Atypical hemolytic uremic syndrome in the era of terminal complement inhibition: an observational cohort study.

Historically, the majority of patients with complement-mediated atypical hemolytic uremic syndrome (CaHUS) progress to end-stage kidney disease (ESKD). Single-arm trials of eculizumab with a short follow-up suggested efficacy. We prove, for the first time to our knowledge, in a genotype matched CaHUS cohort that the 5-year cumulative estimate of ESKD-free survival improved from 39.5% in a control cohort to 85.5% in the eculizumab-treated cohort (hazard ratio, 4.95; 95% confidence interval [CI], 2.75-8.90; P = .000; number needed to treat, 2.17 [95% CI, 1.81-2.73]). The outcome of eculizumab treatment is associated with the underlying genotype. Lower serum creatinine, lower platelet count, lower blood pressure, and younger age at presentation as well as shorter time between presentation and the first dose of eculizumab were associated with estimated glomerular filtration rate >60 ml/min at 6 months in multivariate analysis. The rate of meningococcal infection in the treated cohort was 550 times greater than the background rate in the general population. The relapse rate upon eculizumab withdrawal was 1 per 9.5 person years for patients with a pathogenic mutation and 1 per 10.8 person years for those with a variant of uncertain significance. No relapses were recorded in 67.3 person years off eculizumab in those with no rare genetic variants. Eculizumab was restarted in 6 individuals with functioning kidneys in whom it had been stopped, with no individual progressing to ESKD. We demonstrated that biallelic pathogenic mutations in RNA-processing genes, including EXOSC3, encoding an essential part of the RNA exosome, cause eculizumab nonresponsive aHUS. Recessive HSD11B2 mutations causing apparent mineralocorticoid excess may also present with thrombotic microangiopathy.

Assessing the Impact of Prophylactic Eculizumab on Renal Graft Survival in Atypical Hemolytic Uremic Syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare cause of end-stage kidney disease and associated with poor outcomes after kidney transplantation from early disease recurrence. Prophylactic eculizumab treatment at the time of transplantation is used in selected patients with aHUS. We report a retrospective case note review describing transplant outcomes in patients with aHUS transplanted between 1978 and 2017, including those patients treated with eculizumab. METHODS: The National Renal Complement Therapeutics Centre database identified 118 kidney transplants in 86 recipients who had a confirmed diagnosis of aHUS. Thirty-eight kidney transplants were performed in 38 recipients who received prophylactic eculizumab. The cohort not treated with eculizumab comprised 80 transplants in 60 recipients and was refined to produce a comparable cohort of 33 transplants in 32 medium and high-risk recipients implanted since 2002. Complement pathway genetic screening was performed. Graft survival was censored for graft function at last follow-up or patient death. Graft survival without eculizumab treatment is described by complement defect status and by Kidney Disease: Improving Global Outcomes risk stratification. RESULTS: Prophylactic eculizumab treatment improved renal allograft survival ( P = 0.006) in medium and high-risk recipients with 1-y survival of 97% versus 64% in untreated patients. Our data supports the risk stratification advised by Kidney Disease: Improving Global Outcomes. CONCLUSIONS: Prophylactic eculizumab treatment dramatically improves graft survival making transplantation a viable therapeutic option in aHUS.

A novel method for real-time analysis of the complement C3b:FH:FI complex reveals dominant negative CFI variants in age-related macular degeneration.

Age-related macular degeneration (AMD) is linked to 2 main disparate genetic pathways: a chromosome 10 risk locus and the alternative pathway (AP) of complement. Rare genetic variants in complement factor H (CFH; FH) and factor I (CFI; FI) are associated with AMD. FH acts as a soluble cofactor to facilitate FI's cleavage and inactivation of the central molecule of the AP, C3b. For personalised treatment, sensitive assays are required to define the functional significance of individual AP genetic variants. Generation of recombinant FI for functional analysis has thus far been constrained by incomplete processing resulting in a preparation of active and inactive protein. Using an internal ribosomal entry site (IRES)-Furin-CFI expression vector, fully processed FI was generated with activity equivalent to serum purified FI. By generating FI with an inactivated serine protease domain (S525A FI), a real-time surface plasmon resonance assay of C3b:FH:FI complex formation for characterising variants in CFH and CFI was developed and correlated well with standard assays. Using these methods, we further demonstrate that patient-associated rare genetic variants lacking enzymatic activity (e.g. CFI I340T) may competitively inhibit the wild-type FI protein. The dominant negative effect identified in inactive factor I variants could impact on the pharmacological replacement of FI currently being investigated for the treatment of dry AMD.

C3 Glomerulopathy and Related Disorders in Children: Etiology-Phenotype Correlation and Outcomes.

BACKGROUND AND OBJECTIVES: Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic data for pediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based on retrospective studies without etiologic data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 80 prevalent pediatric patients with membranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using a Cox proportional hazards model. Kidney and transplant graft survival was determined using the Kaplan-Meier method. RESULTS: Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complex membranoproliferative GN, and ten with immune-complex GN. Patients were aged 2-15 (median, 9; interquartile range, 7-11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired (anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% of patients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18 (interquartile range, 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplants performed in eight patients, two of which failed due to recurrent disease. Presence of >50% crescents on the initial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazard ratio, 6.2; 95% confidence interval, 1.05 to 36.6; P<0.05). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on the initial biopsy specimen. CONCLUSIONS: Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric patients with membranoproliferative GN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy.

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.

Large-Scale Whole-Genome Sequencing Reveals the Genetic Architecture of Primary Membranoproliferative GN and C3 Glomerulopathy.

BACKGROUND: Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN. METHODS: We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource-Rare Diseases Study. We examined copy number, rare, and common variants. RESULTS: Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (P=3.29×10-8; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 (P=1.21×10-8; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure. CONCLUSIONS: We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.

Functional Characterization of Rare Genetic Variants in the N-Terminus of Complement Factor H in aHUS, C3G, and AMD.

Membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), atypical haemolytic uraemic syndrome (aHUS) and age-related macular degeneration (AMD) have all been strongly linked with dysfunction of the alternative pathway (AP) of complement. A significant proportion of individuals with MPGN, C3G, aHUS and AMD carry rare genetic variants in the CFH gene that cause functional or quantitative deficiencies in the factor H (FH) protein, an important regulator of the AP. In silico analysis of the deleteriousness of rare genetic variants in CFH is not reliable and careful biochemical assessment remains the gold standard. Six N-terminal variants of uncertain significance in CFH were identified in patients with these diseases of the AP and selected for analysis. The variants were produced in Pichia Pastoris in the setting of FH CCPs 1-4, purified by nickel affinity chromatography and size exclusion and characterized by surface plasmon resonance and haemolytic assays as well as by cofactor assays in the fluid phase. A single variant, Q81P demonstrated a profound loss of binding to C3b with consequent loss of cofactor and decay accelerating activity. A further 2 variants, G69E and D130N, demonstrated only subtle defects which could conceivably over time lead to disease progression of more chronic AP diseases such as C3G and AMD. In the variants S159N, A161S, and M162V any functional defect was below the capacity of the experimental assays to reliably detect. This study further underlines the importance of careful biochemical assessment when assigning functional consequences to rare genetic variants that may alter clinical decisions for patients.

Diseases of complement dysregulation-an overview.

Atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), and paroxysmal nocturnal hemoglobinuria (PNH) are prototypical disorders of complement dysregulation. Although complement overactivation is common to all, cell surface alternative pathway dysregulation (aHUS), fluid phase alternative pathway dysregulation (C3G), or terminal pathway dysregulation (PNH) predominates resulting in the very different phenotypes seen in these diseases. The mechanism underlying the dysregulation also varies with predominant acquired autoimmune (C3G), somatic mutations (PNH), or inherited germline mutations (aHUS) predisposing to disease. Eculizumab has revolutionized the treatment of PNH and aHUS although has been less successful in C3G. With the next generation of complement therapeutic in late stage development, these archetypal complement diseases will provide the initial targets.

Factor H autoantibody is associated with atypical hemolytic uremic syndrome in children in the United Kingdom and Ireland.

Factor H autoantibodies can impair complement regulation, resulting in atypical hemolytic uremic syndrome, predominantly in childhood. There are no trials investigating treatment, and clinical practice is only informed by retrospective cohort analysis. Here we examined 175 children presenting with atypical hemolytic uremic syndrome in the United Kingdom and Ireland for factor H autoantibodies that included 17 children with titers above the international standard. Of the 17, seven had a concomitant rare genetic variant in a gene encoding a complement pathway component or regulator. Two children received supportive treatment; both developed established renal failure. Plasma exchange was associated with a poor rate of renal recovery in seven of 11 treated. Six patients treated with eculizumab recovered renal function. Contrary to global practice, immunosuppressive therapy to prevent relapse in plasma exchange-treated patients was not adopted due to concerns over treatment-associated complications. Without immunosuppression, the relapse rate was high (five of seven). However, reintroduction of treatment resulted in recovery of renal function. All patients treated with eculizumab achieved sustained remission. Five patients received renal transplants without specific factor H autoantibody-targeted treatment with recurrence in one who also had a functionally significant CFI mutation. Thus, our current practice is to initiate eculizumab therapy for treatment of factor H autoantibody-mediated atypical hemolytic uremic syndrome rather than plasma exchange with or without immunosuppression. Based on this retrospective analysis we see no suggestion of inferior treatment, albeit the strength of our conclusions is limited by the small sample size.

Hemolytic Uremic Syndrome in Pregnancy and Postpartum.

BACKGROUND: Pregnancy is associated with various forms of thrombotic microangiopathy, including hemolytic uremic syndrome. A previous small French study suggested that pregnancy-associated hemolytic uremic syndrome was to be included in the spectrum of atypical hemolytic uremic syndrome linked to complement alternative pathway dysregulation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We sought to retrospectively analyze the presentation, outcome, and frequency of complement alternative pathway gene variants in a larger international (France, United Kingdom, Italy) cohort of patients with pregnancy-associated hemolytic uremic syndrome. RESULTS: Eighty-seven patients with pregnancy-associated hemolytic uremic syndrome were included. Hemolytic uremic syndrome occurred mainly during the first pregnancy (58%) and in the postpartum period (76%). At diagnosis, 56 (71%) patients required dialysis. Fifty-six (78%) patients underwent plasma exchanges, 21 (41%) received plasma infusions, and four (5%) received eculizumab. During follow-up (mean duration of 7.2 years), 41 (53%) patients reached ESRD, 15 (19%) had CKD, and 18 (28%) patients experienced hemolytic uremic syndrome relapse. Twenty-four patients (27%) received a kidney transplant and a recurrence of hemolytic uremic syndrome occurred in 13 (54%) patients. Variants in complement genes were detected in 49 (56%) patients, mainly in the CFH (30%) and CFI genes (9%). CONCLUSIONS: Pregnancy-associated hemolytic uremic syndrome and atypical hemolytic uremic syndrome nonrelated to pregnancy have the same severity at onset and during follow-up and the same frequency of complement gene variants.

Thrombotic Microangiopathy in Inverted Formin 2-Mediated Renal Disease.

The demonstration of impaired C regulation in the thrombotic microangiopathy (TMA) atypical hemolytic uremic syndrome (aHUS) resulted in the successful introduction of the C inhibitor eculizumab into clinical practice. C abnormalities account for approximately 50% of aHUS cases; however, mutations in the non-C gene diacylglycerol kinase-ε have been described recently in individuals not responsive to eculizumab. We report here a family in which the proposita presented with aHUS but did not respond to eculizumab. Her mother had previously presented with a post-renal transplant TMA. Both the proposita and her mother also had Charcot-Marie-Tooth disease. Using whole-exome sequencing, we identified a mutation in the inverted formin 2 gene (INF2) in the mutational hotspot for FSGS. Subsequent analysis of the Newcastle aHUS cohort identified another family with a functionally-significant mutation in INF2 In this family, renal transplantation was associated with post-transplant TMA. All individuals with INF2 mutations presenting with a TMA also had aHUS risk haplotypes, potentially accounting for the genetic pleiotropy. Identifying individuals with TMAs who may not respond to eculizumab will avoid prolonged exposure of such individuals to the infectious complications of terminal pathway C blockade.

A De Novo Deletion in the Regulators of Complement Activation Cluster Producing a Hybrid Complement Factor H/Complement Factor H-Related 3 Gene in Atypical Hemolytic Uremic Syndrome.

The regulators of complement activation cluster at chromosome 1q32 contains the complement factor H (CFH) and five complement factor H-related (CFHR) genes. This area of the genome arose from several large genomic duplications, and these low-copy repeats can cause genome instability in this region. Genomic disorders affecting these genes have been described in atypical hemolytic uremic syndrome, arising commonly through nonallelic homologous recombination. We describe a novel CFH/CFHR3 hybrid gene secondary to a de novo 6.3-kb deletion that arose through microhomology-mediated end joining rather than nonallelic homologous recombination. We confirmed a transcript from this hybrid gene and showed a secreted protein product that lacks the recognition domain of factor H and exhibits impaired cell surface complement regulation. The fact that the formation of this hybrid gene arose as a de novo event suggests that this cluster is a dynamic area of the genome in which additional genomic disorders may arise.

An extended mini-complement factor H molecule ameliorates experimental C3 glomerulopathy.

Abnormal regulation of the complement alternative pathway is associated with C3 glomerulopathy. Complement factor H is the main plasma regulator of the alternative pathway and consists of 20 short consensus repeat (SCR) domains. Although recombinant full-length factor H represents a logical treatment for C3 glomerulopathy, its production has proved challenging. We and others have designed recombinant mini-factor H proteins in which 'non-essential' SCR domains have been removed. Here, we report the in vitro and in vivo effects of a mini-complement factor H protein, FH1-5^18-20, using the unique factor H-deficient (Cfh-/-) mouse model of C3 glomerulopathy. FH1-5^18-20 is comprised of the key complement regulatory domains (SCRs 1-5) linked to the surface recognition domains (SCRs 18-20). Intraperitoneal injection of FH1-5^18-20 in Cfh-/- mice reduced abnormal glomerular C3 deposition, similar to full-length factor H. Systemic effects on plasma alternative pathway control were comparatively modest, in association with a short half-life. Thus, FH1-5^18-20 is a potential therapeutic agent for C3 glomerulopathy and other renal conditions with alternative pathway-mediated tissue injury.

Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

The complement inhibitor eculizumab is a humanized monoclonal antibody against C5. It was developed to specifically target cleavage of C5 thus preventing release of C5a and activation of the terminal pathway. Paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) are 2 diseases with distinctly different underlying molecular mechanisms. In PNH, progeny of hematopoietic stem cells that harbor somatic mutations lead to a population of peripheral blood cells that are deficient in complement regulators resulting in hemolysis and thrombosis. In aHUS, germline mutations in complement proteins or their regulators fail to protect the glomerular endothelium from complement activation resulting in thrombotic microangiopathy and renal failure. Critical to the development of either disease is activation of the terminal complement pathway. Understanding this step has led to the study of eculizumab as a treatment for these diseases. In clinical trials, eculizumab is proven to be effective and safe in PNH and aHUS.

Atypical haemolytic uraemic syndrome associated with a CD46 mutation triggered by Shigella flexneri.

We present a case of haemolytic uraemic syndrome (HUS) triggered by Shigella flexneri. Of the Shigella species, only S. dysenteriae type 1 is said to produce Shiga toxin and consequently cause HUS. Investigation of the complement system in this patient revealed a CD46 mutation. In individuals with mutations in complement genes incomplete penetrance of atypical HUS (aHUS) is seen, suggesting that a trigger, such as infection, is required for disease to manifest. In an era of complement modulatory therapy for aHUS it is important to be alert to unusual presentations of diarrhoeal-associated disease.

Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration.

We sequenced the whole exome of 35 cases and 7 controls from 9 age-related macular degeneration (AMD) families in whom known common genetic risk alleles could not explain their high disease burden and/or their early-onset advanced disease. Two families harbored novel rare mutations in CFH (R53C and D90G). R53C segregates perfectly with AMD in 11 cases (heterozygous) and 1 elderly control (reference allele) (LOD = 5.07, P = 6.7 × 10(-7)). In an independent cohort, 4 out of 1676 cases but none of the 745 examined controls or 4300 NHBLI Exome Sequencing Project (ESP) samples carried the R53C mutation (P = 0.0039). In another family of six siblings, D90G similarly segregated with AMD in five cases and one control (LOD = 1.22, P = 0.009). No other sample in our large cohort or the ESP had this mutation. Functional studies demonstrated that R53C decreased the ability of FH to perform decay accelerating activity. D90G exhibited a decrease in cofactor-mediated inactivation. Both of these changes would lead to a loss of regulatory activity, resulting in excessive alternative pathway activation. This study represents an initial application of the whole-exome strategy to families with early-onset AMD. It successfully identified high impact alleles leading to clearer functional insight into AMD etiopathogenesis.

Characterization of a factor H mutation that perturbs the alternative pathway of complement in a family with membranoproliferative GN.

Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype. Genetic analysis revealed a novel heterozygous mutation in complement factor H (R83S) in addition to known risk polymorphisms carried by individuals with MPGN. Patients with MPGN had normal levels of factor H, and structural analysis of the mutant revealed only subtle alterations. However, functional analysis revealed profoundly reduced C3b binding, cofactor activity, and decay accelerating activity leading to loss of regulation of the alternative pathway. In summary, this family showed a confluence of common and rare functionally significant genetic risk factors causing disease. Data from our analysis of these factors highlight the role of the alternative pathway of complement in MPGN.

Making sense of the spectrum of glomerular disease associated with complement dysregulation.

Over recent years, complement has emerged as a major player in the development of a number of glomerular diseases, including atypical haemolytic uraemic syndrome, membranoproliferative glomerulonephritis and the recently described C3 glomerulonephritis. Some patients and pedigrees show overlapping features of these conditions. Intriguingly, a few complement gene mutations are common to different disease phenotypes. In this review, we explore the evidence for complement dysregulation in these diseases and the clinical interface between them, and present a hypothesis to explain the variable phenotype associated with dysregulation of the alternative complement pathway.

Sarcoidosis presenting with hypercalcaemia following withdrawal of long-term immunosuppression in renal transplantation.

Long-term immunosuppression, including corticosteroids, is a hallmark of renal transplantation. We describe a patient who had a failed transplant after 15 years, subsequent graft nephrectomy and withdrawal of his immunosuppression therapy including prednisolone. Within months of complete cessation of prednisolone, he developed hypercalcaemia and subsequent systemic symptoms including ocular, respiratory and dermatological. A skin biopsy demonstrated non-caseating granulomatous lesion and a diagnosis of sarcoidosis was confirmed. Re-commencement with prednisolone resulted in complete resolution of clinical and biochemical features of sarcoidosis. Sarcoidosis is unlikely to present in the immunosuppressed patient. This case highlights that unexplained hypercalcaemia at the time of withdrawal of immunosuppression, including corticosteroids, may be a feature of sarcoidosis.

Complement therapy in atypical haemolytic uraemic syndrome (aHUS).

Central to the pathogenesis of atypical haemolytic uraemic syndrome (aHUS) is over-activation of the alternative pathway of complement. Inherited defects in complement genes and autoantibodies against complement regulatory proteins have been described. The use of plasma exchange to replace non-functioning complement regulators and hyper-functional complement components in addition to the removal of CFH-autoantibodies made this the 'gold-standard' for management of aHUS. In the last 4 years the introduction of the complement inhibitor Eculizumab has revolutionised the management of aHUS. In this review we shall discuss the available literature on treatment strategies to date.