Welcome to KD GO Conversations in Nephrology.
This episode in our complement mediated kidney disease series
titled The role of complement in Kidney Diseases is provided by
KD Go and supported by Apellis and Sobi.
Here's your host, Doctor Carla Nester.
Hello and welcome to KD Go Conversations in Nephrology I'm
doctor Carla nester, professor of internal medicine and
Pediatrics at the stead family Children's Hospital, University
of Iowa, and joining me to discuss the role of complement
in kidney diseases is doctor Matthew Pickering.
Doctor Pickering is Professor of Rheumatology and Welcome Senior
Fellow in Clinical Science at Imperial College London, UK, and
his clinical and research interests include complement and
kidney injury, C3, glomerulopathy and lupus.
Doctor Pickering, welcome to the program.
Thank you very much, Carla. Delighted to be here.
I think we'll get started right away with our first question for
you for this afternoon. What do we need to know about
the complement system? Thanks.
OK. So firstly, it's a protein
network that contributes to immunity.
And we know this because when we look at what happens in
complement deficiency states, we see that there's an increased
susceptibility to encapsulated bacterial infection,
Streptococcus pneumoniae, Haemophilus influenzae, and a
very strong association between terminal pathway deficiency,
that's deficiency of the proteins C5678 or 9 and
increased susceptibility to meningitis due to nicerol
infection. And we need to pay attention to
these observations since these infections will occur when we
generate acquired complement deficiency states using
complement inhibiting therapy. And of course, we can reduce
this infection risk through vaccination and antibiotic use.
Secondly, the system needs to be switched on, activated and
switched off, regulated with great precision to make sure
that it's damaging effects are directed appropriately against
pathogens and prevent and minimize any damage to our own
tissues. Like the kidney, it is switched
on by immune complexes. That's the classical pathway,
carbohydrate patterns along bacterial surface, the selecting
pathway and the spontaneously active but carefully regulated
alternative pathway. And the key effect of proteins
are important to remember. Are C3 important in oxidization
and C5 from which the C5A anaphylar toxin and the membrane
attack complex derive? And thirdly, defective
regulation of complement is the driver of pathology and several
diseases. These include age-related
macular degeneration, rare anemias like paroxysmal
nocturnal hemoglobin, urea, and our subject today, kidney
disease. Thank you for that excellent
description. As I'm listening to you, I'm
wondering, do you think it will be important for the clinician
to understand the difference between the various pathways?
I think this will be key. We are now in a situation where
we're able to target and inhibit activation of those pathways
with great precision. So the question will therefore
arise, which pathway is relevant to kidney injury in a given
disease? Do I need to to switch off?
For instance, complements derived from immune complexes
target the class pathway, or is it the alternative pathway?
Or maybe it's downstream activation through C5.
So I think, as always, understanding the path of
Physiology will be critical to allow us to accurately and
precisely target the complement system to get the beneficial
effect. Excellent point, Excellent
point. So why don't we just jump in
then to how should we think about complement and kidney
disease specifically? OK.
So well complement is very common of course in glomerular
inflammation is the complement staining in the in the kidney
biopsy meetings. So a key question is what is its
contribution to glomerular damage and subsequent kidney
failure. And this in this setting I like
to think about glomerular disease and to those in which we
have evidence that complement activation is the key mediator
of kidney injury would refer to those as complement driven
kidney disease and those in which it may be one of many
different ways in which the kidney injury is occurring.
Complement associated kidney disease as a term I like to to
use there. So where it's the primary
driver, complement driven kidney disease.
Well, examples are atypical hemolytic uremic syndrome, which
in most cases is associated with complement activation along the
glomerular endothelium and is strikingly responsive to C5
inhibition and C3 glomerulopathy.
C3G where you have abnormal regulation of the alternative
pathway and this results in excessive glomerular complement
activation and subsequently inflammation and structural
damage. And perhaps important examples
of complement associated kidney disease include IGA nephropathy,
lupus nephritis, anchor associated vasculitis.
Now in these examples, complement activation has
contributed to kidney injury but is not the key disease driver
which would be the abnormal IGA, antinuclear auto antibodies and
anchor respectively. I note you make a significant
point about the distinction between driven versus associated
and it's a very important approach, I suspect.
But do you have a concept of what the impact of that
distinction may be for the average clinician?
So I think what we need to consider there is we need to
look at experimental evidence that really defines the the
magnitude of of the contribution, if you like, of
complement to kidney injury because that will give us a
feeling for what we can expect from complement inhibition.
So where you have a condition such as atypical HUS where we
know that when we look at this experimentally, the damage to
the glomerular endothelium that triggers the thrombotic
phenotype is entirely dependent on activation through C5, then
you'd accept a expect a big effect of C5 inhibition.
In the clinical setting in conditions like lupus, it's very
important for us to to think about certain scenarios where
where perhaps complement would be key and other scenarios and
where in which it's not driving the damage.
And the only way really to address this, I think this is,
is through experiments. So that makes a good point also.
So you've given us an excellent background, if you will, on the
complement pathways and their potential roles.
So now let's talk about what do we need to know about the
complement therapies with respect to the
glomerulinephritides. Yeah.
Well, this is a really exciting time, but particularly with
respect to C3G therapy since we have phase three clinical trial
efficacy data showing reduction in protein error, reduction in
glomerulus, C3 staining for two complement inhibitors, Pegseta
Coplin AC 3 inhibitor that's administered by infusion twice
weekly and a Tacapan, A complement factor B inhibitor
administered as a tablet twice daily.
Complement associated diseases and therapeutic complement
inhibition. While we can think of anchor
associated vasculitis and IGA nephropathy, of course in anchor
associated vasculitis was strong proof of concept evidence for
C5A receptor blockade in animal models of MPO disease.
And that feeds back to my point about the experiments.
And then of course clinical trials showed efficacy for
Avacapan which is AC5A receptor blocker administers as a tablet
in adjunctive treatments of AAV. And in the trials, Avacapan in
combination with rituximab and cyclophosphamide markedly
reduced the requirement for glucocorticoid in IGA.
There's a phase three trial of a tacopan in patients with a 24
hour urine protein creatinine ratio of 1g per gram or more
despite supportive therapy. And a tacopan showed a
significant reduction in proteinuria as compared to
baseline at the nine month time, .38% lower than changes in
placebo. And of course, the key question
is what will the effect of a tacopan be on kidney function
over time? So you know, I as I'm listening
to you, I think you know coming from the laboratory setting, it
was very satisfying for me to hear you talk about the animal
models and ANKA associated vasculitis and how they
predicted potential success, you know, with these complement
inhibitors. Is there a similar model for IGA
that we can expect has predicted some potential good events here?
No, this has always been a a major limitation in terms of at
least in vivo modeling of IGA is that there is really no, I, I
would argue no good animal model of IGA nephropathy and unlike
for example anchor C3, GA, typical HUS and various forms of
immune complex nephritis. So that has been a limitation.
Yeah, I suspected you were going to tell me that.
So let's take a slightly different direction and let's
discuss how does measuring the complement system in the
circulation help us understand either the complement system or
potentially response to the therapeutics.
Yeah. So measuring circulating C3 and
C4 levels provides useful information.
And the reason for that is C4 is part of the classical electing
pathways, but not the alternative pathway.
All the pathways result in C3 activation and then downstream
of that C5 activation. So measuring C3 and C4 in the
clinic is helpful. If you see a low C4 with low C3
levels then you'd think of classical pathway activation as
typically the cause immune complexes driving that the the
classical pathway activation. Most common cause relevant to us
would be SLE immune complex associated MPGN.
Much rarer but important. What if you see a low C3 with
normal C4 level? Well that tells you there's no
classical or lectin pathway going on.
The C4 level's normal. The C3 is down because of
alternative pathway activation. And then you should think of
post infectious GN and C3 glomerulopathy.
So just looking at those two molecules, C3 and C4, gives you
a lot of information. Excellent.
That's actually a very straightforward depiction of how
to think about these circulating biomarkers, if you will.
So I can't help but ask, do you want to comment on the more
expanded biomarker panel options?
Yes, of course, I think these are very, very important.
There's a lot of work going on to search for biomarkers that
help us identify in the circulation whether or not
there's ongoing glomerular complement activation.
And that's the subject of research.
So investigators are looking at complement activation fragments.
So for example, if you want to understand where the C5 is
activated, a good way to look at that is to measure C5 activation
in the circulation and soluble C5B9 levels rise when C5
activation is occurring. And that's again useful
information if you're targeting, if you're thinking about
targeting C5, if the C5B9 is up, that emboldens you with that
approach. Then there are other important
biomarkers which are disease specific if you like.
So for instance, in in C3 chimerulopathy and idiopathic
immune complex associated PGN, we should be thinking about
measuring C3 nephritic factors. These are very, very helpful and
they come in two flavors. Those that cause C3 activation
alone, typically seen in things like DDD, and those that result
in C3 and C5 activation, typically seen in C3, glomerular
nephritis and ICMPGM. Very good.
Thank you for that explanation. For those just tuning in, you're
listening to the KD Go podcast on the role of complement in
kidney diseases. I'm Doctor Carla Nester, and I'm
speaking with Doctor Matthew Pickering.
Doctor Pickering. So my next question for you is
why is the alternative pathway such an attractive therapeutic
target in C3 glomerulopathy? This is because abnormal
regulation of the alternative pathway is so strongly
associated with C3G. The causes of the abnormal
regulation include auto antibodies, most commonly C3
nephritic factor. This binds to it stabilizes the
alternative pathway enzyme that activates C3.
We call this AC 3 convertase. So C3 neph stabilizes the C3
converters and this causes uncontrolled C3 activation.
So if you measure C3 levels in these patients, they're low,
Some nephritic factor stabilizes, the C5 convert is
causing low C5 levels too. Nephritic factors, as I
mentioned earlier, causing only low C3 levels are typically seen
in dense deposit disease. Those causing C3 and C5
activation are typically seen in C3 glomerulonephritis.
They're also genetic causes which interfere with the normal
regulation of the pathway by factor H And it's important to
consider these. These are very rare, but you
should consider these if there's a family history.
Paraprotein is an important association to consider in
adults with AC-3 dominant glomerulonephritis on biopsy.
And then important for me to point out, in up to perhaps 40%
of of cases, we don't identify A cause for the abnormal
ulcerative pathway activation. So in the terminology that you
have used previously, is it fair to say then that C3G is driven
by abnormalities that affect the alternative pathway?
Yes, I would agree with that. And this can be modelled
experimentally. So if you want to dysregulate
the alternative pathway, good place to start is to take away
the key negative regulator of that pathway and that's a
protein called factor H And if you interfere with factor H
function experimentally in in animals, you get uncontrolled C3
activation through the pathway. C3 levels fall in the
circulation and these animals spontaneously develop.
Accumulation of C3 in the glomeruli and AC-3
glomerulopathy. So at the end of the day, what
are the pros and cons of targeting C3 and or C5 and C3
glomerulopathy? That's an excellent point.
C5 inhibition prevents the production of the pro
inflammatory anathylotoxin C5A and the formation of the
membrane attack complex. And we know that inhibiting C5
with ecolizumab in C3G reduces glomerulol inflammation.
Kidney biopsies on ecolizumab serial biopsies show resolution
of glomerulomatopathy ages and the same is true in ICMPGN.
But, and this is the key, the abnormal glomerular C3 doesn't
change and so the C3 driven glomerular damage continues and
the kidney failure risk remains in the presence of C5 inhibition
and this is what is seen in experimental models of C3G2.
So to effectively treat the condition, we need to target and
prevent C3 activation. And we can now do this using
either Iptakapan or PEG setter Copelin.
In these trials, we saw for the first time resolution of
glomerular C3 on repeat kidney biopsy in some patients.
And if this is sustained, based on everything we know, this
would be expected to stop kidney failure.
You know you can't get C3G without the C3.
Important to restate whether or not we target C3 or C5.
It's important to mitigate the risks of bacterial infection,
particularly meningitis. Very good you, you've actually
made the point very well that it may well be important to know
what is driving a given disease in order to know at what level
of the complement system you should, you know, target or you
should attempt to block. So since therapeutics that may
block various levels are becoming available, what do you
suppose is the best way that we can get with this distinction
out to the clinician? I would think about, for
instance, that there will be the elephant in the room, if you
like with considering how we might use these drugs will be
accessibility due to cost. But let's pretend for a moment
that these were freely available.
Then I would say in situations where you're seeing glomerular
inflammation in the presence of compliments, so you're seeing
glomerular macrophages for example, and if you stain for it
you'll see evidence of C5 activation, then C5 inhibition
would be a very effective anti-inflammatory therapy.
And unlike for instance courses of glucocorticoid, I can't see
any long term side effects of that approach.
It may be used for a limited amount of time to reduce
glomerular inflammation which then resolves and patient comes
off the C5 therapy. For conditions like C3G where
you have ongoing C3 activation, then I think the most
appropriate is to target at the level of C3 because then you're
preventing the C3 mediated damage, the mesangial expansion,
the the deposition of C3 within the mesangial matrix in the
basement membrane and so on. And also preventing any
downstream C5 activation which is driving the glomerul
inflammation. This has been an absolutely
excellent discussion. Thank you very much for all of
your contribution here. Before we close out the session,
Matthew, are there any final messages you'd like to leave
with our listeners? Absolutely.
I think most important is that it is to emphasize we're at a
very exciting time in the therapy of C3G.
But there there is lots to do. Critically important is to
demonstrate that the beneficial changes in the trial surrogate
endpoints translate into what we want to know, reduced kidney
failure and this will require long term monitoring, perhaps
best done using registries. We need to diagnose promptly and
treat patients with these drugs at an early stage before any
kidney damage occurs. And it's my view, I don't think
we can justify indiscriminate immunosuppression in this
patient group anymore. We need to consider understudied
groups, children under 12, patients with paraproteins, and
patients with the kidney transplants.
And we need to think about when we might stop therapy and
whether there's any role, as I referred to earlier, for C5
therapy during periods of acute inflammation.
We need to understand how to recognize success.
Should we use proteinuria targets or would we still be
concerned, for example, about a patient with significantly
reduced proteinuria but ongoing C3 activation in the
circulation? And this speaks to the need for
biomarkers, ideally something in the blood or the urine that we
can measure that tells us if we have stopped C three activation
in the glomeruli and of course then would reduce the need for
repeat kidney biopsy. And perhaps the most important
point, we need to make sure patients can access these
therapies. And this will require
coordinated effort between patients and physicians and
which I'm pleased to say is a very active area with excellent
work from organizations such as Neph Cure Com, Cure Cadigo and
the International Society of Glomerular Disease.
Excellent. You've highlighted all of the
critical aspects that we need to be paying attention to coming
forward. And in fact, that's a great way
to round out our discussion today.
I want to thank my guest, Doctor Matthew Pickering for joining
me. Doctor Pickering, it was just
great having you join our program today.
A pleasure, Carla. Thank you very much.
I'm Doctor Carla Nester. To access this and other
episodes in our series, visit kdego.org podcast.
Thanks for listening.