Introduction La vascularite urticarienne hypocomplementemique (VUH) est une entite rare, associan... more Introduction La vascularite urticarienne hypocomplementemique (VUH) est une entite rare, associant une urticaire recidivante, une hypocomplementemie, une vascularite leucocytoclasique et une atteinte systemique. Nous rapportons les caracteristiques cliniques et therapeutiques de patients presentant une VUH. Materiel et methode Cette etude nationale, francaise, multicentrique et transdisciplinaire a inclus 57 patients ayant une VUH diagnostiquee entre 1992 et 2013. Les criteres d’inclusions etaient la presence de lesions urticariennes recidivantes, une vascularite leucocytoclasique sur la biopsie cutanee et une hypocomplementemie definie par une baisse du C3 et/ou du C4. Resultats La VUH etait isolee (75 %) ou associee a une maladie systemique (25 %), principalement le lupus erythemateux systemique. Les lesions cutanees etaient typiquement des papules erythemateuses fixes, avec une evolution de plus de 24 h, plus souvent prurigineuses (53 %) que douloureuses, associees a un angio-œdeme (51 %), du purpura (35 %) ou un livedo (14 %). Les manifestations extracutanees incluaient une atteinte articulaire (arthralgies/arthrites, 82 %), oculaire (uveite, sclerite/episclerite, conjonctivite, 59 %), respiratoire (toux, dyspnee ou trouble ventilatoire obstructif, 22 %), digestive (16 %) et renale (14 %). Les patients avaient classiquement un C1q abaisse et un C1 inhibiteur normal, alors que les anticorps anti-C1q etaient positifs chez 55 % des patients testes. Sur le plan therapeutique, l’hydroxychloroquine (HCQ) et la colchicine avaient en premiere ligne une efficacite comparable aux corticoides. En cas d’atteinte severe ou refractaire, l’efficacite de la corticotherapie seule ou associee a des immunosuppresseurs comme l’azathioprine (AZA) ou le mycophenolate mofetil (MMF) etait comparable. Le rituximab (RTX) prescrit chez 8 patients semblait avoir une superiorite sur les reponses cutanees et immunologiques. Discussion Les VUH representent un spectre de vascularites systemiques rares et volontiers refractaires aux traitements, ayant des manifestations cliniques variees, principalement articulaires et oculaires. La baisse du C1q represente un marqueur plus specifique que la presence des anticorps antiC1q. L’HCQ et la colchicine constitueraient la premiere ligne therapeutique, alors que les corticoides, seuls ou associes a un immunosuppresseur, AZA, MMF et/ou RTX, representeraient une alternative therapeutique en cas d’atteinte severe et/ou refractaire. Conclusion Cette etude est la plus large serie decrivant les caracteristiques des patients atteints de VUH illustrant le spectre des manifestations cliniques et immunologiques ainsi que la complexite de la prise en charge therapeutique.
Complement is a major innate immune defense against pathogens, tightly regulated to prevent host ... more Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. Atypical hemolytic uremic syndrome (aHUS) is characterized by endothelial damage leading to renal failure and is highly associated with abnormal alternative pathway regulation. We characterized the functional consequences of 2 aHUS-associated mutations (D254G and K325N) in factor B, a key participant in the alternative C3 convertase. Mutant proteins formed high-affinity C3-binding site, leading to a hyperfunctional C3 convertase, resistant to decay by factor H. This led to enhanced complement deposition on the surface of alternative pathway activator cells. In contrast to native factor B, the 2 mutants bound to inactivated C3 and induced formation of functional C3-convertase on iC3b-coated surface. We demonstrated for the first time that factor B mutations lead to enhanced C3-fragment deposition on quiescent and adherent human glomerular cells (GEnCs) and human umbilical v...
Primary hyperoxaluria type 3 (PH3) is characterized by mutations in the 4-hydroxy-2-oxoglutarate ... more Primary hyperoxaluria type 3 (PH3) is characterized by mutations in the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene. PH3 patients are believed to present with a less severe phenotype than those with PH1 and PH2, but the clinical characteristics of PH3 patients have yet to be defined in sufficient detail. The aim of this study was to report our experience with PH3. Genetic analysis of HOGA1 was performed in patients with a high clinical suspicion of PH after the presence of mutations in the alanine-glyoxylate aminotransferase gene had been ruled out. Clinical, biochemical and genetic data of the seven patients identified with HOGA1 mutations were subsequently retrospectively reviewed. Among the seven patients identified with HOGA1 mutations the median onset of clinical symptoms was 1.8 (range 0.4-9.8) years. Five patients initially presented with urolithiasis, and two other patients presented with urinary tract infection. All patients experienced persistent hyperoxaluria. Seven mutations were found in HOGA1, including two previously unreported ones, c.834 + 1G > T and c.3G > A. At last follow-up, two patients had impaired renal function based on estimated glomerular filtration rates (GFRs) of 77 and 83 mL/min per 1.73 m(2), respectively. We found that the GFR was significantly impaired in two of our seven patients with PH3 diagnosed during childhood. This finding is in contrast to the early-impaired renal function in PH1 and PH2 and appears to refute to preliminary reassuring data on renal function in PH3.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2015
Several studies have investigated geographical variations in access to renal transplant waiting l... more Several studies have investigated geographical variations in access to renal transplant waiting lists, but none has assessed the impact on these variations of factors at both the patient and geographic levels. The objective of our study was to identify medical and non-medical factors at both these levels associated with these geographical variations in waiting-list placement in France. We included all incident patients aged 18-80 years in 11 French regions who started dialysis between January 1, 2006, and December 31, 2008. Both a multilevel Cox model with shared frailty and a competing risks model were used for the analyses. At the patient level, old age, comorbidities, diabetic nephropathy, non-autonomous first dialysis, and female gender were the major determinants of a lower probability of being waitlisted. At the regional level, the only factor associated with this probability was an increase in the number of patients on the waiting list from 2005 to 2009. This finding supports...
This chapter provides indicators to describe the specificity of End Stage Renal Disease in childr... more This chapter provides indicators to describe the specificity of End Stage Renal Disease in children in France and to study these patients'outcome and the choices of treatment modalities. In 2011, the incidence and the prevalence of ESRD among patients under 20 years old remained stable at 8 and 53 pmp respectively. The first causes of ESDR remain uropathies and hypodysplasia followed by glomerulonephritis and genetic diseases. Considering the initial treatment, we found a high rate of hemodialysis and a low rate of peritoneal dialysis that is mainly used in younger children. In 2011, 31 preemptive transplantations were performed accounting for 27.7% of new patients. Finally, survival analysis confirm that younger children (under 4 years old) have the highest risk of death (88% survival rate at 2 years vs. 98% in patients over 4 years old) and that the treatment of choice remains the renal transplantation since it increases the expected remaining lifetime of 20 to 40 years depending on the considered age.
Studies in the USA and Europe have demonstrated inequalities in adult access to renal transplants... more Studies in the USA and Europe have demonstrated inequalities in adult access to renal transplants. We previously demonstrate that the centre of treatment was impacting the time to be registered on the renal waiting list. In this study, we sought to ascertain the influence of patient and centre characteristics on the probability of transplantation within 1 year after registration on the waiting list for children. We included patients <18 years awaiting transplantation from the French ESRD National Registry. The effects of patient and centre characteristics were studied by hierarchical logistic regression. Centre effects were assessed by centre-level residual variance. A descriptive survey was performed to investigate differences in the centres' practices, and linear regression was used to confirm findings of different HLA compatibility requirements between centres. The study included 556 patients treated at 54 centres; 450 (80.9%) received transplants in the year after their listing. HLA group scarcity, time of inactive status during the year, pre-emptive listing and listing after age 18 were associated with lower probabilities of transplantation. Patient characteristics explained most of the variability among centres, but patients treated in paediatric centres had a lower probability of transplantation within 1 year because of higher HLA compatibility requirements for transplants. Although patient characteristics explained most of the inter-centre variability, harmonization of some practices might enable us to reduce some inequalities in access to renal transplantation while maintaining optimal transplant survival and chances to get a second transplant when needed.
A child, who presented atypical haemolytic uraemic syndrome (aHUS) at the age of 1 month, develop... more A child, who presented atypical haemolytic uraemic syndrome (aHUS) at the age of 1 month, developed cerebral ischaemic events at the age of 10 years. Stenoses of both carotid arteries, left subclavian and vertebral arteries, several intracranial, right humeral, several coronary, and all pulmonary arteries were demonstrated. At the age of 13 years, left subclavian and right cervical carotid arteries were occluded. Right carotid recanalization induced intracranial dissection and death. The child had a Lys350Asp factor B mutation. Arterial steno-occlusive lesions appear as potential complications of dysregulated complement activation in aHUS. Endovascular treatment should be considered cautiously in this setting.
Introduction La vascularite urticarienne hypocomplementemique (VUH) est une entite rare, associan... more Introduction La vascularite urticarienne hypocomplementemique (VUH) est une entite rare, associant une urticaire recidivante, une hypocomplementemie, une vascularite leucocytoclasique et une atteinte systemique. Nous rapportons les caracteristiques cliniques et therapeutiques de patients presentant une VUH. Materiel et methode Cette etude nationale, francaise, multicentrique et transdisciplinaire a inclus 57 patients ayant une VUH diagnostiquee entre 1992 et 2013. Les criteres d’inclusions etaient la presence de lesions urticariennes recidivantes, une vascularite leucocytoclasique sur la biopsie cutanee et une hypocomplementemie definie par une baisse du C3 et/ou du C4. Resultats La VUH etait isolee (75 %) ou associee a une maladie systemique (25 %), principalement le lupus erythemateux systemique. Les lesions cutanees etaient typiquement des papules erythemateuses fixes, avec une evolution de plus de 24 h, plus souvent prurigineuses (53 %) que douloureuses, associees a un angio-œdeme (51 %), du purpura (35 %) ou un livedo (14 %). Les manifestations extracutanees incluaient une atteinte articulaire (arthralgies/arthrites, 82 %), oculaire (uveite, sclerite/episclerite, conjonctivite, 59 %), respiratoire (toux, dyspnee ou trouble ventilatoire obstructif, 22 %), digestive (16 %) et renale (14 %). Les patients avaient classiquement un C1q abaisse et un C1 inhibiteur normal, alors que les anticorps anti-C1q etaient positifs chez 55 % des patients testes. Sur le plan therapeutique, l’hydroxychloroquine (HCQ) et la colchicine avaient en premiere ligne une efficacite comparable aux corticoides. En cas d’atteinte severe ou refractaire, l’efficacite de la corticotherapie seule ou associee a des immunosuppresseurs comme l’azathioprine (AZA) ou le mycophenolate mofetil (MMF) etait comparable. Le rituximab (RTX) prescrit chez 8 patients semblait avoir une superiorite sur les reponses cutanees et immunologiques. Discussion Les VUH representent un spectre de vascularites systemiques rares et volontiers refractaires aux traitements, ayant des manifestations cliniques variees, principalement articulaires et oculaires. La baisse du C1q represente un marqueur plus specifique que la presence des anticorps antiC1q. L’HCQ et la colchicine constitueraient la premiere ligne therapeutique, alors que les corticoides, seuls ou associes a un immunosuppresseur, AZA, MMF et/ou RTX, representeraient une alternative therapeutique en cas d’atteinte severe et/ou refractaire. Conclusion Cette etude est la plus large serie decrivant les caracteristiques des patients atteints de VUH illustrant le spectre des manifestations cliniques et immunologiques ainsi que la complexite de la prise en charge therapeutique.
Complement is a major innate immune defense against pathogens, tightly regulated to prevent host ... more Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. Atypical hemolytic uremic syndrome (aHUS) is characterized by endothelial damage leading to renal failure and is highly associated with abnormal alternative pathway regulation. We characterized the functional consequences of 2 aHUS-associated mutations (D254G and K325N) in factor B, a key participant in the alternative C3 convertase. Mutant proteins formed high-affinity C3-binding site, leading to a hyperfunctional C3 convertase, resistant to decay by factor H. This led to enhanced complement deposition on the surface of alternative pathway activator cells. In contrast to native factor B, the 2 mutants bound to inactivated C3 and induced formation of functional C3-convertase on iC3b-coated surface. We demonstrated for the first time that factor B mutations lead to enhanced C3-fragment deposition on quiescent and adherent human glomerular cells (GEnCs) and human umbilical v...
Primary hyperoxaluria type 3 (PH3) is characterized by mutations in the 4-hydroxy-2-oxoglutarate ... more Primary hyperoxaluria type 3 (PH3) is characterized by mutations in the 4-hydroxy-2-oxoglutarate aldolase (HOGA1) gene. PH3 patients are believed to present with a less severe phenotype than those with PH1 and PH2, but the clinical characteristics of PH3 patients have yet to be defined in sufficient detail. The aim of this study was to report our experience with PH3. Genetic analysis of HOGA1 was performed in patients with a high clinical suspicion of PH after the presence of mutations in the alanine-glyoxylate aminotransferase gene had been ruled out. Clinical, biochemical and genetic data of the seven patients identified with HOGA1 mutations were subsequently retrospectively reviewed. Among the seven patients identified with HOGA1 mutations the median onset of clinical symptoms was 1.8 (range 0.4-9.8) years. Five patients initially presented with urolithiasis, and two other patients presented with urinary tract infection. All patients experienced persistent hyperoxaluria. Seven mutations were found in HOGA1, including two previously unreported ones, c.834 + 1G > T and c.3G > A. At last follow-up, two patients had impaired renal function based on estimated glomerular filtration rates (GFRs) of 77 and 83 mL/min per 1.73 m(2), respectively. We found that the GFR was significantly impaired in two of our seven patients with PH3 diagnosed during childhood. This finding is in contrast to the early-impaired renal function in PH1 and PH2 and appears to refute to preliminary reassuring data on renal function in PH3.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2015
Several studies have investigated geographical variations in access to renal transplant waiting l... more Several studies have investigated geographical variations in access to renal transplant waiting lists, but none has assessed the impact on these variations of factors at both the patient and geographic levels. The objective of our study was to identify medical and non-medical factors at both these levels associated with these geographical variations in waiting-list placement in France. We included all incident patients aged 18-80 years in 11 French regions who started dialysis between January 1, 2006, and December 31, 2008. Both a multilevel Cox model with shared frailty and a competing risks model were used for the analyses. At the patient level, old age, comorbidities, diabetic nephropathy, non-autonomous first dialysis, and female gender were the major determinants of a lower probability of being waitlisted. At the regional level, the only factor associated with this probability was an increase in the number of patients on the waiting list from 2005 to 2009. This finding supports...
This chapter provides indicators to describe the specificity of End Stage Renal Disease in childr... more This chapter provides indicators to describe the specificity of End Stage Renal Disease in children in France and to study these patients'outcome and the choices of treatment modalities. In 2011, the incidence and the prevalence of ESRD among patients under 20 years old remained stable at 8 and 53 pmp respectively. The first causes of ESDR remain uropathies and hypodysplasia followed by glomerulonephritis and genetic diseases. Considering the initial treatment, we found a high rate of hemodialysis and a low rate of peritoneal dialysis that is mainly used in younger children. In 2011, 31 preemptive transplantations were performed accounting for 27.7% of new patients. Finally, survival analysis confirm that younger children (under 4 years old) have the highest risk of death (88% survival rate at 2 years vs. 98% in patients over 4 years old) and that the treatment of choice remains the renal transplantation since it increases the expected remaining lifetime of 20 to 40 years depending on the considered age.
Studies in the USA and Europe have demonstrated inequalities in adult access to renal transplants... more Studies in the USA and Europe have demonstrated inequalities in adult access to renal transplants. We previously demonstrate that the centre of treatment was impacting the time to be registered on the renal waiting list. In this study, we sought to ascertain the influence of patient and centre characteristics on the probability of transplantation within 1 year after registration on the waiting list for children. We included patients <18 years awaiting transplantation from the French ESRD National Registry. The effects of patient and centre characteristics were studied by hierarchical logistic regression. Centre effects were assessed by centre-level residual variance. A descriptive survey was performed to investigate differences in the centres' practices, and linear regression was used to confirm findings of different HLA compatibility requirements between centres. The study included 556 patients treated at 54 centres; 450 (80.9%) received transplants in the year after their listing. HLA group scarcity, time of inactive status during the year, pre-emptive listing and listing after age 18 were associated with lower probabilities of transplantation. Patient characteristics explained most of the variability among centres, but patients treated in paediatric centres had a lower probability of transplantation within 1 year because of higher HLA compatibility requirements for transplants. Although patient characteristics explained most of the inter-centre variability, harmonization of some practices might enable us to reduce some inequalities in access to renal transplantation while maintaining optimal transplant survival and chances to get a second transplant when needed.
A child, who presented atypical haemolytic uraemic syndrome (aHUS) at the age of 1 month, develop... more A child, who presented atypical haemolytic uraemic syndrome (aHUS) at the age of 1 month, developed cerebral ischaemic events at the age of 10 years. Stenoses of both carotid arteries, left subclavian and vertebral arteries, several intracranial, right humeral, several coronary, and all pulmonary arteries were demonstrated. At the age of 13 years, left subclavian and right cervical carotid arteries were occluded. Right carotid recanalization induced intracranial dissection and death. The child had a Lys350Asp factor B mutation. Arterial steno-occlusive lesions appear as potential complications of dysregulated complement activation in aHUS. Endovascular treatment should be considered cautiously in this setting.
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