Protecting the kidney from complement: atypical haemolytic uraemic syndrome

Diagnosis

aHUS belongs to a group of conditions called thrombotic microangiopathies (TMAs), which are characterised by endothelial injuries that result in occlusive intravascular thrombi in small vessels, with resultant MAHA. Elevated creatinine, lactate dehydrogenase and bilirubin with a low haptoglobin, in addition to a Coombs’-test-negative haemolytic anaemia, and thrombocytopenia are all consistent with a diagnosis of HUS. A normal coagulation profile will exclude disseminated intravascular coagulation (DIC).

Upon identifying a TMA, three major differential diagnoses need to be considered: Stx-HUS, thrombotic thrombocytopenic purpura (TTP) and aHUS. Stx-HUS can occur in the context of outbreaks of Stx-producing E coli, or individually. Cases should be confirmed or excluded on the basis of stool culture and Stx-PCR (Table 1).

TTP occurs when deficiency in a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), an enzyme that usually cleaves von Willebrand factor (vWF), results in unusually large vWF polymers that trigger platelet aggregation.⁵ ADAMTS13 activity measurement must be performed on a blood sample taken prior to commencing plasma exchange (PEX), with a level <10% diagnostic of TTP.⁵ It has been suggested that TTP and aHUS can be presumptively distinguished on the basis of clinical evidence prior to the availability of the ADAMTS13 result, with a serum creatinine of >150–200 μmol/l or a platelet count >30,000 mm³, virtually excluding a diagnosis of severe ADAMTS13 deficiency.⁶

Complement analysis in cases of aHUS should include serum levels of C3, C4, CFH, and CFI. Low C3 levels are seen commonly in patients with mutations in complement genes and may point to a complement-mediated process. However, normal C3 levels do not exclude the presence of a mutation in, or autoantibodies against, the complement system.² A full biochemical and genetic analysis of the complement system is warranted in aHUS (Table 2).

Other causes of renal TMA which can be excluded with specific investigations include the antiphospholipid syndrome, systemic lupus erythematosus, HIV, systemic sclerosis and cobalamin C disease^2,5 (Table 1).

A renal biopsy is not always undertaken – the risk of bleeding complications must be considered – but histological evaluation in aHUS will demonstrate platelet and fibrin thrombi occluding glomerular capillaries and sometimes fibrinoid necrosis.²

Clinical presentation

Presenting symptoms in adults are sudden and include complications of AKI such as biochemical derangement, volume overload and hypertension. Extra-renal manifestations are reported in 10–20% of individuals with aHUS, with neurological symptoms being the most common and comprising a range of symptoms including irritability, seizures, visual abnormalities and coma.^2,3 It may be difficult to differentiate between cerebral TMA and sequelae of severe hypertension, in which case brain magnetic resonance imaging can be helpful.^2,3 Other extra-renal manifestations have been described, including myocardial infarction, digital ischaemic gangrene, ocular involvement, pancreatitis and pulmonary haemorrhage.^2,7

Penetrance and triggering events

The age of onset of aHUS varies, ranging from the neonatal period to adulthood, with approximately 40% presenting for the first time in adulthood.³ In addition, incomplete penetrance has been reported for all of the genes associated with aHUS.² Penetrance is influenced by genetic modifiers, such as common single nucleotide polymorphisms and mutations, as well as environmental modifiers.² Environmental factors include infections, pregnancy, drugs and diarrhoeal illnesses, and are thought to precipitate aHUS by triggering the alternative complement pathway, which in genetically susceptible individuals cannot be regulated appropriately.²

Loss of function mutations

Activating mutations

In recent years, activating mutations in C3 and CFB, complement components from which the amplifying C3 convertase is comprised, have been described. C3 mutations are found in around 2–10% of aHUS cases, whereas CFB mutations are rare.^16,17 They result in increased C3 convertase activity and consequently greater complement mediated damage to glomerular endothelium.¹⁸

Autoantibodies

Acquired, as well as genetic, abnormalities have been described in the pathogenesis of aHUS. In 4–14% of aHUS patients (and reportedly a higher proportion of paediatric patients), autoantibodies to CFH have been identified.^19,20 Autoantibodies to CFI have been reported but are rare. Functional studies have indicated a pathogenic role for CFH autoantibodies²⁰ but there is no convincing evidence for direct pathogenicity with CFI autoantibodies.²¹

Pharmacology

Eculizumab is a humanised recombinant monoclonal antibody that binds with high affinity to human complement component C5^6,7 and prevents cleavage of C5 into C5a and C5b, thereby inhibiting complement pro-inflammatory and lytic activity.^6,7 The drug was designed to be minimally immunogenic, with a hybrid heavy chain comprising IgG2, which does not bind Fc receptors, and IgG4, which does not activate complement.

Eculizumab is administered intravenously, and achieves complete complement block-ade when its serum concentration reaches 35 μg/ml. It was first approved for treatment of paroxysmal nocturnal haemoglobinuria (PNH).^6,7

Use of eculizumab in aHUS

The successful use of eculizumab in aHUS was first reported in two separate case reports published in 2009. More promising case reports followed, which led to two non-randomised prospective trials published in 2013.

The first trial included 17 patients with progressive TMA resistant to PEX, and the second included 20 patients with aHUS who were being maintained on long term PEX.²⁵ In these trials eculizumab was shown to be effective in inducing haematological remission and was associated with significant time-dependent improvement in renal function.²⁵ Eculizumab is now considered optimal treatment for aHUS.

Eculizumab in kidney transplantation

Historically, the overall outcome of renal transplantation in patients with aHUS is poor, largely because of recurrence in the allograft. In one cohort the mortality was 7% and graft failure was 50% after 5 years post-transplantation.²⁶ Recurrence risk is predicted by genotype, with the highest risk associated with CFH mutations and the lowest with CD46 mutations, because allograft cells express functional CD46.^26,27

For patients with defects in complement components that are synthesised in the liver, a combined liver–kidney transplant is a logical strategy which has been successful in conjunction with PEX, although mortality is higher than would be expected for kidney transplantation alone.^5,27

Eculizumab has been successfully used prophylactically at the time of renal transplantation in individuals at high genetic risk of recurrence, and as rescue therapy for aHUS recurrence post-transplantation. Because of this, eculizumab is considered the gold standard in renal transplantation in aHUS patients.

Adverse effects of eculizumab

The membrane attack complex is key in the defence against encapsulated organisms, and patients with congenital C5 deficiency experience recurrent Neisseria meningitidis infections;⁶ this is therefore a fundamental concern in patients receiving eculizumab. In clinical trials of eculizumab in PNH, the Neisseria infection rate was 4.2 cases per 1,000 patient-years.⁶ Current practice is to administer the meningococcal vaccine and long-term prophylactic antibiotics to patients receiving eculizumab.⁵

The consequences of long-term eculizumab are not yet known. It has been reported that renal biopsies in patients on eculizumab have shown evidence of ongoing C3 deposition, as well as eculizumab deposition in the kidney.²⁸

Economics of eculizumab

A barrier to the widespread use of eculizumab is the very high cost. NHS England's economic analysis suggests that the discounted incremental cost-effectiveness ratio for eculizumab, versus standard care, is around £521,000 per QALY gained for a 23-year-old cohort.²⁹

Eculizumab treatment failure

With its increasing use in clinical practice, it has become clear that in rare cases disease will break through despite adequate eculizumab levels. In a Japanese PNH population, a single nucleotide polymorphism in C5 at amino acid R885 resulted in a failure of complement blockade.⁷ Additionally, in around 30% of familial aHUS cases no complement defect has been detected. Recently, mutations in diacylglycerol kinase-epsilon (DGKε) have been reported in aHUS.³⁰ DGKε is part of an intracellular signalling cascade and although its role in the pathogenesis of aHUS has yet to be fully elucidated, it is not thought to participate in the complement system. In keeping with this, several individuals with mutations in DGKε have failed to respond to eculizumab.³⁰

Unanswered questions

It is not yet clear what the optimal duration of eculizumab treatment is, and when – if at all – it might be appropriate to discontinue it. There are anecdotal reports of aHUS relapse when eculizumab was discontinued and when doses were delayed or missed.^7,25 A trial of eculizumab withdrawal in aHUS is required.