Jean-François Augusto

Interpretation of blood pressure signal: physiological bases, clinical relevance, and objectives during shock states

Achievement of a mean blood pressure (MBP) target is one of the hemodynamic goals to ensure an adequate blood perfusion pressure in critically ill patients. Arterial catheter allows for a continuous and precise monitoring of arterial pressure signal. In addition to giving a precise MBP monitoring, analysis of the blood pressure wave provides information that may help the clinician to interpret hemodynamic status. The interpretation of BP wave requires the understanding of simple principles. In this review, we first discuss the physiological mechanism responsible for arterial pressure generation. We then emphasize the interpretation of the static indexes and the dynamic indexes generated by heart–lung interactions derived from arterial pressure wave. Finally, we focus on MBP value as a therapeutic target in critically ill patients. We discuss the recommended target MBP value by reviewing available data from experimental and clinical studies.

A case of sulphasalazine-induced DRESS syndrome with delayed acute interstitial nephritis

Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) is a rare and severe drug-induced hypersensitivity syndrome characterized by haematological abnormalities (hypereosinophilia and/or mononucleosis) and multiorgan involvement. Renal failure has been rarely described. We report the case of a 77-year-old female with sulphasalazine-induced DRESS syndrome who improved rapidly on corticosteroid treatment. After prednisone withdrawal, the patient developed renal failure that necessitated a session of haemodialysis. A kidney biopsy showed acute tubulointerstitial nephritis with an intense lymphocytic infiltrate and tubular necrosis. Kidney function normalized after a further 2 weeks of corticosteroid treatment. This is the first histologically proven case of acute tubulointerstitial nephritis in the setting of sulphasalazine-induced DRESS syndrome.

Septic shock sera containing circulating histones induce dendritic cell-regulated necrosis in fatal septic shock patients.

Objectives:Innate immune system alterations, including dendritic cell loss, have been reproducibly observed in patients with septic shock and correlated to adverse outcomes or nosocomial infections. The goal of this study is to better understand the mechanisms behind this observation in order to better assess septic shock pathogenesis. Design:Prospective, controlled experimental study. Setting:Research laboratory at an academic medical center. Subjects:The study enrolled 71 patients, 49 with septic shock and 22 with cardiogenic shock. Seventeen healthy controls served as reference. In vitro monocyte-derived dendritic cells were generated from healthy volunteers. Interventions:Sera were assessed for their ability to promote in vitro dendritic cell death through flow cytometry detection in each group of patients. The percentage of apoptotic or necrotic dendritic cells was evaluated by annexin-V and propidium iodide staining. Measurements and Main Results:We observed that only patients with septic shock and not patients with pure cardiogenic shock were characterized by a rapid and profound loss of circulating dendritic cells. In vitro analysis revealed that sera from patients with septic shock induced higher dendritic cell death compared to normal sera or cardiogenic shock (p < 0.005). Sera from surviving patients induced dendritic cell death through a caspase-dependent apoptotic pathway, whereas sera from nonsurviving patients induced dendritic cell–regulated necrosis. Dendritic cell necrosis was not due to necroptosis but was dependent of the presence of circulating histone. The toxicity of histones toward dendritic cell could be prevented by recombinant human activated protein C. Finally, we observed a direct correlation between the levels of circulating histones in patients and the ability of the sera to promote dendritic cell–regulated necrosis. Conclusions:The study demonstrates a differential mechanism of dendritic cell death in patients with septic shock that is dependent on the severity of the disease.

Thrombotic microangiopathy due to acquired ADAMTS13 deficiency in a patient receiving interferon-beta treatment for multiple sclerosis

Thrombotic microangiopathies (TMAs) can be due to inherited or acquired ADAMTS13 deficiency. Acquired deficiency is mainly associated with autoantibodies directed to ADAMTS13, including drug-induced forms. A few cases of TMA have been reported in association with interferon-alpha treatment and more rarely with interferon-beta. We report the case of a 52-year-old male with TMA-associated severe renal failure secondary to severe ADAMTS13 deficiency due to an anti-ADAMTS13 IgG antibody which developed after interferon-beta treatment for multiple sclerosis. Treatment included interferon-beta discontinuation, immediate plasma exchange therapy, corticosteroids, and hemodialysis. After an initial hematologic improvement, early hemolysis relapse led us to introduce rituximab allowing durable hematologic recovery. This is the first reported case of interferon-beta-induced TMA due to acquired ADAMTS13 deficiency that was treated by rituximab.

A Higher Risk of Acute Rejection of Human Kidney Allografts Can Be Predicted from the Level of CD45RC Expressed by the Recipients’ CD8 T Cells

Although transplantation is the common treatment for end-stage renal failure, allograft rejection and marked morbidity from the use of immunosuppressive drugs remain important limitations. A major challenge in the field is to identify easy, reliable and noninvasive biomarkers allowing the prediction of deleterious alloreactive immune responses and the tailoring of immunosuppressive therapy in individuals according to the rejection risk. In this study, we first established that the expression of the RC isoform of the CD45 molecule (CD45RC) on CD4 and CD8 T cells from healthy individuals identifies functionally distinct alloreactive T cell subsets that behave differently in terms of proliferation and cytokine secretion. We then investigated whether the frequency of the recipients CD45RC T cell subsets before transplantation would predict acute graft rejection in a cohort of 89 patients who had undergone their first kidney transplantation. We showed that patients exhibiting more than 54.7% of CD8 CD45RChigh T cells before transplantation had a 6 fold increased risk of acute kidney graft rejection. In contrast, the proportions of CD4 CD45RC T cells were not predictive. Thus, a higher risk of acute rejection of human kidney allografts can be predicted from the level of CD45RC expressed by the recipients’ CD8 T cells.

First Report of Lamotrigine-Induced Drug Rash with Eosinophilia and Systemic Symptoms Syndrome with Pancreatitis

Objective: To report a case of lamotrigine-induced drug rash with eosinophilia and systemic symptoms (DRESS) syndrome with pancreatitis as the initial visceral involvement. Case Summary: A 75-year-old man was admitted to the local hospital for generalized tonic-clonic seizures. Results of the clinical examination and neurologic investigations were unremarkable. Lamotrigine treatment was initiated and the patient was discharged a few days later. Forty days after lamotrigine initiation, he developed an exanthematous maculopapular rash with fever, peripheral lymphadenopathies, and hypereosinophilia. Lamotrigine hypersensitivity was suspected and the drug was suspended on day 45. On day 47, the patient presented with acute abdominal pain with an elevated lipase level. Acute pancreatitis was confirmed on computed tomography scan. The patients condition worsened and he was transferred to the intensive care unit with multiorgan failure. The diagnosis of lamotrigine-induced DRESS syndrome was confirmed by a compatible skin histology and concomitant human herpesvirus-6 infection. Discussion: This observation has 2 points of interest. First, pancreatic toxicity of lamotrigine has been rarely reported in the literature. Secondly, pancreatitis is uncommon at the early stage of DRESS syndrome. Only 1 other case of DRESS syndrome, secondary to allopurinol, reports pancreatitis along with an Epstein-Barr virus infection. The Naranjo probability scale indicated a probable causality between lamotrigine and DRESS syndrome in this patient. Conclusions: This is the first reported case of lamotrigine-induced DRESS syndrome with pancreatitis as the initial visceral involvement. Clinicians should be aware of this mode of presentation of DRESS syndrome.

Clusterin facilitates apoptotic cell clearance and prevents apoptotic cell-induced autoimmune responses

Clusterin (Clu), an extracellular chaperone, exhibits characteristics of soluble innate immunity receptors, as assessed by its ability to bind some bacteria strains. In this study, we report that Clu also binds specifically to late apoptotic cells but not to live, early apoptotic, or necrotic cells. Histones, which accumulate on blebs during the apoptotic process, represent privileged Clu-binding motifs at the surface of late apoptotic cells. As a consequence, Clu potentiates, both in vitro and in vivo, the phagocytosis of late apoptotic cells by macrophages. Moreover, the increased phagocytosis of late apoptotic cells induced by Clu favors the presentation and cross-presentation of apoptotic cell-associated antigens. Finally, we observed that, in a model of apoptotic cell-induced autoimmunity, and relative to control mice, Clu−/− mice develop symptoms of autoimmunity, including the generation of anti-dsDNA antibodies, deposition of immunoglobulins and complement components within kidneys, and splenomegaly. These results identify Clu as a new molecule partner involved in apoptotic cell efferocytosis and suggest a protective role for Clu in inflammation and autoimmune diseases.

Relation between pretransplant magnesemia and the risk of new onset diabetes after transplantation within the first year of kidney transplantation.

Background New-onset diabetes after transplantation (NODAT) is a frequent condition associated with a poor outcome. In kidney transplantation, hypomagnesemia is a frequent posttransplant complication and has been associated with calcineurin inhibitors use. Previous studies have analyzed the relationship between posttransplant hypomagnesemia and the risk of NODAT and provided conflicting conclusions. We conducted an observational study to analyze the relationship between pretransplant magnesemia (Mg) and the risk of NODAT within the first year of kidney transplantation. Methods A cohort study was conducted to determine the risk conferred by pretransplant magnesium level on development of NODAT within 1 year posttransplant. First time kidney transplant recipients between January 2005 and December 2010 with more than 6 months of follow-up were included. Mg was measured within the 24 hours preceding kidney transplantation. NODAT was defined according to the American Diabetes Association criteria. Results Among the 154 patients analyzed, 28 (18.2%) developed NODAT at year 1. NODAT patients had lower levels of pretransplant Mg as compared with non-NODAT patients (P<0.02). When patients were divided into tertiles of Mg level, NODAT developed more frequently in patients in the lower tertile (Mg <2 mg/dL) as compared with patients in the higher tertile (Mg >2.3 mg/dL) (log rank, P<0.05). A multivariate analysis after adjustment to several variables demonstrated pretransplant Mg to be an independent risk factor of NODAT. Conclusion This study supports that a low pretransplant Mg level is an independent risk factor of NODAT in kidney transplant recipients.

Transplantation of kidneys from uncontrolled donation after circulatory determination of death: comparison with brain death donors with or without extended criteria and impact of normothermic regional perfusion.

The aim of this study was to compare the outcomes of kidney transplants from uncontrolled DCD (uDCD) with kidney transplants from extended (ECD) and standard criteria donors (SCD). In this multicenter study, we included recipients from uDCD (n = 50), and from ECD (n = 57) and SCD (n = 102) who could be eligible for a uDCD program. We compared patient and graft survival, and kidney function between groups. To address the impact of preservation procedures in uDCD, we compared in situ cold perfusion (ICP) with normothermic regional perfusion (NRP). Patient and graft survival rates were similar between the uDCD and ECD groups, but were lower than the SCD group (P < 0.01). Although delayed graft function (DGF) was more frequent in the uDCD group (66%) than in the ECD (40%) and SCD (27%) groups (P = 0.08 and P < 0.001), graft function was comparable between the uDCD and ECD groups at 3 months onwards post‐transplantation. The use of NRP in the uDCD group (n = 19) was associated with a lower risk of DGF, and with a better graft function at 2 years post‐transplantation, compared to ICP‐uDCD (n = 31) and ECD. In conclusion, the use of uDCD kidneys was associated with post‐transplantation results comparable to those of ECD kidneys. NRP preservation may improve the results of uDCD transplantation.

Low Serum Complement C3 Levels at Diagnosis of Renal ANCA-Associated Vasculitis Is Associated with Poor Prognosis

Background Recent studies have demonstrated the key role of the complement alternative pathway (cAP) in the pathophysiology of experimental ANCA-associated vasculitis (AAV). However, in human AAV the role of cAP has not been extensively explored. In the present work, we analysed circulating serum C3 levels measured at AAV onset and their relation to outcomes. Methods We conducted a retrospective observational cohort study including 45 consecutive patients with AAV diagnosed between 2000 and 2014 with serum C3 measurement at diagnosis, before immunosuppressive treatment initiation. Two groups were defined according to the median serum C3 level value: the low C3 group (C3<120 mg/dL) and the high C3 level group (C3≥120 mg/dL). Patient and renal survivals, association between C3 level and renal pathology were analysed. Results Serum complement C3 concentration remained in the normal range [78–184 mg/dL]. Compared with the high C3 level, the patients in the low C3 level group had lower complement C4 concentrations (P = 0.008) and lower eGFR (P = 0.002) at diagnosis. The low C3 level group had poorer patient and death-censored renal survivals, compared with the high C3 level group (P = 0.047 and P = 0.001, respectively). We observed a significant negative correlation between C3 levels and the percentage of glomeruli affected by cellular crescent (P = 0.017, r = -0.407). According to the Berden et al renal histologic classification, patients in the crescentic/mixed category had low C3 levels more frequently (P<0.01). Interestingly, we observed that when patients with the crescentic/mixed histologic form were analysed according to C3 level, long term renal survival was significantly greater in the high C3 level group than in the low C3 level group (100% vs 40.7% at 6 years, p = 0.046). No relationship between serum C4 and renal outcome was observed. Conclusion A Low C3 serum level in AAV patients at diagnosis is associated with worse long-term patient and renal survival.