scholarly journals Poor allograft outcome in Indian patients with post-transplant C3 glomerulopathy

2019 ◽  
Author(s):  
Ashwani Kumar ◽  
Raja Ramachandran ◽  
Amit Rawat ◽  
Reena Das ◽  
Charan S Rayat ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Graft Loss ◽  
Factor H ◽  
Functional Assay ◽  
Complement Factor ◽  
Complement Pathway ◽  
Post Transplant ◽  
C3 Nephritic Factor ◽  
Dense Deposit ◽  
Allograft Outcome

Abstract Background Complement 3 glomerulopathy (C3G) results from dysfunction of the alternative complement pathway (ACP). No data are available on post-transplant C3G in South Asia. Methods In this study, renal allograft biopsies of C3G patients performed from 2012 to 2017 were analysed for ACP functional assay (APFA), serum complement levels, complement factor H (CFH), complement factor B (CFB) and autoantibodies to CFH and CFB. Limited genetic screening for CFH/CFHR5 genes was carried out. All study patients were also followed up. Results A total of 21 cases of C3G were included, of which 11 had native C3G disease (that is, recurrent C3G). Of these 11 recurrent cases, 7 presented with allograft dysfunction and 4 with proteinuria and renal dysfunction. Early post-transplant recurrence (<1 month) was noted in six patients, whereas recurrence in five patients occurred within 8–17 months of transplant. Biopsies showed mild focal mesangial expansion with or without endocapillary proliferation and thrombotic microangiopathy. Rejection was also noted in six patients. APFA/C3 levels were low in all cases. Serum CFH levels were low [dense deposit disease (DDD), 44%; C3 glomerulonephritis (C3GN), 25%], whereas CFB levels were normal. Autoantibodies to CFH, CFB and C3 nephritic factor were present in 11, 0 and 44% of DDD cases, respectively, and in 17, 17 and 33% of C3GN cases, respectively. Genetic analysis revealed only non-pathogenic CFH gene variants (93%). No novel mutation was found. At follow-up (140 months), stable graft was noted in 28% of cases, progressive renal failure in 19%, graft loss in 34%, and 19% of patients died. Conclusion Post-transplant C3G can present with graft dysfunction and/or proteinuria. Subtle histological findings demand careful interpretation of immunofluorescence results. Autoantibodies to complement pathway regulatory proteins are common, and no novel mutation has been found from limited genetic workup. Clinical outcome is poor.

scholarly journals Complement factor H–related hybrid protein deregulates complement in dense deposit disease

2013 ◽  
Vol 124 (1) ◽  
pp. 145-155 ◽  
Author(s):  
Qian Chen ◽  
Michael Wiesener ◽  
Hannes U. Eberhardt ◽  
Andrea Hartmann ◽  
Barbara Uzonyi ◽  
...  
Keyword(s):  
Factor H ◽  
Dense Deposit Disease ◽  
Complement Factor H ◽  
Complement Factor ◽  
Hybrid Protein ◽  
Dense Deposit

scholarly journals Novel Genetic Variants in Complement-Mediated Thrombotic Microangiopath

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1050-1050 ◽  
Author(s):  
Jennifer Yui ◽  
Roshini S Abraham ◽  
Dong Chen ◽  
Fernando Fervenza ◽  
Ronald S. Go ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Genetic Variants ◽  
In Silico ◽  
Factor H ◽  
Complement Factor ◽  
Complement Pathway ◽  
Microangiopathic Hemolytic Anemia ◽  
Novel Variants ◽  
Alternative Complement ◽  
Unknown Significance

Abstract BACKGROUND: Complement-mediated thrombotic microangiopathies (TMAs) are a subset of TMAs in which the thrombocytopenia, microangiopathic hemolytic anemia, and end organ damage are caused by mutations in genes encoding the alternative complement pathway. Numerous complement genes have been implicated in complement-mediated TMAs including complement factor H (CFH), CD46 (MCP), complement factor I (CFI), complement component 3 (C3), complement factor B (CFB), factor H related 5 (CFHR5), and thrombomodulin (THBD) among others. Genetic analysis typically yields a mutation in 60% of patients whose TMA is presumed to be mediated by complement dysregulation. However, the description of novel disease-associated variants may increase this proportion. METHODS: A retrospective study of patients with TMAs diagnosed between 2000 and 2014 was performed. TMA diagnosis was made based on thrombocytopenia and evidence of microangiopathic hemolytic anemia. Analysis was performed with Alamut¨ software with additional in silico prediction tools (SIFT, MutationTaster, and Polyphen) for classification of gene variants. Variants of unknown significance (VUS) and likely pathogenic variants were further assessed using several mutation databases, including HGMD, ClinVar, and Factor H database RESULTS: Of patients diagnosed with a TMA, genetic analysis was performed in only a 10% of patients. Of the 29 patients with genetic studies performed, mutations were identified in 18 patients (62%). The majority of the mutations had been described previously in the literature, but four novel variants were identified: three missense and one splice-site. The table below summarizes these variants as well as laboratory findings on presentation. These were two variants of CFH, one variant of CFHR5, and one variant of CFI. In silico modeling of these variants revealed two polymorphisms likely to be pathogenic, one polymorphism likely benign given the lack of predicted splicing changes, and one VUS. Table 1. Protein Mutation Classification Age Sex Hemoglobin (g/dL) Platelets (thousands) Creatinine (mg/dL) CFH c.245-10_245-9dup Likely benign 61 F 11.6 51 6.7 CFH c.476G>A, p.Ser159Asn Likely pathogenic 43 F 9.1 101 9.1 CFHR5 c.1412G>A p.Gly471Glu Likely pathogenic 30 F 9.8 129 4.9 CFI c.1190T>A p.Val397Glu Unknown significance 51 M 9.4 125 6.1 DISCUSSION: With therapy available to target the alternative complement pathway, genetic analysis to identify genetic variants capable of causing complement mediated TMAs is an essential part of the evaluation. This genetic data must be interpreted and correlated with functional analysis and clinical phenotype. The reporting of novel variants in clinical databases, with inclusion of relevant clinical findings, is necessary to accurately classify and verify variants as pathologic mutations or benign polymorphisms. The full understanding of this diverse disease requires a more complete understanding of its genetics. While complement pathway-directed therapies are available, their rational use requires thorough interpretation of laboratory data, including genetic analysis. Disclosures Murray: Mayo Clinic: Patents & Royalties: Patent Application Filed.

scholarly journals SaO019EVALUATION OF RECOMBINANT COMPLEMENT FACTOR H IN A MODEL OF DENSE DEPOSIT DISEASE

2015 ◽  
Vol 30 (suppl_3) ◽  
pp. iii32-iii32
Author(s):  
Heather Kerr ◽  
Andrew H Herbert ◽  
Talat Malik ◽  
Anna Richards ◽  
Paul N Barlow ◽  
...  
Keyword(s):  
Factor H ◽  
Dense Deposit Disease ◽  
Complement Factor H ◽  
Complement Factor ◽  
Dense Deposit

scholarly journals COMPLEMENT FACTOR H FUNCTIONAL ASSAY MAY HELP TO MONITOR ATYPICAL HAEMOLYTIC URAEMIC SYNDROME: A PILOT STUDY

2013 ◽  
Vol 68 (1) ◽  
pp. 9-14 ◽  
Author(s):  
A Massart ◽  
S Golmarvi ◽  
S Hachimi-Idrissi ◽  
E Broeders ◽  
Y Tournay ◽  
...  
Keyword(s):  
Pilot Study ◽  
Haemolytic Uraemic Syndrome ◽  
Factor H ◽  
Complement Factor H ◽  
Functional Assay ◽  
Complement Factor ◽  
Atypical Haemolytic Uraemic Syndrome

scholarly journals Identification of human complement factor H as a chemotactic protein for monocytes

1997 ◽  
Vol 326 (2) ◽  
pp. 377-383 ◽  
Author(s):  
Karim NABIL ◽  
Bertrand RIHN ◽  
Marie-Claude JAURAND ◽  
Jean-Michel VIGNAUD ◽  
Jean RIPOCHE ◽  
...  
Keyword(s):  
Malignant Cell ◽  
Factor H ◽  
Alternative Complement Pathway ◽  
Complement Factor H ◽  
Complement Factor ◽  
Complement Pathway ◽  
Pathway Activation ◽  
Chemotactic Protein ◽  
Alternative Complement ◽  
Cellular Immune

We used chromatographic separation to purify to homogeneity a monomeric monocyte chemotactic protein of 150 kDa contained in mesothelioma pleural effusions. It was identified by N-terminal amino acid sequencing and immunoblotting as complement factor H, an inhibitor of the alternative complement pathway. Specific antibodies against factor H inhibited the monocyte chemotactic activity of the purified protein, which was most active at 10 nM. Factor H is a restrictive factor of alternative complement pathway activation. The new chemotactic function assigned to factor H in recruiting monocytes to the mesothelioma site might contribute to malignant cell phagocytosis via the iC3b/complement receptor type 3 pathway. These functions link the humoral and cellular immune systems.

Molecular basis of complement-mediated renal disease

2015 ◽  
Author(s):  
Nicholas Medjeral-Thomas ◽  
Anna Richards ◽  
Matthew C. Pickering
Keyword(s):  
Haemolytic Uraemic Syndrome ◽  
Alternative Pathway ◽  
Protein Family ◽  
Factor H ◽  
Complement Factor ◽  
C3 Glomerulopathy ◽  
Ongoing Research ◽  
Dense Deposit ◽  
Atypical Haemolytic Uraemic Syndrome ◽  
Glomerular Lesions

Abnormal regulation of complement is intimately associated with C3 glomerulopathy and atypical haemolytic uraemic syndrome. Atypical haemolytic uraemic syndrome is characterized by renal thrombotic microangiopathy due to an inability to regulate complement activation along the renal endothelium. The development of thrombosis is critically dependent on the ability to activate C5. Eculizumab, a monoclonal anti-C5 antibody, is an effective therapy for this condition. C3 glomerulopathy refers to glomerular lesions characterized by accumulation of C3 in the absence of immunoglobulin. The prototypic example is dense deposit disease. This condition is associated with impaired regulation of the alternative pathway in plasma. In other subtypes of C3 glomerulopathy, familial studies have identified mutations within the complement factor H-related protein family. Polymorphic variation within this protein family also influences susceptibility to IgA nephropathy. The mechanism underlying these associations remains unknown and is the subject of ongoing research efforts.

scholarly journals Cross-Talk between the Complement Pathway and the Contact Activation System of Coagulation: Activated Factor XI Neutralizes Complement Factor H

2021 ◽  
pp. ji2000398
Author(s):  
Cristina Puy ◽  
Jiaqing Pang ◽  
Stéphanie E. Reitsma ◽  
Christina U. Lorentz ◽  
Erik I. Tucker ◽  
...  
Keyword(s):  
Cross Talk ◽  
Factor H ◽  
Complement Factor H ◽  
Complement Factor ◽  
Complement Pathway ◽  
Contact Activation ◽  
Factor Xi ◽  
Activation System
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