Morrell Eric D, Kellum John A, Pastor-Soler Núria M, Hallows Kenneth R
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
The Center for Critical Care Nephrology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.
Crit Care. 2014 Sep 2;18(5):501. doi: 10.1186/s13054-014-0501-5.
The most common cause of acute kidney injury (AKI) in hospitalized patients is sepsis. However, the molecular pathways and mechanisms that mediate septic AKI are not well defined. Experiments performed over the past 20 years suggest that there are profound differences in the pathogenesis between septic and ischemic AKI. Septic AKI often occurs independently of hypoperfusion, and is mediated by a concomitant pro- and anti-inflammatory state that is activated in response to various pathogen-associated molecular patterns, such as endotoxin, as well as damage-associated molecular patterns. These molecular patterns are recognized by Toll-like receptors (TLRs) found in the kidney, and effectuate downstream inflammatory pathways. Additionally, apoptosis has been proposed to play a role in the pathogenesis of septic AKI. However, targeted therapies designed to mitigate the above aspects of the inflammatory state, TLR-related pathways, and apoptosis have failed to show significant clinical benefit. This failure is likely due to the protean nature of septic AKI, whereby different patients present at different points along the immunologic spectrum. While one patient may benefit from targeted therapy at one end of the spectrum, another patient at the other end may be harmed by the same therapy. We propose that a next important step in septic AKI research will be to identify where patients lie on the immunologic spectrum in order to appropriately target therapies at the inflammatory cascade, TLRs, and possibly apoptosis.
住院患者急性肾损伤（AKI）最常见的病因是脓毒症。然而，介导脓毒症性AKI的分子途径和机制尚未完全明确。过去20年进行的实验表明，脓毒症性AKI和缺血性AKI在发病机制上存在显著差异。脓毒症性AKI常独立于低灌注发生，由伴随的促炎和抗炎状态介导，这种状态是在对各种病原体相关分子模式（如内毒素）以及损伤相关分子模式作出反应时被激活的。这些分子模式被肾脏中发现的Toll样受体（TLRs）识别，并引发下游炎症途径。此外，细胞凋亡也被认为在脓毒症性AKI的发病机制中起作用。然而，旨在减轻炎症状态、TLR相关途径和细胞凋亡上述方面的靶向治疗未能显示出显著的临床益处。这种失败可能是由于脓毒症性AKI的多变性质，即不同患者处于免疫谱的不同点。在免疫谱一端的一名患者可能从靶向治疗中获益，而在另一端的另一名患者可能会因同样的治疗而受到伤害。我们认为，脓毒症性AKI研究的下一个重要步骤将是确定患者在免疫谱上的位置，以便针对炎症级联反应、TLRs以及可能的细胞凋亡进行适当的靶向治疗。
