aHUS/TMA Expert Q&A

Ahead of aHUS Awareness Day, Dr. Richard Burwick answers questions about the disease.

Dearest readers,

This week September 24th is aHUS Awareness Day. In advance, I’d like to introduce you to a very special person - Dr. Richard Burwick. In a sea of chaos, he was such an insightful and kind resource while I was in the hospital. And I’m lucky he was on the team, because he’s an expert in aHUS and TMA.

It was a common refrain when I was in the hospital for Zach to ask me, “What does Dr. Burwick think?”

So for all of you, especially my aHUS community, I’d like to share what Dr. Burwick thinks!

Please share with anyone you think would find it useful.

He’s no longer my doctor, but now I get to call him my friend.

When did you first hear about aHUS? Do you remember your first case?

I first started to learn about aHUS when I started my fellowship in Maternal Fetal Medicine (high-risk pregnancy) at Brigham and Women’s Hospital in Boston, in the summer of 2010. I had a fantastic mentor, Dr. Bruce Feinberg, who taught me about complement proteins, and their potential role in the development of pregnancy disorders like Preeclampsia and HELLP syndrome. As it turns out, these obstetric conditions are very similar to aHUS, and like HELLP syndrome, there was initially no good treatment for aHUS. But in 2011, the first complement blocker (eculizumab) was FDA-approved for treatment for aHUS, and this gave me tremendous hope for patients not only with aHUS, but also those with Preeclampsia and HELLP syndrome.

I remember very well the first case of pregnancy-associated aHUS that I treated myself. It is not common for an OB-GYN to treat aHUS, since such treatment is usually directed by a Hematologist or Nephrologist. But over the years, I have gained a lot of clinical and research experience with the disease aHUS and the complement inhibitor eculizumab. I was working at Cedars-Sinai in Los Angeles at the time, around 2018, and we had a postpartum patient that was very sick and had kidney failure. She was in and out of the intensive care unit, and it seemed likely that she would go home on dialysis. But when I reviewed the case, it was clear that she had aHUS, triggered by pregnancy. I started treatment with eculizumab and she responded very well, coming of dialysis completely, with full recovery of her kidney function.

What do you find most fascinating about the disease?

I am a bit reluctant to refer to it as fascinating, since aHUS is such a terrible disease, but it is truly fascinating in many aspects. First, it is a very rare disease, so it is not easy to detect and the diagnosis is easily missed even among experts. That draws me in as a clinician, because I need to be on high alert for this disease, like a needle in a haystack, to look for signs and symptoms of aHUS that others may have missed. Second, there is a clear-cut and effective treatment, complement inhibition. This is the most important. Since there is a treatment, and since that treatment is very effective when started in a timely fashion, it is critical that we diagnose and treat aHUS quickly. With my unique background in complement proteins, and use of complement inhibitors, I feel great responsibility to identify this disease and to fight for treatment of it, even when others express doubt or hesitancy in making the diagnosis.

What advancements are you looking forward to for folks with this disease?

I look forward to more advancements in treatment of aHUS. We have seen tremendous growth in therapeutics that target the complement pathway, but yet we only have C5 inhibitors approved for use at this time. C5 inhibitors like eculizumab and ravulizumab have also been very expensive, which has limited patient access. There are therapeutic biosimilars to eculizumab that have been approved recently, and it will be interesting to see if this will improve patient access and reduce costs of treatment throughout the world. There are also advancements in complement therapies that may be given subcutaneously, or even in pill form, and these options will expand ease of use and administration.

I know you specialize in Preeclampsia - Can you talk about your work and how complement inhibitors might play a role in treating the condition?

Yes, thank you. As I mentioned earlier, my research on complement proteins and use of complement inhibitors for Preeclampsia and HELLP syndrome is what initially brought me into the world of aHUS. As you may know, there is no existing treatment for preeclampsia and HELLP, other than delivery. But this often leads to delivery of a very premature neonate. My colleague Dr. Bruce Feinberg and I, along with others, have published research studies showing that dysregulation of the complement pathway is critical to the development of preeclampsia and HELLP, and complement inhibition may be a useful treatment. In 2012, Dr. Feinberg and I were the first in the world to treat preeclampsia and HELLP syndrome with the complement inhibitor eculizumab. It was very effective, and outcomes for mom and baby were very good.

But this was only a single case and much more data is needed. The reality is that drug cost, and the difficulty of performing clinical trials in pregnancy, remain major hurdles. However, there remains a tremendous body of work showing that the complement system is involved in the pathogenesis of preeclampsia and HELLP syndrome, quite similar to aHUS. I hope that soon we will get the clinical trials we need to determine if complement inhibitors can provide the same breakthrough for treatment of preeclampsia and HELLP syndrome that we have seen for patients with aHUS.

For doctors in the acute stages of the disease, what labs should the teams be using to help identify aHUS?

This may vary based on the underlying trigger or clinical setting, but the hallmark features of aHUS are microangiopathic hemolysis, thrombocytopenia and kidney failure. Thus, the initial diagnosis may be suspected with standard labs including a CBC (complete blood count) showing anemia and low platelet count, a serum creatinine which is often markedly elevated, and elevated serum LDH (lactate dehydrogenase) and low haptoglobin suggesting red blood cell hemolysis. Further work up for hemolysis may include a peripheral blood smear to look for schistocytes (which is characteristic feature of microangiopathic hemolysis). Other more advanced studies may be helpful including a kidney biopsy to detect TMA, or complement genetic testing to detect a pathogenic variant (but this testing is expensive with a long turnaround time, and normal results don’t rule out aHUS). We do not yet have a definitive blood test to confirm complement mediated TMA and aHUS, and so it remains a clinical diagnosis. But hopefully in the future we will have additional options available.

What recommendations would you make for maternal fetal medicine teams in dealing with a possible case of aHUS?

Many maternal fetal medicine doctors are unfamiliar with aHUS, even those cases triggered by pregnancy. But it is critical for maternal fetal medicine doctors to recognize signs of aHUS, and to alert other subspecialists, such as Hematologists or Nephrologists, when a patient is experiencing rare and unusual complications. For example, it is very rare to have persistent kidney failure after delivery, and Maternal Fetal Medicine doctors should recognize this as atypical and advocate strongly for expanded diagnostic work-up in such cases. As pregnancy specialists, it is our job to advocate for our patients to be certain they obtain the correct diagnosis and treatment, with the hope for a full recovery.

Is there any definitive answer about how to diagnose pregnancy induced aHUS vs HELLP syndrome, in cases where symptoms tend to overlap?

I am always cautious to say any diagnosis is definitive, but I would say yes, there a few ways that the diagnosis of aHUS can be distinguished from HELLP syndrome. First, in nearly all cases, HELLP syndrome resolves shortly after birth because the treatment is delivery. Second, aHUS usually gets worse after delivery rather than better. With aHUS we usually see progressive kidney failure after birth which is not a characteristic feature of HELLP syndrome.

In my research, I have found that when hemolysis and kidney failure persist for more than 72hr postpartum, the diagnosis is aHUS over 95% of the time. The diagnosis can be confirmed in the setting of thrombotic microangiopathy on a kidney biopsy, since that finding is also not expected with HELLP syndrome. Finally, complement genetic testing may discover a pathogenic variant that is known to be causative of aHUS, but this finding is not required.

How often do you see cases of aHUS in your work? What hallmarks seem common in the experiences between patients?

Overall, aHUS is a rare disease and I may see 1-2 new pregnancy-associated cases of aHUS per year, for every 5-6,000 deliveries. Unfortunately, there are no clear hallmark features that predispose to disease. It can occur in anyone of any age and any race/ethnicity. It is slightly more common in first pregnancies, but it may occur in subsequent pregnancies as well. There are certain risk factors, as aHUS occurs more often following pregnancy complications such as preeclampsia, postpartum hemorrhage, and fetal death. For patients with unusually complex disease after birth, especially those involving kidney failure, the diagnosis of aHUS should always be considered as a possibility.

For caregivers, what are important things to keep in mind while advocating for patients with possible aHUS?

If caregivers suspect a diagnosis of aHUS, they must be a strong and committed advocates. There may be disagreements on the diagnosis, and there may be hesitation to perform kidney biopsy or to send complement genetic testing. There may also be strong resistance to treatment, since the drug is expensive and there are infectious risks. But, drugs for treatment of aHUS are FDA-approved because they are very effective at treating the disease and preventing end-stage kidney disease and kidney transplant. Treatment of aHUS can make a tremendous impact on a patient’s life and well-being and it is critical that caregivers advocate for their patients. The difference between treating aHUS with complement blockers, compared to treatment with dialysis alone, is tremendous and we must advocate for prompt treatment to improve long-term health outcomes and quality of life.

aHUS patients are always wondering if they can go off-drug. What should patients keep in mind when making this important decision?

It is very possible to go off-drug in patients who are in remission from their disease, but this decision should be made using shared decision making with their healthcare provider. Technically, aHUS does not go away, because the predisposition is always there and the disease may be triggered by multiple factors such as pregnancy. But, many patients with aHUS respond well to treatment with complete normalization of their lab parameters and kidney function. For patients who have received at least 6 months of treatment, and who are in clinical remission from their disease, they may consider a trial off therapy. While off therapy, a careful monitoring plan should be coordinated with their caregiver.

Many aHUS patients dream of having children after diagnosis. What would you say to them? Would you recommend that someone who has gone off complement inhibitor treatment for aHUS but gets pregnant to go on Soliris for all or part of the pregnancy?

This is an important question and unfortunately no simple answer. Any patient with a diagnosis of aHUS considering pregnancy should speak with a high-risk pregnancy-specialist with experience in this area. There is a high risk for recurrence of aHUS during pregnancy or the postpartum period, particularly if the initial diagnosis of aHUS was triggered by pregnancy.

There is also a very high rate of pregnancy complications such premature birth, preeclampsia and fetal loss. The risk of recurrence, and pregnancy complications, can be reduced with medications such as eculizumab (soliris) but they cannot be completely mitigated. Many of my patients who wish to have children after a diagnosis of aHUS choose surrogacy (gestational carrier), which I agree is the safest option for the patient to avoid the risks of pregnancy with aHUS. For patients who have a strong desire for pregnancy after aHUS, I do recommend eculizumab (soliris) throughout pregnancy and the postpartum period.

One word of caution, I recommend against ravulizumab (ultomiris) during pregnancy and lactation, because its safety is unknown and eculizumab is a better alternative. This is not widely recognized, but it is likely that ravulizumab crosses the placenta and into breastmilk posing risk to the fetus and newborn. Eculizumab, due to its unique design, has not been detected in breastmilk and only crosses the placenta to a minimal degree without impacting the complement system of the newborn. Thus, the safety data is much stronger with eculizumab for pregnancy and breastfeeding.

Many folks have a gene for aHUS, but so many do not. Can you explain what we know about why that’s the case?

It is estimated that 60-70% of patients with aHUS have a known genetic variant associated with the disease. Usually these are abnormalities in genes that control the complement pathway, leading to excessive activation of the complement pathway. But the genetic abnormality is not usually enough to cause disease by itself, and many people do not show signs of aHUS until later in life, often in response to a specific stressor such as pregnancy. For those with aHUS, but without a genetic mutation, it does not mean that they have a different disease. It only means that we don’t know yet know the genetic cause of their excess complement activation, and it remains to be discovered.

Anything else you’d like to share or promote? Are you speaking or attending any conferences soon where folks can connect with you and your work?

I am a member of the Foundation for Women and Girls with Blood Disorders and recently attended the annual conference and spoke about pregnancy TMA. I would encourage others to look into this wonderful foundation and its mission to address blood disorders throughout life, from childhood and adolescence to pregnancy and adulthood. I also have worked with the National Kidney Foundation, and aHUS Alliance, to help advocate for pregnancy TMA and aHUS. These are fantastic groups and I encourage others to get involved with any and all of these organizations if they have an interest in this area. I can be reached through the aHUS alliance clinician network on their website, or through my social media account on X @richardburwick.

Thanks Dr. B! Readers, please share with your aHUS community, medical professionals, and midwives/doulas in your world ahead of aHUS Awareness Day this Tuesday.

More on aHUS:

Welcome to my disease. What is atypical Hemolytic Uremic Syndrome (aHUS) or Complement-Mediated Thrombotic Microangiopathy (CM-TMA)?

I started writing this when I was on dialysis. It’s intended to be both memoir and a practical tool to help folks who might be going through something similar or those caregivers and family supporting someone with a challenging diagnosis. NOTE: This is not intended to replace actual medical guidance. Please consult your doctors on your individual challenges and situations. Please talk to your clinicians before adjusting any of your care protocols. Also names have been changed for most of my medical staff.

Special thanks to new paid subscriber Dana Wood Aka the Carole King of Zach’s students. Your support means so much.

Thank you to CC Couchois, Roy Lenn, and Dr. Richard Burwick for your founding level donation.