Effectiveness of Cyclosporine in a 10-year-old Girl with C3 Glomerulopathy

C3 glomerulopathy (C3G) is a recently defined pathological entity characterized by C3 accumulation with absent or scant immunoglobulin deposition, leading to variable glomerular inflammation. The clinical presentation of patients with C3G is highly variable, as they may present with symptoms ranging from microscopic or mild proteinuria to full-blown nephrotic syndrome, with or without renal impairment. However, there is no consensus recommendation for specific treatment in children with C3G. Recently, new therapies have been suggested to target complement pathways, owing to an improvement in the understanding of the pathogenesis of C3G. C3G complement blockade with eculizumab, a monoclonal antibody targeted against complement C5, inhibits activation of the alternative complement pathway. We could not use eculizumab owing to its high price; thus, we administered oral prednisolone and mycophenolate mofetil (MMF). MMF was replaced with cyclosporine because proteinuria persisted, with a consistently low serum C3 level; we tapered off the prednisolone because of a Cushingoid appearance and amenorrhea. Thereafter, proteinuria improved, and the serum C3 level returned to normal. Thus, we report the effectiveness of cyclosporine in a patient with C3G and an inadequate response to prednisolone and MMF, who was detected via school urinary screening.

Polymorphism of the complement 5 gene is associated with large artery atherosclerosis stroke in Chinese patients / O polimorfismo do gene C5 do complemento está associado a acidentes vasculares cerebrais de grandes artérias com aterosclerose em pacientes chineses

ABSTRACT The complement system has been confirmed to play an increasingly important role in ischemic stroke (IS). This study aimed to determine whether the single-nucleotide polymorphism of the complement 5 (C5) gene independently influences the occurrence, severity, and long-term outcome of IS in Chinese patients. Methods C5 rs17611 genetic variants were investigated in 494 IS patients and 330 control individuals .Ischemic stroke was classified into subtypes and patients were assessed 90 days post-stroke with the modified Rankin Scale to determine stroke outcome. Results The presence of C5 polymorphism was associated with the incidence of large artery atherosclerosis (LAA)-subtype IS (n =2 00; p = 0.031), which even persisted after adjustment for covariates (OR = 1.518; 95%CI = 1.093–2.018; p = 0.013). However, no association was found between genotypes and the severity and outcome of stroke (p = 0.978; p = 0.296). Conclusions The C5 polymorphism might contribute to the risk of LAA-subtype IS independently of other known risk predictors.

RESUMO Já se confirmou que o sistema do complemento exerce um papel cada vez mais importante nos acidentes vasculares cerebrais isquêmicos. Este estudo teve o objetivo de determinar se o polimorfismo de nucleotídeo único (SNP) do gene codificador do componente 5 (C5) influencia de forma independente a ocorrência, a severidade e o desfecho em longo prazo do acidente vascular cerebral isquêmico (AVCI) em pacientes chineses. Métodos Variantes genéticas rs17611 do C5 foram investigadas em 494 pacientes com AVCI e em 330 indivíduos controles. O AVCI foi classificado em subtipos e os pacientes foram avaliados 90 dias após o acidente vascular, através da Escala Modificada de Rankin (mRS), para determinação do desfecho do acidente. Resultados A presença de polimorfismo do C5 foi associada à incidência de AVCI do subtipo com aterosclerose de grandes artérias (AGA) (n = 200; p = 0,031), que persistiu mesmo após os ajustes de covariáveis (RP = 1,518; 95% IC = 1,093–2,018; p = 0,013). Entretanto, nenhuma associação foi observada entre os genótipos e a severidade ou o desfecho do acidente vascular (p = 0,978; p = 0,296). Conclusões O polimorfismo do C5 pode contribuir para o risco de AVCI do tipo com AGA, independentemente de outros riscos preditores conhecidos.

Clinical Practice Guidelines for the Management of Atypical Hemolytic Uremic Syndrome in Korea

Atypical hemolytic uremic syndrome (aHUS) is a rare syndrome characterized by micro-angiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The major pathogenesis of aHUS involves dysregulation of the complement system. Eculizumab, which blocks complement C5 activation, has recently been proven as an effective agent. Delayed diagnosis and treatment of aHUS can cause death or end-stage renal disease. Therefore, a diagnosis that differentiates aHUS from other forms of thrombotic microangiopathy is very important for appropriate management. These guidelines aim to offer recommendations for the diagnosis and treatment of patients with aHUS in Korea. The guidelines have largely been adopted from the current guidelines due to the lack of evidence concerning the Korean population.

Clinical progress of paroxysmal nocturnal hemoglobinuria / 中国实验血液学杂志

Through the applications of high-sensitivity flow cytometry of FLAER and the treatment of eculizumab, it is necessary to understand of paroxysmal nocturnal hemoglobinuria (PNH) from a new point of view. The results of studies demonstrate that treatment with eculizumab alters the natural history of PNH by virtually eradicating thromboembolic complications, inhibiting of intravascular hemolysis and reducing or eliminating transfusion requirements. Eculizumab treatment may also reduce disease-related mortality. This review focuses on the studies to define the relationship between PNH and bone marrow failure syndromes and to characterize the long-term outcome of patients with PNH treated with eculizumab. New therapeutic strategies aimed at controlling extravascular and intravascular hemolysis are discussed.

Effect of C5-siRNA silencing receptor C5 on myocardial ischemia injury in rats / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the effect of C5-siRNA on pathological changes after myocardial ischemia in rats.</p><p><b>METHODS</b>Thirty healthy Sprague-Dawley rats were randomly divided into sham-operated group, ischemia group and C5-siRNA group. The cardiac ischemia models were established in ischemia group and C5-siRNA group by ligating the proximal end of the left anterior descending (LAD) coronary artery. The rats were infused with 100 microl/kg of C5-siRNA into myocardial tissue in C5-siRNA group and equal amount of normal saline in ischemia group and sham-operated group after ligating the LAD coronary artery for 30 min and then performed of ischemia for 4 hours. The cardiac index and left ventricular mass index were determined, morphological changes of myocardial tissue observed under optical microscope and the expression of C5 was detected by immunohistochemical staining and image analysis system.</p><p><b>RESULTS</b>There were no statistically significant difference between the three groups in the left ventricular mass index and cardiac index in the rats after ischemia for 4 hours. Light microscopy indicated edema and degeneration of the myocardial tissue were milder in C5-siRNA group than in ischemia group, a small amount of red blood cells existed in the myocardial stroma of the former. The expression of C5 was increased more significantly in ischemia group and C5-siRNA group than in sham-operated group (P<0.001), but was decreased in C5-siRNA group more than in ischemia group with no statistically significant difference between the two groups (P=0.132).</p><p><b>CONCLUSION</b>C5-siRNA could attenuate myocardial ischemia injury in rats by reducing inflammatory cell infiltration and expression of C5.</p>

Role of complements C5, C6 in the pathogenecity of psoriasis

Psoriasis lesion/scale contains C5a des Arg and C5b-9 [Takematsu et al., 1992; Terui et al., 2000 and Uyemura et al., 1993]. These activation products may have arisen from C5-C9 produced supposedly by keratinocytes [KC]. In this work we have started with C5 and C6 to prove our hypothesis. Since psoriatic lesions contain several pro-inflammatory cytokines, it is important to find out which pro-inflammatory cytokines can differentially regulate the expected synthesis of C5 and C6 by keratinocytes. Human KC have been cultured in the absence and the presence of varying concentrations of pro-inflammatory cytokines and the synthesis of C components C5 and C6 have been measured by ELISA at the protein level and RT-PCR at the mRNA level. To test whether KC also secrete these C components, the same measurements have been performed to find out if these late components are present in the supernatant of the medium where these KC were cultured. The keratinocytes cell-line A431 was also used and the monocytes cultures were considered as the positive control. The results showed that resting KC synthesize C5 mRNAs in detectable amounts. C5 mRNA which is synthesized by resting KC is not translated into detectable amount of protein. Although resting KC did not produce C6 mRNA in detectable amounts the levels of C6 protein were detectable. However, These C6 protein levels were minimally secreted by resting KC, into the culture medium. TCGF induced the secretion of C5 and C6 while TGF-beta induced only the secretion of C6. Normal KC synthesize their own C5 and C6. The synthesis of them is activated by TCGF. While TGF- 2 activated the synthesis of C6 other factors might be responsible for activating the synthesis of C5. These factors could be secreted from other cell types than KC in human skin

Serum terminal complement complex as a prognostic predictor in children with congestive heart failure

The activation of the complement system in pediatric patients with congestive heart failure [CHF] still remains unclear. The objective of this study was to measure the serum levels of terminal complement complex [C5b-9] to determine its predictive value for the prognosis in children with CHF, and to correlate these levels with clinical and echocardiographic assessment of heart failure. Forty cardiac patients with CHF, with a mean age of 5.2 years, were enrolled in the study. According to Ross classification of CHF, they were classified as: Ross class II [12 patients], class III [13 patients], and class IV [15 patients]. Twenty healthy children served as a control group. Serum C5b-9 was assessed with Enzyme lmmunoassay and serum tumor necrosis factor- alpha [TNF- alpha] was measured using ELISA kits. Echocardiographic assessment of left ventricular systolic and diastolic functions was performed. Clinical outcomes were determined at follow-up period of 6months [death or major adverse cardiac events]. The results showed that serum C5b-9 [and also serum TNF- alpha] were significantly higher in patients with CHF as compared to controls [P<0.001] and increased with the severity of the disease, with the highest levels in Ross class IV children and in patients with adverse clinical outcomes by 6 months [P<0.001]. there were significant positive correlations between Ross class of CHF and serum c5b-9 levels, and significant negative correlations between echocardiographic parameters of ventricular function and C5b-9 levels [P<0.001]. Serum C5b-9 [the terminal complement complex] is significantly elevated in children with CHF, increasing with the severity of the disease, and it is a prognostic predictor of adverse clinical outcome. Complement may be a novel target for therapeutic intervention with specific complement inhibitors in patients with CHF

Study on the specificity of complement C5 for the postmortem diagnosis of myocardial infarction / 法医学杂志

In order to explore the specificity of complement C5 in the postmortem diagnosis of myocardial infarction, changes of C5 staining in normal, infarcted and other non-infarcted myocardia with direct or indirect myocardial injuries (myocarditis, mechanical asphyxia, electrocution, hemorrhagic shock, cardiac contusion and organophosphate poisoning) were studied with immunohistochemistry and image analysis. The results showed that positive C5 staining could be observed in groups of myocardial infarction and myocarditis, but not in groups of mechanical asphyxia, electrocution, hemorrhagic shock, cardiac contusion, and organophosphate poisoning. It is indicated that positive reaction of C5 could only be affected by myocarditis, which means that it was more specific for the diagnosis of myocardial infarction.

Role of platelets and complement in the clearance of epimastigote forms of Trypanosoma cruzy

1. Trypanosoma cruzi epimastigote forms are very rapidly removed from the circulation of normal and C5-deficient mice. Depletion of C3 by cobra venom factor results in a significant delay in parasite clearance. 2. During parasite clearance there is a significant decrease in the number of circulating platelets and parasite clearance is considerably delayed in thrombocytopenic animals. 3. In vitro incubation of epimastigote forms with normal mouse serum leads to the formation of parasite clumps provided that platelets are present. Innactivation of factor B or depletion of C3 prevents this phenomenon. 4. When epimastigotes are incubated with normal mouse serum they absorb one or more factors required for their aggregation with platelets. 5. It is suggested that in mice T. cruzi epimastigote forms are removed from circulation by the alternative pathway of complement activation and that both C3 and platelets are required for parasite clearance

Complement and dengue haemorrhagic fever/shock syndrome.

The complement system is activated in DHF/DSS. The peak of activation and the presence of C3a and C5a anaphylatoxins coincided with the onset of shock and leakage. The levels of C3a correlated well with disease severity. This indicated an important role of the complement system in the pathogenesis of shock. Circulating immune complexes as assayed by two standard techniques were not detected in the majority of patients, and if detected were found in small amount. The role of circulating immune complexes in the activation of complement in DHF/DSS needs to be reinvestigated, and other possible mechanisms leading to complement activation should be sought.

Studies on anti-component 5 antibodies in animals infected with Trypanosoma cruzi

Foi usado um teste imunoenzimático competitivo para investigar a presença de anticorpos anticomponente 5 nos soros de sariguês, cäes, coelhos e ratos infectados com o Trypanosoma cruzi. Neste teste, foi utilizado um anticorpo monoclonal contra o antígeno 5 que é específico do T. cruzi. Também foram testados os soros de 51 pacientes venezuelanos com doença de Chagas. Apesar desses anticorpos näo serem detectados nos soros de cäes, ratos e sariguês infectados com o T. cruzi, alguns soros de coelhos infectados apresentaram resultados positivos porém em níveis próximos aos do limite de positividade do teste. Esses achados surgerem que a resposta imune em animais naturalmente ou experimentalmente infectados com o T. cruzi é diferente daquela que é observada na doença de Chagas humana