CME Slides Forum - C. Loirat

A joint Congress by ERA-EDTA and ISN

INDICATIONS TO PLASMA INFUSION AND PLASMA EXCHANGE

Chantal Loirat, Paris, France

Chair: Marina Noris, Bergamo, Italy

Rolf A.K. Stahl, Hamburg, Germany

loirat

Prof. C. Loirat
Service de Nephrologie Pediatrique
Hopital Robert Debre
Paris, France

As we have just seen, one can differentiate the typical post-diarrheal HUS due to STEC I will not speak of that. We know that there is no benefit from either plasma infusions or plasma exchange in this group of HUS. Nevertheless, plasma exchanges are quite often performed in the most severe forms with central nervous system involvement but with a most uncertain benefit. So we will mainly speak of atypical HUS due to hereditary complement disregulation and the other form due to anti-factor H antibodies.

This is just to summarise the overall prognosis of atypical HUS according to genotype.
This is the French paediatric cohort but as you will see in the presentation of Veronique Fremeaux-Bacchi, there are slight differences with adults. This is to remind you that the prognosis of atypical HUS associated with factor H mutation is very poor. As you see, the majority, 70% of patients will end up in ESRD or death, not very frequent death, very early within less than 1 year after onset.
On the opposite those patients with MCP mutations have a much better prognosis. They have relapses but they do not destroy their kidney except for some of them after many, many relapses.
As you see Factor I mutation is in between and it’s striking that some patients will destroy their kidney very early, either at the 1st episode or after one or two relapses. Those who do not, finally do pretty well over the years.
As you see Factor C3 mutation has a poor prognosis like factor H mutation.

So we will try and analyse what we know about the effect of plasmatherapy in those various subgroups.
This is to show that in those patients who have no mutations in neither of the 5 factors and no anti-factor H antibodies the prognosis is in between.

So plasmatherapy has been done for at least 2 decades, long before its logic was demonstrated. We now know that viro inactivated/pathogen reduced fresh frozen plasma brings normal amounts of CFH, CFB C3 and CFI. It doesn’t bring MCP which is a membrane protein. In fact, there is no data as far as I know, about the activity of proteins which are known to be very unstable like factor I or factor B in fresh frozen plasma.
The advantage of plasma exchange, as you know, versus infusions, using infusion plasma for restitution is, first it takes off mutated factors, it takes off anti-factor H antibodies and maybe other noxious factors. But in addition, it allows to bring high quantities of plasma which means of non-mutated factors without the risk of inducing hyperprotidemia and hyperviscosity which is the case if you infuse more than 40 ml/kg/week of plasma and also of course, without the risk of volume overload and cardiac failure.

So what do we know? I tried to analyse the effect of plasmatherapy according to genotype. There are no trials as you know. First let’s start with those rare patients who have a true deficiency in factor H. They have a mutation which induces a lack of factor H and they may be homozygous, it’s very rare or sometimes compound heterozygous. We know of 6 patients with this type of profile, very low factor H who were treated by plasmatherapy. As you see most of them received only plasma infusions, daily plasma infusions at the initial episode and then received preventive plasmatherapy, most of them only with plasma infusions from twice weekly to every 4 weeks. Two of them went to ESRD, one after 7 months when plasma infusions were reduced from twice weekly to once weekly in a homozygous deficiency and the other one after 4 years without relapses who had a relapse which was plasma resistant and ended in ESRD. For the other patients, as you see, some of them have been on preventive plasma therapy for up to 6 years with preserved renal function. They all had relapses which need to be treated by intensified daily plasmatherapy which rescues the relapse.

But as we have seen, heterozygous mutations are much more frequent. I looked at the French paediatric cohort at what had happened over the last years. As you see in the years before 2000 it was quite exceptional that patients were treated like we would do today. They received generally quite late plasma infusions and then only were switched to plasma exchange if it failed and finally, only one out of ten children had preserved renal function.

More recently plasmatherapy performed in France was much more aggressive and it happens that 3 of the 4 children treated that way have preserved renal function.
To go into detail, the few who have heterozygous factor H mutations with again, a quantitative deficiency in factor H, as you see were treated in various ways but generally for the long-term prevention only by plasma infusions and by now these 3 children have preserved renal function up to nearly 5 years under plasmatherapy.

Those much more frequent patients who have heterozygous factor H mutation with a functional deficiency, as you see at the moment we know of 6 patients who are treated more aggressively generally with plasma exchange at the acute phase and then for the long-term preventive plasma exchange from twice weekly to every two weeks. As you see, one child nevertheless, went to ESRD but the others have preserved renal function up to 8 years also with relapses and it’s very important that plasmatherapy is intensified again during relapses to rescue the kidney function.

This is an example of a child with a heterozygous functional mutation and as you see, this child now has a 4-year follow up with weekly plasma exchange intensified any time she has the beginning of a relapse during infections and how long this can go on? Of course may not be for her whole life.

This example paediatrics know well of a family with 2 twin sisters. Both were treated aggressively at the first episode with plasma exchange daily and then the first one plasma exchange was stopped and she only received plasma infusions during relapses but she was in ESRD after 4 months while her sister was maintained on plasma exchange every 2 weeks, intensified during infection and after 8 years on plasma exchange every 2 weeks serum creatinine is normal suggesting that for those kind of mutations functional deficiency, plasma exchange may have a benefit over infusions of plasma. That was for factor H mutations. We don’t know much about the effect of plasmatherapy in patients with factor I mutations.

In the Italian registry and in the French cohort as you see, plasmatherapy appeared to have a benefit in about half of patients.

The few published cases also responded to plasma exchange in the acute phase but nevertheless, these 4 patients went to ESRD maybe because plasmatherapy was stopped probably too early.

What about this gain of function mutations due to factor B mutation? As you know, the prognosis is very severe. There are not many patients, 12 patients from 5 families with severe outcome in all these patients except 3. 5 of them had plasmatherapy with a benefit in 4 of them, 3 of them in the long term. As you see these patients were protected by plasma exchange for 11 years and also some other patients have this kind of evolution.

What about MCP? It’s not logic to do plasmatherapy. MCP is not circulating and as a matter of fact as you see in the Italian Registry or the French paediatric cohort whether episodes are treated or not, the outcome is generally favourable.

I wanted to inform you of a problem which may be interesting for adult nephrologists which is a suspicion that this complement disregulation in atypical HUS could be a cause of accelerated atherosclerosis.

In 1 child with gain of function factor B mutation and in another one with a common factor H mutation, these children developed cerebral transient ischemic events. The first one at the age of 7 years and the other one at the age of 15 years.

As you see, both had a stenosis of many cerebral arteries and quite similar in both children.

The one with the B mutation as you see, has stenosis of the subclavian artery and vertebral artery associated with other stenoses.

Maybe plasmatherapy could have a preventive role. These are the 2 children we just spoke of. As you see, the red is the period on plasmatherapy, none of them and the yellow is the period on dialysis, none of the 2 children with a stenosis had prolonged plasmatherapy while the 2 twin sisters of this child who had the same mutations were treated for years with plasmatherapy and none of them has cerebral artery stenosis.

Just a few words about the cases with antibodies against factor H. It’s mainly paediatric, quite rare in adults.

As you see, if these patients are treated early and aggressively, the prognosis is quite good compared to those with mutations in factor H.

This is an example of a child with delayed diagnosis and delayed treatment. As you see, plasma exchange, steroid therapy, immunosuppressants were started 2 months after onset. The child was on dialysis and this had no effect although the levels of antibodies were decreased. It also shows that if you do only plasma exchange without immunosuppressive treatment, the antibodies will raise again and you will have a relapse.

This child is more recent with treatment started a few days after onset and as you see with plasma exchange, steroids and MMF the antibodies were at very low levels and renal function was normalised after 2 weeks.

So considering this, a group of paediatric nephrologists gave some guidelines about how to proceed with plasmatherapy at least for the years to come

and the guidelines are, start as early as possible.
This is important some patients with factor H mutation will destroy their kidneys very quickly and those with antibodies also can destroy their kidneys quite quickly.
With volume the best is plasma exchange, if it’s not possible plasma infusion.

Which frequency? Quite aggressive, daily during the first weeks. 5 sessions per week during the next 2 weeks, 3 per week during the next 2 weeks and then -- and you try to find the threshold dose and interval for each individual patient. Of course, long-term plasmatherapy is not so easy.

There may be vascular access problems, there may be anaphylactic reaction to plasma. It needs trained centres and there are uncertainties of course, for the long-term secondary resistance and maybe vascular consequences.

So this opens the way to the next drugs to come. This is an example of secondary plasma resistance in a child who you see had several relapses of HUS which were rescued by plasma infusions and finally, the last relapse was resistant and the child was treated with eculizumab with a very, very good result as you see, with a follow up which is now around 6 months.

So in conclusion today plasmatherapy remains the first line treatment of aHUS. Trials with C5 blockers and eculizumab will be started this year and other complement inhibitors; factor H concentrate or recombinant factor H will be evaluated subsequently and hopefully these new therapeutics will allow that aHUS will no longer end up in ESRD and will allow successful kidney transplantation for the many patients who are presently on dialysis.

This is to thank the group of Veronique Fremeaux-Bacchi who performs all the genetic analyses and screening for CFH antibodies and those clinicians who helped us to gather the clinical data. Thank you.

Question: Thank you for your lecture Chantal. I’d like to ask you as far as my experience in London when I was there some chronic atypical HUS patients were treated with albumin and some FFP at the end.

Prof. Loirat: -- you said that some post-diarrheal HUS patients were treated with ..

Question: Atypical HUS were treated in a chronic long run for 47 or 46 plasmapheresis I remember. They were treated not with FFP but with albumin and some had FFP at the end.

Prof. Loirat: Yes well logically it’s better to bring non-mutated factors that is the logic of giving fresh frozen plasma for restitution. So there are not many data with albumin for restitution. Maybe it can work especially if it is a problem of antibodies because you take off the antibodies.

Question: The question is the necessary volume of the factor H replaced with FFP. May be a smaller amount is enough at the end of the plasmapheresis or should you use a one and a half volume of the plasma volume with FFP?

Prof. Loirat: Yes well that’s the recommendation to be quite aggressive with plasma exchange. At least one plasma volume and maybe two to withdraw the most …

Prof. Loirat: I wish to underline that it is very important to know the defect because the response is strongly dependent also on the defect. So I completely agree with Chantal to provide plasma because you have to remove antibodies but if you have a genetic defect, you have to provide the wild-type factor that is missing. A question there.

Question: Repeated removal of the antibodies by plasmapheresis will stimulate the pathologic clone to reproduce the antibodies. Are there any trials to try to perform a bone marrow transplantation or stem cell transplantation earlier before this will proceed to ESRD?

Prof. Loirat: Your question for patients with antibodies against anti-factor H. what must be done in addition to plasma exchange?

Prof. Loirat: -- whether bone marrow transplantation would be an alternative right?

Question: No, no finally at least in the French paediatric cohort the prognosis as you’ve seen is good. In fact, the only two children who entered in ESRD were children not treated at the onset, you see. All the others were treated by plasma exchange and plus steroids and immunosuppression. As a matter of fact if you do only plasma exchange the antibodies will re-increase when you stop plasma exchange. What is not known is which immunosuppression. Anything else we’ve done, azathioprine, cyclophosphamide, MMF, rituximab but nevertheless, doing plasma exchange and this association of immunosuppression allows to withdraw and bring the antibodies to very low levels but the problem will not be suppressed within 3 months, most of these children have needed treatment during at least 1 year, 18 months but finally most of them have preserved renal function and by now some of them have no more treatments and do not re-increase their antibodies.

Prof. Loirat: I wish just to the re-keep the first question from the audience about rituximab. Do you have experience with rituximab in patients with anti-factor H antibodies?

There are a few children who are treated with rituximab, especially one we published in NDT who has one of those children with retrospective diagnosis. She was on dialysis but she still had antibodies, to prepare her for transplantation we did plasma exchange. But any time we stopped antibodies were increased so she received rituximab. This allowed a decrease of antibodies, she could be transplanted and then this transplant has been going on now for nearly 5 years. There have been a few other children who received rituximab, some of them I know of one in France without good results, while subsequently he was well managed with cyclophosphamide, so that can be one of the possibilities. But we don’t know whether one has to start with rituximab or to try more common drugs and less expensive like MMF or cyclophosphamide before.