Understanding How Sepsis Causes Kidney Dysfunction

急性肾功能衰竭是一种严重的疾病，影响了重症监护病房中高达20%的患者。脓毒症和脓毒性休克仍然是危重患者急性肾功能衰竭的最重要原因。尽管我们有能力支持重要器官和复苏患者，脓毒性急性肾衰竭的发病率和死亡率仍然高达55%，令人无法接受。在过去的50年里，我们对其发病机制的理解及其预防或治疗方面没有重大进展。传统观点认为脓毒症引起的肾功能衰竭是由于低血压引起的肾脏灌注减少。然而，在绵羊肾衰竭脓毒症模型中，我们证明了肾血管扩张和血流量增加。此外，肾功能改善后，血管收缩药物治疗，提高血压和肾血流量。这些结果表明，肾缺血不是脓毒症肾功能不全的原因。我们假设脓毒症引起肾血管舒张，降低肾小球滤过率和肾功能，并诱导细胞凋亡的延迟发展。我们将在脓毒症中研究1）增加肾小球滤过率的治疗效果2）细胞凋亡的发展和抗细胞凋亡药物的作用，以及3）脓毒症中肾脏是否存在生物能量衰竭以及治疗对此的影响。最后，在脓毒症患者中，我们将测量肾血流量，并确定我们的新治疗对肾血流量和肾功能的影响。这些研究将显著增加我们对脓毒症引起急性肾功能衰竭的因素的了解。它们可能导致开发新的治疗方法来改善脓毒症的肾功能，并将在脓毒症动物和患者中检查其有效性。

Acute renal failure is a serious condition that affects up to 20% of patients in Intensive Care Units. Sepsis and septic shock remain the most important causes of acute renal failure in critically ill patients. Despite our ability to support vital organs and resuscitate patients, the incidence and mortality of septic acute renal failure remain unacceptably high at up to 55%. There have been no major advances in our understanding of its pathogenesis and in its prevention or treatment over the last 50 years. The traditional view is that sepsis-induced renal failure results from reduced perfusion of the kidney secondary to the low blood pressure. In a model of sepsis in sheep with renal failure, we demonstrated, however, that renal blood vessels dilated and blood flow increased. Furthermore, renal function improved following treatment with vasoconstrictor drugs that raised blood pressure and renal blood flow. These findings indicate that renal ischaemia is not the cause of the renal dysfunction in sepsis. We hypothesise that sepsis causes renal vasodilatation, which reduces glomerular filtration rate and renal function, and induces a delayed development of apopotosis. We will study in sepsis 1) the effects of a treatment to increase glomerular filtration rate 2) the development of apoptosis and the effect of an anti-apoptotic drug, and 3) whether there is bioenergetic failure in the kidney in sepsis and the effects of treatments on this. Finally, in septic patients we will measure renal blood flow and determine the effects of our novel treatment on this and renal function. These studies will significantly increase our understanding of the factors causing acute renal failure in sepsis. They are likely to lead to the development of new therapies to improve renal function in sepsis and their effectiveness will be examined in septic animals and patients.