GN in Ten

In this episode of GN in Ten, hosts Dr. Kenar Jhaveri and Dr. Koyal Jain break down the essential "must-knows" for ANCA-associated vasculitis (AAV). Geared toward board preparation and clinical practice, this bite-sized session covers everything from the initial diagnosis and the role of kidney biopsy to the latest advancements in induction and maintenance therapy.

Key Discussion Points
  • Diagnosis & Biopsy Strategy: Why checking specific MPO and PR3 titers is more reliable than general C/P-ANCA. The hosts also discuss the value of biopsy in older patients to assess chronicity and guide treatment duration.
  • Induction Therapy: Comparing the "three pillars" of induction: Rituximab, Cyclophosphamide (IV vs. oral), and the increasingly popular combination therapy for organ-threatening disease.
  • The Steroid Taper: A shift toward "less is more." Following the PEXIVAS protocol, the hosts explain how to aggressively taper steroids to minimize toxicity, especially when using adjunctive therapies.
  • Plasma Exchange (PLEX): Does it still have a role? A nuanced look at the PEXIVAS trial results and why PLEX is now largely reserved for severe pulmonary hemorrhage or rapidly worsening AKI.
  • Avacopan (C5a Receptor Inhibitor): Insights from the ADVOCATE trial on how this steroid-sparing agent is changing the landscape of AAV treatment.
  • Maintenance: Long-term strategies using Rituximab (typically up to 18 months) or Azathioprine, and when to consider switching agents for refractory cases.

Essential Reading & Resources
To master ANCA vasculitis, the hosts recommend reviewing these landmark studies:

Creators and Guests

Host
Kenar Jhaveri
Chair, ISGD Education Committee. Nephrologist Educator, Rapidly Progressive Glomerular Nephrologist, onconephrologist, cyclist 🚴‍♀️, runner 🏃 Editor in chief: ASN Kidney News
Host
Koyal Jain
ISGD Education Committee Co-Chair | PD @UNCkidney | Director of UME @UNCDeptMedicine | Glomerular Diseases and Vasculitis | Medical Education | Tweets are my own

What is GN in Ten?

A bite-size podcast brought to you by the International Society of Glomerular Disease. Nephrologists and glomerular disease experts Dr. Kenar Jhaveri (Northwell Health/Hofstra University) and Dr. Koyal Jain (UNC Chapel Hill) take a lighthearted look at the latest research, discuss clinical practice, and interview leaders in glomerular medicine — all in a short enough time to listen on your coffee break.

Laurel Damashek: Welcome to GN in
Ten, a bite sized podcast brought

to you by the International
Society of Glomerular Disease.

Our hosts are nephrologists and
glomerular disease experts Dr.

Kenar Jhaveri of Northwell
Health and Hofstra University on

Long Island, New York, and Dr.

Koyal Jain from the University
of North Carolina Chapel Hill.

Koyal Jain: Hello everybody.

Welcome to our new session in GN in Ten.

We are here with our board review basics.

Kenar Jhaveri: Oh, you got
the name right this time,

Koyal Jain: I got it right.

I'm so proud of myself.

I did write it on a piece
of paper although lost it.

We welcome you.

This is our ANCA vasculitis session.

We are going to talk about mostly
treatment, induction and maintenance,

and what do we do with our patients.

So I'm here with my amazing
co-host, Kenar Jhaveri, and we are

really excited to have you here.

Kenar Jhaveri: Welcome.

So I'm gonna throw the
first case at you Koyal.

This is an 88-year-old female and
she comes in with subacute rise in

creatinine, hematuria, non nephrotic
range proteinuria, RBCs in the urine

and you have a positive anti MPO titer.

And that's your presentation.

It's very classic, right?

It's a very board type of question.

It's always the older patient, it's
usually subacute rise over a few months.

And usually they do have hematuria
and proteinuria and hypertension,

and always the question about
do you biopsy or not biopsy.

Koyal Jain: I will say that I'm a
little bit biased because I come

from an institution where we tend
to biopsy most of our patients

unless they're really frail.

We do have some 80 something plus year
old patients who are not as frail as

you would expect and if she can undergo
a biopsy, our preference is to biopsy.

And I think part of the reason why is
we wanna see the degree of chronicity

that's associated with it so that helps
you with not just the treatment now, but

also potentially duration of treatment.

And so my gut feeling is I would
evaluate and see if she's frail,

not frail, can she undergo a biopsy.

Kenar Jhaveri: Yeah, let's assume,
the, because the data on elderly

patients now of ANCA vasculitis, the
treatment outcomes are very good.

So it's worth doing the biopsy to make
sure we're treating the right disease

and the right type of treatment.

Let's not get into the
frailty part of the elderly

because that's a whole different session.

But I think the biopsy does show
crescentic Pauci-immune vasculitis.

You do have an anti MPO titer, and I urge
everybody to make sure they check an NPO

and a PR3 titer and not just a CNP ANCA.

Because those could be falsely elevated
sometimes and not be truly disease

telling in terms of what's actually
causing the whole process, MPO or PR3.

Is that okay?

Koyal Jain: In fact, we have
actually moved towards describing

our patients as not GPA/MPA anymore.

We describe them as PR3 and MPO.

So I say this is my PR3 ANCA vasculitis
patient, my MPO ANCA vasculitis patient.

Kenar Jhaveri: Koyal is already
changing names it'll probably be

lag behind 10 years from KDIGO.

But that being said, it's important
because if you have a discordance,

so for example, if you see ANCA is
positive and it's not MPO say it's PR3.

And if it's a P ANCA and PR3,
that means it's a discordance

and that usually is drug induced.

And if you have low compliments and MPO,
PR3 positive, it's usually drug induced.

Oh, sorry, ANCA and C ANCA and P ANCA.

Koyal Jain: Yes, and also, don't forget
that if you have low compliments,

not just drug induced, always
think could there be an infection?

Kenar Jhaveri: Classic one
to rule out is Bartonella.

That's what we have seen a lot
associated with ANCA type of disease.

And the other one is hydralazine.

It always causes ANCA vasculitis and
cardiologists love to prescribe it.

Koyal Jain: My least referred in fact,
Kenar, you know what we call it at UNC?

We call it hydrANCA.

I like hydraANCAlyzine.

No, it's fine.

We can use either hydra, it's a bad drug.

Just make sure you don't give
that to your ANCA vasculitis

patients or your lupus patients.

The real meat of this is induction
and treatment of the disease.

So biopsy is showing crescentic GN.

You have this elderly
patient in front of you.

What are your options of induction?

It's hard to not mention
vitamin R right off the bat.

Yeah.

The recent recommendations from
KDIGO are very similar to what

we were doing for a long time.

I feel validated because we've been saying
that if patients can tolerate a little

bit of cytoxan we would give them a little
bit of cytoxan and we've been doing a

lot more combination cytoxan, rituximab
therapy with not too much cytoxan, maybe a

couple of doses, and then some rituximab.

That has gotten our patients into
earlier remission, cut down the

steroid use, and also get them
off immunosuppression earlier.

Again, like you said, if this
patient's not frail, and is making

urine then I would give her some
amount of cytoxan and rituximab

combination which is now what KDIGO
is recommending is to consider cytoxan

if you have organ threatening disease.

Kenar Jhaveri: So let's
start from the top.

So this patient has a diagnosis
or a PR3 or MPO vasculitis.

There's no anti GBM disease and we
are dealing with renal involvement.

We're now dealing with life-threatening
organ damage in the kidney.

Acute glomerular nephritis, not GBM.

So you really have three options.

Of course there's steroids,
but you have rituximab.

Which is the one gram dose
times two, two weeks apart, or

you have oral or IV Cytoxan.

Correct.

So you can give the IV version
or you can give the oral

version along with the steroids.

And then you have the third option,
which comes out of the Rituximab

trial, which is a combination.

Of, two doses of Rituxan and
two of Cytoxan, correct IV and

that's what Koyal referring to.

Those are the three
options KDIGO recommends.

So in your patient with not that
bad of a kidney disease or even a

little bit of crescentic, you can
go with Rituximab with steroids.

Both Koyal and I do prefer a com
cytoxan, a little bit of sprinkle

even in the elderly is totally okay.

It's not that cancer causing as we think.

But if you really have
vital organ life-threatening

disease at creatinine over 3.4

I would go with a combination of
rituximab with cyclophosphamide.

I prefer an IV cyclophosphamide dosing
because it actually has less total

amount overall, and I think that's
less, risky for hemorrhagic cystitis

and cancer and also other pancytopenic
side effects when you give oral.

But I would like to hear Koyal's
thoughts on those things.

Koyal Jain: Yeah, we almost
never use oral Cytoxan unless

we are doing like the Ponticelli
protocol or modified Ponticelli.

And so we do IV cyclophosphamide for
the same reasons that you've described.

I think the earlier studies that compared
oral and IV cyclophosphamide, which

said the oral cyclophosphamide had
less relapses, did not have rituximab.

And now with rituximab
we do see less relapsing.

We prefer IV cyclophosphamide.

Okay.

Now I've been answering
some of your questions.

Let me throw something at you.

We've all decided this is the induction.

Are you all doing pheresis?

Do you do pheresis in this patient?

When do you consider pheresis?

Kenar Jhaveri: Yeah.

So before we get onto pheresis, I
just wanna clarify the IV versus oral.

The oral dose is two
milligrams per kilogram.

The IV dose is 15 milligrams per kilogram.

The rituximab is, like you said,
is either the 375 milligrams a

meter square, weekly for four
weeks or one gram at zero and two.

And the combination Rituxan Cytoxan
is rituximab weekly for four weeks

or the one gram every two weeks.

But Cytoxan is 500 milligrams
for two weeks times six.

So it's usually, or some people give
two doses of Cytoxan, 15 milligrams

per kilogram at zero and two weeks
and alternate that with Rituxan.

So before the PEXIVAS trial came out,
I think most people were pheresing.

If you had severe kidney involvement,
maybe creatinine over 3.504,

and on dialysis dependent, they would
pheres, at least seven sessions.

For ANCA vasculitis, the PEXIVAS trial,
which is a randomized control trial, had

other things they we're looking at in
terms of steroid dosing, but it was really

comparing pheresis versus no pheresis in
pretty severe cases of AKI and vasculitis.

And it actually showed no
difference in outcomes.

Then there was this meta-analysis
that was done I believe a couple

of years later that did include the
PEXIVAS, but also included some of the

other observational studies and that,
threw a little wrench into the data.

And it turned out in the meta-analysis
the patients who had like severe

for example, renal disease, creatinine
over four, the need for dialysis are

reduced if you started pheresis early.

But there was no mortality benefit
maybe there was some benefit in

patients with pulmonary hemorrhage
that's where there's a gray zone.

If there were patients not on dialysis
and the creatinine is in the lowest range,

even though it's crescentic disease, I
really believe in the randomized trials

and not in this whole meta-analysis.

I can see that some people will for severe
kidney disease and pulmonary hemorrhage.

That's where the gray
area is in my opinion.

The randomization trial has put a little
bit of a damper on the pheresis part.

Koyal Jain: Absolutely.

If somebody has very mild kidney
disease, and their creatinine is

not rapidly getting worse, we do
not actually end up pheresing them.

We do think that if you have a really
rapidly rising creatinine, which

means that this is an RPGN pattern,
that's when the pheresis is helpful.

I think the PEXIVAS trial did not
include kidney biopsy data, it

just included patients who had
kidney function, less than 50

mLs per minute.

It included patients who had just CKD and
were not going to benefit from pheresis

anyways, and patients who had an AKI
who might have benefit from pheresis.

So I think that's the problem
with the PEXIVAS data.

It did not include the right
population or describe the pathology.

So what we do is if somebody has an AKI
or rapidly worsening kidney function,

we will pheresis, because we do wanna
make sure that we can do everything

possible to save their kidney function.

But if they have CKD or chronicity
in the interstitial fibrosis and

tubular atrophies a lot on a kidney
biopsy, then we would not freeze

them even with a higher creatinine.

The other thing that the PEXIVAS
trial didn't have enough patients

for the severe pulmonary hemorrhage.

It did actually have some indication
that the severe pulmonary hemorrhage,

people would benefit from pheresis, but
just wasn't statistically significant

because it didn't have the numbers.

And so for severe pulmonary hemorrhage,
given that it can be life-threatening

in patients, we will still pherese.

So those are the two patients
population that we will still pherese

for, but most other people we don't.

And we really rely on the amount
of chronicity on a kidney biopsy

and the severity of the kidney
disease and how rapidly it's getting

worse before we would do pheresis.

Kenar Jhaveri: Alright.

I think we should move on.

So the next thing we need to iron
out is, we're giving the Cytoxan

Rituxan combo to this patient.

How much steroids should we be giving
should we be pulsing one gram times

three days, or two 50 milligrams times

three days?

And should we be quickly tapering the
prednisone from 60 to 30 the second week?

Or should we do the standard tapering
over, a longer period of time?

The ADVOCATE trial and the PEXIVAS trial,
one looking at avacopan, one looking at

pheresis, both looked at a sort of reduced

steroid burden over the six month span.

A much faster taper in both compared
to the standard we used to do.

I have switched, to a much faster taper.

As long as the caveat that
the patient can get avacopan

quickly to start taking the drug.

That's been my practice.

Is that what you've been doing?

Koyal Jain: We do a reduced dose.

So for our

Kenar Jhaveri: AVAs one or ADVOCATE one?

Koyal Jain: I would say it's
like a little bit less than

PEXIVAS in terms of duration.

It is faster taper similar to that, but
the duration isn't as long as PEXIVAS,

and I think we've been able to do that
because of the combination therapy

Kenar Jhaveri: Tell me what you
do for the first three days.

We used to give one gram Solu-Medrol
and some rheumatologists still do that.

I disagree.

Koyal Jain: I feel like over the past
one or two decades we've not done that.

So it's prior to my time,
at least for us here.

Kenar Jhaveri: So I think what we do, a
standard weight 70 kilogram person, is 1.5

total over three days,
so not exceeding that.

So maybe 500 times three days, or 250
times three days, Solu-Medrol, and

then followed by 60 of prednisone.

And then within the second week down
to 30 by third and fourth week down to

25, fifth and sixth week down to 20.

By 10th week, you're 12.5.

By 16th week, you're already at five.

Koyal Jain: Yeah, and we do very similar
to what you do in the initial portion,

but our tapers a little bit faster
and we come off by 10 to 12 weeks.

Kenar Jhaveri: So I follow the
PEXIVAS protocol, which by the 12th

week you are down to 10 milligrams.

Koyal Jain: yeah.

Kenar Jhaveri: Yeah.

It depends if avacopan is
available quickly, even faster?

Koyal Jain: Exactly.

If avacopan is there, then makes no
sense to do both at the same rate.

Kenar Jhaveri: So I'm hoping people get
that message that I think we should be

getting rid of steroids as a treatment
option completely eventually, but at least

for now, we're minimizing the need of
steroids in these patients that, they're

elderly, most of them, they're frail,
they have bone issues, fracture risk.

Let's just get down with the
steroids, and that's what KDIGO

recommends is the PEXIVAS protocol.

Koyal Jain: It's not just for
ANCA and other genes as well.

We are like reducing the amount of
steroid use most of our patients.

So less is more.

Kenar Jhaveri: As you are already
on this let's talk about avacopan.

Koyal Jain: Exactly.

Kenar Jhaveri: Will you start
avacopan right off the bat,

Koyal Jain: we try.

It took a while to get it on our formulary
in the hospital so we could continue it.

But we finally now have it on formulary
for starting it, and we are able

to start it, and then we get the
outpatient approval and continue it.

And when somebody's on avacopan,
I will get off steroids faster.

Kenar Jhaveri: Just for everybody to know,
avacopan is a c5a receptor inhibitor, and

it's an adjunctive therapy that showed
you can minimize the steroids, but it

actually showed a benefit in GFR down
the road in terms of these patients.

So it's 30 milligrams BID, that's
usually started at the time of

induction, but it's hard to get sometimes

so you start whenever you can and
once the patient's on the drug, you

can quickly reduce the steroids.

And it really works beautifully.

I think the study was for 12 months,
if I remember, but I know I've used

Avacopan for two years in some patients.

Koyal Jain: I have used it longer.,

but you modify based on your patient
and how they're responding to a drug.

Kenar Jhaveri: And you check liver
function, that's most important

Koyal Jain: of course, yeah.

Kenar Jhaveri: It does affect
the cytochrome PR50 enzyme.

That's probably why your dose
reduce in some patients might

be on good common drugs.

What about giving them.

PCP prophylaxis, do you do that routinely?

Do you do Vitamin D, calcium and ppi?

Koyal Jain: I do the PCP
prophylaxis, the Vitamin D calcium.

The GI prophylaxis is something I
might do for higher dose steroids and

if somebody is tolerating everything
fine and doesn't need it, then I can

come off of it a little bit sooner.

Kenar Jhaveri: Okay.

Koyal Jain: Typically we
prefer PJP prophylaxis with

Trimethoprim-Sulfamethoxazole the
single strength tablet, either daily

or double strength, three times a week.

You can do atovaquone,
you can do pentamidine.

We've had some insurance issues where we
prefer to give pentamidine, and if you're

coming off steroids faster, then it might

get them enough coverage if
given in the hospital setting.

And then atovaquone is 1500
milligrams and can taste really

terrible according to patients.

Dapsone can be used and
G6PD should be checked.

Kenar Jhaveri: So now I guess
this patient does well and you

did the rituximab protocol.

You gave avacopan, you
took them off the steroids.

You're at six month mark.

Creatinine is 1.2.

Proteinuria is still like maybe 0.5

grams.

There's some hematuria.

I'm assuming that most people
are doing rituximab maintenance.

So that's one of the drug
choices for maintenance.

I do up to 18 months.

Of rituximab.

One dose, another dose at
six months, 12 months, and 18

months regardless of the CD19.

Or you could check a CD19
and tailor it based on that.

Some people even do two years
of maintenance, but there's

really no data to support longer
maintenance, but it's possible.

What do you do?

Any other options for
maintenance besides Rituxan?

Koyal Jain: We prefer rituximab
for maintenance similar to you,

and most patients will get the
six month, 12 month mark dosing

and the 12 month mark technically
last them for 18 months, right?

And so that's what we would do.

And then 18 months we'll reevaluate
if we wanna do more or not.

I will say that

what we do, for rituximab, is we've
actually moved away from one gram dosing.

We typically 500 milligram dosing,
similar to maintenance studies where

they used 500 for the maintenance dosing.

And then I have used azathioprine
for maintenance in some patients.

And I would say that there was a patient
who became pregnant and Rituximab has

not been really used in pregnancy.

Azathioprine would be
great for that reason.

And there was one other patient
who had hepatitis B, in those

cases, I might refer something like
azathioprine as opposed to rituximab.

Kenar Jhaveri: So I think if you
use the main Rituxan scheme, it'd

be 500 at six, 12, and 18 months.

If you use the Rituxan scheme, that would
be 1000 milligram dose of rituximab.

The azathioprine is usually for how long?

A year for maintenance?

Probably.

And then MMF

Koyal Jain: One to two year, I feel like.

No, they're so controversial.

Kenar Jhaveri: I know

One

Koyal Jain: to two years
is what I typically

Kenar Jhaveri: it's like lupus, right?

We don't know how long

Koyal Jain: We don't know.

Kenar Jhaveri: I've used
MMF too in some cases.

We

Koyal Jain: have, yes.

Kenar Jhaveri: I think it's easier to just
continue with rituximab in most cases.

Make sure you monitor the IgG
levels if you're doing a lot of

Rituxan and give back some IVIG or
subQ immunoglobulins if need be.

Koyal Jain: I've done more IVIG than
subq immunoglobulin to be very honest.

Kenar Jhaveri: And what
dose do you use for IVIG?

0.5

grams per kilogram?

Koyal Jain: .4

to .5

gram per kilogram.

And

Kenar Jhaveri: try to keep the
IgG levels above a certain range?

Koyal Jain: I will be honest, we
don't do it just for IgG levels.

We do it if somebody's having infections.

Kenar Jhaveri: Fair enough.

Koyal Jain: low I IgG level, like I have
some patients like somewhat low, but

they have no complications whatsoever,
why am I exposing them to more serious?

Kenar Jhaveri: Yeah.

Koyal Jain: Some people go down
a little bit and start having

infections and they get regular IVIGs.

More for patients with
infections and a low IgG level.

I do have one question
for you before we end it.

What if somebody's resistant
to all of this, right?

Like we've now talked about.

Azathioprine, rituximab, cytoxan,
steroids, pheresis, what if somebody's

resistant to all of this treatment?

What do you do?

Kenar Jhaveri: Yeah, so first thing I
think to make sure there's no secondary

trigger to this, like an infection, that
we might missed an echo, that something

is triggering this, and once you ruled
out a secondary cause I think, there

is some literature in methotrexate,
in, really refractory cases, but that's

more in the room world, non-renal.

I would consider obinutuzumab it's
a much more stronger anti-CD20.

It should be, I think it's being
studied in ANCA vasculitis.

I know.

Probably, hopefully getting
approved for membranous and already

approved for lupus nephritis.

So it's probably the go-to drug for me
next if none of these things work given

the caveat that this might be a kidney
that we might not be able to save, so

repeat biopsy might also be helpful.

Koyal Jain: Yeah.

Obinutuzumab is great have used it
for patients who've had reactions

to rituximab and cannot tolerate
lower, slower infusion rates either.

I've seen DARA being mentioned
like in early refractory cases.

I have personally not used
DARA for this indication ever.

Kenar Jhaveri: Can you remind
our listeners what is DARA?

Because you and I might

Koyal Jain: daratumumab,

I know Daratumumab is a drug that's
actually used in MGRS myeloma.

Kenar Jhaveri: How about before we
end, let's just do the go-to papers

that all fellows and people who wanna
know about ANCA vasculitis should read.

I think my two big ones
is PEXIVAS and ADVOCATE.

What are your big ones that they should

Koyal Jain: I think MAINRITSAN and
RITUXVAS, because RITUXVAS is the one

where you had low kidney function.

I think they should know.

And I know it's a little bit
older now with NEJM, but I

still think it's not that old.

It's about a decade and a half old.

So I think those would be important

Kenar Jhaveri: What about
for maintenance therapy?

Any major ones besides
the ones you mentioned?

Koyal Jain: I think
RITAZAREM would be okay.

There was CYCAZAREM and I might
be butchering the name, which

was cytoxan, azathioprine.

But I don't think you need to
go back to the whole paper.

But I think this, these
would be the main ones.

Kenar Jhaveri: Alright, so
ADVOCATE, RAVE,  RITUXVAS.

And then there was one
more we mentioned, right?

The PEXIVAS and.

Koyal Jain: MAINRITSAN.

Kenar Jhaveri: Alright, so those are the
ones that you should have a must read

before you understand this disease better.

Koyal Jain: Okay.

Kenar Jhaveri: I think we'll end
and let Koyal take care of patients.

Koyal Jain: Okay, we'll end there,
because I'm not going anywhere

taking care of patients right now.

Kenar Jhaveri: I actually have
to go take care of patients.

Laurel Damashek: This has been
GN in 10 from the International

Society of Glomerular Disease.

You can listen and subscribe
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and tweet at us at ISGDtweets.

Thank you for joining us.