Reversal of Acute Kidney Injury–Induced Neutrophil Dysfunction: A Critical Role for Resistin*

Abstract

Objectives To assess the reversibility of acute kidney injury (AKI)-induced neutrophil dysfunction and to identify involved mechanisms. Design Controlled laboratory experiment and prospective observational clinical study. Setting University laboratory and hospital. Subjects C57BL/6 wild-type mice. Patients Patients with septic shock with or without AKI. Interventions Murine AKI was induced by i.p. injections of folic acid (nephrotoxic AKI) or by i.m. injections of glycerol (rhabdomyolysis-induced AKI). After 24h, we incubated isolated neutrophils for 3h in normal mouse serum or minimum essential medium (MEM) buffer. We further studied the effects of plasma samples from 13 patients with septic shock (with or without severe AKI) on neutrophilic-differentiated NB4 cells (NB4PMN). Measurements and Main Results Experimental AKI significantly inhibited neutrophil migration and intracellular actin polymerization. Plasma levels of resistin, a pro-inflammatory cytokine and uremic toxin, were significantly elevated during both forms of AKI. Incubation in serum or MEM buffer restored normal neutrophil function. Resistin by itself was able to induce AKI-like neutrophil dysfunction in vitro. Plasma resistin was significantly higher in patients with septic shock with AKI compared to patients with septic shock alone. Compared to plasma from patients with septic shock, plasma from patients with septic shock and AKI inhibited NB4PMN migration. Even after 4d of renal replacement therapy (RRT), plasma from patients with septic shock plus AKI still showed elevated resistin levels and inhibited NB4PMN migration. Resistin inhibited NB4PMN migration and intracellular actin polymerization at concentrations seen during AKI, but not at normal physiological concentrations. Conclusions AKI-induced neutrophil dysfunction is reversible in vitro. However, standard RRT does not correct this defect in patients with septic shock and AKI. Resistin is greatly elevated during AKI, even with ongoing RRT, and is sufficient to cause AKI-like neutrophil dysfunction by itself.

Lung–kidney interactions in critically ill patients: consensus report of the Acute Disease Quality Initiative (ADQI) 21 Workgroup

“…Furthermore, there is lack of reliable data on the time course of the failing organs. Where RRT is initiated, incidences of respiratory failure between 23 and 44% have been reported with several pathophysiological mechanisms implicated in the development of ARDS (ESM Table 7). A study of > 7 million individuals with acute ischaemic stroke showed that the need for IMV was significantly GRADE system for grading recommendations according to strength of recommendation (strong vs. weak) and quality of evidence (high to very low) Modified from Guyatt et al [8] higher among patients with AKI than in those without (3.6% vs. 0.7%; p < 0.0001) [9].…”

“…Notably, not all AKI models demonstrate consistent pulmonary involvement with some suggesting that AKI only worsens pre-existing pneumonia by reducing signalling in neutrophils (e.g. the phosphatidylinositol 3-kinase-γ pathway) leading to impaired formation and localization of F-actin (essential for neutrophil movement), reduced pulmonary neutrophil recruitment and transmigration [19,23,24].…”

Clinical Utility of Extracorporeal Cytokine Hemoadsorption Therapy: A Literature Review

“…Our group and others have demonstrated that CytoSorb effectively extracts serum resistin, an early-phase 12.5 kDa inflammatory cytokine associated with increased sepsis severity, impaired neutrophil migration, and intracellular bacterial clearance [22,23,95,96]. Furthermore, this therapy reverses neutrophil dysfunction DOI: 10.1159/000492379 and restores their bacterial killing function, suggesting a direct benefit to the innate immune system [22].…”

“…Specifically, elevated serum IL-6 and resistin levels appear to correlate with sepsis severity and end-organ damage [23]. By extension, serum levels of key anti-inflammatory cytokines such as IL-10, as well as PAMPs and DAMPs also appear to predict outcomes, presumably due to poor regulation of the proinflammatory response [19].…”

Lunge-Nieren-Interaktionen bei kritisch Kranken

“…B. Migration und Bakterienelimination, hemmt und so zur Verschlechterung einer Pneumonie beitragen kann [41]. Auf diese Weise lassen sich auch die erhöhten Raten an Pneumonien und mediastinalen Infektionen bei postherzchirurgischer AKI erklären [42][43][44][45].…”