c-Jun-N-Terminal Kinase Signaling Is Involved in Cyclosporine-Induced Epithelial Phenotypic Changes

Tubular epithelial cells play a central role in the pathogenesis of chronic nephropathies. Previous toxicogenomic studies have demonstrated that cyclosporine- (CsA-) induced epithelial phenotypic changes (EPCs) are reminiscent of an incomplete epithelial to mesenchymal transition (EMT) in a TGF-β-independent manner. Furthermore, we identified endoplasmic reticulum (ER) stress as a potential mechanism that may participate in the modulation of tubular cell plasticity during CsA exposure. Because c-jun-N-terminal kinase (JNK), which is activated during ER stress, is implicated in kidney fibrogenesis, we undertook the current study to identify the role of JNK signaling in EPCs induced by CsA. In primary cultures of human renal epithelial cells, CsA activates JNK signaling, and the treatment with a JNK inhibitor reduces the occurrence of cell shape changes, E-cadherin downregulation, cell migration, and Snail-1 expression. Our results suggest that CsA activates JNK signaling, which, in turn, may participate in the morphological alterations through the regulation of Snail-1 expression

Early acute microvascular kidney transplant rejection in the absence of anti-HLA antibodies is associated with preformed IgG antibodies against diverse glomerular endothelial cell antigens

International audienceBACKGROUND: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.METHODS: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.RESULTS: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.CONCLUSIONS: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that cell-based assays are needed to improve risk assessments before transplant

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Publisher Copyright: © 2021 The Authors, some rights reserved.Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-alpha and/or IFN-omega (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-beta do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.Peer reviewe

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

SignificanceThere is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population

Conséquences pharmacotoxicologiques des variations d'activité et des polymorphismes génétiques des cytochromes P4503A et de la P-glycoprotéine en transplantation rénale

Une meilleure compréhension des variations du métabolisme des immunosuppresseurs et de leurs effets secondaires pourrait d'améliorer le rapport bénéfice/risque de ces molécules. Nous avons montré que plusieurs des polymorphismes des gènes CYP3A4, CYP3A5 et ABCB1 sont associés à la variabilité interindividuelle de la pharmacocinétique du tacrolimus et de la rapamycine, mais pas de la ciclosporine. Nous avons montré que la P-glycoprotéine intervient dans la protection des cellules tubulaires rénales humaines contre la toxicité de la ciclosporine en favorisant son efflux cellulaire. La rapamycine limite l'efflux cellulaire de ciclosporine et augmente sa concentration intracellulaire, ce mécanisme pouvant expliquer la majoration de la néphrotoxicité de la ciclosporine par la rapamycine, déjà rapportée en clinique mais d'explication inconnue. Nous avons mis en évidence un effet antiprolifératif de la rapamycine sur les cellules épithéliales rénales et en avons exploré les mécanismes.A better understanding of individual variations in metabolism and side effects of immunosuppressive drugs could improve their safety and efficacy. We showed that several genetic polymorphisms of the CYP3A4, CYP3A5 and ABCB1 genes are associated with the interindividual variations of the pharmacokinetic characteristics of tacrolimus and rapamycin but not cyclosporine. We showed that P-glycoprotein is involved in the protection of human renal tubular cells against the cyclosporine toxicity by supporting its cellular efflux. Rapamycin limits the cellular efflux of cyclosporin and increases its intracellular concentration, a mechanism that may explain the exacerbation of cyclosporine nephrotoxicity observed clinically in the presence of rapamycin. We described an antiproliferative effect of rapamycin on human renal tubular cells and explored its mechanism.PARIS-BIUP (751062107) / SudocSudocFranceF

Suivi du patient ayant reçu une transplantation rénale par les biomarqueurs urinaires : de l’innovation technologique au développement clinique

International audienceIn kidney transplantation, the assessment of individual risks remains highly imperfect and highlights the need for robust noninvasive biomarkers with the overall goal to improve patient and graft outcomes. In the field of noninvasive biomarkers discovery, urinary biomarkers are promising tools which use easily accessible biological fluid. During the past decades, the technical revolution in the fields of genetics and molecular biology, and advances in chemistry and data analysis have led to a wealth of studies using urinary cell pellets or supernatants from kidney transplant recipients. Transcriptomic, proteomic and metabonomic analyses have suggested numerous signatures for the diagnoses of acute rejection, delayed-graft function or interstitial fibrosis. Nevertheless, the translation and validation of exploratory findings and their implementation into standard clinical practice remain challenging. This requires dedicated prospective interventional trials demonstrating that the use of these biomarkers avoids invasive procedures and improves patient or transplant outcomes.Dans le suivi des patients transplantés rénaux, le développement de nouveaux biomarqueurs constitue un enjeu important pour s’affranchir des limites actuelles de la biopsie du greffon et pour proposer une médecine de transplantation individualisée. Les biomarqueurs urinaires constituent un domaine de recherche attractif et prometteur compte-tenu de leur caractère strictement non invasif, et du potentiel qu’ont les urines de contenir la somme des évènements survenant dans le greffon. Les avancées majeures dans le développement de méthodes innovantes et performantes permettent désormais la quantification des ARN codants et non-codants dans le culot cellulaire urinaire, et des protéines et des métabolites dans le surnageant urinaire. De nombreuses signatures issues des analyses de transcriptomique, protéomique et métabolomique ont été proposées pour évaluer les risques de rejet cellulaire ou humoral, de reprise retardée de fonction ou encore de fibrose interstitielle. Après 2 décennies de recherche sur le biomarqueurs urinaires, ces résultats doivent encore être confirmés et validés dans des études robustes avant de devenir des outils du quotidien

Precision Transplant Medicine: Biomarkers to the Rescue

The concept that individuals with the same disease and a similar clinical presentation may have very different outcomes and need very different therapies is not novel. With the development of many innovative tools derived from the omics technologies, transplant medicine is slowly entering the era of precision medicine. Biomarkers are the cornerstone of precision medicine, which aims to integrate biomarkers with traditional clinical information and tailor medical care to achieve the best outcome for an individual patient. Here, we discuss the basic concepts of precision medicine and biomarkers, with a specific focus on progress in renal transplantation. We delineate the different types of biomarkers and provide a general assessment of the current applications and shortcomings of previously proposed biomarkers. We also outline the potential of precision medicine in transplantation. Moving toward precision medicine in the field of transplantation will require transplant physicians to embrace the increased complexity and expanded decision algorithms and therapeutic options that are associated with improved disease nosology.status: publishe

MicroARN et maladies rénales

Les microARN (miARN) constituent une classe abondante de petits ARN naturels non codants. Ils jouent un rôle fondamental dans la régulation post-transcriptionnelle des gènes. Des données récentes suggèrent leur implication dans le développement de l’appareil urinaire et des cellules rénales et dans des processus impliqués dans la physiopathologie des maladies rénales comme la fibrogenèse, l’immunité innée et adaptative et les maladies dysimmunitaires ou le rejet du greffon rénal. Nous proposons une revue de la littérature sur l’implication des miARN en physiopathologie rénale

Acute kidney injury during an ultra-distance race

International audiencePURPOSE:Previous studies have noted consequences of ultra-distance trail running on health, but few studies are available regarding the temporal variations of renal biomarker injury during the running. The aim of this study was to assess the of kidney function parameters temporal variation during and on short-term after an ultra-distance race.METHODS:We performed an observational study with 47 subjects participating in an ultra-distance race (80 km). Urine (47 subjects) and blood (21 subjects) samples were serially collected before (baseline-km 0), during (21 and 53 km), on arrival (80 km), and 9 days after the race (d9).RESULTS:Mean serum creatinine increased during the race from 90±14 μmol/L (km0) to 136±32 μmol/L (km 80-p0.05). On day 9, no significant difference remains in blood and urine biomarkers compared to their respective baseline levels.CONCLUSIONS:During an ultra-distance race, despite an acute and transient increase in the serum creatinine levels, urinary biomarkers of AKI displayed only limited changes with a complete regression on day 9. These results suggest the absence of the short-term impact of an ultra-distance race kidney function