title: Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy.
abstract: BACKGROUND
  Survivors of critical illness complicated by acute kidney injury requiring renal replacement therapy (RRT) are at an increased risk of dialysis dependence and death but the mechanisms are unknown.
  
  
  METHODS
  In a multicenter, prospective, cohort study of 817 critically ill patients receiving RRT, we examined association between Day 1 plasma inflammatory [interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-18; macrophage migration inhibitory factor (MIF) and tumor necrosis factor]; apoptosis [tumor necrosis factor receptor (TNFR)-I and TNFR-II and death receptor (DR)-5]; and growth factor (granulocyte macrophage colony stimulating factor) biomarkers and renal recovery and mortality at Day 60. Renal recovery was defined as alive and RRT independent.
  
  
  RESULTS
  Of 817 participants, 36.5% were RRT independent and 50.8% died. After adjusting for differences in demographics, comorbid conditions; premorbid creatinine; nephrotoxins; sepsis; oliguria; mechanical ventilation; RRT dosing; and severity of illness, increased concentrations of plasma IL-8 and IL-18 and TNFR-I were independently associated with slower renal recovery [adjusted hazard ratio (AHR) range for all markers, 0.70-0.87]. Higher concentrations of IL-6, IL-8, IL-10 and IL-18; MIF; TNFR-I and DR-5 were associated with mortality (AHR range, 1.16-1.47). In an analysis of multiple markers simultaneously, increased IL-8 [AHR, 0.80, 95% confidence interval (95% CI) 0.70-0.91, P < 0.001] and TNFR-I (AHR, 0.63, 95% CI 0.50-0.79, P < 0.001) were associated with slower recovery, and increased IL-8 (AHR, 1.26, 95% CI 1.14-1.39, P < 0.001); MIF (AHR, 1.18, 95% CI 1.08-1.28, P < 0.001) and TNFR-I (AHR, 1.26, 95% CI 1.02-1.56, P < 0.03) were associated with mortality.
  
  
  CONCLUSIONS
  Elevated plasma concentrations of inflammatory and apoptosis biomarkers are associated with RRT dependence and death. Our data suggest that future interventions should investigate broad-spectrum immune-modulation to improve outcomes.
authors.affiliation: The Center for Critical Care Nephrology, CRISMA, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Raghavan
authors.initials: R
authors.lastname: Murugan
authors.affiliation: The Center for Critical Care Nephrology, CRISMA, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wen
authors.affiliation: The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: Nilesh
authors.initials: N
authors.lastname: Shah
authors.affiliation: The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Minjae
authors.initials: M
authors.lastname: Lee
authors.affiliation: The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Division of Biostatistics and Bioinformatics, Department of Public Health Sciences, Penn State Hershey College of Medicine, Hershey, PA, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Kong
authors.affiliation: The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Pike
authors.affiliation: The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Keener
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Unruh
authors.affiliation: Division of Renal Diseases and Hypertension, University of Texas Medical School at Houston, Houston, TX, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Finkel
authors.affiliation: Division of Renal Diseases, Washington University, St. Louis, MO, USA.
authors.forename: Anitha
authors.initials: A
authors.lastname: Vijayan
authors.affiliation: The Center for Critical Care Nephrology, CRISMA, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Renal Section, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Palevsky
authors.affiliation: Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Emil
authors.initials: E
authors.lastname: Paganini
authors.affiliation: The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Melinda
authors.initials: M
authors.lastname: Carter
authors.affiliation: The Center for Critical Care Nephrology, CRISMA, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Elder
authors.affiliation: The Center for Critical Care Nephrology, CRISMA, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000401:mortality* / Q000628:therapy; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D016638:Critical Illness / Q000401:mortality*; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D053218:Receptors, Death Domain / Q000097:blood*; D006435:Renal Dialysis / Q000401:mortality*; D015996:Survival Rate
chemical_list: D015415:Biomarkers; D016207:Cytokines; D053218:Receptors, Death Domain
keywords: acute kidney injury; biomarkers; mortality; renal recovery; renal replacement therapy