title: Reversal of Acute Kidney Injury-Induced Neutrophil Dysfunction: A Critical Role for Resistin.
abstract: OBJECTIVE
  To assess the reversibility of acute kidney injury-induced neutrophil dysfunction and to identify involved mechanisms.
  
  
  METHODS
  Controlled laboratory experiment and prospective observational clinical study.
  
  
  METHODS
  University laboratory and hospital.
  
  
  METHODS
  C57BL/6 wild-type mice.
  
  
  METHODS
  Patients with septic shock with or without acute kidney injury.
  
  
  METHODS
  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.
  
  
  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.
authors.affiliation: 1Department 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.
authors.forename: Kai
authors.initials: K
authors.lastname: Singbartl
authors.forename: Lauren
authors.initials: L
authors.lastname: Miller
authors.forename: Victor
authors.initials: V
authors.lastname: Ruiz-Velasco
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000503:physiopathology*; D000818:Animals; D002021:Buffers; D018929:Cell Culture Techniques; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005990:Glycerol; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology*; D011446:Prospective Studies; D052243:Resistin / Q000097:blood / Q000502:physiology*; D012206:Rhabdomyolysis / Q000139:chemically induced; D012772:Shock, Septic / Q000150:complications
chemical_list: D002021:Buffers; D052243:Resistin; D005990:Glycerol