Personalised management of atypical haemolytic uraemic syndrome

Haemolytic Uraemic Syndrome (HUS) is a severe complication of infection with the bacteria E.Coli O157. In ~10% of patients kidney failure occurs due to a toxin released by the bacteria. Atypical HUS is a rarer form of the disease which is not associated with these bacteria and in many cases there is a genetic predisposition to the disease.
Work in Newcastle funded by the MRC previously identified that abnormalities in genes for complement proteins predispose to disease in around 50% of cases. The complement system plays an important role in protecting the body from infection by killing micro-organisms. If these complement proteins are faulty then the body's own kidney cells can be damaged by these same mechanisms. This key discovery ultimately resulted in the introduction of a drug which prevents complement activation, Eculizumab. This revolutionised treatment for patients with this condition and prevented them from developing kidney failure.
More recently we have identified a subgroup of aHUS patients who do not respond to this drug. In these families we are undertaking genetic analysis to identify the underlying cause and are identifying genes that do not appear to be involved in the complement pathway.
By identifying these novel genetic causes of aHUS and by defining simple blood tests that will quickly identify these patients we will prevent ineffective use of complement inhibitory therapy, avoiding the infectious side effects of this medication. Additionally, by identifying new pathways responsible for disease, new drugs can be developed to target these pathway resulting in the same translational benefits seen following our original discover. Ultimately this work will allow personalised treatment for our patients with aHUS.

Haemolytic uraemic syndrome is a thrombotic microangiopathy (TMA) characterised by the clinical triad of thrombocytopenia, microangiopathic haemolytic anaemia, & acute renal failure. The most common form of HUS is associated with a preceding diarrhoeal illness caused by verocytotoxin-producing bacteria, typically Escherichia coli O157:H7. Those not preceded by this infection are classified as atypical HUS (aHUS) (OMIM 235400). Work undertaken in Newcastle first identified the role of complement in aHUS with ~50% of cases carrying mutations in the complement system. This work ultimately resulted in the successful introduction of the complement inhibitor eculizumab into clinical practice. More recently, I have established a dichotomy in response to eculizumab, with a group of patients that do not respond.

I hypothesise that not all aHUS is complement driven and that by identifying individuals who will not respond to complement inhibition we will avoid prolonged exposure of such individuals to the infectious complications of terminal pathway complement blockade.

The patients will be classified into responders and non-responder groups and the adequacy of complement inhibition measured using in house complement haemolytic assays. Whole exome sequencing will be undertaken in those who do not respond despite complete complement inhibition. Using this method I have already identified 3 novel genes associated with aHUS. Where required in vitro analysis will be performed to confirm the functional significance of these rare genetic variants. I will then measure a series of aHUS related biomarkers to establish a predictive marker of eculizumab non-response. I will then confirm the lack of response to complement inhibition in an in vitro cell model of aHUS.

Patients

Until recently Atypical Haemolytic Uraemic Syndrome was a disease with high morbidity (~50% ESRF) and mortality (25%) at first presentation. Additionally for those reaching ESRF the high relapse rate following renal transplantation meant a lifetime on dialysis for these patients. In the late 1990s research in Newcastle elucidated the role of the complement in the pathogenesis of aHUS. This ultimately led to the successful introduction of the complement inhibitor Eculizumab into clinical practice via the NRCTC in Newcastle. This revolutionary treatment is redefining the natural history of aHUS with most patients now responding to treatment.
My work at the NRCTC has recently identified a subsection of patients who do not respond to Eculizumab and in some of these cases I have already identified a novel genetic cause by whole exome sequencing. Currently we do not have a rapid biomarker to identify these patients. My work will identify patients who will not respond to Eculizumab and thus prevent the infectious complications of complement blockade in this subgroup. The identification of novel genes for aHUS will also define new pharmacological targets in aHUS and is likely to lead to similar translational benefits to those from our initial description of the role complement in disease.

NHS Screening / Clinicians

The NRCTC comprises the UK National complement genetics screening laboratory, specialist NHS complement laboratory, genetic counselling services, aHUS clinical and treatment service and the university research lab is fully integrated into the centre. This allows a bidirectional knowledge transfer improving interpretation of genetic screening results and speeding up our translational research. My research will directly improve NHS genetic screening.

NHS / Policy Makers

By identifying those patients that will not respond to treatment, not only will we prevent the risk of ineffective complement blockade, but we will produce substantial cost savings for the NHS. The average cost of treatment with Eculizumab is £327,600 per person per year thus my work identifying non responders at presentation will result in large savings. By preventing only 8 months of ineffective treatment with eculizumab in one patient I will cover the cost of my fellowship.

Pharma

The NRCTC is the only national body regulating Eculizumab treatment worldwide. As such we have an unparalleled cohort of patients with clinical, immunological, genetic, treatment and outcome data. My data identifying biomarkers to predict non response will increase the granularity of our data. This will keep the NRCTC at the front of clinical trials in aHUS and complement mediated disease.