Thiamine as a Renal Protective Agent in Septic Shock

项目摘要/摘要： 感染性休克是一种常见的高度病态的临床综合征，影响着美国20多万患者。 这些疾病每年在各州肆虐，造成40,000多人死亡。肾功能衰竭是脓毒症的常见并发症 感染性休克与更糟糕的结局相关。到目前为止，对脓毒症肾损害的认识和 感染性休克传统上主要集中在血压降低导致肾脏低灌注量。近期 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。 即使在灌流充足的情况下。这些发现表明，替代的病理生理机制可能 在脓毒症相关的肾损伤中起作用。这种机制仍然知之甚少，到目前为止还没有 经过验证的干预措施旨在减轻脓毒症引起的肾损伤。 硫胺素(维生素B1)是丙酮酸脱氢酶的关键辅助因子，是氧化的关键成分 磷酸化(即线粒体的有氧呼吸)。在缺乏硫胺素的情况下，线粒体代谢 转向厌氧能量生产，这是低效的，并导致乳酸的产生。硫胺素 缺乏也与活性氧水平升高有关。我们的研究小组已经 以前证明，硫胺素缺乏在危重疾病中很常见，并与 乳酸水平。我们推测，危重疾病期间硫胺素缺乏可能是由于 新陈代谢需求迅速消耗可用的硫胺素储存。 在一项随机试验中，我们的研究小组发现，给硫胺素的管理缺乏硫胺素 感染性休克患者在24小时内乳酸减少。在对这项研究的事后分析中，我的工作 已经表明，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) 在24小时内肌酸值较低，不太可能需要肾脏替代治疗(例如 透析)。我们的研究小组还显示，脓毒症患者的细胞氧耗有所改善， 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以下途径减轻感染性休克时的肾脏损伤 线粒体有氧代谢。为了验证这一假设，我们计划了一个随机、双盲的 硫胺素改善感染性休克患者肾功能的安慰剂对照试验。这一奖项将 请允许我进一步发展成为一名医生兼研究员，并用潜在的 对败血症和感染性休克患者有显著的治疗效果。

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.