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

Raghavan Murugan; Xiaoyan Wen; Nilesh Shah; Minjae Lee; Lan Kong; Francis Pike; Christopher Keener; Mark Unruh; Kevin Finkel; Anitha Vijayan; Paul M. Palevsky; Emil Paganini; Melinda Carter; Michele Elder; John A. Kellum

doi:10.1093/ndt/gfu051

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

Raghavan Murugan, Xiaoyan Wen, Nilesh Shah, Minjae Lee, Lan Kong, Francis Pike, Christopher Keener, Mark Unruh, Kevin Finkel, Anitha Vijayan, Paul M. Palevsky, Emil Paganini, Melinda Carter, Michele Elder, John A. Kellum

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	1854-1864
Number of pages	11
Journal	Nephrology Dialysis Transplantation
Volume	29
Issue number	10
DOIs	https://doi.org/10.1093/ndt/gfu051
State	Published - Oct 1 2014
Externally published	Yes

Keywords

acute kidney injury
biomarkers
mortality
renal recovery
renal replacement therapy

ASJC Scopus subject areas

Nephrology
Transplantation

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10.1093/ndt/gfu051

Cite this

Murugan, R., Wen, X., Shah, N., Lee, M., Kong, L., Pike, F., Keener, C., Unruh, M., Finkel, K., Vijayan, A., Palevsky, P. M., Paganini, E., Carter, M., Elder, M., & Kellum, J. A. (2014). Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy. Nephrology Dialysis Transplantation, 29(10), 1854-1864. https://doi.org/10.1093/ndt/gfu051

Murugan, R, Wen, X, Shah, N, Lee, M, Kong, L, Pike, F, Keener, C, Unruh, M, Finkel, K, Vijayan, A, Palevsky, PM, Paganini, E, Carter, M, Elder, M & Kellum, JA 2014, 'Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy', Nephrology Dialysis Transplantation, vol. 29, no. 10, pp. 1854-1864. https://doi.org/10.1093/ndt/gfu051

@article{3a0f458dab77416194b2d5e6c52f8de1,

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.",

keywords = "acute kidney injury, biomarkers, mortality, renal recovery, renal replacement therapy",

author = "Raghavan Murugan and Xiaoyan Wen and Nilesh Shah and Minjae Lee and Lan Kong and Francis Pike and Christopher Keener and Mark Unruh and Kevin Finkel and Anitha Vijayan and Palevsky, {Paul M.} and Emil Paganini and Melinda Carter and Michele Elder and Kellum, {John A.}",

note = "Funding Information: BioMaRK was supported by a grant (R01DK070910) from the National Institute of Diabetes and Digestive, and Kidney Diseases (NIDDK). Additional support for J.K., X.W. and F.P. was provided by grant (R01DK083961) and for R.M. from the National Center For Advancing Translational Sciences of the National Institutes of Health under Award Number KL2TR000146. The VA/NIH ATN study was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development (CSP #530) and by NIDDK by interagency agreement Y1-DK-3508. Funding Information: The BioMaRK study was conducted by the BioMaRK investigators. The primary data and samples from the parent trial, {\textquoteleft}A Comparison of Intensive versus Conventional Renal Support in Acute Renal Failure{\textquoteright} (ATN study), from which the analyses reported here were performed, were supplied by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development (CSP #530) and by the NIDDK Central Repositories. This manuscript does not necessarily reflect the opinions or views of the ATN study, NIDDK Central Repositories or the NIDDK. We are indebted to the nurses, respiratory therapists, phlebotomists, physicians and other health-care professionals who participated in the ATN and BioMaRK studies, as well as the patients and their families. Publisher Copyright: {\textcopyright} {\textcopyright} The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.",

year = "2014",

month = oct,

day = "1",

doi = "10.1093/ndt/gfu051",

language = "English (US)",

volume = "29",

pages = "1854--1864",

journal = "Nephrology Dialysis Transplantation",

issn = "0931-0509",

publisher = "Oxford University Press",

number = "10",

}

TY - JOUR

T1 - Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy

AU - Murugan, Raghavan

AU - Wen, Xiaoyan

AU - Shah, Nilesh

AU - Lee, Minjae

AU - Kong, Lan

AU - Pike, Francis

AU - Keener, Christopher

AU - Unruh, Mark

AU - Finkel, Kevin

AU - Vijayan, Anitha

AU - Palevsky, Paul M.

AU - Paganini, Emil

AU - Carter, Melinda

AU - Elder, Michele

AU - Kellum, John A.

N1 - Funding Information: BioMaRK was supported by a grant (R01DK070910) from the National Institute of Diabetes and Digestive, and Kidney Diseases (NIDDK). Additional support for J.K., X.W. and F.P. was provided by grant (R01DK083961) and for R.M. from the National Center For Advancing Translational Sciences of the National Institutes of Health under Award Number KL2TR000146. The VA/NIH ATN study was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development (CSP #530) and by NIDDK by interagency agreement Y1-DK-3508. Funding Information: The BioMaRK study was conducted by the BioMaRK investigators. The primary data and samples from the parent trial, ‘A Comparison of Intensive versus Conventional Renal Support in Acute Renal Failure’ (ATN study), from which the analyses reported here were performed, were supplied by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development (CSP #530) and by the NIDDK Central Repositories. This manuscript does not necessarily reflect the opinions or views of the ATN study, NIDDK Central Repositories or the NIDDK. We are indebted to the nurses, respiratory therapists, phlebotomists, physicians and other health-care professionals who participated in the ATN and BioMaRK studies, as well as the patients and their families. Publisher Copyright: © © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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.

AB - 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.

KW - acute kidney injury

KW - biomarkers

KW - mortality

KW - renal recovery

KW - renal replacement therapy

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AN - SCOPUS:84918804874

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JO - Nephrology Dialysis Transplantation

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ER -

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

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