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Reversal of Acute Kidney Injury-Induced Neutrophil Dysfunction: A Critical Role for Resistin
Kai Singbartl1, Lauren Miller, Victor Ruiz-Velasco
11Department of Anesthesiology, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, PA. 2The Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA. 3The Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Objectives:
To assess the reversibility of acute kidney injury-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 acute kidney injury.
Interventions:
Murine acute kidney injury was induced by intraperitoneal injections of folic acid (nephrotoxic acute kidney injury) or by IM injections of glycerol (rhabdomyolysis-induced acute kidney injury). After 24 hours, we incubated isolated neutrophils for 3 hours in normal mouse serum or minimum essential medium buffer. We further studied the effects of plasma samples from 13 patients with septic shock (with or without severe acute kidney injury) on neutrophilic-differentiated NB4 cells.
Measurements And Main Results:
Experimental acute kidney injury significantly inhibited neutrophil migration and intracellular actin polymerization. Plasma levels of resistin, a proinflammatory cytokine and uremic toxin, were significantly elevated during both forms of acute kidney injury. Incubation in serum or minimum essential medium buffer restored normal neutrophil function. Resistin by itself was able to induce acute kidney injury-like neutrophil dysfunction in vitro. Plasma resistin was significantly higher in patients with septic shock with acute kidney injury compared with patients with septic shock alone. Compared with plasma from patients with septic shock, plasma from patients with septic shock and acute kidney injury inhibited neutrophilic-differentiated NB4 cell migration. Even after 4 days of renal replacement therapy, plasma from patients with septic shock plus acute kidney injury still showed elevated resistin levels and inhibited neutrophilic-differentiated NB4 cell migration. Resistin inhibited neutrophilic-differentiated NB4 cell migration and intracellular actin polymerization at concentrations seen during acute kidney injury, but not at normal physiologic concentrations.
Conclusions:
Acute kidney injury-induced neutrophil dysfunction is reversible in vitro. However, standard renal replacement therapy does not correct this defect in patients with septic shock and acute kidney injury. Resistin is greatly elevated during acute kidney injury, even with ongoing renal replacement therapy, and is sufficient to cause acute kidney injury-like neutrophil dysfunction by itself.
Insights
Acute kidney injury causes neutrophil dysfunction, which is reversible in vitro. However, resistin, a toxin elevated during acute kidney injury, persists after renal replacement therapy and impairs neutrophil function in patients.
Area of Science:
- Nephrology
- Immunology
- Critical Care Medicine
Background:
- Neutrophil dysfunction is a hallmark of acute kidney injury (AKI), impacting patient outcomes.
- Understanding the mechanisms and reversibility of AKI-induced neutrophil dysfunction is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the reversibility of neutrophil dysfunction in experimental AKI models.
- To identify the specific mechanisms underlying AKI-induced neutrophil dysfunction.
- To evaluate the role of resistin in this process and its persistence in patients with septic shock and AKI.
Main Methods:
- Controlled laboratory experiments using mouse models of nephrotoxic and rhabdomyolysis-induced AKI.
- In vitro incubation of isolated neutrophils with normal serum or buffer to assess functional recovery.
- Analysis of plasma samples from patients with septic shock, with or without AKI, to measure resistin levels and assess effects on neutrophil function.
- In vitro studies using NB4 cells to investigate the direct effects of resistin on neutrophil function.
Main Results:
- Experimental AKI significantly impaired neutrophil migration and actin polymerization.
- Plasma resistin levels were elevated in AKI and correlated with neutrophil dysfunction.
- Neutrophil function recovered upon incubation in normal serum but not in plasma from AKI patients.
- Resistin alone induced AKI-like neutrophil dysfunction in vitro at concentrations observed during AKI.
- Elevated resistin and impaired neutrophil function persisted in patients even after renal replacement therapy.
Conclusions:
- Neutrophil dysfunction induced by AKI is reversible in vitro.
- Resistin is a key mediator of AKI-induced neutrophil dysfunction and remains elevated despite renal replacement therapy.
- Current renal replacement therapy is insufficient to correct resistin-mediated neutrophil dysfunction in septic shock patients with AKI.
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