Presse Medicale最新文献

In nature, wild viruses adapted for transmission circulate in many animal species (bats, birds, primates…). Contamination of other animals, including humans, may occur by crossing of the species barrier. Genetic manipulations have been carried out on wild viruses to favor the species jumping and to increase of viral virulence. The aim was to identify the critical genes for pathogenicity. This has been mainly performed on potentially epidemic pathogens, as Myxovirus influenzae of avian flu and coronaviruses of SARS and MERS epidemics. These dangerous experiments were subject to a moratorium in the United States (2014–2017). Three years after the emergence of Covid-19, the origin of du SARS-CoV2 remains a mystery. Covid19 appeared in Wuhan, officially in December 2019, but probably during the autumn 2019. The virus was identified in January 2020. It belongs to the genus Betacoronavirus (subgenus Sarbecovirus). It was at once highly contagious. In addition, the primary isolates were genetically very homogeneous, differing only by two nucleotides without evidence for adaptive mutations. In addition, the Spike protein, a major virulence factor, has a furin site, not found in any other known sarbecovirus. Unlike the SARS and MERS epidemics, no intermediate host has been detected so far. Finally, no other outbreaks were reported at the beginning of the pandemic outside of Wuhan, contrary to what happened with the emergence of SARS (2002) and H7N9 avian influenza (2013). Today, there are two scenarios to explain the emergence of SARS-CoV2. Proponents of the natural origin argue that the bat virus might have directly infected humans, spreading silently at a low level in humans for years, without eliminating the existence of undetected intermediate hosts. This does not explain the origin in Wuhan, far away from the natural virus reservoirs. The furin site would have arisen spontaneously from other coronaviruses. The alternative scenario is that of a laboratory accident after gain-of-function manipulations from a SARS-like virus, or even the occurrence of a human contamination by a natural CoV virus grown on cells in Wuhan.

This article is an update to the Quarterly Medical Review (QMR) devoted to the history of modern pandemics. To access this QMR contents, please go here: https://www.sciencedirect.com/journal/la-presse-medicale/vol/51/issue/3

The pharmacotherapy of type 2 diabetes mellitus (T2DM) has markedly evolved in the last two decades. Classical antidiabetic agents (sulphonylureas, metformin, insulin) are now in competition with new glucose-lowering medications. Alpha-glucosidase inhibitors and thiazolidinediones (glitazones) were not able to replace older agents, because of insufficient efficacy and/or poor tolerability/safety. In contrast, incretin-based therapies, both dipeptidyl peptidase-4 inhibitors (DPP-4is or gliptins, oral agents) and glucagon-like peptide-1 receptor agonists (GLP-1RAs, subcutaneous injections) are a major breakthrough in the management of T2DM. Because they are not associated with hypoglycaemia and weight gain, DPP-4is tend to replace sulphonylureas as add-on to metformin while GLP-1RAs tend to replace basal insulin therapy after failure of oral therapies. Furthermore, placebo-controlled cardiovascular outcome trials demonstrated neutrality for DPP-4is, but cardiovascular protection for GLP-1RAs in patients with T2DM at high cardiovascular risk. More recently sodium-glucose cotransporter 2 inhibitors (SGLT2is or gliflozins, oral agents) also showed cardiovascular protection, especially a reduction in hospitalization for heart failure, as well as a renal protection in patients with and without T2DM, at high cardiovascular risk, with established heart failure and/or with chronic kidney disease. Thus, GLP-1RAs and SGLT2is are now considered as preferred drugs in T2DM patients with or at high risk of atherosclerotic cardiovascular disease whereas SGLT2is are more specifically recommended in patients with or at risk of heart failure and renal (albuminuric) disease. The management of T2DM is moving from a glucocentric approach to a broader strategy focusing on all risk factors, including overweight/obesity, and to an organ-disease targeted personalized approach.

The dysfunction of the internal mechanics within the kidney's filtering units, known as glomeruli, has been linked to the emergence and progression of diabetic kidney disease (DKD). To better understand this crucial aspect of kidney function and the pathology of DKD, a variety of methods are employed in research, from the introduction of external compounds, such as inulin, iohexol, iothalamate and p-aminohippurate, to cutting-edge imaging techniques and computational analysis.

Given the significance of intraglomerular hemodynamic dysfunction in the pathogenesis and treatment of DKD, it is essential to thoroughly examine the available data on this topic. Accordingly, the aim of this review is to provide a comprehensive appraisal of the role of intraglomerular hemodynamic dysfunction in the development of DKD and the effects of current therapies used to mitigate DKD. Through this analysis, we can gain a deeper understanding of the complex pathogenesis of DKD and potentially discover new avenues for tailored therapeutic management of patients with DKD.

Antibody-mediated rejection (ABMR) remains one of the most challenging issues after organ transplantation and particularly after kidney transplantation. Despite many progresses during the last decade, ABMR is still the main cause of kidney graft loss and this all over the post- transplant period.

In this review, we describe the recent knowledge about molecular and cellular mechanisms involved in ABMR. We focused our report on the role of the complement pathway in the process of ABMR and we give some insights into the role of inflammatory cells, NK lymphocytes and the role of endothelial cells. We further describe the potential role of non-HLA antibodies, of which the importance has been increasingly emphasized in recent years.

Overall, this report could be of interest for all physicians who are working in the field of organ transplantation or who are working in the field of immunology. It gives essential information to understand new diagnosis advances and further therapeutic approaches.

Antibody-mediated rejection (ABMR) is the leading cause of graft failure ([1,2]). In contrast to T-cell mediated rejection usually sensitive to steroids, active ABMR remains a therapeutic challenge. ABMR diagnosis relies on the presence of renal injuries and donor-specific antibodies (DSA) (HLA and non HLA antibodies) with sometimes the evidence of interaction between DSA and graft endothelium. Regularly revised during expert conferences, ABMR definition is currently categorized as active or chronic active. [3] The emergence of validated molecular assays targeting a better phenotyping of ABMR and the recent advances regarding the detrimental effect of DSA directed against minor antigens open the way to a better assessment of the heterogeneity of ABMR. In this review, we will address new aspects of ABMR regarding its mechanisms, diagnosis and treatments.

Type 1 diabetes is a disease resulting from autoimmune destruction of the insulin-producing beta cells in the pancreas. When type 1 diabetes develops into severe secondary complications, in particular end-stage nephropathy, or life-threatening severe hypoglycemia, the best therapeutic approach is pancreas transplantation, or more recently transplantation of the pancreatic islets of Langerhans. Islet transplantation is a cell therapy procedure, that is minimally invasive and has a low morbidity, but does not display the same rate of functional success as the more invasive pancreas transplantation because of suboptimal engraftment and survival. Another issue is that pancreas or islet transplantation (collectively known as beta cell replacement therapy) is limited by the shortage of organ donors and by the need for lifelong immunosuppression to prevent immune rejection and recurrence of autoimmunity.

A bioartificial pancreas is a construct made of functional, insulin-producing tissue, embedded in an anti-inflammatory, immunomodulatory microenvironment and encapsulated in a perm-selective membrane allowing glucose sensing and insulin release, but isolating from attacks by cells of the immune system. A successful bioartificial pancreas would address the issues of engraftment, survival and rejection. Inclusion of unlimited sources of insulin-producing cells, such as xenogeneic porcine islets or stem cell-derived beta cells would further solve the problem of organ shortage.

This article reviews the current status of clinical islet transplantation, the strategies aiming at developing a bioartificial pancreas, the clinical trials conducted in the field and the perspectives for further progress.

The COVID-19 pandemic affects the transplant recipients since March 2020. Transplant centers quickly organized themselves to optimize the management of the immunocompromised patients and to progress in the knowledge of this new disease. To this end, a French Registry was created, which includes all solid organ transplant patients who have developed a SARS Cov2 infection. Numerous studies have been carried out using these data to describe this new disease in transplant patients, to characterize its clinical and biological risk factors and to define its prognosis. The 60 days-mortality of transplant patients hospitalized for COVID-19 was evaluated at 23% and renal failure plays a major role in the poor prognosis in addition to the classical risk factors described in the general population. The advent of vaccination has been a great relief but transplanted patients have shown a poor vaccine response keeping them at risk of severe disease even after an adapted vaccination scheme. Specific strategies was proposed in this particularly fragile population like increasing vaccine doses or using anti SARS Cov-2 monoclonal antibodies.

Lung transplantation has been accepted as a viable treatment for end-stage respiratory failure. While regression models continue to be a standard approach for attempting to predict patients’ outcomes after lung transplantation, more sophisticated supervised machine learning (ML) techniques are being developed and show encouraging results. Transplant clinicians could utilize ML as a decision-support tool in a variety of situations (e.g. waiting list mortality, donor selection, immunosuppression, rejection prediction). Although for some topics ML is at an advanced stage of research (i.e. imaging and pathology) there are certain topics in lung transplantation that needs to be aware of the benefits it could provide.

Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival.

Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection.

The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials.

Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.

The shortage of organs for transplantation has led health professionals to look for alternative sources of donors. One of the avenues concerns donors who have died after circulatory arrest. This is a special situation because the organs from these donors are exposed to warm ischaemia-reperfusion lesions that are unavoidable during the journey of the organs from the donor to the moment of transplantation in the recipient. We will address and discuss the key issues from the perspective of team organization, legislation and its evolution, and the ethical framework. In a second part, the avenues to improve the quality of organs will be presented following the itinerary of the organs between the donor and the recipient. The important moments from the point of view of therapeutic strategy will be put into perspective. New connections between key players involved in pathophysiological mechanisms and implications for innate immunity and injury processes are among the avenues to explore. Technological developments to improve the quality of organs from these recipients will be analyzed, such as perfusion techniques with new modalities of temperatures and oxygenation. New molecules are being investigated for their potential role in protecting these organs and an analysis of potential prospects will be proposed. Finally, the important perspectives that seem to be favored will be discussed in order to reposition the use of deceased donors after circulatory arrest. The use of these organs has become a routine procedure and improving their quality and providing the means for their evaluation is absolutely inevitable.