scholarly journals Low factor H–related 5 levels contribute to infection-triggered haemolytic uraemic syndrome and membranoproliferative glomerulonephritis

2020 ◽  
Author(s):  
Irene Gómez Delgado ◽  
Josué Gutiérrez-Tenorio ◽  
Gloria M Fraga Rodríguez ◽  
Teresa Cavero ◽  
Emilia Arjona ◽  
...  
Keyword(s):  
Membranoproliferative Glomerulonephritis ◽  
Haemolytic Uraemic Syndrome ◽  
Bacterial Infections ◽  
Factor H ◽  
Renal Diseases ◽  
Complement Pathway ◽  
Atypical Haemolytic Uraemic Syndrome ◽  
Chronic Hepatitis C Virus ◽  
Alternative Complement ◽  
Combined Liver Kidney Transplant

Abstract Dysregulation of the alternative complement pathway is a major pathogenic mechanism in two rare renal diseases: atypical haemolytic uraemic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN). We report on a 66-year-old male with chronic hepatitis C virus (HCV) infection and a combined liver–kidney transplant that was diagnosed with MPGN at the age of 63 years and a 5-year-old boy who presented with aHUS at the age of 21 months following a Streptococcus pneumoniae infection. Both patients carried similar frameshift variants in the complement CFHR5 gene that segregate with reduced levels of factor H–related 5 (FHR-5). We conclude that low FHR-5 levels may predispose to viral and bacterial infections that then trigger different renal phenotypes.

scholarly journals A patient with a homozygous diacylglycerol kinase epsilon (DGKE) gene mutation with atypical haemolytic uraemic syndrome and low C3 responded well to eculizumab: a case report

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Muneera Alabdulqader ◽  
Khalid Alfakeeh
Keyword(s):  
Case Report ◽  
Gene Mutation ◽  
Haemolytic Uraemic Syndrome ◽  
Diacylglycerol Kinase ◽  
Alternative Complement Pathway ◽  
Complement C3 ◽  
Complement Pathway ◽  
Atypical Haemolytic Uraemic Syndrome ◽  
Alternative Complement ◽  
Nephrotic Range Proteinuria

Abstract Background Atypical haemolytic uraemic syndrome (aHUS) is a rare systemic syndrome characterized by non-immune haemolytic anaemia, thrombocytopenia, and kidney injury. In most cases, alternative complement pathway dysregulation is the identifying cause. Recently, other genetic causes have been identified, including a mutation in the diacylglycerol kinase epsilon (DGKE) gene, which theoretically affect the coagulation pathway and does not affect the complement pathway. Data about the management of these patients are limited. Ideal management and definitive treatment protocols have not yet been established. Case presentation A three-year-old boy presented with features of atypical haemolytic uraemic syndrome (aHUS) and low complement C3. He was presumed to have complement-mediated aHUS and was managed empirically with eculizumab. Two weeks after starting eculizumab, his haemoglobin levels, platelet count, and complement C3 level normalized but he continued to have non-nephrotic range proteinuria. His genetic testing revealed a homozygous DGKE mutation, with no other mutation detected. Six months after presentation, the patient was still in remission with no features of aHUS, a trial of weaning eculizumab by increasing dose interval was followed by nephrotic range proteinuria and severe oedema. His proteinuria improved and his oedema resolved after resuming his recommended eculizumab dose. Conclusions DGKE gene mutation can lead to aHUS with theoretically no complement dysregulation. However, some patients with this mutation show alternative complement pathway activation. This case report describes a patient with aHUS due to a DGKE gene mutation and low C3 levels who responded to eculizumab, adding to the previously reported cases of patients with DGKE gene mutations who had complete remission with no relapse with C5 blockers and/or plasma exchange. A randomized controlled study on patients with DGKE mutations might be beneficial in understanding the disease and generating a management protocol.

scholarly journals Simple Method To Distinguish between Primary and Secondary C3 Deficiencies

2003 ◽  
Vol 10 (2) ◽  
pp. 216-220
Author(s):  
Marlene Pereira de Carvalho Florido ◽  
Patrícia Ferreira de Paula ◽  
Lourdes Isaac
Keyword(s):  
Human Serum ◽  
Complement System ◽  
Factor H ◽  
Normal Human Serum ◽  
Alternative Complement Pathway ◽  
Complement Pathway ◽  
Factor B ◽  
Alternative Complement ◽  
Normal Human ◽  
The Complement System

ABSTRACT Due to the increasing numbers of reported clinical cases of complement deficiency in medical centers, clinicians are now more aware of the role of the complement system in the protection against infections caused by microorganisms. Therefore, clinical laboratories are now prepared to perform a number of diagnostic tests of the complement system other than the standard 50% hemolytic component assay. Deficiencies of alternative complement pathway proteins are related to severe and recurrent infections; and the application of easy, reliable, and low-cost methods for their detection and distinction are always welcome, notably in developing countries. When activation of the alternative complement pathway is evaluated in hemolytic agarose plates, some but not all human sera cross-react to form a late linear lysis. Since the formation of this linear lysis is dependent on C3 and factor B, it is possible to use late linear lysis to routinely screen for the presence of deficiencies of alternative human complement pathway proteins such as factor B. Furthermore, since linear lysis is observed between normal human serum and primary C3-deficient serum but not between normal human serum and secondary C3-deficient serum caused by the lack of factor H or factor I, this assay may also be used to discriminate between primary and secondary C3 deficiencies.

scholarly journals Combined Roles of Human IgG Subclass, Alternative Complement Pathway Activation, and Epitope Density in the Bactericidal Activity of Antibodies to Meningococcal Factor H Binding Protein

2011 ◽  
Vol 80 (1) ◽  
pp. 187-194 ◽  
Author(s):  
Serena Giuntini ◽  
Donald C. Reason ◽  
Dan M. Granoff
Keyword(s):  
Bactericidal Activity ◽  
Type Strain ◽  
Wild Type Strain ◽  
Factor H ◽  
Complement Pathway ◽  
Wild Type ◽  
Alternative Complement ◽  
Igg1 Mabs ◽  
Human Igg1 ◽  
Epitope Density

ABSTRACTMeningococcal vaccines containing factor H binding protein (fHbp) are in clinical development. fHbp binds human fH, which enables the meningococcus to resist complement-mediated bacteriolysis. Previously, we found that chimeric human IgG1 mouse anti-fHbp monoclonal antibodies (MAbs) had human complement-mediated bactericidal activity only if the MAb inhibited fH binding. Since IgG subclasses differ in their ability to activate complement, we investigated the role of human IgG subclasses on antibody functional activity. We constructed chimeric MAbs in which three different murine fHbp-specific binding domains were each paired with human IgG1, IgG2, or IgG3. Against a wild-type group B isolate, all three IgG3 MAbs, irrespective of their ability to inhibit fH binding, had bactericidal activity that was >5-fold higher than the respective IgG1 MAbs, while the IgG2 MAbs had the least activity. Against a mutant with increased fHbp expression, the anti-fHbp MAbs elicited greater C4b deposition (classical pathway) and greater bactericidal activity than against the wild-type strain, and the IgG1 MAbs had similar or greater activity than the respective IgG3 MAbs. The bactericidal activity against both wild-type and mutant strains also was dependent, in part, on activation of the alternative complement pathway. Thus, at lower epitope density in the wild-type strain, the IgG3 anti-fHbp MAbs had the greatest bactericidal activity. At a higher epitope density in the mutant, the IgG1 MAbs had similar or greater bactericidal activity than the IgG3 MAbs, and the activity was less dependent on the inhibition of fH binding than at a lower epitope density.

Atypical haemolytic uraemic syndrome: a case of rare genetic mutation

2021 ◽  
Vol 14 (7) ◽  
pp. e244190
Author(s):  
Geminiganesan Sangeetha ◽  
Jaippreetha Jayaraj ◽  
Swathi Ganesan ◽  
Sreeapoorva Puttagunta
Keyword(s):  
Haemolytic Uraemic Syndrome ◽  
Kidney Injury ◽  
Genetic Mutation ◽  
Complement Factor ◽  
Thrombotic Microangiopathies ◽  
Course Of Illness ◽  
Factor I ◽  
Multiple Organs ◽  
Atypical Haemolytic Uraemic Syndrome ◽  
Alternative Complement

Complement-mediated kidney disease has been an evolving area in the field of nephrology. Atypical haemolytic uraemic syndrome (aHUS) is a rare thrombotic microangiopathy that affects multiple organs, particularly kidneys. The disease is characterised by a triad of haemolytic anaemia, thrombocytopenia and acute kidney injury (AKI). aHUS is most commonly caused by dysregulation of alternative complement pathway. In contrast to shiga toxin-associated haemolytic uraemic syndrome, diarrheal prodrome is usually absent in children with aHUS. We report a 2-year, 9-month-old boy who presented with acute dysentery and AKI. He had an unusual prolonged course of illness with hypocomplementaemia; hence, genetic testing was performed. He had a storming course in the hospital and succumbed to complications of the disease. Genetic study revealed digenic mutation in Complement Factor I and C3. Therefore, it is important to differentiate aHUS from other thrombotic microangiopathies to improve the outcome.

Pathological aspects of membranoproliferative glomerulonephritis (MPGN) and haemolytic uraemic syndrome (HUS) / thrombocytic thrombopenic purpura (TTP)

2009 ◽  
Vol 101 (02) ◽  
pp. 265-270 ◽  
Author(s):  
Kerstin Benz ◽  
Kerstin Amann
Keyword(s):  
Membranoproliferative Glomerulonephritis ◽  
Haemolytic Uraemic Syndrome ◽  
Alternative Pathway ◽  
Regulatory Protein ◽  
Factor H ◽  
Morphological Alteration ◽  
Vascular Morphology ◽  
Electron Microscopical Level ◽  
Electron Microscopical ◽  
Von Willebrand

SummaryIn this paper, epidemiology, pathogenesis and typical morphological aspects of all three types of membranoproliferative glomerulonephritis (MPGN), of the haemolytic uraemic syndrome (HUS) as well as of thrombotic thrombopenic purpura (TTP) will be reviewed on the light microscopical, immunohistological or immunofluorescence and electron microscopical level. In particular, differences in the pathogenesis of these diseases are discussed. Important recent molecular and genetic insights into the pathogenesis of the three types of MPGN, of typical and atypical HUS and of TTP, i.e. dysregulation of the complement system, distinct molecular defects in C3 and factor H, the major regulatory protein of the alternative pathway of complement activation, and deficiency of a von Willebrand factor (VWF) -cleaving protease, i.e. ADAMTS13, are highlighted. Finally, particular emphasis will be put on differences in glomerular and vascular morphology in the three types of MPGN and in thrombotic microangiopathy (TMA), which is the characteristic morphological alteration of the kidney in HUS and TTP, respectively.

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