Someone has to be the first

Twenty years ago today, in 1998, an article appeared in Kidney International , the Journal of the International Society of Nephrology , which would be of enormous significance to those with aHUS , although the term “aHUS” does not feature anywhere in the article.

The article was about some clinical and genetic research undertaken by a young doctor, Paul Warwicker, under the direction of ,the then, Doctor Tim Goodship, from Newcastle upon Tyne in the UK.

Dr Paul Warwicker

By the mid 1990s there were a number of theories about the cause of aHUS ,and of which the article lists:

– allergic prostacyclin metabolism;

-unusual Von Willibrand Factor multimers;

-increased level of plasminogen activator inhibitor 1;

-the presence of platelet activator and agglutinator factor;

-increased Complement activity.

But no  one really knew which it was.

Although all these may be implicated in Thrombotic Microangiopathy  (TMA) , it is the last in the list which is perhaps best known to aHUS patients . This research was to be become pivotal in understanding aHUS as a Complement  Mediated TMA.

The study group also acknowledged that there was also a need for a trigger, not just by E.Coli 1057:H7 but others such as oral contraception, cyclosporine, quinine, pregnancy, tumour, connective  tissue disorders.

For decades kidney research specialists in Newcastle had been aware of a cluster of HUS occurrences in a family living in the County of Devon in the South West of England. With a population of less than 1 million people, the prevalence of aHUS patients could be expected to be no more than 2, but Devon had many more times that, mostly from one family.

Paul’s research  aims were to find out if there was anything genetic that could explain that, and if so , could it lead to some insight into the mechanism of the disease Haemolytic Uraemic Syndrome , the “typical” version as we could call it now, or STEC-HUS.

He produced a family tree for the subject family ; but while doing so he heard about another family living near  by who also had experience of several HUS onsets, and so he included them. No actual familial link was evident in the generations mapped but one was suspected from sometime in the past. He also heard about another one off HUS patient in a another  family.

At that time genetic testing was in its relative infancy and expensive, but Paul had access to a genetics laboratory run by another Doctor Goodship, Tim’s wife Judith. DNA tests were carried out. These tests were  not of the whole genome, but of genes relating to factors in the blood complement system which were suspected as causing the disease in some very rare members of the population. It was a “candidate gene” approach specifically of Complement Factor H ,which, although the group did not know specifically where it was located in the chromosomes, they  had an idea of where to look.

It is now known that some members of the two families did have a rare variant in that component of Complement , Complement Factor H. CFH was known to be regulatory protein to stop excessive and damaging Complement activation. The variant was in a part of the protein,  which was made up of 20 bits, ( or short consensus repeats made up amino such was the microscopic level that was being looked at) and  which  was needed to attach to other proteins in Complement to stop their excessive activation, but could not because part of it was defective.

The article describes in detail the protocols used to collect blood and tissue sample as well as the methods /technology used to analyse the DNA and how controls were put in place the  protocols to eliminate error, to ensure confidence in the accuracy of the results.

The variant in Complement Factor H that Paul and his collaborators found was described as:

c.3643C>G; p. Arg1215Gly

The “Arg” refers to Argenine which should have been present,  but it had been replaced by Glycine. The study team concluded that as Argenine was “polar” and Glycine was not, it  meant that CFH could not attract and stick to other complement components as it was intended to do. Those in the family that had the variant had onset with HUS, others with out it had not,although some carrying the predisposing mutation had not at that time.The variant was not seen in the test undertaken of a control group of non family members from the general population, which confirmed its rarity and significance for HUS.                                                                                                            Less well known was that study also found in one family some components of Complement which were related to CFH and had an effect on helping its performance – the so called Complement Factor H Related (CFHR)  proteins – had been deleted.

These findings represent the first reported molecular evidence of the involvement of Complement Factor H in the disease. Knowing this meant a search was needed for a complement inhibitor. A search which would lead eventually  to one that was already in existence at that time , eculizumab.

The group concluded quite correctly that, although it was abnormalities of factor H that they had shown to be associated with HUS in this study: it was possible that abnormalities of other regulators of the  alternative pathway, such as  complement factor I, could also be implicated.

There were, and by end of 2017 at least 413 variants had been found collectively for C3 , CFH, CFI and MCP many of which had a link to aHUS , including  a large number of the 193 for FH alone distributed over the 20 bits that make up FH. ( see table below) though most are to be found in that 20th SCR that Newcastle group had looked at 2o years ago.

Percentage of mutations in each domain of FH

No.Of Mutations Percentage
Introgenic Region 1 1%
SCR 1 11 6%
SCR 2 7 4%
SCR 3 3 2%
SCR 4 5 3%
SCR 5 1 1%
SCR 6 3 2%
SCR 7 6 3%
SCR 8 5 3%
SCR 9 6 3%
SCR 10 8 4%
SCR 11 8 4%
SCR 12 3 2%
SCR 13 7 4%
SCR 14 7 4%
SCR 15 15 8%
SCR 16 9 5%
Linker Region 16 1 1%
SCR 17 11 6%
SCR 18 7 4%
SCR 19 14 8%
SCR 20 44 24%

Source :UCL Complement Database of CFH variants click here for moreinformation

Although, now  so many significant variants implicated with aHUS  have been found by researchers ,someone had to be the first.

The full article can been seen by clicking here.

Where are they now?

PAUL WARWICKER  qualified as a Doctor and continues to practice as a Consultant Nephrologist at the East and North Hertfordshire Hospital Trust in Stevenage, Hertfordshire UK, He retains an interest in HUS.  ( Click here  to view a short video (58 seconds) of Paul speaking up on behalf of UK aHUS patients to get access to eculizumab)

TIMOTHY H.J. GOODSHIP, became an internationally  renowned researcher on Complement Mediated HUS/aHUS and a Professor at the Newcastle upon Tyne University. He was clinical lead in the successful evaluation process for eculizumab to be available to treat aHUS in the UK . He is now retired.

ROSEMARY L. DONNE continues to practice part time as a Consultant Nephrologist at Salford Royal Hospital in the North West of England  and continues to include HUS in her research interests.

YVES PIRSON, became a Professor of Nephology at the Clinique Universitaires, Brussels Belgium with a special interest in inherited genetic kidney diseases.

ANTHONY NICHOLLS nothing further known

ROY M. WARD, nothing further known

PETER TURNPENNY nothing further known

JUDITH A. GOODSHIP continued her work in genetics at Newcastle upon Tyne University and became a Professor of Genetics. She is now retired.