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Observational Study
. 2014 Oct;29(10):1854-64.
doi: 10.1093/ndt/gfu051. Epub 2014 Mar 11.

Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy

Raghavan Murugan  1 , Xiaoyan Wen  1 , Nilesh Shah  2 , Minjae Lee  3 , Lan Kong  4 , Francis Pike  2 , Christopher Keener  2 , Mark Unruh  5 , Kevin Finkel  6 , Anitha Vijayan  7 , Paul M Palevsky  8 , Emil Paganini  9 , Melinda Carter  10 , Michele Elder  1 , John A Kellum  1 ; Biological Markers for Recovery of Kidney (BioMaRK) Study Investigators
Affiliations
Observational Study

Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy

Raghavan Murugan et al. Nephrol Dial Transplant. 2014 Oct.

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.

Keywords: acute kidney injury; biomarkers; mortality; renal recovery; renal replacement therapy.

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Figures

FIGURE 1:
FIGURE 1:
Plasma inflammatory and apoptosis biomarker concentrations in subjects receiving RRT, stratified by renal recovery. Boxplot summaries of plasma inflammatory (A) and apoptosis (B) biomarker concentrations are displayed in natural logarithm scale and labeled with their corresponding biomarker concentration in picograms/milliliter. The vertical box represents the 25th percentile (bottom line), median (middle line) and 75th percentile (top line) values. The lowest datum (lower whisker) represents 1.5 times the interquartile range of the lower quartile and the highest datum (upper whisker) represent 1.5 times the interquartile range of the upper quartile. The open circles represent the outliers. *P < 0.05.
FIGURE 2:
FIGURE 2:
Kaplan–Meier failure plots showing time to renal recovery stratified by quartiles of plasma inflammatory (A) and apoptosis (B) biomarker concentrations. Markers were compared across quartiles for trend using a log-rank test for ordered survival curves. Higher plasma IL-8, IL-18 and TNFR-I concentrations are associated with slower renal recovery.
FIGURE 3:
FIGURE 3:
Plasma inflammatory and apoptosis biomarker concentrations stratified by 60-day mortality. Boxplot summaries of plasma inflammatory (A) and apoptosis (B), biomarker concentrations are displayed in natural logarithm scale and labeled with their corresponding biomarker concentration in picograms/milliliter. The vertical box represents the 25th percentile (bottom line), median (middle line) and 75th percentile (top line) values. The lowest datum (lower whisker) represents 1.5 times the interquartile range of the lower quartile and the highest datum (upper whisker) represents 1.5 times the interquartile range of the upper quartile. The open circles represent the outliers. *P < 0.05.
FIGURE 4:
FIGURE 4:
Kaplan–Meier failure plots showing time to death stratified by quartiles of plasma inflammatory (A) and apoptosis (B) biomarker concentrations. Markers were compared across quartiles for trend using a log-rank test for ordered survival curves. Higher plasma IL-6, IL-8, IL-18, MIF and TNFR-I concentrations are associated with faster time to death.
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Comment in

  • Stigmata of death: for kidneys and patients.
    Ronco C, Bonventre JV. Ronco C, et al. Nephrol Dial Transplant. 2014 Oct;29(10):1797-8. doi: 10.1093/ndt/gfu103. Epub 2014 May 2. Nephrol Dial Transplant. 2014. PMID: 24792373 Free PMC article. No abstract available.

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