Welcome to KD GO Conversations in Nephrology.
This episode in our complement mediated kidney disease series
titled Diagnosis and Management of C3G is provided by KD GO and
supported by Apellus 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, Stead Family
Children's Hospital, University of Iowa, and joining me to
discuss diagnosis and management of C3G is Doctor David
Kavanaugh. Dr. Kavanaugh is Professor of
Complement Therapeutics at the National Renal Complement
Therapeutic Center, Newcastle, England, and his clinical and
research interests include complement mediated renal and
retinal diseases. Doctor Kavanaugh, welcome to the
podcast. Thanks very much, Carla.
It's a pleasure to be here. Always great to discuss
complement mediated renal disease.
Let's begin our discussion with how do patients present and
particularly how do you make the diagnosis of C3G or immune
complex in PGN. C3 glomerulopathy is an ultra
rare kidney disease. We estimate that there will be
about 10,000 patients in the United States with C3G.
The clinical presentation of C3G can be buried from asymptomatic
presentations on routine screening with hematuria or
proteuria on debt stick, nephrotic syndrome, or acute
kidney failure. Serum complement C3 levels are
low in the majority of cases and this is one of the first
indications that C3G should form part of the differential
diagnosis. The diagnosis of C3G however, is
made on renal biopsy and it's based on the presence of
dominant C3D position on immunofluorescence.
Sub classification of C3G into dense deposit disease and C3
glomerulonephritis is then based on the appearances on electron
microscopy. There is substantial overlap
between immune complex MPGN and C3G.
When we see the biopsy feature then we need to establish what
may be driving disease and to exclude any secondary causes.
C3 dominant glomerulonephritis is not necessarily C3G.
So that's an excellent point that C3 dominant
glomerulonephritis is not necessarily C3G.
So then the follow up question becomes to your mind, is there
anything on the biopsy that helps you rule out those
confounders? C3 may accumulate an areas of
glomerular or tubular interstitial scarring and due to
prior inflammation or ischemia. I do see this very commonly.
It tends to be focal and it's limited to areas of scarring.
The intensity of C3 staining tends to be a bit more modest
and moderate at most and the EM may show non specific deposits
are scoring. However, when we get a boxy with
AC-3 dominant picture, we should undertake a diagnostic work up.
So what do you consider is the bare minimum diagnostic work up
and why? When we get a renal bopsy that
shows AC 3 dominant glomerulonephritis, it may point
to AC 3G either due to a quadrant inherited complement
defects. There are a few caveats however.
This may depend on where in the course of the illness you
bought. See for instance, 30% of post
infectious glomerulonephritis will be C3 dominant and sub
epithelial humps are not passing pneumonic for post infectious
glomerulonephritis. So I'll ask for the history of
pharyngitis or impetigo. I'll measure ASO titers if it's
a post infectious glomerulonephritis.
The hematuria, proteinuria and low complement levels we
normally see initially will resolve within about 3 months.
I will look for a paraprotein mediated disease.
The renal biopsy may give us a clue to a monoclonal gammopathy
driven disease. We may see Kappa or Lambda
restriction on immunohistice chemistry and it's really
important that this is done. Pronase digestion may reveal
hidden aminoglobulin or light chains deposited that would
otherwise not be seen and C4D Studying of the biopsy may also
help to suggest a para protein mediate disease.
Clearly we need to do serum and urine protein electrophoresis
and serum free light chains are important too.
This is a disorder that's more common as you age.
About 1.6% of people over 50 will have a monoclonal gemopathy
and this rises to about 6 1/2% in those over 80.
It must be remembered, however, that rarely younger patients
with lymphomas can present like this.
We must also rule out secondary infectious causes such as
hepatitis, B&C, and other chronic infections such as
endocarditis. Depending on the travel history,
we should also look for tropical diseases such as
schistosomiasis. We should also try to exclude
autoimmune diseases such as SLE, rheumatoid arthritis, and
cryoglopial anemia. More specialist complement tests
may be available in some centers.
Nephritic factors and auto antibodies to complement
proteins are frequently found in C3G and provide reassurance as
to the diagnosis. Likewise, genetic analysis may
be performed and in rare cases an underlying mutation and
factory HRC three may be found. An array of complement tests are
available that assess the state of complement activation in C3.
However, although these may speak of the underlying
pathogenesis, they do not confirm a diagnosis of C3G or,
as yet, gait treatment. It is likely, however, that as
Complement Therapeutics enter the real world, we'll work out
how to use these tests to guide treatment.
Thank you. That's actually a very nice list
of ways we can rule out some of these confounders.
And I also like the way you portray the finding of auto
antibodies, for instance, as quote UN quote reassurance of
the diagnosis. I think with that in mind, I'll
take that one step further and just ask you, is testing for
these auto antibodies required for the diagnosis of C3G or
immune complex MPGN? No, the diagnosis of C3G, an
immune complex MPGN, is a bumpy diagnosis.
These are really just additional tests that may allow you to
confirm that this is driven by complement over activation.
If you're just tuning in, you're listening to the KD Go podcast
on diagnosis and management of C3G.
I'm Carla Nester, and I'm speaking with Doctor David
Kavanaugh. So let's jump to our next
question. How do you treat your newly
diagnosed C3G patient? As with most proteinuric renal
diseases, I start with nonspecific approaches such as
optimization of blood pressure and proteinuria control with
renal angiosystem inhibition and SGL 2 inhibitors.
I'll give lipid loading agents when required.
In patients with more than half a gram of proteinuria, worsening
renal function or severe inflammation in the renal
biopsy, I will try non specific immunosuppression in the form of
steroids and MMF. I would say the evidence for
this is all retrospective, but until now it's the only
treatment I had. And Despite that most patients
progress to end stage kidney failure.
We know that C3G is a disorder of the alternative pathway of
complement and therefore eclusumab acts too far
downstream to effectively treat C3G.
The new alternative pathway targeted agents at Tacapan and
Pigsetic Plan are a pivotal moment for patients with C3G as
we can now effectively target the site of complement over
activation. This is a really exciting time
for patients with C3G. I agree 100%, But before we get
to the new therapeutics, I'm sure as glomerular disease
doctors, we've both had some successes with mycophenolate and
steroids with other diseases. Would you like to take a stab at
why this approach may be effective, or for that matter
not effective in this particular setting?
Yeah, that's a very interesting point, Carla.
I mean, we have all treated some patients with steroids and MMS
and seen good response. Now I suppose all the evidence
is retrospective, so we don't know if people would have got
better anyway. And indeed, I've seen some
patients just get better without any treatment.
So the evidence for this is all retrospective.
However, as I said, most patients in MMS and steroid will
progress to end stage whatever we do now.
I think that's because we might see an initial response to
steroids and that's just treating the nonspecific
inflammation we see in the kidney.
However, we do not get rid of the underlying driver of disease
at complement activation, C3 depositing in the kidney and
that ultimately leads to end stage renal failure.
And although we might feel MMS may be targeting auto antibodies
as it may do in other diseases, we've had really poor success in
eliminating nephritic factors. Whatever we do, we have not
really been able to get rid of these nephritic factors.
And I believe you don't require terribly much C3 NAV to cause
disease. That all makes sense to me.
Thank you. Now let's move forward.
So when the new therapeutic options are available to you,
how do you plan to use them moving forward?
Clearly we all await the updated K Daigo guidance on treatment,
but as a personal view, I will start ACE inhibitors and SGL 2
inhibitors as I would in any proteinuric renal disease.
I view alternative pathway inhibition as first line
therapy. I will not start MMS and
steroids first and see if there's a response.
We exquisitely know the pathogenesis of C3G and these
alternative pathway agents target this Tachopan and
Pigsetica plant have been shown to be effective and gold
standard randomized placebo-controlled trials.
That has never been a randomized controlled trial of MMF and
steroids in C3G and these agents come with marked side effects.
Despite their use, most patients progressed to end stage renal
failure anyway. Thus, I would not want to see a
gatekeeper role for MMF and steroids part accessing the
evidence based treatment, pixetical plan and Tachopan.
Many questions remain about alternative pathway agents
optimal use, such as how long we need to continue and what
constitutes successful treatments, and whether we need
to swap between agents if we're not seeing successful treatment.
I think, however, many of these questions will only be answered
when we use these agents in the real world.
I think that those are all excellent points.
So I'm going to push back a little bit and ask you maybe a
harder question. What if your ACE inhibitor plus
your SGLT 2 inhibitor takes a patient, let's say from 1.9
grams of urine protein down to 0.7g of urine protein?
Are you still going to consider one of the new therapies?
Yes, not all reduction in proteinuria is the same.
ACE inhibitors, SGL 2 inhibitors will have a known specific
effect on proteinuria, however they're not going to prevent
that ongoing complement activation damaging the kidney.
It's really the alternative pathway agents that hit the
disease at the source. Well, I think that's pretty
straightforward. Thank you very much for that.
So now let's jump over to transplantation.
Are there issues about transplantation that you would
like to chat about? One of the most desperately
disappointing features of this disease for our patients was an
up to 80% of cases the disease relapsed after transplantation.
Our patients had seen their native kidney function
deteriorate to the point where they needed dialysis, and then
they were fortunate enough to get a transplant.
But frequently we had to tell them that the disease had come
back and there was little we could do to stop this.
Both at TACPAN and phase two trials and Picksetica plan and
phase two and three trials have been used in transplant
recurrence with good result. That does not appear to be a
safety signal when used in combination with transplant
immunosuppression. The infectious risks of
complement blockade is well known but can be mitigated with
antibiotic prophylaxis, vaccination, and patient
awareness. That's been my experience also,
that the prognosis post transplant can be just as
daunting as it was in the native kidney.
Can I ask you, just for our audience more than anything,
what constitutes recurrence in that transplant for you?
Well, that does seem like an easy question, but actually it's
not quite as straightforward. You could say I need to see
evidence of proteinuria worsening renal function or
should we do a renal biopsy? But if we do a renal biopsy, is
C3D position enough or do I also need to see a
glomerulonephritis? My feeling is that we know the
pathogenesis of disease and I don't want to wait until there's
marked proteinurian worsening renal function.
If I do a kidney biopsy and I'm seeing pathological recurrence
with a glomerulonephritis, I'm going to want to treat.
Now that is a reactive treatment and there is one other
complement mediated condition, atypical HUS that also recurs
post transplant, but in that we give eclizumab prophylactically
to prevent disease. Now that's a very acute
presentation and these patients with atypical HUS can lose their
kidneys very quickly. In C3G it tends to be far
slower. So we will have time to react
and do a biopsy. I don't, however, rule out
giving prophylactic tacpan or pixetical plan in certain cases
where there might be a high risk of recurrence.
But as yet, we'll need to see how this pans out in the real
world. Again, all excellent points I
think you're making and thank you for a wonderful discussion
about the C3 GI. Want to thank my guest, Doctor
David Kavanaugh for joining me. Doctor Kavanaugh, it was great
having you on the podcast. It's always a pleasure.
I'm Doctor Carla Nester, To access this and other episodes
in our series, visit kdgo.org/podcast.
Thanks for listening.