C3 Glomerulopathy and Atypical Hemolytic Uremic Syndrome: Two Important Manifestations of Complement System Dysfunction

Bajwa, Ravneet; Depalma, John A.; Khan, Taimoor; Cheema, Anmol; Kalathil, Sheila; Hossain, Mohammad A.; Haroon, Attiya; Anne, Madhurima; Zheng, Min; Nayer, Ali; Asif, Arif

doi:10.1159/000486848

Cited by 4 publications

(4 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Однако при большей длительности нефропатии поздние стадии ХБП в нашем исследовании наблюдались реже, чем при аГУС. Таким образом, создается впечатление о более благоприятном, чем при аГУС, течении и медленном темпе прогрессирования нефропатии при С3-ГП [13].…”

Section: Discussionunclassified

Comparative characteristics of the complement system in patients with C3-glomerulopathy and atypical hemolytic uremic syndrome of chronic course who suffered an acute episode of thrombotic microangiopathy

Yurova,

Kozlovskaya,

Bobrova

et al. 2023

Terapevticheskii arkhiv

View full text Add to dashboard Cite

Aim. To compare changes in the complement system in C3-glomerulopathy (C3-GP) and atypical hemolytic uremic syndrome (aHUS) after the relief of an acute episode of thrombotic microangiopathy. Materials and methods. The study included 8 patients diagnosed with C3-GP and 8 with aHUS in remission. The blood levels of the complement system components were determined: C3, C4, C3a, C5a, factor H (CFH), factor B (CFB), membrane-attacking complex (MAC), antibodies to C3b (anti-C3b-AT), the level of hemolytic activity (CH50), the content of factor D (CFD) in the urine. Results. C3 and CH50 levels were within the reference range in both groups, however, in the C3-GP group they were at the lower limit, and C3 level was significantly lower than in the aHUS group: 0.56 [0.44; 0.96] vs 1.37 [1.16; 2.52] (p=0.003). CFB increased level was detected in both groups, but in the C3-GP group it was significantly lower than in the aHUS group 275.1 [222.1; 356.6] vs 438.7 [323.3; 449.3] (p=0.010). C3a, C5a and MAC levels were increased in both groups, but the maximum was in the C3-GP group, and the MAC level in the C3-GP group was 2 times higher than that in aHUS, and these differences reached statistical significance 123 5556686 vs 56031294 (p=0.036). CFH and CFD levels was increased in both groups, but their highest values was in the aHUS group. Conclusion. Alternative complement pathway activation signs were present in both groups of patients with complement-mediated nephropathies, regardless the stage of the disease. In C3-GP, alternative complement pathway activation was more pronounced than in aHUS after the relief of an acute episode of thrombotic microangiopathy.

show abstract

Section: Discussionunclassified

Comparative characteristics of the complement system in patients with C3-glomerulopathy and atypical hemolytic uremic syndrome of chronic course who suffered an acute episode of thrombotic microangiopathy

Yurova,

Kozlovskaya,

Bobrova

et al. 2023

Terapevticheskii arkhiv

View full text Add to dashboard Cite

show abstract

“…Next to aHUS patients, C3 glomerulopathy patients suffer from dysregulation of the AP as well. In contrast to aHUS patients, these patients are characterized by C3 deposits in glomeruli, which leads to disruption of kidney function, but the disease is not associated with thrombocytopenia, anemia, or other systemic involvement ( 93 ). The pathophysiology of disease is not always clear, but in some cases it is known to be caused by autoantibody formation against C3bBb, which stabilizes the convertase and thus increases its activity, or by mutations in C3 or the complement regulatory proteins FH or FI ( 94 – 96 ).…”

Section: The Role Of Complement Regulators In Pathologiesmentioning

confidence: 99%

Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease

Mourik

Jongerius

2020

Front. Immunol.

View full text Add to dashboard Cite

The complement system is an important part of the innate immune system, providing a strong defense against pathogens and removing apoptotic cells and immune complexes. Due to its strength, it is important that healthy human cells are protected against damage induced by the complement system. To be protected from complement, each cell type relies on a specific combination of both soluble and membrane-bound regulators. Their importance is indicated by the amount of pathologies associated with abnormalities in these complement regulators. Here, we will discuss the current knowledge on complement regulatory protein polymorphisms and expression levels together with their link to disease. These diseases often result in red blood cell destruction or occur in the eye, kidney or brain, which are tissues known for aberrant complement activity or regulation. In addition, complement regulators have also been associated with different types of cancer, although their mechanisms here have not been elucidated yet. In most of these pathologies, treatments are limited and do not prevent the complement system from attacking host cells, but rather fight the consequences of the complement-mediated damage, using for example blood transfusions in anemic patients. Currently only few drugs targeting the complement system are used in the clinic. With further demand for therapeutics rising linked to the wide range of complement-mediated disease we should broaden our horizon towards treatments that can actually protect the host cells against complement. Here, we will discuss the latest insights on how complement regulators can benefit therapeutics. Such therapeutics are currently being developed extensively, and can be categorized into full-length complement regulators, engineered complement system regulators and antibodies targeting complement regulators. In conclusion, this review provides an overview of the complement regulatory proteins and their links to disease, together with their potential in the development of novel therapeutics.

show abstract

“…Mutations in FI can impair its secretion or enzymatic function, which can lead to tissue damage and disease (11)(12)(13), including agerelated macular degeneration (AMD) and atypical uremic syndrome (aHUS) (9,10,14). In both diseases, insufficient complement regulation drives the disease pathogenesis (15,16).…”

Section: Introductionmentioning

confidence: 99%

Functional evaluation of complement factor I variants by immunoassays and SDS-PAGE

Gerogianni,

Baas,

Sjöström

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

Factor I (FI) is an essential regulator of the complement system. Together with co-factors, FI degrades C3b, which inhibits further complement activation. Genetic mutations in FI are associated with pathological conditions like age-related macular degeneration and atypical hemolytic uremic syndome. Here, we evaluated eight recombinant FI genetic variants found in patients. We assessed FI’s co-factor activity in the presence of two co-factors; Factor H and soluble CR1. Different analytical assays were employed; SDS-PAGE to evaluate the degradation of C3b, ELISA to measure the generation of fluid phase iC3b and the degradation of surface-bound C3b using a novel Luminex bead-based assay. We demonstrate that mutations in the FIMAC and SP domains of FI led to significantly reduced protease activity, whereas the two analyzed mutations in the LDLRA2 domain did not result in any profound changes in FI’s function. The different assays employed displayed a strong positive correlation, but differences in the activity of the genetic variants Ile55Phe and Gly261Asp could only be observed by combining different methods and co-factors for evaluating FI activity. In conclusion, our results provide a new perspective regarding available diagnostic tools for assessing the impact of mutations in FI.

show abstract

C3 Glomerulopathy and Atypical Hemolytic Uremic Syndrome: Two Important Manifestations of Complement System Dysfunction

Cited by 4 publications

References 29 publications

Comparative characteristics of the complement system in patients with C3-glomerulopathy and atypical hemolytic uremic syndrome of chronic course who suffered an acute episode of thrombotic microangiopathy

Comparative characteristics of the complement system in patients with C3-glomerulopathy and atypical hemolytic uremic syndrome of chronic course who suffered an acute episode of thrombotic microangiopathy

Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease

Functional evaluation of complement factor I variants by immunoassays and SDS-PAGE

Contact Info

Product

Resources

About