Atypical hemolytic uraemic syndrome

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Review

Atypical hemolytic uraemic syndrome夽 Miquel Blasco Pelicano a,∗ , Santiago Rodríguez de Córdoba b , Josep M. Campistol Plana a a b

Servicio de Nefrología y Trasplante Renal, Hospital Clínic, Barcelona, Spain Departamento de Medicina Celular y Molecular, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain

a r t i c l e

i n f o

Article history: Received 29 April 2014 Accepted 29 August 2014 Available online xxx Keywords: Atypical hemolytic uraemic syndrome Alternative pathway of complement system Plasma therapy Eculizumab

a b s t r a c t The hemolytic uraemic syndrome (HUS) is a clinical entity characterized by thrombocytopenia, nonimmune hemolytic anaemia and renal impairment. Kidney pathology shows thrombotic microangiopathy (TMA) with endothelial cell injury leading to thrombotic occlusion of arterioles and capillaries. Traditionally, HUS was classified in 2 forms: typical HUS, most frequently occurring in children and caused by Shiga-toxin-producing bacteria, and atypical HUS (aHUS). aHUS is associated with mutations in complement genes in 50–60% of patients and has worse prognosis, with the majority of patients developing end stage renal disease. After kidney transplantation HUS may develop as a recurrence of aHUS or as de novo disease. Over the last years, many studies have demonstrated that complement dysregulation underlies the endothelial damage that triggers the development of TMA in most of these patients. Advances in our understanding of the pathogenic mechanisms of aHUS, together with the availability of novel therapeutic options, will enable better strategies for the early diagnosis and etiological treatment, which are changing the natural history of aHUS. This review summarizes the aHUS clinical entity and describes the role of complement dysregulation in the pathogenesis of aHUS. Finally, we review the differential diagnosis and the therapeutic options available to patients with aHUS. ˜ S.L.U. All rights reserved. © 2014 Elsevier Espana,

Síndrome hemolítico urémico atípico r e s u m e n Palabras clave: Síndrome hemolítico urémico atípico Vía alternativa del complemento Tratamiento plasmático Eculizumab

El síndrome hemolítico urémico (SHU) es una entidad clínica caracterizada por la presencia de trom˜ renal, demostrando el estudio histológico la bocitopenia, anemia hemolítica microangiopática y dano presencia de microangiopatía trombótica (MAT). Tradicionalmente el SHU ha sido clasificado en 2 for˜ y es debido mayoritariamente a infecciones mas: el SHU típico, que ocurre más frecuentemente en ninos entéricas por bacterias productoras de toxina Shiga, y el SHU atípico (SHUa), que se asocia en el 50-60% de los pacientes con mutaciones en genes del sistema del complemento y que tiene un peor pronóstico, causando en la mayoría de los pacientes una insuficiencia renal crónica terminal. En el trasplante renal, el SHU se manifiesta como consecuencia de la recurrencia del SHUa o como un proceso de novo pos˜ trasplante. Durante los últimos anos, numerosos estudios han puesto de manifiesto que la desregulación ˜ endotelial que dispara el desarrollo de del sistema del complemento es la causa responsable del dano la MAT en la mayoría de los pacientes con SHUa. Estos avances en el conocimiento de los mecanismos fisiopatológicos responsables del SHUa, junto con la aparición reciente de nuevas opciones terapéuticas, han permitido desarrollar mejores estrategias para conseguir un diagnóstico precoz y un tratamiento etiológico, que están cambiando la historia natural del SHUa.Esta revisión resumirá, en primer lugar, la entidad clínica del SHUa, para a continuación centrarse en la desregulación de la vía alternativa del complemento como responsable de dicha enfermedad. Finalmente, revisaremos el diagnóstico diferencial y las opciones terapéuticas del paciente con diagnóstico clínico de SHUa. ˜ S.L.U. Todos los derechos reservados. © 2014 Elsevier Espana,

夽 Please cite this article as: Blasco Pelicano M, Rodríguez de Córdoba S, Campistol Plana JM. Síndrome hemolítico urémico atípico. Med Clin (Barc). 2015. http://dx.doi.org/10.1016/j.medcli.2014.08.006 ∗ Corresponding author. E-mail address: [email protected] (M. Blasco Pelicano). ˜ S.L.U. All rights reserved. 2387-0206/© 2014 Elsevier Espana,

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Introduction Haemolytic uraemic syndrome (HUS) is characterized by the triad of microangiopathic haemolytic anaemia (nonimmune), thrombocytopenia and acute renal failure.1 The histopathological lesion responsible for the clinical condition and present in the different territories affected is thrombotic microangiopathy (TMA), characterized by the presence of platelet thrombi in microcirculation. 90% of HUS cases are caused by enteric infections, the most frequent being Shiga toxin-producing Escherichia coli (STEC-HUS or typical HUS). In most of the cases included in the remaining 10%, HUS is associated with dysregulation of the alternative complement pathway, causing endothelial damage resulting in the subsequent development of TMA. This entity is called atypical haemolytic uraemic syndrome (aHUS), an ultra-rare, severe systemic disease with high morbidity and mortality. The fact that the TMA is a lesion present in many diseases, its high clinical variability and its low incidence make aHUS diagnosis and choice of treatment difficult. Since the first communication from Gasser et al.,2 but especially the constant progress in the study of the alternative complement pathway in recent decades, has resulted in a greater pathophysiological knowledge of aHUS. This knowledge has justified the implementation of therapeutic strategies based on blocking the terminal complement pathway, which are showing high efficacy and safety compared to the conventional process using plasma treatment (PT). The main objective of this review is to put together the recent advances in pathophysiologic studies as well as in the treatment of aHUS. Both have contributed to change the natural history of the disease through early diagnosis and the implementation of high efficacy etiologic treatments. Clinical entity

present a great variability of clinical manifestations (Table 1), making its differential diagnosis very difficult. Patients often have significant high blood pressure at the start, probably in the context of systemic-renal endothelial damage and fluid retention.8,12,14,15 The initial laboratory findings will show signs of intravascular haemolysis, such as elevation of lactate dehydrogenase (LDH) values, haptoglobin consumption, presence of schistocytes in the peripheral blood smear, an increase in the reticulocyte count and a negative direct Coombs test (non-immune). Thrombocytopenia (common finding) may not be present, although most patients experience a significant decline from baseline platelet count during the progression (>25%). Pathological lesion Given these clinical findings, the presence of TMA in the different affected organs will result in pathological suspicion. This lesion is characterized by the existence of thrombi within the arterioles and/or glomerular capillaries (formed by platelets and fibrin) as seen through light microscopy, usually with the accumulation of red blood cells fragmented in the light, and focal ischaemic or congestive glomerular tufts.1 There may also be subendothelial widening by accumulation of proteins and cell lysis material, endothelial cell detachment and thickening and inflammation of the vascular wall28 (Fig. 1). Fibrin or fibrinogen deposition in the glomerulus, the mesangial and the vessel wall can be observed on immunofluorescence. Complement factors or fragments and immunoglobulins in the glomerular capillaries can also be seen.29 Renal biopsy, main organ affected, is not essential in aHUS diagnosis, as this is a clinical diagnosis entity and presents renal histology lesions characteristic of TMA, which are not pathognomonic of aHUS. However, in adults and after stabilizing the clinical condition (minimizing the risk of bleeding), a renal biopsy is often recommended, as it can be useful for diagnosis confirmation and, above all, as a prognostic value.10

Epidemiology aHUS development can occur at any time during life, however it occurs most often in children and young adults. In 60–67% of cases the onset occurs in children under 18 years of age.3–6 There are no significant differences between the sexes, but when the disease appears in adulthood it has a greater preference for women.5,6 In the USA its incidence is estimated at about one to two cases per million inhabitants-year.7 The exact incidence is unknown in Europe, however, more than 1000 cases have been reported in different series or records,5–9 and a recent international multicenter study shows an incidence of 0.11 cases/million inhabitants from 0 to 18 years of age.10

Table 1 Clinical manifestations associated with atypical haemolytic uraemic syndrome. Extra-renal manifestations

Symptomatology

References

Renal

Acute renal failure, chronic renal failure, proteinuria, haematuria

Central Nervous System

Confusion, facial paralysis, dysarthria, aphasia, dysphagia, altered level of consciousness, psychomotor agitation, seizures, stroke, coma Diarrhoea, abdominal pain, vomiting, pancreatitis, diabetes mellitus, intestinal ischaemia, hepatitis Hypertension, myocardial infarction, heart failure, stenosing vascular lesions

Caprioli et al.3 , Sellier-Leclerc et al.5 , Al-Akash et al.14 , Köse et al.15 , Mache et al.18 , Prescott et al.19 , Waters et al.20 and Lapeyraque et al.21 Sellier-Leclerc et al.5 , Noris et al.8 , Neuhaus et al.12 , Ohanian et al.16 and Koehl et al.17

Clinical signs and symptoms The initial clinical suspicion is established when the triad of microangiopathic haemolytic anaemia (non-immune), thrombocytopenia and damage in various target organs1 coexist. The kidney is the main organ affected,1,11 predominantly in the form of acute renal failure, although the onset can be insidious in up to 20% of cases, and even with preserved renal function.5 Microhematuria and/or moderate proteinuria can also appear. Despite the preference for the renal microvasculature endothelium, extra renal manifestations are not uncommon (20–48% of cases);5,8,12 stands out the involvement of the central nervous system (most common extra renal symptoms),12 cardiovascular, gastrointestinal (diarrhoea being an initial symptom in up to 30% of patients)13 and pulmonary.5 Because of its systemic condition, the aHUS can

Gastrointestinal

Cardiovascular

Lungs

Other

Dyspnoea, acute pulmonary oedema, alveolar haemorrhage Ocular involvement, adrenal insufficiency, peripheral vascular disease

Noris et al.8 , Zuber et al.13 , Ohanian et al.16 , Dragon-Durey et al.22 and Lee et al.23 Noris et al.8 , Neuhaus et al.12 , Al-Akash et al.14 , Köse et al.15 , Dragon-Durey et al.22 and Sallée et al.24 Sellier-Leclerc et al.5 and Al-Akash et al.14 Larakeb et al.25 , Hosler et al.26 and Malina et al.27

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Fig. 1. Renal histology in patients diagnosed with atypical haemolytic uraemic syndrome. A. Intraglomerular thrombosis. B. Ischaemic and retracted glomerulus. C. Artery occluded by platelet thrombi. D. Arteriole with complete occlusion by thrombi. Images courtesy of Dr. M. Sole (Department of Pathology, Hospital Clínic, Barcelona).

Pathophysiology The complement system is a key component of the innate immune system with important functions in the defence against infections, processing of immune complexes, antibody response and elimination of apoptotic debris. In recent decades, numerous studies have established a close association between aHUS and the presence of mutations in several complement genes, whose functional consequence is the deregulation of complement activation and tissue damage. Complement activation via the classical pathway (CP, mediated by antibodies), lectins (LP, carbohydrate mediated) or alternative (AP, constitutive activation) leads to the formation of enzymatic complexes called C3-convertase (CP/LP, C4b2a, AP, C3bBb), whose function is the proteolytic activation of C3 into C3a and C3b. The C3b is the molecule responsible for opsonisation, as well as a component of the AP C3-convertase, so that its generation involves exponential complement activation, promoting the formation of AP C3-convertase (amplification loop).30 Covalent attachment of an additional C3b molecule to the AP C3-convertases on cell surfaces will generate C3bBbC3b complexes with C5-convertase activity. This enzyme will split the C5 protein in 2 molecules again: C5a, a potent anaphylatoxin that mediates in leucocyte selection, and C5b, which will participate in the formation of the membrane attack complex leading to cell lysis (C5b–C9). In order to avoid an uncontrolled hyperactivation leading to the total consumption of the complement, causing damage to its own tissues, complement activation is tightly controlled by phase regulatory proteins (circulating in plasma) and on cell surfaces. The complement factor H (FH) is the main regulator of AP complement

both in fluid phase (in plasma) as well as on cell surfaces. Another regulator is factor I (FI), which also cleaves the C3b molecule in the presence of other cofactors such as FH, the Membrane Cofactor Protein (MCP [CD46]) or the complement receptor 1(CR1, CD35). 2 other membrane proteins limit complement activation on cell surfaces: decay acceleration factor, by dissociation of the C3 and C5 convertases, and CD59, inhibiting the membrane attack complex formation. Between 40 and 60% of patients with clinical diagnosis of aHUS carry mutations and/or polymorphisms in genes encoding complement proteins.3–9 Different trials have demonstrated that these mutations lead to a dysregulation of the AP complement either by a loss/decreased activity of regulatory proteins (mutations in CFH, CFI, MCP) or by an abnormally high activity of C3-convertase (C3 mutations and CFB; gain of function), and that this deregulation mainly affects the protection of cell surfaces to damage caused by the complement. Between 5 and 10% of aHUS patients are carriers of autoantibodies against FH.31,32 These antibodies have high affinity for the C-terminal region of the FH, resulting in CFH function deficiency. It is important to note that aHUS expresses an incomplete penetrance (about 50%) among carriers of mutations in the complement genes.33 This shows that for the disease to occur, additional genetic and/or environmental factors acting as triggers must coexist (multiple hits theory). Regarding additional genetic factors, between 5 and 10% of patients with aHUS have more than one mutation in the complement genes.4,8,34 Regarding environmental factors, at least 50% of aHUS cases8 (80% in paediatric cohort) include an infection as the trigger,4,5 being mainly infections of the upper respiratory tract and gastroenteritis.

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Table 2 Causes of thrombotic microangiopathy. Primary thrombotic microangiopathies (A) HUS associated with infections: represent 90% of HUS cases. Infection associated with Shiga toxin-producing Enterobacteriaceae, the most frequent being Escherichia coli, serotype 0157:H7. Shiga toxin produces a direct injury to the vascular endothelium causing the development of TMA. There are other causing infections such as: Shigella, Campylobacter and Streptococcus pneumoniae (neuraminidase producer, giving false positives in the direct Coombs test) (B) TTP: the cause is severe deficiency (<5–10%) in ADAMTS13 metalloprotease activity. The said severe deficiency (the presence of autoantibodies or mutations) prevents von Willebrand factor’s ultra large multimers cleaving into smaller multimers, promoting thrombus formation in the microvasculature platelet (TMA) (C) aHUS: deregulation of the alternative complement pathway leads to endothelial damage mediated by the complement itself, precipitating the development of TMA Secondary thrombotic microangiopathies (A) Drugs: oral contraceptives, mitomycin C, gemcitabine, cisplatin, inhibitors of vascular endothelial growth factor, anticalcineurinic agents (cyclosporine and tacrolimus), interferon, valaciclovir, inhibitors of mTOR (sirolimus, everolimus), ionizing radiation, ticlopidine, clopidogrel (B) Related to pregnancy: Postpartum HUS, HELLP syndrome, pregnancy-associated TTP (C) Related to transplantation: Bone marrow transplantation (graft-versus-host disease, TMA associated with conditioning treatment), solid organ transplant (acute humoral rejection, opportunistic infections: cytomegalovirus, parvovirus B19, BK virus, toxicity calcineurin) (D) Systemic diseases: systemic lupus erythematosus, antiphospholipid syndrome, scleroderma, rheumatoid arthritis (E) Related to other diseases: HIV, malignant hypertension, H1N1 virus infection, methylmalonic aciduria with homocystinuria, neoplastic growths, cytomegalovirus infection, infection by Epstein–Barr virus ADAMTS13: disintegrin and metalloproteinase with thrombospondin type 1, pattern 13; TMA: thrombotic microangiopathy; m-TOR: mammalian target of rapamycin (“target of rapamycin in mammalian cells”); HUS: haemolytic uraemic syndrome; AHUS: atypical haemolytic uraemic syndrome; TTP: thrombotic thrombocytopenic purpura.

Besides mutations and polymorphisms in complement genes, mutations have been identified in the gene encoding thrombomodulin (THBD),35 an anticoagulant protein that acts as thrombin cofactor and that also regulates FI-mediated C3b inactivation as well as homozygous mutations in the gene encoding the diacylglycerol kinase protein ␧.36 Although the aHUS diagnosis is clinical (after excluding other causes of TMA), it is highly recommended to perform a molecular genetic study of the alternative pathway complement, having to collect the samples before starting any treatment (especially PT). These studies provide useful information, allowing genotypic–phenotypic relationships such as: individually estimate the prognosis of our patients, know the response to different treatments and the risk of disease recurrence after renal transplantation. However, the molecular genetic study should never postpone the diagnosis or the application of most effective treatment. Prognosis Both, the severe damage occurred in the microvasculature, as well as the systemic nature of aHUS, carry a high disease morbidity and mortality. The prognosis varies depending on the age at disease onset, genotype and clinical severity. It has been reported that mortality during the first year after diagnosis is higher in children than in adults (6.7 vs 0.8%),37 while these are progressing more often to End-Stage Renal Disease (ESRD; 46 vs 16%).37 Regarding the genotype, patients with isolated mutations in MCP have a better prognosis (6% at 3 years8 and 35% at 5 years develop ESRD37 ). In contrast, patients with mutations in FH, CFI, C3 and CFB have a worse prognosis. Between 3 and 5 years of progression, up to 77% of patients with mutations in FH develop ESRD or die.8,37 Similar percentages have been reported in patients with mutations in CFI and C3 (60–70% die or develop ESRD at 5 years).8,37 Differential diagnosis When there is clinical suspicion and/or a histologically confirmed TMA, a wide range of diagnostic possibilities is opened, among which aHUS is included. The classification of clinical entities that may present with TMA is under constant review; however, the distinction between primary and secondary TMA seems to be gaining popularity, making possible a clinical and/or etiological overlap between the two10 (Table 2). As with other diseases, it will be essential to complete a detailed medical history and physical examination to initially address the diagnosis of TMA. The clinical presentation and the age of

the patient are useful for the initial approach, but the signs and symptoms of different types of TMA are not specific.1 The typical HUS or STEC-HUS affects predominantly children (between 6 months and 5 years of age), starting with gastrointestinal involvement as abdominal pain, nausea, vomiting and diarrhoea (initially bloody), with acute renal failure typically appearing 4–10 days later.38,39 However, the concept of HUS associated with diarrhoea tends to be less used in typical HUS, since a high percentage of patients no longer present this at the time of consultation, and up to 30% of patients with aHUS may start with these clinical symptoms.8 In infants and children <6 years of age, the most frequent diagnosis is aHUS, however, methylmalonic aciduria,40 congenital thrombotic thrombocytopenic purpura (TTP) and infection by Streptococcus pneumoniae,41 must also be ruled out, among other. In adolescents and young adults, the most frequent TMA are aHUS and acquired TTP. The usual clinical presentation of TTP is characterized by a significant central nervous system involvement, while aHUS usually produces severe renal impairment. However, up to 48% of patients with aHUS may exhibit neurological symptoms,12 and 50% of TTP patients, renal involvement. Due to the systemic nature of the different causes of TMA, clinical presentation can offer high variability, therefore, the different diagnoses should be confirmed through a set of complementary tests after the initial clinical approach. In Table 3 we propose a list of tests required for that purpose. Regarding the aHUS, it should be noted that the diagnosis is clinical and shall be established by excluding other TMA causes.

Treatment Supportive care All patients with clinical suspicion of TMA should be transferred to a specialized centre, fully competent, with extensive experience in performing treatments such as dialysis, PT and intensive care, should they be required. An initial period, which may even comprise days, should be needed in order to establish the final diagnosis. In this period, an advanced life support treatment for these patients is essential, as it has shown a reduction in morbidity and mortality. Among others, an optimal control of blood pressure, initiation of dialysis, should it be indicated, and red blood cell transfusion support are essential. By contrast, platelet transfusion is contraindicated (except in patients with active bleeding or when an invasive procedure is to be performed with a high risk of bleeding), as it may worsen the TMA process.

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Table 3 Additional tests in the differential diagnosis of atypical haemolytic uraemic syndrome. 1. STEC infection

2. Pneumococcal infection

3. Congenital or acquired ADAMTS13 deficiency 4. Changes in complement regulation 5. Methylmalonic aciduria

6. Pregnancy

7. Other

Stool sample or rectal swab for: STEC culture; PCR for Stx 0157:H7 gene and other serotypes; ELISA and/or Vero cell culture assay for serum Stx; anti-LPS antibodies against prevalent serotypes Bacterial culture of sterile body fluids; DAT (Coombs test), respiratory viral test; Chest radiography; cytochemistry and culture of CSF in cases of pneumococcal meningitis ADAMTS13 plasma activity or quantitation (ELISA). Antibody inhibitors detection C3, C4 (plasma/serum), CH50. FH, FI, FB (plasma/serum). Anti-FH antibodies. Surface MCP expression in leukocytes. Analysis of mutation in FH, FI, MCP, C3, FB ± THBD ± DKED Chromatography of amino acids in plasma/urine (hyperhomocysteinemia; hypomethioninemia; homocystinuria). Chromatography of organic acids in urine (methylmalonic aciduria). MMACHC gene mutation analysis Pregnancy test; liver enzymes; ADAMTS13 activity study and molecular genetic study of alternative complement pathway Serology and HIV viral load; culture and PCR H1N1; PCR cytomegalovirus; PCR Epstein–Barr virus; screening for neoplasms; antinuclear antibodies; Anti-DNA antibodies; anti-Scl70 antibodies; lupus anticoagulant antibodies; anti-phospholipase antibodies; fundus (malignant hypertension)

ADAMTS13: disintegrin and metalloproteinase with type 1 thrombospondin, pattern 13; DAT: direct antiglobulin test (“Direct antiglobulin test” [direct Coombs test]); ELISA: enzyme-linked immunosorbent assay; FB: complement factor B; FH: complement factor H; FI: complement factor I; HBP: high blood pressure; CSF: cerebrospinal fluid; LPS: outer membrane lipopolysaccharide; MCP: membrane cofactor protein; PCR: polymerase chain reaction (“polymerase chain reaction”); aHUS: atypical haemolytic uraemic syndrome; STEC: Shiga toxin-producing Escherichia coli; Stx: Shiga toxin; THBD: thrombomodulin; HIV: Human Immunodeficiency Virus. Adapted from Loirat and Frémeaux-Bacchi1 and Campistol et al.10

Plasma treatment Despite the absence of randomized prospective clinical trials, PT was, for decades, the treatment of choice against aHUS as it reduced mortality in that entity. Fresh frozen plasma was meant to infuse normofunctional regulatory proteins of the alternative complement pathway,42 whereas with plasma exchange (PE) also sought to eliminate the mutant proteins (dysfunctional), anti-FH antibodies, should they be present, as well as potential endothelial aggression triggers (thrombogenic and/or inflammatory factors). Most of the evidence has been provided through retrospective records,5,8 showing PT hematologic and renal full recovery rates below 50%. Patients with FH mutations, PT treated, have achieved full recovery only in 5% of cases, and up to 37% of patients developed ESRD or died.8 Regarding patients with CFI mutations, 75% developed ESRD or died during progression, despite the PT.8 MCP is a non-circulating protein (anchored in cell membranes), so the PT is not considered effective in patients with mutations in the said protein.5,8 In patients with anti-FH antibodies, the treatment with PE associated with different immunosuppressant regimens has proved highly effective.22,43 Evidence in patients with THBD, C3 and CFB mutations treated with PT is very scarce. The most effective therapeutic regimen is unknown, although consensus guidelines recommended an early onset of PT, which should also be intense (daily sessions of PE using 2 plasma volumes in adults and 100 ml/kg in children) and maintained (slow decrease

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after control of haemolysis to prevent disease recurrence and ESRD, especially in children when infection is present). Eculizumab Eculizumab, recombinant humanized monoclonal antibody is an IgG2/4␬ with a high affinity for the C5 molecule. Binding to the said molecule, it blocks its cleavage into C5a (potent anaphylatoxin) and especially C5b, thus preventing the formation of the membrane attack complex (C5b–C9), which is responsible for the endothelial damage generated by the development of TMA in aHUS patients. There are numerous clinical cases using eculizumab in patients with aHUS in the three possible scenarios: disease onset (native kidneys), disease recurrence and recurrence prevention/prophylaxis (kidney transplant).13–16,18,19,21,44–55 The results in these clinical cases show that eculizumab is highly effective in treating aHUS (both native kidneys as well as renal transplants), achieving a complete hematologic recovery in most of them and significant renal recovery in patients with early drug use. Regarding the kidney posttransplant preventive/prophylactic use, eculizumab may constitute a valid alternative in patients at high risk of recurrence and graft loss. The most decisive results regarding eculizumab safety and efficacy come from two (phase II) international, multicenter, prospective, open-label clinical trials carried out in adolescent and adult patients diagnosed with aHUS, both resistant to PT (n = 17 patients; study C08-002) as well as patients on prolonged treatment with PT (n = 20 patients; study C08-003).56 The studies were designed for analysis at 26 weeks of treatment, showing hematologic normalization rates (normalization of platelet counts and LDH in at least 2 consecutive measurements) of 76% in the resistant patients and 90% in those with prolonged treatment. TMA episodefree patient rates (endpoint defined as no decrease in platelet count > 25% from baseline and no new dialysis requirement and no new PT sessions) were 88% and 80%. The PT could be discontinued in 88% of cases in the study of resistant patients and 100% in the case of prolonged treatment. Eculizumab treatment was associated with a continuous, significant and time-dependent improvement of the estimated glomerular filtration rate (eGFR) in both studies (PT resistant: +31 ml/min/1.73 m2 , p = 0.0001; PT prolonged: +6.1 ml/min/1.73 m2 , p = 0.0003). Both studies showed that early intervention (shortest time interval between the onset of the disease and treatment with eculizumab) was associated with a greater likelihood of improvement in eGFR. Patients who began treatment only ten days after the start of aHUS had an improvement in eGFR of +59 ml/min/1.73 m2 as an average, compared to +7 ml/min/1.73 m2 (p = 0.03) of those in which the use of eculizumab was delayed between 2 and 4 months.56 The use of eculizumab was also associated with a significant improvement in quality of life and only 4 serious adverse effects were reported during the study (peritonitis, influenza infection, severe hypertension and venous disorder). No significant differences were observed in response to eculizumab among patients with mutations identified in the complement regulatory proteins and those in which mutations were not identified. Following these results, the use of eculizumab in adult and paediatric patients with aHUS was approved by the Food and Drug Administration in May 2011 and the European Medicines Agency in August of the same year. Blocking the terminal phase of the complement results in a predisposition to infections by encapsulated bacteria, especially increasing the risk of infection by Neisseria meningitidis (N. meningitidis). Therefore, all patients who are going to receive treatment with eculizumab must be previously vaccinated against N. meningitidis (quadrivalent conjugate vaccine against serotypes A, C, Y and W135). Antibiotic prophylaxis is also necessary against this germ until the vaccine generates an adequate immune response

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aHUS exclusion diagnosis

Post kidney transplant TMA clinical suspicion (Microangiopathic hemolytic anemia +/– acute renal failure)

Sample collection (ADAMTS13; genetic study = Vaccination +/– prophylaxis neisseria meningitidis

Viral serology; immunomonitoring; immunosuppressive levels; etc…

Pediatric patients:

Adult patients:

Early eculizumab +/– Support treatment

Early eculizumab (early and intensive PE until eculizumab availability +/– Support treatment)

Individualized assessment of the need for renal graft biopsy

ESRD secondary to aHUS

TMA with no aHUS history

Treatment monitoring aHUS recurrence

Fig. 2. Treatment recommendations in patients with atypical haemolytic uraemic syndrome. ADAMTS13: disintegrin and metalloproteinase with thrombospondin type 1, pattern 13; PE: plasma exchange; aHUS: atypical haemolytic uraemic syndrome. Adapted from Campistol et al.10

(approximately 2 weeks in immunocompetent patients). Some countries, such as France, recommend such antibiotic prophylaxis throughout the treatment with eculizumab in paediatric patients (at least until the vaccine against serotype B is available) because of the risk of infection.1 It is also recommended to vaccinate paediatric patients against Haemophilus influenzae and pneumococcus. The dose of eculizumab according to the SmPC in adult patients is 900 mg weekly, during 4 weeks. From the fifth week, the maintenance dose becomes 1200 mg every 2 weeks. The dose in paediatric and adolescent patients is adjusted by weight. Treatment recommendations In light of the evidence described, a Spanish group of experts in aHUS has recently published treatment recommendations for patients with a high clinical suspicion of aHUS.10 The early use of eculizumab is recommended for both paediatric and adults patients with an exclusion diagnosis of aHUS as the first therapeutic option (with special emphasis on paediatric patients because of the complications and difficulties associated with PT). If drug therapy is delayed, PE should be started early and intensively until eculizumab is available (Fig. 2). The early onset of PE is also recommended when the differential diagnosis is only between TTP and aHUS, with the possibility of suspending the said technique and starting with eculizumab once the definitive diagnosis of aHUS has been established.

HUS de novo

Evaluate early eculizumab

Associated with IS

Remove IS + PE

Secondary forms: AHR, CMV, BK, ....

Etiological treatment

Evaluate eculizumab in resistant cases

Fig. 3. Microangiopathy after kidney transplantation, diagnostic and therapeutic algorithm. BK: human polyomavirus; CMV, cytomegalovirus; ESRD: end-stage renal disease; IS: immunosuppressant; TMA thrombotic microangiopathy; AHR: acute humoral rejection; PE: plasma exchange; aHUS: atypical haemolytic uraemic syndrome. Adapted from Campistol et al.10

Table 4 Clinical characteristics of patients with atypical haemolytic uraemic syndrome depending on the genetic abnormality. Gene

Recurrence risk

Risk of recurrence after kidney transplantation

CFH CFI MCP C3 CFB THBD Anti-CFH

75–90% 10–30% 70–90% 50% 3/3 without ESRD 30% 40–60%

75–90% 45–80% <20% 40–70% 100% One patient Higher with elevated titres

Anti-CFH: anti-factor H complement antibodies; CFB: complement factor B; CFH: complement factor H; CFI: Complement factor I; ESRD: End-Stage Renal Disease; MCP: membrane cofactor protein gene; THBD: thrombomodulin. Adapted from Loirat and Frémeaux-Bacchi1 and Campistol et al.10

Kidney transplant Thrombotic microangiopathy after kidney transplantation TMA can develop after kidney transplantation in the context of aHUS recurrence (in patients with ESRD secondary to the said syndrome) or in the form of HUS de novo. In both cases, the clinical presentation may be very variable, from the classical triad (microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure) to acute deterioration of renal function without hematologic manifestations. It is essential to perform a biopsy of the renal graft after stabilizing the patient to get an accurate diagnosis and provide an effective etiological treatment strategy. The incidence of HUS de novo varies between 0.8 and 14% in those who have had a kidney transplant.57,58 There is a large number of renal graft endothelial aggressors that could contribute to the development of TMA in such patients, among which are: immunosuppressive therapy (calcineurin inhibitors,58

m-TOR inhibitors and a combination of both), opportunistic infections (cytomegalovirus, parvovirus B19, polyomavirus), ischaemia-reperfusion injury, acute humoral rejection, and other less frequent as neoplasms and antiphospholipid syndrome. In a series of 24 kidney transplants it was demonstrated that up to 29% of them had mutations in FH and CFI,59 showing that certain patients may have genetic susceptibility for the development of HUS de novo. Once the diagnosis has been established through biopsy and the appropriate complementary tests, an early and specific etiologic treatment should be offered for each patient and circumstances (Fig. 3). Advances in molecular genetic studies of the alternative complement pathway have determined that the risk of aHUS recurrence after renal transplantation and its prognosis are closely linked to genetic abnormalities inherent to patients (Table 4). The present Spanish consensus document11 recommends that patients with ESRD secondary to aHUS who have a recurrence of this syndrome

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after renal transplantation should receive early treatment with eculizumab (Fig. 3). Renal transplantation in patients with atypical haemolytic uraemic syndrome Since the prognosis of kidney transplant (risk of recurrence and graft loss) in patients with aHUS is directly related to the genetic abnormality present, all patients with ESRD secondary to aHUS should have a molecular genetic study of the alternative complement pathway before being included in the waiting list for a kidney transplant. In patients with a high risk of recurrence (mutations of FH, C3, CFB, CFI; high titres of anti-FH antibodies), it is recommended to avoid the recurrence of aHUS by a prophylactic approach (PE or eculizumab) or evaluate a kidney–liver transplantation (as most regulatory proteins are synthesized in the liver). By contrast, in patients considered at low risk of recurrence (isolated mutations in MCP or negative anti-FH antibodies), kidney transplant alone could be performed. Conclusions aHUS is a very rare systemic disease, associated high morbidity and mortality. The cause is a deregulation in the alternative complement pathway that produces endothelial damage, triggering the development of TMA at histological level. Its onset can occur at any time of life, suspecting it when clinical findings and laboratory tests show signs of microangiopathic haemolytic anaemia (non-immune), thrombocytopenia and involvement of different target organs (especially kidney). Its diagnosis is clinical, after excluding all causes of TMA, although a complete genetic-molecular study of the alternative complement pathway in all patients is recommended (allowing to establish genotype–phenotype relationships). The introduction of PT in the 1980s led to a significant decrease in mortality in patients with aHUS. However, an adequate control of chronic organ damage has not been demonstrated. Eculizumab, monoclonal antibody to C5 fraction, blocks the terminal phase of the complement avoiding the production of inflammation by C5a as well as the formation of the membrane attack complex, which is responsible for the endothelial damage in patients with aHUS. Recent clinical trials have demonstrated its efficacy and safety in paediatric and adult patients with aHUS, leading to its approval by regulatory agencies. Such evidence has prompted a Spanish group of experts to recommend its use as first-choice therapy to patients with a high clinical suspicion of aHUS. Conflict of interests Dr. Blasco, Dr. Campistol and Dr. Rodríguez de Córdoba have engaged in consulting and teaching activities for Alexion Pharmaceuticals. Dr. Blasco and Dr. Campistol have participated in studies sponsored by Alexion Pharmaceuticals. References 1. Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60. 2. 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 (German). 3. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108:1267–79. 4. Loirat C, Noris M, Fremeaux-Bacchi V. Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2008;23:1957–72.

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