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Welcome to KD GO Conversations 
in Nephrology. 

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This episode in our complement 
mediated kidney disease series 

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titled The role of complement in
Kidney Diseases is provided by 

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KD Go and supported by Apellis 
and Sobi. 

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Here's your host, Doctor Carla 
Nester. 

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Hello and welcome to KD Go 
Conversations in Nephrology I'm 

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doctor Carla nester, professor 
of internal medicine and 

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Pediatrics at the stead family 
Children's Hospital, University 

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of Iowa, and joining me to 
discuss the role of complement 

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in kidney diseases is doctor 
Matthew Pickering. 

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Doctor Pickering is Professor of
Rheumatology and Welcome Senior 

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Fellow in Clinical Science at 
Imperial College London, UK, and

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his clinical and research 
interests include complement and

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kidney injury, C3, 
glomerulopathy and lupus. 

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Doctor Pickering, welcome to the
program. 

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Thank you very much, Carla. 
Delighted to be here. 

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I think we'll get started right 
away with our first question for

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you for this afternoon. 
What do we need to know about 

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the complement system? 
Thanks. 

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OK. 
So firstly, it's a protein 

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network that contributes to 
immunity. 

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And we know this because when we
look at what happens in 

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complement deficiency states, we
see that there's an increased 

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susceptibility to encapsulated 
bacterial infection, 

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Streptococcus pneumoniae, 
Haemophilus influenzae, and a 

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very strong association between 
terminal pathway deficiency, 

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that's deficiency of the 
proteins C5678 or 9 and 

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increased susceptibility to 
meningitis due to nicerol 

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infection. 
And we need to pay attention to 

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these observations since these 
infections will occur when we 

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generate acquired complement 
deficiency states using 

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complement inhibiting therapy. 
And of course, we can reduce 

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this infection risk through 
vaccination and antibiotic use. 

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Secondly, the system needs to be
switched on, activated and 

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switched off, regulated with 
great precision to make sure 

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that it's damaging effects are 
directed appropriately against 

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pathogens and prevent and 
minimize any damage to our own 

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tissues. 
Like the kidney, it is switched 

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on by immune complexes. 
That's the classical pathway, 

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carbohydrate patterns along 
bacterial surface, the selecting

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pathway and the spontaneously 
active but carefully regulated 

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alternative pathway. 
And the key effect of proteins 

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are important to remember. 
Are C3 important in oxidization 

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and C5 from which the C5A 
anaphylar toxin and the membrane

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attack complex derive? 
And thirdly, defective 

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regulation of complement is the 
driver of pathology and several 

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diseases. 
These include age-related 

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macular degeneration, rare 
anemias like paroxysmal 

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nocturnal hemoglobin, urea, and 
our subject today, kidney 

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disease. 
Thank you for that excellent 

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description. 
As I'm listening to you, I'm 

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wondering, do you think it will 
be important for the clinician 

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to understand the difference 
between the various pathways? 

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I think this will be key. 
We are now in a situation where 

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we're able to target and inhibit
activation of those pathways 

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with great precision. 
So the question will therefore 

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arise, which pathway is relevant
to kidney injury in a given 

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disease? 
Do I need to to switch off? 

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For instance, complements 
derived from immune complexes 

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target the class pathway, or is 
it the alternative pathway? 

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Or maybe it's downstream 
activation through C5. 

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So I think, as always, 
understanding the path of 

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Physiology will be critical to 
allow us to accurately and 

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precisely target the complement 
system to get the beneficial 

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effect. 
Excellent point, Excellent 

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point. 
So why don't we just jump in 

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then to how should we think 
about complement and kidney 

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disease specifically? 
OK. 

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So well complement is very 
common of course in glomerular 

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inflammation is the complement 
staining in the in the kidney 

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biopsy meetings. 
So a key question is what is its

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contribution to glomerular 
damage and subsequent kidney 

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failure. 
And this in this setting I like 

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to think about glomerular 
disease and to those in which we

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have evidence that complement 
activation is the key mediator 

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of kidney injury would refer to 
those as complement driven 

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kidney disease and those in 
which it may be one of many 

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different ways in which the 
kidney injury is occurring. 

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Complement associated kidney 
disease as a term I like to to 

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use there. 
So where it's the primary 

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driver, complement driven kidney
disease. 

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Well, examples are atypical 
hemolytic uremic syndrome, which

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in most cases is associated with
complement activation along the 

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glomerular endothelium and is 
strikingly responsive to C5 

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inhibition and C3 
glomerulopathy. 

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C3G where you have abnormal 
regulation of the alternative 

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pathway and this results in 
excessive glomerular complement 

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activation and subsequently 
inflammation and structural 

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damage. 
And perhaps important examples 

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of complement associated kidney 
disease include IGA nephropathy,

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lupus nephritis, anchor 
associated vasculitis. 

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Now in these examples, 
complement activation has 

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contributed to kidney injury but
is not the key disease driver 

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which would be the abnormal IGA,
antinuclear auto antibodies and 

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anchor respectively. 
I note you make a significant 

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point about the distinction 
between driven versus associated

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and it's a very important 
approach, I suspect. 

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But do you have a concept of 
what the impact of that 

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distinction may be for the 
average clinician? 

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So I think what we need to 
consider there is we need to 

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look at experimental evidence 
that really defines the the 

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magnitude of of the 
contribution, if you like, of 

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complement to kidney injury 
because that will give us a 

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feeling for what we can expect 
from complement inhibition. 

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So where you have a condition 
such as atypical HUS where we 

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know that when we look at this 
experimentally, the damage to 

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the glomerular endothelium that 
triggers the thrombotic 

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phenotype is entirely dependent 
on activation through C5, then 

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you'd accept a expect a big 
effect of C5 inhibition. 

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In the clinical setting in 
conditions like lupus, it's very

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important for us to to think 
about certain scenarios where 

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where perhaps complement would 
be key and other scenarios and 

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where in which it's not driving 
the damage. 

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And the only way really to 
address this, I think this is, 

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is through experiments. 
So that makes a good point also.

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So you've given us an excellent 
background, if you will, on the 

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complement pathways and their 
potential roles. 

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So now let's talk about what do 
we need to know about the 

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complement therapies with 
respect to the 

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glomerulinephritides. 
Yeah. 

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Well, this is a really exciting 
time, but particularly with 

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respect to C3G therapy since we 
have phase three clinical trial 

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efficacy data showing reduction 
in protein error, reduction in 

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glomerulus, C3 staining for two 
complement inhibitors, Pegseta 

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Coplin AC 3 inhibitor that's 
administered by infusion twice 

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weekly and a Tacapan, A 
complement factor B inhibitor 

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administered as a tablet twice 
daily. 

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Complement associated diseases 
and therapeutic complement 

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inhibition. 
While we can think of anchor 

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associated vasculitis and IGA 
nephropathy, of course in anchor

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associated vasculitis was strong
proof of concept evidence for 

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C5A receptor blockade in animal 
models of MPO disease. 

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And that feeds back to my point 
about the experiments. 

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And then of course clinical 
trials showed efficacy for 

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Avacapan which is AC5A receptor 
blocker administers as a tablet 

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in adjunctive treatments of AAV.
And in the trials, Avacapan in 

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combination with rituximab and 
cyclophosphamide markedly 

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reduced the requirement for 
glucocorticoid in IGA. 

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There's a phase three trial of a
tacopan in patients with a 24 

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hour urine protein creatinine 
ratio of 1g per gram or more 

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despite supportive therapy. 
And a tacopan showed a 

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significant reduction in 
proteinuria as compared to 

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baseline at the nine month time,
.38% lower than changes in 

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placebo. 
And of course, the key question 

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is what will the effect of a 
tacopan be on kidney function 

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over time? 
So you know, I as I'm listening 

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to you, I think you know coming 
from the laboratory setting, it 

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was very satisfying for me to 
hear you talk about the animal 

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models and ANKA associated 
vasculitis and how they 

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predicted potential success, you
know, with these complement 

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inhibitors. 
Is there a similar model for IGA

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that we can expect has predicted
some potential good events here?

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No, this has always been a a 
major limitation in terms of at 

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least in vivo modeling of IGA is
that there is really no, I, I 

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would argue no good animal model
of IGA nephropathy and unlike 

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for example anchor C3, GA, 
typical HUS and various forms of

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immune complex nephritis. 
So that has been a limitation. 

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Yeah, I suspected you were going
to tell me that. 

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So let's take a slightly 
different direction and let's 

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discuss how does measuring the 
complement system in the 

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circulation help us understand 
either the complement system or 

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potentially response to the 
therapeutics. 

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Yeah. 
So measuring circulating C3 and 

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C4 levels provides useful 
information. 

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And the reason for that is C4 is
part of the classical electing 

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pathways, but not the 
alternative pathway. 

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All the pathways result in C3 
activation and then downstream 

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of that C5 activation. 
So measuring C3 and C4 in the 

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clinic is helpful. 
If you see a low C4 with low C3 

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levels then you'd think of 
classical pathway activation as 

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typically the cause immune 
complexes driving that the the 

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classical pathway activation. 
Most common cause relevant to us

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would be SLE immune complex 
associated MPGN. 

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Much rarer but important. 
What if you see a low C3 with 

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normal C4 level? 
Well that tells you there's no 

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classical or lectin pathway 
going on. 

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The C4 level's normal. 
The C3 is down because of 

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alternative pathway activation. 
And then you should think of 

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post infectious GN and C3 
glomerulopathy. 

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So just looking at those two 
molecules, C3 and C4, gives you 

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a lot of information. 
Excellent. 

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That's actually a very 
straightforward depiction of how

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to think about these circulating
biomarkers, if you will. 

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So I can't help but ask, do you 
want to comment on the more 

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expanded biomarker panel 
options? 

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Yes, of course, I think these 
are very, very important. 

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There's a lot of work going on 
to search for biomarkers that 

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help us identify in the 
circulation whether or not 

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there's ongoing glomerular 
complement activation. 

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And that's the subject of 
research. 

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So investigators are looking at 
complement activation fragments.

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So for example, if you want to 
understand where the C5 is 

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activated, a good way to look at
that is to measure C5 activation

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in the circulation and soluble 
C5B9 levels rise when C5 

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activation is occurring. 
And that's again useful 

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information if you're targeting,
if you're thinking about 

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targeting C5, if the C5B9 is up,
that emboldens you with that 

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approach. 
Then there are other important 

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biomarkers which are disease 
specific if you like. 

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So for instance, in in C3 
chimerulopathy and idiopathic 

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immune complex associated PGN, 
we should be thinking about 

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measuring C3 nephritic factors. 
These are very, very helpful and

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they come in two flavors. 
Those that cause C3 activation 

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alone, typically seen in things 
like DDD, and those that result 

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in C3 and C5 activation, 
typically seen in C3, glomerular

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nephritis and ICMPGM. 
Very good. 

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Thank you for that explanation. 
For those just tuning in, you're

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listening to the KD Go podcast 
on the role of complement in 

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kidney diseases. 
I'm Doctor Carla Nester, and I'm

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speaking with Doctor Matthew 
Pickering. 

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Doctor Pickering. 
So my next question for you is 

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why is the alternative pathway 
such an attractive therapeutic 

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target in C3 glomerulopathy? 
This is because abnormal 

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regulation of the alternative 
pathway is so strongly 

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associated with C3G. 
The causes of the abnormal 

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regulation include auto 
antibodies, most commonly C3 

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nephritic factor. 
This binds to it stabilizes the 

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alternative pathway enzyme that 
activates C3. 

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We call this AC 3 convertase. 
So C3 neph stabilizes the C3 

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converters and this causes 
uncontrolled C3 activation. 

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So if you measure C3 levels in 
these patients, they're low, 

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Some nephritic factor 
stabilizes, the C5 convert is 

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causing low C5 levels too. 
Nephritic factors, as I 

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mentioned earlier, causing only 
low C3 levels are typically seen

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in dense deposit disease. 
Those causing C3 and C5 

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activation are typically seen in
C3 glomerulonephritis. 

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They're also genetic causes 
which interfere with the normal 

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regulation of the pathway by 
factor H And it's important to 

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consider these. 
These are very rare, but you 

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should consider these if there's
a family history. 

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Paraprotein is an important 
association to consider in 

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adults with AC-3 dominant 
glomerulonephritis on biopsy. 

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And then important for me to 
point out, in up to perhaps 40% 

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of of cases, we don't identify A
cause for the abnormal 

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ulcerative pathway activation. 
So in the terminology that you 

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have used previously, is it fair
to say then that C3G is driven 

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by abnormalities that affect the
alternative pathway? 

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Yes, I would agree with that. 
And this can be modelled 

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experimentally. 
So if you want to dysregulate 

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the alternative pathway, good 
place to start is to take away 

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the key negative regulator of 
that pathway and that's a 

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protein called factor H And if 
you interfere with factor H 

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function experimentally in in 
animals, you get uncontrolled C3

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activation through the pathway. 
C3 levels fall in the 

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circulation and these animals 
spontaneously develop. 

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Accumulation of C3 in the 
glomeruli and AC-3 

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glomerulopathy. 
So at the end of the day, what 

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are the pros and cons of 
targeting C3 and or C5 and C3 

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glomerulopathy? 
That's an excellent point. 

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C5 inhibition prevents the 
production of the pro 

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inflammatory anathylotoxin C5A 
and the formation of the 

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membrane attack complex. 
And we know that inhibiting C5 

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with ecolizumab in C3G reduces 
glomerulol inflammation. 

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Kidney biopsies on ecolizumab 
serial biopsies show resolution 

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of glomerulomatopathy ages and 
the same is true in ICMPGN. 

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But, and this is the key, the 
abnormal glomerular C3 doesn't 

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change and so the C3 driven 
glomerular damage continues and 

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the kidney failure risk remains 
in the presence of C5 inhibition

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and this is what is seen in 
experimental models of C3G2. 

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So to effectively treat the 
condition, we need to target and

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prevent C3 activation. 
And we can now do this using 

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either Iptakapan or PEG setter 
Copelin. 

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In these trials, we saw for the 
first time resolution of 

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glomerular C3 on repeat kidney 
biopsy in some patients. 

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And if this is sustained, based 
on everything we know, this 

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would be expected to stop kidney
failure. 

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You know you can't get C3G 
without the C3. 

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Important to restate whether or 
not we target C3 or C5. 

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It's important to mitigate the 
risks of bacterial infection, 

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particularly meningitis. 
Very good you, you've actually 

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made the point very well that it
may well be important to know 

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what is driving a given disease 
in order to know at what level 

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of the complement system you 
should, you know, target or you 

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should attempt to block. 
So since therapeutics that may 

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block various levels are 
becoming available, what do you 

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suppose is the best way that we 
can get with this distinction 

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out to the clinician? 
I would think about, for 

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instance, that there will be the
elephant in the room, if you 

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like with considering how we 
might use these drugs will be 

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accessibility due to cost. 
But let's pretend for a moment 

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that these were freely 
available. 

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Then I would say in situations 
where you're seeing glomerular 

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inflammation in the presence of 
compliments, so you're seeing 

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glomerular macrophages for 
example, and if you stain for it

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you'll see evidence of C5 
activation, then C5 inhibition 

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would be a very effective 
anti-inflammatory therapy. 

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And unlike for instance courses 
of glucocorticoid, I can't see 

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any long term side effects of 
that approach. 

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It may be used for a limited 
amount of time to reduce 

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glomerular inflammation which 
then resolves and patient comes 

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off the C5 therapy. 
For conditions like C3G where 

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you have ongoing C3 activation, 
then I think the most 

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appropriate is to target at the 
level of C3 because then you're 

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preventing the C3 mediated 
damage, the mesangial expansion,

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the the deposition of C3 within 
the mesangial matrix in the 

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basement membrane and so on. 
And also preventing any 

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downstream C5 activation which 
is driving the glomerul 

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inflammation. 
This has been an absolutely 

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excellent discussion. 
Thank you very much for all of 

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your contribution here. 
Before we close out the session,

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Matthew, are there any final 
messages you'd like to leave 

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with our listeners? 
Absolutely. 

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I think most important is that 
it is to emphasize we're at a 

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very exciting time in the 
therapy of C3G. 

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But there there is lots to do. 
Critically important is to 

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demonstrate that the beneficial 
changes in the trial surrogate 

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endpoints translate into what we
want to know, reduced kidney 

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failure and this will require 
long term monitoring, perhaps 

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best done using registries. 
We need to diagnose promptly and

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treat patients with these drugs 
at an early stage before any 

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kidney damage occurs. 
And it's my view, I don't think 

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we can justify indiscriminate 
immunosuppression in this 

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patient group anymore. 
We need to consider understudied

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00:18:02,320 --> 00:18:06,560
groups, children under 12, 
patients with paraproteins, and 

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00:18:06,560 --> 00:18:08,480
patients with the kidney 
transplants. 

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00:18:08,920 --> 00:18:11,360
And we need to think about when 
we might stop therapy and 

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00:18:11,360 --> 00:18:14,440
whether there's any role, as I 
referred to earlier, for C5 

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00:18:14,440 --> 00:18:16,840
therapy during periods of acute 
inflammation. 

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00:18:17,680 --> 00:18:20,440
We need to understand how to 
recognize success. 

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00:18:20,720 --> 00:18:23,840
Should we use proteinuria 
targets or would we still be 

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00:18:23,840 --> 00:18:26,680
concerned, for example, about a 
patient with significantly 

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00:18:26,680 --> 00:18:30,320
reduced proteinuria but ongoing 
C3 activation in the 

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00:18:30,320 --> 00:18:32,320
circulation? 
And this speaks to the need for 

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00:18:32,320 --> 00:18:36,080
biomarkers, ideally something in
the blood or the urine that we 

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00:18:36,080 --> 00:18:39,960
can measure that tells us if we 
have stopped C three activation 

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00:18:40,000 --> 00:18:43,720
in the glomeruli and of course 
then would reduce the need for 

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00:18:43,720 --> 00:18:47,960
repeat kidney biopsy. 
And perhaps the most important 

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00:18:47,960 --> 00:18:50,600
point, we need to make sure 
patients can access these 

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00:18:50,600 --> 00:18:52,160
therapies. 
And this will require 

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00:18:52,160 --> 00:18:56,040
coordinated effort between 
patients and physicians and 

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00:18:56,040 --> 00:18:59,360
which I'm pleased to say is a 
very active area with excellent 

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00:18:59,360 --> 00:19:04,360
work from organizations such as 
Neph Cure Com, Cure Cadigo and 

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00:19:04,360 --> 00:19:07,120
the International Society of 
Glomerular Disease. 

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00:19:07,560 --> 00:19:09,400
Excellent. 
You've highlighted all of the 

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00:19:09,400 --> 00:19:12,360
critical aspects that we need to
be paying attention to coming 

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00:19:12,360 --> 00:19:14,840
forward. 
And in fact, that's a great way 

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to round out our discussion 
today. 

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I want to thank my guest, Doctor
Matthew Pickering for joining 

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me. 
Doctor Pickering, it was just 

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00:19:22,440 --> 00:19:24,480
great having you join our 
program today. 

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00:19:25,000 --> 00:19:27,160
A pleasure, Carla. 
Thank you very much. 

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I'm Doctor Carla Nester. 
To access this and other 

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episodes in our series, visit 
kdego.org podcast. 

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Thanks for listening.