Untargeted NMR-based metabolomics analysis of kidney allograft perfusates identifies a signature of delayed graft function.

INTRODUCTION: Kidney transplantation (KTx) necessarily conveys an ischemia/reperfusion (I/R) process, which impacts on allograft outcomes. Delayed graft function (DGF) is defined as a non-decrease of serum creatinine by at least 10% daily on 3 consecutive days during the first 7 days post-KTx. DGF significantly conditions both short- and long-term graft outcomes. Still there is a lack of DGF predictive biomarkers. OBJECTIVES: This study aimed to explore the potential of kidney graft perfusate metabolomics to predict DGF occurrence. METHODS: 49 human perfusates from grafts categorized upon donor type [donation after brain death (DBD)/donation after circulatory death (DCD)] and DGF occurrence and 19 perfusates from a murine model classified upon death type (DBD/DCD) were collected and analyzed by NMR-based metabolomics. RESULTS: The multivariate analysis of the murine data highlighted significant differences between perfusate metabolomes of DBD versus DCD. These differences were similarly observed in the human perfusates. After correcting for the type of donor, multivariate analysis of human data demonstrated a metabolomics signature that could be correlated with DGF occurrence. CONCLUSIONS: The metabolome of kidney grafts is influenced by the donor's type in both human and pre-clinical studies and could be correlated with DGF in the human DBD cohort. Thus, metabolomic analysis of perfusate applied prior to KTx may represent a new predictive tool for clinicians in a more personalized management of DGF. Moreover, our data paves the way to better understand the impact of donor's types on the biochemical events occurring between death and the hypothermic storage.

[The glomerulus in all its states]. / Le glomérule dans tous ses états.

Glomerulonephritis are the result of an inflammatory hit to the glomerulus. They are rare and heterogeneous renal diseases. Each glomerular compartment can be affected. The clinical manifestations present with hematuria, proteinuria and/or impaired renal function, either isolated or combined. Two main clinico-biological syndromes are described: nephrotic syndrome and nephritic syndrome. The latter can present in a more severe form i.e. rapidly progressive glomerulonephritis with the worst prognosis. These different clinical pictures are related to specific glomerular lesions. Thus, podocytic damage is mainly responsible for nephrotic syndromes, mesangial damage is responsible for proteinuria and hematuria and, finally, endothelial damage is responsible for nephritic syndrome and rapidly progressive glomerulonephritis. Therapeutic approaches include non-specific measures, combining both life-style and pharmacological interventions with the aim to reduce risk factors, and specific measures with the use of different immunosuppressive agents.

: Les glomérulonéphrites sont des atteintes inflammatoires du glomérule. Il s'agit de pathologies rénales rares et hétérogènes. Tous les compartiments glomérulaires peuvent être touchés. Les répercussions cliniques sont diverses. Elles se manifestent par une hématurie, une protéinurie et/ou une altération de la fonction rénale, présente chacune de manière isolée ou combinée. Deux principaux syndromes clinico-biologiques sont décrits : le syndrome néphrotique et le syndrome néphritique. Au sein de cette dernière entité, on distingue une forme plus sévère, les glomérulonéphrites rapidement progressives grevées du plus mauvais pronostic. Ces différents tableaux cliniques sont en lien avec des lésions glomérulaires spécifiques. Ainsi, les atteintes podocytaires sont principalement responsables des syndromes néphrotiques, les atteintes mésangiales sont responsables de protéinurie et d'hématurie et les atteintes endothéliales sont responsables de syndromes néphritiques et de glomérulonéphrites rapidement progressives. Les approches thérapeutiques comprennent des mesures non spécifiques, hygiéno-diététiques et pharmacologiques, visant à réduire les différents facteurs de risque, et des mesures spécifiques avec l'utilisation de divers médicaments immunosuppresseurs.

[Diagnosis and management of renal allograft rejection]. / Diagnostic et prise en charge thérapeutique du rejet en transplantation rénale.

Renal allograft rejection involves many mechanisms of innate and adaptive immunity, responsible for parenchymal inflammatory lesions that negatively impact the long-term outcomes of the renal allograft. The heterogeneous presentations of rejections in terms of clinical, biological and histological aspects make them difficult to manage in daily clinical practice. Indeed, current therapeutic strategies are disappointing in term of long-term outcomes, including graft survival. In this article, we will discuss the main effector mechanisms of rejection and their histological classification, as well as the existing treatments and those currently under evaluation.

: Le rejet du greffon rénal fait intervenir de nombreux mécanismes de l'immunité innée et adaptative, responsables de lésions inflammatoires parenchymateuses impactant négativement le devenir au long cours du greffon rénal. La grande hétérogénéité dans la présentation clinique, biologique et histologique des rejets de greffe en fait des entités difficiles à prendre en charge en pratique clinique quotidienne. En effet, les stratégies thérapeutiques actuelles montrent des résultats assez décevants pour le traitement des rejets, ce qui a comme conséquence une diminution significative de la survie des greffons. Nous aborderons dans cet article les principaux mécanismes effecteurs des rejets, leur classification histologique ainsi que les traitements existants et en cours de validation.

[Cellular immunotherapy at the University Hospital of Liege : advances, challenges and prospects]. / Immunothérapie cellulaire au CHU de Liège : avancées, défis et perspectives.

Cellular immunotherapy consists in using the cells of the immune system as a therapeutic weapon. In this constantly evolving field, the therapeutic strategies developed at the University Hospital of Liege are hematopoietic stem cell transplantation, mesenchymal stromal cells and targeted therapy with CAR-T cells (Chimeric Antigen Receptor T cells). The first two modalities represent a form of non-targeted cell therapy that has been developed over the past decades. While hematopoietic stem cell transplantation is established as the reference treatment for many hematological diseases, mesenchymal stromal cells are still under investigation in various pathologies (notably Crohn's disease, organ transplantation, COVID-19 and pulmonary fibrosis). By contrast, CAR-T cells represent a recently developed and extremely promising targeted immunotherapy. This therapeutic approach has already revolutionized the treatment of B-cell lymphopathies, and has the potential to do the same for many other diseases in the near future.

L'immunothérapie cellulaire consiste en l'utilisation de cellules du système immunitaire comme arme thérapeutique. Dans ce domaine en évolution constante, les stratégies thérapeutiques développées au CHU de Liège sont la greffe de cellules souches hématopoïétiques, les cellules stromales mésenchymateuses et la thérapie ciblée par cellules CAR-T («Chimeric Antigen Receptor T cells¼). Les deux premières approches représentent une forme de thérapie cellulaire non ciblée, développées depuis de nombreuses années. Si la greffe de cellules souches hématopoïétiques est établie comme le traitement de référence de nombreuses hémopathies, les cellules stromales mésenchymateuses sont, quant à elles, toujours à l'étude dans diverses pathologies (notamment maladie de Crohn, transplantation d'organes, COVID-19 et fibrose pulmonaire). À l'opposé, les cellules CAR-T représentent une immunothérapie ciblée, développée récemment et extrêmement prometteuse. Cette modalité thérapeutique a déjà révolutionné le traitement des lymphopathies B, et elle possède le potentiel d'en faire de même pour de nombreuses autres pathologies dans un avenir proche.

[Kidney injury in COVID-19]. / Atteintes rénales de la COVID-19.

The SARS-CoV-2 virus causes a respiratory distress syndrome, the main symptom of COVID-19 (for "COronaVIrus Disease 2019"). This infectious disease has been causing a major health and socio-economic pandemic since December 2019. The pulmonary alveolus is regarded as the main target of SARS-CoV-2. However, this coronavirus is capable of directly or indirectly affecting other organs, including the kidneys. Here, we summarize the presumed pathophysiology of COVID-19 renal disease. The incidence of acute kidney injury ranges from 0,5 to 22 % of all patients infected with SARS-CoV-2. The need for renal replacement therapy is reported in 5-9 % of patients in intensive care. Histological analysis of renal biopsies mainly shows acute tubular necrosis of varying severity, as well as the congestion of glomerular and peri-tubular capillaries. Endothelitis has been described in few cases. Evidence for a factual inflammation of the glomerulus remains controversial. The medium/long term consequences of COVID-19 nephropathy are unknown and will deserve a tight follow-up.

Le virus SARS-CoV-2 provoque un syndrome de détresse respiratoire aiguë, le symptôme principal de l'infection COVID-19 (pour «COronaVIrus Disease 2019¼). Cette maladie infectieuse provoque une pandémie de gravité sanitaire et socio-économique majeure depuis décembre 2019. La cible principale du SARS-CoV-2 serait l'alvéole pulmonaire. Néanmoins, ce coronavirus est capable d'affecter directement ou indirectement d'autres organes, y compris les reins. Nous résumons ici la physiopathologie présumée de l'atteinte rénale de la COVID-19. L'incidence de l'insuffisance rénale aiguë varie entre 0,5 à 22 % de tous les patients infectés par le SARS-CoV-2. La nécessité d'une épuration extra-rénale est rapportée chez 5-9 % des patients pris en charge aux soins intensifs. L'analyse histologique de biopsies rénales montre, principalement, une nécrose tubulaire aiguë de sévérité variable, ainsi qu'une congestion des capillaires glomérulaires et péri-tubulaires. Une endothélite a parfois été décrite. L'atteinte inflammatoire du glomérule reste débattue. Les conséquences à moyen/long termes de la néphropathie COVID-19 sont inconnues et mériteront un suivi étroit.

Mesenchymal Stromal Cells Accelerate Epithelial Tight Junction Assembly via the AMP-Activated Protein Kinase Pathway, Independently of Liver Kinase B1.

BACKGROUND: Mesenchymal stromal cells (MSC) are fibroblast-like multipotent cells capable of tissue-repair properties. Given the essentiality of tight junctions (TJ) in epithelial integrity, we hypothesized that MSC modulate TJ formation, via the AMP-activated kinase (AMPK) pathway. Liver kinase-ß1 (LKB1) and Ca2+-calmodulin-dependent protein kinase kinase (CaMKK) represent the main kinases that activate AMPK. METHODS: The in vitro Ca2+ switch from 5 µM to 1.8 mM was performed using epithelial Madin-Darby canine kidney (MDCK) cells cultured alone or cocultured with rat bone marrow-derived MSC or preexposed to MSC-conditioned medium. TJ assembly was measured by assessing ZO-1 relocation to cell-cell contacts. Experiments were conducted using MDCK stably expressing short-hairpin-RNA (shRNA) against LKB1 or luciferase (LUC, as controls). Compound STO-609 (50 µM) was used as CaMKK inhibitor. RESULTS: Following Ca2+ switch, ZO-1 relocation and phosphorylation/activation of AMPK were significantly higher in MDCK/MSC compared to MDCK. No difference in AMPK phosphorylation was observed between LKB1-shRNA and Luc-shRNA MDCK following Ca2+ switch. Conversely, incubation with STO-609 prior to Ca2+ switch prevented AMPK phosphorylation and ZO-1 relocation. MSC-conditioned medium slightly but significantly increased AMPK activation and accelerated TJ-associated distribution of ZO-1 post Ca2+ switch in comparison to regular medium. CONCLUSIONS: MSC modulate the assembly of epithelial TJ, via the CaMKK/AMPK pathway independently of LKB1.

[Mesenchymal stromal cells and organ transplantation]. / Cellules stromales mésenchymateuses et transplantation d'organes.

Mesenchymal stromal cells (MSC) are multipotent and self-renewing cells. MSC are studied for their in vivo and in vitro immunomodulatory effects, in the prevention or the treatment of isehemic injury, and for their potential properties of tissue or organ reconstruction. Over the last few years, the potential role of MSC in organ transplantation has been studied both in vitro and in vivo, and their properties make them an ideal potential cell therapy after solid organ transplantation. A prospective, controlled, phase 1-2 study has been initiated at the CHU of Liege, Belgium. This study assesses the potential risks and benefits of MSC infusion after liver or kidney transplantation. Even if the preliminary results of this study look promising, solely a prospective, randomized, large scale, phase 3 study will allow the clinical confirmation of the theoretical benefits of MSC in solid organ transplantation.

[Interest of chronotherapy in arterial hypertension]. / Intérêt de la chronothérapie dans le traitement de l'hypertension artérielle.

The interest of chronotherapy in the field of arterial hypertension is progressively rising, especially in treated hypertensive patients characterized by a small decrease of their blood pressure during the night, and therefore often presenting a high cardiovascular risk. There are more and more data showing that administration of one antihypertensive drug in the evening (and even aspirin) can improve the blood pressure control during the night and the day/night blood pressure pattern, and so can diminish the level of risk. The role of chronotherapy also emphasizes the interest of 24 h ambulatory blood pressure monitoring in the management of high risk hypertensive patients.

Early thoracoscopy for the management of empyema in children.

BACKGROUND: Empyema is a significant cause of morbidity in children. Treatment is still a matter of controversy between surgical and non-surgical options. We reviewed our experience with the use of video-assisted thoracoscopy (VATS) in the treatment of empyema and proposed an algorithm. PATIENTS AND METHODS: We retrospectively reviewed all the pediatric patients recorded at our institution from January 2003 to December 2007 who were diagnosed with empyema and treated by surgery. RESULTS: 23 children with empyema were treated with VATS during the review period. Mean age was 58.9 months and the duration of symptoms before admission was 6.1 days. All patients had a parapneumonic empyema treated by preoperative antibiotics (17/23 by parenteral antibiotics and 6/23 by oral antibiotics). Pre-operative imaging included chest X-ray in all cases and ultrasonography in all cases but one and computed tomography in 3 (13%). Our 23 patients underwent VATS within 5.3 days of hospitalisation, the most recent patients within 2 days. Chest tubes were removed after 2.7 days (range 2 to 4) resulting in a postoperative length of stay (LOS) of 10.3 days (range 6 to 28). Total LOS was 13.3 days (range 8 to 30). One patient required a conversion to thoracotomy. One patient required prolonged mechanical ventilation due to a severe myopathy during the post operative course, but there were no complications or deaths. Followup was available for all patients who all remained symptom-free and suffered no recurrence (clinical and radiological). CONCLUSION: Early thoracoscopy for empyema in children is safe and efficient in the short and mid-term outcome. We describe an algorithm based on our initial experience and review the literature for the management of empyema in children.

[Clinical evaluation of 23 children with neuroblastoma. The experience of a single institution]. / Les neuroblastomes de l'enfant. A propos de 23 cas.

In this retrospective study, we analyse epidemiology, clinical symptoms and therapeutic results in a group of 23 children with neuroblastoma. Half of them were less than 2 years of age; in 19 of 23, the primitive tumour was abdominal; 35% of them were initially metastatic. The overall survival was 83% at 5 years and the event free survival, 75% at 5 years. Pronostic factors are age, extension of the disease at diagnosis, biologic parameters and genetic study of the neuroblast cells (amplification of N-myc oncogen). Our study shows the deleterious effect of bone lesions.

[Retrospective study of childhood lymphomas. Report of 27 children treated at a single institution]. / Etude rétrospective des lymphomes de l'enfant. A propos de 27 cas traités dans une même institution.

Childhood lymphomas represent a heterogeneous group of disorders that are quite different from adult lymphomas. Over the past three decades, empirical chemotherapeutic management has transformed survival figures, and more recently greater understanding of the biology is offering hope for improved management of resistant disease. We present here the experience of a single institution in the management of 27 childhood lymphomas; epidemiological and clinical characteristics are described as well as survival rates. The median follow up of the patients is 4 years 7 months. The five-year overall survival for the entire group is more than 95 %; the 5-year disease free survival is 91,6 % for Hodgkin's lymphomas, 92,8% for non Hodgkin's lymphomas and 100% for Burkitt diseases. Two relapses have occurred and all of them appeared within the 18 months of the diagnosis. No toxic death has been reported.

[Paroxystic abdominal pain in children]. / Les douleurs abdominales paroxystiques chez l'enfant.

Acute abdominal pain in children is a frequent symptom of a wide spectrum of abdominal and extra-abdominal pathologies. Some of them are more common in specific age groups. Prompt diagnosis and treatment are facilitated by a good knowledge of the etiologies. Although surgery is mandatory in most of the cases of perforation, torsion, ischemia or necrosis, a medical treatment will prevent an unnecessary laparotomy in some circumtances.

Sacrococcygeal teratoma: results of a retrospective multicentric study in Belgium and Luxembourg.

Eighteen patients, operated upon for sacrococcygeal teratoma in 7 different centres in Belgium and Luxembourg between 1992 and 1996, were reviewed. From an epidemiological point of view, this series compares very well to others. Although excellent results were obtained, with all patients surviving, some imperfection in diagnosis, timing of delivery and of operation, and in operative technique was observed. Therefore, it is stated that for optimal treatment of sacrococcygeal teratoma to be achieved, these cases should be treated in just a very few centres of neonatal surgery.

[Importance of long-term follow-up of infants operated of sacro-coccygeal teratoma]. / Importance du suivi à long terme des enfants opérés d'un tératome sacro-coccygien.

Sacro-coccygeal teratoma is the tumor which is most frequently diagnosed in infants. In spite of the sometimes spectacular appearance of the tumor, the surgical treatment generally permits a definitive cure of the disease without any significant functional or esthetic sequellae. The risk of malignant recurrence, even after removal of an apparently benign mass is not totally excluded and may imply to resort to combined treatment by surgery and chemotherapy. The baby must be carefully followed-up and the serum levels of alpha-foetoprotein (a specific tumor marker), and sometimes beta-HCG must be regularly measured. Local surveillance is mandatory to prevent any loss of time in case of recurrence.