Atypical hemolytic uremic syndrome: from diagnosis to treatment

Massimo Franchini 1
  • 1 Department of Transfusion Medicine and Hematology, Mantova, Italy
Massimo Franchini

Abstract

Thrombotic microangiopathy (TMA) is a relatively rare condition but a medical urgency requiring immediate intervention to avoid irreversible organ damage or death. Symptoms on presentation include microangiopathic haemolytic anaemia, thrombocytopenia and organ damage. The most frequent direct causes of TMA are thrombotic thrombocytopenic purpura (TTP) and haemolytic uremic syndrome (HUS). The most common form of HUS is related to Shiga toxin producing Escherichia coli (STEC) infection while approximately 10% of cases are due to dysregulation of the complement pathway (atypical haemolytic uremic syndrome, aHUS). Optimal treatment regimens differ depending on the underlying cause; however, differential diagnosis may be difficult. The most accurate method of diagnosis is based on exclusion and should consider, beyond the symptoms common to TMA, ADAMTS13 activity levels and STEC infection status. For the management of TTP, plasma exchange (PE) is the most important acute intervention and is associated with lower mortality and better outcomes than plasma infusion. In most patients with STEC-HUS, the course of disease is self-limiting although management of acute kidney injury is often required. Until recently, the management of aHUS consisted of early and intensive PE, although this was mostly ineffective in protecting from subsequent organ damage. Eculizumab, an inhibitor of the alternative complement pathway, produces a rapid and sustained inhibition of the TMA process, with significant improvements in long-term clinical outcomes. Due to the significant improvement achieved, eculizumab has subsequently been approved as first-line therapy when an unequivocal diagnosis of aHUS has been made.

Introduction

Thrombotic microangiopathy (TMA) is a relatively rare disorder which may be initiated by numerous causes and manifests as microangiopathic haemolytic anaemia, thrombocytopenia and organ damage. The condition is life-threatening and requires immediate management to avoid irreversible organ damage or death. In recent years major improvements have been made in understanding the nature of TMA, thus opening the door for specific, more effective treatment [1].

The most common causes of TMA are thrombotic thrombocytopenic purpura (TTP) and haemolytic uremic syndrome (HUS). In both TTP and HUS, TMA is an integral part of the disease. TMA may also present in other contexts, e.g., malignancy, chemotherapy or bone marrow transplantation [2], but the medical history of the patient can usually rule out these causes.

Here, I will first review the pathophysiology, epidemiology and clinical presentation of TMAs. Then, I will describe in more detail how recent advances in diagnostic and therapeutic processes can help differentiate amongst TMAs and describe how the use of eculizumab has transformed the treatment paradigm for atypical haemolytic uremic syndrome (aHUS).

Pathophysiology

TMA is defined by thickened arterioles and capillaries, swollen and detached endothelial cells, widened subendothelial spaces and accumulation of proteins and cell debris. Blood vessel obstruction occurs due to aggregated platelets, along with haemolysis, and blood smears show fragmented or distorted erythrocytes [3]. This causes widespread thrombosis and organ ischaemia giving rise to the classical clinical features of TMA and organ failure in TTP, aHUS and Shiga toxin producing Escherichia coli (STEC)-HUS.

Thrombotic thrombocytopenic purpura

In TTP, deficiency of plasma ADAMTS13 (adisintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity causes the accumulation of ultra-large multimers of von Willebrand Factor (VWF) on the endothelium. Under normal physiological conditions, ADAMTS13 cleaves the ultra-large VWF released from activated endothelial cells or following vascular injury. This process is crucial to control VWF activity and maintain equilibrium of haemostasis and thrombosis in plasma. Severely reduced ADAMTS13 activity (<5%–10%) results in aggregation of platelets on the ultra-large VWF and widespread microthrombi formation in small arterioles and capillaries throughout the body – the characteristic pathological feature of TTP [4].

There are two variants of TTP; the hereditary form, also called Upshaw-Schulman syndrome, with mutations in the ADAMTS13 gene and the acquired form caused by autoantibodies directed against ADAMTS13. Patients with both congenital and acquired TTP have been shown to lack ADAMTS13 in the plasma or have autoantibodies severely reducing its function, respectively [5–7].

Haemolytic uraemic syndrome

The most common form of HUS (90% of cases) is that caused by a prodromal bacterial infection (Shiga toxin Escherichia coli – STEC). The link to Shiga toxin was first proposed in 1983 [8]. Destruction of endothelial cells is likely key to the pathogenesis of STEC-HUS. Cellular damage is believed to be mediated through the transport of Shiga toxins produced in the bowel to capillary beds where the toxin initiates cell death via inhibition of protein synthesis [9]. Shiga toxin has also been found to directly activate complement and interact with complement factor H (CFH) in vitro, suggesting a mechanistic link between complement regulation and STEC infection. Damage of endothelial cells would in itself activate complement [10]. Together the platelet and complement activation and endothelial damage leads to platelet aggregation, small vessel obstruction, mechanical haemolysis and TMA, mainly in the kidney but also in other organs, notably the central nervous system (CNS) and gastrointestinal tract [9, 11, 12].

Atypical haemolytic uraemic syndrome

In aHUS, the pathophysiological consequences result directly from damage caused by the uncontrolled activation of the alternative complement pathway leading to excessive complement activation on cell membranes [13, 14]. A link between complement and aHUS was first reported in 1981 in two brothers who had a deficiency of CFH and mutations in the gene encoding CFH were recognised to be associated with aHUS in 1998 [15, 16]. Since then, mutations in multiple other factors that facilitate uncontrolled complement activation by the alternative pathway have been identified in patients with aHUS [17].

A brief overview of the complement cascade showing the central role of the C3 convertase in the generation of the final membrane attack complex (C5b-9) is shown in Figure 1. The different roles of cleavage products in microbial defence and removal of dead or damaged cells is also shown. Mutations in complement system genes have been identified in 50%–60% of patients with aHUS [13, 14]. The mutations identified impair regulation in the alternative pathway at the level of the C3 convertase and Figure 2 describes these mechanisms.

Figure 1:
Figure 1:

A simplified overview of the complement cascade.

The alternative pathway involves the constitutive low level activation of C3 and the subsequent deposit of C3b on cell membranes, ultimately leading to the generation of the membrane attack complex, (MAC), C5b-9. Regulation of the complement cascade is described in Figure 2.

Citation: Clinical Chemistry and Laboratory Medicine (CCLM) 53, 11; 10.1515/cclm-2015-0024

Figure 2:
Figure 2:

Model for the mechanisms leading from impaired regulation of the alternative pathway to thrombotic microangiopathy.

In a normal endothelial cell (A), complement factor H (CFH) binds to the endothelial surface and to C3b and together with membrane cofactor protein (MCP) acts as a cofactor for cleavage of C3b, which is mediated by complement factor I (CFI), a process that prevents its interaction with factor B. CFH also dissociates the C3 convertase of the alternative pathway (C3b). Thrombomodulin (TM) enhances CFI-mediated inactivation of C3b in the presence of CFH and promotes activation of the thrombin-activatable fibrinolysis inhibitor (TAFIa), which degrades C3a and C5a. In patients with loss-of-function mutations in complement regulatory genes [CFH, CFI, MCP, and THBD (the gene encoding thrombomodulin)] (B), C3b is not degraded efficiently and forms the C3 and C5 convertases of the alternative pathway. A similar situation applies to patients with gain-of-function mutations in CFB and C3. Mutant CFB forms a superconvertase that is resistant to dissociation by CFH. Mutant C3b does not bind CFH and MCP and is resistant to degradation by CFI. From Noris et al. [14]. Reprinted with permission from Massachusetts Medical Society.

Citation: Clinical Chemistry and Laboratory Medicine (CCLM) 53, 11; 10.1515/cclm-2015-0024

Mutations in patients with aHUS have also been identified in the coagulation pathway (thrombomodulin and plasminogen), linking these two pathways to the development of aHUS [18, 19]. Recently, mutations in diacylglycerol kinase ε (DGKE) have been found to cause HUS-like disease. Currently, it has only been described in paediatric patients younger than 1 year [20] and has also been associated with a membranoproliferative glomerulonephritis (MPGN)-like syndrome in nine patients from three families [21]. Some of these patients with mutations in DGKE have been found to carry additional mutations in complement genes, and therefore the involvement of complement dysregulation in patients with DGKE mutations remains unclear [18].

Epidemiology and clinical presentation

Interestingly all three clinical entities have variable penetrance. Although onset of the hereditary form of TTP is in the neonatal period or early childhood, approximately 10%–20% remain asymptomatic until over 20 years of age [22]. It is not clear what determines this variability, but further environmental and possible genetic triggers may be involved [17, 23].

A similar situation is true for STEC-HUS where not all patients with STEC infection develop STEC-HUS. In the German outbreak in 2011, 19% of patients infected with STEC developed STEC-HUS [24].

Penetrance is also incomplete in aHUS, and seems to be 40%–50% among carriers of CFH, membrane cofactor protein (MCP), and CFI mutations [25]; healthy carriers of C3 and CFB mutations have also been described [26, 27]. There are numerous reports describing the onset of aHUS symptoms in association with an environmental trigger. Infectious diseases have been associated with 22%–55% of clinical cases of patients with mutations in CFH, MCP, CFI or C325 and diarrhoea (including STEC diarrhoea) may also precede aHUS in as many as 30% of cases [28, 29]. Pregnancy, drugs, malignancy, connective tissue disorders and specific metabolic defects are also known triggers [30]. The full range and function of environmental parameters associated with onset of aHUS is not completely understood.

Thrombotic thrombocytopenic purpura

The first known description of what is now considered as TTP was by Moschcowitz in 1924. He described a 16-year-old girl presenting with pallor, weakness, purpura and haemiparesis who died within 2 weeks [31]. It is now well understood that most cases in adults are caused by the acquired form with autoantibodies to ADAMTS13. Classically TTP is described by widespread VWF and platelet rich microthrombi classically affecting the CNS, but TMA can occur in any organ.

The hereditary form of TTP is rare and only accounts for 2%–4% of all TTP cases [32, 33]. It occurs primarily in neonates and children, but adult onset cases have been reported [33, 34]. Acquired TTP occurs mostly in adults [35]. While it is a rare disease (approximately six cases per million per year in the UK) [36], the prognosis if untreated is very poor and today mortality remains at 10%–20% in acute TTP [17, 37].

HUS: STEC-HUS and aHUS

The term HUS was first used in 1955 by Gasser et al. to describe five children, aged 2 months to 7 years, with acquired haemolytic anaemia, unusual poikilocytes and renal insufficiency, three of whom had thrombocytopenia; all the patients died [38]. The pathological hallmarks of HUS are platelet-fibrin rich microthrombi causing small vessel thrombosis, schistocytosis, and TMA in the kidney and also other organs [39].

Overall, approximately 90% of HUS cases are due to STEC, which although predominantly considered a paediatric disease, is well known to also affect adults [24]. The frequency of STEC-HUS in North America has been reported as approximately two or three cases per 100,000 in children under 5 years of age [9]. Worldwide the reported incidence varies widely, and it should also be noted that large, localised outbreaks occur due to the ingestion of contaminated food or water [9, 24]. For example, the outbreak in Germany in 2011 resulted in almost 4000 people being infected with a particularly virulent enteroaggregative E. coli strain, leading to 854 cases of HUS of which 54 (6.3%) died [24]. A pooled analysis of almost 3500 patients from 49 studies of STEC-HUS found that overall the incidence of death or end-stage renal disease (ESRD) was 12% and clinically significant renal damage occurred in 25% of patients [11].

Generally, the prognosis of STEC-HUS is favourable in the majority of children, although serious systemic complications, such as haemorrhagic colitis and CNS involvement, can occur and mortality is between 1% and 5% [40–42]. In patients aged over 65 years, a lethal outcome occurs in up to 50% of cases [43]. Long-term consequences affect up to 20% of children with STEC-HUS and include arterial hypertension, neurological impairment, chronic kidney disease, or diabetes mellitus [40, 41, 44].

The atypical form of HUS is a very rare disease with a very poor prognosis. In the US, aHUS is estimated to have an annual incidence rate of ∼1–2 cases/million inhabitants [45] and in Europe, a recent international, multi-centre study reported an incidence of 0.11 cases/million inhabitants between the ages of 0 and 18 years [13]. Age of initial onset of aHUS is approximately equal in adults and children [28, 29] and distribution is similar between males and females, although there is a slight predominance in females among adult onset patients [28]. Prognosis is poor with a mortality up to 25% and over half of patients developing ESRD after the first presentation of aHUS [12, 17, 25, 46, 47].

However, the disease is heterogeneous and unpredictable and the clinical characteristics of patients with aHUS and the risk of TMA after renal transplant seem to vary based on specific complement mutation and environmental factors (Table 1). Factor H is the most common mutation which also has the worst prognosis leading to renal impairment, ESRD or death in up to 79% of patients at 3 years post-initial presentation. Although lesions typically affect the kidney, in approximately 20% of patients extra-renal symptoms are present and can involve the CNS, cardiovascular system, lungs, skin, skeletal muscle and gastrointestinal tract [49].

Table 1:

Genetic abnormalities and clinical outcome in patients with aHUS.

Complement abnormalityMain effectFrequency, %Death or ESRD within one year of first presentation, %TMA post-transplantation, %
Factor H mutationsIncreased activity of C3 convertase (decreased inhibition)20–3050–6075–90
Factor I mutationsDecreased C3b inactivation2–1242–5045–80
C3 mutationsC3 convertase resistant to inhibition5–1043–6340–70
Factor B mutationsC3 convertase stabilisation (increased activity)1–250100
Thrombomodulin (THBD) mutationsReduced C3b inactivation0–5501/1
Membrane cofactor Protein (MCP) mutationsIncreased activity of C3 convertase (decreased inhibition)3–150–63≤20
Factor H antibodiesInactive factor H (increased activity of C3)6–1030–40Greater with elevated antibody levels

Adapted from Noris and Remuzzi [14], Campistol et al. [13], Zuber et al. [48] and Fremeaux-Bacchi et al. [46].

Diagnosis

As discussed, TMA can be due to several causes and may be further precipitated by other underlying diseases, drugs, bone marrow transplant, or pregnancy [13]. In these cases, intervention to discontinue the event which initiated the onset of symptoms (if possible, e.g., stopping a drug treatment) may lead to resolution of TMA. If TMA persists, the event may have been the precipitating factor exposing an underlying predisposition to aHUS in the patient.

TTP may potentially be accurately differentiated from aHUS by severe deficiency of the ADAMTS13 protease [13, 50] and, if the facilities are available, ADAMTS13 activity can be assessed within 2 days. It is important to take samples for analysis before any plasma has been given. An analysis of serum creatinine and platelet count at initial presentation was performed in patients with severe ADAMTS13 deficiency versus patients with aHUS to develop a predictive score [51]. Although less definitive, a diagnosis of severe ADAMTS13-deficiency (TTP) can almost be excluded based on a serum creatinine level above 150–200 μmol/L or a platelet count >30×109/L at presentation [51, 52].

Clinical presentation does not always accurately differentiate the aetiology of TMA. Although STEC-HUS is more common in children and TTP is more common in adults there are frequent exceptions and patients with aHUS can present at any age. So age is not considered a reliable guide to the cause of TMA.

Sometimes renal versus CNS involvement has been proposed to distinguish between STEC-HUS/aHUS and TTP. While aHUS and STEC-HUS almost always have renal involvement and while severe renal injury requiring haemodialysis is less common in patients with severe ADAMTS13 deficiency, acute renal failure has been reported in up to 10% of TTP patients [50, 53]. CNS involvement has been considered a hallmark of TTP, with neurologic injury reported in 25%–79% of patients at presentation, it is also the most frequent extra-renal symptom in aHUS, occurring in 10%–48% of patients [49] and can occur in patients with STEC-HUS [41]. Thus the type of organ involvement cannot be used as a reliable diagnostic tool.

If the patient has a history of gastrointestinal symptoms, STEC-HUS may be thought more likely than aHUS and testing for the presence of Shiga toxin genes and serum reactivity by PCR and ELISA, respectively, and STEC culture for E. coli strains is indicated. Again, however, a caveat exists in that prodromal diarrhoea does not define STEC-HUS as up to 30% of cases of aHUS include a previous diarrhoea episode [28, 29] and not all patients with STEC-HUS report diarrhoea.

Ultimately, therefore, differentiating between causes of TMA is a diagnosis of exclusion and an algorithm for differential diagnosis has been proposed by Campistol et al. (Figure 3) [13]. Therefore, to confirm a diagnosis of aHUS, it is necessary that tests for STEC (Shiga toxin) and pneumococcus infections are negative and ADAMTS13 activity is normal (>5%–10%). Measurement of serum levels of C3, C4, CFH and CFI, and complement antibody and genetic mutation screening can give an indication [13, 54], although it should be noted that normal complement protein levels or the absence of a mutation does not exclude a diagnosis of aHUS as serum activity does not correlate with complement activity on the endothelial surface [46, 55, 56].

Figure 3:
Figure 3:

An algorithm for the differential diagnosis of TMA.

ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aHUS, atypical haemolytic uraemic syndrome; HUS, haemolytic uraemic syndrome; LDH, lactate dehydrogenase; STEC, Shiga toxin producing Escherichia coli; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura. aNegative direct Coombs test; bThe Shiga toxin test/STEC is indicated when the patient has a history of digestive system involvement or gastrointestinal symptoms; cIn some patients with aHUS, STEC infection can trigger the underlying disease. From Campistol J, et al. [13]. Reprinted with permission from the Nefrologia Publishing Group.

Citation: Clinical Chemistry and Laboratory Medicine (CCLM) 53, 11; 10.1515/cclm-2015-0024

Treatment

Treatment of aHUS

Until Gruppo and Rother published data describing the successful treatment of aHUS with eculizumab [57] management of aHUS consisted of early and intensive PE at high volumes at variable frequency (based upon clinical presentation). While PE initially manages haematological symptoms in some patients, up to 65% of aHUS patients require dialysis, develop permanent kidney damage or die within 1 year despite PE or plasma infusion (PI) [25]. However, haematologic improvement does not mean that TMA is not ongoing in organs, and unlike in the treatment of TTP, it has been demonstrated that the use of PE in aHUS is mostly ineffective [46].

When the diagnosis of aHUS is unequivocal, eculizumab is recommended in both adult and paediatric patients as first-line therapy, in order to protect organ function [13]. Eculizumab is a monoclonal antibody that binds with high affinity to complement protein C5, blocking the formation of the C5b-9 cell membrane attack complex, leaving proximal functions (opsonisation and immune clearance) intact. Two pivotal prospective studies in a total of 37 patients with aHUS have shown that administration of eculizumab produces a rapid and sustained inhibition of the TMA process, with significant improvements in clinical outcomes (haemolysis, long-term platelet counts and renal function), and discontinuation of plasma management and a 80% reduction in need for dialysis [58].

In trial 1, the mean increase in platelet count from baseline to week 26 was 73×109/L (primary outcome), and dialysis was discontinued in four of five patients. In the second trial, 80% of patients had TMA event-free status (primary outcome; ≥12 weeks of no reduction in platelet count >25%, no PE/PI and no new dialysis) during eculizumab treatment. Earlier intervention was associated with improved glomerular filtration rate and treatment improved renal function across patient subgroups, including those with long-standing, substantial kidney damage who had previously been managed on chronic plasma exchange or infusion.

Two further trials in 22 paediatric and 41 adult aHUS patients have recently reported data – a total of prospective trial data in 100 patients with aHUS. In paediatric patients, early intervention with eculizumab (median time from diagnosis to treatment of 6 days) was associated with haematological normalisation (platelet and LDH normalisation) in 18 (82%) patients and a complete TMA response (primary outcome; haematological normalisation and ≥25% improvement in serum creatinine from baseline) in 14 (64%) patients [59]. The trial in adult patients with aHUS recruited a broad population: 30 (73%) patients were newly diagnosed, six (15%) patients had no PE/PI during the current aHUS manifestation, 24 (59%) patients were on dialysis at baseline, nine (22%) patients had a prior kidney transplant and 20 (49%) patients had an identified complement factor mutation [60]. The majority of patients achieved platelet and haematological normalisation as well as a complete TMA response (primary outcome; haematological normalisation and <25% increase in serum creatinine from baseline). Also in these studies plasma management was discontinued and 80% of patients on dialysis at baseline were able to discontinue dialysis.

No cumulative toxicity or unexpected serious infection-related adverse events, were observed through the trial period or the extension phase and survival was 100% in the studies [58, 61]. However, there were two cases of meningococcal infections that were resolved with antibiotic treatment [61]. Due to the mechanism of action of eculizumab, preventative measures (vaccination and if needed prophylactic antibiotics) should be initiated against Neisseria meningitides prior to starting treatment [13]. The long-term safety and efficacy of eculizumab is being further studied in a non-interventional global aHUS registry [62].

Kidney transplantation

Due to the high rates of recurrence of TMA and graft loss, aHUS is a contraindication for live kidney donation [63, 64]. Prior to transplant a complete genetic analysis should be performed to detect known complement mutations and anti-CFH antibodies. TMA presents in the transplanted kidney in around 50% of patients who undergo transplantation (ranging from 15% to 100% in patients), and graft failure occurs in 80%–100% of those with TMA [14]. With a lack of treatment guidelines, patients in whom a kidney transplant is considered should be evaluated on an individual basis, based on the risk of graft failure and availability of eculizumab [13, 64].

Plasma administration on occurrence of TMA in aHUS patients with a kidney transplant is of limited value [65, 66]. Prophylactic plasma can decrease graft loss. Of nine patients who received pre-emptive plasma, four had an event-free successful renal transplantation. TMA occurred in three other patients who were successfully treated with eculizumab in each case [66].

As the liver is the source of some complement proteins, combined liver-kidney transplantation could be an option for the prevention of further TMA in aHUS patients with ESRD and a mutated protein produced in the liver. The procedure is associated with a not inconsiderable mortality risk; all patients died when no prevention of complement activation was used. However, when either prophylactic eculizumab or PE was used outcomes were good in 80% with a mortality rate of 15% [64]. In aHUS patients with functioning kidney, isolated liver transplantation should no longer be recommended as the risks related to lifelong immunosuppressive therapy far outweigh those associated with long-term eculizumab therapy [67].

Eculizumab has been used successfully to treat aHUS following transplant in a number of cases and as prophylaxis in transplants at high risk of recurrence. For this group, eculizumab prophylactic therapy has been proposed as preferable to PE for several reasons, including failure of PE to prevent TMA, the unpredictable risk of TMA when PE is tapered and subclinical progression of disease [46, 48, 66, 68].

Conclusions

A patient presenting with TMA needs careful investigation to distinguish between TTP, STEC-HUS and aHUS. Characterisation of aHUS is performed by the presence of non-immune microangiopathic haemolytic anaemia, thrombocytopenia, and organ injury an ADAMTS13 activity (>5%) and no evidence of STEC. TMA is a medical urgency and it is important to initiate specific treatment early to avoid irreversible damage to organs. Multiple organ involvement has to be considered. Assessment of platelet levels and serum creatinine while waiting for STEC and ADAMTS13 test results may give an indication whether TTP or aHUS is present.

In aHUS, mutations and polymorphisms in the genes of certain complement factors that are involved in either the regulation or activation of the alternative complement system pathway have been identified. In 30%–40% of patients no mutation has been identified yet. The prognosis of aHUS is complex but depends upon predisposing factors like the genetic mutation, background of polymorphisms and also precipitating factors like the complement activating environment. Eculizumab is currently the only licensed therapy for aHUS in both the USA and Europe and it is effective in all patients with aHUS whether or not a complement mutation has been identified and whether the patient has a native or transplanted kidney. Consensus guidelines recommend its early use in all patients with aHUS for optimal outcomes [13, 52].

Acknowledgments

Medical writing support (funded by Alexion Pharma International) was provided by Matthew deSchoolmeester of Bioscript Medical.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Financial support: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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    Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, et al. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci USA 2007;104:240–5.

    • Crossref
    • Export Citation
  • 27.

    Fremeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J, Brown AL, et al. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 2008;112:4948–52.

    • Crossref
    • Export Citation
  • 28.

    Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, et al.; French Society of Pediatric Nephrology. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2007;18:2392–400.

    • Crossref
    • Export Citation
  • 29.

    Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844–59.

    • Crossref
    • Export Citation
  • 30.

    Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, et al.; European Paediatric Study Group for HUS. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 2009;24:687–96.

    • Crossref
    • Export Citation
  • 31.

    Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc N Y Pathol Soc 1924;24:21–4.

  • 32.

    Kokame K, Matsumoto M, Soejima K, Yagi H, Ishizashi H, Funato M, et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci U S A 2002;99:11902–7.

    • Crossref
    • Export Citation
  • 33.

    Fujimura Y, Matsumoto M, Isonishi A, Yagi H, Kokame K, Soejima K, et al. Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan. J Thromb Haemost 2011;9(Suppl 1):283–301.

    • Crossref
    • Export Citation
  • 34.

    Schneppenheim R, Budde U, Oyen F, Angerhaus D, Aumann V, Drewke E, et al. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood 2003;101: 1845–50.

    • Crossref
    • Export Citation
  • 35.

    Blombery P, Scully M. Management of thrombotic thrombocytopenic purpura: current perspectives. J Blood Med 2014;5:15–23.

  • 36.

    Scully M, Yarranton H, Liesner R, Cavenagh J, Hunt B, Benjamin S, et al. Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features. Br J Haematol 2008;142:819–26.

    • Crossref
    • Export Citation
  • 37.

    Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine 1966;45:139–59.

    • Crossref
    • Export Citation
  • 38.

    Gasser C, Gautier E, Steck A, Siebenmann RE, Oechslin R. Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia. Schweiz Med Wochenschr 1955;85:905–9.

  • 39.

    Richardson SE, Karmali MA, Becker LE, Smith CR. The histopathology of the hemolytic uremic syndrome associated with verocytotoxin-producing Escherichia coli infections. Hum Pathol 1988;19:1102–8.

    • PubMed
    • Export Citation
  • 40.

    Siegler R, Oakes R. Hemolytic uremic syndrome; pathogenesis, treatment, and outcome. Curr Opin Pediatr 2005;17:200–4.

    • Crossref
    • PubMed
    • Export Citation
  • 41.

    Oakes RS, Siegler RL, McReynolds MA, Pysher T, Pavia AT. Predictors of fatality in postdiarrheal hemolytic uremic syndrome. Pediatrics 2006;117:1656–62.

    • Crossref
    • Export Citation
  • 42.

    Espie E, Grimont F, Mariani-Kurkdjian P, Bouvet P, Haeghebaert S, Filliol I, et al. Surveillance of hemolytic uremic syndrome in children less than 15 years of age, a system to monitor O157 and non-O157 Shiga toxin-producing Escherichia coli infections in France, 1996–2006. Pediatr Infect Dis J 2008;27:595–601.

    • Crossref
    • Export Citation
  • 43.

    Dundas S, Todd WT, Stewart AI, Murdoch PS, Chaudhuri AK, Hutchinson SJ. The central Scotland Escherichia coli O157:H7 outbreak: risk factors for the hemolytic uremic syndrome and death among hospitalized patients. Clin Infect Dis 2001;33:923–31.

    • Crossref
    • Export Citation
  • 44.

    Sharma AP, Filler G, Dwight P, Clark WF. Chronic renal disease is more prevalent in patients with hemolytic uremic syndrome who had a positive history of diarrhea. Kidney Int 2010;78:598–604.

    • Crossref
    • PubMed
    • Export Citation
  • 45.

    Constantinescu AR, Bitzan M, Weiss LS, Christen E, Kaplan BS, Cnaan A, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis 2004;43: 976–82.

    • Crossref
    • PubMed
    • Export Citation
  • 46.

    Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaimé F, Dragon-Durey MA, Ngo S, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 2013;8:554–62.

  • 47.

    Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol 1998;9:1126–33.

    • PubMed
    • Export Citation
  • 48.

    Zuber J, Le Quintrec M, Krid S, Bertoye C, Gueutin V, Lahoche A, et al.; French Study Group for Atypical HUS. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant 2012;12:3337–54.

    • Crossref
    • Export Citation
  • 49.

    Hofer J, Rosales A, Fischer C, Giner T. Extra-renal manifestations of complement-mediated thrombotic microangiopathies. Front Pediatr 2014;2:97.

    • Crossref
    • PubMed
    • Export Citation
  • 50.

    Cataland SR, Wu HM. Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: clinically differentiating the thrombotic microangiopathies. Eur J Intern Med 2013;24:486–91.

    • Crossref
    • Export Citation
  • 51.

    Coppo P, Schwarzinger M, Buffet M, Wynckel A, Clabault K, Presne C, et al.; French Reference Center for Thrombotic Microangiopathies. Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience. PLoS One 2010;5:e10208.

    • Crossref
    • Export Citation
  • 52.

    Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V; French Study Group for aHUS/C3G. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol 2012;8:643–57.

  • 53.

    Kremer Hovinga JA, Vesely SK, Terrell DR, Lammle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010;115:1500–11.

    • Crossref
    • Export Citation
  • 54.

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

    • Crossref
    • Export Citation
  • 55.

    Noris M, Remuzzi G. Cardiovascular complications in atypical haemolytic uraemic syndrome. Nat Rev Nephrol 2014;10: 174–80.

    • PubMed
    • Export Citation
  • 56.

    Noris M, Galbusera M, Gastoldi S, Macor P, Banterla F, Bresin E, et al. Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood 2014;124:1715–26.

    • Crossref
    • Export Citation
  • 57.

    Gruppo RA, Rother RP. Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med 2009;360:544–6.

    • Crossref
    • Export Citation
  • 58.

    Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013;368:2169–81.

    • Crossref
    • Export Citation
  • 59.

    Greenbaum LA, Fila M, Tsimaratos M. Eculizumab (ECU) inhibits thrombotic microangiopathy (TMA) and improves renal function in pediatric atypical hemolytic uremic syndrome (aHUS) patients (pts). Presented at American Society of Nephrology (ASN) Kidney Week 2013, Atlanta, Ga., November 9, 2013. Abstract SA-PO849.

  • 60.

    Fakhouri F, Hourmant M, Campistol JM. Eculizumab (ECU) inhibits thrombotic microangiopathy (TMA) and improves renal function in adult patients (pts) with atypical hemolytic uremic syndrome (aHUS). Presented at American Society of Nephrology (ASN) Kidney Week 2013, Atlanta, Ga., November 8, 2013. Abstract FR-OR057.

  • 61.

    Keating GM. Eculizumab: a review of its use in atypical haemolytic uraemic syndrome. Drugs 2013;73:2053–66.

    • Crossref
    • Export Citation
  • 62.

    Vande Walle J, Johnson S, Fremeaux-Bacchi V. Increased understanding of atypical haemolytic uraemic syndrome (aHUS): characteristics of patients recruited into the global aHUS registry. Nephrol Dial Transplant 2014. [Epub ahead of print].

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    Chan MR, Thomas CP, Torrealba JR, Djamali A, Fernandez LA, Nishimura CJ, et al. Recurrent atypical hemolytic uremic syndrome associated with factor I mutation in a living related renal transplant recipient. Am J Kidney Dis 2009;53:321–6.

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    Saland J. Liver-kidney transplantation to cure atypical HUS: still an option post-eculizumab? Pediatr Nephrol 2014;29:329–32.

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    Noris M, Remuzzi G. Thrombotic microangiopathy after kidney transplantation. Am J Transplant 2010;10:1517–23.

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    Le Quintrec M, Zuber J, Moulin B, Kamar N, Jablonski M, Lionet A, et al. Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am J Transplant 2013;13: 663–75.

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    Zuber J, Le Quintrec M, Morris H, Frémeaux-Bacchi V, Loirat C, Legendre C. Targeted strategies in the prevention and management of atypical HUS recurrence after kidney transplantation. Transplant Rev (Orlando) 2013;27:117–25.

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    Davin JC, Buter N, Groothoff J, van Wijk J, Bouts A, Strain L, et al. Prophylactic plasma exchange in CD46-associated atypical haemolytic uremic syndrome. Pediatr Nephrol 2009;24:1757–60.

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    Cataland SR, Yang S, Wu HM. The use of ADAMTS13 activity, platelet count, and serum creatinine to differentiate acquired thrombotic thrombocytopenic purpura from other thrombotic microangiopathies. Br J Haematol 2012;157:501–3.

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    Besbas N, Karpman D, Landau D, Loirat C, Proesmans W, Remuzzi G, et al. A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int 2006;70:423–31.

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    Campistol JM, Arias M, Ariceta G, Blasco M, Espinosa M, Grinyó JM, et al. An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document. Nefrologia 2013;33:27–45.

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    Bu F, Maga T, Meyer NC, Wang K, Thomas CP, Nester CM, et al. Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2014;25:55–64.

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    Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 2013;45:531–6.

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    Ozaltin F, Li B, Rauhauser A, An SW, Soylemezoglu O, Gonul II, et al. DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J Am Soc Nephrol 2013;24:377–84.

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    Lotta LA, Garagiola I, Cairo A. Genotype-phenotype correlation in congenital ADAMTS13 deficient patients. Blood 2008;112:Abstract 273.

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    Frank C, Werber D, Cramer JP, Askar M, Faber M, an der Heiden M, et al.; HUS Investigation Team. Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med 2011;365:1771–80.

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    Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, et al.; International Registry of Recurrent and Familial HUS/TTP. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006;108:1267–79.

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  • 26.

    Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, et al. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci USA 2007;104:240–5.

    • Crossref
    • Export Citation
  • 27.

    Fremeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J, Brown AL, et al. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 2008;112:4948–52.

    • Crossref
    • Export Citation
  • 28.

    Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, et al.; French Society of Pediatric Nephrology. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2007;18:2392–400.

    • Crossref
    • Export Citation
  • 29.

    Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844–59.

    • Crossref
    • Export Citation
  • 30.

    Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, et al.; European Paediatric Study Group for HUS. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 2009;24:687–96.

    • Crossref
    • Export Citation
  • 31.

    Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc N Y Pathol Soc 1924;24:21–4.

  • 32.

    Kokame K, Matsumoto M, Soejima K, Yagi H, Ishizashi H, Funato M, et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci U S A 2002;99:11902–7.

    • Crossref
    • Export Citation
  • 33.

    Fujimura Y, Matsumoto M, Isonishi A, Yagi H, Kokame K, Soejima K, et al. Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan. J Thromb Haemost 2011;9(Suppl 1):283–301.

    • Crossref
    • Export Citation
  • 34.

    Schneppenheim R, Budde U, Oyen F, Angerhaus D, Aumann V, Drewke E, et al. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood 2003;101: 1845–50.

    • Crossref
    • Export Citation
  • 35.

    Blombery P, Scully M. Management of thrombotic thrombocytopenic purpura: current perspectives. J Blood Med 2014;5:15–23.

  • 36.

    Scully M, Yarranton H, Liesner R, Cavenagh J, Hunt B, Benjamin S, et al. Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features. Br J Haematol 2008;142:819–26.

    • Crossref
    • Export Citation
  • 37.

    Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine 1966;45:139–59.

    • Crossref
    • Export Citation
  • 38.

    Gasser C, Gautier E, Steck A, Siebenmann RE, Oechslin R. Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia. Schweiz Med Wochenschr 1955;85:905–9.

  • 39.

    Richardson SE, Karmali MA, Becker LE, Smith CR. The histopathology of the hemolytic uremic syndrome associated with verocytotoxin-producing Escherichia coli infections. Hum Pathol 1988;19:1102–8.

    • PubMed
    • Export Citation
  • 40.

    Siegler R, Oakes R. Hemolytic uremic syndrome; pathogenesis, treatment, and outcome. Curr Opin Pediatr 2005;17:200–4.

    • Crossref
    • PubMed
    • Export Citation
  • 41.

    Oakes RS, Siegler RL, McReynolds MA, Pysher T, Pavia AT. Predictors of fatality in postdiarrheal hemolytic uremic syndrome. Pediatrics 2006;117:1656–62.

    • Crossref
    • Export Citation
  • 42.

    Espie E, Grimont F, Mariani-Kurkdjian P, Bouvet P, Haeghebaert S, Filliol I, et al. Surveillance of hemolytic uremic syndrome in children less than 15 years of age, a system to monitor O157 and non-O157 Shiga toxin-producing Escherichia coli infections in France, 1996–2006. Pediatr Infect Dis J 2008;27:595–601.

    • Crossref
    • Export Citation
  • 43.

    Dundas S, Todd WT, Stewart AI, Murdoch PS, Chaudhuri AK, Hutchinson SJ. The central Scotland Escherichia coli O157:H7 outbreak: risk factors for the hemolytic uremic syndrome and death among hospitalized patients. Clin Infect Dis 2001;33:923–31.

    • Crossref
    • Export Citation
  • 44.

    Sharma AP, Filler G, Dwight P, Clark WF. Chronic renal disease is more prevalent in patients with hemolytic uremic syndrome who had a positive history of diarrhea. Kidney Int 2010;78:598–604.

    • Crossref
    • PubMed
    • Export Citation
  • 45.

    Constantinescu AR, Bitzan M, Weiss LS, Christen E, Kaplan BS, Cnaan A, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis 2004;43: 976–82.

    • Crossref
    • PubMed
    • Export Citation
  • 46.

    Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaimé F, Dragon-Durey MA, Ngo S, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol 2013;8:554–62.

  • 47.

    Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol 1998;9:1126–33.

    • PubMed
    • Export Citation
  • 48.

    Zuber J, Le Quintrec M, Krid S, Bertoye C, Gueutin V, Lahoche A, et al.; French Study Group for Atypical HUS. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant 2012;12:3337–54.

    • Crossref
    • Export Citation
  • 49.

    Hofer J, Rosales A, Fischer C, Giner T. Extra-renal manifestations of complement-mediated thrombotic microangiopathies. Front Pediatr 2014;2:97.

    • Crossref
    • PubMed
    • Export Citation
  • 50.

    Cataland SR, Wu HM. Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: clinically differentiating the thrombotic microangiopathies. Eur J Intern Med 2013;24:486–91.

    • Crossref
    • Export Citation
  • 51.

    Coppo P, Schwarzinger M, Buffet M, Wynckel A, Clabault K, Presne C, et al.; French Reference Center for Thrombotic Microangiopathies. Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience. PLoS One 2010;5:e10208.

    • Crossref
    • Export Citation
  • 52.

    Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V; French Study Group for aHUS/C3G. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol 2012;8:643–57.

  • 53.

    Kremer Hovinga JA, Vesely SK, Terrell DR, Lammle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010;115:1500–11.

    • Crossref
    • Export Citation
  • 54.

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

    • Crossref
    • Export Citation
  • 55.

    Noris M, Remuzzi G. Cardiovascular complications in atypical haemolytic uraemic syndrome. Nat Rev Nephrol 2014;10: 174–80.

    • PubMed
    • Export Citation
  • 56.

    Noris M, Galbusera M, Gastoldi S, Macor P, Banterla F, Bresin E, et al. Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood 2014;124:1715–26.

    • Crossref
    • Export Citation
  • 57.

    Gruppo RA, Rother RP. Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med 2009;360:544–6.

    • Crossref
    • Export Citation
  • 58.

    Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013;368:2169–81.

    • Crossref
    • Export Citation
  • 59.

    Greenbaum LA, Fila M, Tsimaratos M. Eculizumab (ECU) inhibits thrombotic microangiopathy (TMA) and improves renal function in pediatric atypical hemolytic uremic syndrome (aHUS) patients (pts). Presented at American Society of Nephrology (ASN) Kidney Week 2013, Atlanta, Ga., November 9, 2013. Abstract SA-PO849.

  • 60.

    Fakhouri F, Hourmant M, Campistol JM. Eculizumab (ECU) inhibits thrombotic microangiopathy (TMA) and improves renal function in adult patients (pts) with atypical hemolytic uremic syndrome (aHUS). Presented at American Society of Nephrology (ASN) Kidney Week 2013, Atlanta, Ga., November 8, 2013. Abstract FR-OR057.

  • 61.

    Keating GM. Eculizumab: a review of its use in atypical haemolytic uraemic syndrome. Drugs 2013;73:2053–66.

    • Crossref
    • Export Citation
  • 62.

    Vande Walle J, Johnson S, Fremeaux-Bacchi V. Increased understanding of atypical haemolytic uraemic syndrome (aHUS): characteristics of patients recruited into the global aHUS registry. Nephrol Dial Transplant 2014. [Epub ahead of print].

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    Saland J. Liver-kidney transplantation to cure atypical HUS: still an option post-eculizumab? Pediatr Nephrol 2014;29:329–32.

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    Le Quintrec M, Zuber J, Moulin B, Kamar N, Jablonski M, Lionet A, et al. Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am J Transplant 2013;13: 663–75.

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    Davin JC, Buter N, Groothoff J, van Wijk J, Bouts A, Strain L, et al. Prophylactic plasma exchange in CD46-associated atypical haemolytic uremic syndrome. Pediatr Nephrol 2009;24:1757–60.

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Clinical Chemistry and Laboratory Medicine ( CCLM) publishes articles on novel teaching and training methods applicable to laboratory medicine. CCLM welcomes contributions on the progress in fundamental and applied research and cutting-edge clinical laboratory medicine. It is one of the leading journals in the field, with an impact factor of over three. CCLM is the official journal of nine national clinical societies and associated with EFLM.

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    A simplified overview of the complement cascade.

    The alternative pathway involves the constitutive low level activation of C3 and the subsequent deposit of C3b on cell membranes, ultimately leading to the generation of the membrane attack complex, (MAC), C5b-9. Regulation of the complement cascade is described in Figure 2.

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    Model for the mechanisms leading from impaired regulation of the alternative pathway to thrombotic microangiopathy.

    In a normal endothelial cell (A), complement factor H (CFH) binds to the endothelial surface and to C3b and together with membrane cofactor protein (MCP) acts as a cofactor for cleavage of C3b, which is mediated by complement factor I (CFI), a process that prevents its interaction with factor B. CFH also dissociates the C3 convertase of the alternative pathway (C3b). Thrombomodulin (TM) enhances CFI-mediated inactivation of C3b in the presence of CFH and promotes activation of the thrombin-activatable fibrinolysis inhibitor (TAFIa), which degrades C3a and C5a. In patients with loss-of-function mutations in complement regulatory genes [CFH, CFI, MCP, and THBD (the gene encoding thrombomodulin)] (B), C3b is not degraded efficiently and forms the C3 and C5 convertases of the alternative pathway. A similar situation applies to patients with gain-of-function mutations in CFB and C3. Mutant CFB forms a superconvertase that is resistant to dissociation by CFH. Mutant C3b does not bind CFH and MCP and is resistant to degradation by CFI. From Noris et al. [14]. Reprinted with permission from Massachusetts Medical Society.

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    An algorithm for the differential diagnosis of TMA.

    ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aHUS, atypical haemolytic uraemic syndrome; HUS, haemolytic uraemic syndrome; LDH, lactate dehydrogenase; STEC, Shiga toxin producing Escherichia coli; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura. aNegative direct Coombs test; bThe Shiga toxin test/STEC is indicated when the patient has a history of digestive system involvement or gastrointestinal symptoms; cIn some patients with aHUS, STEC infection can trigger the underlying disease. From Campistol J, et al. [13]. Reprinted with permission from the Nefrologia Publishing Group.