An aHUS research agenda case study

Last summer an aHUS awareness article appeared in the magazine of the charity Kidney Research UK. ( see article here).

Ostensibly it is about aHUS and pregnancy which is one of the top topics for discussion in the aHUS community.

So much so that the “pregnancy trigger” is a separate question on the Global aHUS Patients ‘ Research Agenda.

Do aHUS Families have all the correct  information needed to make informed family planning decisions?

But this article , although addressing the pregnancy research question, illustrates so much more about  why aHUS patients have developed the research agenda they have now. It is a case study for the agenda itself.

The aHUS Patient’s story is that from an early age she had kidney problems which continued throughout her childhood and then gradually as an adult led to end stage Renal failure needing renal replacement therapy.No reason for the kidney failure is given in the article ,nor whether the patient experienced a life on dialysis, until she gets a living donor transplant from a family member. Two years pass and her kidney graft begins to fail. In looking for reasons for that, she is diagnosed with aHUS. She receives eculizumab. It works. A few years pass and the now  aHUS patient,  with a still functioning transplant seeks to start a family. Advice is sought and although contradictory it  is followed by a pregnancy which runs into problems half way through and in the third trimester and the baby is born prematually. Mother and child recover eventually. The family are now happily settled to the new life.

The first topic to consider:

Was there a diagnosis sweet spot which could have been found before a developing thrombotic microangiopathy  turns into a catastrophic episode of aHUS?

The catastrophic episode happened two years after a transplant. The timeline in diagnosis is not clear but it is likely that a TMA had been identified  The prescription of eculizumab suggests that it was independently confirmed , although no mention is given  of whether a corroborating  significant genetic variant or antibody was found.The patient’s original kidney failure did not happen suddenly it took decades. No explanation is given for that,  or , with hindsight,  was there was anything about this which could have suggested there had been an underlying TMA .

A sweet spot.

There may have a diagnosis at that time, but it was not aHUS. If she had been diagnosed with aHUS she would not have got eculizumab to support a transplant , it was not available at that time, and even if it had been a living donor would not have been permitted without genetic tests because of the risk of “de novo” aHUS in the donor.

Another Agenda topic is pertinent here.

Are the predisposing genetic and triggering factors of aHUS fully catalogued and understood and will it help to know how variable are the risks of these between individuals.

Transplant is a known triggering factor of aHUS and there are risks . If other family members are involved, knowledge from genetic testing could benefit potential donors.

In this “blind to aHUS” case another research topic is relevant.

Is there a significant difference in outcome between having a complement inhibitor before or after a kidney transplant.

Without a diagnosis , but predisposed to aHUS,  the patient had a transplant. For her there could be no conscious decision about supporting it with eculizumab or not. The patient falls into the third category of aHUS transplant  patients – the undiagnosed- potentially at risk of the worst of clinical outcomes as recent evidence now shows.

Fortunately in the time from when the transplant operation took place in 2011, and 2013 ,when the catastrophic episode began, her country had introduced an interim policy(  not by NICE as the article claims , it would take another two years and a lot of work for NICE to make its decision ) for prescribing eculizumab  and  she would get rescue therapy. Otherwise the kidney graft  would have been lost like others  had experienced before.

For her there was an answer to ” Can a clinically efective therapy be developed that is affordable for all aHUS patients”

Eculizumab would have been there for the donor too in 2013 if “de novo aHUS” had ocured , but fortunately it was not needed.

It would seem that the patient’s  clinical outcome with rescue therapy was not at the poorest end and life with the kidney graft moved along.

The next pivotal point arrived was when the patient wanted to start a family. She sought advice. Apart from the research topic referred to at the top of this article there are others which overlap.

Starting with the child’s chance of inheriting a predisposition to aHUS or even genetic testing of the foetus ( and what to do with that knowledge). Then whether eculizumab would be harmful to the foetus, if so whether  a temporary withdrawal from eculizumab was advisable given the risks of recurrence,  even if in remission. The patient has had a history of having kidney disease and had a transplant,  both of which have on going ailments and side effects independent of the aHUS issue. Would pregnancy require a different optimal dose strategy to normal complement “tick over” circumstances?

Whilst  most of these did have answers in 2015 it is unlikely that a non specialist clinician would know what they would be , it would need an Expert Centre expertise probably with contributions of advice from  a network of such centres. At that time even patient organisations would have had some answers. A couple of examples  of information available about pregnancy can be seen by clicking Kelly Brit J Hematol 2010 and Ardissino G et al. [ecu aHUS pregnancy]. Obstet Gynecol. 2013;122 487-9 and here

Is there an optimal way in which a complement inhibitor can be delivered to suit an individual’s need?

Is it more cost effective, as well as clinically effective, for the management of an aHUS patient’s treatment to undertake genetic testing?

Can a complement inhibitor be stopped safely when not needed by some aHUS patients and what makes them different?

Can the side effects of treatment using a Complement inhibitor be distinguisheed from those temporary and permanent on going ailments which follow initial onset.

Are  there long-term studies of outcomes of those in remission whether treated by a complement inhibitor or not?

Although a pregnancy went ahead it is not clear whether it was with or without eculizumab . But prior knowledge of an aHUS diagnosis was now a help. An aHUS /Eculizumab pregnancy for someone with a renal  transplant would need very close monitoring.

There was a problem, pre-eclampsia led to a premature birth 11 weeks before due date. If on eculizumab  then why was there an aHUS   breakthrough. If  not on eculizumab pregnancy is a very well known trigger, as is a transplant. Would withdrawal be  a safe strategy?   If  it was an aHUS  onset it did not happen when it would normally  be expected to i.e post partum. There are other reasons for TMA during pregnancy particularly at that time in a pregnancy. High blood pressure is not uncommon too .Why was” a big dose” of eculizumab given following birth? An adjusted dose suited to the post-partum circumstance maybe.

Mother and child recovered and the patients testimony gives some answers to  other topics.

Does the anxiety and self-esteem of aHUS patients vary significantly between treatment types and what can be done to reduce and boost them respectively.

How does living with aHUS impact on education and work?

The patient had experienced all treatment types dialysis ( possibly ) transplant and eculizumab. The testimony reveals her self esteem from being a nurse after completing education. Her child thrives and life is good.

But the testimony also reveals that the patient became aware of other aHUS patients like her at least as far as the “pregancy” topic is concerned and  something expressed by patients globally . How many aHUS patients  are there in my local area , my country and the world and how do they differ?”

Although the genetics of aHUS does not feature in the article the parents are clearly interested in the physical development of the child. It would not be unusual  to think as part of the development whether there might be an inherited predisposition to aHUS but whether to the family needs to know is a choice that they will make. That is why sufficient aHUS patients around the world thought this was also a topic for research.

When it comes to genetic testing of aHUS Family members what is best – to know or not to know – and what can be done with the knowledge?”

So an awareness article like this shows how individual aHUS patients from around the world working together have come up with a research agenda for aHUS patients. It is for one as well as for the many.

One topic not directly addressed in the article was “Will there be a cure eventually?”

It is implicit ,however, in what Kidney Research UK is and does.

Kidney Research UK is the leading charity for funding kidney research into prevention, treatment and management of kidney disease the U.K. It has done so for nearly 60 years.Through research funded by such charities more answers move us closer to a cure eventually.

KRUK holds a fund specifically for aHUS research

Donations  can be made directly to the aHUS research fund to help get further answers  to shape more lives throughout the world. ( Note:Donations in non £sterling may incur currency exchange  fees).

Click  on the picture to go to the donations page.)

You are not alone . We can find a way.