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Atypical Haemolytic Uraemic Syndrome (aHUS) is a thrombotic microangiopathy that often provokes irreversible renal damage and post-transplantation recurrence. Studies performed during the last decade have shown that 50–60% of aHUS patients present genetic or acquired defects in the complement system that enhance the initial endothelial damage and favour disease development. This review analyses the complement proteins and processes that are disturbed in aHUS patients, and outlines the relevance of a prompt genetic/molecular diagnosis for improving clinical management and prognosis. [ABSTRACT FROM AUTHOR]

Genetic studies have demonstrated the involvement of the complement regulator factor H in nondiarrheal, nonverocytotoxin (i.e., atypical) cases of hemolytic uremic syndrome. Different factor H mutations have been identified in 10%-30% of patients with atypical hemolytic uremic syndrome (aHUS), and most of these mutations alter single amino acids in the C-terminal region of factor H. Although these mutations are considered to be responsible for the disease, the precise role that factor H plays in the pathogenesis of aHUS is unknown. We report here the structural and functional characterization of three different factor H proteins purified from the plasma of patients with aHUS who carry the factor H mutations W1183L, V1197A, or R1210C. Structural anomalies in factor H were found only in R1210C carriers; these individuals show, in their plasma, a characteristic high-molecular-weight factor H protein that results from the covalent interaction between factor H and human serum albumin. Most important, all three aHUS-associated factor H proteins have a normal cofactor activity in the proteolysis of fluidphase C3b by factor I but show very low binding to surface-bound C3b. This functional impairment was also demonstrated in recombinant mutant factor H proteins expressed in COS7 cells. These data support the hypothesis that patients with aHUS carry a specific dysfunction in the protection of cellular surfaces from complement activation, offering new possibilities to improve diagnosis and develop appropriate therapies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract The complement system is a complex and autoregulated multistep cascade at the interface of innate and adaptive immunity. It is activated by immune complexes or apoptotic cells (classical pathway), pathogen-associated glycoproteins (lectin pathway) or a variety of molecular and cellular surfaces (alternative pathway). Upon activation, complement triggers the generation of proteolytic fragments that allow the elimination of the activating surface by enhancing inflammation, opsonization, phagocytosis, and cellular lysis. Moreover, complement efficiently discriminates self from non-self surfaces by means of soluble and membrane-bound complement regulators which are critical for innate self-tolerance. Complement deficiency or dysfunction disturb complement homeostasis and give rise to diseases as diverse as bacterial infections, autoimmunity, or renal and neurological disorders. Research on complement-targeted therapies is an expanding field that has already improved the prognosis of severe diseases such as atypical Haemolytic Uremic syndrome or Paroxysmal Nocturnal Haemoglobinuria. Therefore, complement analysis and monitoring provides valuable information with deep implications for diagnosis and therapy. In addition to its important role as an extracellular defense system, it has now become evident that complement is also present intracellularly, and its activation has profound implications for leukocyte survival and function. In this review, we summarize the essential, up-to-date information on the use of complement as a diagnostic and therapeutic tool in the clinics. [ABSTRACT FROM AUTHOR]

Factor H (FH) autoantibodies are present in 6–10% of atypical hemolytic uremic syndrome (aHUS) patients, most of whom have homozygous deficiency of the FH-related protein FHR-1. Although the pathogenic role of the autoantibodies is established, little is known about their molecular characteristics and changes over time. Here, we describe the specificity and other immunological features of anti-FH autoantibodies in the Spanish and Hungarian aHUS cohorts. A total of 19 patients were included and serial samples of 14 of them were available. FH autoantibodies from FHR-1 deficient patients ( n = 13) mainly recognized FH, its SCR19-20 fragment and FHR-1, but autoantibody specificity in patients who are homo- or heterozygous for the CFHR1 gene ( n = 6) was heterogeneous. No significant changes apart from total antibody titer were observed during follow-up in each patient. Fine epitope mapping with recombinant FH SCR19-20 containing single amino acid mutations showed significantly reduced binding in 6 out of 14 patients. In most cases, autoantibody binding to residues 1183–1189 and 1210–1215 was impaired, revealing a major common autoantibody epitope. Avidities showed variations between patients, but in most cases the avidity index did not change upon time. Most autoantibodies were IgG3, and all but three presented only with kappa or with lambda light chains. Although the pathogenic role of anti-FH autoantibodies in aHUS is well established, this study shows autoantibody heterogeneity among patients, but no significant variation in their characteristics over time in each patient. The presence of a single light chain in 16 out of 19 patients and the limited number of recognized epitopes suggest a restricted autoantibody response in most patients. [ABSTRACT FROM AUTHOR]

Atypical hemolytic uremic syndrome (aHUS) is a severe thrombotic microangiopathy affecting the renal microvasculature and is associated with complement dysregulation caused by mutations or autoantibodies. Disease penetrance and severity is modulated by inheritance of “risk” polymorphisms in the complement genes MCP , CFH and CFHR1 . We describe the prevalence of mutations, the frequency of risk polymorphisms and the occurrence of anti-FH autoantibodies in a Spanish aHUS cohort ( n = 367). We also report the identification of a polymorphism in CFHR3 (c.721C>T; rs379370) that is associated with increased risk of aHUS (OR = 1.78; CI 1.22–2.59; p = 0.002), and is most frequently included in an extended risk haplotype spanning the CFH-CFHR3-CFHR1 genes. This extended haplotype integrates polymorphisms in the promoter region of CFH and CFHR3 , and is associated with poorer evolution of renal function and decreased FH levels. The CFH-CFHR3-CFHR1 aHUS-risk haplotype seems to be the same as was previously associated with protection against meningococcal infections, suggesting that the genetic variability in this region is limited to a few extended haplotypes, each with opposite effects in various human diseases. These results suggest that the combination of quantitative and qualitative variations in the complement proteins encoded by CFH , CFHR3 and CFHR1 genes is key for the association of these haplotypes with disease. [ABSTRACT FROM AUTHOR]

Atypical hemolytic uremic syndrome (aHUS) associates with complement dysregulation caused by mutations and polymorphisms in complement activators and regulators. However, the reasons why some mutations in complement proteins predispose to aHUS are poorly understood. Here, we have investigated the functional consequences of three aHUS-associated mutations in C3, R592W, R161W and I1157T. First, we provide evidence that penetrance and disease severity for these mutations is modulated by inheritance of documented “risk” haplotypes as has been observed with mutations in other complement genes. Next, we show that all three mutations markedly reduce the efficiency of factor I-mediated C3b cleavage when catalyzed by membrane cofactor protein (MCP), but not when catalyzed by factor H. Biacore analysis showed that each mutant C3b bound sMCP (recombinant soluble MCP; CD46) at reduced affinity, providing a molecular basis for its reduced cofactor activity. Lastly, we show by electron microscopy structural analysis a displacement of the TED domain from the MG ring in C3b in two of the C3 mutants that explains these defects in regulation. As a whole our data suggest that aHUS-associated mutations in C3 selectively affect regulation of complement on surfaces and provide a structural framework to predict the functional consequences of the C3 genetic variants found in patients. [ABSTRACT FROM AUTHOR]

Highlights: [•] Autoantibodies to complement proteins are relevant to kidney diseases and treatment. [•] Pathogenic factor H autoantibodies are common in aHUS, rare in C3 glomerulopathy. [•] C3 nephritic factor is common in C3 glomerulopathy, but detection is challenging. [•] Autoantibodies to factor B, factor I and C3b are rare, with unknown significance. [Copyright &y& Elsevier]

Highlights: [•] FH circulating in complexes can cause discrepancies in FH quantification. [•] We propose an ELISA assay with two monoclonal antibodies to quantify FH. [•] This assay allows us to estimate the amount of free circulating FH. [•] This method detects FH-C3b and FH-IgG complexes in FI-deficients and aHUS patients. [Copyright &y& Elsevier]

Background: Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by dysregulation of the complement system. Outcomes of kidney transplantation are poor owing to aHUS recurrence and loss of graft. Patients carrying CFH mutations or CFH/CFHR1 hybrid genes present a very high risk of recurrence despite preventive plasmapheresis. Evaluation of recent data suggests that prophylactic eculizumab pretransplant might be the preferred therapy if available. Case-diagnosis/treatment: We report 3-year follow-up data in a 9-year-old boy with aHUS and successful renal transplant treated with prophylactic eculizumab without recurrence. He presented with aHUS at age 3, irreversible renal failure and uncontrolled severe hypertension with concentric left ventricular hypertrophy, recurrent acute pulmonary edema, and congestive heart failure despite five hypotensive agents and bilateral nephrectomy. Complement analysis demonstrated the presence of a CFH/CFHR1 hybrid gene inherited from his mother and a SNP risk CFH haplotype inherited from his father. Kidney transplant was performed with prophylactic eculizumab and subsequent fortnightly administration. Three years post-transplant, graft function remains stable (serum creatinine 0.9 mg/dl), hypertension is controlled, no left ventricular hypertrophy, no opportunistic infections, and negative clinical chemistry parameters for hemolysis. Conclusion: Eculizumab is a safe and effective therapy for preventing TMA recurrence and provides long-term graft function in aHUS with the CFH/CFHR1 hybrid gene. [ABSTRACT FROM AUTHOR]

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 dysfunction. [ABSTRACT FROM AUTHOR]

C3 glomerulopathies (C3G) are a group of severe renal diseases with distinct patterns of glomerular inflammation and C3 deposition caused by complement dysregulation. Here we report the identification of a familial C3G-associated genomic mutation in the gene complement factor H--related 1 (CFHR1), which encodes FHR1. The mutation resulted in the duplication of the N-terminal short consensus repeats (SCRs) that are conserved in FHR2 and FHR5. We determined that native FHR1, FHR2, and FHR5 circulate in plasma as homo- and hetero-oligomeric complexes, the formation of which is likely mediated by the conserved N-terminal domain. In mutant FHR1, duplication of the N-terminal domain resulted in the formation of unusually large multimeric FHR complexes that exhibited increased avidity for the FHR1 ligands C3b, iC3b, and C3dg and enhanced competition with complement factor H (FH) in surface plasmon resonance (SPR) studies and hemolytic assays. These data revealed that FHR1, FHR2, and FHR5 organize a combinatorial repertoire of oligomeric complexes and demonstrated that changes in FHR oligomerization influence the regulation of complement activation. In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G. [ABSTRACT FROM AUTHOR]

C3 glomerulopathies (C3G) are a group of severe renal diseases with distinct patterns of glomerular inflammation and C3 deposition caused by complement dysregulation. Here we report the identification of a familial C3G-associated genomic mutation in the gene complement factor H–related 1 (CFHR1), which encodes FHR1. The mutation resulted in the duplication of the N-terminal short consensus repeats (SCRs) that are conserved in FHR2 and FHR5. We determined that native FHR1, FHR2, and FHR5 circulate in plasma as homo- and hetero-oligomeric complexes, the formation of which is likely mediated by the conserved N-terminal domain. In mutant FHR1, duplication of the N-terminal domain resulted in the formation of unusually large multimeric FHR complexes that exhibited increased avidity for the FHR1 ligands C3b, iC3b, and C3dg and enhanced competition with complement factor H (FH) in surface plasmon resonance (SPR) studies and hemolytic assays. These data revealed that FHR1, FHR2, and FHR5 organize a combinatorial repertoire of oligomeric complexes and demonstrated that changes in FHR oligomerization influence the regulation of complement activation. In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G. [ABSTRACT FROM AUTHOR]

C3 glomerulopathies (C3G) are a group of severe renal diseases with distinct patterns of glomerular inflammation and C3 deposition caused by complement dysregulation. Here we report the identification of a familial C3G-associated genomic mutation in the gene complement factor H-related 1 (CFHR1), which encodes FHR1. The mutation resulted in the duplication of the N-terminal short consensus repeats (SCRs) that are conserved in FHR2 and FHR5. We determined that native FHR1, FHR2, and FHR5 circulate in plasma as homo- and hetero-oligomeric complexes, the formation of which is likely mediated by the conserved N-terminal domain. In mutant FHR1, duplication of the N-terminal domain resulted in the formation of unusually large multimeric FHR complexes that exhibited increased avidity for the FHR1 ligands C3b, iC3b, and C3dg and enhanced competition with complement factor H (FH) in surface plasmon resonance (SPR) studies and hemolytic assays. These data revealed that FHR1, FHR2, and FHR5 organize a combinatorial repertoire of oligomeric complexes and demonstrated that changes in FHR oligomerization influence the regulation of complement activation. In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G. [ABSTRACT FROM AUTHOR]

Atypical hemolytic uremic syndrome (aHUS) is a renal disease associated with complement alternative pathway dysregulation and is characterized by endothelial injury. Pentraxin 3 (PTX3) is a soluble pattern recognition molecule expressed by endothelial cells and upregulated under inflammatory conditions. PTX3 activates complement, but it also binds the complement inhibitor factor H. In this study, we show that native factor H, factor H-like protein 1, and factor H-related protein 1 (CFHR1) bind to PTX3 and that PTX3-bound factor H and factor H-Iike protein 1 maintain their complement regulatory activities. PTX3, when bound to extracellular matrix, recruited functionally active factor H. Residues within short consensus repeat 20 of factor H that are relevant for PTX3 binding were identified using a peptide array. aHUS-associated factor H mutations within this binding site caused a reduced factor H binding to PTX3. Similarly, seven of nine analyzed anti-factor H autoantibodies isolated from aHUS patients inhibited the interaction between factor H and PTX3, and five autoantibodies also inhibited PTX3 binding to CFHR1. Moreover, the aHUS-associated CFHR1*B variant showed reduced binding to PTX3 in comparison with CFHR1*A. Thus, the interactions of PTX3 with complement regulators are impaired by certain mutations and autoantibodies affecting factor H and CFHR1, which could result in an enhanced local complement-mediated inflammation, endothelial cell activation, and damage in aHUS. [ABSTRACT FROM AUTHOR]

Complement alternative pathway dysregulation seems to be the pathophysiological basis of Dense Deposit Disease (DDD). Here, we describe a monoclonal anti-factor H (FH) autoantibody in a woman diagnosed with DDD with a monoclonal gammapathy. Enzyme-linked immunosorbent assays evidenced the presence of anti-FH antibodies in the patient's serum and showed that they were associated with the monoclonal IgG-λ fraction. These autoantibodies recognize the N-terminal region of FH and interfere with its regulatory function. In summary, in the DDD patient described here, the activation of complement alternative pathway was favoured by the presence of anti-FH autoantibodies that recognize the regulatory region of this protein and impede its function and which could ultimately cause the glomerulopathy. [ABSTRACT FROM PUBLISHER]

Mutations and polymorphisms in the gene-encoding factor H (CFH) are associated with atypical hemolytic uremic syndrome, dense deposit disease, and age-related macular degeneration. Many of these CFH genetic variations disrupt the regulatory role of factor H, supporting the concept that dysregulation of complement is a unifying pathogenic feature of these disorders. Evidence of a causal relationship with the disease is, however, not available for all CFH genetic variations found in patients, which is a potential cause of misinterpretations with important consequences for the patients and their relatives. CFH I890 and L1007 are two genetic variations repeatedly associated with atypical hemolytic uremic syndrome and also found in patients with dense deposit disease and age-related macular degeneration. Here we report an extensive genetic and functional analysis of these CFH variants. Our results indicate that I890 and L1007 segregate together as part of a distinct and relatively infrequent CFH haplotype in Caucasians. Extensive analysis of the S890/V1007 (control) and I890/L1007 (disease-associated) factor H protein variants failed to provide evidence that these amino acid changes have functional implications. Thus, the presence of the I890 and L1007 variants in healthy individuals and their high frequency in sub-Saharan African and African-American populations strongly suggest that I890 and L1007 are rare factor H polymorphisms unrelated to disease. [ABSTRACT FROM AUTHOR]

Mutations and polymorphisms in the gene-encoding factor H (CFH) are associated with atypical hemolytic uremic syndrome, dense deposit disease, and age-related macular degeneration. Many of these CFH genetic variations disrupt the regulatory role of factor H, supporting the concept that dysregulation of complement is a unifying pathogenic feature of these disorders. Evidence of a causal relationship with the disease is, however, not available for all CFH genetic variations found in patients, which is a potential cause of misinterpretations with important consequences for the patients and their relatives. CFH I890 and L1007 are two genetic variations repeatedly associated with atypical hemolytic uremic syndrome and also found in patients with dense deposit disease and age-related macular degeneration. Here we report an extensive genetic and functional analysis of these CFH variants. Our results indicate that I890 and L1007 segregate together as part of a distinct and relatively infrequent CFH haplotype in Caucasians. Extensive analysis of the S890/V1007 (control) and I890/L1007 (disease-associated) factor H protein variants failed to provide evidence that these amino acid changes have functional implications. Thus, the presence of the I890 and L1007 variants in healthy individuals and their high frequency in sub-Saharan African and African-American populations strongly suggest that I890 and L1007 are rare factor H polymorphisms unrelated to disease. [ABSTRACT FROM AUTHOR]

The autoimmune form of atypical hemolytic uremic syndrome (HUS) is characterized by circulating autoantibodies against the complement regulator factor H, and is often associated with deficiency of the factor H-related proteins CFHR1 and CFHR3. Here we studied whether anti-factor H autoantibodies crossreact with CFHR1, and determined functional consequences of this. In ELISA, anti-factor H immunoglobulin G (IgG) autoantibodies from 24 atypical HUS patients bound to the short consensus repeat 20 domain of factor H, 21 antibodies also recognized CFHR1, but none CFHR3. Three patients also had anti-factor H IgA autoantibodies crossreacting with CFHR1. Analysis of the IgG fractions in CFHR1-deficient patients found that CFHR1-IgG complexes were formed during plasma exchange treatment, indicating that autoantibodies recognize CFHR1 in vivo. Recombinant CFHR1 prevented hemolysis of sheep erythrocytes caused by patient plasma containing anti-factor H IgG, but it did not inhibit red cell lysis caused by a factor H mutation (W1183 L) in the short consensus repeat 20 domain. Thus, exogenous CFHR1 provided during plasma exchange therapy may neutralize anti-factor H autoantibodies and help in the treatment of autoimmune atypical HUS. [ABSTRACT FROM AUTHOR]

Abstract: Age-related macular degeneration (AMD) and membranoproliferative glomerulonephritis type II (MPGN2) are dense deposit diseases that share a genetic association with complement genes and have complement proteins as important components of the dense deposits. Here, we present the case of a 64-year-old smoker male who developed both AMD and MPGN2 in his late 50s. The patient presented persistent low plasma levels of C3, factor H levels in the lower part of the normal range and C3NeF traces. Genetic analyses of the CFH, CFB, C3, CFHR1-CFHR3 and LOC387715/HTRA1 genes revealed that the patient was heterozygote for a novel missense mutation in exon 9 of CFH (c.1292 G>A) that results in a Cys431Tyr substitution in SCR7 of the factor H protein. In addition, he was homozygote for the His402 CFH allele, heterozygote for the Ser69 LOC387715 allele, homozygote for the Arg32 (BFS) CFB allele, heterozygote for the Gly102 (C3F) C3 allele and carried no deletion of the CFHR1/CFHR3 genes. Proteomic and functional analyses indicate absence in plasma of the factor H allele carrying the Cys431Tyr mutation. As a whole, these data recapitulate a prototypical complement genetic profile, including a partial factor H deficiency and the presence of major risk factors for AMD and MPGN2, which support the hypothesis that these dense deposit diseases have a common pathogenic mechanism involving dysregulation of the alternative pathway of complement activation. [Copyright &y& Elsevier]

Abstract: Complement Factor I (CFI) is a regulator of the classical and alternative pathways. CFI has enzymatic activity and is able to cleave C3b and C4b. Homozygous Factor I deficiency is associated with infectious and/or autoimmune diseases. Here we describe the biochemical and genetic characterization in two Spanish families with complete Factor I deficiency. In Family 1, the propositus suffered from several episodes of meningitis for more than a year. Biochemical complement studies showed undetectable Factor I levels in the propositus and in her sister, while their parents and a brother had partial Factor I deficiency and were healthy. In Family 2, three out of five children were homozygous for Factor I deficiency, two of whom suffered from meningitis and the third one from several infections. The parents and the other two siblings were healthy and heterozygous for Factor I deficiency. Molecular studies showed that the two families had different mutations at exon 5 of the Factor I gene, which codifies for module LDLr1. One mutation corresponds to a 772G>A change at the donor splice site that was originally found in a family from Northern England. The second is a new missense mutation 739T>G, that generates a Cys to Gly change. [Copyright &y& Elsevier]

Hemolytic uremic syndrome (HUS) is an important cause of acute renal failure in children. Mutations in one or more genes encoding complement-regulatory proteins have been reported in approximately one-third of nondiarrheal, atypical HUS (aHUS) patients, suggesting a defect in the protection of cell surfaces against complement activation in susceptible individuals. Here, we identified a subgroup of aHUS patients showing persistent activation of the complement alternative pathway and found within this subgroup two families with mutations in the gene encoding factor B (BF), a zymogen that carries the catalytic site of the complement alternative pathway convertase (C3bBb). Functional analyses demonstrated that F286L and K323E aHUS-associated BF mutations are gain-of-function mutations that result in enhanced formation of the C3bBb convertase or increased resistance to inactivation by complement regulators. These data expand our understanding of the genetic factors conferring predisposition to aHUS, demonstrate the critical role of the alternative complement pathway in the pathogenesis of aHUS, and provide support for the use of complement-inhibition therapies to prevent or reduce tissue damage caused by dysregulated complement activation. [ABSTRACT FROM AUTHOR]

Abstract: Mutations in the complement regulators factor H, membrane cofactor protein (MCP), and factor I are associated with atypical hemolytic uremic syndrome (aHUS, MIM 235400), suggesting that the disease develops as a consequence of the inefficient protection of the renal endothelium from damage by the complement system. Incomplete penetrance of the disease in individuals carrying these mutations is, however, relatively frequent. Here, we report the identification of a large, multiple affected aHUS pedigree in which there is independent segregation of three different aHUS risk factors: a MCP missense mutation (c.-598C>T; Pro165Ser) that decreases MCP expression on the cell surface, a dinucleotide insertion in the coding sequence of factor I (c.-1610insAT) that introduces a premature stop codon in the factor I protein, and the MCPggaac SNP haplotype block that was previously shown to decrease the transcription activity from the MCP promoter. Interestingly, individuals affected by aHUS in the pedigree are only those who have inherited the three aHUS risk factors. These data show an additive effect for mutations in MCP and factor I and provide definitive support to the conclusion that aHUS results from a defective protection of cellular surfaces from complement activation. Furthermore, they help to explain the incomplete penetrance of the disease, illustrating that concurrence of multiple hits in complement regulatory proteins may be necessary to significantly impair host tissue protection and to confer susceptibility to aHUS. [Copyright &y& Elsevier]

Factor H is an essential regulatory protein that plays a critical role in the homeostasis of the complement system in plasma and in the protection of bystander host cells and tissues from damage by complement activation. Genetic and structural data generated during recent years have been instrumental to delineate the functional domains responsible for these regulatory activities in factor H, which is helping to understand the molecular basis underlying the different pathologies associated to factor H. This review summarises our current knowledge of the role of factor H in health and disease. [Copyright &y& Elsevier]

Atypical haemolytic uraemic syndrome (aHUS) is a rare and life-threatening disease caused by complement system dysregulation leading to uncontrolled complement activation and thrombotic microangiopathy. We report the case of an adult patient with plasmaphaeresis-resistant aHUS and hypertension treated with the complement inhibitor eculizumab. Eculizumab was shown to completely inhibit haemolysis, normalize thrombocyte levels and increase diuresis. Full recovery of renal function was not possible due to irreversible renal damage prior to eculizumab initiation. These findings highlight the importance of early treatment with eculizumab in patients with poor response to standard therapy, in order to avoid irreversible renal damage. [ABSTRACT FROM PUBLISHER]