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


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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    • "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.
    Journal of Clinical Research in Pediatric Endocrinology 03/2014; 6(1):47-50. DOI:10.4274/Jcrpe.1128
    • "Serum creatinine at the first episode determines renal survival in the 1st year.[19] Familial or sporadic occurrence, age and C3 level are not responsible for the final prognosis.[12] "
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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.
    International journal of preventive medicine 01/2013; 4(1):6-14.
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    • "In typical hemolytic uremic syndrome, renal function is preserved in 75% of cases, whereas the majority of patients with atypical hemolytic uremic syndrome develop end-stage renal disease or die.8,9,15,16 In the acute phase of hemolytic uremic syndrome, mortality is 3%–5%. "
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    ABSTRACT: This case report describes how eculizumab reversed neurologic impairment and improved renal damage in severe atypical hemolytic uremic syndrome. A 50-year-old female, after presenting with diarrhea and abdominal pain, developed pancolitis, acute renal failure, and thrombocytopenia. The patient underwent total abdominal colectomy. Pathology confirmed ischemic colitis with scattered mesenteric microthrombi. Due to mental and respiratory decline, she remained intubated. Continuous venovenous hemodialysis was initiated. Renal failure, neurologic changes, hemolysis, thrombotic microangiopathy, and low complement levels all suggested atypical hemolytic uremic syndrome. Eculizumab 900 mg was administered intravenously on hospital day 6 and continued weekly for four doses followed by maintenance therapy. She recovered neurologically and renally after the third dose, and hematologically by the sixth dose. Her recovery has been sustained on long-term eculizumab treatment. In severe atypical hemolytic uremic syndrome, eculizumab safely reverses neurologic impairment and eliminates the need for dialysis. The optimal duration of treatment with eculizumab remains to be determined.
    Clinical Pharmacology: Advances and Applications 05/2011; 3(1):5-12. DOI:10.2147/CPAA.S17904
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