scholarly journals Primer komplementdefektusok által okozott atípusos haemolyticus uraemiás szindróma

2018 ◽  
Vol 159 (23) ◽  
pp. 929-936 ◽  
Author(s):  
György Reusz
Keyword(s):  
Complement Activation ◽  
Alternative Pathway ◽  
Critical Role ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Genetic Diagnostics ◽  
Activation Process ◽  
Phagocytic Cells ◽  
Uremic Syndrome ◽  
The Complement System

Abstract: Complement is one of the most archaic parts of the innate immune system, which enhances the ability of antibodies and phagocytic cells to clear cell debris, and microorganisms. The complement system promotes inflammation and attacks the pathogen’s plasma membrane. Malfunction of the system may lead to the development of autoimmunity or uncontrolled infections. Further, dysregulation of the tightly controlled complement activation process may lead to thrombotic microangiopathies with consequent multiorgan involvement. The present paper gives a short overview of the different pathways of complement activation. It focuses on primary genetic defects of components of the alternative pathway that result in dysregulation as well as on pathomechanism, classification, diagnostics and treatment of atypical hemolytic uremic syndrome (aHUS) based on the most recent international recommendations and guidelines. Finally the critical role of complement in host immunity and genetic diagnostics of complement deficiencies are illustrated with two cases of aHUS. Orv Hetil. 2018; 159(23): 929–936.

ATYPICAL HEMOLYTIC UREMIC SYNDROME IN CHILDREN: PRACTICAL ASPECTS OF DIFFERENTIAL DIAGNOSTICS AND TREATMENT

2021 ◽  
Vol 100 (4) ◽  
pp. 64-73
Author(s):  
S.V. Baiko ◽  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Differential Diagnostics ◽  
E Coli ◽  
Uremic Syndrome ◽  
Stage Renal Disease ◽  
End Stage ◽  
The Complement System ◽  
Terminal Complement

Atypical hemolytic uremic syndrome (aHUS) is a rare progressive form of systemic thrombotic microangiopathy (TMA) that develops as a result of uncontrolled activation of the alternative pathway of the complement system. In the case of late diagnosis and inadequate treatment, aHUS has an unfavorable outcome with death rates as high as 25% during the acute phase and up to 50% of cases progressing to end-stage renal disease. Clinically, aHUS is very similar to disseminated intravascular coagulation, other TMAs: HUS associated with enterohemorrhagic E. coli, thrombotic thrombocytopenic purpura, etc. The article presents the sequence and scope of studies for the differential diagnosis of aHUS. Eculizumab and its biosimilars, blocking the terminal complement complex, have changed the future of patients with aHUS, so timely diagnosis and early treatment are crucial in the outcome of the disease.

scholarly journals Complement activation in atypical hemolytic uremic syndrome and scleroderma renal crisis: a critical analysis of pathophysiology

2018 ◽  
Vol 40 (1) ◽  
pp. 77-81 ◽  
Author(s):  
Roman Zuckerman ◽  
Arif Asif ◽  
Eric J. Costanzo ◽  
Tushar Vachharajani
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Complement System ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Scleroderma Renal Crisis ◽  
Multiple Systems ◽  
Uremic Syndrome ◽  
The Complement System ◽  
Renal Crisis ◽  
Complement Pathways

ABSTRACT Scleroderma is an autoimmune disease that affects multiple systems. While pathophysiologic mechanisms governing the development of scleroderma are relatively poorly understood, advances in our understanding of the complement system are clarifying the role of complement pathways in the development of atypical hemolytic uremic syndrome and scleroderma renal crisis. The abundant similarities in their presentation as well as the clinical course are raising the possibility of a common underlying pathogenesis. Recent reports are emphasizing that complement pathways appear to be the unifying link. This article reviews the role of complement system in the development of atypical hemolytic uremic syndrome and scleroderma renal crisis, and calls for heightened awareness to the development of thrombotic angiopathy in patients with scleroderma.

Hemorrhagic syndrome and complement system: is there a connection?

2020 ◽  
Author(s):  
С.Е. Работинский
Keyword(s):  
Complement System ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Massive Bleeding ◽  
The Body ◽  
Critical Conditions ◽  
Contact Activation ◽  
Uremic Syndrome ◽  
The Complement System

Неспецифическую защиту организма от повреждений различной природы обеспечивает взаимодействие системы гемостаза, комплемента и кининов. В настоящей статье отражена попытка автора разобраться в этих взаимодействиях на основании обзора литературы, а также использования опыта работы выездной реанимационной гематологической бригады г. Москвы. Рассмотрены связи комплемент–гемостаз–кинины как с позиции контактной активации свёртывания, так и с позиции клеточной теории гемостаза. Отмечена роль фактора Хагемана как одного из связующих агентов между системой гемостаза и комплемента. В результате проведенного анализа прямая связь между системой комплемента и массивными кровотечениями найдена не была, однако отмечена связь патологии системы комплемента и системы гемостаза в патогенезе так называемых тромбогеморрагических состояний. В статье представлены такие критические состояния, как эмболия околоплодными водами, атипичный гемолитико-уремический синдром, гепарин-индуцированная тромбоцитопения 2-го типа, разобраны современные подходы к диагностике и лечению. The interaction of hemostasis, complement and kinins provides non-specific protection of the body from damage of various nature. This review reflects the author’s attempt to understand these interactions based on literature review, as well as using the experience of the fi eld offsite hematologic service in Moscow. The relationships of complement–hemostasis–kinins had been observed from the perspective of both the contact activation of coagulation, and cellular theory of hemostasis. The role of the Hageman factor as one of the binding agents between hemostasis and complement was noted. As a result of the analysis, direct association between the complement system and massive bleeding was not found, but the connection between the pathology of the complement system and hemostasis in the pathogenesis of the so-called thrombohemorrhagic states was noted. The review presents such critical conditions as amniotic fluid embolism, atypical hemolytic-uremic syndrome, heparin-induced thrombocytopenia type 2, describes current approaches to diagnosis and treatment.

scholarly journals Unravelling the effect of a potentiating anti-Factor H antibody on atypical hemolytic uremic syndrome associated factor H variants

2020 ◽  
Author(s):  
Gillian Dekkers ◽  
Mieke Brouwer ◽  
Jorn Jeremiasse ◽  
Angela Kamp ◽  
Robyn M. Biggs ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Complement System ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Regulatory Function ◽  
Age Related ◽  
Uremic Syndrome ◽  
The Complement System

AbstractThe complement system plays an important role in our innate immune system. Complement activation results in clearance of pathogens, immune complex and apoptotic cells. The host is protected from complement-mediated damage by several complement regulators. Factor H (FH) is the most important fluid-phase regulator of the alternative pathway of the complement system. Heterozygous mutations in FH are associated with complement-related diseases such as atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration.We recently described an agonistic anti-FH monoclonal antibody that can potentiate the regulatory function of FH. This antibody could serve as a potential new drug for aHUS patients and alternative to C5 blockade by Eculizumab. However, it is unclear whether this antibody can potentiate FH mutant variants in addition to wild type FH. Here, the functionality and potential of the agonistic antibody in the context of pathogenic aHUS-related FH mutant proteins was investigated. The binding affinity of recombinant WT FH, and the FH variants, W1183L, V1197A, R1210C, and G1194D to C3b was increased upon addition of the potentiating antibody and similarly, the decay accelerating activity of all mutants is increased. The potentiating anti-FH antibody is able to restore the surface regulatory function of most of the tested FH mutants to WT FH levels. In conclusion, our potentiating anti-FH is broadly active and able to enhance both WT FH function as well as most aHUS-associated FH variants tested in this study.

scholarly journals A Simplified Approach to the Diagnosis of Atypical HUS: Clinical Considerations and Practical Implications

2014 ◽  
Vol 7 (1) ◽  
pp. 91-94 ◽  
Author(s):  
Arif Asif ◽  
Tushar Vachharajani ◽  
Loay Salman ◽  
Ali Nayer
Keyword(s):  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Organ Injury ◽  
High Morbidity ◽  
Simplified Approach ◽  
Recent Success ◽  
Humanized Monoclonal Antibody ◽  
Uremic Syndrome ◽  
The Complement System ◽  
Specific Diagnostic Test

Although rare, atypical hemolytic-uremic syndrome (aHUS) carries a high morbidity and mortality. Widespread microvascular thrombosis, thrombocytopenia and microangiopathic hemolytic anemia are the hallmark of aHUS. Virtually any organ (particularly the kidney) can be a target for the devastating effects of this syndrome. Uncontrolled activation of the alternative pathway of the complement system lies at the heart of the pathogenesis of aHUS. While significant advances have been made in our understanding of aHUS, establishing timely diagnosis of this syndrome has been challenging. This, in part, is due to the absence of a sensitive and specific diagnostic test and a relatively lack of our familiarity with the syndrome. With the recent success and approval of a humanized monoclonal antibody (eculizumab) in the treatment of aHUS, prompt and accurate diagnosis is of paramount importance to limit the target organ injury. This article presents a simplified approach to establishing the diagnosis of aHUS.

Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome

Blood ◽  
2013 ◽  
Vol 122 (2) ◽  
pp. 282-292 ◽  
Author(s):  
Marie Frimat ◽  
Fanny Tabarin ◽  
Jordan D. Dimitrov ◽  
Caroline Poitou ◽  
Lise Halbwachs-Mecarelli ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Hemolytic Uremic Syndrome ◽  
Complement Activation ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Cell Surfaces ◽  
Complement Alternative Pathway ◽  
Key Points ◽  
Uremic Syndrome

Key Points Heme activates complement alternative pathway in serum and on endothelial cell surfaces. Heme-induced complement activation in the presence of complement mutations contributes as a secondary hit to the development of aHUS.

scholarly journals Complement-Mediated Thrombotic Microangiopathy Associated with Lupus Nephritis Treated with Eculizumab: A Case Report

2021 ◽  
pp. 95-102
Author(s):  
Everardo Arias Torres ◽  
Yongen Chang ◽  
Sheetal Desai ◽  
Ian Chang ◽  
Jonathan E. Zuckerman ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Homozygous Deletion ◽  
Multiple Organ ◽  
Thrombotic Microangiopathies ◽  
Clinical Criteria ◽  
Organ Systems ◽  
Oral Steroids ◽  
Uremic Syndrome

Thrombotic microangiopathies (TMAs) involve multiple organ systems due to the presence of microangiopathic hemolysis. One such condition, atypical hemolytic uremic syndrome (aHUS), is a complement-mediated process that is part of a spectrum of disorders that have underlying complement dysfunction of the alternative pathway due to overactivity or decreased self-nonself discrimination by innate immunity. Complement-amplifying conditions such as pregnancy may unmask a diagnosis of aHUS. We present an important case of a pregnant 23-year-old Hispanic female who presented in mid-gestation (21 weeks) with an initial diagnosis of systemic lupus erythematosus (SLE) complicated by aHUS. She met clinical criteria for aHUS on presentation and was found to have a pathogenic CFHR1–3 homozygous deletion. She has been treated with intravenous and oral steroids, cyclophosphamide, subsequently also with plasma exchange, and finally with eculizumab with partial improvement in renal function. This case adds to the emerging literature showing that SLE and aHUS (or complement-mediated TMA) can be successfully treated with C5 blockade.

scholarly journals HUS and the case for complement

Blood ◽  
2015 ◽  
Vol 126 (18) ◽  
pp. 2085-2090 ◽  
Author(s):  
Edward M. Conway
Keyword(s):  
Escherichia Coli ◽  
Renal Failure ◽  
Shiga Toxin ◽  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Response To Treatment ◽  
Microangiopathic Hemolytic Anemia ◽  
New Knowledge ◽  
Uremic Syndrome

Abstract Hemolytic-uremic syndrome (HUS) is a thrombotic microangiopathy that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Excess complement activation underlies atypical HUS and is evident in Shiga toxin–induced HUS (STEC-HUS). This Spotlight focuses on new knowledge of the role of Escherichia coli–derived toxins and polyphosphate in modulating complement and coagulation, and how they affect disease progression and response to treatment. Such new insights may impact on current and future choices of therapies for STEC-HUS.

scholarly journals Deregulation of Factor H by Factor H-Related Protein 1 Depends on Sialylation of Host Surfaces

2021 ◽  
Vol 12 ◽  
Author(s):  
Arthur Dopler ◽  
Selina Stibitzky ◽  
Rachel Hevey ◽  
Marco Mannes ◽  
Mara Guariento ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Immune Surveillance ◽  
Factor H ◽  
Sialic Acid Binding ◽  
Uremic Syndrome ◽  
High Concentrations ◽  
Complement Regulator ◽  
Physiological Impact ◽  
The Complement System

To discriminate between self and non-self surfaces and facilitate immune surveillance, the complement system relies on the interplay between surface-directed activators and regulators. The dimeric modulator FHR-1 is hypothesized to competitively remove the complement regulator FH from surfaces that strongly fix opsonic C3b molecules—a process known as “deregulation.” The C-terminal regions of FH and FHR-1 provide the basis of this competition. They contain binding sites for C3b and host surface markers and are identical except for two substitutions: S1191L and V1197A (i.e., FH “SV”; FHR-1 “LA”). Intriguingly, an FHR-1 variant featuring the “SV” combination of FH predisposes to atypical hemolytic uremic syndrome (aHUS). The functional impact of these mutations on complement (de)regulation, and their pathophysiological consequences, have largely remained elusive. We have addressed these questions using recombinantly expressed wildtype, mutated, and truncated versions of FHR-1 and FH. The “SV” to “LA” substitutions did not affect glycosaminoglycan recognition and had only a small effect on C3b binding. In contrast, the two amino acids substantially affected the binding of FH and FHR-1 to α2,3-linked sialic acids as host surfaces markers, with the S-to-L substitution causing an almost complete loss of recognition. Even with sialic acid-binding constructs, notable deregulation was only detected on host and not foreign cells. The aHUS-associated “SV” mutation converts FHR-1 into a sialic acid binder which, supported by its dimeric nature, enables excessive FH deregulation and, thus, complement activation on host surfaces. While we also observed inhibitory activities of FHR-1 on C3 and C5 convertases, the high concentrations required render the physiological impact uncertain. In conclusion, the SV-to-LA substitution in the C-terminal regions of FH and FHR-1 diminishes its sialic acid-binding ability and results in an FHR-1 molecule that only moderately deregulates FH. Such FH deregulation by FHR-1 only occurs on host/host-like surfaces that recruit FH. Conversion of FHR-1 into a sialic acid binder potentiates the deregulatory capacity of FHR-1 and thus explains the pathophysiology of the aHUS-associated FHR-1 “SV” variant.

scholarly journals Case Report: Lipoprotein Glomerulopathy Complicated by Atypical Hemolytic Uremic Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Lara Kollbrunner ◽  
Patricia Hirt-Minkowski ◽  
Javier Sanz ◽  
Elena Bresin ◽  
Thomas J. Neuhaus ◽  
...  
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
Complement Factor ◽  
Inherited Disease ◽  
Lipoprotein Glomerulopathy ◽  
Gene Encoding ◽  
Alternative Complement ◽  
Uremic Syndrome ◽  
The Complement System

Lipoprotein glomerulopathy (LPG) is a rare inherited disease caused by mutations in the APOE gene, encoding apolipoprotein E (apoE). Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by overactivation of the alternative complement pathway. Here we report the case of a 21-year-old man with LPG who developed aHUS. A functional complement assay demonstrated an overactivation of the complement system. Complementary genetic analysis revealed a homozygous aHUS risk allele for complement factor-H related 1 (CFHR1), CFHR1*B. To the best of our knowledge, this is the first report of an aHUS in a patient with LPG.

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