Acute Lung Injury and Acute Kidney Injury Are Established by Four Hours in Experimental Sepsis and Are Improved with Pre, but Not Post, Sepsis Administration of TNF-α Antibodies

Abstract

IntroductionAcute kidney injury (AKI) and acute lung injury (ALI) are serious complications of sepsis. AKI is often viewed as a late complication of sepsis. Notably, the onset of AKI relative to ALI is unclear as routine measures of kidney function (BUN and creatinine) are insensitive and increase late. In this study, we hypothesized that AKI and ALI would occur simultaneously due to a shared pathophysiology (i.e., TNF-α mediated systemic inflammatory response syndrome [SIRS]), but that sensitive markers of kidney function would be required to identify AKI.MethodsSepsis was induced in adult male C57B/6 mice with 5 different one time doses of intraperitoneal (IP) endotoxin (LPS) (0.00001, 0.0001, 0.001, 0.01, or 0.25 mg) or cecal ligation and puncture (CLP). SIRS was assessed by serum proinflammatory cytokines (TNF-α, IL-1β, CXCL1, IL-6), ALI was assessed by lung inflammation (lung myeloperoxidase [MPO] activity), and AKI was assessed by serum creatinine, BUN, and glomerular filtration rate (GFR) (by FITC-labeled inulin clearance) at 4 hours. 20 µgs of TNF-α antibody (Ab) or vehicle were injected IP 2 hours before or 2 hours after IP LPS.ResultsSerum cytokines increased with all 5 doses of LPS; AKI and ALI were detected within 4 hours of IP LPS or CLP, using sensitive markers of GFR and lung inflammation, respectively. Notably, creatinine did not increase with any dose; BUN increased with 0.01 and 0.25 mg. Remarkably, GFR was reduced 50% in the 0.001 mg LPS dose, demonstrating that dramatic loss of kidney function can occur in sepsis without a change in BUN or creatinine. Prophylactic TNF-α Ab reduced serum cytokines, lung MPO activity, and BUN; however, post-sepsis administration had no effect.ConclusionsALI and AKI occur together early in the course of sepsis and TNF-α plays a role in the early pathogenesis of both.

Suppression of Mitochondrial Biogenesis through Toll-Like Receptor 4–Dependent Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signaling in Endotoxin-Induced Acute Kidney Injury

“…1A). These findings are consistent with other studies reporting markedly reduced glomerular filtration rate and elevated BUN with 4 hours of endotoxin exposure in mice (Bhargava et al, 2013).…”

Can neutrophil–lymphocyte ratio be independent risk factor for predicting acute kidney injury in patients with severe sepsis?

“…Experimental studies showed that TNF-a plays a role in the early pathogenesis of sepsis-related-AKI. 28,29 Clinical studies revealed that IL-6, procalcitonin (PCT) can be used as a predictive marker for sepsis-related-AKI in patients with sepsis. 30,31 In accordance with these studies, we showed that baseline NLR is fruitful and strong predictor of sepsis-related-AKI.…”

The Beneficial Effects of Agomelatine in Experimental Model of Sepsis Related Acute Kidney Injury

“…While detection of acute lung injury is not easy in early stages, the authors suggested that it can indicate severity of sepsis. [26] Increased levels of BUN and creatinine were used to define AKI. Craciun et al reported that creatinine is a predictor of glomerular filtration rate, which, though influenced by factors such as gender and age, can be used to detect AKI.…”