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We report the case of a patient followed for a mixed connective tissue disease with signs of systemic sclerosis and systemic lupus, who presented an acute renal failure with severe neurological symptoms (confusion, obnubilation) and hypertension. The distinction between scleroderma renal crisis and lupus nephritis was challenging and hence, the decision to use or not high dose of corticosteroids. Kidney biopsy was of major importance for the diagnosis and therapeutic strategy. The diagnosis of neurological symptoms was also made difficult given the clinical presentation and the results of imaging. Neurolupus, malignant hypertension, or posterior reversible encephalopathy syndrome were the evoked diagnosis.

Background Renal involvement in ANCA-associated vasculitis (AAV) is associated with poor outcomes. The clinical significance of arteritis of the small kidney arteries has not been evaluated in detail. Methods In a multicenter cohort of patients with AAV and renal involvement, we sought to describe the clinicopathologic characteristics of patients with AAV who had renal arteritis at diagnosis, and to retrospectively analyze their prognostic value. Results We included 251 patients diagnosed with AAV and renal involvement between 2000 and 2019, including 34 patients (13.5%) with arteritis. Patients with AAV-associated arteritis were older, and had a more pronounced inflammatory syndrome compared with patients without arteritis; they also had significantly lower renal survival (P=0.01). In multivariable analysis, the ANCA renal risk score, age at diagnosis, history of diabetes mellitus, and arteritis on index kidney biopsy were independently associated with ESKD. The addition of the arteritis status significantly improved the discrimination of the ANCA renal risk score, with a concordance index (C-index) of 0.77 for the ANCA renal risk score alone, versus a C-index of 0.80 for the ANCA renal risk score plus arteritis status (P=0.008); ESKD-free survival was significantly worse for patients with an arteritis involving small arteries who were classified as having low or moderate risk, according to the ANCA renal risk score. In two external validation cohorts, we confirmed the incidence and phenotype of this AAV subtype. Conclusions Our findings suggest AAV with renal arteritis represents a different subtype of AAV with specific clinical and histologic characteristics. The prognostic contribution of the arteritis status remains to be prospectively confirmed.

The long-term consequences of pre-eclampsia (PrE) for renal function have never been determined in patients with sickle cell disease (SCD). Between 2008 and 2015, we screened 306 pregnancies in women with SCD and identified 40 with PrE (13%). The control group consisted of 65 pregnant SCD patients without PrE. In multivariable analysis, PrE events were associated with an increase of 1 log of lactate dehydrogenase level (adjusted odds ratio, aOR = 3·83, P = 0·05), a decrease of 10 g/l of haemoglobin levels (aOR = 2·48, P = 0·006) and one or more vaso-occlusive crisis during pregnancy (aOR = 16·68, P = 0·002). Estimated glomerular filtration rate (eGFR) was similar in the two groups at steady state but was significantly lower in the PrE group after one year of follow-up and at last follow-up (130 vs 148 ml/min/1·73 m2 , P < 0·001 and 120 vs 130 ml/min/1·73 m2 , P < 0·001, respectively). In multivariable analysis, eGFR had returned to steady-state levels one year after pregnancy in patients without PrE but continued to decrease in patients with PrE (β = -18·15 ml/min/1·73 m2 , P < 0·001). This decline was more marked at the end of follow-up (β = -31·15 ml/min, P < 0·001). In conclusion, PrE episodes are associated with a significant risk of subsequent renal function decline in SCD patients.

The glomerular endothelium produces the key complement regulator factor H (FH), but its role in the endothelial cells protection and functional integrity is unclear. In this edition of Kidney International, Mahajan et al. demonstrate that the endothelial-intrinsic FH is important for the cytoskeletal architecture, monolayer integrity, proliferation control, metabolism, and inflammatory signaling regulation. These findings place the endothelium-derived FH in the center of the pathological process of diseases, characterized with FH genetic abnormalities.

The risk of acute renal failure (ARF) following iodinated contrast media injection has long been overestimated because of the previous use of more toxic ICPs and uncontrolled studies. Nowadays, this concept is being questioned. Patients with severe renal failure and/or ARF are the only group still considered at risk. In these patients, it is necessary to discuss an alternative without an iodinated contrast agent. Contrast-enhanced ultrasound, MRI, spectral CT or PET-CT scan can be used instead of contrast-enhanced CT. Preventive measures should be applied when appropriate substitute to CT is not available or not diagnosed (minimum necessary dose of ICP, interruption of some treatments and prior hydration). These recommendations formalized by the European Society of Urogenital Radiology (ESUR) in 2018 address most situations faced by clinicians. In complex situations, an opinion from a nephrologist remains necessary after asking the radiologist about the availability of acceptable substitutes.

BACKGROUND AND AIMS In rhabdomyolysis—characterized by massive striated muscle damage—main complication is Acute Kidney Injury (AKI) occurring in up to 50% cases. Physiopathology of rhabdomyolysis induced AKI (RIAKI) was historically described as the association of intrarenal vasoconstriction, tubular obstruction by myoglobin casts and direct tubular toxicity (by oxidative stress, lipid peroxidation). Recently, it became evident that the innate immunity also plays a role. Macrophages infiltrate contributes to direct tubular toxicity and we found activation of the complement system in patients and mice with RIAKI, in part mediated by myoglobin released heme [1]. Still, the mechanisms by which the innate immunity contribute to the RIAKI kidney injury and to which extend there are comparable to ischemia reperfusion injury (IRI) are not fully understood. METHOD We performed a kinetic model of glycerol (GLY) induced RIAKI in C57BL/6 mice at 1, 3, 12, 24 hours and 7 days and analysed kidney function (biochemical parameters, histology), injury markers (Quantigene: analyse simultaneously expression of 80 genes, chosen from RIAKI transcriptomic signature (1)), complement deposits (immunofluorescence). We evaluated the abundance of tissue-infiltrating immune and stromal cell populations using gene expression (MCP counter), validated by flow cytometry. Kinetic of expression of RIAKI genes was compared to scRNAseq of IRI model [2]. We compared WT mice to ones deficient of the classical (C1q–/–, C4–/–), alternative (C3–/– and FB–/–) and lectin (Collectin-11-/-) pathways. Finally, we analysed complement activation fragments in the urine of 15 RIAKI patients as compared to controls (n = 5) and IRI patients (n = 5). RESULTS Upon rhabdomyolysis, AKI in mice starts as early as 3 h post-GLY injection. Despite early upregulation of cytoprotective transcription factors (Maff, Myc, Sox9 within 3 h) and genes implicated in heme detoxification (HO1 and ferritin), both proximal and distal tubules are affected between 6 and 12 h post injury and endothelial injury is evident from 3 h. Granulocytes, monocytes and eosinophils increased in blood and infiltrated the kidney at 12 h due to preceding overexpression of chemoattractants (Cxcl1, Lgals3, Ccl2, Ccl7, Ccl12), likely by injured tubules. At 24 h, the phenotype of RIAKI kidney infiltrating inflammatory monocytes, eosinophils and resident macrophages revealed strong upregulation of C5aR1 (5x, 7x and 2x), while its levels in neutrophils tend to decrease, suggesting C5a-mediated activation. This was paralleled by intrarenal complement deposits on injured tubules and complement biomarkers in urine. To underscore the pathological relevance of complement, we found that alternative and to some extend lectin pathway deficient mice were partially protected, as opposed to mice deficient for classical pathway (Figure 1). Complement activation byproducts, notably Ba, C3a and C5a were increased in RIAKI patient urine as compared to control (including when normalized by proteinuria) (Figure 2). CONCLUSION The kinetic of RIAKI follows the pattern of IRI acute kidney injury with specificities regarding early response to heme overload. Despite numerous protective mechanisms initiated, kidney tubules and blood vessels are rapidly affected. This results in early kidney inflammation, complement deposition and chemoattraction of immune cell with complement responsive phenotype. Complement biomarkers are increased in urine of RIAKI mice and patients alike. Our study underlines the importance to study the first hours post injury to understand the mechanisms involved in order to propose specific treatment. Complement targeting has to be explored as a therapeutic strategy in this disease.

Background Patients on maintenance haemodialysis (HD) have an increased risk of severe coronavirus disease 2019 (COVID-19) and a reduced response to vaccines. Data are needed to identify immune correlates of protection in this population. Methods Following a COVID-19 outbreak among vaccinated patients in a HD unit, clinical data and serological response to BNT162b2 vaccine were retrospectively recorded. Results Among 53 patients present in the dialysis room, 14 were infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) alpha variant (COVID_Pos) and 39 were not. Compared with uninfected patients, COVID_Pos patients more frequently had additional causes of immunosuppression (50% versus 21%; P = .046) and were more often scheduled on the Monday–Wednesday–Friday (MWF) shift (86% versus 39%; P = .002). Moreover, COVID_Pos had lower anti-spike (S) immunoglobulin G (IgG) titres than uninfected patients {median 24 BAU/mL [interquartile range (IQR) 3–1163] versus 435 [99–2555]; P = .001} and lower neutralization titres [median 108 (IQR 17–224) versus 2483 (481–43 908); P = .007]. Anti-S and neutralization antibody titres are correlated (r = 0.92, P 284 BAU/mL got infected. Ten of 14 COVID_Pos patients were treated with casirivimab and imdevimab. No patient developed severe disease. Conclusions Anti-S IgG titre measured prior to exposure correlates to protection from SARS-CoV-2 infection in HD patients. BNT162b2 vaccination alone or in combination with monoclonal antibodies prevented severe COVID-19.

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-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-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω 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 subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals70 years, 2.3% between 70 and 80 years, and 6.3%80 years. By contrast, auto-Abs neutralizing IFN-β 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.

The three pathways of the complement system converge toward the cleavage of the central complement component C3 into its activated fragments, with C3b being able to bind covalently to the activating surface. The endothelial cells are among the major targets for complement attack in pathological conditions, as the atypical hemolytic uremic syndrome. Therefore, study of complement C3 deposition on endothelial cells by flow cytometry is a sensitive test to measure complement activation. This test can be used as a research or clinical tool to test complement activation induced by patients' sera or to test the functional consequences of newly discovered complement mutations as well as different triggers of endothelial cells injury.

A typical hemolytic uremic syndrome (aHUS) is a prototypic thrombotic microangiopathy attributable to complement dysregulation. Hypertensive emergency, characterized by elevation of systolic (>180 mmHg) or diastolic (>120 mmHg) blood pressure together with end-organ damage, can cause thrombotic microangiopathy which may mimic aHUS. We retrospectively evaluated the clinical, biological and complement genetic characteristics of 76 and 61 aHUS patients with and without hypertensive emergency, respectively. Patients with hypertensive emergency-aHUS were more frequently males, with neurological involvement, and a slightly higher hemoglobin level. At least one rare complement variant was identified in 51.3% (39/76) and 67% (41/61) patients with or without hypertensive emergency, respectively (P=0.06). In both groups, renal prognosis was severe with 23% and 40% of patients reaching end-stage renal disease after a 5-year follow-up (P=0.1). The 5-year renal survival was 77% in patients without hypertensive emergency or a complement variant, and below 25% in the three groups of patients with hypertensive emergency and/or a complement variant (P=0.02). Among patients without hypertensive emergency, the 5-year renal survival was 100% vs 40% in those treated or not with eculizumab, respectively (P

The three pathways of the complement system converge toward the cleavage of the central complement component C3 into its activated fragments, with C3b being able to bind covalently to the activating surface. The endothelial cells are among the major targets for complement attack in pathological conditions, as the atypical hemolytic uremic syndrome. Therefore, study of complement C3 deposition on endothelial cells by flow cytometry is a sensitive test to measure complement activation. This test can be used as a research or clinical tool to test complement activation induced by patients' sera or to test the functional consequences of newly discovered complement mutations as well as different triggers of endothelial cells injury.

Introduction L’insuffisance renale aigue (IRA) qui complique frequemment la rhabdomyolyse, sans traitement specifique, entraine une lourde morbi-mortalite en reanimation. L’IRA induite par la rhabdomyolyse (IRAAR) etait classiquement consideree comme l’association d’une vasoconstriction renale, d’une toxicite et obstruction tubulaire par la myoglobine. Plus recemment, un role de l’inflammation et notamment des macrophages a ete propose. Description Notre objectif etait d’evaluer le role du complement dans l’IRAAR chez les patients et dans un modele murin de rhabdomyolyse induite par glycerol. Methodes Nous avons realise chez des patients presentant une IRAAR, l’etude de biomarqueurs histologiques (n = 10) par immunohistochimie et immunofluorescence, plasmatiques (n = 10) et urinaires (n = 15) par ELISA et Western Blot du complement. Chez les souris WT-GLY nous avons etudie a 24 h, la fonction et l’histologie renale, les biomarqueurs du complement, la signature transcriptomique de l’IRAAR par RNAseq, les parametres d’inflammation renale par Quantigen, le profil de l’infiltrat macrophagique chez des souris Wild type ou KO pour des proteines de chaque voie d’activation du complement (facteur B, Collectine-11, C4 et C3 KO). L’injection preventive d’un inhibiteur du complement est en cours de realisation. Resultats Des depots de C3d et C5b9 sont retrouves dans les 10 biopsies renales d’IRAAR. Il s’agit d’une activation locale (dosage plasmatique normal mais fragments urinaires de clivage de C3, Bb C5b9s, C3a, C5a et FH). De meme les souris injectees par glycerol presentaient des depots de C3b et une activation urinaire du complement. Les C3 -/- GLY etaient protegees des lesions renales et presentaient une signature transcriptomique de l’IRAAR attenuee ( Fig. 1 ). Les modeles de souris KO suggerent l’implication de la voie des lectines – possiblement par fucosylation cellulaire excessive – et/ou alterne. Nous attendons un benefice therapeutique de l’inhibition pharmacologique du complement sur la survenue d’IRAAR. Conclusion Le complement est une potentielle cible therapeutique dans l’IRAAR.

Background: The coronavirus disease 2019 pandemic has affected millions of people worldwide but medium and long-term consequences are unknown. Clinical series of Kawasaki-like multisystem inflammatory syndrome in children (MIS-C), occurring after SARS-Cov-2 spreading, have been recently described. Case presentation: We describe a case of post COVID-19 MIS in a 46-year-old man, with biopsy-proven renal thrombotic microangiopathy (TMA). Specific complement inhibition with Eculizumab was initiated promptly and lead to a dramatic improvement of renal function. Conclusion: Our case suggests that post COVID-19 MIS is not restricted to children and that TMA could play a central role in the pathophysiology of this syndrome

International audience; The complement system is an innate immune defense cascade that can cause tissue damage when inappropriately activated. Evidence for complement over activation has been reported in small cohorts of patients with sickle cell disease (SCD). However, the mechanism governing complement activation in SCD has not been elucidated. Here, we observe that the plasma concentration of sC5b-9, a reliable marker for terminal complement activation, is increased at steady state in 61% of untreated SCD patients. We show that greater complement activation in vitro is promoted by SCD erythrocytes compared to normal ones, although no significant differences were observed in the regulatory proteins CD35, CD55, and CD59 in whole blood. Complement activation is positively correlated with the percentage of dense sickle cells (DRBCs). The expression levels of CD35, CD55, and CD59 are reduced in DRBCs, suggesting inefficient regulation when cell density increases. Moreover, the surface expression of the complement regulator CD46 on granulocytes was inversely correlated with the plasma sC5b-9. We also show increased complement deposition in cultured human endothelial cells incubated with SCD serum, which is diminished by the addition of the heme scavenger hemopexin. Treatment of SCD patients with hydroxyurea produces substantial reductions in complement activation, measured by sC5b-9 concentration and upregulation of CD46, as well as decreased complement activation on RBCs in vitro. In conclusion, complement over activation is a common pathogenic event in SCD that is associated with formation of DRBCs and hemolysis. And, it affects red cells, leukocytes and endothelial cells. This complement over activation is partly alleviated by hydroxyurea therapy.

International audience; Rhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury is lacking and the mechanisms of the injury are unclear. To clarify this, we studied intra-kidney complement activation (C3d and C5b-9 deposits) in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. The lectin complement pathway was found to be activated in the kidney; likely via an abnormal pattern of Fut2-dependent cell fucosylation, recognized by the pattern recognition molecule collectin-11 and this proceeded in a C4-independent, bypass manner. Concomitantly, myoglobin-derived heme activated the alternative pathway. Complement deposition and acute kidney injury were attenuated by pre-treatment with the heme scavenger hemopexin. This indicates that complement was activated in a unique double-trigger mechanism, via the alternative and lectin pathways. The direct pathological role of complement was demonstrated by the preservation of kidney function in C3 knockout mice after the induction of rhabdomyolysis. The transcriptomic signature for rhabdomyolysis-induced acute kidney injury included a strong inflammatory and apoptotic component, which were C3/complement-dependent, as they were normalized in C3 knockout mice. The intra-kidney macrophage population expressed a complement-sensitive phenotype, overexpressing CD11b and C5aR1. Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. Hence, heme scavenging and complement inhibition represent promising therapeutic strategies.

International audience; Vascular diseases are multifactorial, often requiring multiple challenges, or 'hits', for their initiation. Intra-vascular hemolysis illustrates well the multiple-hit theory where a first event lyses red blood cells, releasing hemolysis-derived products, in particular cell-free heme which is highly toxic for the endothelium. Physiologically, hemolysis derived-products are rapidly neutralized by numerous defense systems, including haptoglobin and hemopexin which scavenge hemoglobin and heme, respectively. Likewise, cellular defense mechanisms are involved, including heme-oxygenase 1 upregulation which metabolizes heme. However, in cases of intra-vascular hemolysis, those systems are overwhelmed. Heme exerts toxic effects by acting as a damage-associated molecular pattern and promoting, together with hemoglobin, nitric oxide scavenging and ROS production. In addition, it activates the complement and the coagulation systems. Together, these processes lead to endothelial cell injury which triggers pro-thrombotic and pro-inflammatory phenotypes. Moreover, among endothelial cells, glomerular ones display a particular susceptibility explained by a weaker capacity to counteract hemolysis injury. In this review, we illustrate the 'multiple-hit' theory through the example of intra-vascular hemolysis, with a particular focus on cell-free heme, and we advance hypotheses explaining the glomerular susceptibility observed in hemolytic diseases. Finally, we describe therapeutic options for reducing endothelial injury in hemolytic diseases.

Intravascular hemolysis is a hallmark of a large spectrum of diseases, including the sickle cell disease (SCD), and is characterized by liberation of red blood cell (RBC) degradation products in the circulation. Released Hb, heme, RBC fragments and microvesicles (MVs) exert pro-inflammatory, pro-oxidative and cytotoxic effects and contribute to vascular and tissue damage. The innate immune complement system not only contributes to the RBC lysis, but it is also itself activated by heme, RBC MVs and the hypoxia-altered endothelium, amplifying thus the cell and tissue damage. This review focuses on the implication of the complement system in hemolysis and hemolysis-mediated injuries in SCD and in cases of delayed hemolytic transfusion reactions (DHTR). We summarize the evidences for presence of biomarkers of complement activation in patients with SCD and the mechanisms of complement activation in DHTR. We discuss the role of antibodies-dependent activation of the classical complement pathway as well as the heme-dependent activation of the alternative pathway. Finally, we describe the available evidences for the efficacy of therapeutic blockade of complement in cases of DHTR. In conclusion, complement blockade is holding promises but future prospective studies are required to introduce Eculizumab or another upcoming complement therapeutic for DHTR and even in SCD.

International audience; Therapeutic intravenous immunoglobulin preparations (IVIg) are used for treatment of wide range of auto-immune and inflammatory diseases. Versatile mechanisms have been reported to contribute to the im-munomodulatory effects of IVIg. Here we demonstrate that IVIg has a strong potential to inhibit pro-in-flammatory effect of extracellular heme. Indeed, the presence of immunoglobulins reduced the potential of heme to activate the complement system on the surface of human endothelial cells. Since extracellular heme is considered as one of the principal pathogenic factors in hemolytic disorders, its therapeutic scavenging by IVIg may have significant clinical repercussions.

Rationale: Crystal sorting histiocytosis (CSH) is a rare disorder that is morphologically characterized by the accumulation of monoclonal immunoglobulin crystals, predominantly of a kappa light chain type, within lysosomes of macrophages. CSH may result in a variety of clinical manifestations depending on the involved organs. In this case report, we aim to describe a patient with ophthalmic manifestations which lead to the diagnosis of multiple myeloma with crystal-storing histiocytosis, crystalline podocytopathy, and light chain proximal tubulopathy. Patient concerns: A 60-year-old male patient presented with progressive bilateral decreased vision for 2 years. Diagnosis: Ophthalmic explorations showed bilateral macular and papillary edema, and multiple crystalline deposits in the anterior stromal cornea and in the retina. Laboratory tests showed nephrotic syndrome and renal dysfunction. Further work-up revealed IgG kappa multiple myeloma, with biopsy-proven combined crystalline podocytopathy and tubulopathy. Interventions: The patient received chemotherapy (bortezomib, cyclophosphamide, and dexamethasone for 3 cycles, then bortezomib, lenalidomide, and dexamethasone). Outcomes: Despite partial hematologic response and improvement of the papilledema and macular edema, the patient developed dialysis-dependent end-stage renal failure. Lessons: This report, highlighting the protean presentation of paraprotein-mediated injuries, provides additional information on the ocular anomalies not previously described that may be associated with crystal-storing histiocytosis.

Introduction Le risque d’insuffisance renale terminale au cours des vascularites a ANCA est evalue par le score de Brix, selon les pourcentages de glomerules normaux, de fibrose interstitielle et la fonction renale au diagnostic. L’arterite des petites arteres renales, n’est pas prise en compte. L’objectif de cette etude est de decrire les caracteristiques clinico-histologiques et l’impact pronostique de l’arterite des petites arteres renales, au diagnostic d’une vascularite a ANCA. Description Entre 2000 et 2019, nous avons analyse les biopsies renales adressees par 5 centres, au diagnostic d’une vascularite a ANCA. L’atteinte des petites arteres renales etait definie par la presence d’une necrose fibrinoide de la paroi arterielle et/ou une inflammation de la media. Methodes La survie renale etait analysee selon la methode de Kaplan–Meier. Les variables predictives de la survie renale par modele de Cox et la discrimination pronostique par les index de concordance. Resultats Deux cent cinquante et un patients ont ete inclus dont 13,5 % avec une atteinte vasculaire (ANCA_V+) ( Fig. 1 A–B) et 86,5 % sans atteinte vasculaire (ANCA_V−). Au diagnostic, les ANCA_V+ etaient plus âges (72 ans vs 63 ans, p = 0,005) et presentaient un taux de CRP plus eleve (176 mg/L vs 64 mg/L, p Fig. 1 C). En analyse multivariee, le risque d’insuffisance renale terminale etait significativement augmente en cas d’atteinte vasculaire (HR = 3,10, IC95 % = 1,65–5,81, p = 0,001). L’ajout du statut vasculaire (V+/V−) ameliorait la discrimination pronostique du score de Brix, chez les patients a risque faible ou modere selon le score de Brix ( Fig. 1 D–F). Conclusion Les vascularites a ANCA avec arterite des petites arteres renales au diagnostic, sont une forme particuliere de vascularite a ANCA, au pronostic renal pejoratif.

Introduction L’insuffisance renale aigue (IRA) est la principale complication de la rhabdomyolyse. La myoglobine joue un role important dans sa physiopathologie par vasoconstriction intra-renale (favorisant l’ischemie-reperfusion), obstruction intra-tubulaire, et liberation d’heme. L’heme libre est capable d’activer le systeme du complement en cas d’hemolyse intravasculaire, mais l’existence d’un tel mecanisme au cours de la rhabdomyolyse reste par contre inconnu. L’objectif de cette etude est d’analyser le role et les mecanismes d’activation du complement dans l’IRA de la rhabdomyolyse. Methodes Nous avons utilise un modele murin de rhabdomyolyse par injection intramusculaire de glycerol induisant une destruction musculaire associee a une insuffisance renale aigue. Les depots de C3 clive (C3b/iC3b) etaient evalues en immunofluorescence. Des souris C3−/−, C1q−/−, C4−/− et TLR4−/− ont ete utilisees pour dissequer les mecanismes d’activation du complement. L’analyse de l’expression des genes a ete realisee par RNAseq et validee par RTqPCR. L’infiltration des macrophages a ete etudiee par cytometrie en flux. Dix biopsies humaines sont en cours d’analyse. Resultats obtenus ou attendus Les souris WT, apres injection de glycerol, presentaient des depots profus de C3 tubulaire, diminues chez les souris TLR4−/− au contraire des souris C1q−/−, en faveur d’une activation du complement mediee par l’heme (A). Comme attendue, la rhabdomyolyse etait associee chez les souris WT a une sur-expression des genes d’agression tubulaire (NGAL). De maniere plus etonnante, on retrouvait des signes d’activation endotheliale (sur-expression de P-selectin, E-selectin, ICAM1, sous-expression de VEGFR2) ainsi qu’une sur-expression renale des transcrits de C3 et C5aR1. Remarquablement, les souris C3−/− etaient protegees de l’atteinte tubulaire et de l’agression vasculaire tout comme les souris TLR4−/−, et leurs fonctions renales restaient normales (B–D). Conclusion Ces resultats suggerent un lien entre la voie heme/TLR4, l’activation du complement et l’IRA de la rhabdomyolyse. A l’avenir, des strategies bloquant l’activation du complement pourraient etre envisagees a la phase aigue de la rhabdomyolyse.

Introduction La drepanocytose, l’hemoglobinopathie congenitale la plus frequente dans le monde est une cause croissante de maladie renale chronique et est a l’origine d’une morbimortalite considerable. Les femmes drepanocytaires sont a haut risque de complications au cours de la grossesse, notamment de pre-eclampsie (PE), cependant, le pronostic renal a long terme n’a jamais ete evalue chez ces patientes. Patients/materiels et methodes Etude cas-temoin dans 2 centres Parisiens entre 2011 et 2016 incluant les femmes presentant un syndrome drepanocytaire majeur et un episode de PE appariees a un groupe de patientes drepanocytaires (groupe T) n’ayant pas presente de PE au cours de la grossesse et appariees sur le genotype et la date du debut de grossesse. Resultats Nous avons identifie 30 patientes drepanocytaires avec un episode de PE et 30 T (60 seront recueillies au total). Le suivi moyen etait de 4 ans dans le groupe PE versus 3,4 ans dans le groupe T. La PE survenait, en moyenne, a 33 SA avec, comme criteres de severite : 3 HELLP syndrome, 1 eclampsie et 13 insuffisances renales aigues stade 1 selon les criteres KDIGO. La moyenne d’âge etait de 30 ans dans le groupe PE versus 29 ans chez les T (p = 0,6). Il n’y avait pas de difference significative entre les patientes PE et les T concernant l’hemoglobine de base : 8,7 g/dL versus 8,5 g/dL et les LDH : 522 ui/L versus 402 ui/L respectivement. Le DFG de base etait de 139 mL/min/1,73 m2 dans le groupe PE versus 149 mL/min/1,73 m2 dans le groupe T (p = 0,2). On notait 78 % de cesariennes dans le groupe PE contre 56 % dans le groupe T (p = 0,1). Le poids de naissance des nouveaux nes etait de 2037 g versus 2268 g a un terme de 34 SA versus 36 SA dans les groupes PE et T respectivement (p = 0,2). Au sein du groupe PE, la creatinine etait significativement plus elevee au moment de la PE par rapport au controle 3 mois plus tard (60 μmol/L versus 43 μmol/L respectivement, p = 0,02). A la fin du suivi, le DFG moyen etait de 127,1 mL/min/1,73 m2 dans le groupe PE versus 146,6 mL/min/1,73 m2 dans le groupe T (p = 0,04). Discussion L’association drepanocytose et PE pourrait s’expliquer par l’ischemie-reperfusion iterative favorisee par la falciformation des globules rouges entrainant un relargage de facteurs pro-angiogeniques dans la circulation. Conclusion Les donnees preliminaires de ce travail suggerent que la pre-eclampsie pourrait entrainer une degradation acceleree de la fonction renale chez les patientes drepanocytaires.

Introduction L’urgence hypertensive (UH) est definie par une poussee hypertensive severe associee a une atteinte d’organe. L’UH peut se compliquer de Syndrome Hemolytique et Uremique (UH-SHU) est caracterise par une anemie hemolytique mecanique, une thrombopenie et une insuffisance renale aigue. Des anomalies du complement (C), genetiques ou acquises, sont retrouvees dans plus de 50 % des cas des SHU atypiques (SHUa). L’objectif de cette etude est de definir le phenotype clinicobiologique des patients atteints d’UH avec SHU, et de rechercher une susceptibilite genetique. Patients/Materiels et methodes Analyse clinicobiologique retrospective de la cohorte francaise de SHU, apres classification des patients avec ou sans UH (criteres European Society of Cardiology), et etude genetique des facteurs de regulation du complement. Observation/Resultats Parmi 137 patients identifies, 76 presentaient un UH-SHU (55 %). Dans le groupe UH-SHU en majorite des hommes (58 % versus 28 %, p Discussion/Conclusion Le pronostic renal des patients UH-SHU est severe, similaire a celui des SHUa sans UH. Cette etude demontre la frequence elevee de variants rares du complement chez les patients presentant une UH-SHU. La presence d’une UH et de variants du complement permet de stratifier le pronostic a long terme. Les patients avec UH ont une moins bonne reponse therapeutique a l’Eculizumab et ont un pronostic pejoratif. Projet soutenu par une allocation recherche de la SFNDT – 2017.

Introduction La maladie de Fabry est une maladie hereditaire du metabolisme due a un deficit en alphagalactosidase A, enzyme lysosomale qui, lorsqu’elle fonctionne normalement clive les sphingolipides permettant leur degradation et leur elimination. En cas d’anomalie quantitative ou qualitative de cette enzyme, la globotriaosylceramide (Gb3) se depose a l’interieur des cellules. Les principales atteintes sont cardiaque, renale et neurologique mais l’atteinte digestive est probablement sous-estimee [1] . Patients/Materiels et methodes/Observation Nous rapportons le cas d’un patient de 45 ans atteint d’une maladie de FABRY diagnostiquee en mars 2014 avec atteinte renale, cardiaque et neurologique peripherique. La biopsie renale mettait en evidence des depots glomerulaires de sphingolipides. Le diagnostic etait confirme par une diminution de l’alpha galactosidase et une elevation de la Gb3 urinaire. L’analyse genetique retrouvait une mutation AGAL : c.1277_1278del/chrY. Malgre une enzymotherapie substitutive–agalsidase beta, Fabrazyme®–, l’evolution renale est defavorable et le patient est transplante pour la premiere fois le 20/06/2017 avec le rein de son epouse. L’evolution est favorable avec une reprise de fonction immediate et un nadir de creatinine a 100 μmol/L. Un an plus tard, il est adresse pour une douleur epigastrique evoluant depuis 48 h partiellement soulagee par la morphine. La biologie (creatinine, cycle de troponine, lipase, LDH, Lactates, CRP) est normale. Le traitement par IPP est inefficace. Enfin, la TDM abdominopelvienne injectee elimine l’ischemie mesenterique mais retrouve une colectasie transverse importante. Une colo-exsufflation est alors pratiquee et soulage le patient. Le diagnostic de colectasie transverse en lien avec la maladie de Fabry est retenu. Resultats/Discussion Le pronostic des patients transplantes renaux dans le cadre d’une maladie de Fabry est bon mais ne prevaut pas de l’apparition d’autres atteintes. La frequence des atteintes digestives varie de 19 a 69 % [1] , parfois au premier plan, parfois plus difficiles a diagnostiquer comme dans le cas present. La physiopathologie est liee a une dysfonction du systeme nerveux autonome a l’origine de troubles de la motilite intestinale. On retrouve ainsi des glycosphingolipides au sein des cellules nerveuses du plexus mesenterique. L’apparition sous enzymotherapie conduit par ailleurs a rechercher des anticorps anti-Fabrazyme®. Conclusion Meme apres transplantation renale et sous enzymotherapie substitutive, de nouvelles atteintes de la maladie de Fabry peuvent survenir, notamment au niveau digestif.

Introduction Les glomerulopathies a depots de C3 (GC3) regroupent un ensemble heterogene de glomerulopathies chroniques qui ont recemment ete individualisees au sein des glomerulonephrites membrano-proliferatives (GNMP) [1] , [2] . Certaines formes de GC3 sont associees a des mutations des genes regulant l’activation de la voie alterne du complement [3] . Observation Nous rapportons le cas d’une patiente transplantee renale en 2005 a l’âge de 42 ans apres evolution defavorable d’une glomerulopathie d’etiologie indeterminee associee a des stigmates biologiques de microangiopathie thrombotique. Le bilan etiologique initial avait mis en evidence une consommation de la voie alterne (baisse du C3 et du facteur B avec un C4 normal) associe a un deficit quantitatif du facteur I sans anticorps anti-C3 convertase de la voie alterne. Le mecanisme en cause etait une mutation homozygote jamais rapportee au niveau de l’exon 10. Dans les suites de la transplantation renale qui se deroule sans incident notable (creatinemie 97 μmol/L en 2009), la patiente beneficie en 2009 d’une premiere ponction biopsie du greffon pour l’apparition d’une proteinurie a 1,3 g/j dans un contexte d’apparition de DSA. Cet examen met en evidence une GNMP avec proliferation endocapillaire associee a un marquage exclusif de C3 au niveau sous-endothelial, mesangial et parietal. Devant la parfaite stabilite de la fonction renale et la diminution de la proteinurie sous IEC, une simple surveillance est preconisee. Le bilan immunologique en 2009 retrouve des anomalies identiques a celles decrites lors de la prise en charge initiale. Deux nouvelles biopsies du greffon en 2014 et 2015 montrent une parfaite stabilite des lesions histologiques alors que la proteinurie reste inferieure a 0,3 g/j et la fonction renale stable (96 μmol/L en 2016) Discussion Des mutations heterozygotes du facteur I peuvent etre associees a des GC3 mais une mutation homozygote du facteur I qui est habituellement associee a des infections recidivantes constitue une observation exceptionnelle et une cause inhabituelle de GC3. Conclusion Apres plus de 10 ans de greffe renale sans traitement specifique (anti-C5, echanges plasmatiques), la recidive de GC3 sur le greffon en rapport avec une mutation homozygote du facteur I peut etre purement histologique sans traduction clinique.