aHUS is considered an ultra-rare disease. Data available on its incidence and prevalence are limited, as well as the knowledge of the actual epidemiology of the disease. The annual incidence of aHUS in the US has been estimated to be of ∼1–2cases/million inhabitants.36 A recent multicentre study in Europe reported an incidence of 0.11cases/million inhabitants. According to the European Medicines Agency (EMA), the prevalence may be of ∼3.3patients/million inhabitants/year among patients below the age of 18, with lower rates among adults.

Children and adults are predominantly affected by aHUS, although it may develop at any time in life.11,12 The onset of the disease usually occurs before the age of 18 (60% vs. 40%) and sex characteristics are well-balanced (women are primarily affected when the disease is developed in adulthood).11,13

Clinical onset is often abrupt, although 20% of patients may develop it progressively (in weeks or months), accompanied by subclinical anaemia, fluctuating thrombocytopenia, and preserved renal function.11 The clinical picture comprises the triad of nonimmune microangiopathic haemolytic anaemia, thrombocytopenia, and acute renal failure.1 High levels of lactate dehydrogenase (LDH), undetectable haptoglobin and schistocytes confirm the presence of intravascular hemolysis20 associated with haematuria, proteinuria, and/or acute renal failure (with or without oligoanuria). High blood pressure resulting from volume overload or vascular lesion is common.1 In some patients, the single manifestation of TMA may be proteinuria with high blood pressure and progressive renal failure without haematological abnormalities.

Even though aHUS lesions are predominantly observed in renal vessels, the diffuse and systemic nature of the TMA phenomenon leads to the involvement of the microvasculature of other organs (including, but not limited to the brain, heart, intestine, pancreas, and lungs),1 therefore accounting for common extrarenal symptoms.11,12 Neurological symptoms are the most common (48%),37 including irritability, somnolence, confusion, convulsions, encephalopathy, stroke, hemiparesis, visual abnormalities, hemiplegia, and coma.1,12,37,38 Myocardial infarction has been described in up to 3% of aHUS patients in relation to sudden death.12,39 Myocardiopathy, heart failure, and peripheral ischaemic vasculopathy have also been reported,19,37,40,41 as well as diarrhoea (30%) and other digestive symptoms (including, but not limited to colitis, nausea, vomit, abdominal pain, hepatitis, cholestasis, and pancreatitis).12,19,38,42 Skin involvement including ulcer lesions in lower limbs has recently been reported in aHUS patients.43 Heterogeneity of symptoms has posed a challenge for companion diagnostics of other causes of TMA.

The complement system, consisting of several circulating plasma and membrane-associated proteins, is part of innate immunity and is vital for fighting infections, processing immune complexes, antibody response, and the elimination of apoptotic residues. Activation by any of the existing pathways (classical, lentin, and alternative) leads to the formation of multiprotein complexes with C3-convertase activity splitting the C3 protein and resulting in C3b (Fig. 3). The covalent binding of this molecule to the surfaces activating the complement favours phagocytosis by polymorphonuclear leukocytes and macrophages, therefore resulting in activated C5, directing the attack complex to the membrane and causing cell lysis. In addition, the resulting C3b leads to a rapidly enhanced complement activation by promoting the formation of further C3-convertases, since it is one of the components of C3-convertase of the alternative pathway.44 In order to avoid total uptake by complement activation, as well as damage to self tissues (C3b binds indiscriminately to both pathogens and self cells), a number of process-regulating proteins, such as FH, the membrane cofactor protein (MCP), and complement factor I (FI) dissociate C3-convertases and result in C3b degradation. C3b levels, therefore, remain low under normal conditions and they build up following complement activation only in the structures related to this activity.

Fig. 3.

Complement dysregulation in atypical haemolytic uraemic syndrome. Complement activation by any of the 3 pathways (detection of foreign antigens, alternative pathway; of antibodies, classical; or mannan polysaccharides, lectin) leads to the build-up of large quantities of C3b on the activator cell membrane, causing opsonisation and C5 activation (terminal or lytic pathway), resulting in the formation of the membrane attack complex and cell lysis. Complement activation results in inflammation and leucocyte recruitment. The key process in complement activation is C3b formation, which depends on unstable enzymatic complexes – C3-convertases – catalysing the rupture of C3 to create C3b. In turn, C3b has the ability to form further C3-convertase of the alternative pathway (C3bBb), thus enhancing the initial activation. The mediation of C3B production is two-fold: dissociation of C3-convertases and proteolytic inactivation of C3b and C4b. Several regulatory proteins in plasma and the cell membrane carry out this regulatory activities, including, factor H, MCP and factor I, which play an essential role in the dissociation of C3-convertase of the alternative pathway (C3bBb) and the proteolytic degradation of C3b. Mutations in these proteins found in patients with aHUS interfere with this regulatory activity of the alternative pathway activation. Some patients with aHUS are carriers of mutations in proteins C3 and factor B organising C3-convertase. These mutations are particular, as they increase the activity of mutated proteins (gain-of-function mutations), resulting in increased complement activation and exceeding the capacity of regulatory proteins.

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Several studies have shown that around 60% of aHUS patients are carriers of mutations in complement-regulating genes (CFH, MCP, CFI, thrombomodulin [THBD], or in the components of C3-convertase, factor B [FB], and C3).45–54 All these mutations cause the dysregulation of the alternative pathway (Table 1). FH acts in plasma by controlling complement homeostasis and in cell surfaces by preventing damage to self components. Mutations in the C-terminal region of FH are characteristic of aHUS. Because the altered FH region mediates complement activation in cell surfaces, cell protection against accidental damage resulting from complement activation is decreased by these mutations, with no involvement of complement regulation in plasma.55 The functional assay of aHUS-associated mutations found in other complement genes, including MCP, CFI, CFB or C3, has also confirmed that all of them result in a defective protection of cell surfaces and this loss of complement regulation may be due to the decreased activity of regulating proteins or to the abnormally high activity of C3-convertases. Thus, while the regulatory activity of these proteins is impaired by mutations in FH, MCP, and FI, mutations in FB or C3 result in further activation of the C3-convertase.

Around 5–10% of aHUS patients develop anti-FH antibodies targeted to the C-terminal region, with similar effects to those observed in FH mutations.56,57 Their role in the pathogenesis of aHUS has not been fully established, but seems to be associated with disease onset or recurrence. Given that antibody titres may decrease over time, they should be screened early in the course of aHUS. Anti-FH antibodies are associated with complement factor H-related protein 1 deficiency (FHR1) in patients with aHUS.58

Penetrance of aHUS in carriers of mutations in some genes is around 50%, with only a few carriers from families with identified mutations commonly developing aHUS and showing a variable clinical presentation. Clinical heterogeneity, which results from the existence of additional (genetic and environmental) risk factors mediating the development and the outcome of the disease, is largely observed among unrelated carriers of this mutation. Screening for complement mutations in aHUS patients and conducting case-control studies based on genetic polymorphisms in candidate genes or genetic markers in the human genome has allowed for the identification of some variants (polymorphisms) in CFH and MCP genes modulating the penetrance and severity of the disease (Table 1).49,59,60

Haplotypes CFH-H3 and MCPggaac are the most relevant polymorphisms associated with the risk of aHUS. Both haplotypes include single-nucleotide polymorphisms (SNP) in the CFH and MCP gene-promoter region, downregulating FH and MCP. The presence of both polymorphisms in homozygosis may provide a rationale for aHUS disposition in patients with no mutations in any of the genes associated with aHUS. A recent collaborative study by the European Working Party on Complement Genetics in Renal Diseases including 795 patients with aHUS has shown that 3% of these patients were carriers of combined mutations in more than one gene. Additionally, this large study has proved that concomitant risk haplotypes CFH-H3 and MCPggaac also lead to significantly increased disease penetrance in carriers of combined mutations, stressing the idea that genotyping of these risk polymorphisms helps predict the risk of aHUS in mutation carriers.61

Along with the previous genetic alterations, a number of triggering environmental factors are also implicated in the onset of aHUS. The above mutations are predisposing factors of the disease, preventing adequate complement regulation in cell surfaces when the system becomes activated in microvessels. aHUS is triggered by infectious events in 50–80% of patients,11,12,40 particularly those involving the upper respiratory tract (influenza H1N1 virus). Diarrhoea caused by gastroenteritis may precede aHUS in up to 30% of cases (including diarrhoea by STEC11,12,19).12 Pregnancy, particularly during post-partum, is a common predisposing factor of aHUS among women,12,29 together with the use of oral anovulatory agents.

Mutations in the gene coding for thrombomodulin (THBD), an anticoagulant protein acting as thrombin cofactor and also regulating the FI-mediated C3b inactivation, have been associated with aHUS.62 Based on complement dysregulation typical of patients with aHUS, the functional analysis of THBD mutations associated with aHUS has shown that thrombomodulin mutations impair the complement regulatory activity.62 Nevertheless, the impairment of the anticoagulation activity by thrombodulin mutations associated with aHUS and the relevance of these abnormalities in aHUS remains unknown. In this regard, a recent study conducted in 36 patients with aHUS has assessed the presence of mutations in the genes of the complement system and coagulation through massive DNA sequencing, detecting mutations in genes from both systems.63 The gene in the coagulation system with the largest number of mutations was plasminogen (PLG), a cymogene which plays an important role in fibrinolysis following conversion to plasmin. Even though these data suggest that coagulation genes may add to aHUS disposition (particularly PLG), further studies are required to confirm these observations.

The search of new genes associated with aHUS has also been addressed by Lemaire et al.21 through exome sequencing. The authors have identified homozygotic mutations in the DGKE gene coding for the DGK-¿ protein in 13 patients with aHUS from 9 families. These patients had a very early onset of aHUS, generally within their first year of life, followed by multiple recurrences and common progression to end-stage renal failure in the second decade of life.21 Deficiency of DGK-¿ in endothelial cells has been recently shown to induce the expression of ICAM-1 and tissue factor by means of increased p36-MAPK-mediated signalling, leading to apoptosis, altering the angiogenic response, and determining a proinflammatory and prothrombotic phenotype. Yet, the absence of DGK-¿ is not detrimental to complement activation in cell surfaces.21,22 The absence of DGK-¿ in podocytes and endothelial cells may probably impair the diaphragm of glomerular filtration, which would account for massive proteinuria and the susceptibility to glomerular conditions among these patients,21,23 although the reason why these patients tend to develop several glomerular conditions remains uncertain. Finally, despite the role of the complement in the development of renal disease among carriers of DGKE, mutations had been initially ruled out,21 patients with DGKE mutations additionally associated with other genes previously related to aHUS, including THBD and C3,64 have been recently identified, thus suggesting that complement dysregulation may play a role in the modulation of disease onset and outcome at least in some carriers of DGKE mutations.

The availability of Eculizumab has significantly revolutionised the prognosis of patients living with aHUS, a very severe disease in most cases in spite of intensive treatment with plasma therapy (PT; Table 2). Following a first episode of aHUS, overall mortality was higher than 10% and more than half of the patients required dialysis and/or developed a more permanent renal damage in the next 12 months.11,12,20 The clinical outcome changes relatedly depending on the patient's mutation. In this respect, outcome seemed to be particularly poor in patients with FH and C3 mutations, with mortality and end-stage chronic renal failure (ESCRF) rates over 50% within one year from the first episode of aHUS. Furthermore, half of these patients relapsed. Mutations in FI, FB, and THBD were also associated with high rates of mortality and ESCRF at one year (50%), with relapses occurring in nearly one in 3 patients overcoming the first episode of aHUS. On the other side, less than 10% of patients with MCP mutations died or progressed to ESCRF, although the risk of relapse among these patients was higher and up to 90% of them developed new episodes of aHUS. Between 50 and 75% of patients with mutations in FH, CI, C3, FB or THBD died or developed ESCRF within 3–5 years from the first episode of aHUS.1

The outcome of renal transplantation (RT) among patients with ESCRF due to aHUS has been historically limited by the increased percentage of recurrences of post-transplant disease (∼50%; graft loss rate: 80–90%65,66), although it changes significantly based on the type of alteration. In a series of 57 patients with aHUS receiving RT, 5-year recurrence-free graft survival was significantly lower in patients with mutations in the genes coding for complement proteins compared to patients in whom only polymorphisms but no genetic abnormalities were found.67 Yet, it should be stressed that the risk of recurrence of aHUS following RT in patients with no genetic abnormalities is also deemed high. 68 Mutations in FH are associated with a higher risk of recurrence or graft loss following RT (75–90%; specifically those related to abnormalities in terminal 3′ and gene conversion between CFH and CFHR1, resulting in the hybrid gene CFH/CFHR1 [both abnormalities impair the functionality of the C-terminal domain of FH]), posing a high risk with mutations in C3 and FI as well (40–80%; Table 2).12,42,48,65,67,69–71 To date, very few transplants have been performed in patients with FB mutations, though recurrence of aHUS and graft loss were reported in all cases.49,72 In general, plasma factors of the complement involved in aHUS are synthesised in the liver, and so patients with mutations in the complement genes coding for these factors remain prone to aHUS following RT, as dysfunctional factors are still being produced. MCP is a transmembrane protein that is highly expressed in the kidney and, as a result, this defect can be corrected by RT by delivering unchanged MCP into the graft. Over 80% of patients with MCP mutations develop no recurrence of aHUS following RT, with a long-term survival rate comparable to that of patients receiving transplants for other reasons.40,65,66 The risk of post-transplant recurrence in patients with THBD62 mutations or anti-FH antibodies is not well-established, although it seems to be related to high and persistent titres of antibodies in the latter.19,73

PT can be delivered as plasma infusion (PI) and plasma exchange (PE). In PI, patients are given virus-inactivated, non-native fresh frozen plasma (FFP), adding functional complement regulators.81 In PE, a patient's plasma is replaced with FFP, which not only results in the administration of high doses of complement-regulating proteins, but also in the elimination of dysfunctional endogenous soluble complement inhibitors, minimising the risk of volume overload. In addition, anti-FH antibodies are also cleared in PE, together with potential inflammatory/thrombogenic factors involved in endothelial damage and platelet hyperaggregation. The treatment of choice recommended for episodes of aHUS traditionally consisted of early and intensive PE at high volumes and of variable frequency based on disease activity. PIs are usually ineffective except in a few patients with complete deficiency of FH82 (circulating levels of complement proteins are normal in most patients). Overall, PT is not considered effective in patients with isolated MCP mutations, as this is a non-circulating protein attached to the cell membrane, with virtually all patients relapsing following an episode of aHUS irrespective of the use of PT.12

Even though no prospective clinical trials are available, PT has empirically been the treatment of choice in aHUS for years as mortality in patients with TTP-HUS decreased over the last 3 decades. Table 5 summarises the results of the largest international registry of PT in patients with aHUS (International Registry of Recurrent and Familial HUS/TTP), including 273 patients diagnosed between 1996 and 2007.12 Complete haematological and renal recovery rates with PT in this registry are generally below 50% (except for patients with mutations in THBD and MCP), and particularly low rates in patients with mutations in FH and FI (5 y 12.5%).12 Mortality and/or outcome of ESRF are generally high in 3 out of 4 patients with FI mutations. Some papers prove that early intensive PE is essential to prevent patients from developing aHUS, and maintenance can prevent disease recurrence and ESRF,11,81 though the most effective management strategy is still not known, nor is the long-term impact on renal function.

Concomitant immunosuppression and PT may improve outcomes in patients with anti-FH antibodies.19,83,84 High antibody titres are correlated with a higher risk of relapse and renal sequels in these cases.19 Even though further trials are required to conclude on how anti-FH antibodies are developed by patients with aHUS, the fact that the vast majority of these patients have complete deficiency of FHR1 leads to the idea that these antibodies are really targeted against the FHR1 protein, and that the anti-FH activity is a cross reaction resulting from the remarkable homology existing between these 2 proteins. This possibility is a warning of the potential anti-FHR1/anti-FH sensitisation in homozygotes for CFHR3-CFHR1 deletion by the exposure to exogenous FHR1, discouraging the use of PI in these individuals.

The potential complications of PI are anaphylactic reactions to FFP, hypervolemia, high blood pressure, heart failure, or hyperproteinaemia. The main complications of PE are obstructed venous access (6%), low blood pressure (5%), and allergy (4%)85, with a higher frequency among paediatric patients.85 A study conducted in 71 paediatric patients with aHUS (59 treated with PE) showed that 80% of children had some renal sequels within one month of follow-up, 17% were dialysis-dependant, and 31% developed catheter-related complications.86

Eculizumab is a humanised monoclonal IgG2/4 kappa antibody that binds to the C5 complement protein with high affinity, blocking the excision into C5a and C5b, and preventing the formation of the C5b-9 complex of the terminal complement (membrane attack complex) (Fig. 3).4 In aHUS, the dysregulation of the alternative complement pathway leads to the uncontrolled activation of C5, causing a damage to self structures via the formation of the membrane attack complex. This process is rapidly and sustainably reduced as a result of the blockade of the terminal complement pathway by Eculizumab. A large number of patients with aHUS have shown a good clinical response to the drug (Table 6).

The efficacy and safety of Eculizumab in aHUS were initially assessed in two phase II, prospective, multicentre trials, including 37 patients older than 12 years of age and with primary or recurrent disease following RT, who received Eculizumab for 26 weeks, followed by long-term extension periods.5 Seventeen patients with aHUS (mean time from diagnosis: 9.7 months) with evidence of progressive TMA following ≥4 sessions of PT the week before their inclusion (C08-002) were enrolled in the first study. The second study recruited 20 patients (mean time from diagnosis: 48.3 months) receiving PT (1 session every 2 weeks and 3 sessions a week) where no decrease >25% was reported in platelet count for at least 8 weeks prior to first dosing of Eculizumab (C08-003). Genetic or anti-FH antibody mutations were observed in 76% and 70% of patients from the first and the second study, respectively. Primary outcomes in both studies were: (a) inhibition of complement-mediated TMA (study 1: increased platelet count; study 2: TMA-free patient ≥12 weeks [no decrease in platelet count >25%, no PT and no dialysis]), and (b) haematological normalisation (≥2 normal consecutive measurements of platelets and LDH, with a minimum interval of 4 weeks). Secondary outcomes included change in the rate of daily interventions for TMA (PI or PE sessions, dialysis, or both, per patient/day), renal function, quality of life, safety and tolerability. Primary outcomes reported at 26 weeks and in extension studies are described in Table 7. With regard to primary outcome, following 26 weeks of treatment, in study 1 treatment with Eculizumab was associated with a significant increase in the number of platelets from baseline (p<0.001) and a rate of haematological normalisation of 76%. In study 2, 80% of patients were free of TMA episodes following 26 weeks of treatment with Eculizumab and 90% had haematological normalisation. In terms of secondary outcomes, treatment with Eculizumab at 26 weeks was associated with a significant reduction in the rate of daily interventions for TMA vs. baseline (p<0.001), as well with a continuous improvement of estimated GFR (+32ml/min/1.73m2 [p=0.001 vs. baseline] and +6ml/min/1.73m2 [p<0.001 vs. baseline] in studies 1 and 2, respectively), a decrease in proteinuria (p<0.05) and a reduced need for dialysis. Also, the earlier Eculizumab is introduced in trials (less time of evolution between the clinical manifestation of aHUS and the drug), the more significant the improvement of the estimated GFR (p<0.05). The results of extension trials at 1 and 3 years prove that long-term treatment with Eculizumab is associated with maintenance or progressive improvement of the haematological response and renal function.87,88 All these positive results with Eculizumab were observed irrespectively in patients with or without genetic or anti-FH antibody abnormalities.

Overall, tolerability of Eculizumab was good, and severe treatment-related adverse effects were only reported in 4 patients in each study, probably in the context of the background condition, aHUS (study 1: malignant hypertension,2 severe hypertension, and asymptomatic bacteriuria; study 2: influenza infection, peritonitis, venous sclerosis at the time of the infusion, and fever Q). Increased risk of infection by encapsulated germs, especially Neisseria meningitides, results from the mode of action of Eculizumab, and so all patients were vaccinated against Neisseria (tetravalent vaccine) 14 days before treatment and/or received antibiotics, with no reports of meningitis. Only one patient died of digestive bleeding 3 years later (unrelated to Eculizumab).

The safety and efficacy of Eculizumab during pregnancy has recently been studied in patients with paroxysmal nocturnal haemoglobinuria. Data from 61 women with 75 pregnancies while on treatment with Eculizumab suggest a good tolerability profile of Eculizumab during pregnancy, with high rates of foetal and maternal survival (96% and 100%, respectively). Eculizumab was observed in 7 out of 20 blood samples of umbilical cord and in none of the 10 samples of human milk.89

Two phase III, multicentre, prospective, open-label trials of Eculizumab in aHUS are currently ongoing, one in adult patients (n=41; C10-004)90 and the other in paediatric patients (n=22; C10-003 22).91 Unlike previous trials, these new studies primarily involve patients who have been recently diagnosed with aHUS (73%). In the adult trial, mean time from diagnosis to inclusion was ∼3 weeks, whereas mean time from clinical onset to Eculizumab was 2 weeks (15% of patients had not been treated with PT prior to Eculizumab).90 The paediatric trial involves patients with aHUS ≤18 years with a mean time from diagnosis to inclusion of ∼2 weeks and a mean time from clinical onset to Eculizumab of ∼1 week (55% had not been treated with PT).91 Results from these 26-week trials confirm the significant haematological and renal function improvements seen in previous studies, as well as the benefits of early use of Eculizumab (Table 7).90,91 The safety profile was similar, although two patients developed meningococcal meningitis (5%) in the adult study. Both infections were well-managed, and one of the patients continued treatment with Eculizumab. Survival in patients from both studies was 100%.

Blood samples from adult patients enrolled in the C10-004 trial were collected at baseline (before treatment with Eculizumab) and in subsequent visits up to Weeks 49–54 in order to measure the impact of Eculizumab on biomarkers related to TMA and endothelial damage in aHUS.92 Patients with aHUS (irrespective of the presence or absence of related mutations, PT, or haematological values) showed activated complement system and inflammation, coagulation, activation, endothelial damage, and renal injuries prior to treatment. Eculizumab led to normalisation of complement activation-related biomarkers and significantly reduced biomarkers of inflammation, thrombotic risk, endothelial and organic damage. Eculizumab also reduced biomarkers related to the activation of the alternative complement pathway and endothelial activation, although they did not completely return to normal. These findings underline the persistent chronic of complement activation in patients with aHUS and a continuous risk of TMA and potential organ damage.92

There is also a retrospective study including 19 paediatric patients with aHUS receiving Eculizumab in a clinical setting for a mean time of 28 weeks (C09-001).3 Eighty nine percent of patients in this study had a normalised platelet count and 68% remained free of TMA episodes, although most of them were under haematological remission with prior treatment with PE. The rate of interventions for TMA was reduced from 0.3 per patient/week to 0 (p<0.0001). GFR increased to ≥15ml/min/1.73m2 in 47% of patients and 50% required no dialysis at all. Pyrexia (47%), diarrhoea (32%), and upper respiratory tract infections (32%) were the most common adverse effects.

In view of technical difficulties of PT in paediatric patients (by body size) and potential complications, in addition to the superiority of Eculizumab for the recovery of renal function (and the resulting improved prognosis), early first-line treatment with Eculizumab is highly recommended in this population, therefore avoiding the use of PE. Consequently, early administration of Eculizumab is recommended as treatment of choice in first line in paediatric patients with suspected aHUS (Fig. 5).91 Eculizumab should be initiated earlier in adult patients with suspected aHUS following PE.90 PE is only recommended in adults when diagnosis is unclear. The use of Eculizumab may only be disregarded in patients with haematological complete recovery and improved renal function following PE. In this study, the aHUS French Study Group recommended switching the patient to Eculizumab if platelet count or LDH levels do not return to normal following the fifth PE, or reducing plasma creatinine ≥25%.93 Eculizumab is the treatment of choice recommended whenever the diagnosis of aHUS is unequivocal (positive personal or family history or disease recurrence following RT). Early administration ensures reversibility of haematological parameters and prevents renal injuries.

Fig. 5.

Treatment for atypical haemolytic uraemic syndrome. PE: plasma exchange; aHUS: atypical haemolytic uraemic syndrome. * When the diagnosis of aHUS is unequivocal (positive personal or family history or disease recurrence following renal transplant), Eculizumab should be use earlier as treatment of choice.

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All patients should be vaccinated against N. meningitides (preferably with conjugate tetravalent vaccines against serotypes A, C, Y, and W135, and serotype B) prior to treatment with Eculizumab. If treatment with Eculizumab cannot be delayed until vaccine response, associated treatment with antibiotics against N. meningitides may be initiated and antibiotic prophylaxis may be established3 as per the hospital protocol. Given the higher frequency of invasive meningococcal infection among paediatric patients, and the absence of serotype B protection (currently the most prevalent following systemic vaccination in the population for other serotypes), this age group should continue to use antibiotic prophylaxis, including penicillin or amoxicillin, in combination with Eculizumab,2 although these prophylaxis protocols may be adjusted following the recent availability of the new serotype B vaccine. The maintenance of antibiotic prophylaxis in adult patients receiving Eculizumab is at the physician's own discretion and should be individually assessed. Continued antibiotic prophylaxis should be considered in immunodepressed patients receiving Eculizumab as a result of the lower response to the vaccine among these patients (particularly among those receiving renal transplants). In paediatric patients, Haemophilus influenzae and pneumococcal vaccines are also required, together with strong compliance of local effective recommendations on compulsory vaccines for each age group.

If response to Eculizumab is good, treatment should be maintained indefinitely as recommended in the summary of product characteristics.3 No recommendations can be made so far on the right treatment duration, though increasing experience with drug use may help better define this as well as treatment strategies in the future.

Withdrawal and/or individual dose titration of Eculizumab may be considered for specific cases, but only among low-risk patients (with isolated mutation in MCP and negative family history), always individually and following at least 12 months of treatment.94,95 Patients who withdraw treatment as per clinical indication should be carefully monitored for at least 12 weeks for potential abnormalities suggestive of TMA and/or relapse.3,96 In these patients immediate readministration with Eculizumab should be considered.3,96

Eculizumab should be maintained for at least 3 months in patients with aHUS and acute renal failure requiring dialysis in order to assess the improvement of renal function. Progressive increase of diuresis with good pressure management are positive parameters guiding the management of the TMA process and improvement of renal injuries. Renal biopsies in patients receiving dialysis may help decision-making associated with treatment continuation. If treatment fails in patients and they still require dialysis for renal failure, Eculizumab should be withdrawn, except in patients with systemic disease manifestations, where treatment continuation should be assessed individually.

Whenever PT is considered for a patient with aHUS, PE should preferably be performed with FFP replacement (1.5 per plasma volume [60–75ml/kg] per session to add complement factors). Sessions should be performed until platelet count returns to normal, end of haemolysis ends, and sustained improvement of renal function for several days occurs. Five weekly sessions should be conducted thereafter for the first 2 weeks and 3 weekly sessions for the next 2 weeks, while PE continuation should be individually assessed.2,82

Patients with aHUS who develop anti-FH antibodies while on PT should use concomitant immunosuppressants to prevent antibody formation.19,73,83,84 Treatment response among these patients should be monitored based on the outcome of antibody titres.73

General supportive measures are necessary to ensure acceptable conditions for patients until TMA is managed. High blood pressure is common among patients with aHUS and should be treated with angiotensin II blockers (ACEI or AIIRA). Volemic control is also vital due to common hypervolemia and acute risk of pulmonary oedema. Transfusions of red blood cells concentrates and/or the use of erythropoiesis-stimulating factors should be considered for the treatment of anaemia. Platelet transfusions should be reserved for cases of severe low platelet counts (<30,000/mm3) or exceptionally for severe bleeding and/or prior to invasive procedures with risk of bleeding, as the TMA phenomenon may become worse. Potential agents leading to aHUS should also be identified and managed. Paediatric patients with aHUS should be referred to specialised centres for paediatric nephrology including expert staff and an intensive care unit for paediatric patients in order to ensure adequate treatment.