Impaired balance between neutrophil extracellular trap formation and degradation by DNases in COVID-19 disease.

BACKGROUND: Thrombo-inflammation and neutrophil extracellular traps (NETs) are exacerbated in severe cases of COVID-19, potentially contributing to disease exacerbation. However, the mechanisms underpinning this dysregulation remain elusive. We hypothesised that lower DNase activity may be associated with higher NETosis and clinical worsening in patients with COVID-19. METHODS: Biological samples were obtained from hospitalized patients (15 severe, 37 critical at sampling) and 93 non-severe ambulatory cases. Our aims were to compare NET biomarkers, functional DNase levels, and explore mechanisms driving any imbalance concerning disease severity. RESULTS: Functional DNase levels were diminished in the most severe patients, paralleling an imbalance between NET markers and DNase activity. DNase1 antigen levels were higher in ambulatory cases but lower in severe patients. DNase1L3 antigen levels remained consistent across subgroups, not rising alongside NET markers. DNASE1 polymorphisms correlated with reduced DNase1 antigen levels. Moreover, a quantitative deficiency in plasmacytoid dendritic cells (pDCs), which primarily express DNase1L3, was observed in critical patients. Analysis of public single-cell RNAseq data revealed reduced DNase1L3 expression in pDCs from severe COVID-19 patient. CONCLUSION: Severe and critical COVID-19 cases exhibited an imbalance between NET and DNase functional activity and quantity. Early identification of NETosis imbalance could guide targeted therapies against thrombo-inflammation in COVID-19-related sepsis, such as DNase administration, to avert clinical deterioration. TRIAL REGISTRATION: COVERAGE trial (NCT04356495) and COLCOV19-BX study (NCT04332016).

Impact of dexamethasone in severe COVID-19-induced acute kidney injury: a multicenter cohort study.

BACKGROUND: Acute kidney injury (AKI) in intensive care unit (ICU) patients with severe COVID-19 is common (> 50%). A specific inflammatory process has been suggested in the pathogenesis of AKI, which could be improved by dexamethasone (DXM). In a small monocenter study (n = 100 patients), we reported a potential protective effect of DXM on the risk of AKI. This study aimed to investigate the preventive impact of DXM on AKI in a multicenter study of patients with severe COVID-19. METHODS: We conducted a multicenter study in three French ICUs from March 2020 to August 2021. All patients admitted to ICU for severe COVID-19 were included. Individuals with preexistent AKI or DXM administration before admission to ICU were excluded. While never used during the first wave, DXM was used subsequently at ICU entry, providing two treatment groups. Multivariate Cause-specific Cox models taking into account changes in ICU practices over time, were utilized to determine the association between DXM and occurrence of AKI. RESULTS: Seven hundred and ninety-eight patients were included. Mean age was 62.6 ± 12.1 years, 402/798 (50%) patients had hypertension, and 46/798 (6%) had previous chronic kidney disease. Median SOFA was 4 [3-6] and 420/798 (53%) required invasive mechanical ventilation. ICU mortality was 208/798 (26%). AKI was present in 598/798 (75%) patients: 266/598 (38%), 163/598 (27%), and 210/598 (35%) had, respectively, AKI KDIGO 1, 2, 3, and 61/598 (10%) patients required renal replacement therapy. Patients receiving DXM had a significantly decreased hazard of AKI occurrence compared to patients without DXM (HR 0.67; 95CI 0.55-0.81). These results were consistent in analyses that (1) excluded patients with DXM administration to AKI onset delay of less than 12 h, (2) incorporating the different 'waves' of the COVID-19 pandemic. CONCLUSIONS: DXM was associated with a decrease in the risk of AKI in severe COVID-19 patients admitted to ICU. This supports the hypothesis that the inflammatory injury of AKI may be preventable.

Serum lactate and acute mesenteric ischaemia: An observational, controlled multicentre study.

BACKGROUND: Early diagnosis and prompt management of acute mesenteric ischaemia (AMI) are key to survival but remain extremely difficult, due to vague and non-specific symptoms. Serum lactate (SL) is commonly presented as a useful biomarker for the diagnosis or prognosis of AMI. The aim of our study was test SL (1) as a diagnostic marker and (2) as a prognostic marker for AMI. STUDY DESIGN: This was an ancillary multicentre case-control study. Patients with AMI at intensive care unit (ICU) admission were included (AMI group) and matched to ICU patients without AMI (control group). SL was measured and compared on day 0 (D0) and day 1 (D1). Diagnosis and prognosis accuracy were assessed by receiver operating characteristic (ROC) and their area under the curve (AUC). RESULTS: Each group consisted of 137 matched ICU patients. There was no significant difference of SL between the two groups at D0 or at D1 (p = 0.26 and p = 0.29 respectively). SL was a poor marker of AMI: at D0 and D1, AUC were respectively 0.57 [0.51; 0.63] and 0.60 [0.53; 0.67]. SL at D0 and D1 correctly predicted ICU mortality, independently of AMI (AUC D0: 0.69 [0.59; 0.79] vs. 0.74 [0.65; 0.82]; p = 0.51 and D1: 0.74 [0.64; 0.84] vs. 0.76 [0.66; 0.87]; p = 0.77, respectively, for control and AMI groups]. CONCLUSIONS: SL has no specific link with AMI, both for diagnosis and prognosis. SL should not be used for the diagnosis of AMI but, despite its lack of specificity, it may help to assess severity.

Plasma Markers of Neutrophil Extracellular Trap Are Linked to Survival but Not to Pulmonary Embolism in COVID-19-Related ARDS Patients.

Introduction: Coronavirus disease 2019 (COVID-19) can cause life-threatening acute respiratory distress syndrome (ARDS). Recent data suggest a role for neutrophil extracellular traps (NETs) in COVID-19-related lung damage partly due to microthrombus formation. Besides, pulmonary embolism (PE) is frequent in severe COVID-19 patients, suggesting that immunothrombosis could also be responsible for increased PE occurrence in these patients. Here, we evaluate whether plasma levels of NET markers measured shorty after admission of hospitalized COVID-19 patients are associated with clinical outcomes in terms of clinical worsening, survival, and PE occurrence. Patients and Methods: Ninety-six hospitalized COVID-19 patients were included, 50 with ARDS (severe disease) and 46 with moderate disease. We collected plasma early after admission and measured 3 NET markers: total DNA, myeloperoxidase (MPO)-DNA complexes, and citrullinated histone H3. Comparisons between survivors and non-survivors and patients developing PE and those not developing PE were assessed by Mann-Whitney test. Results: Analysis in the whole population of hospitalized COVID-19 patients revealed increased circulating biomarkers of NETs in patients who will die from COVID-19 and in patients who will subsequently develop PE. Restriction of our analysis in the most severe patients, i.e., the ones who enter the hospital for COVID-19-related ARDS, confirmed the link between NET biomarker levels and survival but not PE occurrence. Conclusion: Our results strongly reinforce the hypothesis that NETosis is an attractive therapeutic target to prevent COVID-19 progression but that it does not seem to be linked to PE occurrence in patients hospitalized with COVID-19.

[Acute kidney injury in intensive care unit: A review]. / Insuffisance rénale aiguë en soins intensifs-réanimation et ses conséquences : mise au point.

Acute kidney injury is a common complication in intensive care unit. Its incidence is variable according to the studies. It is considered to occur in more than 50 % of patients. Acute kidney injury is responsible for an increase in morbidity (length of hospitalization, renal replacement therapy) but also for excess mortality. The commonly accepted definition of acute kidney injury comes from the collaborative workgroup named Kidney Disease: Improving Global Outcomes (KDIGO). It made it possible to standardize practices and raise awareness among practitioners about monitoring plasma creatinine and also diuresis. Acute kidney injury in intensive care unit is a systemic disease including circulatory, endothelial, epithelial and cellular function involvement and an acute kidney injury is not accompanied by ad integrum repair. After prolonged injury, inadequate repair begins with a fibrotic process. Several mechanisms are involved (cell cycle arrest, epithelial-mesenchymal transition, mitochondrial dysfunction) and result in improper repair. A continuum exists between acute kidney disease and chronic kidney disease, characterized by different renal recovery phenotypes. Thus, preventive measures to prevent the occurrence of kidney damage play a major role in management. The nephrologist must be involved at every stage, from the prevention of the first acute kidney injury (upon arrival in intensive care unit) to long-term follow-up and the care of a chronic kidney disease.

Prognostic Impact of Early Recovering Acute Kidney Injury Following Liver Transplantation: A Multicenter Retrospective Study.

BACKGROUND: Acute kidney injury (AKI) is a common complication after liver transplantation (LT), but the specific impact of rapidly resolving AKI is not elucidated. This study investigates the factors associated with early recovery from AKI and its association with post-LT outcomes. METHODS: Retrospective analysis of 441 liver transplant recipients with end-stage liver disease without pretransplant renal impairment. AKI was defined according to Kidney Disease Improving Global Outcomes criteria and early renal recovery by its disappearance within 7 d post-LT. RESULTS: One hundred forty-six patients (32%) developed a post-LT AKI, of whom 99 (69%) recovered early and 45 (31%) did not. Factors associated with early recovery were Kidney Disease Improving Global Outcomes stage 1 (odds ratio [OR],14.11; 95% confidence interval [CI], 5.59-40.22; P < 0.0001), minimum prothrombin time >50 % (OR, 4.50; 95% CI, 1.67-13.46; P = 0.003) and aspartate aminotransferase peak value <1000 U/L (OR, 4.07; 95% CI, 1.64-10.75; P = 0.002) within 48 h post-LT. Patients with early recovery had a renal prognosis similar to that of patients without AKI with no difference in estimated glomerular filtration rate between day 7 and 1 y. Their relative risk of developing chronic kidney disease was 0.88 (95% CI, 0.55-1.41; P = 0.6) with survival identical to patients without AKI and better than patients without early recovery (P < 0.0001). CONCLUSIONS: Most patients with post-LT AKI recover early and have a similar renal prognosis and survival to those without post-LT AKI. Factors associated with early renal recovery are related to the stage of AKI, the extent of liver injury, and the early graft function. Patients at risk of not recovering may benefit the most from perioperative protective strategies, particularly those aimed at minimizing the adverse effects of calcineurin inhibitors.

High mean arterial pressure target to improve sepsis-associated acute kidney injury in patients with prior hypertension: a feasibility study.

BACKGROUND: The optimal mean arterial pressure (MAP) in cases of septic shock is still a matter of debate in patients with prior hypertension. An MAP between 75 and 85 mmHg can improve glomerular filtration rate (GFR) but its effect on tubular function is unknown. We assessed the effects of high MAP level on glomerular and tubular renal function in two intensive care units of a teaching hospital. Inclusion criteria were patients with a history of chronic hypertension and developing AKI in the first 24 h of septic shock. Data were collected during two 6 h periods of MAP regimen administered consecutively after haemodynamic stabilisation in an order depending on the patient's admission unit: a high-target period (80-85 mmHg) and a low-target period (65-70 mmHg). The primary endpoint was the creatinine clearance (CrCl) calculated from urine and serum samples at the end of each MAP period by the UV/P formula. RESULTS: 26 patients were included. Higher urine output (+0.2 (95%:0, 0.4) mL/kg/h; P = 0.04), urine sodium (+6 (95% CI 0.2, 13) mmol/L; P = 0.04) and lower serum creatinine (- 10 (95% CI - 17, - 3) µmol/L; P = 0.03) were observed during the high-MAP period as compared to the low-MAP period, resulting in a higher CrCl (+25 (95% CI 11, 39) mL/mn; P = 0.002). The urine creatinine, urine-plasma creatinine ratio, urine osmolality, fractional excretion of sodium and urea showed no significant variation. The KDIGO stage at inclusion only interacted with serum creatinine variation and low level of sodium excretion at inclusion did not interact with these results. CONCLUSIONS: In the early stage of sepsis-associated AKI, a high-MAP target in patients with a history of hypertension was associated with a higher CrCl, but did not affect the kidneys' ability to concentrate urine, which may reflect no effect on tubular function.

Amino acids and vitamins status during continuous renal replacement therapy: An ancillary prospective observational study of a randomised control trial.

BACKGROUND: Continuous renal replacement therapy (CRRT) is associated with micronutrients loss. Current recommendations are to administer 1-1.5g/kg/day of proteins during CRRT. We aim to evaluate the net effect of CRRT on amino acids (AA), vitamins A and C (Vit A, Vit C) levels. METHODS: This is a prospective observational study embedded within a randomised controlled trial comparing two CRRT doses in patients with septic shock. CRRT was provided in continuous veno-venous haemofiltration mode at a dose of either 35ml/kg/h or 70ml/kg/h. All patients received parenteral nutrition with standard trace elements and vitamins (protein intake 1g/kg/d). We measured serum levels of glutamine, valine and alanine as well as Vit A and Vit C upon randomisation, study day four and eight. In addition, we measured a larger panel of AA in a subset of 11 patients. RESULTS: We included 30 patients (17 allocated to 70ml/kg/h and 13 to 35ml/kg/h CRRT). Before CRRT initiation, mean plasma levels of glutamine and valine, Vit A and Vit C were low. CRRT was not associated with any significant change in AA levels except for a decrease in cystein. It was associated with an increase in Vit A and a decrease in Vit C levels. CRRT dose had no impact on those nutrients blood levels. CONCLUSIONS: Irrespective of dose, CRRT was associated with a decrease in cysteine and Vit C and an increase in Vit A with no significant change in other AA. Further studies should focus on lean mass wasting during CRRT.

Characterization of acute kidney injury in critically ill patients with severe coronavirus disease 2019.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-associated acute kidney injury (AKI) frequency, severity and characterization in critically ill patients has not been reported. METHODS: Single-centre cohort performed from 3 March 2020 to 14 April 2020 in four intensive care units in Bordeaux University Hospital, France. All patients with COVID-19 and pulmonary severity criteria were included. AKI was defined using Kidney Disease: Improving Global Outcomes (KDIGO) criteria. A systematic urinary analysis was performed. The incidence, severity, clinical presentation, biological characterization (transient versus persistent AKI; proteinuria, haematuria and glycosuria) and short-term outcomes were evaluated. RESULTS: Seventy-one patients were included, with basal serum creatinine (SCr) of 69 ± 21 µmol/L. At admission, AKI was present in 8/71 (11%) patients. Median [interquartile range (IQR)] follow-up was 17 (12-23) days. AKI developed in a total of 57/71 (80%) patients, with 35% Stage 1, 35% Stage 2 and 30% Stage 3 AKI; 10/57 (18%) required renal replacement therapy (RRT). Transient AKI was present in only 4/55 (7%) patients and persistent AKI was observed in 51/55 (93%). Patients with persistent AKI developed a median (IQR) urine protein/creatinine of 82 (54-140) (mg/mmol) with an albuminuria/proteinuria ratio of 0.23 ± 20, indicating predominant tubulointerstitial injury. Only two (4%) patients had glycosuria. At Day 7 after onset of AKI, six (11%) patients remained dependent on RRT, nine (16%) had SCr >200 µmol/L and four (7%) had died. Day 7 and Day 14 renal recovery occurred in 28% and 52%, respectively. CONCLUSION: Severe COVID-19-associated AKI is frequent, persistent, severe and characterized by an almost exclusive tubulointerstitial injury without glycosuria.

CD154 Induces Interleukin-6 Secretion by Kidney Tubular Epithelial Cells under Hypoxic Conditions: Inhibition by Chloroquine.

Inflammation is a major contributor to tubular epithelium injury in kidney disorders, and the involvement of blood platelets in driving inflammation is increasingly stressed. CD154, the ligand of CD40, is one of the mediators supporting platelet proinflammatory properties. Although hypoxia is an essential constituent of the inflammatory reaction, if and how platelets and CD154 regulate inflammation in hypoxic conditions remain unclear. Here, we studied the control by CD154 of the proinflammatory cytokine interleukin- (IL-) 6 secretion in short-term oxygen (O2) deprivation conditions, using the HK-2 cell line as a kidney tubular epithelial cell (TEC) model. IL-6 secretion was markedly stimulated by CD154 after 1 to 3 hours of hypoxic stress. Both intracellular IL-6 expression and secretion were stimulated by CD154 and associated with a strong upregulation of IL-6 mRNA and increased transcription. Searching for inhibitors of CD154-mediated IL-6 production by HK-2 cells in hypoxic conditions, we observed that chloroquine, a drug that has been repurposed as an anti-inflammatory agent, alleviated this induction. Therefore, CD154 is a potent early stimulus for IL-6 secretion by TECs in O2 deprivation conditions, a mechanism likely to take part in the deleterious inflammatory consequences of platelet activation in kidney tubular injury. The inhibition of CD154-induced IL-6 production by chloroquine suggests the potential usefulness of this drug as a therapeutic adjunct in conditions associated with acute kidney injury.

Effect of Hydroxyethyl Starch vs Saline for Volume Replacement Therapy on Death or Postoperative Complications Among High-Risk Patients Undergoing Major Abdominal Surgery: The FLASH Randomized Clinical Trial.

Importance: It is not known if use of colloid solutions containing hydroxyethyl starch (HES) to correct for intravascular deficits in high-risk surgical patients is either effective or safe. Objective: To evaluate the effect of HES 130/0.4 compared with 0.9% saline for intravascular volume expansion on mortality and postoperative complications after major abdominal surgery. Design, Setting, and Participants: Multicenter, double-blind, parallel-group, randomized clinical trial of 775 adult patients at increased risk of postoperative kidney injury undergoing major abdominal surgery at 20 university hospitals in France from February 2016 to July 2018; final follow-up was in October 2018. Interventions: Patients were randomized to receive fluid containing either 6% HES 130/0.4 diluted in 0.9% saline (n = 389) or 0.9% saline alone (n = 386) in 250-mL boluses using an individualized hemodynamic algorithm during surgery and for up to 24 hours on the first postoperative day, defined as ending at 7:59 am the following day. Main Outcomes and Measures: The primary outcome was a composite of death or major postoperative complications at 14 days after surgery. Secondary outcomes included predefined postoperative complications within 14 days after surgery, durations of intensive care unit and hospital stays, and all-cause mortality at postoperative days 28 and 90. Results: Among 826 patients enrolled (mean age, 68 [SD, 7] years; 91 women [12%]), 775 (94%) completed the trial. The primary outcome occurred in 139 of 389 patients (36%) in the HES group and 125 of 386 patients (32%) in the saline group (difference, 3.3% [95% CI, -3.3% to 10.0%]; relative risk, 1.10 [95% CI, 0.91-1.34]; P = .33). Among 12 prespecified secondary outcomes reported, 11 showed no significant difference, but a statistically significant difference was found in median volume of study fluid administered on day 1: 1250 mL (interquartile range, 750-2000 mL) in the HES group and 1500 mL (interquartile range, 750-2150 mL) in the saline group (median difference, 250 mL [95% CI, 83-417 mL]; P = .006). At 28 days after surgery, 4.1% and 2.3% of patients had died in the HES and saline groups, respectively (difference, 1.8% [95% CI, -0.7% to 4.3%]; relative risk, 1.76 [95% CI, 0.79-3.94]; P = .17). Conclusions and Relevance: Among patients at risk of postoperative kidney injury undergoing major abdominal surgery, use of HES for volume replacement therapy compared with 0.9% saline resulted in no significant difference in a composite outcome of death or major postoperative complications within 14 days after surgery. These findings do not support the use of HES for volume replacement therapy in such patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02502773.

Benefits of intraoperative analgesia guided by the Analgesia Nociception Index (ANI) in bariatric surgery: An unmatched case-control study.

INTRODUCTION: Analgesia Nociception Index (ANI) has been proposed for the evaluation of the nociception-antinociception balance in the perioperative period. In obese patients, where the management of analgesia may be rendered difficult by pharmacological changes, we hypothesised that the monitoring of analgesia with ANI would reduce intraoperative opioid consumption during bariatric surgery. METHODS: This monocentric, observational, unmatched case-control study aimed to compare perioperative data from obese subjects (body mass index ≥35kgm-2) during bariatric surgery with or without the use of ANI monitoring (ANI+ group versus ANI- group). Intraoperative analgesia was provided by injection of sufentanil, which was performed according to the clinician's assessment in the ANI- group or to the ANI value in the ANI+ group. The primary outcome was the mean hourly intraoperative sufentanil requirement. Secondary outcomes included the need for postoperative morphine titration, incidence of nausea and vomiting, respiratory distress and pain scores in the first 24hours. RESULTS: Between December 2013 and September 2016, 60 obese patients (i.e. 30 per group) were included. The mean hourly consumption of sufentanil was significantly lower in the ANI+ group (0.15±0.05µgkg-1h-1 versus 0.17±0.05µgkg-1h-1, P=0.038). We found no difference between groups regarding the incidence of nausea and vomiting, acute respiratory distress, the need for postoperative morphine titration, or pain scores in the first 24 postoperative hours. CONCLUSION: The use of ANI monitoring might reduce intraoperative consumption of sufentanil during bariatric surgery but does not appear to be accompanied by a reduction in its side effects.

Health related quality of life and predictive factors six months after intensive care unit discharge.

BACKGROUND: Advances in critical care medicine have improved patients' survival rate. However, physical and cognitive sequels after Intensive Care Unit (ICU) discharge remain substantial. Our objectives were to evaluate the Health-related Quality of Life (HRQL) at 6-month after ICU discharge and identify the risk factors of this outcomes. METHODS: We performed a single-centre prospective observational study. The components of Short Form 36 (SF-36) were analysed for assessing HRQL on preadmission and at 3- and 6-month after ICU discharge. RESULTS: During the study period, 438 patients were eligible for recruitment and 220 of them were included in the trial. During the follow-up period, bodily pain and role limitations relating to emotion were both improved in comparison to the preadmission status while physical role component was lower at 3- and 6- month after ICU discharge. There was no other significant change in the SF-36 domains. Mental as well as physical aggregates remained also unchanged. Most of preadmission SF-36 scores were lower in patients who died within the first 6 months of follow-up compared to those who are still alive. Factors independently associated with the 6-month HRQL were age, preadmission HRQL score, SAPS II, prolonged mechanical ventilation (>3 days) and the occurrence of acute respiratory distress syndrome. CONCLUSION: In our Cohort, ICU stay does not seem to alter globally neither the mental nor the physical component of the HRQL at 6-month after the discharge. However, some domains of the SF-36 are subject to significant changes.

Pharmacokinetics and Pharmacodynamics of Anti-infective Agents during Continuous Veno-venous Hemofiltration in Critically Ill Patients: Lessons Learned from an Ancillary Study of the IVOIRE Trial.

BACKGROUND: Hemofiltration rate, changes in blood and ultrafiltration flow, and discrepancies between the prescribed and administered doses strongly influence pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial agents during continuous veno-venous hemofiltration (CVVH) in critically ill patients. METHODS: Ancillary data were from the prospective multicenter IVOIRE (hIgh VOlume in Intensive caRE) study. High volume (HV, 70 mL/kg/h) was at random compared with standard volume (SV, 35 mL/kg/h) CVVH in septic shock patients with acute kidney injury (AKI). PK/PD parameters for all antimicrobial agents used in each patient were studied during five days. RESULTS: Antimicrobial treatment met efficacy targets for both percentage of time above the minimal inhibitory concentration and inhibitory quotient. A significant correlation was observed between the ultrafiltration flow and total systemic clearance (Spearman test: P < 0.005) and between CVVH clearance and drug elimination half-life (Spearman test: P < 0.005). All agents were easily filtered. Mean sieving coefficient ranged from 38.7% to 96.7%. Mean elimination half-life of all agents was significantly shorter during HV-CVVH (from 1.29 to 28.54 h) than during SV-CVVH (from 1.51 to 33.85 h) (P < 0.05). CONCLUSIONS: This study confirms that CVVH influences the PK/PD behavior of most antimicrobial agents. Antimicrobial elimination was directly correlated with convection rate. Current antimicrobial dose recommendations will expose patients to underdosing and increase the risk for treatment failure and development of resistance. Dose recommendations are proposed for some major antibiotic and antifungal treatments in patients receiving at least 25 mL/kg/h CVVH.

Correction to: Blood platelets and sepsis pathophysiology: A new therapeutic prospect in critically ill patients?

Upon publication of the original article [1], it was noticed that the title was incorrect. Instead of 'critical', it should read 'critically', and therefore, the correct title should be.

Blood platelets and sepsis pathophysiology: A new therapeutic prospect in critically [corrected] ill patients?

Beyond haemostasis, platelets have emerged as versatile effectors of the immune response. The contribution of platelets in inflammation, tissue integrity and defence against infections has considerably widened the spectrum of their role in health and disease. Here, we propose a narrative review that first describes these new platelet attributes. We then examine their relevance to microcirculatory alterations in multi-organ dysfunction, a major sepsis complication. Rapid progresses that are made on the knowledge of novel platelet functions should improve the understanding of thrombocytopenia, a common condition and a predictor of adverse outcome in sepsis, and may provide potential avenues for management and therapy.

A Role for CD154, the CD40 Ligand, in Granulomatous Inflammation.

Granulomatous inflammation is a distinctive form of chronic inflammation in which predominant cells include macrophages, epithelioid cells, and multinucleated giant cells. Mechanisms regulating granulomatous inflammation remain ill-understood. CD154, the ligand of CD40, is a key mediator of inflammation. CD154 confers a proinflammatory phenotype to macrophages and controls several macrophagic functions. Here, we studied the contribution of CD154 in a mouse model of toxic liver injury with carbon tetrachloride and a model of absorbable suture graft. In both models, granulomas are triggered in response to endogenous persistent liver calcified necrotic lesions or by grafted sutures. CD154-deficient mice showed delayed clearance of carbon tetrachloride-induced liver calcified necrotic lesions and impaired progression of suture-induced granuloma. In vitro, CD154 stimulated phagocytosis of opsonized erythrocytes by macrophages, suggesting a potential mechanism for the altered granulomatous inflammation in CD154KO mice. These results suggest that CD154 may contribute to the natural history of granulomatous inflammation.

Modulation by Polymyxin-B Hemoperfusion of Inflammatory Response Related to Severe Peritonitis.

Conflicting results have been reported on the influence of Polymyxin-B hemoperfusion treatment on systemic inflammation markers. The aim of the study was to assess in a randomized control trial the influence on plasma cytokine concentrations of Polymyxin-B hemoperfusion in septic shock due to peritonitis. A panel of 10 pro- or anti-inflammatory cytokines was measured in 213 patients with peritonitis-induced septic shock enrolled in the randomized trial ABDOMIX testing the impact of 2 Polymyxin-B hemoperfusion sessions with standard treatment. Gram-negative bacteria were identified in 69% of patients. In the overall population, baseline plasma cytokine concentrations were not different between the two groups. Circulating tumor necrosis factor-α, interleukin (IL)-1ß, IL-10, IL-6, and IL-1RA decreased significantly over time in both groups (P <0.0001 for all in controls, and P = 0.0002, 0.003, and <0.0001 in patients treated with Polymyxin-B hemoperfusion). IL-17A decreased significantly in patients treated with Polymyxin B hemoperfusion (P = 0.045) but not in controls. At the end of the second Polymyxin-B hemoperfusion session or at corresponding time in controls, plasma levels of cytokines did not differ between the two groups. Similar results were found in the subgroup of patients with gram-negative peritonitis who completed two Polymyxin-B hemoperfusion sessions. These results do not support a significant influence of Polymyxin-B hemoperfusion on circulating cytokines assessed except for IL-17A which clinical significance remains to be elucidated.

CD40 signaling and hepatic steatosis: Unanticipated links.

Obesity predisposes to an increased risk of nonalcoholic fatty liver disease (NAFLD). Hepatic steatosis is the key pathological feature of NAFLD and has emerged as a metabolic disorder in which innate and adaptive arms of the immune response play a central role in disease pathogenesis. Recent studies have revealed unexpected relationships between CD40 signaling and hepatic steatosis in high fat diet rodent models. CD154, the ligand of CD40, is a mediator of inflammation and controls several critical events of innate and adaptive immune responses. In the light of these reports, we discuss potential links between CD40 signaling and hepatic steatosis in NAFLD.

CD154 Induces Matrix Metalloproteinase-9 Secretion in Human Podocytes.

Matrix remodeling is a key feature of glomerulosclerosis secondary to diabetes or hypertension. Podocytes contribute to glomerular basement membrane (GBM) turnover by producing matrix components and matrix remodelling enzymes, including matrix metalloproteinases (MMPs). The CD40/CD154 signaling pathway modulates matrix remodeling through the synthesis of MMPs and tissue inhibitors of MMPs. Platelets are a primary blood reservoir of CD154. Here we studied, the impact of the CD154/CD40 pathway on MMP-9 expression by cultured human podocytes. The role of CD40/CD154 was evaluated upon exposure of podocytes to recombinant human CD154 (rhCD154) or activated platelet supernatants from healthy human subjects. We first showed by protein and mRNA expression that CD40 was synthesized by podocytes and detectable on kidney tissue sections. CD40 expression was acquired during podocyte differentiation and enhanced upon exposure to rhCD154. In podocytes, rhCD154 induced an increase of MMP-9 production as shown by RT-PCR, Western blot and and gelatin zymography. Activated platelet supernatants induced MMP-9 mRNA synthesis in podocytes, an effect reduced by anti-CD40 antibody. Our results underscore a potential role for platelets through the CD40/CD154 signaling pathway in the control of GBM synthesis and degradation, via its regulatory role on MMP-9 production. CD154 secretion by activated platelets may contribute to GBM alterations in proteinuric nephropathies. J. Cell. Biochem. 117: 2737-2747, 2016. © 2016 Wiley Periodicals, Inc.