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Atypical Hemolytic Uremic Syndrome

David Kavanagh, Tim H. Goodship, Anna Richards

Seminars in Nephrology · 2013 · Review · CC BY

doi:10.1016/j.semnephrol.2013.08.003

Abstract

Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The atypical form of HUS is a disease characterized by complement overactivation. Inherited defects in complement genes and acquired autoantibodies against complement regulatory proteins have been described. Incomplete penetrance of mutations in all predisposing genes is reported, suggesting that a precipitating event or trigger is required to unmask the complement regulatory deficiency. The underlying genetic defect predicts the prognosis both in native kidneys and after renal transplantation. The successful trials of the complement inhibitor eculizumab in the treatment of atypical HUS will revolutionize disease management.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

The hemolytic uremic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The most common form of HUS is secondary to shiga toxin (Stx)-producing bacteria, typically Escherichia coli O157:H7. Atypical HUS (aHUS) has been used to classify any HUS not caused by Stx. A variety of precipitating events have been associated with aHUS including infections, drugs, autoimmune conditions, transplants, pregnancy, and metabolic conditions (Table 1). These have frequently been called secondary aHUS. With the discovery of the role of complement gene mutations in aHUS, primary aHUS has been used to refer to those cases with documented complement dysregulation. Although a useful aide memoir, these terms do not account for the increasing recognition that patients with an underlying complement risk factor often require a secondary trigger for aHUS to manifest. Classifications that take account of both the genetic background and etiologic trigger are beginning to be introduced. The best estimate of aHUS incidence is 2 of 106 in a North American population, although the precise proportion with an underlying complement defect is not known.

Pathology

In acute aHUS, the pathologic picture is of capillary thrombosis. Glomerular capillary wall thickening is seen as a result of endothelial cell swelling and accumulation of flocculent material between the endothelial cell and the basement membrane. Platelet and fibrin thrombi result in occlusion of the glomerular capillaries. Fibrinoid necrosis of the afferent arteriole associated with thrombosis also may be seen. Mesangiolysis occurs early in the disease process and subsequently is replaced by sclerotic changes. Early arterial changes are variable, ranging from only mild endothelial swelling to fibrinoid necrosis with occlusive thrombus formation. Subsequently, there is mucoid intimal hyperplasia with narrowing of the vessel lumen. Deposition of fibrin or fibrinogen in the glomeruli and in the mesangium, as well as within the vessel walls, are seen on immunofluorescence. Complement and immunoglobulin deposits along the capillary loops of glomeruli may be seen.

The Complement System

The complement system is an ancient defense mechanism that stimulates the inflammatory response and destroys pathogens through opsonization and lysis (Fig. 1). In addition to protecting the host against invading pathogens, it bridges innate and adaptive immunity and it disposes of immune complexes and injured tissues and cells.

The alternative pathway of complement (AP), which plays a key role in the pathogenesis of aHUS, is continually activated by a tick-over mechanism, and can also be triggered by the classic and lectin pathways.

In the AP, complement C3 undergoes spontaneous hydrolysis, depositing C3b onto the surface of foreign and host cells in the vicinity. On an activating surface such as a bacterium, C3b joins with factor B, which then is cleaved by factor D to form the C3 convertase, C3bBb. The binding of properdin stabilizes this enzyme. This enzyme complex then cleaves more C3 to C3b to initiate a feedback loop. Downstream of this amplification loop, C3b also may join with the C3 convertase to form the C5 convertase. C5 is cleaved to the anaphylatoxin C5a and C5b, which initiates formation of the lytic membrane attack complex (C5b–9) (Fig. 1). To protect host cells from collateral complement damage, many soluble and membrane-associated complement regulatory proteins function to inactivate complement on their surface. It is the imbalance between complement activation and regulation on host cell surfaces that underlies the pathogenesis of aHUS.

Complement Factor H

Mutations in complement factor H (CFH) account for approximately 25% of the genetic predisposition to aHUS (Table 2).,,,,,,,, CFH is the most important fluid-phase regulator of the AP of complement. CFH is composed of 20 complement control protein modules (CCPs) (Fig. 2). The four N-terminal CCPs (CCPs 1-4) mediate the complement regulatory functions of the protein by the following: (1) acting as a cofactor for factor I–mediated proteolytic inactivation of C3b, (2) competing with factor B for C3b binding, and (3) accelerating the decay of the C3 convertase into its components.

In addition to regulating complement in the fluid phase, CFH also can protect host surfaces by binding to polyanions such as the glycosaminoglycans. CFH has two glycosaminoglycan binding domains in CCPs 6 to 8 and CCPs 19 and 20, which have different sulfate specificities resulting in the C-terminal domains (CCP 19 and 20) being predominantly responsible for binding to kidney, and CCPs 6 to 8 being responsible for binding in the eye. Other recent studies have shown that CFH also binds to the lipid peroxidation product malondialdehyde, the acute phase proteins, C-reactive protein,,, and pentraxin 3, as well as necrotic cells.

The majority of mutations in CFH are heterozygous, are located in CCPs 19 and 20 (Fig. 2), and do not usually result in a quantitative deficiency of CFH. Structural and functional analysis of the C-terminal mutants has revealed variable consequences on binding to heparin, C3b, and endothelial cells; however, cell surface complement regulation is consistently impaired as measured using sheep erythrocyte lysis assays,, (Table 3). Thus, these C-terminal mutants are predicted to fail to control complement activation at the glomerular endothelium. In keeping with this, renal biopsy data from an aHUS patient with a C-terminal mutant showed reduced CFH binding to renal endothelium compared with wild type. C-terminal CFH mutants also have been shown to have impaired binding to platelets resulting in increased complement activation with consequent platelet activation, aggregation, and release of tissue factor–expressing microparticles.

Although CFH mutations cluster in the C-terminus, genetic changes are reported throughout the molecule. Mutations in the N-terminal region of CFH (CCP 1-4) have been reported and functional analysis has shown that they are defective in their ability to control the AP both in the fluid phase and on cell surfaces. Sequence variants also have been described in the intervening CCPs of CFH, although for many of these changes the functional consequences and importance in pathogenesis remains uncertain. Tortajada et al examined two of these variants of uncertain significance (VUS) and showed no functional consequences. They went on to show that these variants form part of an infrequent ancient CFH haplotype in Caucasians that is not enriched in the aHUS population, highlighting the importance of modeling genetic mutations before ascribing functional significance.

CFH resides in the Regulators of Complement Activation (RCA) cluster and the architecture of this region makes it particularly prone to genomic rearrangements. The gene for CFH is in close proximity to the genes encoding the five factor H–related proteins that are thought to have arisen from several large genomic duplications and thus have a very high degree of sequence identity to CFH.

This homology predisposes to gene conversions and genomic rearrangements through nonallelic homologous recombination and microhomology-mediated end joining. The CFH mutations S1191L, V1197A, and combined S1191L/V1197A arose through gene conversion between CFHR1 and CFH. A hybrid (fusion) gene comprising the 21 N-terminal exons of CFH and the 2 C-terminal exons of CFHR1 was shown to have arisen through nonallelic homologous recombination and resulted in aHUS. More recently, a hybrid gene consisting of the 22 N-terminal exons of CFH and the 5 C-terminal domains of CFHR3 arising through microhomology-mediated end joining was reported in aHUS. As with C-terminal point mutations in CFH, these hybrid genes also result in loss of cell-surface complement regulation.

A transgenic mouse lacking the C-terminal domains of CFH (Cfh-/-Δ16–20) was generated to provide an in vivo model of aHUS. These mice spontaneously developed aHUS, confirming the importance of local endothelial cell complement regulation in vivo. Goicoechea de Jorge et al also have crossed the Cfh-/-Δ16–20 mouse with a C5-deficient mouse to investigate the role of C5 activation in the pathogenesis of aHUS. These C5-/- CFH-/-Δ16–20 mice do not develop aHUS, suggesting a critical role downstream of C3b generation in aHUS.

Complement Factor I

Mutations in complement factor I (CFI) account for between 5% and 10% of aHUS (Table 2, Table 4).,,,,,,,, CFI is a serum serine protease that functions as a critical mediator of complement regulation by cleaving C3b and C4b in the presence of its cofactors (CFH for C3b; C4b binding protein for C4b; membrane cofactor protein [MCP] and complement receptor 1 for both). It is synthesized predominantly by the liver. The CFI mutations described in aHUS are all heterozygous. These mutations cluster in the serine protease domain (Fig. 3 and Table 4).

Functional analysis has been performed for a number of mutants and shows a loss of both alternative and classic pathway regulatory activity in the fluid phase and on cell surfaces (Table 4).,, As seen in CFH, several VUS have been described in CFI in which analysis has failed to show any alteration in secretion or function (eg, G261D). Such variants may not be involved in the pathogenesis of disease.

Membrane Cofactor Protein

Mutations in MCP (CD46) are found in approximately 10% of patients with aHUS,,,,,, (Table 2). MCP is a surface-bound complement regulatory protein that acts as a cofactor for the CFI-mediated cleavage of C3b and C4b that are deposited on host cells.

The majority of mutations described in aHUS are found in the extracellular four CCP domains that are responsible for C3b and C4b binding (Table 5 and Fig. 4). Most MCP mutations described to date have resulted in a quantitative defect in MCP (~75%). The remaining mutations have been shown to result in a secreted, nonfunctional protein (Table 5).

Activating Mutations in Complement Components

Mutations have been described more recently in the complement components C3 and complement factor B (CFB). C3 is cleaved to form the anaphylatoxins C3a and C3b, which are highly reactive, and can bind to cell surfaces via their reactive thioester. C3b then can interact with CFB in the presence of factor D to form the AP C3 convertase (C3bBb), which cleaves further C3, introducing a positive-feedback loop.

Mutations in C3 have been reported in several cohorts of aHUS patients,,,,,,,, at a frequency of 2% to 10% (Table 2). Initial functional analysis showed that MCP was unable to bind to mutant C3, preventing its cleavage to iC3b. Two C3 mutations have been described that resulted in decreased secretion and their role in pathogenesis remains uncertain. More recently, two mutations in C3 have been reported that bind to CFB with higher affinity, resulting in increased C3 convertase formation., These mutations result in increased complement activation on platelets and glomerular endothelium (Fig. 5 and Table 6).

Gain-of-function mutations also have been reported in CFB although these appear to be rare.,,,,, Goicoechea de Jorge et al described two mechanisms through which these separate mutations led to increased complement activation. One mutant (F286L) showed enhanced formation of the C3bB proenzyme that resulted in a more active enzyme in vivo. The other mutant (K323E) formed a C3bBb enzyme more resistant to decay by the complement regulators decay accelerating factor (CD55) and CFH. This also caused increased enzyme activity. Subsequent analysis of two further mutants located in the von Willebrand type A domain (D279G and K350N) showed increased convertase formation and resistance to CFH dissociation, ultimately resulting in increased complement deposition on endothelial cells.

Thrombomodulin

Thrombomodulin (THBD) facilitates the activation of protein C by thrombin and enhances thrombin-mediated activation of plasma procarboxypeptidase B (CPB2), an inhibitor of fibrinolysis that also inactivates complement-derived anaphylatoxins C3a and C5a. It has also been shown to down-regulate the AP by accelerating CFI-mediated inactivation of C3b in the presence of cofactors. Mutations in THBD recently were described in aHUS. The variations reported were heterozygous missense mutations, with no mutations resulting in a loss of secretion. These mutations resulted in a loss of cofactor activity. Maga et al also have reported THBD genetic variants in aHUS, although they suggested that at least one of the previously reported mutations was a polymorphism present in 3% of the population and that several THBD variants were present with an additional mutation. No isolated THBD mutations were described in a large French cohort of patients (n = 214), although a few individuals carried THBD genetic variants in addition to a mutation in a known complement gene. Several large cohorts of aHUS have yet to report on the frequency of genetic variants in THBD in aHUS.

Other Genetic Variants

Genetic screening of complement factor H–related 5 protein (CFHR5) in 3 separate cohorts of aHUS patients was performed.,, Monteferrante et al did not detect any causative mutations in an Italian cohort. Westra et al reported 3 VUS in CFHR5 in a panel of 65 aHUS patients whereas Maga et al reported 3 VUS in aHUS (n = 144) patients, 2 of whom carried an additional known mutation. No mutation was seen to segregate in a large pedigree with the reported cases being sporadic. The current limited understanding of the functional role of CFHR5 further adds to the uncertainty of its role in aHUS pathogenesis and replication studies are required.

A functionally significant mutation (Q433P) in the membrane attack complex regulator, clusterin, has been reported in a family with aHUS. The affected individual also carried a functionally significant mutation in MCP; therefore, it is unclear whether mutations in clusterin are sufficient alone to cause aHUS.

Factor H Autoantibodies

In addition to the genetic abnormalities described in aHUS, autoantibodies to CFH also have been linked to disease in 4% to 14% of aHUS patients (Table 7).,,,,,, In a pediatric-only cohort, this figure was reported to be as high at 25%.

CFH autoantibodies in aHUS are strongly associated with an 80-kb–long genomic homozygous deletion of CFHR1 and CFHR3.,,, More recent analysis also has shown that some aHUS patients with CFHR1 deficiency resulting from point mutations in CFHR1 or from a deletion incorporating CFHR1 and CFHR4, have developed anti-CFH antibody (Ab). This may suggest that deficiency of CFHR1 is the predominant predisposing factor in the development of autoantibodies. Despite this, deficiency of CFHR1 is not a prerequisite for formation of autoantibodies because several aHUS patients have been reported with high titers of Ab with no evidence of deficiency of CFHR1 or CFHR3.,,, In many cases, aHUS patients with anti-CFH Ab also carried functionally significant mutations in other complement genes.

The anti-CFH antibodies reported to date have been predominantly of the IgG class, although a few IgA anti-CFH Ab have been described. Mapping of the epitopes initially suggested that the anti-CFH Ab bound predominantly to the C-terminus,,,, however, recently it was reported that the response was polyclonal to multiple epitopes throughout CFH. There was also cross-reactivity with CFHR1,, and CFHR2, but it was not reported for CFHR3 or CFHR4A.

Several studies have shown various functional consequences of anti-CFH Abs. The antibodies have been shown to reduce binding to C3b, and other C3 fragments. They perturb CFH-mediated cell surface protection, and in some individuals the autoantibodies also impair cofactor activity or decay accelerating activity. In keeping with this, low C3 levels frequently are seen in the autoimmune form (Table 7).

It also has been shown that CFH autoantibodies form immune complexes in the serum,, which may explain the low CFH levels seen in 28% of the cases. In addition, these immune complexes correlated with disease activity. In summary, these functional studies suggest a pathogenic role for CFH autoantibodies in aHUS.

Factor I Autoantibodies

Autoantibodies to CFI also have been described in aHUS but are much rarer than anti-CFH Abs (0%-2%)., Unlike anti-CFH Abs they are not associated with a deletion of CFHR1 and 3. Anti-CFI Abs were seen to form immune complexes in serum, however, functional analysis showed only a minor effect in fluid phase cofactor activity. The co-existence of functionally significant mutants in the majority of patients, added to the lack of correlation of anti-CFI Ab titer and disease activity, raise the possibility that they are an epiphenomenon rather than a direct cause of disease. Large replication studies will be needed to confirm this initial observation.

Genetic Susceptibility Factors

A number of single-nucleotide polymorphisms (SNPs) in CFH have been shown to be associated with aHUS in several studies.,,,,, A haplotype in CFH (CFH-H3; tgtgt) composed of these SNPs increases this risk of aHUS two- to four-fold., This haplotype contains a SNP in the region of CFH responsible for cofactor activity. Functional analysis has shown that the risk variant, CFH-Val62, has a subtle decrease in cofactor activity compared with the protective variant,,, in keeping with the minor structural differences between these SNPs.

A haplotype block in MCP (MCPggaac) comprising 2 SNPs in the promoter region has been associated with a two- to three-fold increased risk of aHUS.,, Some of these studies have suggested that this risk occurs exclusively in those patients already carrying complement mutations., Reporter gene assays have suggested that this haplotype reduces transcriptional activity by 25%, however, this did not correlate with MCP cell surface expression in vivo.,, Further experiments on human umbilical vein endothelial cells (HUVECs) with risk and protective MCP haplotypes showed equal MCP expression whether in the resting state, after cytokine treatment, or free heme treatment. Likewise, no increase in complement deposition could be shown on HUVECs bearing the MCP risk haplotype.

A SNP in C4b binding protein (R240H) was associated with aHUS in cohorts from the United Kingdom and France. C4b binding protein is the predominant classic pathway fluid phase regulator but also has weak AP regulatory activity. Functional analysis showed inefficient AP regulation compared with wild type. In a replication study in a Spanish cohort this association could not be confirmed.

A CFHR1 polymorphism (CFHR1*B) resulting from a gene conversion between CFH and CFHR1 is associated strongly with aHUS in the homozygous state, an association replicated by Fremeaux-Bacchi et al. It has been suggested that because the CFHR1*B is identical to CFH in CCP18 that it may compete with CFH at the glomerular endothelium, thus impairing complement regulation.

In a study examining SNPs in 47 complement genes in two separate cohorts, SNPs in CFHR2 and CFHR4 were also associated with aHUS. In this study there were no reproducible associations between SNPs and aHUS outside the RCA cluster.

Incomplete Penetrance

Incomplete penetrance has been reported for all the genes associated with aHUS. Penetrance has been reported at around 50% for individuals carrying CFH, CFI, MCP, and CFB mutations,, and slightly lower for C3 mutations, albeit with small numbers. In index cases, the age-related penetrance is significantly higher than their mutation-positive relatives regardless of gene. This suggests that the penetrance is altered by other genetic and environmental modifiers.

Patients have been reported with mutations in more than one complement gene,,,, or mutations in one complement gene in addition to autoantibodies to complement components., In a study of 795 aHUS patients the European Working Party on Complement Genetics showed that at least 3.4% of aHUS cases will have more than one mutation. Eight percent to 10% of patients with mutations in CFH, C3, or CFB had combined mutations whereas 25% of patients with mutations in CFI or MCP had combined mutations. The penetrance increased as the number of mutations in a patient increased. As described, haplotypes and SNPs act together with mutations and inhibitory autoantibodies to increase the penetrance of disease.

Even in the situation in which a patient has multiple genetic risk factors, disease may not manifest until middle age, suggesting a triggering stimulus is required for disease to manifest. In such cases, it is likely that aHUS results from an otherwise innocuous stimulus that triggers the AP and sets off a self-amplifying cycle that cannot be controlled adequately in susceptible individuals.

Triggering Events

Historically, many agents have been linked to aHUS (Table 1). Although many of these associated conditions are common, aHUS is rare, suggesting an underlying predisposition.

Recent analysis of cohorts of aHUS patients with complement mutations have identified upper respiratory tract infections, fevers, pregnancy, drugs, and non E coli diarrheal illnesses as potential triggers.,,, Non-Stx diarrhea preceded aHUS in 23% of a French cohort and in 28% of an Italian cohort. Infectious events, mainly upper respiratory tract infections or diarrhea/gastroenteritis, trigger onset of aHUS in at least half of patients., Likewise, in pregnancy-associated aHUS, Fakhouri et al showed that 86% of patients for whom this was a trigger carried a complement gene mutation. Drugs also may unmask latent complement defects resulting in aHUS.,

Complement Screening in aHUS

Once the initial diagnosis of a thrombotic microangiopathy (TMA) has been made, the initial management involves differentiating between Stx-HUS, thrombotic thrombocytopenic purpura, and aHUS (for a diagnostic algorithm see the article by Loirat and Fremeaux-Bacchi). Rapid exclusion by analysis of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity and microbiological analysis for Stx-producing E coli can lead to a diagnosis of aHUS. After exclusion of Stx-HUS and thrombotic thrombocytopenic purpura, precipitating events and the underlying genetic defects predisposing to aHUS should be sought (Table 8).

Complement analysis in cases of aHUS should include serum levels of C3, C4, CFH, and CFI before plasma exchange. Low C3 levels are seen commonly in patients with mutations in CFH, CFI, MCP, C3, and CFB and may point to a complement-mediated process, however, normal C3 levels do not exclude the presence of a mutation in, or autoantibodies against, the complement system (Table 2). Fluorescence-activated cell sorter analysis of peripheral blood mononuclear cells provides a quick and relatively inexpensive screening option for MCP mutations, although genetic analysis still is required to detect all changes.

Genetic screening in aHUS is challenging because most of the disease-associated mutations are individually rare. In the case of nonsense mutations, large gene rearrangements, and frame shift mutations, the functional consequences are certain. In aHUS, missense mutations or splice-site variations in complement genes comprise a high proportion of the variants found and the changes may be of uncertain biologic or clinical relevance. These VUS pose a challenge when reporting the genetic results. Although predictions can be made as to the likely significance of a VUS, ultimately, functional assays are required to assess the importance of a variant. Such analysis often has led to the reclassification of a previously described mutation as an irrelevant polymorphism. Care always should be taken when interpreting these VUS and screening laboratories should revisit past genetic data in light of new evidence. In addition to direct DNA sequencing, the not-insubstantial number of gene conversions and genomic rearrangements found in aHUS makes copy number analysis essential in aHUS screening (see www.genetests.org for national screening laboratories).

Prognosis

The overall prognosis for patients with aHUS has been poor. Initial mortality has been reported to be higher in children (6.7% versus 0.8% at 1 year), although adults progress to end-stage renal disease (ESRD) more frequently at initial presentation (46% versus 16%). At 3 to 5 years after onset, 36% to 48%, of children and 64% to 67%, of adults had died or reached ESRD.

Prognosis varies with genotype, with MCP mutations carrying the best prognosis,,, although in one study this was true only if the first presentation of aHUS occurred in childhood (Table 2). No patient with an MCP mutation from either the French or Italian cohorts died at first episode and none of the children and only 25% of adults with an MCP mutation developed ESRD at first episode. At 3 years only 6% of all patients with MCP mutations had developed ESRD and by 5 years only 35% had developed ESRD.

Individuals with mutations in CFH, CFI, or C3 all had poor outcomes. In patients with a CFH mutation the initial mortality rate was 30% in children and 4% in adults, and evolution to ESRD at first episode in survivors was 19% to 33% in children and 48% in adults., At 3 to 5 years of follow-up evaluation, up to 77% of patients with CFH mutations had developed ESRD or had died. Only 30% to 40% of individuals with CFI and C3 mutations will be alive with native kidney function at 3 to 5 years., The prognosis of aHUS with CFB mutations also is poor.,,

A proportion of patients will have combined mutations. In patients with either CFH or CFI mutations, the presence of mutations in other genes did not modify prognosis. In contrast, the prognosis for individuals with an MCP mutation was worse if they also carried an additional mutation.

In those patients with CFH autoantibodies, 36.5% to 63% die or reach ESRD in the long term,,,,, (Table 7).

Extrarenal Manifestations

Extrarenal manifestations are reported in only 10% to 20% of patients with aHUS. The most frequently reported symptoms (~10%) are neurologic, with symptoms ranging from irritability to coma. It is unclear how many of these symptoms are the direct result of a cerebral TMA, with severe hypertension and posterior reversible encephalopathy syndrome possible differential diagnoses that may be differentiated on magnetic resonance imaging. Many case reports of other organ involvement occurring concurrently with aHUS have been described (Table 9), but in the majority, definitive biopsy evidence of TMA in the organ was lacking. Extrarenal manifestations have been reported more commonly in CFH-autoantibody–mediated disease, with 23.5% having seizures and 23.1% developing pancreatitis.

Plasma Exchange

Until the beginning of this decade, plasma exchange (PE) was considered the gold standard for management of aHUS. The replacement of nonfunctioning complement proteins and removal of CFH autoantibodies and hyperfunctional complement components (eg, gain-of-function mutations) made PE a logical choice (reviewed in European and UK guidelines on aHUS treatment). The consensus-based guidelines recommended that PE should be commenced as soon as possible after diagnosis of aHUS, using 1 to 2 plasma volumes per session in adults and 50 to 100 mL/kg in children. Initially, PE should be performed daily and the dose titrated to control hemolysis. Once hemolysis has been controlled, PE can be withdrawn slowly, although individuals with genetic defects in the complement system are frequently plasma dependent and require long-term plasma therapy (weekly/biweekly) to maintain remission. Only once ADAMTS13 deficiency is excluded should eculizumab be considered. The price of eculizumab will mean that PE will remain the only currently available option in many countries.

Eculizumab

Eculizumab, a recombinant humanized monoclonal antibody directed against C5, blocks the cleavage of C5 into its effector components C5a and C5b. Since the initial use of this complement inhibitor in aHUS in 2009, the effectiveness of eculizumab has been communicated in many case reports,,,,,,,,,,,,, meeting abstracts,,,,,, and a recently published prospective trial.

Eculizumab appears highly effective, with approximately 85% of patients becoming disease-free in both plasma-resistant and plasma-dependent aHUS (reviewed by Wong et al). It is effective in patients with and without identified complement mutations. Similar to PE, the earlier eculizumab is commenced, the greater the preservation of kidney function. It has been suggested that eculizumab achieves better control of disease as witnessed by improvement in renal function after switching from PE and in rescuing plasma-resistant individuals. It should be noted, however, that a randomized trial of eculizumab against PE was not, and is unlikely to be, performed.

Treatment with eculizumab should begin as soon as Stx-HUS and ADAMTS13 deficiency can be eliminated. Current protocols suggest life-long treatment with eculizumab will be required, however, as we gain more clinical experience it is likely that there will be certain subgroups in whom the treatment can be stopped (eg, those with isolated MCP mutations). Eculizumab has been used safely during pregnancy in patients with paroxysmal nocturnal hemoglobinuria.

Because host defense against encapsulated organisms is dependent on the ability to form a membrane attack complex (C5b-9), vaccination against Neisseria meningitides is required before treatment with eculizumab. However, because the current vaccine (tetravalent) does not cover the most prevalent strain (serogroup B), long-term prophylactic antibiotic cover also has been suggested.

Renal Transplantation in aHUS

The outcome of renal transplantation in patients with aHUS is poor. In one adult series of 71 renal transplants, the 5-year death-censored graft survival was only 51%, with a 7% mortality rate at 5 years. Graft failure is predominantly due to aHUS recurrence which occurs in 60% to 70% of patients,, and occurs early after transplant (70% in the first year after transplant).

The outcome of renal transplantation is predicted largely by the underlying genetic abnormality. In individuals with mutations in CFH the recurrence rate is greater than 80%. Similarly, activating mutations in C3 and CFB also have a high risk of renal recurrence. Initial studies all suggested that mutations in CFI carried a poor prognosis, although more recently one study failed to replicate these data. It is likely that this variation in data reflects the functional consequences of genetic variants in the different populations.

Unlike the complement proteins described earlier, MCP is membrane-tethered and is not a plasma protein. As such, a renal allograft will correct the complement defect and protect against aHUS. In keeping with this, the outcome after transplantation in those with mutations in MCP is much better, with a recurrence rate of only approximately 20%. It has been suggested that in those who do recur, an additional genetic predisposition such as an at-risk haplotype may be present or endothelial microchimerism may occur. In keeping with this, outcomes were worse in individuals with combined MCP mutations compared with patients with an isolated MCP change. Only one individual with a loss-of-function mutation in THBD has undergone transplantation to date and they had recurrent disease.

It is perhaps not surprising that individuals with underlying genetic defects have a high recurrence rate because the post-transplant milieu provides the necessary disease triggers (eg, viral diseases, ischemia reperfusion injury, donor-specific antibodies, immunosuppressive drugs, and so forth) to cause endothelial cell damage and activation of the complement cascade. Calcineurin inhibitors (tacrolimus and cyclosporin), although consistently linked as a trigger for aHUS, were not shown to be associated significantly in two recent studies of aHUS recurrence post-transplant., Mammalian target of rapamycin inhibitors (eg, sirolimus), however, have been reported to increase the risk of recurrence.

Although plasma therapy has a low success rate in rescuing recurrent aHUS after renal transplantation, pre-emptive plasma exchange has been associated with a trend to decrease recurrence. Such a regimen may now be superseded by pre-emptive eculizumab.

Autoantibodies

There is limited information regarding the outcome after transplantation in individuals with CFH autoantibodies. Two patients have been reported to have CFH autoantibodies and recurrent aHUS., Two individuals had successful renal transplants using pre-emptive removal of CFH autoantibodies using rituximab and PE., Five individuals with factor H autoantibodies have successfully undergone renal transplantation in the absence of specific therapy aimed at reducing CFH autoantibody titers with follow-up evaluation ranging from 2 to 17 years with no recurrence., An additional confounding factor is that CFH autoantibodies frequently are found in association with other mutations. A pragmatic approach would be to use a regimen designed to remove CFH autoantibodies in those with a high titer.

Living Related Transplantation

Live related transplantation is a particularly unattractive option in aHUS given the high recurrence rate and graft loss in the recipient. In addition, de novo aHUS has been recorded in four donors within a year of donation.,,, In at least one of these cases, a CFH mutation in the donor subsequently was reported. Although genotyping may reveal a known mutation in a family member, the additional presence of risk haplotypes and the fact that further genetic risk factors remain to be discovered makes it impossible to rule out subsequent aHUS for a donor.

Liver/Kidney Transplantation

Because CFH, CFI C3, and CFB are synthesized predominantly in the liver; combined liver/kidney transplantation has been viewed as a mechanism to correct the underlying genetic deficiency of complement regulation. Twenty liver/kidney transplants have been reported in the literature to date.,,,,,,,,,,, The initial attempts were not successful because they did not include preoperative PE to correct the underlying complement defects., In this setting, ischemia-reperfusion injury triggered the complement cascade, resulting in primary liver nonfunction.

Subsequently, Saland et al introduced perioperative PE in addition to aspirin and heparin, which has resulted in improved outcomes. Treatment guidelines for the use of liver-kidney transplantation in aHUS were recently proposed by a consensus conference. Despite this, of the 14 patients who underwent the revised procedure, 2 died (14% surgical mortality), and the availability of eculizumab may change the risk-benefit profile of this type of surgery.

De Novo aHUS After Renal Transplant

The role of genetic defects in the complement system has also been shown in de novo aHUS after renal transplant. In a series of transplant patients whose initial diagnosis was not aHUS, 29% were seen to have a mutation in CFI or CFH. This may be an under-representation of the genetic predisposition because the genes for CFB and C3 were not screened. The majority of these patients had chronic glomerulonephritis or malignant hypertension as their initial diagnosis. Mesangiocapillary glomerulonephritis/C3 glomerulopathy share many of the same complement risk factors as aHUS and the transformation from mesangiocapillary glomerulonephritis to aHUS is well recognized. Likewise, a patient presenting at ESRD with a biopsy picture of malignant hypertension is indistinguishable from aHUS. We would recommend that such patients also should be screened for complement mutations before transplantation.

More recently, a liver transplant recipient was shown to have developed de novo aHUS. Genetic analysis showed that the recipient carried a risk MCP haplotype but did not have a mutation. DNA from the donor liver, however, was shown to carry a mutant CFH. This is further evidence of the role of susceptibility genes in predisposing to post-transplant aHUS.

Eculizumab Use in Renal Transplantation

Eculizumab has also been used successfully in renal transplantation in those experiencing recurrent aHUS in a transplant,,,,, and as prophylaxis before transplantation in those with a known mutation.,,, In a recent review, Zuber et al reported that of 9 patients with complement mutations, 8 had successful renal transplants under eculizumab prophylaxis and 13 patients had successful salvage treatment for recurrent aHUS after transplant. In those individuals with ESRD secondary to complement-mediated aHUS requiring renal transplantation, it is probable that prophylactic eculizumab will become the treatment of choice.

Summary

Overactivity of the AP is central to the pathogenesis of aHUS. Many underlying genetic complement predispositions have been described but disease only manifests after an environmental trigger. The understanding of the role of complement in the pathogenesis of aHUS has facilitated the introduction of a successful treatment in the form of the complement C5 inhibitor, eculizumab.

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    Deletion of Complement Factor H–Related Genes CFHR1 and CFHR3 Is Associated with Atypical Hemolytic Uremic Syndrome · 2007
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    Not in our library10.1093/hmg/ddp289

  85. 85.

    Hocking H.G., Herbert A.P., Kavanagh D., Soares D.C., Ferreira V.P., Pangburn M.K. Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations. J Biol Chem. 2008;283:9475-9487.

    Not in our library10.1074/jbc.m709587200

  86. 86.

    Esparza-Gordillo J., Jorge E.G., Garrido C.A., Carreras L., Lopez-Trascasa M., Sanchez-Corral P. Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree. Mol Immunol. 2006;43:1769-1775.

    Not in our library10.1016/j.molimm.2005.11.008

  87. 87.

    Frimat M., Roumenina L., Tabarin F., Halbwachs-Mecarelli L., Fremeaux-Bacchi V. Membrane cofactor protein (MCP) haplotype, which predisposes to atypical hemolytic and uremic syndrome, has no consequence on neutrophils and endothelial cells MCP levels or on HUVECs ability to activate complement. Immunobiology. 2012;217:1187-1188.

    Not in our library

  88. 88.

    Blom A.M., Bergstrom F., Edey M., Diaz-Torres M., Kavanagh D., Lampe A. A novel non-synonymous polymorphism (p.Arg240His) in C4b-binding protein is associated with atypical hemolytic uremic syndrome and leads to impaired alternative pathway cofactor activity. J Immunol. 2008;180:6385-6391.

    Not in our library10.4049/jimmunol.180.9.6385

  89. 89.

    Martinez-Barricarte R., Goicoechea de Jorge E., Montes T., Layana A.G., Rodriguez de Cordoba S. Lack of association between polymorphisms in C4b-binding protein and atypical haemolytic uraemic syndrome in the Spanish population. Clin Exp Immunol. 2009;155:59-64.

    Not in our library10.1111/j.1365-2249.2008.03798.x

  90. 90.

    Kavanagh D., Goodship T. Genetics and complement in atypical HUS. Pediatr Nephrol. 2010;25:2431-2442.

    Not in our library10.1007/s00467-010-1555-5

  91. 91.

    Sullivan M., Rybicki L.A., Winter A., Hoffmann M.M., Reiermann S., Linke H. Age-related penetrance of hereditary atypical hemolytic uremic syndrome. Ann Hum Genet. 2011;75:639-647.

    Not in our library10.1111/j.1469-1809.2011.00671.x

  92. 92.

    Cruzado J.M., de Cordoba S.R., Melilli E., Bestard O., Rama I., Sanchez-Corral P. Successful renal transplantation in a patient with atypical hemolytic uremic syndrome carrying mutations in both factor I and MCP. Am J Transplant. 2009;9:1477-1483.

    Not in our library10.1111/j.1600-6143.2009.02647.x

  93. 93.

    Bienaime F., Dragon-Durey M.A., Regnier C.H., Nilsson S.C., Kwan W.H., Blouin J. Mutations in components of complement influence the outcome of factor I-associated atypical hemolytic uremic syndrome. Kidney Int. 2010;77:339-349.

    Not in our library10.1038/ki.2009.472

  94. 94.

    Sellier-Leclerc A.L., Fremeaux-Bacchi V., Dragon-Durey M.A., Macher M.A., Niaudet P., Guest G. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007;18:2392-2400.

    Not in our library10.1681/asn.2006080811

  95. 95.

    Edey M.M., Mead P.A., Saunders R.E., Strain L., Perkins S.J., Goodship T.H. Association of a factor H mutation with hemolytic uremic syndrome following a diarrheal illness. Am J Kidney Dis. 2008;51:487-490.

    Not in our library10.1053/j.ajkd.2007.08.030

  96. 96.

    Fakhouri F., Roumenina L., Provot F., Sallee M., Caillard S., Couzi L. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol. 2010;21:859-867.

    Not in our library10.1681/asn.2009070706

  97. 97.

    Goodship T.H., Kavanagh D. Pulling the trigger in atypical hemolytic uremic syndrome: the role of pregnancy. J Am Soc Nephrol. 2010;21:731-732.

    Not in our library10.1681/asn.2010030308

  98. 98.

    Fakhouri F., Roumenina L., Provot F., Sallee M., Caillard S., Couzi L. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol. 2010;21:859-867.

    Not in our library10.1681/asn.2009070706

  99. 99.

    Le Quintrec M., Zuber J., Moulin B., Kamar N., Jablonski M., Lionet A. Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am J Transplant. 2013;13:663-675.

    Not in our library10.1111/ajt.12077

  100. 100.
    Atypical hemolytic uremic syndrome · 2011
    No notice
  101. 101.

    Kavanagh D., Richards A., Fremeaux-Bacchi V., Noris M., Goodship T., Remuzzi G. Screening for complement system abnormalities in patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2007;2:591-596.

    Not in our library10.2215/cjn.03270906

  102. 102.

    Kavanagh D., Anderson H.E. Interpretation of genetic variants of uncertain significance in atypical hemolytic uremic syndrome. Kidney Int. 2012;81:11-13.

    Not in our library10.1038/ki.2011.330

  103. 103.

    Koehl B., Boyer O., Biebuyck-Gouge N., Kossorotoff M., Fremeaux-Bacchi V., Boddaert N. Neurological involvement in a child with atypical hemolytic uremic syndrome. Pediatr Nephrol. 2010;25:2539-2542.

    Not in our library10.1007/s00467-010-1606-y

  104. 104.

    Ariceta G., Besbas N., Johnson S., Karpman D., Landau D., Licht C. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2009;24:687-696.

    Not in our library10.1007/s00467-008-0964-1

  105. 105.

    Taylor C.M., Machin S., Wigmore S.J., Goodship T.H. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol. 2010;148:37-47.

    Not in our library10.1111/j.1365-2141.2009.07916.x

  106. 106.

    Rother R.P., Rollins S.A., Mojcik C.F., Brodsky R.A., Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol. 2007;25:1256-1264.

    Not in our library10.1038/nbt1344

  107. 107.

    Gruppo R.A., Rother R.P. Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med. 2009;360:544-546.

    Not in our library10.1056/nejmc0809959

  108. 108.

    Ariceta G., Arrizabalaga B., Aguirre M., Morteruel E., Lopez-Trascasa M. Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants. Am J Kidney Dis. 2012;59:707-710.

    Not in our library10.1053/j.ajkd.2011.11.027

  109. 109.

    Dorresteijn E.M., van de Kar NCAJ, Cransberg K. Eculizumab as rescue therapy for atypical hemolytic uremic syndrome with normal platelet count. Pediatr Nephrol. 2012;27:1193-1195.

    Not in our library10.1007/s00467-012-2130-z

  110. 110.

    Lapeyraque A.-L., Fremeaux-Bacchi V., Robitaille P. Efficacy of eculizumab in a patient with factor-H-associated atypical hemolytic uremic syndrome. Pediatr Nephrol. 2011;26:621-624.

    Not in our library10.1007/s00467-010-1719-3

  111. 111.

    Ohanian M., Cable C., Halka K. Eculizumab safely reverses neurologic impairment and eliminates need for dialysis in severe atypical hemolytic uremic syndrome. Clin Pharmacol. 2011;3:5-12.

    Not in our library10.2147/cpaa.s17904

  112. 112.

    Prescott H.C., Wu H.M., Cataland S.R., Baiocchi R.A. Eculizumab therapy in an adult with plasma exchange-refractory atypical hemolytic uremic syndrome. Am J Hematol. 2010;85:976-977.

    Not in our library10.1002/ajh.21862

  113. 113.

    Tschumi S., Gugger M., Bucher B.S., Riedl M., Simonetti G.D. Eculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findings. Pediatr Nephrol. 2011;26:2085-2088.

    Not in our library10.1007/s00467-011-1989-4

  114. 114.

    Koese O., Zimmerhackl L.-B., Jungraithmayr T., Mache C., Nuernberger J. New treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab. Semin Thromb Hemost. 2010;36:669-672.

    Not in our library10.1055/s-0030-1262889

  115. 115.

    Kim JJ, Waller SC, Reid CJ. Eculizumab in atypical haemolytic-uraemic syndrome allows cessation of plasma exchange and dialysis. Clin Kidney J. 2012;5:34-6

    Not in our library10.1093/ndtplus/sfr174

  116. 116.

    Malina M. Peripheral gangrene in children with atypical hemolytic uremic syndrome. Paper presented at: 44th Annual Meeting of the European Society for Pediatric Nephrology 14 Sept 2011 Dubrovnik, Croatia

    Not in our library

  117. 117.

    Fremont OT. Eculizumab treatment for aHUS in a child with positive family history. Paper presented at: 42nd Annual Meeting of the American Society of Nephrology. 27 Oct 2009 San Diego CA

    Not in our library

  118. 118.

    Garjau M. Early treatment with eculizumab may be beneficial in atypical haemolytic uraemic syndrome. Clin Kidney J. 2012;5:31-33.

    Not in our library10.1093/ndtplus/sfr157

  119. 119.

    Haffner K. Effective eculizumab therapy of familiar atypical HUS in a 4 year old patient Paper presented at: 2nd International Conference on HUS, MPGN and PNH 13 June 2010 Innsbruck, Austria

    Not in our library

  120. 120.

    Muus P. Safety and efficacy of eculizumab in aHUS patients on chronic plasma therapy: Interim analysis of a phase II trial. Paper presented at: 43rd Annual Meeting of the American Society of Nephrology November 16, 2010; Denver, CO

    Not in our library

  121. 121.

    Licht C. Phase II study of eculizumab in patients with atypical HUS receiving chronic plasma exchange/infusion. Paper presented at 44th Annual Meeting of the American Society of Nephrology November 8, 2011; Philadelphia, PA

    Not in our library

  122. 122.

    Greenbaum LA. Eculizumab is an effective long-term treatment in patients with atypical haemolytic uremic syndrome previously receiving chronic plasma exchange/infusion: extension study results. Presented at the 53rd Annual Meeting of the American Society of Hematology; December 10, 2011; San Diego, CA

    Not in our library

  123. 123.

    Muus PM. Safety and efficacy of eculizumab in aHUS patients on chronic plasma therapy: interim analysis of a phase II trial. Presented at the 43rd Annual Meeting of the American Society of Nephrology; November 16, 2010; Denver, CO

    Not in our library

  124. 124.

    Greenbaum LA. Continued improvement in renal function with sustained eculizumab in patients with atypical HUS resistant to plasma exchange/infusion. Paper presented at 44th Annual Meeting of the American Society of Nephrology November 8, 2011; Philadelphia, PA

    Not in our library

  125. 125.

    Licht C. Eculizumab is an effective long-term treatment in patients with atypical haemolytic uremic syndrome previously receiving chronic plasma exchange/infusion: Extension study results. Presented at the 53rd Annual Meeting of the American Society of Hematology; December 10, 2011; San Diego, CA

    Not in our library

  126. 126.

    Legendre C.M., Licht C., Muus P., Greenbaum L.A., Babu S., Bedrosian C. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. New Engl J Med. 2013;368:2169-2181.

    Not in our library10.1056/nejmoa1208981

  127. 127.

    Wong EK, Goodship TH, Kavanagh D. Complement therapy in atypical haemolytic uraemic syndrome (aHUS). Mol Immunol. 2013;56:199-212

    Not in our library10.1016/j.molimm.2013.05.224

  128. 128.

    Bresin E., Daina E., Noris M., Castelletti F., Stefanov R., Hill P. Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background. Clin J Am Soc Nephrol. 2006;1:88-99.

    Not in our library10.2215/cjn.00050505

  129. 129.

    Loirat C., Fremeaux-Bacchi V. Hemolytic uremic syndrome recurrence after renal transplantation. Pediatr Transplant. 2008;12:619-629.

    Not in our library10.1111/j.1399-3046.2008.00910.x

  130. 130.

    Fremeaux-Bacchi V., Arzouk N., Ferlicot S., Charpentier B., Snanoudj R., Durrbach A. Recurrence of HUS due to CD46/MCP mutation after renal transplantation: a role for endothelial microchimerism. Am J Transplant. 2007;7:2047-2051.

    Not in our library10.1111/j.1600-6143.2007.01888.x

  131. 131.

    Lorcy N., Rioux-Leclercq N., Lombard M.L., Le Pogamp P., Vigneau C. Three kidneys, two diseases, one antibody? Nephrol Dial Transplant. 2011;26:3811-3813.

    Not in our library10.1093/ndt/gfr436

  132. 132.

    Le Quintrec M., Zuber J., Noel L.H., Thervet E., Fremeaux-Bacchi V., Niaudet P. Anti-factor H autoantibodies in a fifth renal transplant recipient with atypical hemolytic and uremic syndrome. Am J Transplant. 2009;9:1223-1229.

    Not in our library10.1111/j.1600-6143.2009.02586.x

  133. 133.

    Kwon T., Dragon-Durey M.A., Macher M.A., Baudouin V., Maisin A., Peuchmaur M. Successful pre-transplant management of a patient with anti-factor H autoantibodies-associated haemolytic uraemic syndrome. Nephrol Dial Transplant. 2008;23:2088-2090.

    Not in our library10.1093/ndt/gfn063

  134. 134.

    Donne R.L., Abbs I., Barany P., Elinder C.G., Little M., Conlon P. Recurrence of hemolytic uremic syndrome after live related renal transplantation associated with subsequent de novo disease in the donor. Am J Kidney Dis. 2002;40:E22.

    Not in our library10.1053/ajkd.2002.36938

  135. 135.

    Bergstein J., Michael A., Kellstrand C., Simmons R., Najarian J. Hemolytic-uremic syndrome in adult sisters. Transplantation. 1974;17:487-490.

    Not in our library10.1097/00007890-197405000-00007

  136. 136.

    Kaplan B.S., Papadimitriou M., Brezin J.H., Tomlanovich S.J., Zulkharnain. Renal transplantation in adults with autosomal recessive inheritance of hemolytic uremic syndrome. Am J Kidney Dis. 1997;30:760-765.

    Not in our library10.1016/s0272-6386(97)90079-2

  137. 137.

    Remuzzi G., Ruggenenti P., Codazzi D., Noris M., Caprioli J., Locatelli G. Combined kidney and liver transplantation for familial haemolytic uraemic syndrome. Lancet. 2002;359:1671-1672.

    Not in our library10.1016/s0140-6736(02)08560-4

  138. 138.

    Remuzzi G., Ruggenenti P., Colledan M., Gridelli B., Bertani A., Bettinaglio P. Hemolytic uremic syndrome: a fatal outcome after kidney and liver transplantation performed to correct factor h gene mutation. Am J Transplant. 2005;5:1146-1150.

    Not in our library10.1111/j.1600-6143.2005.00783.x

  139. 139.

    Cheong H.I., Lee B.S., Kang H.G., Hahn H., Suh K.S., Ha I.S. Attempted treatment of factor H deficiency by liver transplantation. Pediatr Nephrol. 2004;19:454-458.

    Not in our library10.1007/s00467-003-1371-2

  140. 140.

    Jalanko H., Peltonen S., Koskinen A., Puntila J., Isoniemi H., Holmberg C. Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H. Am J Transplant. 2008;8:216-221.

    Not in our library10.1111/j.1600-6143.2007.02029.x

  141. 141.

    Saland J.M., Shneider B.L., Bromberg J.S., Shi P.A., Ward S.C., Magid M.S. Successful split liver-kidney transplant for factor H associated hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2009;4:201-206.

    Not in our library10.2215/cjn.02170508

  142. 142.

    Haller W., Milford D.V., Goodship T.H., Sharif K., Mirza D.F., McKiernan P.J. Successful isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in complement factor H. Am J Transplant. 2010;10:2142-2147.

    Not in our library10.1111/j.1600-6143.2010.03228.x

  143. 143.

    Wilson C., Torpey N., Jaques B., Strain L., Talbot D., Manas D. Successful simultaneous liver-kidney transplant in an adult with atypical hemolytic uremic syndrome associated with a mutation in complement factor H. Am J Kidney Dis. 2011;58:109-112.

    Not in our library10.1053/j.ajkd.2011.04.008

  144. 144.

    Sanchez-Corral P., Melgosa M. Advances in understanding the aetiology of atypical haemolytic uraemic syndrome. Br J Haematol. 2010;150:529-542.

    Not in our library10.1111/j.1365-2141.2010.08295.x

  145. 145.

    Saland J.M., Emre S.H., Shneider B.L., Benchimol C., Ames S., Bromberg J.S. Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation. Am J Transplant. 2006;6:1948-1952.

    Not in our library10.1111/j.1600-6143.2006.01375.x

  146. 146.

    Kavanagh D., Richards A., Goodship T., Jalanko H. Transplantation in atypical hemolytic uremic syndrome. Semin Thromb Hemost. 2010;36:653-659.

    Not in our library10.1055/s-0030-1262887

  147. 147.

    Saland J.M., Ruggenenti P., Remuzzi G. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2009;20:940-949.

    Not in our library10.1681/asn.2008080906

  148. 148.

    Le Quintrec M., Lionet A., Kamar N., Karras A., Barbier S., Buchler M. Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation. Am J Transplant. 2008;8:1694-1701.

    Not in our library10.1111/j.1600-6143.2008.02297.x

  149. 149.

    Brown J.H., Tellez J., Wilson V., Mackie I.J., Scully M., Tredger M.M. Postpartum aHUS secondary to a genetic abnormality in factor H acquired through liver transplantation. Am J Transplant. 2012;12:1632-1636.

    Not in our library10.1111/j.1600-6143.2012.03991.x

  150. 150.

    Nuernberger J., Witzke O., Saez A.O., Vester U., Baba H.A., Kribben A. Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med. 2009;360:542-544.

    Not in our library10.1056/nejmc0808527

  151. 151.

    Al-Akash S.I., Almond P.S., Savell V.H., Gharaybeh S.I., Hogue C. Eculizumab induces long-term remission in recurrent post-transplant HUS associated with C3 gene mutation. Pediatr Nephrol. 2011;26:613-619.

    Not in our library10.1007/s00467-010-1708-6

  152. 152.

    Chatelet V, Fremeaux-Bacchi V, Lobbedez T, Ficheux M, de Ligny BH. Safety and long-term efficacy of eculizumab in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome. Am J Transplant. 2009;9:2644-5

    Not in our library10.1111/j.1600-6143.2009.02817.x

  153. 153.

    Chatelet V., Lobbedez T., Fremeaux-Bacchi V., Ficheux M., Ryckelynck J.P., de Ligny BH. Eculizumab: safety and efficacy after 17 months of treatment in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome: case report. Transplant Proc. 2010;42:4353-4355.

    Not in our library10.1016/j.transproceed.2010.09.125

  154. 154.

    Larrea CF-d Cofan F., Oppenheimer F., Campistol J.M., Escolar G., Lozano M. Efficacy of eculizumab in the treatment of recurrent atypical hemolytic-uremic syndrome after renal transplantation. Transplantation. 2010;89:903-904.

    Not in our library10.1097/tp.0b013e3181ccd80d

  155. 155.

    Zuber J., Le Quintrec M., Sberro-Soussan R., Loirat C., Fremeaux-Bacchi V., Legendre C. New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol. 2011;7:23-35.

    Not in our library10.1038/nrneph.2010.155

  156. 156.

    Nester C., Stewart Z., Myers D., Jetton J, Nair R, Reed A. Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2011;6:1488-1494.

    Not in our library10.2215/cjn.10181110

  157. 157.

    Krid S., Roumenina L., Beury D., Charbit M., Boyer O., Fremeaux-Bacchi V. Renal transplantation under prophylactic eculizumab in atypical hemolytic uremic syndrome with CFH/CFHR1 hybrid protein. Am J Transplant. 2012;12:1938-1944.

    Not in our library10.1111/j.1600-6143.2012.04051.x

  158. 158.

    Weitz M., Amon O., Bassler D., Koenigsrainer A., Nadalin S. Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr Nephrol. 2011;26:1325-1329.

    Not in our library10.1007/s00467-011-1879-9

  159. 159.

    Zimmerhackl L.B., Hofer J., Cortina G., Mark W., Wurzner R., Jungraithmayr T.C. Prophylactic eculizumab after renal transplantation in atypical hemolytic-uremic syndrome. N Engl J Med. 2010;362:1746-1748.

    Not in our library10.1056/nejmc1001060

  160. 160.

    Zuber J., Le Quintrec M., Krid S., Bertoye C., Gueutin V., Lahoche A., French Study Group. Atypical HUS. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant. 2012;12:3337-3354.

    Not in our library10.1111/j.1600-6143.2012.04252.x

  161. 161.

    Roversi P., Johnson S., Caesar J.J., McLean F., Leath K.J., Tsiftsoglou S.A. Structural basis for complement factor I control and its disease-associated sequence polymorphisms. Proc Natl Acad Sci U S A. 2011;108:12839-12844.

    Not in our library10.1073/pnas.1102167108

  162. 162.

    Sugimoto T., Ogawa N., Aoyama M., Sakaguchi M., Isshiki K., Kanasaki M. Haemolytic uraemic syndrome complicated with norovirus-associated gastroenteritis. Nephrol Dial Transplant. 2007;22:2098-2099.

    Not in our library10.1093/ndt/gfm104

  163. 163.

    Lee B.H., Kwak S.H., Shin J.I., Lee S.H., Choi H.J., Kang H.G. Atypical hemolytic uremic syndrome associated with complement factor H autoantibodies and CFHR1/CFHR3 deficiency. Pediatr Res. 2009;66:336-340.

    Not in our library10.1203/pdr.0b013e3181b1bd4a

  164. 164.

    Carter J.E., Cimolai N. Hemolytic-uremic syndrome associated with acute Campylobacter upsaliensis gastroenteritis. Nephron. 1996;74:489.

    Not in our library10.1159/000189403

  165. 165.

    Alvarado A.S., Brodsky S.V., Nadasdy T., Singh N. Hemolytic uremic syndrome associated with Clostridium difficile infection. Clin Nephrol. 2013.

    Not in our library10.5414/cn107691

  166. 166.

    Berner R., Krause M.F., Gordjani N., Zipfel P.F., Boehm N., Krueger M. Hemolytic uremic syndrome due to an altered factor H triggered by neonatal pertussis. Pediatr Nephrol. 2002;17:190-192.

    Not in our library10.1007/s00467-001-0798-6

  167. 167.

    Waters A.M., Kerecuk L., Luk D., Haq M.R., Fitzpatrick M.M., Gilbert R.D. Hemolytic uremic syndrome associated with invasive pneumococcal disease: the United Kingdom experience. J Pediatr. 2007;151:140-144.

    Not in our library10.1016/j.jpeds.2007.03.055

  168. 168.

    Chand D.H., Brady R.C., Bissler J.J. Hemolytic uremic syndrome in an adolescent with Fusobacterium necrophorum bacteremia. Am J Kidney Dis. 2001;37:E22.

    Not in our library10.1053/ajkd.2001.22099

  169. 169.

    Kwon T., Belot A., Ranchin B., Baudouin V., Fremeaux-Bacchi V., Dragon-Durey M.A. Varicella as a trigger of atypical haemolytic uraemic syndrome associated with complement dysfunction: two cases. Nephrol Dial Transplant. 2009;24:2752-2754.

    Not in our library10.1093/ndt/gfp166

  170. 170.

    Waiser J., Budde K., Rudolph B., Ortner M.A., Neumayer H.H. De novo hemolytic uremic syndrome postrenal transplant after cytomegalovirus infection. Am J Kidney Dis. 1999;34:556-559.

    Not in our library10.1016/s0272-6386(99)70085-5

  171. 171.

    Bento D., Mapril J., Rocha C., Marchbank K.J., Kavanagh D., Barge D. Triggering of atypical hemolytic uremic syndrome by influenza A (H1N1). Ren Fail. 2010;32:753-756.

    Not in our library10.3109/0886022x.2010.486491

  172. 172.

    Tagle M., Barriga J.A., Gutierrez S., Valdez L.M., Castle J., Antunez De Mayolo A. [Relapsing viral hepatitis type A complicated with renal failure]. Rev Gastroenterol Peru. 2004;24:92-96.

    Not in our library

  173. 173.

    Baid S., Pascual M., Williams W.W., Tolkoff-Rubin N., Johnson S.M., Collins B. Renal thrombotic microangiopathy associated with anticardiolipin antibodies in hepatitis C-positive renal allograft recipients. J Am Soc Nephrol. 1999;10:146-153.

    Not in our library10.1681/asn.v101146

  174. 174.

    Benitez M., Boto A., Colchero J., Fernandez-Giron F., Rodriguez P., Paralle M. Haemolytic-uraemic syndrome in a patient infected by HIV. Nephrol Dial Transplant. 1997;12:362-363.

    Not in our library10.1093/ndt/12.2.362

  175. 175.

    Austin T.W., Ray C.G., Coxsackie virus group. B infections and the hemolytic-uremic syndrome. J Infect Dis. 1973;127:698-701.

    Not in our library10.1093/infdis/127.6.698

  176. 176.

    Watanabe T. Hemolytic uremic syndrome associated with Epstein-Barr virus infection. Pediatr Nephrol. 2004;19:569.

    Not in our library10.1007/s00467-004-1416-1

  177. 177.

    Wiersinga W.J., Scheepstra C.G., Kasanardjo J.S., de Vries PJ, Zaaijer H, Geerlings SE. Dengue fever-induced hemolytic uremic syndrome. Clin Infect Dis. 2006;43:800-801.

    Not in our library10.1086/507111

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    Matsuda Y., Hara J., Miyoshi H., Osugi Y., Fujisaki H., Takai K. Thrombotic microangiopathy associated with reactivation of human herpesvirus-6 following high-dose chemotherapy with autologous bone marrow transplantation in young children. Bone Marrow Transplant. 1999;24:919-923.

    Not in our library10.1038/sj.bmt.1702003

  179. 179.

    Hartel C., Herz A., Vieth S., Lensing C., Schultz C. Renal complications associated with human parvovirus B19 infection in early childhood. Klin Padiatr. 2007;219:74-75.

    Not in our library10.1055/s-2007-970071

  180. 180.

    Adonis-Koffy L. [May Plasmodium falciparum induce a hemolytic uremic syndrome?]. Arch Pediatr. 2004;11:55-56.

    Not in our library10.1016/j.arcped.2003.09.049

  181. 181.

    Noris M., Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676-1687.

    Not in our library10.1056/nejmra0902814

  182. 182.

    Canpolat C., Pearson P., Jaffe N. Cisplatin-associated hemolytic uremic syndrome. Cancer. 1994;74:3059-3062.

    Not in our library10.1002/1097-0142(19941201)74:11<3059::aid-cncr2820741125>3.0.co;2-z

  183. 183.

    Boeck S., Geiger S., Schulz C., Heinemann V. Hemolytic-uremic syndrome associated with gemcitabine treatment for metastatic pancreatic cancer. J Clin Gastroenterol. 2008;42:551-552.

    Not in our library10.1097/mcg.0b013e31802da22e

  184. 184.

    Ariyoshi K., Shinohara K., Ruirong X. Thrombotic thrombocytopenic purpura caused by ticlopidine, successfully treated by plasmapheresis. Am J Hematol. 1997;54:175-176.

    Not in our library

  185. 185.

    Andersohn F., Hagmann F.G., Garbe E. Thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome associated with clopidogrel: report of two new cases. Heart. 2004;90:e57.

    Not in our library10.1136/hrt.2004.039214

  186. 186.

    Aster R.H. Quinine sensitivity: a new cause of the hemolytic uremic syndrome. Ann Intern Med. 1993;119:243-244.

    Not in our library10.7326/0003-4819-119-3-199308010-00012

  187. 187.

    Gottschall J.L., Neahring B., McFarland J.G., Wu G.G., Weitekamp L.A., Aster R.H. Quinine-induced immune thrombocytopenia with hemolytic uremic syndrome: clinical and serological findings in nine patients and review of literature. Am J Hematol. 1994;47:283-289.

    Not in our library10.1002/ajh.2830470407

  188. 188.

    Ubara Y., Hara S., Takedatu H., Katori H., Yamada K., Yoshihara K. Hemolytic uremic syndrome associated with beta-interferon therapy for chronic hepatitis C. Nephron. 1998;80:107-108.

    Not in our library10.1159/000045147

  189. 189.

    Badid C., McGregor B., Faivre J.M., Guerard A., Juillard L., Fouque D. Renal thrombotic microangiopathy induced by interferon-alpha. Nephrol Dial Transplant. 2001;16:846-848.

    Not in our library10.1093/ndt/16.4.846

  190. 190.

    Keir L., Moorsel F., Saleem M.A., Richards A. Beware renal adverse effects of anti-vascular endothelial growth factor treatment. BMJ. 2012;344:e3838.

    Not in our library10.1136/bmj.e3838

  191. 191.

    Bonatti H., Brandacher G., Boesmueller C., Cont M., Hengster P., Rosenkranz A.R. Hemolytic uremic syndrome following Campath-1H induction. Transpl Int. 2007;20:386-389.

    Not in our library10.1111/j.1432-2277.2006.00445.x

  192. 192.

    Abraham K.A., Little M.A., Dorman A.M., Walshe J.J. Hemolytic-uremic syndrome in association with both cyclosporine and tacrolimus. Transpl Int. 2000;13:443-447.

    Not in our library10.1007/s001470050727

  193. 193.

    Allan D.S., Thompson C.M., Barr R.M., Clark W.F., Chin-Yee I.H. Ciprofloxacin-associated hemolytic-uremic syndrome. Ann Pharmacother. 2002;36:1000-1002.

    Not in our library10.1345/aph.1a350

  194. 194.

    Blumberg A., Studer U., Briner J. [Hemolytic-uremic syndrome in a young woman following the use of ovulation inhibitors]. Schweiz Med Wochenschr. 1975;105:1324-1327.

    Not in our library

  195. 195.

    Ashouri O.S., Marbury T.C., Fuller T.J., Gaffney E., Grubb W.G., Cade J.R. Hemolytic uremic syndrome in two postmenopausal women taking a conjugated estrogen preparation. Clin Nephrol. 1982;17:212-215.

    Not in our library

  196. 196.

    Au W.Y., Chan K.W., Lam C.C., Young K. A post-menopausal woman with anuria and uterus bulk: the spectrum of estrogen-induced TTP/HUS. Am J Hematol. 2002;71:59-60.

    Not in our library10.1002/ajh.10162

  197. 197.

    Tumlin J.A., Sands J.M., Someren A. Hemolytic-uremic syndrome following “crack” cocaine inhalation. Am J Med Sci. 1990;299:366-371.

    Not in our library10.1097/00000441-199006000-00002

  198. 198.

    Ardiles L.G., Olavarria F., Elgueta M., Moya P., Mezzano S. Anticardiolipin antibodies in classic pediatric hemolytic-uremic syndrome: a possible pathogenic role. Nephron. 1998;78:278-283.

    Not in our library10.1159/000044936

  199. 199.

    Barre P., Kaplan B.S., de Chadarevian JP, Drummond KN. Hemolytic uremic syndrome with hypocomplementemia, serum C3NeF, and glomerular deposits of C3. Arch Pathol Lab Med. 1977;101:357-361.

    Not in our library

  200. 200.

    Nesher G., Hanna V.E., Moore T.L., Hersh M., Osborn T.G. Thrombotic microangiographic hemolytic anemia in systemic lupus erythematosus. Semin Arthritis Rheum. 1994;24:165-172.

    Not in our library10.1016/0049-0172(94)90072-8

  201. 201.

    Hale G.A., Bowman L.C., Rochester RJ, Benaim E, Heslop HE, Krance RA. Hemolytic uremic syndrome after bone marrow transplantation: clinical characteristics and outcome in children. Biol Blood Marrow Transplant. 2005;11:912-920.

    Not in our library10.1016/j.bbmt.2005.07.012

  202. 202.

    Lechner K., Obermeier H.L. Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases. Medicine (Baltimore). 2012;91:195-205.

    Not in our library10.1097/md.0b013e3182603598

  203. 203.

    Kind T., Levy J., Lee M., Kaicker S., Nicholson J.F., Kane S.A. Cobalamin C disease presenting as hemolytic-uremic syndrome in the neonatal period. J Pediatr Hematol Oncol. 2002;24:327-329.

    Not in our library10.1097/00043426-200205000-00023

  204. 204.

    Lehtinen M.J., Rops A.L., Isenman D.E., van der Vlag J., Jokiranta T.S. Mutations of factor H impair regulation of surface-bound C3b by three mechanisms in atypical hemolytic uremic syndrome. J Biol Chem. 2009;284:15650-15658.

    Not in our library10.1074/jbc.m900814200

  205. 205.

    Morgan H.P., Schmidt C.Q., Guariento M., Blaum B.S., Gillespie D., Herbert A.P. Structural basis for engagement by complement factor H of C3b on a self surface. Nat Struct Mol Biol. 2011;18:463-470.

    Not in our library10.1038/nsmb.2018

  206. 206.

    Jozsi M., Heinen S., Hartmann A., Ostrowicz C.W., Halbich S., Richter H. Factor H and atypical hemolytic uremic syndrome: mutations in the C-terminus cause structural changes and defective recognition functions. J Am Soc Nephrol. 2006;17:170-177.

    Not in our library10.1681/asn.2005080868

  207. 207.

    Jokiranta T.S., Cheng Z.Z., Seeberger H., Jozsi M., Heinen S., Noris M. Binding of complement factor H to endothelial cells is mediated by the carboxy-terminal glycosaminoglycan binding site. Am J Pathol. 2005;167:1173-1181.

    Not in our library10.1016/s0002-9440(10)61205-9

  208. 208.

    Manuelian T., Hellwage J., Meri S., Caprioli J., Noris M., Heinen S. Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J Clin Invest. 2003;111:1181-1190.

    Not in our library10.1172/jci16651

  209. 209.

    Sanchez-Corral P., Gonzalez-Rubio C., Rodriguez de Cordoba S, Lopez-Trascasa M. Functional analysis in serum from atypical hemolytic uremic syndrome patients reveals impaired protection of host cells associated with mutations in factor H. Mol Immunol. 2004;41:81-84.

    Not in our library10.1016/j.molimm.2004.01.003

  210. 210.

    Sanchez-Corral P., Perez-Caballero D., Huarte O., Simckes A.M., Goicoechea E., Lopez-Trascasa M. Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome. Am J Hum Genet. 2002;71:1285-1295.

    Not in our library10.1086/344515

  211. 211.

    Morgan H.P., Jiang J., Herbert A.P., Kavanagh D., Uhrin D., Barlow P.N. Crystallographic determination of the disease-associated T1184R variant of complement regulator factor H. Acta Crystallogr D Biol Crystallogr. 2011;67:593-600.

    Not in our library10.1107/s0907444911015423

  212. 212.

    Herbert A.P., Kavanagh D., Johansson C., Morgan H.P., Blaum B.S., Hannan J.P. Structural and functional characterization of the product of disease-related factor H gene conversion. Biochemistry. 2012;51:1874-1884.

    Not in our library10.1021/bi201689j

  213. 213.

    Boyer O., Balzamo E., Charbit M., Biebuyck-Gouge N., Salomon R., Dragon-Durey M.A. Pulse cyclophosphamide therapy and clinical remission in atypical hemolytic uremic syndrome with anti-complement factor H autoantibodies. Am J Kidney Dis. 2010;55:923-927.

    Not in our library10.1053/j.ajkd.2009.12.026

  214. 214.

    Geelen J., van den Dries K., Roos A., van de Kar N, de Kat Angelino C, Klasen I. A missense mutation in factor I (IF) predisposes to atypical haemolytic uraemic syndrome. Pediatr Nephrol. 2007;22:371-375.

    Not in our library10.1007/s00467-006-0320-2

  215. 215.

    Chan M.R., Thomas C.P., Torrealba J.R., Djamali A., Fernandez L.A., Nishimura C.J. Recurrent atypical hemolytic uremic syndrome associated with factor I mutation in a living related renal transplant recipient. Am J Kidney Dis. 2009;53:321-326.

    Not in our library10.1053/j.ajkd.2008.06.027

  216. 216.

    Cayci F.S., Cakar N., Hancer V.S., Uncu N., Acar B., Gur G. Eculizumab therapy in a child with hemolytic uremic syndrome and CFI mutation. Pediatr Nephrol. 2012;27:2327-2331.

    Not in our library10.1007/s00467-012-2283-9

  217. 217.

    Fang C.J., Fremeaux-Bacchi V., Liszewski M.K., Pianetti G., Noris M., Goodship T.H. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood. 2008;111:624-632.

    Not in our library10.1182/blood-2007-04-084533

  218. 218.

    Noris M., Brioschi S., Caprioli J., Todeschini M., Bresin E., Porrati F. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet. 2003;362:1542-1547.

    Not in our library10.1016/s0140-6736(03)14742-3

  219. 219.

    Fremeaux-Bacchi V., Sanlaville D., Menouer S., Blouin J., Dragon-Durey M.A., Fischbach M. Unusual clinical severity of complement membrane cofactor protein-associated hemolytic-uremic syndrome and uniparental isodisomy. Am J Kidney Dis. 2007;49:323-329.

    Not in our library10.1053/j.ajkd.2006.10.022

  220. 220.

    Volokhina E., Westra D., Xue X., Gros P., van de Kar N, van den Heuvel L. Novel C3 mutation p.Lys65Gln in aHUS affects complement factor H binding. Pediatr Nephrol. 2012;27:1519-1524.

    Not in our library10.1007/s00467-012-2183-z

  221. 221.

    Malina M., Gulati A., Bagga A., Majid M.A., Simkova E., Schaefer F. Peripheral gangrene in children with atypical hemolytic uremic syndrome. Pediatrics. 2013;131:e331-e335.

    Not in our library10.1542/peds.2012-0903

  222. 222.

    Ozel A., Caliskan U., Gucer S. Peripheral gangrene complicating hemolytic uremic syndrome in a child. Pediatr Nephrol. 2003;18:465-467.

    Not in our library10.1007/s00467-002-0973-4

  223. 223.

    Kaplan B.S., Garcia C.D., Chesney R.W., Segar W.E., Giugno K., Chem R. Peripheral gangrene complicating idiopathic and recessive hemolytic uremic syndromes. Pediatr Nephrol. 2000;14:985-989.

    Not in our library10.1007/s004670050058

  224. 224.

    Loirat C., Macher M.A., Elmaleh-Berges M., Kwon T., Deschenes G., Goodship T.H. Non-atheromatous arterial stenoses in atypical haemolytic uraemic syndrome associated with complement dysregulation. Nephrol Dial Transplant. 2010;25:3421-3425.

    Not in our library10.1093/ndt/gfq319

  225. 225.

    Vergouwen M.D., Adriani K.S., Roos Y.B., Groothoff J.W., Majoie C.B. Proximal cerebral artery stenosis in a patient with hemolytic uremic syndrome. AJNR Am J Neuroradiol. 2008;29:e34.

    Not in our library10.3174/ajnr.a0965

  226. 226.

    Sallee M., Daniel L., Piercecchi M.D., Jaubert D., Fremeaux-Bacchi V., Berland Y. Myocardial infarction is a complication of factor H-associated atypical HUS. Nephrol Dial Transplant. 2010;25:2028-2032.

    Not in our library10.1093/ndt/gfq160

  227. 227.

    Larakeb A., Leroy S., Fremeaux-Bacchi V., Montchilova M., Pelosse B., Dunand O. Ocular involvement in hemolytic uremic syndrome due to factor H deficiency--are there therapeutic consequences? Pediatr Nephrol. 2007;22:1967-1970.

    Not in our library10.1007/s00467-007-0540-0

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