Blood transfusion improves renal oxygenation and renal function in sepsis-induced acute kidney injury in rats

Background: The effects of blood transfusion on renal microcirculation during sepsis are unknown. This study aimed to investigate the effect of blood transfusion on renal microvascular oxygenation and renal function during sepsis-induced acute kidney injury. Methods: Twenty-seven Wistar albino rats were randomized into four groups: a sham group (n = 6), a lipopolysaccharide (LPS) group (n = 7), a LPS group that received fluid resuscitation (n = 7), and a LPS group that received blood transfusion (n = 7). The mean arterial blood pressure, renal blood flow, and renal microvascular oxygenation within the kidney cortex were recorded. Acute kidney injury was assessed using the serum creatinine levels, metabolic cost, and histopathological lesions. Nitrosative stress (expression of endothelial (eNOS) and inducible nitric oxide synthase (iNOS)) within the kidney was assessed by immunohistochemistry. Hemoglobin levels, pH, serum lactate levels, and liver enzymes were measured. Results: Fluid resuscitation and blood transfusion both significantly improved the mean arterial pressure and renal blood flow after LPS infusion. Renal microvascular oxygenation, serum creatinine levels, and tubular damage significantly improved in the LPS group that received blood transfusion compared to the group that received fluids. Moreover, the renal expression of eNOS was markedly suppressed under endotoxin challenge. Blood transfusion, but not fluid resuscitation, was able to restore the renal expression of eNOS. However, there were no significant differences in lactic acidosis or liver function between the two groups. Conclusions: Blood transfusion significantly improved renal function in endotoxemic rats. The specific beneficial effect of blood transfusion on the kidney could have been mediated in part by the improvements in r

Sepsis and septic shock in patients with malignancies : a Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique study

Objectives: Cancer affects up to 20% of critically ill patients, and sepsis is one of the leading reasons for ICU admission in this setting. Early signals suggested that survival might be increasing in this population. However, confirmation studies have been lacking. The goal of this study was to assess trends in survival rates over time in cancer patients admitted to the ICU for sepsis or septic shock over the last 2 decades. Data Source: Seven European ICUs. Study Selection: A hierarchical model taking into account the year of admission and the source dataset as random variables was used to identify risk factors for day 30 mortality. Data Extraction: Data from cancer patients admitted to ICUs for sepsis or septic shock were extracted from the Groupe de Recherche Respiratoire en Reanimation Onco-Hematologique database (1994-2015). Data Synthesis: Overall, 2,062 patients (62% men, median [interquartile range] age 59 yr [48-67 yr]) were included in the study. Underlying malignancies were solid tumors (n = 362; 17.6%) or hematologic malignancies (n = 1,700; 82.4%), including acute leukemia (n = 591; 28.7%), non-Hodgkin lymphoma (n = 461; 22.3%), and myeloma (n = 244; 11.8%). Two-hundred fifty patients (12%) underwent allogeneic hematopoietic stem cell transplantation and 640 (31.0%) were neutropenic at ICU admission. Day 30 mortality was 39.9% (823 deaths). The year of ICU admission was associated with significant decrease in day 30 mortality over time (odds ratio, 0.96; 95% CI, 0.93-0.98; p = 0.001). Mechanical ventilation (odds ratio, 3.25; 95% CI, 2.52-4.19; p < 0.01) and vasopressors use (odds ratio, 1.42; 95% CI, 1.10-1.83; p < 0.01) were independently associated with day 30 mortality, whereas underlying malignancy, allogeneic hematopoietic stem cell transplantation, and neutropenia were not. Conclusions: Survival in critically ill oncology and hematology patients with sepsis improved significantly over time. As outcomes improve, clinicians should consider updating admission policies and goals of care in this population

Agents intervening against delirium in the intensive care unit (AID-ICU) - Protocol for a randomised placebo-controlled trial of haloperidol in patients with delirium in the ICU

Background Delirium among patients in the intensive care unit (ICU) is a common condition associated with increased morbidity and mortality. Haloperidol is the most frequently used pharmacologic intervention, but its use is not supported by firm evidence. Therefore, we are conducting Agents Intervening against Delirium in the Intensive Care Unit (AID‐ICU) trial to assess the benefits and harms of haloperidol for the treatment of ICU‐acquired delirium. Methods AID‐ICU is an investigator‐initiated, pragmatic, international, randomised, blinded, parallel‐group, trial allocating adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. Trial participants will receive intravenous 2.5 mg haloperidol three times daily or matching placebo (isotonic saline 0.9%) if they are delirious. If needed, a maximum of 20 mg/daily haloperidol/placebo is given. An escape protocol, not including haloperidol, is part of the trial protocol. The primary outcome is days alive out of the hospital within 90 days post‐randomisation. Secondary outcomes are number of days without delirium or coma, serious adverse reactions to haloperidol, usage of escape medication, number of days alive without mechanical ventilation; mortality, health‐related quality‐of‐life and cognitive function at 1‐year follow‐up. A sample size of 1000 patients is required to detect a 7‐day improvement or worsening of the mean days alive out of the hospital, type 1 error risk of 5% and power 90%. Perspective The AID‐ICU trial is based on gold standard methodology applied to a large sample of clinically representative patients and will provide pivotal high‐quality data on the benefits and harms of haloperidol for the treatment ICU‐acquired delirium

Calpaines et microparticules (exemple du sepsis et de l'angiogénèse)

Les calpaïnes sont des protéases ubiquitaires activées par le calcium dont l activité est limitée par la calpastatine, un inhibiteur endogène spécifique. Afin d étudier le rôle des calpaïnes au cours du sepsis nous avons analysé le modèle de ligature et perforation caecale chez des souris sauvages et transgéniques surexprimant constitutivement la calpastatine. Nous avons démontré que les calpaïnes étaient capable d induire la libération de microparticules plaquettaires favorisant ainsi la coagulation intravasculaire disséminée au cours du sepsis, aggravant les défaillances rénales, hépatiques et pulmonaires et responsables d une surmortalité. Le rôle des calpaïnes ne se limite cependant pas à leur action intracellulaire. Nous avons mis en évidence des calpaïnes externalisées à partir de cellules endothéliales, capables de générer des fragments pro-angiogéniques de fibronectine, favorisant ainsi la réparation vasculaire dans un modèle de glomérulonéphrite et un modèle de cicatrisation cutanée chez la souris. Nous avons identifié la calpaïne extracellulaire dans des microparticules issues de cellules endothéliales, explorant ainsi pour la première fois le mécanisme de sécrétion active des calpaïnes.Ainsi, le lien entre les microparticules et les calpaïnes est double : d une part, les calpaïnes régulent la libération des microparticules circulantes qui constituent un réservoir finement régulé d effecteurs cellulaires et d autre part les calpaïnes s externalisent à l intérieur même de ces microparticules. La régulation pharmacologique possible du nombre et du contenu des microparticules, via la modulation de l activité calpaïne, ouvre la voie à de nouvelles thérapeutiquesCalpains are calcium-activated cysteine proteases and calpastatin is a specific endogenous inhibitor of calpain activity. To study the role of calpains during sepsis, we induced polymicrobial sepsis by cecal ligation and puncture in wild type (WT) mice and transgenic (TG) mice expressing high levels of calpastatin. Calpastatin overexpression improved survival, organ dysfunction (including lung, kidney and liver damage), and lymphocyte apoptosis. It decreased the sepsis induced systemic proinflammatory response and disseminated intravascular coagulation, by reducing the rate of procoagulant circulating microparticles and therefore delaying thrombin generation. In addition, calpains can be externalized. Interestingly, intra- and extracellular calpains have differential effects. We demonstrated in vitro and in vivo in 2 different animal models ( glomerulonephritis and cutaneous wound models) that externalized calpains participate in angiogenesis and vascular repair, likely by promoting fibronectin cleavage. Moreover, we showed that extracellular calpains can be conveyed in microparticles. There is an intimate connection between calpains and microparticles for two reasons: first, calpain can modulate microparticle release into the circulation. Second, calpain can be conveyed in microparticles. The pharmacological modulation of circulating levels of microparticles via the modulation of calpain activity can be of particular interest in a therapeutic perspectivePARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Severe Thrombotic Thrombocytopenic Purpura (TTP) with Organ Failure in Critically Ill Patients

Thrombotic thrombocytopenic purpura (TTP) is a multiorgan disorder. Organ dysfunction occurs as a consequence of widespread microvascular thrombosis, especially in the heart, brain and kidney, causing transient or partial occlusion of vessels, resulting in organ ischemia. Intensive care unit (ICU) admission varies between 40% and 100% of patients with TTP, either because of severe organ failure or in order to initiate emergency plasma exchange (PEx). Severe neurologic manifestations and cardiac involvement have been associated with higher mortality. Acute kidney injury, although usually less severe than that in hemolytic and uremic syndrome, is common during TTP. Initial management in the ICU should always be considered in TTP patients. The current treatment of TTP in the acute phase is based on urgent PEx, combined with corticosteroid therapy, B-cell-targeted immunotherapy, rituximab and inhibition of the interaction between ultra-large Von Willebrand factor multimers and platelets, using caplacizumab, a monoclonal antibody. ICU management permits close monitoring and the rapid introduction of life-sustaining therapies. This review details the epidemiology of TTP in the ICU, organ failures of critically ill patients with TTP, and the initial management of TTP patients in the ICU

Microcirculation in Acute and Chronic Kidney Diseases

The renal microvasculature is emerging as a key player in acute and chronic kidney diseases. Renal microvascular disease involves alterations in endothelial barrier permeability, exaggerated inflammation, impairment of endothelium-dependent vasorelaxation involving the nitric oxide system, increased oxidative stress, and loss of angiogenic factors. Moreover, evidence suggests that there is a microvascular component to the pathogenesis of renal scarring. New technology is being developed to explore renal microcirculation in vivo in experimental models and humans. This technology will provide a better understanding of the pathogenesis of kidney diseases and will help guide specific therapeutic strategies aimed at restoring the renal microcirculation. This article reviews the cellular and molecular mechanisms of renal microvascular dysfunction in acute and chronic kidney diseases and the potential diagnostic and therapeutic implications of these findings. Recent developments in the monitoring of renal microcirculation are described with respect to their advantages and limitations, and future directions are outline

Neutropénies chez le patient transplanté rénal (caractéristiques, causes et conséquences)

Bien que les neutropénies constituent un problème fréquemment rencontré en transplantation rénale, ces épisodes ont très peu été étudiés dans la littérature et aucune recommandation n existe à ce jour quant à leur prise en charge. Le but de cette étude était donc de définir l incidence, le délai de survenue et les conséquences de ces neutropénies en transplantation rénale. Trois cent quatre vingt quinze patients transplantés entre mars 2005 et mars 2007 ont été inclus dans cette étude rétrospective, monocentrique. Une neutropénie, définie par un taux de polynucléaires neutrophiles inférieur à 2000/ l, était observée au moins une fois chez 112 patients durant la première année de greffe. Seule l association tacrolimus-mycophénolate mofétil est apparue comme associée à la survenue d une neutropénie (71% des receveurs recevant du tacrolimus dans le groupe de patients neutropéniques contre 49% des receveurs du groupe sans neutropénie, p 1000/ l en moyenne en 1,5 jours. Ainsi, les neutropénies surviennent chez 30% des patients transplantés rénaux. Elles conduisent à une augmentation de l incidence des infections, notamment lorsque le taux de polynucléaires neutrophiles est < 1000/ l. Elles peuvent être responsables d une augmentation du risque de rejet du greffon en cas d arrêt prolongé du mycophénolate mofétil, particulièrement au-delà de 6 jours. Le G-CSF peut être proposé en cas de neutropénie sévère.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Acute Kidney Injury in Cancer Immunotherapy Recipients

Cancer immunotherapy has now entered clinical practice and has reshaped the standard of care for many cancer patients. With these new strategies, specific toxicities have emerged, and renal side effects have been described. In this review, we will describe the causes of acute kidney injury in CAR T cell, immune checkpoint inhibitors and other cancer immuno-therapy recipients. CAR T cell therapy and bispecific T cell engaging antibodies can lead to acute kidney injury as a consequence of cytokine release syndrome, tumor lysis syndrome, sepsis or specific CAR T cell infiltration. Immune checkpoint blockade most often results in acute tubular interstitial nephritis, but glomerular diseases have also been described. Although the pathophysiology remains mostly elusive, we will describe the mechanisms of renal damage in these contexts, its prognosis and treatment. As the place of immunotherapy in the anti-cancer armamentarium is exponentially increasing, close collaboration between nephrologists and oncologists is of utmost importance to provide the best standard of care for these patients