Inflammation associée à l'agression rénale aiguë : contribution de la polarisation macrophagique, visualisation de VCAM-1 en imagerie moléculaire

L'agression rénale aigüe (ARA) secondaire à la rhabdomyolyse est une situation fréquente, mais les données histologiques sont rares, et la physiopathologie est surtout attribuée à la toxicité de la myoglobine. Nous avons fait l'hypothèse que cette entité nosologique pouvait impliquer des macrophages (MØ), polarisés vers le phénotype M1 (pro-inflammatoire) ou M2 (réparateur). Dans un modèle murin, nous avons phénotypé les MØ rénaux. A J2, des R1 (F4/80loCD11bhi) sont recrutés, alors qu'à J8, des R2 (F4/80hiCD11b+) réparateurs deviennent dominants. Une étude transcriptionnelle sur cellule unique révèle que R1 et R2 sont dans un état de polarisation mixte et co-expriment des marqueurs M1 et M2. La déplétion des MØ par le clodronate liposomal (CL) réduit la mortalité des souris, et indique que les R1 jouent un rôle clé dans l'évolution de la pathologie via la sécrétion de composants de la matrice extra-cellulaire et de chimiokines. La myoglobine per se entraîne la production de chimiokines par les cellules rénales et les MØ, et polarise ces derniers. A 7 mois, alors que la fonction rénale est quasi-restaurée, on note une fibrose rénale, qui est partiellement réduite par le CL. Ces données indiquent: l'existence de lésions infra-cliniques de fibrose rénale à distance d'une rhabdomyolyse et le rôle pronostique déterminant des MØ inflammatoires. En parallèle, nous avons pu appliquer une technique non-invasive de mesure de l'inflammation endothéliale à l'étude de différents modèles d'ARA en ciblant VCAM-1 (vascular cell adhesion molecule-1) par imagerie moléculaire. Ce travail établit l'importance des phénomènes inflammatoires dans l'ARA, qu'elle soit d'origine immune ou non.Rhabdomyolysis is a frequent cause of acute kidney injury (AKI). The toxic effect of myoglobin was thought to be the main factor involved in this disease. Since macrophages (MØ) have been suspected to populate the kidney after rhabdomyolysis, we set out to investigate their role and polarization status, whereby MØ are classified as either M1 (pro-inflammatory) or M2 (wound-healing). Diverse renal MØ phenotypes were observed in a mouse model: two days after rhabdomyolysis, R1 (F4/80loCD11bhi) were dominant. By day 8, R2 (F4/80hiCD11b+) became dominant. Liposomal clodronate (CL)-mediated MØ depletion indicated that the early infiltration of R1 was deleterious. Transcriptionally regulated targets, such as chemokines and extra-cellular matrix components were identified and verified to be expressed in a MØ-dependent manner. Via single-cell analysis R1 and R2 were shown to express both M1 and M2 markers. Inflammatory processes seemed to be directly favoured by myoglobin since it induced in vitro tubular cells to secrete chemokines and MØ to change their polarization status. Early CL-mediated MØ depletion improved kidney repair and mouse survival. Seven months after rhabdomyolysis, the fibrotic lesions were significantly reduced in the CL-treated group, suggesting that early MØ depletion limits long-term injuries. We also performed a study to assess the interest of detecting endothelial inflammation during AKI via enhanced molecular imaging targeting VCAM-1 (vascular cell adhesion molecule-1). This non-invasive technology appears to be a relevant approach

Case Report Beneficial Effect of Conversion to Belatacept in Kidney-Transplant Patients with a Low Glomerular-Filtration Rate

Belatacept has been found to be efficient at preserving good kidney function in maintenance kidney-transplant patients. Herein, we report on the use of belatacept as a rescue therapy for two kidney-transplant patients presenting with severe adverse events after treatment with calcineurin inhibitors (CNIs) and mammalian target-of-rapamycin (mTOR) inhibitors. Two kidney-transplant patients developed severely impaired kidney function after receiving CNIs. The use of everolimus was associated with severe angioedema. Belatacept was then successfully used to improve kidney function in both cases, even though estimated glomerularfiltration rate before conversion was <20 mL/min. These case reports show that belatacept can be used as a rescue therapy, even if kidney function is very low in kidney-transplant patients who cannot tolerate CNIs and/or mTOR inhibitors

Incidence and outcomes of kidney replacement therapy for end-stage kidney disease due to primary glomerular disease in Europe:Findings from the ERA Registry

Background and hypothesis: Primary glomerular disease (PGD) is a major cause of end-stage kidney disease (ESKD) leading to kidney replacement therapy (KRT). We aimed to describe incidence (trends) in individuals starting KRT for ESKD due to PGD and to examine their survival and causes of death.Methods: We used data from the European Renal Association (ERA) Registry on 69,854 patients who started KRT for ESKD due to PGD between 2000 and 2019. ERA primary renal disease codes were used to define six PGD subgroups. We examined age and sex standardized incidence, trend of the incidence, and survival.Results: The standardized incidence of KRT for ESKD due to PGD was 16.6 per million population (pmp), ranging from 8.6 pmp in Serbia to 20.0 pmp in France. IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) had the highest incidence of 4.6 pmp and 2.6 pmp, respectively. Histologically non-examined PGDs represented over 50% of cases in Serbia, Bosnia and Herzegovina, and Romania and were also common in Greece, Estonia, Belgium, and Sweden. The incidence declined from 18.6 pmp in 2000 to 14.5 pmp in 2013, after which it stabilized. All PGD subgroups had five-year survival probabilities above 50%, with crescentic glomerulonephritis having the highest risk of death (adjusted hazard ratio: 1.8 [95% confidence interval: 1.6-1.9]) compared with IgAN. Cardiovascular disease was the most common cause of death (33.9%).Conclusion: The incidence of KRT for ESKD due to PGD showed large differences between countries and was highest for IgAN and FSGS. Lack of kidney biopsy facilities in some countries may have affected accurate assignment of the cause of ESKD. The recognition of the incidence and outcomes of KRT among different PGD subgroups may contribute to a more individualized patient care approach

Ubiquinone Analogs: A Mitochondrial Permeability Transition Pore-Dependent Pathway to Selective Cell Death

International audienceBACKGROUND: Prolonged opening of the mitochondrial permeability transition pore (PTP) leads to cell death. Various ubiquinone analogs have been shown to regulate PTP opening but the outcome of PTP regulation by ubiquinone analogs on cell fate has not been studied yet. METHODOLOGY/PRINCIPAL FINDINGS: The effects of ubiquinone 0 (Ub(0)), ubiquinone 5 (Ub(5)), ubiquinone 10 (Ub(10)) and decyl-ubiquinone (DUb) were studied in freshly isolated rat hepatocytes, cultured rat liver Clone-9 cells and cancerous rat liver MH1C1 cells. PTP regulation by ubiquinones differed significantly in permeabilized Clone-9 and MH1C1 cells from that previously reported in liver mitochondria. Ub(0) inhibited PTP opening in isolated hepatocytes and Clone-9 cells, whereas it induced PTP opening in MH1C1 cells. Ub(5) did not affect PTP opening in isolated hepatocytes and MH1C1 cells, but it induced PTP opening in Clone-9 cells. Ub(10) regulated PTP in isolated hepatocytes, whereas it did not affect PTP opening in Clone-9 and MH1C1 cells. Only DUb displayed the same effect on PTP regulation in the three hepatocyte lines tested. Despite such modifications in PTP regulation, competition between ubiquinones still occurred in Clone-9 and MH1C1 cells. As expected, Ub(5) induced a PTP-dependent cell death in Clone-9, while it did not affect MH1C1 cell viability. Ub(0) induced a PTP-dependent cell death in MH1C1 cells, but was also slightly cytotoxic in Clone-9 by an oxidative stress-dependent mechanism. CONCLUSIONS/SIGNIFICANCE: We found that various ubiquinone analogs regulate PTP in different ways depending on the cell studied. We took advantage of this unique property to develop a PTP opening-targeted strategy that leads to cell death specifically in cells where the ubiquinone analog used induces PTP opening, while sparing the cells in which it does not induce PTP opening

Le recours de l'article 37 du décret du 4 mars 1991 relatif à l'aide à la jeunesse

Master [120] en droit, Université catholique de Louvain, 201

Renal Complications Related to Checkpoint Inhibitors: Diagnostic and Therapeutic Strategies

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have unprecedentedly improved global prognosis in several types of cancers. However, they are associated with the occurrence of immune-related adverse events. Despite their low incidence, renal complications can interfere with the oncologic strategy. The breaking of peripheral tolerance and the emergence of auto- or drug-reactive T-cells are the main pathophysiological hypotheses to explain renal complications after ICI exposure. ICIs can induce a large spectrum of renal symptoms with variable severity (from isolated electrolyte disorders to dialysis-dependent acute kidney injury (AKI)) and presentation (acute tubule-interstitial nephritis in >90% of cases and a minority of glomerular diseases). In this review, the current trends in diagnosis and treatment strategies are summarized. The diagnosis of ICI-related renal complications requires special steps to avoid confounding factors, identify known risk factors (lower baseline estimated glomerular filtration rate, proton pump inhibitor use, and combination ICI therapy), and prove ICI causality, even after long-term exposure (weeks to months). A kidney biopsy should be performed as soon as possible. The treatment strategies rely on ICI discontinuation as well as co-medications, corticosteroids for 2 months, and tailored immunosuppressive drugs when renal response is not achieved

IL6-R blocking with tocilizumab in critically ill patients with hemophagocytic syndrome

International audienc