Membrane Cofactor Protein Mutations Research Articles

Thrombotic microangiopathy and smoldering multiple myeloma after kidney transplant in a patient with MCP mutation

The most frequent cause of atypical hemolytic uremic syndrome (aHUS) is defective regulation of complement activation because of genetic anomalies. We present the case of 53-year-old man with a kidney transplant and stabilized kidney function (creatinine 2.5 mg/dL; proteinuria 0.4 g/24 h) with mycophenolate/tacrolimus/prednisone who was diagnosed of Thrombotic Microangiopathy (TMA). This diagnosis was associated with creatinine and proteinuria rise (3 mg/dL; 2.4 g/24 h) and a new monoclonal IgA/lambda component. Renal biopsy showed membranoproliferative glomerulonephritis; a pathogenic variant in the Membrane cofactor protein (MCP) gene with a polymorphism ggaac, typically associated to secondary aHUS, was identified. We suspected that immunoglobulin could be acting as a trigger for TMA in a genetically susceptible patient, so “clone-directed” therapy with bortezomib and dexamethasone was initiated.

De Novo and Recurrent Thrombotic Microangiopathy After Renal Transplantation: Current Concepts in Management.

Thrombotic microangiopathy is a well-recognized complication of kidney transplantation that leads frequently to allograft failure. This serious outcome can greatly depend on the underlying etiology and on the timing of therapeutic interventions. Thrombotic microangiopathy syndrome may occur with no previous history of thrombotic microangiopathy (that is, de novo thrombotic microangiopathy), mostly due to medica tions or infections. More frequently, it may recur after kidney transplant in patients with endstage renal failure due to atypical hemolytic uremic syndrome. However, for patients with Shiga-toxininduced hemolytic uremic syndrome, particularly pediatric patients, there is a favorable prognosis. A fundamental tool for management of this disease is genetic screening for abnormal mutations; this can recognize the suggested approach of therapy and may determine the outcome of the disease to a large extent. Although patients with complement factor H and I mutations have worse prognosis, other patients with membrane cofactor protein mutations, for example, have a more favorable prognosis. Accordingly, the plan of therapy can be tailored with a better chance of cure. Unfortunately, the successful use of the biological agent eculizumab, an anti-C5 agent, in some of these syndromes is largely impeded by its high cost, which is linked to its use as a life-long therapy. However, newly suggested therapeutic options may ameliorate this drawback.

Different approaches to long-term treatment of aHUS due to MCP mutations: a multicenter analysis

BackgroundAtypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening microangiopathy, frequently causing kidney failure. Inhibition of the terminal complement complex with eculizumab is the only licensed treatment but mostly requires long-term administration and risks severe side effects. The underlying genetic cause of aHUS is thought to influence the severity of initial and recurring episodes, with milder courses in patients with mutations in membrane cofactor protein (MCP).MethodsTwenty pediatric cases of aHUS due to isolated heterozygous MCP mutations were reported from 12 German pediatric nephrology centers to describe initial presentation, timing of relapses, treatment, and kidney outcome.ResultsThe median age of onset was 4.6 years, with a female to male ratio of 1:3. Without eculizumab maintenance therapy, 50% (9/18) of the patients experienced a first relapse after a median period of 3.8 years. Kaplan-Meier analysis showed a relapse-free survival of 93% at 1 year. Four patients received eculizumab long-term treatment, while 3 patients received short courses. We could not show a benefit from complement blockade therapy on long term kidney function, independent of short-term or long-term treatment. To prevent 1 relapse with eculizumab, the theoretical number-needed-to-treat (NNT) was 15 for the first year and 3 for the first 5 years after initial presentation.ConclusionOur study shows that heterozygous MCP mutations cause aHUS with a risk of first relapse of about 10% per year, resulting in large NNTs for prevention of relapses with eculizumab. More studies are needed to define an optimal treatment schedule for patients with MCP mutations to minimize the risks of the disease and treatment.

Steroid Responsive Atypical Hemolytic Uremic Syndrome Triggered by Influenza B Infection

Atypical hemolytic uremic syndrome (aHUS) is characterized by uncontrolled complement activation leading to thrombotic microangiopathy and severe end-organ damage. The most common trigger for an episode of aHUS in the background of genetic deregulation of the alternative complement pathway is systemic infection. There are only 4 reported cases of aHUS triggered by influenza B thus far. Current accepted therapies for aHUS include plasma exchange and eculizumab. We describe a unique patient with aHUS with a rare membrane cofactor protein mutation triggered by influenza B infection, who achieved complete remission with treatment with high-dose corticosteroids after failure of plasmapheresis.

Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome

Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, life-threatening disease. The Global aHUS Registry collects real-world data on the natural history of the disease. Here we characterize end-stage renal disease (ESRD)-free survival, the rate of thrombotic microangiopathy, organ involvement and the genetic background of 851 patients in the registry, prior to eculizumab treatment. A sex-specific difference was apparent according to age at initial disease onset as the ratio of males to females was 1.3:1 for childhood presentation and 1:2 for adult presentation. Complement Factor I and Membrane Cofactor Protein mutations were more common in patients with initial presentation as adults and children, respectively. Initial presentation in childhood significantly predicted ESRD risk (adjusted hazard ratio 0.55 [95% confidence interval 0.41-0.73], whereas sex, race, family history of aHUS, and time from initial presentation to diagnosis, did not. Patients with a Complement Factor H mutation had reduced ESRD-free survival, whereas Membrane Cofactor Protein mutation was associated with longer ESRD-free survival. Additionally extrarenal organ manifestations occur in 19%-38% of patients within six months of initial disease presentation (dependent on organ). Thus, our real-world results provide novel insights regarding phenotypic variables and genotypes on the clinical manifestation and progression of aHUS.

Mutations in membrane cofactor protein (CD46) gene in Indian children with hemolytic uremic syndrome.

BackgroundMutations in the CD46 gene account for an important proportion of patients with atypical hemolytic uremic syndrome (aHUS) who characteristically show multiple relapses, no response to plasma exchange and low recurrence risk in allograft. We screened for mutations in CD46 in patients with and without circulating anti-factor H (FH) antibodies–associated aHUS.MethodsWe estimated CD46 surface expression by flow cytometry and sequenced the CD46 gene in 23 and 56 patients with and without circulating anti-FH antibodies, respectively. Human Splicing Finder and PolyPhen2 were used for in silico prediction of pathogenicity.ResultsTwo novel and three known (c.286 +2T > G, c.104G > A and c.565T > G) mutations in CD46 were found in nine (11.4%) patients; one patient had a variant of unknown significance and two patients presented during the first year of life. Novel intronic (c.1127 + 46C > G) and exonic (c.911C > T) mutations are proposed to activate cryptic splicing sites or alter protein conformation. Markedly reduced CD46 surface expression was found in homozygous states in five patients.ConclusionPatients with mutations in CD46 present at all ages, including the first year of life. Mutations in intron 2, (c.286 +2T > G) may be a potential hot spot in Indian children. Flow cytometry for CD46 expression is a satisfactory screening tool enabling early diagnosis.

Case report - atypical hemolytic uremic syndrome triggered by influenza B

BackgroundInfluenza A infections have been described to cause secondary hemolytic uremic syndrome and to trigger atypical hemolytic uremic syndrome (aHUS) in individuals with an underlying genetic complement dysregulation. To date, influenza B has not been reported to trigger aHUS.Case presentationA 6-month-old boy presented with hemolytic uremic syndrome triggered by influenza B infection. Initially the child recovered spontaneously. When he relapsed Eculizumab treatment was initiated, resulting in complete and sustained remission. A pathogenic mutation in membrane cofactor protein (MCP) was detected.ConclusionInfluenza B is a trigger for aHUS and might be underreported as such. Influenza vaccination may protect patients at risk.

Murine systemic thrombophilia and hemolytic uremic syndrome from a factor H point mutation

AbstractComplement plays a key role in host defense, but its dysregulation can cause autologous tissue injury. Complement activation is normally controlled by regulatory proteins, including factor H (FH) in plasma and membrane cofactor protein (MCP) on the cell surface. Mutations in FH and MCP are linked to atypical hemolytic uremic syndrome, a type of thrombotic microangiopathy (TMA) that causes renal failure. We describe here that disruption of FH function on the cell surface can also lead to disseminated complement-dependent macrovascular thrombosis. By gene targeting, we introduced a point mutation (W1206R) into murine FH that impaired its interaction with host cells but did not affect its plasma complement-regulating activity. Homozygous mutant mice carrying this mutation developed renal TMA as well as systemic thrombophilia involving large blood vessels in multiple organs, including liver, lung, spleen, and kidney. Approximately 30% of mutant mice displayed symptoms of stroke and ischemic retinopathy, and 48% died prematurely. Genetic deficiency of complement C3 and factor D prevented both the systemic thrombophilia and renal TMA phenotypes. These results demonstrate a causal relationship between complement dysregulation and systemic angiopathy and suggest that complement activation may contribute to various human thrombotic disorders involving both the micro- and macrovasculature.

Thrombotic microangiopathy mimicking membranoproliferative glomerulonephritis.

A 4-year-old boy presented with proteinuria and developed progressive renal failure over 6 years. In the patient's family, five individuals were affected with atypical haemolytic uraemic syndrome (aHUS) but not the patient. Renal biopsies (n = 3) showed glomerular basement membrane thickening with double contours, endothelial swelling and deposits of C3 and C1q. Electron microscopy revealed mesangial and subendothelial electron-dense deposits. Complement mutations in membrane cofactor protein (Y155D) and C3 (R713W and G1094R) were detected in all affected family members. The patient also had transient autoantibodies to factor H. The findings suggest that aHUS and glomerulopathy resembling membranoproliferative glomerulonephritis may have a common molecular background.

Comprehensive Analysis of Complement Genes in Patients with Atypical Hemolytic Uremic Syndrome

Background: Genetic defects in complement proteins reportedly contribute to the atypical hemolytic uremic syndrome (aHUS). Numerous genetic studies have been published in recent years, but limited data have been gathered from Asian countries. Methods: Genetic variants of 11 complement genes were analyzed in 23 Chinese patients with aHUS by high-throughput sequencing. The genotype-phenotype relationship in the Han population was evaluated and compared with the relationship that existed in other ethnicities. Results: We identified 20 causative mutations in complement genes, including 19 missense mutations and 1 splicing mutation. Six previously reported mutations, 6 mutations detected for the first time, and 8 rare polymorphisms were noted. Twelve out of 23 patients harbored complement mutations. Among the patients, one was a homozygote (Arg142Cys in CFHR3), and 4 carried combined mutations. Chinese patients have a similar prevalence of complement mutations as European, Japanese, and American patients. Complement factor H (CFH) mutations were common in aHUS in different ethnicities, but Chinese patients exhibited a higher percentage of complement factor B mutations than were found in European patients and a lower percentage of component 3 (C3) mutations than in Japanese patients. Compared with non-carriers, the aHUS patients carrying mutations had reduced C3 levels. In particular, patients with CFH mutations had a worse renal function than those with membrane cofactor protein mutations, a higher level of serum creatinine at the disease onset and a higher percentage of renal insufficiency during follow-up. Conclusions: Because complement genetic dysfunction has clinical significance in aHUS, a comprehensive assessment of variants is necessary for the proper management of aHUS patients in China.

Atypical Hemolytic Uremic Syndrome Recurrence after Renal Transplantation: C3-Glomerulonephritis as an Initial Presentation.

Risk for atypical hemolytic uremic syndrome (aHUS) recurrence after renal transplantation is low with an isolated membrane cofactor protein mutation (MCP). We report the case of a 32-year-old woman with a MCP who underwent kidney transplantation with a good evolution at 12 months. At 15 and 35 months, 2 episodes of thrombotic microangiopathy (TMA), after a miscarriage and a preeclampsia, were misinterpreted as triggered by tacrolimus. After each episode however serum creatinine returned to baseline. Five years after transplantation, she had a self-limited rhinosinusitis followed 3 weeks later by an oliguric renal failure. Her complement profile was normal. Graft biopsy showed C3 glomerulonephritis with no “humps” on electron microscopy. No significant renal function improvement followed methylprednisolone pulsing. A second biopsy showed severe acute TMA lesions with C3 glomerular deposits. Despite weekly eculizumab for 1 month, dialysis was resumed. A new workup identified the “at-risk” complement factor H haplotype. Thus, aHUS recurrence should be ruled out in aHUS patients considered at low recurrence risk when a TMA is found in graft biopsy. Prompt eculizumab therapy should be considered to avoid graft loss as aHUS recurrence can first present as a C3 glomerulonephritis.

Identification Of aHUS and Complement Mutations In Patients Presenting With Acute Thrombotic Microangiopathy

Increasing understanding of abnormalities within the alternative complement pathway in atypical hemolytic uremic syndrome (aHUS) is changing the way the disease is both diagnosed and treated. It is rarely possible to definitively diagnose aHUS at the time of initial acute presentation and treatment, with plasma exchange, is initiated on clinical grounds. With the risk of further acute episodes and increasing availability of terminal complement inhibitors accurate molecular diagnosis is imperative. Aimto determine the clinical phenotype and nature of complement abnormalities within a cohort of aHUS patients referred to a large thrombotic thrombocytopenic purpura (TTP) referral centre. Patients and methodsData from 14 patients with a clinical diagnosis of aHUS was retrospectively analysed. 13 patients were referred with thrombotic microangiopathy not initially requiring renal replacement therapy (RRT). 1 patient presented to another institution requiring urgent RRT and was subsequently transferred to our care following recovery of renal function. All patients had ADAMTS13 levels above 30% and negative anti-ADAMTS13 antibody levels at presentation to exclude a diagnosis of TTP. 3 patients had diarrhoea at presentation; all were enterotoxin negative. Patients were subsequently assessed for mutations within complement factors H (CFH), I (CFI), B (CFB), C3 and membrane cofactor protein (MCP), at risk haplotypes and CFH antibodies. A control group of 14 acute acquired TTP patients with confirmed ADAMTS13 levels <5% were assessed for the same abnormalities within complement regulatory proteins. ResultsIn the aHUS cohort, the median age of presentation was 25.5 years (11 months to 72 years). The median serum creatinine was 275 µmol/l (range 79-1812 µmol/l), platelet count 27 x109/l (10-115) and LDH was 2016 IU (342-4621). In the TTP group, presenting creatinine was 106 µmol/l (61-353) µmol/l, platelets 13 x109/l (5-74) and LDH 1954 IU (756-3518). aHUS precipitants at initial presentation or relapse included pregnancy (n=2), upper respiratory tract infection (n=6), vaccination (n=1), abdominal sepsis (n=4). In 3 cases, there was no identified trigger. Headache was a common presenting symptom; only one hypertensive patient (72 years) had a transient ischemic attack; no other neurological events were documented in the aHUS group.In 57% (8/14 patients) variants of the alternative complement pathway were identified; 5 with MCP mutations, encoding p.R59X, p.C157Y (present in 2 brothers), p.C64F and c.286+2T>C/c.286+2T>G (both present in the same patient); 2 with CFH mutations, encoding c.3134-5T>C and p.R1215X; and 1 with a CFB mutation (p.D371G). All of the mutations identified, except CFH c.3134-5T>C, are of clear functional significance. 2 of the patients with MCP mutations had a normal serum creatinine at presentation. C3/4 levels were low in 3/8 patients. In the control group of TTP patients with ADAMTS13 <5% no complement mutations were identified.13/14 aHUS patients were treated initially with plasma exchange; 1 received eculizumab subsequently. 3 patients required temporary RRT and 1 died within 24 hours of presentation with progressive cardiorespiratory failure. At follow-up, all patients had platelet counts >150 x109/l and 12/13 had normal serum creatinine levels; one patient had a creatinine of 122 µmol/l. 5/13 patients had recurrent episodes, 4 of whom had confirmed complement pathway abnormalities (3 MCP mutated, 1 CFB mutated). None required long-term RRT or progressed to end-stage renal failure (ESRD) at a median follow-up of 2 years (range 0.25-28 years). ConclusionsThis aHUS cohort, without ESRD, demonstrates the difficulty in clinically differentiating TTP from complement mediated TMAs. We demonstrate that diagnostic differentiation based on platelet count, renal function and serum C3/C4 levels is insufficient to predict an underlying complement mutation. This distinction is increasingly important with the proven efficacy of complement inhibitor therapy in targeting complement activation in aHUS. Specifically, we demonstrate a very high frequency of functionally significant MCP mutations which mimic relapsing/remitting TTP. An ADAMTS13 activity >5% in a patient with a TMA should necessitate genetic screening for complement gene mutations prior to consideration of complement inhibitor therapy. Disclosures:No relevant conflicts of interest to declare.

Managing and preventing atypical hemolytic uremic syndrome recurrence after kidney transplantation

Several genetic and acquired abnormalities leading to abnormal activation of the alternative pathway of complement have been identified in patients with atypical hemolytic uremic syndrome (aHUS). The purpose of this review is to shed light on how advances in the understanding of aHUS pathogenesis have impacted on prevention and cure of aHUS recurrence after kidney transplantation. Studies over the past decade have shown that the risk of posttransplant recurrence of aHUS depends on the underlying genetic abnormality. The risk is high in patients with mutations in genes encoding circulating complement proteins and regulators, whereas patients with mutations in membrane cofactor protein generally show good transplant outcome. Given the poor outcome associated with recurrence, isolated renal transplantation had been contraindicated in aHUS patients. Combined kidney-liver transplantation and prophylactic plasma exchange have been used to prevent posttransplant recurrences. More recent data have provided evidence about the efficacy of the anti-C5 monoclonal antibody eculizumab in the prevention and treatment of posttransplant aHUS recurrences. This review summarizes recent advances on preventing and managing aHUS recurrence after kidney transplantation and discusses the issues that still need clarification.

Physiopathologie du Syndrome Hémolytique et Urémique atypique

Hemolytic Uremic Syndrome (HUS) is characterized by the triad of hemolytic anemia, thrombocytopenia and acute renal failure. The most frequent form in children is caused by Shiga-toxin producing Escherichia coli. In absence of Shiga-toxin infection, the HUS is called atypical (aHUS). Some HUS are secondary to Streptococcus pneumonia or human immunodeficiency virus infection, cancer, anti-cancer drugs, or cyclosporine. During the last decade, aHUS has been demonstrated to be a disorder of complement alternative pathway regulation. aHUS must be regarded as a complex polygenic disease which results from a combination of genetic risk factors. Approximately 60% of patients have mutations in the genes encoding complement factor H (20-30% of patients), MCP (10-15%), factor I (4-10%), factor B (1-2%) or C3 (5-10%), and 6% have anti-factor H antibodies. Prognosis is severe whereas the clinical features vary according to complement abnormality. aHUS touches both children and adults, but in children very early onset is characteristic of factor H and factor I-HUS, while MCP-HUS is not observed before the age of 1. Half of patients with adult onset have a rapid evolution to end-stage renal disease, but half recover. The best prognosis is in patients with MCP (Membrane Cofactor Protein) mutation and a pediatric onset of the disease, who have a relapsing course, but a risk of end-stage renal disease of only 15-30% at 5 years follow-up. Anti-factor H antibodies-HUS is mainly observed in (pre)adolescents and appears to have a favourable outcome if treated early. There is a high risk of post-transplant recurrence in all groups, except MCP-HUS. These findings have paved the way for innovative therapeutic strategies based on complement blockade, and eculizumab, a monoclonal antibody targeting the human complement component 5, is now widely used to treat aHUS. Mutations in the gene of thrombomodulin and diacylglycerol kinase epsilon (DGKe) have been reported, suggesting the possibility of an alternative or more complex disease-causing mechanism than previously thought.

Atypical hemolytic uremic syndrome with MCP mutations preceded by respiratory infection.

A 14-year-old boy was referred to our hospital with general fatigue and sore throat. A chest X-ray and computed tomography revealed diffuse bilateral bronchitis. A laboratory examination showed anemia, thrombocytopenia, and renal insufficiency. He had a past medical history of hemolytic uremic syndrome (HUS) without diarrhea at the age of 3; moreover, his elder brother suffered from HUS at the age of 12. These findings indicated that the patient had a familial relapsing form of HUS (atypical HUS). Therefore, he was immediately treated with plasma exchange (PE), as suggested by guidelines, obtaining complete remission. Fifteen months later, he suffered another relapse of atypical HUS preceded by respiratory infection and was cured again with PE. His ADAMTS-13 activity was normal and its inhibitory antibody was undetectable. Two different mutations were found in the gene encoding membrane cofactor protein (MCP). Respiratory infections preceded all three episodes of HUS, but we could not detect the pathogenic agent. Although the long-term outcomes of patients with atypical HUS who have mutations in the MCP gene appear favorable, recurrences are nevertheless frequent. Few reports have described Japanese patients with atypical HUS and complement regulatory abnormalities. This is the first report of a Japanese patient with atypical HUS and mutations in the MCP gene.

A case–control study of membrane cofactor protein mutations in two populations of patients with early pregnancy loss

Mouse models have demonstrated a strong link between complement activation and pregnancy loss. The purpose of this study was to assess if mutations or polymorphisms in the complement regulatory gene membrane cofactor protein (MCP) are associated with recurrent miscarriage (RM) or sporadic fetal loss (FL). This was a case-control study comprising two different populations of cases and controls: subjects with recurrent miscarriage (RM) and controls and maternal-fetal pairs with early fetal loss (at 10-20 weeks' gestation) and controls. In the RM cases and controls, we studied maternal DNA extracted from either whole blood or saliva samples. In the FL cases and controls, fetal DNA was obtained from evacuated products of conception (cases) or cord blood (controls). Exons from the MCP gene, previously identified as having functional mutations, were amplified with flanking primers, purified, and sequenced. Sequences were analyzed against the published reference sequence, the presence of known mutations and polymorphisms and novel polymorphisms. We enrolled and obtained maternal DNA from 75 women with RM and 115 controls. In the FL group, we identified 33 cases and 37 controls. We detected the previously described A304V variant, but neither genotype nor allele frequencies differed significantly between cases and controls in any of the populations (RM, FL (maternal) or FL (fetal)). Although other variants and mutations in MCP were identified, no significant differences were found between the groups. Thus, we conclude that the A304V mutation in the MCP gene is not strongly associated with RM or FL.

Thrombotic microangiopathy mimicking membranoproliferative glomerulonephritis

A 4-year-old boy presented with proteinuria and developed progressive renal failure over 6 years. In the patient's family, five individuals were affected with atypical haemolytic uraemic syndrome (aHUS) but not the patient. Renal biopsies (n = 3) showed glomerular basement membrane thickening with double contours, endothelial swelling and deposits of C3 and C1q. Electron microscopy revealed mesangial and subendothelial electron-dense deposits. Complement mutations in membrane cofactor protein (Y155D) and C3 (R713W and G1094R) were detected in all affected family members. The patient also had transient autoantibodies to factor H. The findings suggest that aHUS and glomerulopathy resembling membranoproliferative glomerulonephritis may have a common molecular background.

Plasmatherapy in Atypical Hemolytic Uremic Syndrome

Plasmatherapy has become empirically first-line treatment in atypical hemolytic uremic syndrome (aHUS), although no prospective controlled trials have been conducted. Patients with mutations that induce complete or partial factor H (FH) quantitative deficiency may be controlled by plasma infusions (PI), but plasma exchanges appear more efficient than PI in patients with mutations that result in a mutant dysfunctional FH in the circulation. Early treatment is crucial. Long-term prophylactic plasmatherapy appears more efficient to prevent end-stage renal disease (ESRD) than plasmatherapy only during relapses. However, the longest follow-up with preserved renal function under plasmatherapy is only 6.5 years. Plasmatherapy does not appear to influence the outcome of aHUS with membrane cofactor protein mutation, and its efficacy in patients with factor I, C3, or factor B mutations is suggested by a few reports. We hope complement blockers will offer patients a better chance to avoid ESRD and provide a better quality of life.

AHUS caused by complement dysregulation: new therapies on the horizon

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00467-010-1556-4) contains supplementary material, which is available to authorized users.

93: Functional mutations in membrane cofactor protein are not associated with idiopathic recurrent pregnancy loss in a caucasian population

Murine models have suggested a link between functional mutations in complement regulatory proteins and pregnancy loss. Our purpose was to evaluate known functional MCP mutations in patients with idiopathic recurrent pregnancy loss (iRPL).