Imaging acute kidney injury and its pathogenesis
Acute kidney injury is defined by a rapid decline in renal function and urine output over a short period of time. Sepsis is a major cause of acute kidney injury (AKI) among patients in the intensive care unit. The golden standard of treatment is fluid resuscitation and administration of vasopressors. However, it often fails to restart the urine flow and the patients need dialysis. Therefore, our purpose is to explore the pathophysiological mechanism of septic AKI and for developing more targeted therapy. Septic AKI shows only modest histological changes despite severe functional decline; thus, it requires real-time functional analysis. In this talk, I will introduce our research information on the subject of septic AKI, including data acquired with multiphoton intravital imaging. In the rodent models of septic AKI, we found that lipopolysaccharide accumulated and disrupted tight junction barrier in the proximal tubules, segments located just downstream from the glomeruli, in the kidney. Thus, the filtrate from glomeruli leaked through proximal tubular wall thereby reducing urine output. This could be a mechanism of septic AKI, and, moreover, it could form resistance against the current therapy. While it is presumed that fluid resuscitation regains glomerular filtration, this leakage limits the increased filtrate passing through the nephron. The conditional knockout of TLR4 in the proximal tubules or prophylactic treatment with TLR4 antagonist ameliorated early phase AKI, whereas treatment with TLR4 antagonist after the onset of AKI did not, indicating that proximal tubular TLR4 could be a trigger, but not sustaining factor, for the changes. Targeting this leakage may improve the efficacy of fluid therapy during endotoxemic AKI, but of course, further experiments are needed to find the sustaining factor(s).
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