Advances in understanding of pathogenesis of aHUS and HELLP (original) (raw)
Related papers
Experimental Hematology, 2016
HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) is a severe variant of preeclampsia whose pathogenesis remains unclear. Recent evidence and clinical similarities suggest a link to atypical hemolytic uremic syndrome (aHUS), a disease of excessive activation of the alternative complement pathway effectively treated with a complement inhibitor, eculizumab. Therefore, we utilized a functional complement assay, the modified Ham test, to test sera of women with classic or atypical HELLP syndrome, preeclampsia with severe features, normal pregnancies and healthy non-pregnant women. Sera were also evaluated using levels of the terminal product of complement activation (C5b-9). We tested the in vitro ability of eculizumab to inhibit complement activation in HELLP serum. Increased complement activation was found in participants with classic or atypical HELLP compared to normal pregnancy and non-pregnant controls. Mixing HELLP serum with eculizumab containing serum resulted in a significant decrease in cell killing compared to HELLP serum alone. In conclusion, HELLP syndrome is associated with increased complement activation demonstrated by the modified Ham test. This assay may aid in the diagnosis of HELLP syndrome and confirm its pathophysiology relates to aHUS.
Evaluation of complement regulatory components in patients with atypical hemolytic uremic syndrome
Central European Journal of Immunology, 2014
Background: atypical hemolytic uremic syndrome (aHus), a rare disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure, is associated with mutations and polymorphisms in various components and regulators of the complement alternative pathway (aP), including factor H, factor i, membrane cofactor protein (mCP or Cd46) and factor b. this impaired regulation of the alternative pathway leads to a procoagulant state with microthrombi formation in the renal vasculature, which influences disease onset and progression.
Atypical hemolytic-uremic syndrome: the interplay between complements and the coagulation system
Iranian journal of kidney diseases, 2013
Hemolytic-uremic syndrome (HUS) is a rare life-threatening disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and impaired renal function. A thrombotic microangiopathy underlies the clinical features of HUS. In the majority of cases, HUS follows an infection with toxin-producing bacteria such as verotoxin-producing Escherichia coli. In some cases, HUS is not preceded by a clinically apparent infection, and therefore, is named atypical HUS. The prognosis of atypical HUS is poor. While mortality approaches 25% during the acute phase, end-stage renal disease develops in nearly half of patients within a year. Evidence is accumulating that complement activation through the alternative pathway is at the heart of the pathophysiology leading to atypical HUS. Genetic abnormalities involving complement regulatory proteins and complement components form the molecular basis for complement activation. Since microvascular thrombosis is a quintessential feature of atypi...
Complement therapy in atypical haemolytic uraemic syndrome (aHUS)
Molecular Immunology, 2013
Central to the pathogenesis of atypical haemolytic uraemic syndrome (aHUS) is over-activation of the alternative pathway of complement. Inherited defects in complement genes and autoantibodies against complement regulatory proteins have been described. The use of plasma exchange to replace nonfunctioning complement regulators and hyper-functional complement components in addition to the removal of CFH-autoantibodies made this the 'gold-standard' for management of aHUS. In the last 4 years the introduction of the complement inhibitor Eculizumab has revolutionised the management of aHUS. In this review we shall discuss the available literature on treatment strategies to date.
The American journal of the medical sciences, 2016
Complement-mediated atypical hemolytic uremic syndrome (aHUS) comprises approximately 90% of cases of aHUS, and results from dysregulation of endothelial-anchored complement activation with resultant endothelial damage. The discovery of biomarker ADAMTS13 has enabled a more accurate diagnosis of thrombotic thrombocytopenic purpura (TTP) and an appreciation of overlapping clinical features of TTP and aHUS. Given our present understanding of the pathogenic pathways involved in aHUS, it is unlikely that a specific test will be developed. Rather the use of biomarker data, complement functional analyses, genomic analyses and clinical presentation will be required to diagnose aHUS. This approach would serve to clarify whether a thrombotic microangiopathy present in a complement-amplifying condition arises from the unmasking of a genetically driven aHUS versus a time-limited complement storm-mediated aHUS due to direct endothelial damage in which no genetic predisposition is present. Altho...
aHUS caused by complement dysregulation: new therapies on the horizon
Pediatric Nephrology, 2010
Atypical hemolytic uremic syndrome (aHUS) is a heterogeneous disease that is caused by defective complement regulation in over 50% of cases. Mutations have been identified in genes encoding both complement regulators [complement factor H (CFH), complement factor I (CFI), complement factor H-related proteins (CFHR), and membrane cofactor protein (MCP)], as well as complement activators [complement factor B (CFB) and C3]. More recently, mutations have also been identified in thrombomodulin (THBD), an anticoagulant glycoprotein that plays a role in the inactivation of C3a and C5a. Inhibitory autoantibodies to CFH account for an additional 5-10% of cases and can occur in isolation or in association with mutations in CFH, CFI, CFHR 1, 3, 4, and MCP. Plasma therapies are considered the mainstay of therapy in aHUS secondary to defective complement regulation and may be administered as plasma infusions or plasma exchange. However, in certain cases, despite initiation of plasma therapy, renal function continues to deteriorate with progression to end-stage renal disease and renal transplantation. Recently, eculizumab, a humanized monoclonal antibody against C5, has been described as an effective therapeutic strategy in the management of refractory aHUS that has failed to respond to plasma therapy. Clinical trials are now underway to further evaluate the efficacy of eculizumab in the management of both plasma-sensitive and plasma-resistant aHUS.
Pathogenesis of Atypical Hemolytic Uremic Syndrome
Journal of Atherosclerosis and Thrombosis, 2018
Atypical hemolytic uremic syndrome (aHUS) is a type of thrombotic microangiopathy (TMA) defined by thrombocytopenia, microangiopathic hemolytic anemia, and renal failure. aHUS is caused by uncontrolled complement activation in the alternative pathway (AP). A variety of genetic defects in complement-related factors or acquired autoantibodies to the complement regulators have been found in 50 to 60% of all cases. Recently, however, the classification and diagnosis of aHUS are becoming more complicated. One reason for this is that some factors, which have not been regarded as complement-related factors, have been reported as predisposing factors for phenotypic aHUS. Given that genotype is highly correlated with the phenotype of aHUS, careful analysis of underlying genetic abnormalities or acquired factors is needed to predict the prognosis or to decide an optimal treatment for the disease. Another reason is that complement dysregulation in the AP have also been found in a part of other types of TMA such as transplantation-related TMA and pregnancy-related complication. Based on these findings, it is now time to redefine aHUS according to the genetic or acquired background of abnormalities. Here, we review the pathogeneses and the corresponding phenotypes of aHUS and complement-related TMAs. aosylceramide on target cell surface and leads to cytotoxicity including protein synthesis and apoptosis, and also induces the secretion of unusually large VWF multimers from endothelial cells 4). Historically, the term "atypical HUS (aHUS)" was used to describe HUS not caused by the infection of STEC. Therefore, a category of aHUS included not only complement-related TMA, but also TMAs caused by various factors, such as drug, malignancy, pregnancy, transplantation, etc. However, since 1980s, various clinical and experimental studies have shown that 50% to 60% cases of aHUS arise from inherited and/or acquired complement abnormalities in the alternative pathway (AP). According to these progresses, the term "aHUS" came to be used to only describe complement-mediated aHUS and was distinguished from TMAs with coexisting disease or triggers, which were named "secondary TMA" in the criteria of Japan 5, 6). The classification of aHUS and secondary TMA, however, remains controversial. More
Atypical hemolytic-uremic syndrome due to complement factor I mutation
World journal of nephrology, 2017
Atypical hemolytic-uremic syndrome (aHUS) is a rare disease of complement dysregulation leading to thrombotic microangiopathy (TMA). Renal involvement and progression to end-stage renal disease are common in untreated patients. We report a 52-year-old female patient who presented with severe acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia. She was managed with steroid, plasma exchange, and dialysis. Kidney biopsy shows TMA and renal cortical necrosis. Genetic analysis reveals heterozygous complement factor I (CFI) mutation. Eculizumab was initiated after 3 mo of presentation, continued for 9 mo, and stopped because of sustained hematologic remission, steady renal function, and cost issues. Despite this, the patient continued to be in hematologic remission and showed signs of renal recovery, and peritoneal dialysis was stopped 32 mo after initiation. We report a case of aHUS due to CFI mutation, which, to the best of our knowledge, has not been reported b...