Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains

Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype–phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS.

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Characterization of complement factor H–related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome

Blood ◽

10.1182/blood-2009-05-223834 ◽

2009 ◽

Vol 114 (19) ◽

pp. 4261-4271 ◽

Cited By ~ 134

Author(s):

Cynthia Abarrategui-Garrido ◽

Rubén Martínez-Barricarte ◽

Margarita López-Trascasa ◽

Santiago Rodríguez de Córdoba ◽

Pilar Sánchez-Corral

Keyword(s):

Hemolytic Uremic Syndrome ◽

Sequence Similarity ◽

Atypical Hemolytic Uremic Syndrome ◽

Factor H ◽

Age Related Macular Degeneration ◽

Complement Factor H ◽

Complement Factor ◽

Age Related ◽

Uremic Syndrome

Abstract The factor H–related protein family (CFHR) is a group of minor plasma proteins genetically and structurally related to complement factor H (fH). Notably, deficiency of CFHR1/CFHR3 associates with protection against age-related macular degeneration and with the presence of anti-fH autoantibodies in atypical hemolytic uremic syndrome (aHUS). We have developed a proteomics strategy to analyze the CFHR proteins in plasma samples from controls, patients with aHUS, and patients with type II membranoproliferative glomerulonephritis. Here, we report on the identification of persons carrying novel deficiencies of CFHR1, CFHR3, and CFHR1/CFHR4A, resulting from point mutations in CFHR1 and CFHR3 or from a rearrangement involving CFHR1 and CFHR4. Remarkably, patients with aHUS lacking CFHR1, but not those lacking CFHR3, present anti-fH autoantibodies, suggesting that generation of these antibodies is specifically related to CFHR1 deficiency. We also report the characterization of a novel CFHR1 polymorphism, resulting from a gene conversion event between CFH and CFHR1, which strongly associates with aHUS. The risk allotype CFHR1*B, with greater sequence similarity to fH, may compete with fH, decreasing protection of cellular surfaces against complement damage. In summary, our comprehensive analyses of the CFHR proteins have improved our understanding of these proteins and provided further insights into aHUS pathogenesis.

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Complement factor H and the hemolytic uremic syndrome

Journal of Experimental Medicine ◽

10.1084/jem.20070664 ◽

2007 ◽

Vol 204 (6) ◽

pp. 1245-1248 ◽

Cited By ~ 56

Author(s):

John P. Atkinson ◽

Timothy H.J. Goodship

Keyword(s):

Hemolytic Uremic Syndrome ◽

Alternative Pathway ◽

Factor H ◽

Age Related Macular Degeneration ◽

Immune Recognition ◽

Complement Factor ◽

Genetic Changes ◽

Debris Accumulation ◽

Age Related ◽

Uremic Syndrome

Immune recognition is coupled to powerful proinflammatory effector pathways that must be tightly regulated. The ancient alternative pathway of complement activation is one such proinflammatory pathway. Genetic susceptibility factors have been identified in both regulators and activating components of the alternative pathway that are associated with thrombotic microangiopathies, glomerulonephritides, and chronic conditions featuring debris deposition. These observations indicate that excessive alternative pathway activation promotes thrombosis in the microvasculature and tissue damage during debris accumulation. Intriguingly, distinct genetic changes in factor H (FH), a key regulator of the alternative pathway, are associated with hemolytic uremic syndrome (HUS), membranoproliferative glomerulonephritis (dense deposit disease), or age-related macular degeneration (AMD). A mouse model of HUS designed to mirror human mutations in FH has now been developed, providing new understanding of the molecular pathogenesis of complement-related endothelial disorders.

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

10.1101/2020.04.08.026906 ◽

2020 ◽

Cited By ~ 1

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.

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Novel Complement Factor H mutation, a case report of atypical hemolytic uremic syndrome

Case Reports in Internal Medicine ◽

10.5430/crim.v4n2p13 ◽

2017 ◽

Vol 4 (2) ◽

pp. 13 ◽

Cited By ~ 1

Author(s):

Rodrigo Andrés Sepúlveda ◽

Rodrigo Tagle ◽

Aquiles Jara

Keyword(s):

Renal Failure ◽

Hemolytic Uremic Syndrome ◽

Alternative Pathway ◽

Atypical Hemolytic Uremic Syndrome ◽

Factor H ◽

Complement Factor H ◽

Complement Factor ◽

Severe Renal Failure ◽

Uremic Syndrome ◽

I Factor

Atypical hemolytic uremic syndrome (aHUS) is a rare but catastrophic disease. It is characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. When the aHUS is primary, the cause is due to mutations in proteins that regulate the alternative pathway of complement, such as Factor H, Factor I, Factor B, C3, Membrane Co-Factor Protein and Thrombomodulin. Usually primary aHUS is associated with other amplifiers complement factors. We present a case of aHUS in a 25-year-old female patient; she presented with malignant hypertension and severe renal failure. After a widespread study, the etiology of the aHUS was a mutation in the complement factor H, not previously described in the literature (p.Tyr1177His). After treatment with Eculizumab (C5 inhibitor monoclonal antibody), she recovered renal function with not hemodialysis requirements.

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COVID-19: a trigger for severe thrombotic microangiopathy in a patient with complement gene variant

Romanian Journal of Internal Medicine ◽

10.2478/rjim-2021-0040 ◽

2022 ◽

Vol 0 (0) ◽

Author(s):

Larisa Pinte ◽

Bogdan Marian Sorohan ◽

Zoltán Prohászka ◽

Mihaela Gherghiceanu ◽

Cristian Băicuş

Keyword(s):

Hemolytic Uremic Syndrome ◽

Thrombotic Microangiopathy ◽

Alternative Pathway ◽

Atypical Hemolytic Uremic Syndrome ◽

Factor H ◽

Complement C3 ◽

Uncontrolled Hypertension ◽

Complement Factor ◽

Uremic Syndrome ◽

Complement Gene

Abstract The evidence regarding thrombotic microangiopathy (TMA) related to Coronavirus Infectious Disease 2019 (COVID-19) in patients with complement gene mutations as a cause of acute kidney injury (AKI) are limited. We presented a case of a 23-year-old male patient admitted with an asymptomatic form of COVID-19, but with uncontrolled hypertension and AKI. Kidney biopsy showed severe lesions of TMA. In evolution patient had persistent microangiopathic hemolytic anemia, decreased level of haptoglobin and increased LDH level. Decreased complement C3 level and the presence of schistocytes were found for the first time after biopsy. Kidney function progressively decreased and the patient remained hemodialysis dependent. Complement work-up showed a heterozygous variant with unknown significance in complement factor I (CFI) c.-13G>A, affecting the 5' UTR region of the gene. In addition, the patient was found to be heterozygous for the complement factor H (CFH) H3 haplotype (involving the rare alleles of c.-331C>T, Q672Q and E936D polymorphisms) reported as a risk factor of atypical hemolytic uremic syndrome. This case of AKI associated with severe TMA and secondary hemolytic uremic syndrome highlights the importance of genetic risk modifiers in the alternative pathway dysregulation of the complement in the setting of COVID-19, even in asymptomatic forms.

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Functional Analysis of Variants in Complement Factor I Identified in Age-Related Macular Degeneration and Atypical Hemolytic Uremic Syndrome

Frontiers in Immunology ◽

10.3389/fimmu.2021.789897 ◽

2022 ◽

Vol 12 ◽

Author(s):

Sarah de Jong ◽

Anita de Breuk ◽

Bjorn Bakker ◽

Suresh Katti ◽

Carel B. Hoyng ◽

...

Keyword(s):

Hemolytic Uremic Syndrome ◽

Macular Degeneration ◽

Atypical Hemolytic Uremic Syndrome ◽

Age Related Macular Degeneration ◽

Complement Factor ◽

Serum Samples ◽

Factor I ◽

Complement Factor I ◽

Age Related ◽

Uremic Syndrome

Complement factor I (FI) is a central inhibitor of the complement system, and impaired FI function increases complement activation, contributing to diseases such as age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (aHUS). Genetic variation in complement factor I (CFI) has been identified in both AMD and aHUS, with more than half of these variants leading to reduced FI secretion levels. For many of the variants with normal FI secretion, however, functional implications are not yet known. Here we studied 11 rare missense variants, with FI secretion levels comparable to wildtype, but a predicted damaging effects based on the Combined Annotation Dependent Depletion (CADD) score. Three variants (p.Pro50Ala, p.Arg339Gln, and p.Ser570Thr) were analyzed in plasma and serum samples of carriers affected by AMD. All 11 variants (nine for the first time in this study) were recombinantly expressed and the ability to degrade C3b was studied with the C3b degradation assay. The amount of degradation was determined by measuring the degradation product iC3b with ELISA. Eight of 11 (73%) mutant proteins (p.Pro50Ala, p.Arg339Gln, p.Ile340Thr, p.Gly342Glu, p.Gly349Arg, p.Arg474Gln, p.Gly487Cys, and p.Gly512Ser) showed significantly impaired C3b degradation, and were therefore classified as likely pathogenic. Our data indicate that genetic variants in CFI with a CADD score >20 are likely to affect FI function, and that monitoring iC3b in a degradation assay is a useful tool to establish the pathogenicity of CFI variants in functional studies.

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Anti-Factor H Antibodies in Egyptian Children with Hemolytic Uremic Syndrome

International Journal of Nephrology ◽

10.1155/2021/6904858 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Shereen Shawky ◽

Hesham Safouh ◽

Mona Gamal ◽

Mohammed M. Abbas ◽

Azza Aboul-Enein ◽

...

Keyword(s):

Hemolytic Uremic Syndrome ◽

High Frequency ◽

Alternative Pathway ◽

Atypical Hemolytic Uremic Syndrome ◽

Disease Onset ◽

Factor H ◽

Enzyme Linked Immunosorbent Assay ◽

Complement Factor ◽

Egyptian Children ◽

Uremic Syndrome

Background. Atypical hemolytic uremic syndrome (aHUS) is an important cause of acute kidney injury in children. It is primarily caused by dysregulation of the complement alternative pathway due to genetic mutations, mainly in complement factor H genes, or due to anti-factor H autoantibodies (anti-FH), leading to uncontrolled overactivation of the complement system. Early diagnosis and treatment of autoimmune HUS (AI-HUS) is essential and leads to a favorable outcome. Methods. Fifty pediatric HUS patients and 50 age- and sex-matched controls were included in the study. Patients were subjected to full history taking, clinical examination, and laboratory testing. All candidates were subjected to an assessment of anti-FH in serum by a homemade enzyme-linked immunosorbent assay technique. Results. A high frequency of serum anti-FH was detected in our aHUS patients. The disease onset of AI-HUS was mainly observed in March and April, with significantly higher rates in school-aged males. All patients who started immunosuppressives early together with plasmapheresis upon detection of their anti-FH had complete renal function recovery. Conclusion. The high frequency of AI-HUS revealed in Egyptian HUS children in our study highlights the importance of implementing anti-FH testing in Egypt to provide early recognition for immediate proper management, including early immunosuppressive therapy, and hence improving patient outcomes.

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Anti-Factor H Antibody-Associated Atypical Hemolytic Uremic Syndrome: A Case Report

PRILOZI ◽

10.2478/prilozi-2021-0029 ◽

2021 ◽

Vol 42 (2) ◽

pp. 109-115

Author(s):

Nora Abazi-Emini ◽

Emilija Sahpazova ◽

Jovana Putnik ◽

Velibor Tasic

Keyword(s):

Case Report ◽

Hemolytic Uremic Syndrome ◽

Alternative Pathway ◽

Atypical Hemolytic Uremic Syndrome ◽

Disease Onset ◽

Factor H ◽

Complement Factor ◽

Uremic Syndrome ◽

One Year ◽

Urine Testing

Abstract Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy, caused by dysregulation of the complement alternative pathway. Deletion of the complement factor H–related genes, CFHR1 and CFHR3, together with the presence of CFH autoantibodies are reported in aHUS patients, representing 10% of cases of patients with aHUS. Case presentation: We report here on a case of 4-year-old girl with anti-CFH antibody-associated aHUS. The measurement of complement factors and anti-factor H antibodies, was the main guideline for making an accurate diagnosis and providing the appropriate therapy, with the patient responding positively to plasma exchanges (PEs) and cyclophosphamide pulses. We then, one year after disease onset, continued with glucocorticoids and mycophenolate mofetil (MMF), as maintenance therapy. There were no complications during the therapy other than neutropenia. Now, one year after the cessation of the immune suppression therapy, she is in remission with normal kidney function, no signs of hemolysis, normal C3 levels, and normal range proteinuria. The anti-factor H autoantibody titer decreased but still remained positive, the factor H antigen values remained low all throughout. Close follow-up is applied with frequent urine testing and complete blood count with an intention for early detection of relapse of the disease. Conclusion: The purpose of this case report is to emphasize the value of complement factor measurements and also to separate anti-CFH antibody-associated aHUS as an entity, because immunosuppressive therapy provides an excellent response..

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