiamine deficiency has also been linked to increased levels of reactive oxygen species. Our research group has previously demonstrated that thiamine deficiency is common in critical illness and inversely associated with lactate levels. We hypothesize that thiamine deficiency during critical illness may occur due to increased metabolic demand which rapidly consumes available thiamine stores. In a randomized trial, our research group has found that the administration of thiamine to thiamine deficient patients with septic shock leads to reduced lactate at 24-hours. In a post-hoc analysis of that study, my work has shown that patients (including both thiamine replete and thiamine deficient patients) who received thiamine had lower creatinine values at 24-hours and were less likely to require kidney replacement therapy (e.g. dialysis). Our research group has also shown improved cellular oxygen consumption in septic patients and cardiac surgery patients who receive thiamine. Given the above, we hypothesize that thiamine attenuates kidney injury during septic shock by supporting aerobic mitochondrial metabolism. To test this hypothesis, we have planned a randomized, double-blind placebo-controlled trial of thiamine to improve in kidney function in patients with septic shock. This award will allow me to further develop as a physician-investigator and to test important hypotheses with potentially significant therapeutic benefits for patients with sepsis and septic shock.

项目摘要/摘要： 感染性休克是一种常见且发病率很高的临床综合征，影响着美国超过 200,000 名患者 每年都会导致超过 40,000 人死亡。肾功能衰竭是脓毒症的常见并发症， 败血性休克与更糟糕的结果相关。迄今为止，人们对脓毒症肾损伤的认识和 脓毒性休克传统上集中于血压降低导致肾脏灌注不足。最近的 然而，研究对这一范式提出了挑战，表明脓毒症相关的肾损伤经常发生 即使灌注充足。这些发现表明替代的病理生理机制可能 在败血症相关的肾损伤中发挥作用。人们对其机制仍知之甚少，目前还没有 旨在减轻脓毒症引起的肾损伤的经过验证的干预措施。 硫胺素（维生素 B1）是丙酮酸脱氢酶的关键辅助因子，是氧化酶的重要组成部分。 磷酸化（即线粒体有氧呼吸）。在缺乏硫胺素的情况下，线粒体代谢 转向无氧能量生产，这种方式效率低下并导致乳酸生产。硫胺素 缺乏也与活性氧水平升高有关。我们的研究小组有 先前证明硫胺素缺乏在危重疾病中很常见，并且与 乳酸水平。我们假设危重病期间硫胺素缺乏可能是由于硫胺素增加所致 代谢需求迅速消耗可用的硫胺素储备。 在一项随机试验中，我们的研究小组发现，硫胺素缺乏症患者服用硫胺素 感染性休克患者会导致 24 小时乳酸降低。在对该研究的事后分析中，我的工作 研究表明，接受硫胺素治疗的患者（包括硫胺素充足和硫胺素缺乏的患者） 24 小时肌酐值较低，并且不太可能需要肾脏替代治疗（例如 透析）。我们的研究小组还表明，脓毒症患者的细胞耗氧量有所改善， 接受硫胺素治疗的心脏手术患者。 鉴于上述情况，我们假设硫胺素通过支持来减轻脓毒性休克期间的肾损伤 有氧线粒体代谢。为了检验这个假设，我们计划了一项随机、双盲试验 硫胺素改善脓毒性休克患者肾功能的安慰剂对照试验。该奖项将 让我进一步发展成为一名医师研究员，并用潜在的能力来检验重要的假设 对败血症和败血性休克患者有显着的治疗益处。