Publications by authors named "Matijs van Meurs"

89 Publications

Association between oxidized nucleobases and mitochondrial DNA damage with long-term mortality in patients with sepsis.

Free Radic Biol Med 2022 Feb 21;179:156-163. Epub 2021 Dec 21.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, the Netherlands; Department of Internal Medicine, University of Groningen, University Medical Center Groningen, the Netherlands. Electronic address:

Background: Sepsis not only leads to short-term mortality during hospitalization, but is also associated with increased mortality during long-term follow-up after hospital discharge. Metabolic stress during sepsis may cause oxidative damage to both nuclear and mitochondrial DNA (mtDNA) and RNA, which could affect long-term health and life span. Therefore, the aim of this study was to assess the association of sepsis with oxidized nucleobases and (mt)DNA damage and long-term all-cause mortality in septic patients.

Methods: 91 patients with sepsis who visited the emergency department (ED) of the University Medical Center Groningen between August 2012 and June 2013 were included. Urine and plasma were collected during the ED visit. Septic patients were matched with 91 healthy controls. Death rate was obtained until June 2020.The degree of oxidation of DNA, RNA and free nucleobases were assessed in urine by mass-spectrometry. Lipid peroxidation was assessed in plasma using a TBAR assay. Additionally, plasma levels of mtDNA and damage to mtDNA were determined by qPCR.

Results: Sepsis patients denoted higher levels of oxidated DNA, RNA, free nucleobases and lipid peroxidation than controls (all p < 0.01). Further, sepsis patients displayed an increase in plasma mtDNA with an increase in mtDNA damage compared to matched controls (p < 0.01). Kaplan meier survival analyses revealed that high degrees of RNA- and nucleobase oxidation were associated with higher long-term all-cause mortality after sepsis (p < 0.01 and p = 0.01 respectively). Of these two, high RNA oxidation was associated with long-term all-cause mortality, independent of adjustment for age, medical history and sepsis severity (HR 1.29 [(1.17-1.41, 95% CI] p < 0.01).

Conclusions: Sepsis is accompanied with oxidation of nuclear and mitochondrial DNA and RNA, where RNA oxidation is an independent predictor of long-term all-cause mortality. In addition, sepsis causes mtDNA damage and an increase in cell free mtDNA in plasma.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.12.305DOI Listing
February 2022

Plasma from patients undergoing coronary artery bypass graft surgery does not activate endothelial cells under shear stress .

Int J Crit Illn Inj Sci 2021 Jul-Sep;11(3):142-150. Epub 2021 Sep 25.

Department of Pathology and Medical Biology, Oldenburg, Germany.

Background: Cardiac surgery with cardiopulmonary bypass (CPB) is commonly associated with acute kidney injury, and microvascular endothelial inflammation is a potential underlying mechanism. We hypothesized that pro-inflammatory components of plasma from patients who underwent coronary artery bypass graft surgery with CPB induce endothelial adhesion molecule expression when incorporating altered shear stress in the model.

Methods: The clinical characteristics and markers of systemic inflammation and kidney injury were analyzed pre and postoperatively in 29 patients undergoing coronary artery bypass grafting with CPB. The effects of tumor necrosis factor (TNF)-α and patient plasma on the expression of endothelial inflammation and adhesion markers were analyzed .

Results: Plasma TNF-α was elevated 6 h postoperation (median: 7.3 pg/ml (range: 2.5-94.8 pg/ml)). Neutrophil gelatinase-associated lipocalin in plasma peaked 6 h (99.8 ng/ml (52.6-359.1 ng/ml)) and in urine 24 h postoperation (1.6 ng/mg (0.2-6.4 ng/mg)). Urinary kidney injury molecule-1 concentration peaked 24 h postoperation (0.5 ng/mg (0.2-1.2 ng/mg). , the expression of E-selectin was induced by 20 pg/ml TNF-α. In addition, the expression of interleukin-8, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 was induced by 100 pg/ml TNF-α. Compared to healthy control plasma exposure, postoperative plasma did not increase the expression of markers of endothelial inflammation and adhesion under shear stress .

Conclusion: Patients undergoing CPB surgery showed mild systemic inflammation and kidney injury. However, the plasma components did not stimulate endothelial inflammation and adhesion molecule expression .
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http://dx.doi.org/10.4103/IJCIIS.IJCIIS_197_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547679PMC
September 2021

Renal microvascular endothelial cell responses in sepsis-induced acute kidney injury.

Nat Rev Nephrol 2021 Oct 19. Epub 2021 Oct 19.

Dept. Pathology and Medical Biology, Medical Biology section, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Microvascular endothelial cells in the kidney have been a neglected cell type in sepsis-induced acute kidney injury (sepsis-AKI) research; yet, they offer tremendous potential as pharmacological targets. As endothelial cells in distinct cortical microvascular segments are highly heterogeneous, this Review focuses on endothelial cells in their anatomical niche. In animal models of sepsis-AKI, reduced glomerular blood flow has been attributed to inhibition of endothelial nitric oxide synthase activation in arterioles and glomeruli, whereas decreased cortex peritubular capillary perfusion is associated with epithelial redox stress. Elevated systemic levels of vascular endothelial growth factor, reduced levels of circulating sphingosine 1-phosphate and loss of components of the glycocalyx from glomerular endothelial cells lead to increased microvascular permeability. Although coagulation disbalance occurs in all microvascular segments, the molecules involved differ between segments. Induction of the expression of adhesion molecules and leukocyte recruitment also occurs in a heterogeneous manner. Evidence of similar endothelial cell responses has been found in kidney and blood samples from patients with sepsis. Comprehensive studies are needed to investigate the relationships between segment-specific changes in the microvasculature and kidney function loss in sepsis-AKI. The application of omics technologies to kidney tissues from animals and patients will be key in identifying these relationships and in developing novel therapeutics for sepsis.
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http://dx.doi.org/10.1038/s41581-021-00489-1DOI Listing
October 2021

Intra-abdominal hypertension and abdominal compartment syndrome in critically ill patients: A narrative review of past, present, and future steps.

Scand J Surg 2021 Oct 3:14574969211030128. Epub 2021 Oct 3.

Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background And Objective: Intra-abdominal hypertension is frequently present in critically ill patients and is an independent predictor for mortality. In this narrative review, we aim to provide a comprehensive overview of current insights into intra-abdominal pressure monitoring, intra-abdominal hypertension, and abdominal compartment syndrome. The focus of this review is on the pathophysiology, risk factors and outcome of intra-abdominal hypertension and abdominal compartment syndrome, and on therapeutic strategies, such as non-operative management, surgical decompression, and management of the open abdomen. Finally, future steps are discussed, including propositions of what a future guideline should focus on.

Conclusions: Pathological intra-abdominal pressure is a continuum ranging from mild intra-abdominal pressure elevation without clinically significant adverse effects to substantial increase in intra-abdominal pressure with serious consequences to all organ systems. Intra-abdominal pressure monitoring should be performed in all patients at risk of intra-abdominal hypertension. Although continuous intra-abdominal pressure monitoring is feasible, this is currently not standard practice. There are a number of effective non-operative medical interventions that may be performed early in the patient's course to reduce intra-abdominal pressure and decrease the need for surgical decompression. Abdominal decompression can be life-saving when abdominal compartment syndrome is refractory to non-operative treatment and should be performed expeditiously. The objectives of open abdomen management are to prevent fistula and to achieve delayed fascial closure at the earliest possible time. There is still a lot to learn and change. The 2013 World Society of Abdominal Compartment Syndrome guidelines should be updated and multicentre studies should evaluate the effect of intra-abdominal hypertension treatment on patient outcome.
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http://dx.doi.org/10.1177/14574969211030128DOI Listing
October 2021

Plausibility Limits Imagination.

Crit Care Med 2021 10;49(10):e1047

Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1097/CCM.0000000000005043DOI Listing
October 2021

Requirement of respiratory support in acute bronchiolitis in infants is linked to endothelial and neutrophil activation.

Pediatr Pulmonol 2021 12 27;56(12):3908-3915. Epub 2021 Sep 27.

Academic Pediatric Center Suriname, Academic Hospital Paramaribo, Paramaribo, Suriname.

Background: Evidence shows that activation of pulmonary vascular endothelium and neutrophils are involved in the pathophysiology of acute bronchiolitis. We hypothesized that levels of markers of endothelial activation and leukocyte counts are associated with requirement and duration of respiratory support.

Methods: Thirty-four infants with bronchiolitis and eight controls were included. Nasopharyngeal swabs and blood samples were taken at admission. Serum levels of Angiopoietin (Ang)-1, Ang-2, sP-selectin, sE-selectin, vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), and leukocyte counts were measured. For univariate analysis, bronchiolitis cases were grouped into two groups, namely those not requiring and those requiring any form of respiratory support. To control for known risk factors for poor outcome (i.e., age, prematurity, and congenital heart disease), and for days post symptom onset, linear regression analysis was performed with duration of any type of respiratory support in days.

Results: Ang-2 levels, Ang-2/Ang-1 ratios, sE-selectin levels, immature neutrophil count, and neutrophil/lymphocyte ratio (NLR) were higher in acute bronchiolitis versus controls. Ang-2, and NLR levels were significantly higher, and lymphocyte counts significantly lower, in infants that required respiratory support versus those that did not. Ang-2 levels (β: .32, 95% confidence interval [CI]: 0.19-1.19) and NLR (β: .68, 95% CI: 0.17-1.19) were positive predictors for the duration of respiratory support.

Conclusions: Markers of endothelial and neutrophil activation are associated with respiratory support for acute bronchiolitis. Admission Ang-2 levels and NLR may be promising markers to determine requirement of respiratory support and deserve further study.
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http://dx.doi.org/10.1002/ppul.25663DOI Listing
December 2021

DAMPening COVID-19 Severity by Attenuating Danger Signals.

Front Immunol 2021;12:720192. Epub 2021 Aug 12.

Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, Netherlands.

COVID-19 might lead to multi-organ failure and, in some cases, to death. The COVID-19 severity is associated with a "cytokine storm." Danger-associated molecular patterns (DAMPs) are proinflammatory molecules that can activate pattern recognition receptors, such as toll-like receptors (TLRs). DAMPs and TLRs have not received much attention in COVID-19 but can explain some of the gender-, weight- and age-dependent effects. In females and males, TLRs are differentially expressed, likely contributing to higher COVID-19 severity in males. DAMPs and cytokines associated with COVID-19 mortality are elevated in obese and elderly individuals, which might explain the higher risk for severer COVID-19 in these groups. Adenosine signaling inhibits the TLR/NF-κB pathway and, through this, decreases inflammation and DAMPs' effects. As vaccines will not be effective in all susceptible individuals and as new vaccine-resistant SARS-CoV-2 mutants might develop, it remains mandatory to find means to dampen COVID-19 disease severity, especially in high-risk groups. We propose that the regulation of DAMPs adenosine signaling enhancement might be an effective way to lower the severity of COVID-19 and prevent multiple organ failure in the absence of severe side effects.
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http://dx.doi.org/10.3389/fimmu.2021.720192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397524PMC
September 2021

Preservation of renal endothelial integrity and reduction of renal edema by aprotinin does not preserve renal perfusion and function following experimental cardiopulmonary bypass.

Intensive Care Med Exp 2021 Jun 25;9(1):30. Epub 2021 Jun 25.

Department of Anesthesiology, Experimental Laboratory for Vital Signs, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands.

Background: Acute kidney injury is a severe complication following cardiopulmonary bypass (CPB) and is associated with capillary leakage and microcirculatory perfusion disturbances. CPB-induced thrombin release results in capillary hyperpermeability via activation of protease-activated receptor 1 (PAR1). We investigated whether aprotinin, which is thought to prevent thrombin from activating PAR1, preserves renal endothelial structure, reduces renal edema and preserves renal perfusion and reduces renal injury following CPB.

Methods: Rats were subjected to CPB after treatment with 33.000 KIU/kg aprotinin (n = 15) or PBS (n = 15) as control. A secondary dose of 33.000 KIU/kg aprotinin was given 60 min after initiation of CPB. Cremaster and renal microcirculatory perfusion were assessed using intravital microscopy and contrast echography before CPB and 10 and 60 min after weaning from CPB. Renal edema was determined by wet/dry weight ratio and renal endothelial structure by electron microscopy. Renal PAR1 gene and protein expression and markers of renal injury were determined.

Results: CPB reduced cremaster microcirculatory perfusion by 2.5-fold (15 (10-16) to 6 (2-10) perfused microvessels, p < 0.0001) and renal perfusion by 1.6-fold (202 (67-599) to 129 (31-292) au/sec, p = 0.03) in control animals. Both did not restore 60 min post-CPB. This was paralleled by increased plasma creatinine (p < 0.01), neutrophil gelatinase-associated lipocalin (NGAL; p = 0.003) and kidney injury molecule-1 (KIM-1; p < 0.01). Aprotinin treatment preserved cremaster microcirculatory perfusion following CPB (12 (7-15) vs. 6 (2-10) perfused microvessels, p = 0.002), but not renal perfusion (96 (35-313) vs. 129 (31-292) au/s, p > 0.9) compared to untreated rats. Aprotinin treatment reduced endothelial gap formation (0.5 ± 0.5 vs. 3.1 ± 1.4 gaps, p < 0.0001), kidney wet/dry weight ratio (4.6 ± 0.2 vs. 4.4 ± 0.2, p = 0.046), and fluid requirements (3.9 ± 3.3 vs. 7.5 ± 3.0 ml, p = 0.006) compared to untreated rats. In addition, aprotinin treatment reduced tubulointerstitial neutrophil influx by 1.7-fold compared to untreated rats (30.7 ± 22.1 vs. 53.2 ± 17.2 neutrophil influx/section, p = 0.009). No differences were observed in renal PAR1 expression and plasma creatinine, NGAL or KIM-1 between groups.

Conclusions: Aprotinin did not improve renal perfusion nor reduce renal injury during the first hour following experimental CPB despite preservation of renal endothelial integrity and reduction of renal edema.
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http://dx.doi.org/10.1186/s40635-021-00393-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225734PMC
June 2021

Comparison of renal histopathology and gene expression profiles between severe COVID-19 and bacterial sepsis in critically ill patients.

Crit Care 2021 06 10;25(1):202. Epub 2021 Jun 10.

Department of Critical Care, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.

Background: The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury.

Methods: This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (n = 6) and bacterial sepsis (n = 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (n = 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3-4 days for bacterial sepsis patients.

Results: We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42, p = 0.0002) and bacterial sepsis patients (fold change 0.24, p < 0.0001) were low compared to control. The mRNA levels of injury markers NGAL and KIM-1 were unaltered compared to control tissue but increased in sepsis-AKI patients. Markers for inflammation and endothelial activation were unaltered in COVID-19 suggesting a lack of renal inflammation. Renal mRNA levels of endothelial integrity markers CD31, PV-1 and VE-Cadherin did not differ from control individuals yet were increased in bacterial sepsis patients (CD31 fold change 2.3, p = 0.0006, PV-1 fold change 1.5, p = 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27, p < 0.0001) and bacterial sepsis patients (fold change 0.67, p < 0.0001) compared to controls. Moreover, low Tie2 mRNA expression (fold change 0.33, p = 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09, p < 0.0001) suggest decreased microvascular flow in COVID-19.

Conclusions: In a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset.
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http://dx.doi.org/10.1186/s13054-021-03631-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190989PMC
June 2021

The effect of targeting Tie2 on hemorrhagic shock-induced renal perfusion disturbances in rats.

Intensive Care Med Exp 2021 May 17;9(1):23. Epub 2021 May 17.

Department of Anesthesiology, Experimental Laboratory for Vital Signs, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.

Background: Hemorrhagic shock is associated with acute kidney injury and increased mortality. Targeting the endothelial angiopoietin/Tie2 system, which regulates endothelial permeability, previously reduced hemorrhagic shock-induced vascular leakage. We hypothesized that as a consequence of vascular leakage, renal perfusion and function is impaired and that activating Tie2 restores renal perfusion and function.

Methods: Rats underwent 1 h of hemorrhagic shock and were treated with either vasculotide or PBS as control, followed by fluid resuscitation for 4 h. Microcirculatory perfusion was measured in the renal cortex and cremaster muscle using contrast echography and intravital microscopy, respectively. Changes in the angiopoietin/Tie2 system and renal injury markers were measured in plasma and on protein and mRNA level in renal tissue. Renal edema formation was determined by wet/dry weight ratios and renal structure by histological analysis.

Results: Hemorrhagic shock significantly decreased renal perfusion (240 ± 138 to 51 ± 40, p < 0.0001) and cremaster perfusion (12 ± 2 to 5 ± 2 perfused vessels, p < 0.0001) compared to baseline values. Fluid resuscitation partially restored both perfusion parameters, but both remained below baseline values (renal perfusion 120 ± 58, p = 0.08, cremaster perfusion 7 ± 2 perfused vessels, p < 0.0001 compared to baseline). Hemorrhagic shock increased circulating angiopoietin-1 (p < 0.0001), angiopoietin-2 (p < 0.0001) and soluble Tie2 (p = 0.05), of which angiopoietin-2 elevation was associated with renal edema formation (r = 0.81, p < 0.0001). Hemorrhagic shock induced renal injury, as assessed by increased levels of plasma neutrophil gelatinase-associated lipocalin (NGAL: p < 0.05), kidney injury marker-1 (KIM-1; p < 0.01) and creatinine (p < 0.05). Vasculotide did not improve renal perfusion (p > 0.9 at all time points) or reduce renal injury (NGAL p = 0.26, KIM-1 p = 0.78, creatinine p > 0.9, renal edema p = 0.08), but temporarily improved cremaster perfusion at 3 h following start of fluid resuscitation compared to untreated rats (resuscitation + 3 h: 11 ± 3 vs 8 ± 3 perfused vessels, p < 0.05).

Conclusion: Hemorrhagic shock-induced renal impairment cannot be restored by standard fluid resuscitation, nor by activation of Tie2. Future treatment strategies should focus on reducing angiopoietin-2 levels or on activating Tie2 via an alternative strategy.
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http://dx.doi.org/10.1186/s40635-021-00389-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126531PMC
May 2021

Role of endothelial microRNA 155 on capillary leakage in systemic inflammation.

Crit Care 2021 02 22;25(1):76. Epub 2021 Feb 22.

Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.

Background: Capillary leakage is a key contributor to the pathological host response to infections. The underlying mechanisms remain incompletely understood, and the role of microRNAs (MIR) has not been investigated in detail. We hypothesized that specific MIRs might be regulated directly in the endothelium thereby contributing to vascular leakage.

Methods: SmallRNA sequencing of endotoxemic murine pulmonary endothelial cells (ECs) was done to detect regulated vascular MIRs. In vivo models: transgenic zebrafish (flk1:mCherry/l-fabp:eGFP-DPB), knockout/wildtype mouse (B6.Cg-Mir155tm1.1Rsky/J); disease models: LPS 17.5 mg/kgBW and cecal ligation and puncture (CLP); in vitro models: stimulated human umbilical vein EC (HUVECs), transendothelial electrical resistance.

Results: Endothelial MIR155 was identified as a promising candidate in endotoxemic murine pulmonary ECs (25 × upregulation). Experimental overexpression in a transgenic zebrafish line and in HUVECs was sufficient to induce spontaneous vascular leakage. To the contrary, genetic MIR155 reduction protects against permeability both in vitro and in endotoxemia in vivo in MIR155 heterozygote knockout mice thereby improving survival by 40%. A tight junction protein, Claudin-1, was down-regulated both in endotoxemia and by experimental MIR155 overexpression. Translationally, MIR155 was detectable at high levels in bronchoalveolar fluid of patients with ARDS compared to healthy human subjects.

Conclusions: We found that MIR155 is upregulated in the endothelium in mouse and men as part of a systemic inflammatory response and might contribute to the pathophysiology of vascular leakage in a Claudin-1-dependent manner. Future studies have to clarify whether MIR155 could be a potential therapeutic target.
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http://dx.doi.org/10.1186/s13054-021-03500-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901081PMC
February 2021

Sepsis is associated with mitochondrial DNA damage and a reduced mitochondrial mass in the kidney of patients with sepsis-AKI.

Crit Care 2021 01 25;25(1):36. Epub 2021 Jan 25.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, EB70, 9700 RB, Groningen, The Netherlands.

Background: Sepsis is a life-threatening condition accompanied by organ dysfunction subsequent to a dysregulated host response to infection. Up to 60% of patients with sepsis develop acute kidney injury (AKI), which is associated with a poor clinical outcome. The pathophysiology of sepsis-associated AKI (sepsis-AKI) remains incompletely understood, but mitochondria have emerged as key players in the pathogenesis. Therefore, our aim was to identify mitochondrial damage in patients with sepsis-AKI.

Methods: We conducted a clinical laboratory study using "warm" postmortem biopsies from sepsis-associated AKI patients from a university teaching hospital. Biopsies were taken from adult patients (n = 14) who died of sepsis with AKI at the intensive care unit (ICU) and control patients (n = 12) undergoing tumor nephrectomy. To define the mechanisms of the mitochondrial contribution to the pathogenesis of sepsis-AKI, we explored mRNA and DNA expression of mitochondrial quality mechanism pathways, DNA oxidation and mitochondrial DNA (mtDNA) integrity in renal biopsies from sepsis-AKI patients and control subjects. Next, we induced human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS) for 48 h to mimic sepsis and validate our results in vitro.

Results: Compared to control subjects, sepsis-AKI patients had upregulated mRNA expression of oxidative damage markers, excess mitochondrial DNA damage and lower mitochondrial mass. Sepsis-AKI patients had lower mRNA expression of mitochondrial quality markers TFAM, PINK1 and PARKIN, but not of MFN2 and DRP1. Oxidative DNA damage was present in the cytosol of tubular epithelial cells in the kidney of sepsis-AKI patients, whereas it was almost absent in biopsies from control subjects. Oxidative DNA damage co-localized with both the nuclei and mitochondria. Accordingly, HUVECs induced with LPS for 48 h showed an increased mnSOD expression, a decreased TFAM expression and higher mtDNA damage levels.

Conclusion: Sepsis-AKI induces mitochondrial DNA damage in the human kidney, without upregulation of mitochondrial quality control mechanisms, which likely resulted in a reduction in mitochondrial mass.
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http://dx.doi.org/10.1186/s13054-020-03424-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831178PMC
January 2021

Plasma neutrophil gelatinase-associated lipocalin at intensive care unit admission as a predictor of acute kidney injury progression.

Clin Kidney J 2020 Dec 17;13(6):994-1002. Epub 2020 Feb 17.

Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Acute kidney injury (AKI) is a common complication in patients during intensive care unit (ICU) admission. AKI is defined as an increase in serum creatinine (SCr) and/or a reduction in urine output. SCr is a marker of renal function with several limitations, which led to the search for biomarkers for earlier AKI detection. Our aim was to study the predictive value of plasma neutrophil gelatinase-associated lipocalin (NGAL) at admission as a biomarker for AKI progression during the first 48 h of ICU admission in an unselected, heterogeneous ICU patient population.

Methods: We conducted a prospective observational study in an academic tertiary referral ICU population. We recorded AKI progression in all ICU patients during the first 48 h of ICU admission in a 6-week period. Plasma NGAL was measured at admission but levels were not reported to the attending clinicians. As possible predictors of AKI progression, pre-existing AKI risk factors were recorded. We examined the association of clinical parameters and plasma NGAL levels at ICU admission with the incidence and progression of AKI within the first 48 h of the ICU stay.

Results: A total of 361 patients were included. Patients without AKI progression during the first 48 h of ICU admission had median NGAL levels at admission of 115 ng/mL [interquartile range (IQR) 81-201]. Patients with AKI progression during the first 48 h of ICU admission had median NGAL levels at admission of 156 ng/mL (IQR 97-267). To predict AKI progression, a multivariant model with age, sex, diabetes mellitus, body mass index, admission type, Acute Physiology and Chronic Health Evaluation score and SCr at admission had an area under the receiver operating characteristics (ROC) curve of 0.765. Adding NGAL to this model showed a small increase in the area under the ROC curve to 0.783 (95% confidence interval 0.714-0.853).

Conclusions: NGAL levels at admission were higher in patients with progression of AKI during the first 48 h of ICU admission, but adding NGAL levels at admission to a model predicting this AKI progression showed no significant additive value.
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http://dx.doi.org/10.1093/ckj/sfaa002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769547PMC
December 2020

Serum Levels of Markers of Endothelial Activation Are Not Associated with a Positive Blood Culture in Surinamese Children with Suspected Severe Infection.

J Trop Pediatr 2021 01;67(1)

Academic Pediatric Center Suriname, Academic Hospital Paramaribo, Paramaribo, Suriname.

Background: Systemic serum levels of markers of endothelial activation are associated with infection. We hypothesize that levels of markers of endothelial activation are associated with the presence of a positive blood culture as a manifestation of a systemic infection in children with a suspected severe infection in Suriname.

Methods: In this prospective observational cohort study, children between 1 month and 18 years of age suspected of severe infection as assessed by the threating physician, and in whom laboratory testing and blood culturing was performed before start of intravenous antibiotic treatment, were recruited at the emergency department of the Academic Hospital Paramaribo, Suriname. Serum was collected at blood culturing and after 48-72 h of admission. Serum was stored for measurement of levels of Angiopoietin (Ang)-1, Ang-2, soluble (s)P-selectin, sE-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and platelet and endothelial cell adhesion molecule-1.

Results: Fifty-one children were included of whom 10 had a positive blood culture. Baseline characteristics were similar between children with and without a positive blood culture. No significant differences in serum levels of the Angiopoietins or soluble cellular adhesion molecules between groups were observed at start of antibiotic treatment nor after 48-72 h.

Conclusions: The data from this study indicate that in children with severe infection, serum levels of markers of endothelial cell activation are not associated with a positive blood culture. Thus, having a positive bacterial blood culture may not be the only factor driving endothelial activation in this patient population.
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http://dx.doi.org/10.1093/tropej/fmaa091DOI Listing
January 2021

Pharmacological inhibition of focal adhesion kinase 1 (FAK1) and anaplastic lymphoma kinase (ALK) identified via kinome profile analysis attenuates lipopolysaccharide-induced endothelial inflammatory activation.

Biomed Pharmacother 2021 Jan 13;133:111073. Epub 2020 Dec 13.

Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Sepsis is a life-threatening condition often leading to multiple organ failure for which currently no pharmacological treatment is available. Endothelial cells (EC) are among the first cells to respond to pathogens and inflammatory mediators in sepsis and might be a sentinel target to prevent the occurrence of multiple organ failure. Lipopolysaccharide (LPS) is a Gram-negative bacterial component that induces endothelial expression of inflammatory adhesion molecules, cytokines, and chemokines. This expression is regulated by a network of kinases, the result of which in vivo enables leukocytes to transmigrate from the blood into the underlying tissue, causing organ damage. We hypothesised that besides the known kinase pathways, other kinases are involved in the regulation of EC in response to LPS, and that these can be pharmacologically targeted to inhibit cell activation. Using kinome profiling, we identified 58 tyrosine kinases (TKs) that were active in human umbilical vein endothelial cells (HUVEC) at various timepoints after stimulation with LPS. These included AXL tyrosine kinase (Axl), focal adhesion kinase 1 (FAK1), and anaplastic lymphoma kinase (ALK). Using siRNA-based gene knock down, we confirmed that these three TKs mediate LPS-induced endothelial inflammatory activation. Pharmacological inhibition with FAK1 inhibitor FAK14 attenuated LPS-induced endothelial inflammatory activation and leukocyte adhesion partly via blockade of NF-κB activity. Administration of FAK14 after EC exposure to LPS also resulted in inhibition of inflammatory molecule expression. In contrast, inhibition of ALK with FDA-approved inhibitor Ceritinib attenuated LPS-induced endothelial inflammatory activation via a pathway that was independent of NF-κB signalling while it did not affect leukocyte adhesion. Furthermore, Ceritinib administration after start of EC exposure to LPS did not inhibit inflammatory activation. Combined FAK1 and ALK inhibition attenuated LPS-induced endothelial activation in an additive manner, without affecting leukocyte adhesion. Summarising, our findings suggest the involvement of FAK1 and ALK in mediating LPS-induced inflammatory activation of EC. Since pharmacological inhibition of FAK1 attenuated endothelial inflammatory activation after the cells were exposed to LPS, FAK1 represents a promising target for follow up studies.
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http://dx.doi.org/10.1016/j.biopha.2020.111073DOI Listing
January 2021

Acute Kidney Injury is Associated with Lowered Plasma-Free Thiol Levels.

Antioxidants (Basel) 2020 Nov 16;9(11). Epub 2020 Nov 16.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, 9713GZ Groningen, The Netherlands.

Acute kidney injury (AKI) is associated with the abrupt loss of kidney function. Oxidative stress plays an important role in the pathophysiology of AKI. Free thiols (R-SH) are crucial components of the extracellular antioxidant machinery and reliably reflect systemic oxidative stress. Lower levels of thiols represent higher levels of oxidative stress. In this preliminary study, we hypothesized that plasma-free thiols are associated with AKI upon admission to the intensive care unit (ICU). In this study, 301 critically ill patients were included. Plasma samples were taken upon admission, and albumin-adjusted plasma-free thiols were determined. Albumin-adjusted plasma-free thiols were lower in patients with AKI (n = 43, median (interquartile range) 7.28 µmol/g (3.52, 8.95)) compared to patients without AKI (8.50 μmol/g (5.82, 11.28); < 0.05) upon admission to the ICU. Higher age (B = -0.72), higher levels of neutrophil gelatinase-associated lipocalin (B = -0.002), creatinine (B = -0.01) and lower serum albumin (B = 0.47) were associated with lower free thiol levels. Further, albumin-adjusted free thiol levels were significantly reduced in patients with sepsis (8.30 (5.52-10.64) µmol/g) compared to patients without sepsis (6.95 (3.72-8.92) µmol/g; < 0.05). Together, albumin-adjusted plasma-free thiols were significantly reduced in patients with AKI and patients with sepsis compared with patients without AKI and sepsis.
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http://dx.doi.org/10.3390/antiox9111135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696918PMC
November 2020

Post-Mortem Diagnostics in COVID-19 AKI, More Often but Timely.

J Am Soc Nephrol 2021 01 5;32(1):255. Epub 2020 Nov 5.

Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1681/ASN.2020091263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894667PMC
January 2021

A Method to Improve Continuous Renal Replacement Therapy Circuit Survival Time in Critically Ill Coronavirus Disease 2019 Patients With Acute Kidney Injury.

Crit Care Explor 2020 Oct 15;2(10):e0258. Epub 2020 Oct 15.

Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Objectives: Optimizing continuous renal replacement therapy circuit survival in coronavirus disease 2019 patients admitted to the ICU.

Design: Single-center prospective observational cohort study.

Setting: Tertiary academic teaching ICU.

Patients: Between March 19, 2020, and May 18, 2020, 11 out of 101 coronavirus disease 2019 patients were treated with continuous renal replacement therapy comprising 127 continuous renal replacement therapy days.

Interventions: A nonrandomized observational comparison of circuit anticoagulation modalities using standard regional citrate anticoagulation, continuous IV heparin anticoagulation, or the combination of regional citrate anticoagulation with either continuous IV heparin or therapeutic dose nadroparin.

Measurements And Main Results: Circuit patency was shorter than 24 hours using standard regional citrate anticoagulation or continuous IV heparin anticoagulation. Median circuit survival increased with at least 165% when the combination of regional citrate anticoagulation with either continuous IV heparin or therapeutic dose nadroparin was applied.

Conclusions: Continuous renal replacement therapy circuit patency is diminished in coronavirus disease 2019 ICU patients. Combining regional citrate anticoagulation with either continuous IV heparin or therapeutic dose nadroparin increases filter survival as compared with regional citrate anticoagulation alone in this nonrandomized observational study.
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http://dx.doi.org/10.1097/CCE.0000000000000258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566862PMC
October 2020

Intra-abdominal hypertension and abdominal compartment syndrome in patients admitted to the ICU.

Ann Intensive Care 2020 Oct 1;10(1):130. Epub 2020 Oct 1.

Department of Critical Care (BA 49), University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands.

Background: Intra-abdominal hypertension is frequently present in critically ill patients and is an independent predictor for mortality. Risk factors for intra-abdominal hypertension and abdominal compartment syndrome have been widely investigated. However, data are lacking on prevalence and outcome in high-risk patients. Our objectives in this study were to investigate prevalence and outcome of intra-abdominal hypertension and abdominal compartment syndrome in high-risk patients in a prospective, observational, single-center cohort study.

Results: Between March 2014 and March 2016, we included 503 patients, 307 males (61%) and 196 females (39%). Patients admitted to the intensive care unit with a diagnosis of pancreatitis, elective or emergency open abdominal aorta surgery, orthotopic liver transplantation, other elective or emergency major abdominal surgery and trauma were enrolled. One hundred and sixty four (33%) patients developed intra-abdominal hypertension and 18 (3.6%) patients developed abdominal compartment syndrome. Highest prevalence of abdominal compartment syndrome occurred in pancreatitis (57%) followed by orthotopic liver transplantation (7%) and abdominal aorta surgery (5%). Length of intensive care stay increased by a factor 4 in patients with intra-abdominal hypertension and a factor 9 in abdominal compartment syndrome, compared to patients with normal intra-abdominal pressure. Rate of renal replacement therapy was higher in abdominal compartment syndrome (38.9%) and intra-abdominal hypertension (8.2%) compared to patients with normal intra-abdominal pressure (1.2%). Both intensive care mortality and 90-day mortality were significantly higher in intra-abdominal hypertension (4.8% and 15.2%) and abdominal compartment syndrome (16.7% and 38.9%) compared to normal intra-abdominal pressure (1.2% and 7.1%). Body mass index (odds ratio 1.08, 95% confidence interval 1.03-1.13), mechanical ventilation at admission (OR 3.52, 95% CI 2.08-5.96) and Apache IV score (OR 1.03, 95% CI 1.02-1.04) were independent risk factors for the development of intra-abdominal hypertension or abdominal compartment syndrome.

Conclusions: The prevalence of abdominal compartment syndrome was 3.6% and the prevalence of intra-abdominal hypertension was 33% in this cohort of high-risk patients. Morbidity and mortality increased when intra-abdominal hypertension or abdominal compartment syndrome was present. The patient most at risk of IAH or ACS in this high-risk cohort has a BMI > 30 kg/m and was admitted to the ICU after emergency abdominal surgery or with a diagnosis of pancreatitis.
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http://dx.doi.org/10.1186/s13613-020-00746-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530150PMC
October 2020

Bundled care in acute kidney injury in critically ill patients, a before-after educational intervention study.

BMC Nephrol 2020 09 3;21(1):381. Epub 2020 Sep 3.

Department of Critical Care, University of Groningen, University Medical Center Groningen, Postbus 30.001, 9700, RB, Groningen, The Netherlands.

Background: Acute kidney injury (AKI) often occurs in critically ill patients. AKI is associated with mortality and morbidity. Interventions focusing on the reduction of AKI are suggested by the Kidney Disease: Improving Global Outcomes guideline. We hypothesized that these educational interventions would improve outcome in patients admitted to the Intensive Care Unit (ICU).

Methods: This was a pragmatic single-centre prospective observational before-after study design in an ICU in a tertiary referral hospital. All consecutive patients admitted to the ICU irrespective their illness were included. A 'Save the Kidney' (STK) bundle was encouraged via an educational intervention targeting health care providers. The educational STK bundle consisted of optimizing the fluid balance (based on urine output, serum lactate levels and/or central venous oxygen saturation), discontinuation of diuretics, maintaining a mean arterial pressure of at least 65 mmHg with the potential use of vasopressors and critical evaluation of the indication and dose of nephrotoxic drugs. The primary outcome was the composite of mortality, renal replacement therapy (RRT), and progression of AKI. Secondary outcomes were the components of the composite outcome the severity of AKI, ICU length of stay and in-hospital mortality.

Main Results: The primary outcome occurred in 451 patients (33%) in the STK group versus 375 patients (29%) in the usual care group, relative risk (RR) 1.16, 95% confidence interval (CI) 1.03-1.3, p < 0.001. Secondary outcomes were, ICU mortality in 6.8% versus 5.6%, (RR 1.22, 95% CI 0.90-1.64, p = 0.068), RRT in 1.6% versus 3.6% (RR 0.46, 95% CI 0.28-0.76, p = 0.002), and AKI progression in 28% versus 24% (RR 1.18, 95% CI 1.04-1.35, p = 0.001).

Conclusions: Providing education to uniformly apply an AKI care bundle, without measurement of the implementation in a non-selected ICU population, targeted at prevention of AKI progression was not beneficial.
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http://dx.doi.org/10.1186/s12882-020-02029-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469422PMC
September 2020

Leptin levels in SARS-CoV-2 infection related respiratory failure: A cross-sectional study and a pathophysiological framework on the role of fat tissue.

Heliyon 2020 Aug 20;6(8):e04696. Epub 2020 Aug 20.

Department of Critical Care, University of Groningen, University Medical Center Groningen, 9700, RB, Groningen, the Netherlands.

Obesity is a risk factor for SARS-CoV-2 infected patients to develop respiratory failure. Leptin produced in visceral fat might play a role in the deterioration to mechanical ventilation. A cross sectional study was performed. The mean BMI was 31 kg/m (range 24.8-48.4) for the 31 SARS-CoV-2 ventilated patients and 26 kg/m (range 22.4-33.5) for 8 critically ill non-infected control patients. SARS-CoV-2 infected patients with a similar BMI as control patients appear to have significantly higher levels of serum leptin. The mean leptin level was 21.2 (6.0-85.2) vs 5.6 (2.4-8.2) ug/L for SARS-CoV-2 and controls respectively (p = 0.0007). With these findings we describe a clinical and biological framework that may explain these clinical observations. The ACE2 utilization by the virus leads to local pulmonary inflammation due to ACE2-ATII disbalance. This might be enhanced by an increase in leptin production induced by SARS-CoV-2 infection of visceral fat. Leptin receptors in the lungs are now more activated to enhance local pulmonary inflammation. This adds to the pre-existent chronic inflammation in obese patients. Visceral fat, lung tissue and leptin production play an interconnecting role. This insight can lead the way to further research and treatment.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439829PMC
August 2020

Kidney Infarction in Patients With COVID-19.

Am J Kidney Dis 2020 09 29;76(3):431-435. Epub 2020 May 29.

Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Coronavirus disease 2019 (COVID-19) is a contagious life-threatening infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent findings indicate an increased risk for acute kidney injury during COVID-19 infection. The pathophysiologic mechanisms leading to acute kidney injury in COVID-19 infection are unclear but may include direct cytopathic effects of the virus on kidney tubular and endothelial cells, indirect damage caused by virus-induced cytokine release, and kidney hypoperfusion due to a restrictive fluid strategy. In this report of 2 cases, we propose an additional pathophysiologic mechanism. We describe 2 cases in which patients with COVID-19 infection developed a decrease in kidney function due to kidney infarction. These patients did not have atrial fibrillation. One of these patients was treated with therapeutic doses of low-molecular-weight heparin, after which no further deterioration in kidney function was observed. Our findings implicate that the differential diagnosis of acute kidney injury in COVID-19-infected patients should include kidney infarction, which may have important preventive and therapeutic implications.
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http://dx.doi.org/10.1053/j.ajkd.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7258815PMC
September 2020

AKI: an enlightening acronym with a shadow side.

Kidney Int 2020 06;97(6):1301

Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1016/j.kint.2020.03.016DOI Listing
June 2020

Heterogenous Renal Injury Biomarker Production Reveals Human Sepsis-Associated Acute Kidney Injury Subtypes.

Crit Care Explor 2019 Oct 14;1(10):e0047. Epub 2019 Oct 14.

Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

To identify mechanisms associated with sepsis-acute kidney injury based on the expression levels of renal injury biomarkers, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 in renal biopsies which may allow the identification of sepsis-acute kidney injury patient subtypes.

Design: Prospective, clinical laboratory study using "warm" human postmortem sepsis-acute kidney injury kidney biopsies.

Setting: Research laboratory at university teaching hospital.

Subjects: Adult patients who died of sepsis in the ICU and control patients undergoing tumor nephrectomy.

Measurements And Main Results: Reverse transcription quantitative polymerase chain reaction and immunohistochemical staining were used to quantify messenger RNA and protein expression levels of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in the kidney of sepsis-acute kidney injury patients and control subjects. Morphometric analysis was used to quantify renal and glomerular neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 protein levels. Neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 messenger RNA and protein levels were increased in kidneys of sepsis-acute kidney injury patients compared with control kidney tissue. Neutrophil gelatinase-associated lipocalin was localized in the distal tubules, collecting ducts, the adventitia of the renal arterioles, and in the glomerular tufts of renal biopsies from sepsis-acute kidney injury patients. In contrast, kidney injury molecule-1 was localized at the brush border of the proximal tubules. There was no correlation between neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 levels. Furthermore, renal neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 levels were not associated with the extent of renal injury, the severity of critical illness, or serum creatinine levels at either ICU admission or day of expiration. By laser microdissecting glomeruli, followed by reverse transcription quantitative polymerase chain reaction, we identified heterogenous glomerular neutrophil gelatinase-associated lipocalin production in the kidney of sepsis-acute kidney injury patients.

Conclusion: We found differences in the expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in patients with the same syndrome "sepsis-acute kidney injury" meaning there is no single pathway leading to sepsis-acute kidney injury. This underscores the beliefs that there are many/different pathophysiological pathways that can cause sepsis-acute kidney injury. Hence, patients with criteria that meet the definitions of both acute kidney injury and sepsis can be divided into subtypes based on pathophysiological features.
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http://dx.doi.org/10.1097/CCE.0000000000000047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063889PMC
October 2019

Markers of endothelial cell activation in suspected late onset neonatal sepsis in Surinamese newborns: a pilot study.

Transl Pediatr 2019 Dec;8(5):412-418

Academic Pediatric Center Suriname, Academic Hospital Paramaribo, Paramaribo, Suriname.

Background: Serum levels of markers of endothelial cell activation are associated with bacteremia and mortality in sepsis in adults, children, and newborns with early onset sepsis. We hypothesize that levels of these markers are associated with these outcomes in hospitalized newborns with suspected late onset neonatal sepsis (LONS).

Methods: In this prospective cohort study, newborns admitted to the tertiary neonatal care facility of Suriname were included upon clinical suspicion of LONS and before start of antibiotic treatment, between April 1, 2015 and May 31, 2016. Serum concentrations of angiopoietin-1, angiopoietin-2, and soluble isoforms of P-selectin, E-selectin, vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), platelet and endothelial cell adhesion molecule-1 (sPECAM-1), matrix metalloproteinase-9 (MMP-9), neutrophil elastase, and tissue-inhibitor of metalloproteinases-1 (TIMP-1) were measured.

Results: Twenty-thee newborns were included. Baseline characteristics were similar between newborns with and without bacteremia and between non-survivors and survivors. Only soluble E-selectin (sE-selectin) was higher in newborns with bacteremia versus non-bacteremia (P=0.04) and lower in non-survivors (P=0.04). No conclusions could be made for sVCAM-1 due to high serum concentrations.

Conclusions: In conclusion, the data from this pilot study indicate that serum levels of markers of endothelial cell activation are poorly associated with bacteremia and mortality.
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http://dx.doi.org/10.21037/tp.2019.11.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970123PMC
December 2019

Neutrophil-endothelial interactions in respiratory syncytial virus bronchiolitis: An understudied aspect with a potential for prediction of severity of disease.

J Clin Virol 2020 02 31;123:104258. Epub 2019 Dec 31.

Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) causes significant morbidity and mortality among young infants worldwide. It is currently widely accepted that neutrophil influx into the airways is a hallmark of the pathophysiology. However, the exact mechanism of neutrophil migration from the vasculature into the alveolar space in RSV LRTI has received little attention. Data shows that endothelial cells become activated upon RSV infection, driving a 'pro-adhesive state' for circulating neutrophils with upregulation of endothelial intercellular adhesion molecule-1 (ICAM-1). During RSV LRTI different subsets of immature and mature neutrophils are present in the bloodstream, that upregulate integrins lymphocyte-function associated antigen (LFA)-1 and macrophage (Mac)-1, serving as ICAM-1 ligands. An alveolar gradient of interleukin-8 may serve as a potent chemoattractant for circulating neutrophils. Neutrophils from lung aspirates of RSV-infected infants show further signs of inflammatory and migratory activation, while soluble endothelial cell adhesion molecules (sCAMs), such as sICAM-1, have become measurable in the systemic circulation. Whether these mechanisms are solely responsible for neutrophil migration into the alveolar space remains under debate. However, data indicate that the currently postulated neutrophil influx into the lungs should rather be regarded as a neutrophil efflux from the vasculature, involving substantial neutrophil-endothelial interactions. Molecular patterns of these interactions may be clinically useful to predict outcomes of RSV LRTI and deserve further study.
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http://dx.doi.org/10.1016/j.jcv.2019.104258DOI Listing
February 2020

Identifying Sepsis Phenotypes.

JAMA 2019 10;322(14):1416

Department of Critical Care, University Medical Center Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.1001/jama.2019.12587DOI Listing
October 2019

Identification of LPS-Activated Endothelial Subpopulations With Distinct Inflammatory Phenotypes and Regulatory Signaling Mechanisms.

Front Immunol 2019 24;10:1169. Epub 2019 May 24.

Medical Biology Section, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Endothelial cells (EC) are actively involved in sepsis-associated (micro)vascular disturbances and subsequent organ dysfunction. Lipopolysaccharide (LPS), a Gram-negative bacterial product, can activate EC leading to the expression of pro-inflammatory molecules. This process is molecularly regulated by specific receptors and distinct, yet poorly understood intracellular signaling pathways. LPS-induced expression of endothelial adhesion molecules E-selectin and VCAM-1 in mice was previously shown to be organ- and microvascular-specific. Here we report that also within renal microvascular beds the endothelium expresses different extents of E-selectin and VCAM-1. This heterogeneity was recapitulated in LPS-activated human umbilical vein EC (HUVEC). Within 2 h after LPS exposure, four distinct HUVEC subpopulations were visible by flow cytometric analysis detecting E-selectin and VCAM-1 protein. These encompassed E-selectin/VCAM-1 (-/-), E-selectin/VCAM-1 (E-sel+), E-selectin/VCAM-1 (+/+), and E-selectin/VCAM-1 (VCAM-1+) subpopulations. The formation of subpopulations was a common response of endothelial cells to LPS challenge. Using fluorescence-activated cell sorting (FACS) we demonstrated that the +/+ subpopulation also expressed the highest levels of inflammatory cytokines and chemokines. The differences in responsiveness of EC subpopulations could not be explained by differential expression of LPS receptors TLR4 and RIG-I. Functional studies, however, demonstrated that the formation of the E-sel+ subpopulation was mainly TLR4-mediated, while the formation of the +/+ subpopulation was mediated by both TLR4 and RIG-I. Pharmacological blockade of NF-κB and p38 MAPK furthermore revealed a prominent role of their signaling cascades in E-sel+ and +/+ subpopulation formation. In contrast, the VCAM-1+ subpopulation was not controlled by any of these signaling pathways. Noteworthy is the existence of a "quiescent" subpopulation that was devoid of the two adhesion molecules and did not express cytokines or chemokines despite LPS exposure. Summarizing, our findings suggest that LPS activates different signaling mechanisms in EC that drive heterogeneous expression of EC inflammatory molecules. Further characterization of the signaling pathways involved will enhance our understanding of endothelial heterogeneous responses to sepsis related stimuli and enable the future design of effective therapeutic strategies to interfere in these processes to counteract sepsis-associated organ dysfunction.
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http://dx.doi.org/10.3389/fimmu.2019.01169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543489PMC
September 2020

Rapid free thiol rebound is a physiological response following cold-induced vasoconstriction in healthy humans, primary Raynaud and systemic sclerosis.

Physiol Rep 2019 03;7(6):e14017

Department of Internal Medicine, Division Vascular Medicine, University of Groningen - University Medical Centre Groningen, Groningen, The Netherlands.

Raynaud's phenomenon (RP) is often the first sign of systemic sclerosis (SSc). Molecular mechanisms involved are incompletely understood, but reactive oxygen, nitrogen, and sulfur species are thought to play an important role in the pathogenesis of SSc. Free thiol groups play a protective role against oxidative stress and may represent an attractive therapeutic target. We aimed to investigate the effects of hypothermia-induced vasoconstriction on the responsiveness of redox-related markers. Thirty participants (n = 10/group [SSc, primary Raynaud's phenomenon (PRP), healthy controls (HC)]) were included in this study. Fingertip photoelectric plethysmography was performed during a standardized cooling and recovery experiment. Venous blood was collected at four predetermined time points. Free thiols, NO-derived species (nitros(yl)ated species, nitrite, nitrate), sulfate and endothelin-1 were measured. Lower baseline concentrations of free thiols were observed in PRP and SSc patients (HC: 5.87 [5.41-5.99] μmol/g; PRP: 5.17 [4.74-5.61]; SSc 5.28 [4.75-5.80], P = 0.04). Redox-related markers remained unchanged during cooling. However, an unexpected increase in systemic free thiol concentrations was observed in all groups during the recovery phase. The response of this marker differed between groups, with a higher increase found in SSc patients (HC Δ = 1.30 [1.48-1.17]; PRP Δ = 1.04 [1.06-1.03]; SSc Δ = 1.72 [1.13-1.49], P = 0.04). NO-derived species, sulfate and endothelin-1 levels remained unchanged throughout the recovery phase. This exploratory study sheds light on the rapid responsiveness of systemic free thiol concentrations following reperfusion, which may reflect overall redox balance. The robust response to reperfusion in SSc patients suggests that reductive systems involved in this response are functionally intact in these patients.
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http://dx.doi.org/10.14814/phy2.14017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436142PMC
March 2019

Commentary: Precision Immunotherapy for Sepsis.

Front Immunol 2019;10:20. Epub 2019 Jan 31.

Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

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http://dx.doi.org/10.3389/fimmu.2019.00020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365442PMC
July 2019
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