Atypical haemolytic uraemic syndrome presenting initially as suspected meningococcal disease: a case report

<p>Abstract</p> <p>Background</p> <p>Haemolytic uraemic syndrome (HUS) is the most common cause of acute renal failure in children and is usually linked with Escherichia coli O157 infection. With a fatality rate of around 5%, some reports have associated antibiotic treatment with a worsening prognosis.</p> <p>Case Presentation</p> <p>We describe a female infant patient, initially treated for suspected meningococcal septicaemia, who went on to develop renal complications and thrombocytopenia characteristic of HUS. A subsequent positive stool sample for <it>E. coli </it>O157 confirmed HUS as an appropriate diagnosis, although there was no evidence of diarrhoea or vomiting throughout the course of her management.</p> <p>Conclusion</p> <p>The urgency of early recognition and treatment for suspected meningococcal disease in very young children while entirely appropriate can initially divert attention from other serious conditions. Evidence of infection with <it>E. coli </it>O157 infection in this case also highlights what can be a blurred distinction between atypical (non-diarrhoeal) HUS from classical HUS of infective origin.</p

The major autoantibody epitope on factor H in atypical hemolytic uremic syndrome is structurally different from its homologous site in factor H-related protein 1, supporting a novel model for induction of autoimmunity in this disease

Atypical hemolytic uremic syndrome (aHUS) is characterized by complement attack against host cells due to mutations in complement proteins or autoantibodies against complement factor H (CFH). It is unknown why nearly all patients with autoimmune aHUS lack CFHR1 (CFH-related protein-1). These patients have autoantibodies against CFH domains 19 and 20 (CFH19-20), which are nearly identical to CFHR1 domains 4 and 5 (CFHR14-5). Here, binding site mapping of autoantibodies from 17 patients using mutant CFH19-20 constructs revealed an autoantibody epitope cluster within a loop on domain 20, next to the two buried residues that are different in CFH19-20 and CFHR14-5. The crystal structure of CFHR14-5 revealed a difference in conformation of the autoantigenic loop in the C-terminal domains of CFH and CFHR1, explaining the variation in binding of autoantibodies from some aHUS patients to CFH19-20 and CFHR14-5. The autoantigenic loop on CFH seems to be generally flexible, as its conformation in previously published structures of CFH19-20 bound to the microbial protein OspE and a sialic acid glycan is somewhat altered. Cumulatively, our data suggest that association of CFHR1 deficiency with autoimmune aHUS could be due to the structural difference between CFHR1 and the autoantigenic CFH epitope, suggesting a novel explanation for CFHR1 deficiency in the pathogenesis of autoimmune aHUS

Both Monoclonal and Polyclonal Immunoglobulin Contingents Mediate Complement Activation in Monoclonal Gammopathy Associated-C3 Glomerulopathy

C3 glomerulopathy (C3G) results from acquired or genetic abnormalities in the complement alternative pathway (AP). C3G with monoclonal immunoglobulin (MIg-C3G) was recently included in the spectrum of “monoclonal gammopathy of renal significance.” However, mechanisms of complement dysregulation in MIg-C3G are not described and the pathogenic effect of the monoclonal immunoglobulin is not understood. The purpose of this study was to investigate the mechanisms of complement dysregulation in a cohort of 41 patients with MIg-C3G. Low C3 level and elevated sC5b-9, both biomarkers of C3 and C5 convertase activation, were present in 44 and 78% of patients, respectively. Rare pathogenic variants were identified in 2/28 (7%) tested patients suggesting that the disease is acquired in a large majority of patients. Anti-complement auto-antibodies were found in 20/41 (49%) patients, including anti-FH (17%), anti-CR1 (27%), anti-FI (5%) auto-antibodies, and C3 Nephritic Factor (7%) and were polyclonal in 77% of patients. Using cofactor assay, the regulation of the AP was altered in presence of purified IgG from 3/9 and 4/7 patients with anti-FH or anti-CR1 antibodies respectively. By using fluid and solid phase AP activation, we showed that total purified IgG of 22/34 (65%) MIg-C3G patients were able to enhance C3 convertase activity. In five documented cases, we showed that the C3 convertase enhancement was mostly due to the monoclonal immunoglobulin, thus paving the way for a new mechanism of complement dysregulation in C3G. All together the results highlight the contribution of both polyclonal and monoclonal Ig in MIg-C3G. They provide direct insights to treatment approaches and opened up a potential way to a personalized therapeutic strategy based on chemotherapy adapted to the B cell clone or immunosuppressive therapy

Functional Characterization of the Disease-associated N-Terminal complement Factor H Mutation W198R

Dysregulation of the complement alternative pathway is involved in the pathogenesis of several diseases, including the kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). In a patient, initially diagnosed with chronic glomerulonephritis, possibly C3G, and who 6 years later had an episode of aHUS, a heterozygous missense mutation leading to a tryptophan to arginine exchange (W198R) in the factor H (FH) complement control protein (CCP) 3 domain has previously been identified. The aim of this study was to clarify the functional relevance of this mutation. To this end, wild-type (FH1-4(WT)) and mutant (FH1-4(W198R)) CCPs 1-4 of FH were expressed as recombinant proteins. The FH1-4(W198R) mutant showed decreased C3b binding compared with FH1-4(WT). FH1-4(W198R) had reduced cofactor and decay accelerating activity compared with the wild-type protein. Hemolysis assays demonstrated impaired capacity of FH1-4(W198R) to protect rabbit erythrocytes from human complement-mediated lysis, and also to prevent lysis of sheep erythrocytes in human serum induced by a monoclonal antibody binding in FH CCP5 domain, compared with that of FH1-4(WT). Thus, the FH W198R exchange results in impaired complement alternative pathway regulation. The heterozygous nature of this mutation in the index patient may explain the manifestation of two diseases, likely due to different triggers leading to complement dysregulation in plasma or on cell surfaces

Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome

Genetic studies have shown that mutations of complement inhibitors such as membrane cofactor protein, Factors H, I, or B and C3 predispose patients to atypical hemolytic uremic syndrome (aHUS). Factor I is a circulating serine protease that inhibits complement by degrading C3b and up to now only a few mutations in the CFI gene have been characterized. In a large cohort of 202 patients with aHUS, we identified 23 patients carrying exonic mutations in CFI. Their overall clinical outcome was unfavorable, as half died or developed end-stage renal disease after their first syndrome episode. Eight patients with CFI mutations carried at least one additional known genetic risk factor for aHUS, such as a mutation in MCP, CFH, C3 or CFB; a compound heterozygous second mutation in CFI; or mutations in both the MCP and CFH genes. Five patients exhibited homozygous deletion of the Factor H-related protein 1 (CFHR-1) gene. Ten patients with aHUS had one mutation in their CFI gene (Factor I-aHUS), resulting in a quantitative or functional Factor I deficiency. Patients with a complete deletion of the CFHR-1 gene had a significantly higher risk of a bad prognosis compared with those with one Factor I mutation as their unique vulnerability feature. Our results emphasize the necessity of genetic screening for all susceptibility factors in patients with aHUS

An engineered construct combining complement regulatory and surface-recognition domains represents a minimal-size functional Factor H

Complement is an essential humoral component of innate immunity; however, its inappropriate activation leads to pathology. Polymorphisms, mutations, and autoantibodies affecting factor H (FH), a major regulator of the alternative complement pathway, are associated with various diseases, including age-related macular degeneration, atypical hemolytic uremic syndrome, and C3 glomerulopathies. Restoring FH function could be a treatment option for such pathologies. In this article, we report on an engineered FH construct that directly combines the two major functional regions of FH: the N-terminal complement regulatory domains and the C-terminal surface-recognition domains. This minimal-size FH (mini-FH) binds C3b and has complement regulatory functions similar to those of the full-length protein. In addition, we demonstrate that mini-FH binds to the FH ligands C-reactive protein, pentraxin 3, and malondialdehyde epitopes. Mini-FH was functionally active when bound to the extracellular matrix and endothelial cells in vitro, and it inhibited C3 deposition on the cells. Furthermore, mini-FH efficiently inhibited complement-mediated lysis of host-like cells caused by a disease-associated FH mutation or by anti-FH autoantibodies. Therefore, mini-FH could potentially be used as a complement inhibitor targeting host surfaces, as well as to replace compromised FH in diseases associated with FH dysfunctio

Actualización en síndrome hemolítico urémico atípico: diagnóstico y tratamiento. Documento de consenso. Revisión

Podeu consultar la versió en castellà del document a: http://dx.doi.org/10.1016/j.nefro.2015.07.005Haemolytic uraemic syndrome (HUS) is a clinical entity defined as the triad of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). Different causes can induce the TMA process that characterises HUS. In this document we consider atypical HUS (aHUS) a sub-type of HUS in which the TMA phenomena are the consequence of the endotelial damage in the microvasculature of the kidneys and other organs due to a disregulation of the activity of the complement system. In recent years, a variety of aHUs-related mutations have been identified in genes of the complement system, which can explain approximately 60% of the aHUS cases, and a number of mutations and polymorphisms have been functionally characterised. These findings have stablished that aHUS is a consequence of the insufficient regulation of the activation of the complement on cell surfaces, leading to endotelial damage mediated by C5 and the complement terminal pathway. Eculizumab is a monoclonal antibody that inhibits the activation of C5 and blocks the generation of the pro-inflammatory molecule C5a and the formation of the cell membrane attack complex. In prospective studies in patients with aHUS, the use of Eculizumab has shown a fast and sustained interruption of the TMA process and it has been associated with significative long-term improvements in renal function, the interruption of plasma therapy and important reductions in the need of dialysis. According to the existing literature and the accumulated clinical experience, the Spanish aHUS Group published a consensus document with recommendations for the treatment of aHUs (Nefrologia 2013;33[1]:27-45). In the current online version of this document, we update the aetiological classification of TMAs, the pathophysiology of aHUS, its differential diagnosis and its therapeutic management

Thrombomodulin enhances complement regulation through strong affinity interactions with factor H and C3b-Factor H complex

Introduction Coagulation and complement systems are simultaneously activated at sites of tissue injury, leading to thrombin generation and opsonisation with C3b. Thrombomodulin (TM) is a cell-bound regulator of thrombin activation, but can also enhance the regulatory activity of complement factor H (FH), thus accelerating the degradation of C3b into inactive iC3b. Objectives This study sought to determine the biophysical interaction affinities of two recombinant TM analogs with thrombin, FH and C3b in order to analyze their ability to regulate serum complement activity. Methods Surface plasmon resonance (SPR) analysis was used to determine binding affinities of TM analogs with FH and C3b, and compared to thrombin as positive control. The capacity of the two recombinant TM analogs to regulate complement in serum was tested in standard complement hemolytic activity assays. Results SPR analysis showed that both TM analogs bind FH and C3b-Factor H with nanomolar and C3b with micromolar affinity; binding affinity for its natural ligand thrombin was several fold higher than for FH. At a physiological relevant concentration, TM inhibits complement hemolytic activity in serum via FH dependent and independent mechanisms. Conclusions TM exhibits significant binding affinity for complement protein FH and C3b-FH complex and its soluble form is capable at physiologically relevant concentrations of inhibiting complement activation in serum

Factor H family proteins and human diseases

Complement is a major defense system of innate immunity and aimed to destroy microbes. One of the central complement regulators is factor H, which belongs to a protein family that includes CFHL1 and five factor H-related (CFHR) proteins. Recent evidence shows that factor H family proteins (factor H and CFHRs) are associated with diverse and severe human diseases and are also used by human pathogenic microbes for complement evasion. Therefore, dissecting the exact functions of the individual CFHR proteins will provide insights into the pathophysiology of such inflammatory and infectious diseases and will define the therapeutic potential of these proteins