Laurent Jacob

Human neutrophils produce interferon gamma upon stimulation by interleukin-12

Interferon γ (IFNγ) is a Th1 cytokine mainly produced by T cells, NK cells and macrophages in response to interleukin (IL)-12. As polymorphonuclear neutrophils (PMN) have been shown to produce and to release numerous cytokines, in particular upon IL-12 stimulation, we investigated the ability of highly purified PMN to secrete IFNγ. We found that PMN contained a small store of IFNγ, and that this store was rapidly secreted upon stimulation by degranulating agents such as formyl peptides. Moreover, after a few hours of stimulation with appropriate agents, PMN synthesized IFNγ. The effect of IL-12 was time- and concentration-dependent, and IL-12 combinations with IL-2, IL-15, IL-18 or LPS were highly synergistic. Cycloheximide inhibited IFNγ release in such optimal conditions, confirming the ability of PMN to synthesize IFNγ. IFNγ synthesis was associated with an increase in specific mRNA content, pointing to a transcriptional mechanism. The IFNγ produced by PMN was biologically active, as demonstrated by its ability to induce TNFα synthesis by PMN themselves or to induce IL-10 synthesis by peripheral blood mononuclear cells. These findings reveal a novel pathway of autocrine and paracrine PMN activation. They also identified a new role for IFNγ, bridging innate and adaptive immune responses.

Plasma neutrophil gelatinase-associated lipocalin in kidney transplantation and early renal function prediction.

Background. This prospective observational study aimed to assess the relevance of serial postoperative plasma neutrophil gelatinase-associated lipocalin (NGAL) measurements on prediction of early renal transplant function. Methods. Plasma NGAL (pNGAL) was measured (Triage NGAL Test; Biosite Inc., Inverness Medical) in 41 patients scheduled for kidney transplantation from deceased or living donors, immediately before and after surgery, and at 12 hr, day 1, day 3, and day 7. A delayed graft function (DGF) was defined as the need for dialysis during the first week. The results were expressed as median (Q1, Q3). Results. Of the 41 consecutive patients enrolled, all had a high preoperative pNGAL level: 453 ng/mL (382, 595). Fifteen (36.6%) presented a DGF. In patients with DGF, pNGAL was significantly higher at 12 hr (571 [467, 634] vs. 242 [158, 299] ng/mL, P<0.0001) and at day 1 (466 [356, 627] vs. 165 [91, 248] ng/mL, P<0.0001). A pNGAL higher than 400 ng/mL 12 hr after transplantation predicted DGF with a sensitivity of 93.3%, a specificity of 88.5%, and an odds ratio of 63.2 (P=0.0004). This predictive performance was higher than for plasma creatinine. Conclusions. pNGAL level early and accurately predicted DGF after renal transplantation. pNGAL measurements allowed monitoring of the renal function in this striking situation of ischemia-reperfusion aggression. Early identification of patients at risk of DGF, before graft lesions are consolidated, opens the field of a precise monitoring of renal injury and the impact of future protective therapeutics.

Early Identification of Patients With Out-of-Hospital Cardiac Arrest With No Chance of Survival and Consideration for Organ Donation.

A cardinal principle of medical ethics is that medical professionals act first and foremost for the benefit of the patient. For patients with out-of-hospital cardiac arrest (OHCA), the prehospital emergency medical services (EMS) team must perform standard cardiopulmonary resuscitation (CPR) and consider all available technologies (such as automated active compression-decompression CPR devices, extracorporeal life support, and therapeutic hypothermia) to save the patients life. However, despite improvements in resuscitation techniques used by prehospital EMS and in-hospital intensivists, most patients with OHCA do not survive: Mortality remains as high as 92% to 94% (14). Clinical decision rules known as termination-of-resuscitation rules help to identify cases where further resuscitation with the aim of avoiding ambulance transport and its associated costs and risks is futile (57). Authors of large series on termination-of-resuscitation rules agree that a survival rate of 1% in patients with OHCA reflects medical futility and that stopping CPR is reasonable (812). These rules do not, however, take into consideration the potential utility of transporting dead patients to the hospital for organ donation. The major problem facing transplantation worldwide is the unavailability of organs. Because of this, transplantation programs using organs from uncontrolled donation after cardiac death (UDCD) have been implemented in many Western countries (1317). The 2015 American Heart Association guidelines for CPR recommend that patients who do not have return of spontaneous circulation (ROSC) after resuscitation efforts and who would otherwise have termination of efforts may be considered candidates for organ donation in settings where such programs exist (class IIb recommendation) (18). Delays in recognizing futile resuscitative efforts result in lost opportunities to direct efforts toward donation of potentially viable organs. Rapid referral to an organ donation institution under mechanical ventilation and continuous automated external cardiac massage must be considered only for patients with no chance of survival whose organs are reasonably likely to be suitable for transplantation (17). This UDCD consideration rule differs from the termination-of-resuscitation rule in 3 respects. First, it is intended exclusively for patients with absolutely no chance of survival, because the first medical concern is patient care and use of a UDCD protocol for potential survivors is unacceptable. Second, the patient must be eligible to donate organs according to local legislation. Finally, the patient must be rapidly transported to an appropriate hospital under continuous resuscitative maneuvers. This study sought to evaluate objective and practical criteria for identifying patients with OHCA and no chance of survival during the first minutes of advanced CPR. Methods Setting and Participants This study evaluated patients from 2 published registries and 1 published clinical trial managed by 2 EMS systems in France and the United States, both of which perform CPR according to international guidelines (19). Paris Sudden Death Expertise Center Cohort The Paris Sudden Death Expertise Center (SDEC) registry is a population-based registry that covers Paris and its suburbs (about 6.6 million inhabitants). The registrys methods have been reported previously (Supplement) (20). In this study, we considered patients included during the first 3 years of the registry, from 16 May 2011 to 15 May 2014. Supplement. Multidisciplinary Approach of the Paris Sudden Death Expertise Center Every case of unexpected OHCA in persons older than 18 years was prospectively included in the Paris SDEC registry. Exclusion criteria were a prior terminal condition, a documented do-not-resuscitate directive, no attempt at advanced cardiac life support (ACLS) by EMS personnel, or an obvious noncardiac cause according to Utstein templates for resuscitation registries reporting data on cardiac arrest (21). The appropriate institutional review boards approved all aspects of the registry. PRESENCE Cohort The PRESENCE study was a prospective, multicenter, cluster randomized, controlled trial (22). Its principal aim was to determine whether offering relatives of patients the choice of observing CPR would reduce the likelihood of symptoms of posttraumatic stress disorder. The study was approved by the appropriate institutional review board and was registered at ClinicalTrials.gov (NCT01009606). It enrolled 570 relatives of adult patients with cardiac arrest at home who received CPR from 15 French prehospital EMS units from November 2009 to October 2011. For this study, we excluded 84 patients with OHCA with obvious extracardiac causes and analyzed 486 patients. King County Cohort The King County EMS in Washington has collected data on all EMS-treated cardiac arrest cases since 1976 (23). The registry contains information about survival to hospital discharge and is maintained in the Utstein format. For this study, all patients aged 18 to 54 years who had OHCA without an obvious extracardiac cause and received ACLS from EMS personnel were included. The date of OHCA was restricted to 2006 to 2011 and patient age was restricted to 18 to 54 years (the age range for UDCD [24, 25]) because information on 1 criterion (epinephrine dosage) was available for this period and age range. The appropriate institutional ethics board approved all aspects of the registry. Study Design Objective Criteria for Identifying Patients With OHCA With No Chance of Survival Among all criteria identified in the literature as being associated with lack of survival, we selected those that were the most reliable, robust, objective, easy to use in different EMS systems, and obtainable during the first minutes of resuscitation and assessed patient outcomes associated with them. The objective criteria we tested were 1) OHCA not witnessed by EMS personnel (firefighters [who are first responders trained in automated external defibrillation] or medical team members), 2) nonshockable initial cardiac rhythm (defined according to whether a shock was given at arrival, either by a firefighter trained in automated external defibrillation or a medical team member), and 3) no sustainable ROSC before receipt of a third 1-mg dose of epinephrine given according to international guidelines (1 mg every 3 to 5 minutes). Thus, resuscitation length was indirectly measured by the epinephrine dose. These 3 objective criteria are known to be associated with lack of survival (1, 12, 20, 26, 27) and can be accurately assessed at the scene by responders (20, 28, 29). Other independent predictors of mortality at the population level have been considered, particularly time from collapse to basic life support (no-flow duration), time from basic life support to ROSC (low-flow duration), and performance of CPR by a bystander (30). However, international guidelines note that, at the individual level, the retrospective accuracy of the no-flow and low-flow durations is often imprecise, and the quality and duration of CPR are often questionable (21, 23). We evaluated these objective criteria in 1771 patients with OHCA from the first year of the SDEC registry (16 May 2011 to 15 May 2012). We then conducted an internal prospective validation of these criteria for the next 2 years of registry data (16 May 2012 to 15 May 2014) and external validation of the PRESENCE and King County cohorts (5192 patients). UDCD Eligibility Criteria We applied the eligibility criteria used in the French national protocol for kidney retrieval from UDCD, established by the Agence de la biomdecine in compliance with the Declaration of Helsinki (24). The protocol of care has been described in detail (17). The UDCD eligibility criteria included age 18 to 54 years; no medical history of hypertension, diabetes, cancer, sepsis, active viral infection (hepatitis B virus, hepatitis C virus, HIV, or human T-cell lymphotropic virus), or renal disease; and cardiac arrest not due to highkinetic energy polytraumatism. In addition, the time between collapse and CPR initiation had to be less than 30 minutes, and the time between collapse and intra-aortic double-balloon catheter insertion had to be less than 150 minutes (warm ischemia). These eligibility criteria were applied to patients identified as having no chance of survival to evaluate their potential for organ donation. End Points The primary end point was the survival rate at hospital discharge among patients with OHCA who met the proposed objective criteria. For the PRESENCE cohort (22), the survival rate at day 28 instead of at hospital discharge was considered because the latter information was unavailable. The secondary end point was the number of patients eligible for organ donation according to the French protocol for kidney retrieval from UDCD in the SDEC cohorts. Statistical Analysis Data are reported as means and SDs or medians and interquartile ranges (IQRs) for continuous variables and as percentages for qualitative variables. The survival rate and 95% CI were determined for patients with OHCA who fulfilled the objective criteria. We used standard 22 diagnostic test result tables to report prehospital or in-hospital mortality among patients meeting the objective criteria. We estimated the sensitivity (the probability that the criteria identify patients with no chance of survival [for patients who died]), specificity (the probability that the criteria recommend continuing ACLS [for patients discharged alive]), positive predictive value (PPV) (the probability of death when the criteria are met), and negative predictive value (NPV) (the probability of survival when 1 criterion is not met) and their respective 95% CIs for the objective criteria. The specificity and PPV were identified as the key test characteristics at the study design stage. We described the amount of missing data for each variable of interest. Sens

Modifications péri-opératoires de la fonction rénale

Impaired microcirculation and tubule injuries explain the changes in kidney function during and after surgery. Surgery is a risk factor for acute renal failure, the incidence of which ranges from 0.8% to 40%, depending on the kind of surgery. Mortality due to perioperative acute renal failure ranges from 17% to 60%, depending on the kind of surgery. For almost 10 to 20% of survivors, acute renal failure becomes chronic. Of the various definitions of acute renal failure, the RIFLE classification(risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, end-stage kidney disease)is a consensus definition for predicting hospital mortality. Preoperative renal function was based on serum creatinine and creatinine clearance, calculated with either the Cockcroft and Gault or modification of diet in renal disease (MDRD) formula. Predictors of postoperative acute renal failure include: previous renal dysfunction (most predictive), age older than 56 years, peripheral vascular occlusive disease, chronic obstructive pulmonary disease, congestive heart failure, hypertension and diabetes mellitus, body mass index over 32, use of a vasopressor infusion and diuretic administration, emergency or major surgery, and liver disease. Biomarkers for acute kidney injury are useful for diagnosis of early renal dysfunction. The most promising of these isneutrophil gelatinase-associated lipocalin(NGAL). Renal protection consists in maintaining an optimal blood volume and cardiac output. Nephrotoxic agents always must be removed.

Metabolism and Renal Functions

The kidney is the principal organ that ensures homeostatic control of fluid and electrolytes in the human body, contributing to regulation of blood volume and pressure. To perform these critical functions, the kidney possesses a remarkable anatomical organization. Renal vascularization is very specific and is restricted based on metabolic needs. In fact, there exists heterogeneity in the renal tissue with regard to perfusion and energy demand. In order to understand the coupling between these distinct requirements, the specific role of each part of the nephron, as well as its functional and regulatory mechanisms, must be considered. Notably, properties of renal circulation have been highlighted by several studies investigating pathological situations as well as therapeutic interventions.

The cardiac surgery–associated neutrophil gelatinase–associated lipocalin score for postoperative acute kidney injury: Does subclinical acute kidney injury matter?

(AKI) may have acute tubular damage that is associated with poor outcomes. Kalisnik and colleagues and de Geus and colleagues have advocated that the routine use of biomarkers such as neutrophil gelatinase–associated lipocalin and cystatin C should be added to conventional creatinine as necessary perioperative tests, particularly in patients with existing renal dysfunction. Although a recent meta-analysis supports the potential benefits of biomarkers in the early detection (ie, subclinical) of CSA-AKI, there is still no evidence that using them to make this diagnosis alters outcomes. Therefore, although Kalisnik and colleagues have called for the routine use of subclinical AKI biomarkers to improve the accuracy of early detection of CSA-AKI, this would appear to be putting the cart before the horse. Use of these tests without systematic study would result in additional costs and clinical confusion because teams will be faced with new data in the absence of information on what to do with these results. It is hoped that detection of subclinical AKI will provide the bedside clinician ‘‘the best time to apply interventions or new therapeutics aimed at reducing CSA-AKI is a very early stage.’’ However, to date no proven intervention of this nature has been demonstrated and the notion remains theoretical. Therefore, we reiterate a previous statement that the routine clinical use of these biomarkers may not yet be ready for prime time and urge such important efforts as led by de Geus and colleagues and Kalisnik and colleagues to continue to systematically generate robust evidence that first supports the diagnostic value of these biomarkers and second evaluates therapeutic strategies for taking advantage of them. Until then, the ‘‘must do’’ in the field of CSAAKI is working to obtain these crucial data.