Hemofiltration induces generation of leukocyte-derived CD31+/CD41− microvesicles in sepsis

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Abstract

Background

Microvesicles (MV) are extracellular vesicles known to be associated with cellular activation and inflammation. Hemofiltration is an effective blood purification technique for patients with renal failure and possibly also eliminates inflammatory mediators in the setting of sepsis. On the other hand, proinflammatory stimuli are induced by blood contacting the artificial membrane during extracorporeal blood purification. In chronic dialysis patients a systemic increase in MV has been described. The aim of the study was to investigate whether hemofilter passage of blood in continuous veno-venous hemofiltration (CVVH) alters MV composition and levels in critically ill patients with sepsis.

Methods

Pre- and postfilter bloods as well as ultrafiltrate samples from intensive care unit patients with severe sepsis were obtained during CVVH with regional citrate anticoagulation. MV subtypes in blood were analyzed by high-sensitivity flow cytometry. Additionally, tissue factor (TF) levels and MV-associated TF activities as well as MV activities were quantified. All parameters were corrected for hemoconcentration applied during CVVH.

Results

Twelve patients were analyzed. A significant increase in presumably mostly leukocyte-derived CD31+/CD41− MV (1.32 (1.09–1.93)-fold [median (25th–75th quartiles)], p = 0.021) was observed post- to prefilter, whereas platelet-derived MV as well as AnnexinV-binding MV were unaltered. Increments of AnnexinV+, CD42b+ and CD31+/CD41− MV post- to prefilter correlated with filtration fraction (FF) (all p < 0.05). Significant reductions in MV activity [0.72 (0.62–0.84)-fold, p = 0.002] and TF level [0.95 (0.87–0.99)-fold, p = 0.0093] were detected postfilter compared to prefilter. No MV activity was measurable in ultrafiltrate samples.

Conclusions

Despite clearing a fraction of small PS-exposing MV CVVH does not eliminate larger MV. Concurrently, CVVH induces the release of CD31+/CD4− MV that indicate leukocyte activation during hemofilter passage in septic patients. Increments of several MV subtypes within the hemofilter correlate with FF, which supports common recommendations to keep FF low. A fraction of TF is being cleared by CVVH via ultrafiltration.

Electronic supplementary material

The online version of this article (doi:10.1186/s13613-017-0312-3) contains supplementary material, which is available to authorized users.

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Most cited references 22

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A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study.

J R Le Gall, S Lemeshow, F Saulnier (1993)

To develop and validate a new Simplified Acute Physiology Score, the SAPS II, from a large sample of surgical and medical patients, and to provide a method to convert the score to a probability of hospital mortality. The SAPS II and the probability of hospital mortality were developed and validated using data from consecutive admissions to 137 adult medical and/or surgical intensive care units in 12 countries. The 13,152 patients were randomly divided into developmental (65%) and validation (35%) samples. Patients younger than 18 years, burn patients, coronary care patients, and cardiac surgery patients were excluded. Vital status at hospital discharge. The SAPS II includes only 17 variables: 12 physiology variables, age, type of admission (scheduled surgical, unscheduled surgical, or medical), and three underlying disease variables (acquired immunodeficiency syndrome, metastatic cancer, and hematologic malignancy). Goodness-of-fit tests indicated that the model performed well in the developmental sample and validated well in an independent sample of patients (P = .883 and P = .104 in the developmental and validation samples, respectively). The area under the receiver operating characteristic curve was 0.88 in the developmental sample and 0.86 in the validation sample. The SAPS II, based on a large international sample of patients, provides an estimate of the risk of death without having to specify a primary diagnosis. This is a starting point for future evaluation of the efficiency of intensive care units.

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Elevation of circulating endothelial microparticles in patients with chronic renal failure.

Jennifer Sabatier, P Brunet, Y Berland … (2006)

Chronic renal failure patients are at high risk of cardiovascular events and display endothelial dysfunction, a critical element in the pathogenesis of atherosclerosis. Upon activation, the endothelium sheds microparticles, considered as markers of endothelial dysfunction that also behave as vectors of bioactive molecules. To measure plasma levels of endothelial microparticles (EMPs) in chronic renal failure patients (CRF), either undialyzed or hemodialyzed (HD), and to investigate the ability of uremic toxins to induce EMP release in vitro. Circulating EMPs were numerated by flow cytometry, after staining of platelet-free plasma with phycoerythrin (PE)-conjugated anti-CD144 (CD144+ EMP) or anti-CD146 (CD146+ EMP) monoclonal antibodies. Platelet MP (CD41+ PMP), leukocyte MP (CD45+ leukocyte microparticles (LMP)), and annexin-V+ MPs were also counted. In parallel, MPs were counted in supernatant of human umbilical vein endothelial cells incubated with uremic toxins [oxalate, indoxyl sulfate, p-cresol, and homocysteine (Hcy)], at concentrations found in patients. CD144+ EMP and CD146+ EMP levels were significantly higher in CRF and HD patients than in healthy subjects. Furthermore, annexin-V+ MPs were elevated in both groups of uremic patients, and CD41+ PMP and CD45+ LMP were increased in CRF and HD patients, respectively. In vitro, p-cresol and indoxyl sulfate significantly increased both CD146+ and annexin-V+ EMP release. Increased levels of circulating EMP in CRF and HD patients represent a new marker of endothelial dysfunction in uremia. The ability of p-cresol and indoxyl sulfate to increase EMP release in vitro suggests that specific uremic factors may be involved in EMP elevation in patients.

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Impact of continuous venovenous hemofiltration on organ failure during the early phase of severe sepsis: a randomized controlled trial.

Eric Vicaut, Joaquim Matéo, … (2009)

The impact of continuous venovenous hemofiltration on sepsis-induced multiple organ failure severity is controversial. We sought to assess the effect of early application of hemofiltration on the degree of organ dysfunction and plasma cytokine levels in patients with severe sepsis or septic shock. Prospective, randomized, open, multicenter study setting, 12 French intensive care units. A total of 80 patients were enrolled within 24 hours of development of the first organ failure related to a new septic insult. Patients were randomized to group 1 (HF), who received hemofiltration (25 mL/kg/hr) for a 96-hour period, or group 2 (C) who were managed conventionally. The primary end point was the number, severity, and duration of organ failures during 14 days, as evaluated by the Sepsis-Related Organ Failure Assessment score, on an intention-to-treat analysis. Strict guidelines were provided to perform continuous hemofiltration under the same conditions and bearing the same objectives in all centers. Because of inclusion stagnation, the trial was discontinued after an interim analysis by which time 76 patients had been randomized. The number and severity of organ failures were significantly higher in the HF group (p 35 mL/kg/hr) on the course of sepsis.

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Author and article information

Contributors

Georg Franz Lehner: georg.lehner@i-med.ac.at

Ulrich Harler: ulrich.harler@gmail.com

Clemens Feistritzer: clemens.feistritzer@i-med.ac.at

Viktoria Maria Haller: viktoria.haller@i-med.ac.at

Julia Hasslacher: Julia.hasslacher@i-med.ac.at

Romuald Bellmann: romuald.bellmann@i-med.ac.at

Michael Joannidis: +43 512 504 24181 , michael.joannidis@i-med.ac.at

Journal

Journal ID (nlm-ta): Ann Intensive Care

Journal ID (iso-abbrev): Ann Intensive Care

Title: Annals of Intensive Care

Publisher: Springer International Publishing (Cham )

ISSN (Electronic): 2110-5820

Publication date (Electronic): 4 September 2017

Publication date PMC-release: 4 September 2017

Publication date Collection: 2017

Volume: 7

Electronic Location Identifier: 89

Affiliations

[1 ]ISNI 0000 0000 8853 2677, GRID grid.5361.1, Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, , Medical University Innsbruck, ; Anichstrasse 35, 6020 Innsbruck, Austria

[2 ]ISNI 0000 0000 8853 2677, GRID grid.5361.1, Department of Internal Medicine V - Haematology and Oncology, , Medical University Innsbruck, ; Anichstrasse 35, 6020 Innsbruck, Austria

Article

Publisher ID: 312

DOI: 10.1186/s13613-017-0312-3

PMC ID: 5583134

PubMed ID: 28871391

SO-VID: fa099f34-2db4-4fbd-a9cf-e3e3007e0ffa

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 30 March 2017

Date accepted : 18 August 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004061, Oesterreichische Nationalbank;

Award ID: 13861

Award ID: 15708

Award Recipient : Michael Joannidis

Custom metadata

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: sepsis,microvesicles,microparticles,hemofiltration,continuous veno-venous hemofiltration,renal replacement therapy,tissue factor,leukocytes,platelets

Data availability:

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: sepsis, microvesicles, microparticles, hemofiltration, continuous veno-venous hemofiltration, renal replacement therapy, tissue factor, leukocytes, platelets

Hemofiltration induces generation of leukocyte-derived CD31+/CD41− microvesicles in sepsis

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Irish Journal of Paramedicine

Most cited references 22

A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study.

Elevation of circulating endothelial microparticles in patients with chronic renal failure.

Impact of continuous venovenous hemofiltration on organ failure during the early phase of severe sepsis: a randomized controlled trial.

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