Decision Process: Discontinuing aHUS Treatment 

Article No 441

18 June 2021

     What topics and questions are likely to frame conversations about treating patients who have atypical HUS? Since aHUS diagnosis begins with ruling out medical conditions with similar symptoms and clinical profile, a diagnosis of exclusion, delayed diagnosis for aHUS often results due to this lack of a single and definitive test for this very rare disease. 

     Whether a slow ramping up with vague symptoms or a sudden and life-threatening aHUS episode, patients and those who treat them begin with consideration of treatment options then move toward finer points to include duration of treatment. For decades the only treatment available for atypical HUS was some form of plasma therapy: infusion (adding units of donor plasma) or plasma exchange to replace the patient’s plasma component of their blood with donor plasma (aka apheresis, pheresis, or plasmapheresis). As noted in a 2019 article by Yadav et al, “Plasma exchange (PEX) remains the standard therapy for the management of atypical hemolytic-uremic syndrome (aHUS) in regions where eculizumab is not available. Where even PEX is not feasible or afforded, patients are managed with plasma infusion (PI).”

     Treatment for atypical HUS took a leap forward in 2011 with the approval of eculizumab by the U.S. Food and Drug Administration to treat aHUS patients. Although approved in 2014 in England and subsequently for other nations, more than two-thirds of the world’s aHUS patients do not have access to eculizumab or the next-gen therapeutic drug ravulizumab in either version (all three produced by Alexion Pharma). Originally this new class of drugs, or complement inhibitors, was thought to be needed as a ‘lifelong drug’ due to the genetics of atypical HUS and the likelihood that aHUS would recur with what was then little understood as “relapse risk”. More is known about atypical HUS, complement activation, and damage from tiny clots resulting from thrombotic microangiopathy – but many more questions need answers regarding aHUS relapse risk and patient monitoring.

     Some aHUS treatment options are limited. Some patients do not respond to plasma infusions or exchange. Physicians in a majority of the world’s nations face restrictions on drug access or lack the ability to prescribe complement inhibitors at all, due to their high cost or their country’s rare disease policy (see our guest article by two physicians in South Africa). Patient clinical profiles range widely in severity and organs affected, and sadly outdated information and misperceptions about aHUS basics continue to float about the internet. 

     Atypical HUS genetics and wide variations in terminology for complement and thrombotic microangiopathy can be stumbling blocks as well. Use of ‘p-aHUS’ for pregnancy triggered aHUS is usually accepted, but use of CM-aHUS for complement mediated aHUS is a bit obscured given “nomenclature make interpretation difficult: aHUS may refer specifically to complement mediated TMA, or be more loosely applied to any TMA that is not TTP or STEC-HUS.” (Brocklebank et al, 2017) Complement doesn’t seem to be implicated for all cases of aHUS, as S Quaggin noted in DGKE and aHUS “Notably, mutations in DGKE are not associated with activation of the complement pathway.” Regardless of treatment or genetics, questions surrounding discontinuing treatment often include topics such as these:

*We’ve been told that atypical HUS is due to a genetic flaw, and since that fact is unchanging over time, will aHUS treatment have to be a lifelong issue?

*If I stop treatment, what’s the risk of an aHUS relapse?

*I’ve seen a bit of information about other options to treat my aHUS. If I consider a switch in treatment, how do I (and my doctor) find out the latest research as well as the pros & cons of switching? 

*Are certain genetic profiles more likely to have their aHUS recur?

*If I’ve been in remission for awhile, how can my doctor and I obtain information on new aHUS drugs in clinical trial?

*What might be a trigger for aHUS activity into ‘ramping up’?

*Is there a window of time or ‘sweet spot’ during which early detection of aHUS activity can be spotted, preventing the most severe forms of damage to major organs or body systems?

*Since I’ve had a kidney transplant, I know aHUS can recur and attack my new kidney. Does this mean I have to stay on a complement inhibitor forever?

*If I was healthy until my pregnancy triggered atypical HUS, does that mean I’m at less risk to discontinue treatment as aHUS may be less likely to come back?

*How do you define ‘remission’ from aHUS activity, and when my aHUS episode has subsided?

*What kind of follow up monitoring will my doctor do so that we’re sure there’s no ‘smouldering’ or low level aHUS damage happening? What can I do at home to be vigilant about aHUS activity?

     Why a complement inhibitor to treat aHUS, and its ability to reduce the chance of a potential relapse? Comprised of nearly 60 proteins, the complement system is part of the body’s immune response which removes dead cells and foreign matter while fulfilling a major role in protecting the body from infection. Some people’s genetic makeup is such that these ‘protector proteins’ to stop complement are deficient in some way. People with atypical HUS experience clotting (thrombotic microangiopathy or TMA) within small blood vessels & resulting organ damage from complement activation, which can attack the body’s own cells. Given the unpredictability of severity and frequency of aHUS episodes or relapses, one can understand reluctance of families and medical personnel to venture into the unknown of discontinuing treatment. 

     Common sense and a holistic view of the patient both need to be factored in. People may forget that aHUS patients have lives filled with relationships, school or work commitments, and plans for the future. If your teen is going to college, timing of discontinuing treatment will include nearby medical facilities and self-advocacy – or perhaps a summer job at home to ensure ease of monitoring and a familiar healthcare team. If your household is moving to a new city, it’s difficult to connect with a new medical team then start a discussion on discontinuing treatment when your specialist doesn’t have a sense of your aHUS journey. Conversations about stopping aHUS treatment will have different tone and content for those with severely limited kidney function or for those on dialysis. Many aHUS patients have no or restricted access to a complement inhibitor, but still others are overwhelmed by their high cost or other patient/family economic burdens. Geographic location can impact treatment access as well, with some aHUS patients finding it a stretch to leave work or home to travel to a healthcare center serving specialist needs. Situations matter.

     A major consideration is ‘patient monitoring’, an area which needs more study and subsequent development of guidelines. Urine dip strips can be utilized for home testing, to provide trace evidence of hemolyzation as an early identifier of aHUS relapse (Brambilla et al, 2021). Clinical trials for complement disease and for thrombotic microangiopathy – which may include aHUS patients – often mention endpoints for improvement of platelets, LDH, and creatinine levels but need to better define what constitutes successful levels of complement blockade or a complete TMA response. At what point would total complement activity (such as CH50) or complement protein C3 and C4 assays be run, and with what testing frequency? What are the differences in monitoring patients on different treatments, or specifics to watch such as Cataland et al noted regarding CH50 and ravulizumab, “In clinical practice, this has potential to cause different interpretations of complement blockade and highlights the important limitations of CH50 as a technique for assessing complete terminal complement blockade in patients receiving ravulizumab.” From Willrich et al 2021 on monitoring ravulizumab, given that “Ravulizumab is a C5 inhibitor with 4 amino acids difference from eculizumab in the heavy chain region of the monoclonal antibody.” it isn’t surprising that “The effect of ravulizumab in complement routine laboratory tests is slightly different than eculizumab.”

     The aHUS community is most fortunate to have multiple studies underway on the topic of determining optimal duration of treatment, and to understand what ‘safe withdrawal’ means for those treated with a complement inhibitor.  We are eager to learn more about upcoming clinical trials for new types of aHUS therapeutic drugs, as well as drugs currently in pharma pipelines with potential to be delivered via shot or pill. We are grateful for – and look forward to learning more from – the research teams, clinical trial leads, and clinicians around the world for their dedication in finding answers and working toward better aHUS patient outcomes. 


Studies on treatment withdrawal are being conducted in multiple nations, to include the France, Italy, the Netherlands, and the UK.  Below are some of the research publications on this topic, and some of the original content by aHUS Alliance Global Action team.

There are some websites specific to discontinuing treatment or studying optimal dosing, such as CUREiHUS (NL) and SETS aHUS (UK), but much more exists outside this overview so we encourage readers to delve deeper into expert opinion and research.

*Our 4 part series on aHUS Relapse: A Family View  (from Recognizing Warning Signs to Patient Monitoring)

*KDIGO Reports (Jan 2023)  Noris M & Remuzzi   Eculizumab-Every Fifteen Days Forever?  An article with a literature review that includes 280 aHUS patients from 40 publications

Stopping Eculizumab: On Treatment Withdrawal

Evidence Helps Eculizumab Access

Eculizumab Withdrawal – Safe & Reasonable?

Eculizumab Withdrawal Risk Profiling (Acosta  Medina Group, re TMA at ASH20)

StopEcu: The French Study Reports

Withdrawal Evidence Patients Need to Know

aHUS  “A Constellation of Symptoms”

aHUS Relapse:  A Family View (3 part Series)


Ravulizumab:  Cost effectiveness & Patient Quality of Life

Eculizumab aHUS Treatment:  PESaM

Ravulizumab Costs Less over a Lifetime

Is Ravulizumab Affordable for aHUS?

aHUS Community Answers the Call

On Clinical Trials

Clinical Trials Watch, series:  Updates & News  (part of our aHUS Key Resources page)

Breaking Down Barriers in aHUS Clinical Trials

2020 aHUS Therapeutic Drug Overview

RESEARCH Publications

Discontinuing Treatment / Relapse

Atypical HUS Research & Publications   A ‘virtual library’ of 1,000+ aHUS-specific research, organized by topic such as: Diagnosis, Treatments, Critical Care, Pregnancy, Multi-Organ Involvement, Discontinuing Treatment/Relapse and More. 

An entire scroll is specific to this topic, to include this sampling:

Acosta-Medina, et al, 2020  Determination of Relapse Risk By Complement Gene Variants after Eculizumab Discontinuation in Complement-Mediated Thrombotic Microangiopathy: A Retrospective Review

Ardissino, et al, 2014  Discontinuation of eculizumab maintenance treatment for atypical hemolytic uremic syndrome: a report of 10 cases 

Brambilla et al. 2020  Haemoglobinuria for the early identification of aHUS relapse: data from the ItalKId-HUS Network

Brodsky et al. 2021  Eculizumab and aHUS: to stop or not

Chaturvedi et al, 2021  Outcomes of a clinician-directed protocol for discontinuation of complement inhibition therapy in atypical hemolytic uremic syndrome

Duineveld et al, 2020  Outcome of atypical haemolytic uraemic syndrome relapse after eculizumab withdrawal

Fakhouri et al, 2020  Eculizumab discontinuation in children and adults with atypical haemolytic uremic syndrome: a prospective multicentric study

Fakhouri et al, 2016  Pathogenic Variants in Complement Genes and Risk of Atypical Hemolytic Uremic Syndrome Relapse after Eculizumab Discontinuation

Macia et al, 2017  Current evidence on the discontinuation of eculizumab in patients with atypical haemolytic uraemic syndrome

Menne et al, 2019  Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study

Laurence et al, 2020  Defining Treatment Duration in Atypical Hemolytic Uremic Syndrome in Adults: A Clinical and Pathological Approach

Neave et al, 2019  Atypical haemolytic uraemic syndrome in the eculizumab era: presentation, response to treatment and evaluation of an eculizumab withdrawal strategy

Olson et al, 2018  When to Stop Eculizumab in Complement-Mediated Thrombotic Microangiopathies

Quiroga et al, 2016  A Case Report and Literature Review of Eculizumab Withdrawal in Atypical Hemolytic-Uremic Syndrome

Sahutoglu et al, 2016  Can eculizumab be discontinued in aHUS?

Wetzels and van de Kar, 2015  Discontinuation of Eculizumab Maintenance Treatment for Atypical Hemolytic Uremic Syndrome

Willrich et al, 2021  Monitoring Ravulizumab effect on complement assays

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