Article No. 408
7 January 2021
An aHUS onset is an anxious and exhausting event.
It may have bubbled under unnoticed for some time and then the symptoms appear. What is happening must be perplexing and worrying for those who had no idea about the disease and instantly alarming for those who did know.
Diagnosis leads to treatment. A clinical or family history of aHUS helps get that diagnosis quicker and therefore getting quicker on to treatment; but this is, more often than not, unlikely to be the case.
Going through the logistics of getting an effective treatment is not always straightforward.
These days for more and more, treatment means having an infusion of eculizumab to inhibit their complement and eventually the first eculizumab dose gets into the blood stream. What then?
I have got aHUS and have had a dose of eculizumab, so when do I get better?
It all depends, these things take time.
So you don’t know!
All I know is that the first thing is for eculizumab to do what it has been designed to do. And that is not to cure what ever it was that kicked off your aHUS in the first place ( your trigger ) nor repair the damage your own immune system has done to itself.
You saying my body did this to itself?
Yes but I will come back to that. Firstly eculizumab’s job is to find all the C5 in your blood stream.
Yes it is a part of your immune system called Complement. Normally C5 is no bother but when Complement is activated C5 has a job to do in any inflammation and immune response to something that is not right in your body ( caused by your trigger). In aHUS your C5 becomes the problem.
OK so what happens when eculizumab finds C5?
t sticks to it but in such a way that it can no longer be a part of that inflammation and immune response. The damage that C5 has already done was due to something called the Membrane Attack Complex (MAC) , that is something that C5 is pushed into creating. Sometimes it is pushed into doing too much and your body gets damaged . Eculizumab cannot stick to any C5 that is already a part of that attack complex , so for a while it will continue to cause damage. But if it sticks to C5 before it forms MAC , no new MAC is going to be created because eculizumab won’t let it happen.
How long will it take to find all C5.
You will have had a small dose of eculizumab and you will get another dose in a week. By day 3 after the first infusion eculizumab will likely have attached to a lot of the C5 that there was at the time of infusion and any C5 that the body has made in the three days since the infusion.
Three days, will I feel better then?
Not by then. Eculizumab does not remedy what triggered your illness nor the damage that your immune and other body systems e.g clotting has done to itself. So symptoms from those continue. Once bound to C5 eculizumab stops any new damage being done and by day 3 your doctor may see clinical signs that it is working.
What does my doctor see that I cannot?
Yes one of the clinical signs of your aHUS is thrombocytopenia. Yes “thrombocytopenia”, before you ask, thrombocytes are the platelets and penia means that there are little or none of them in the blood because your aHUS caused them to be used up quicker than the body can replace them. Those platelets contributed to the damage that has been done by causing clotting in the blood vessels. They are being replaced by your bone marrow but at its own pace, between 5000 to 10000 each day. The normal level of platelets for someone who is healthy is between 140,000 to 450,000. It may take 7 to 8 days or more to get back to normal levels. But importantly an increase in the number of platelets shows that the damage causing aspect of your aHUS is being brought under control. Now the damage done needs to be resolved.
Complement and platelets forming a clot on a damaged blood vessel- a thrombotic microangiopathy
What damage needs to be resolved and how is it going to happen?
aHUS is the result of uncontrolled complement due to genetic defects in parts of your Complement system. Or it could be your complement is not genetically defective but another thing is are just hampering control of yours. Your body has been damaged by your uncontrolled complement attack against your blood vessel lining including a response by your coagulation system. The damage that causes it , is then responsible for your red blood cells to deplete , bursting apart when trying to squeeze through blood vessels lined with micro clots which are closing the space for blood cells to pass through. This is haemolysis the H part of aHUS, the process is a thrombotic angiopathy (TMA). And the blood flow to your kidneys is hindered by the residue of the red blood cells some parts of the kidney are damaged, some irreparably, but some may come back having protected themselves. Your body is going to have to repair itself, but there may be some clinical interventions by your doctor.
How will I know things are getting repaired?
There will be clinical signs. You may find your doctors mention your LDH
Yes it stands for Lactate Dehydrogenase. When all is well, it is something that helps cells throughout the body. When those cells are damaged the LDH is released into the blood stream and the normal low levels become elevated and high. A high level is an indicator of damage. If LDH levels fall the damage is reducing.
When will LDH get back to normal?
In time. It could take between two to seven weeks after the first eculizumab infusion.
Will I feel better then?
You will be feeling better than you did before the eculizumab was infused. The catastrophic episode of aHUS is behind you, further damage is stopped and some damage repaired but the symptoms of anaemia and kidney failure , particularly if acute dialysis was needed, may take longer to resolve for you to feel much better.
What will resolve them?
Well ,in the case of the red blood cells to get back to normal the bone marrow will need to replace them at a higher rate than they are either are being used up or they are naturally degrading. The normal range of hemoglobin is between 12 to 18 grams/dL with different ranges for males and females and your aHUS may have depleted them to half those levels. One intervention you might get is a blood transfusion which raises your red blood cells temporarily and you feel better for it until your levels fall again. The gradual return to normal levels will take weeks to months ,even with out kidney damage, but it does not mean you will not feel better until then, there should be gradual feeling of improving. Some days it will be better than others.
But I do have some kidney damage?
Yes you would not have aHUS if there has been no symptoms of kidney damage. Some people will lose more than 85 to 90% of their kidney function ( as measured by eFGR ( estimated glomulerar filtration rate) when aHUS onsets. They will need dialysis. Their lost kidney function can return once the body, including the kidneys, clears the damage done ( as measured by LDH mentioned earlier) but also the high level of urea, a sign of kidneys not working, (hence uraemic in aHUS) or also creatinine in the blood begins to fall. Those needing dialysis will stop needing it. But there is “catch 22” the red blood cell destruction and damage to the lining of blood vessels led to kidney damage. But the kidney is important for the production of red blood cells by your bone marrow. Kidneys produce something, a hormone, that stimulates its production. Failing kidneys either do not produce it ,or not enough of it, so the replenishment takes longer.
Can anything be done about it?
It will come back naturally in time but your bone marrow can be helped with a synthetic version of the hormone, erythropoietin. You may hear your doctor mention EPO or Arenesp which comes in a syringe. Once delivered it can take up to 4 weeks before its effect is noticed.
But what about the condition that triggered my aHUS?
There is a good chance that has been resolved and that train has already left the station. If not it will need separate treatment. So too will those complement control hampering conditions you might have. Both the triggers and the hampering conditions may be occasional and transitory and not ongoing.
So these things take time and it depends on how much damage my aHUS does and what can be repaired .
Yes I agree with you?! And I have only covered the anemia and the renal failure, there may be other consequences of an aHUS onset, not least will be getting any high blood pressure under control , because damaged blood vessels and kidneys contribute to hypertension too.
It is your aHUS and so good progress to recovery will be yours too over the weeks and months after that first eculizumab infusion.
Although you may have not been aware of it at the time but there was underlying spiral downwards which resulted in your aHUS. Once rock bottom is reached there is progressive spiral upwards towards to feeling better.
And as you say it all depends and takes time.
Note: it is important that aHUS patients listen to their clinician’s explanation of what is happening during an episode of aHUS and the way it is resolved. This imaginary conversation is what a patient advocate might sayand may help with understanding. It does not replace medical advice or opinion.