Article

Complement and the atypical hemolytic uremic syndrome

Hôpitaux de Paris, Université Paris 7, Hôpital Robert Debré, Pediatric Nephrology, Paris, France.
Pediatric Nephrology (Impact Factor: 2.86). 08/2008; 23(11):1957-72. DOI: 10.1007/s00467-008-0872-4
Source: PubMed

ABSTRACT

Over the past decade, atypical hemolytic uremic syndrome (aHUS) has been demonstrated to be a disorder of the regulation of the complement alternative pathway. Among approximately 200 children with the disease, reported in the literature, 50% had mutations of the complement regulatory proteins factor H, membrane cofactor protein (MCP) or factor I. Mutations in factor B and C3 have also been reported recently. In addition, 10% of children have factor H dysfunction due to anti-factor H antibodies. Early age at onset appears as characteristic of factor H and factor I mutated patients, while MCP-associated HUS is not observed before age 1 year. Low C3 level may occur in patients with factor H and factor I mutation, while C3 level is generally normal in MCP-mutated patients. Normal plasma factor H and factor I levels do not preclude the presence of a mutation in these genes. The worst prognosis is for factor H-mutated patients, as 60% die or reach end-stage renal disease (ESRD) within the first year after onset of the disease. Patients with mutations in MCP have a relapsing course, but no patient has ever reached ESRD in the first year of the disease. Half of the patients with factor I mutations have a rapid evolution to ESRD, but half recover. Early intensive plasmatherapy appears to have a beneficial effect, except in MCP-mutated patients. There is a high risk of graft loss for HUS recurrence or thrombosis in all groups except the MCP-mutated group. Recent success of liver-kidney transplantation combined with plasmatherapy opens this option for patients with mutations of factors synthesized in the liver. New therapies such as factor H concentrate or complement inhibitors offer hope for the future.

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    • "We found mutations in CD46 in 14.8% of patients, this rate is corresponding to the previously published European and American cohorts, while mutations in CFH, CFI, C3 and CFB occurred more frequently than in previously published large cohorts: we found 13 mutations in CFH (48.1% versus 20–30%), 4 mutations in CFI (14.8% versus 4–10%), 3 mutations in C3 (11.1% versus 2–10%) as well as 3 mutations in CFB (11.1% versus 1–4%), and no mutation was found in THBD (previously reported frequency is 3–5%) (Caprioli et al., 2006; Loirat and Fremeaux-Bacchi, 2011; Maga et al., 2010; Noris et al., 2010). We found more than one mutation in 8 patients (26.7%) a rate which is also higher than the previously published occurrence (3–12%) (Loirat and Fremeaux-Bacchi, 2011; Noris et al., 2010). Frequency of H3 risk haplotype was 0.26 in our patients while frequency of MCP ggaac risk haplotype was found to be 0.57, corresponding to the previously published frequencies in aHUS patients (0.29–0.37 and 0.44–0.61, "
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    ABSTRACT: Atypical hemolytic uremic syndrome (aHUS) is a rare disorder caused by dysregulation of the complement alternative pathway, and associated with mutations in genes of complement components and regulators. In the recent years several studies have been published describing these mutations, however, no data is available from the Central and Eastern European region. In this study we present a detailed genetic analysis of our 30 patients, hospitalized with the diagnosis of aHUS in the past 7 years. We analyzed the genetic variants of genes CFH, CFI, CD46, THBD, CFB and C3; furthermore the possible effect of mutations that may alter the function or level of factor H protein was also investigated. We identified 27 (12 novel and 15 previously described) potentially disease-causing mutations in the candidate genes in 23 patients. Genetic analysis of family members revealed that in most cases the disease develops in individuals with multiple genetic risk factors, which may explain the low penetrance of the mutations. Here we showed that two novel mutations (p.W198R, p.P1161T) and a previously reported one (p.R1215Q) in CFH caused impaired regulation as indicated by increased lysis in hemolytic test, while four CFH mutations (p.V609D, p.S722X, p.T1216del and p.C448Y) were associated with decreased factor H protein level in serum as determined by allele-specific immunoassay. These results further point to the necessity of complete genetic workup of patients with aHUS and to the importance of functional characterization of novel variations.
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    • "Atypical HUS is responsible for 10-15 percent of all HUS cases encountered in children and is associated with various non-enteric infections, drugs, malignancies, transplantation and other underlying autoimmune diseases such as scleroderma, anti-phospholipid syndrome and SLE. Although thrombotic thrombocytopenic purpura (TTP) is related to the deficiency of metalloprotease ADAMTS 13 which is involved in the regulation of von Willebrand factor, both HUS and TTP share the same findings (5,6,7,8). Therefore, HUS and TTP fall into the broader category of thrombotic microangiopathies. Atypical HUS mainly develops due to mutations in the genes encoding the complement proteins including C3, factors H, B, I and CD46 (membrane cofactor protein, MCP). "
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    ABSTRACT: Autoimmune polyglandular syndrome (APS) is a disorder which is associated with multiple endocrine gland insufficiency and also with non-endocrine manifestations. The pathophysiology of APS is poorly understood, but the hallmark evidence of APS is development of autoantibodies against multiple endocrine and non-endocrine organs. These autoantibodies are responsible for the dysfunction of the affected organs and sometimes may also cause non-endocrine organ dysfunction. The hemolytic-uremic syndrome (HUS) is a serious and life-threatening disease which develops due to many etiological factors including autoimmune disorders. Here, we present an unusual case of APS. Ectodermal dysplasia with immune deficiency and HUS occurred concomitantly in the same patient with APS type 3c. Once the autoantibody generation was initiated in the human body, development of multiple disorders due to organ dysfunction and also autoantibody-related diseases may have occurred.
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    ABSTRACT: Hemolytic uremic syndrome (HUS) is a heterogeneous group of hemolytic disorders. Different terminologies have been described in HUS, which are as follows: (1) D+ HUS: Presentation with a preceding diarrhea; (2) typical HUS: D+ HUS with a single and self-limited episode; (3) atypical HUS (aHUS): Indicated those with complement dysregulation; (4) recurrent HUS: Recurrent episodes of thrombocytopenia and/or microangiopathic hemolytic anemia (MAHA) after improvement of hematologic abnormalities; and (5) familial HUS: Necessary to distinct synchronous outbreaks of D+ HUS in family members and asynchronous disease with an inherited risk factor. aHUS is one of the potential causes of end-stage renal disease (ESRD) in children. It has a high recurrence after renal transplantation in some genetic forms. Therefore, recognition of the responsible mechanism and proper prophylactic treatment are recommended to prevent or delay the occurrence of ESRD and prolong the length of survival of the transplanted kidney. A computerized search of MEDLINE and other databases was carried out to find the latest results in pathogenesis, treatment, and prevention of aHUS.
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