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

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

doi:10.1093/ndt/gfu051

Cited by 63 publications

(62 citation statements)

References 38 publications

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“…Our recent work suggests that higher circulating concentrations of pro-and anti-inflammatory cytokines and apoptosis markers found in patients at the time of initiation of RRT are independently associated with nonrecovery of renal function and death. Specifically, we found that IL-6, IL-8, IL-10, IL-18, macrophage migration inhibitory factor (MIF), and TNF receptor-I (TNFR-I) and TNFR-II were associated with both reduced survival and renal recovery (3). Death receptor-5 (DR-5) was also associated with reduced survival (3).…”

Section: Introductionmentioning

confidence: 95%

“…Specifically, we found that IL-6, IL-8, IL-10, IL-18, macrophage migration inhibitory factor (MIF), and TNF receptor-I (TNFR-I) and TNFR-II were associated with both reduced survival and renal recovery (3). Death receptor-5 (DR-5) was also associated with reduced survival (3). High-intensity RRT has been proposed to clear inflammatory markers in patients with AKI and improve outcomes (4,5).…”

Section: Introductionmentioning

confidence: 99%

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Associations between Intensity of RRT, Inflammatory Mediators, and Outcomes

Murugan

Wen

Keener

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Critically ill patients requiring RRT have higher circulating plasma concentrations of inflammatory and apoptosis markers that are associated with subsequent RRT dependence and death. Whether intensive dosing of RRT is associated with changes in specific mediators is unknown.Design, setting, participants, & measurements A multicenter, prospective, cohort study of 817 critically ill patients receiving RRT ancillary to the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network study was conducted between November 2003 and July 2007. Plasma inflammatory (IL-6, IL-8, IL-10, IL-18, and macrophage migration inhibitory factor) and apoptosis (TNF receptor-I [TNFR-I], TNFR-II, and death receptor-5) biomarkers on days 1 and 8 were examined after initiation of intensive RRT. Whether intensive RRT, given day 1 biomarkers, is associated with RRT independence and lower mortality at day 60 was also examined.Results Overall, no differences were found in day 8 biomarker concentrations between intensive and lessintensive RRT groups. When adjusted for day 1 biomarkers and clinical variables, intensive RRT was not associated with renal recovery (adjusted odds ratio [OR], 0.80; 95% confidence interval, 0.56 to 1.14) or mortality (adjusted OR, 1.15; 95% confidence interval, 0.81 to 1.64). Use of intensive RRT, however, was associated with lower day 8 concentrations when day 1 plasma IL-6, macrophage migration inhibitory factor, and TNFR-I concentrations were high (interaction P value for all markers, ,0.01). In contrast, day 8 marker concentrations were higher when day 1 levels were low (P,0.01). Elevated biomarker concentrations on day 8 among 476 participants were associated with lower renal recovery (adjusted OR range, 0.19-0.87) and higher mortality (adjusted OR range, 1.26-3.18).Conclusions Among critically ill patients receiving RRT, intensive dosing of RRT has variable association with biomarker concentration and no association with renal recovery and mortality. However, elevated concentrations of inflammatory and apoptosis markers on day 8 of RRT were associated with RRT dependence and death.

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Associations between Intensity of RRT, Inflammatory Mediators, and Outcomes

Murugan

Wen

Keener

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…47 Our study also expands on the literature of these cytokines in the perioperative setting, which has generally been conducted with small cohorts, in single-center settings, and with lack of defined hard outcomes. While some larger studies have reported inconsistent results, 48,49 a majority of these were not undertaken in the perioperative setting. The discrepancies may primarily be due to the complications by other underlying abnormalities in the patient cohorts, such as sepsis or other critical illnesses.…”

Section: J Am Soc Nephrol 26: 3123-3132 2015mentioning

confidence: 99%

Plasma IL-6 and IL-10 Concentrations Predict AKI and Long-Term Mortality in Adults after Cardiac Surgery

Zhang

Garg

Coca

et al. 2015

Journal of the American Society of Nephrology

176

119

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Inflammation has an integral role in the pathophysiology of AKI. We investigated the associations of two biomarkers of inflammation, plasma IL-6 and IL-10, with AKI and mortality in adults undergoing cardiac surgery. Patients were enrolled at six academic centers (n=960). AKI was defined as a $50% or $0.3-mg/dl increase in serum creatinine from baseline. Pre-and postoperative IL-6 and IL-10 concentrations were categorized into tertiles and evaluated for associations with outcomes of in-hospital AKI or postdischarge all-cause mortality at a median of 3 years after surgery. Preoperative concentrations of IL-6 and IL-10 were not significantly associated with AKI or mortality. Elevated first postoperative IL-6 concentration was significantly associated with higher risk of AKI, and the risk increased in a dose-dependent manner (second tertile adjusted odds ratio [OR], 1.61 [95% confidence interval (95% CI), 1.10 to 2.36]; third tertile adjusted OR, 2.13 [95% CI, 1.45 to 3.13]). First postoperative IL-6 concentration was not associated with risk of mortality; however, the second tertile of peak IL-6 concentration was significantly associated with lower risk of mortality (adjusted hazard ratio, 0.75 [95% CI, 0.57 to 0.99]). Elevated first postoperative IL-10 concentration was significantly associated with higher risk of AKI (adjusted OR, 1.57 [95% CI, 1.04 to 2.38]) and lower risk of mortality (adjusted HR, 0.72 [95% CI, 0.56 to 0.93]). There was a significant interaction between the concentration of neutrophil gelatinase-associated lipocalin, an established AKI biomarker, and the association of IL-10 concentration with mortality (P=0.01). These findings suggest plasma IL-6 and IL-10 may serve as biomarkers for perioperative outcomes. AKI is a common complication of cardiac surgery, leading to increased morbidity and mortality. 1 Current paradigms of diagnosis and treatment are based on serum creatinine and are thus insensitive. These limitations have spurred the search for novel proteins that are involved in the process of kidney injury. 2,3 While AKI is traditionally recognized and diagnosed by renal functional impairment and structural damage, it is also an inflammatory condition. Understanding and measuring the processes of inflammation in AKI may provide unique tools for its assessment and prediction.To this end, we developed an ancillary study to our large, multicenter cohort study of adult patients

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“…More than half of patients receiving RRT die, and only a third are alive and independent of RRT by 2 months after acute illness (1). Despite decades of research, no specific treatment has improved outcomes from severe AKI.…”

Section: Introductionmentioning

confidence: 99%

“…We previously found that higher circulating concentrations of plasma inflammatory (IL-6, -8, -10, and -18 and macrophage migration inhibitory factor) and apoptosis (tumor necrosis factor receptor (TNFR) I and II and death receptor-5) biomarkers were strongly associated with RRT dependence and death using the Biologic Markers of Recovery for the Kidney (BioMaRK) study cohort (1). BioMaRK was as an ancillary study to the Veterans Affairs (VA)/National Institutes of Health (NIH) Acute renal failure Trial Network (ATN) study (3).…”

Section: Introductionmentioning

confidence: 99%

Biomarker Enhanced Risk Prediction for Adverse Outcomes in Critically Ill Patients Receiving RRT

Pike

Murugan

Keener

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Higher plasma concentrations of inflammatory and apoptosis markers in critically ill patients receiving RRT are associated with RRT dependence and death. This study objective was to examine whether plasma inflammatory ; macrophage migration inhibitory factor) and apoptosis (death receptor-5, tumor necrosis factor receptor I and II) biomarkers augment risk prediction of renal recovery and mortality compared with clinical models.Design, setting, participants, & measurements The Biologic Markers of Recovery for the Kidney study (n=817) was a prospective, nested, observational cohort study conducted as an ancillary to the Veterans Affairs/ National Institutes of Health Acute renal failure Trial Network study, a randomized trial of intensive versus less intensive RRT in critically ill patients with AKI conducted between November 2003 and July 2007 at 27 Veterans Affairs-and university-affiliated centers. Primary outcomes of interest were renal recovery and mortality at day 60. Conclusions This study suggests that a simple four-variable clinical model with plasma IL-8 had predictive value for renal recovery and mortality. These findings require external validation but could easily be used by clinicians.

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

Abstract: 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.

Cited by 63 publications

References 38 publications

Associations between Intensity of RRT, Inflammatory Mediators, and Outcomes

Associations between Intensity of RRT, Inflammatory Mediators, and Outcomes

Plasma IL-6 and IL-10 Concentrations Predict AKI and Long-Term Mortality in Adults after Cardiac Surgery

Biomarker Enhanced Risk Prediction for Adverse Outcomes in Critically Ill Patients Receiving RRT

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