Associations between Intensity of RRT, Inflammatory Mediators, and Outcomes

Abstract

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.

Cytokine Clearances in Critically Ill Patients on Continuous Renal Replacement Therapy

“…Importantly the levels of the cytokines that we measured were comparable to those measured by other investigations (including TNF-alpha, IL-6, IL-10) [12,14,28]. A post hoc sub-study of the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study demonstrated that increased intensity and dose of RRT may impact biomarker and cytokine levels [28].…”

“…A post hoc sub-study of the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study demonstrated that increased intensity and dose of RRT may impact biomarker and cytokine levels [28]. Murugan et al [28] demonstrated in a cohort of 817 critically ill patients that intensive RRT, defined as 6 times a week intermittent dialysis or CVVHDF prescribed at a dose of 35 mL/kg·h, was associated with lower concentrations of IL-6 and tumor necrosis factor receptor one on day 8 when these levels were elevated on day 1. We did not collect samples beyond the first 48 h in our study and as such could not validate this prior finding.…”

“…Additionally, in our pilot trial, as the dose of CRRT was held constant across the 2 modalities (35 mL/kg/h), so we were not in the position to assess the impact of dose on cytokine clearances. Murugan et al [28] were not the only group to look at the impact of CRRT on cytokines. Servillo et al [29] investigated the impact of high-flux CVVH on IL-6 gene expression in patients with AKI and septic shock.…”

“…Our study is also limited by the number of cytokines that were examined; we cannot exclude the possibility that other molecules not included in this analysis could not be filtered differently by CRRT modalities and contribute to differential patient outcomes. However, the cytokines that were chosen for this analysis were a combination of those with previously published data, validated commercial assays, with known clinical relevance and a mix of pro-and anti-inflammatory actions [2,6,28,29].…”

Validity of low-efficacy continuous renal replacement therapy in critically ill patients

“…These included RCTs, as well as some observational studies, and found essentially the same result, namely that higher intensity does not improve outcome. Based on these findings, the KDIGO guidelines, the only international guidelines for AKI, recommends dose of 20 to 25 mL kg -1 h -1 for CRRT, with the recommendation grade of 1A [20].…”