GN in Ten

Episode 5: Board Review Bonus: Renal Amyloidosis

In this "Board Review Bonus" (BRB) episode, hosts Dr. Kenar Jhaveri and Dr. Koyal Jain provide a comprehensive clinical overview of amyloidosis—a complex and often enigmatic disease with significant renal implications. From the initial "mushy, smudgy" appearance on light microscopy to the precise measurements of electron microscopy, our hosts break down the essential knowledge required for both board preparation and clinical practice.

The discussion moves beyond the common AL and AA variants to explore rare types like LECT2 and the hereditary forms. Dr. Jain and Dr. Jhaveri emphasize that "the tissue is the issue," highlighting the diagnostic necessity of biopsying the affected organ and the critical role of mass spectrometry in directing therapy.

Key Topics Covered:

Classification of Amyloidosis: A detailed look at AL, AA, LECT2, and the hereditary variants including ATTR, fibrinogen A alpha-chain, and Apolipoprotein.
The Diagnostic Workup: Understanding the utility of Congo red staining, the significance of birefringence, and the institutional variability of fat pad biopsies.
Electron Microscopy (EM) Pearls: A guide to differentiating amyloid fibrils from mimics such as fibrillary GN, immunotactoid GN, and cryoglobulinemia based on diameter and arrangement.
Clinical Management: Navigating the multidisciplinary approach between nephrology, hematology, and cardiology, including the nuances of RAAS inhibition and diuretic therapy in proteinuric patients.
Transplantation Outcomes: Evaluating recurrence rates and survival benefits for different amyloid types post-kidney transplant.

Recommended Resources and Literature:

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

Producer

Angel Morales

Project Manager @ International Society of Glomerular Disease

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.

Board Review Bonus 5: Renal Amyloidosis
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[00:00:00]

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: Hi everybody. Welcome to our new episode in GN in Ten with Kenar Jhaveri and me Koyal Jain as your host, we are really excited to have another board review bonus

Kenar Jhaveri: BRB.

Koyal Jain: BRB episode on amyloidosis. Everybody's favorite disease, and we will be talking to Kenar about different pathology. So how are you doing, Kenar?

Kenar Jhaveri: Good. Good. I love amyloidosis. It's a very enigmatic disease, I think, but renal amyloidosis is even more challenging and it's a board favorite. It's something that is very challenging to diagnose, but I think [00:01:00] a lot of you need to know the different types of amyloidosis.

So I think we'll start with the types of amyloid. Is that okay? Koyal

that is the biggest challenge for most people.

Koyal Jain: I think so. I think diagnosis, the types of amyloidosis, these are great board review questions and it's always very confusing with all the different varieties that exist out there. So why don't you take us through the different types of amyloid.

Kenar Jhaveri: So the most common amyloidosis is your AL or AH amyloid. So that is light chain or heavy chain amyloidosis, which is your paraproteinemic amyloid, which is also malignancy amyloid, right? So that is the one that we get the most common diagnosis on a kidney biopsy, and then we refer those patients for treatment for a myeloma specialist or a hematologic specialist.

And you know that AL Amyloidosis kidney involvement is like 50 to 80%. And it's the heart, the kidney, wherever these deposits happen is usually AL amyloidosis, and that is a light chain [00:02:00] disease. And then you could have one of those heavy chains do the same thing.

And you can call it a variant of myeloma or some sort of paraproteinemic process. I can't stress that enough. That is, a kidney biopsy diagnosis. The other big one that we see is due to inflammation. The chronic inflammatory condition, could be a cancer, could be hep C, could be rheumatoid arthritis, familial Mediterranean fever.

That chronic inflammation leads to what we call AA amyloidosis or amyloid A disease, and that is due to interleukins and chronic cytokine release from that inflammation, and that's what causes amyloidosis. The other ones are now the rare stuff. One I do want you guys to be aware of is called, the leukocyte cell-derived chemotaxin 2 (LECT2) amyloidosis.

This has a predominant kidney liver involvement. It is common in North America, but mostly the Mexican descent or Indian descent, Punjabis. [00:03:00] It's very common in Egypt. And it's actually the second most common in Egypt, and nobody knows the real reason why it is. We think it's inflammatory,

but it's not a genetic variant. It's actually an inflammatory disease. The outcomes are much better with this type of amyloid. They actually have a more slow, progressive chronic kidney disease. Then we come to hereditary amyloidosis. Okay. They're a slew of them. And you probably hear about the most common one that we see on television ads or radio ads and patients in the office:

that is the ATTR or transthyretin amyloidosis. That one it's more of a cardiac involvement. It does have kidney involvement - we're seeing there is 30 to 40% renal involvement - but it's hard to tell if it's direct deposition of that amyloid in the kidney or just from chronic cardiorenal syndrome.

So biopsy data on that is very limited, but it is a fairly common cause of genetic amyloid. And there are drugs now that directly target the [00:04:00] transthyretin amyloid in the cardiology world. The other genetic amyloidosis are lysozyme. There is the gelsolin amyloidosis.

There is a few apolipoprotein amyloidosis, very different types. There is one called the fibrinogen A alpha-chain amyloidosis; these are all rare genetic amyloidosis. The most common renal one is fibrinogen A Alpha chain or AFIB amyloidosis and it has massive glomerular disease involvement. The one that does not have much of a glomerular involvement, but more of a vascular slash tubular involvement is apolipoprotein amyloidosis.

So, this is the slew of different types of amyloids to think about. It's not just always AL or AA. There are these genetic and inflammatory amyloids that we should be thinking about Right. Koyal.

Koyal Jain: Absolutely. And I will say that we actually have a multidisciplinary amyloid clinic here, [00:05:00] which I'm a part of. We actually get a lot of consults also from people who are doing Renasight. And so they run Renasight testing, they get the TTR results back, and if the patient has any degree of proteinuria, even if it's for something else, sometimes you get a consult saying, hey, is this TTR in the kidney?

And so you might be seeing more consultations and thinking about other causes of amyloidosis. So with that, I think the other big portion that becomes really important for board review is: how do you diagnose these different patients with amyloidosis? And I think a biopsy of some sort, whether it's a cardiac biopsy, whether it's a fat pad biopsy or a kidney biopsy, is really important.

I will say fat pad biopsies, depending on which institution you're getting the biopsy at, will have different amounts of sensitivities, right? Like, I know for a fact that certain institutions have had sensitivities as high as 60 to 80%, and certain places as low as 20%. So.

It's really institution dependent , whether you get a good fat pad biopsy or not. So at our institution, we do a lot [00:06:00] more of cardiac biopsies and kidney biopsies, depending on the area of involvement. And so once we get a kidney biopsy, what you're really looking for in that light microscopy is this presence of Congo red positive material, right?

That mushy smudgy material that you can see. And that material typically has birefringence under polarized microscopy, and that is your typical amyloid deposit. It is often in the mesangial region, but it can also be the capillary loops. I will say that there have been times where people may not have glomerular involvement with amyloidosis, and it is only present either in the tubular space or in the vascular space.

So it's really important to be looking at all your spaces, even though most commonly in the glomerular region, it can be involving other regions as well. Once you see this on like microscopy, you know you're getting your EM, you're getting your IF for your electron microscopy. And this is a board question I think that comes up regularly is what is the size of these fibrils?

So [00:07:00] essentially you see this fibrillary structure under electron microscopy. And if you see 8 to 12 nanometers, I see around 10 ish, plus minus two. If you see the diameter of fibrils, you're really thinking this is amyloid deposition that's happening in the capillary walls and the mesangial or other spaces.

Kenar Jhaveri: I always get confused with this. Just because you have Congo red positivity, does that mean you have AL amyloid or just any amyloid?

Koyal Jain: So, great question. Just having Congo Red positivity doesn't mean that you only have AL Amyloidosis to figure out whether you have AL or not. You either need immunofluorescence or Mass Spec.

Kenar Jhaveri: So I think that's very important, right?

Koyal Jain: Yes, extremely important. This was a hint for everybody listening. This is a hint from Dr. Koyal. You need to say, this is really important.

This is only amyloid, not all AL amyloidosis.

Kenar Jhaveri: And I had another question for Koyal, because she threw in this like random fibril what did you say? 10 to 12 nano meters. So they're randomly arranged, you said. But then, [00:08:00] people say there's something called fibrillary GN that also has fibrils and there's tactiod GN that also has fibrils and even lupus can have fibrils.

So how do I know this is amyloid fibrils and not the others?

Koyal Jain: It's the size of the fibrils. So I say that's important. So around 10 is amyloidosis. Fibrillary is close to 20 ish, immunotactoid is close to 30 ish. And immunotactoid can have a tubular structure as well.

Kenar Jhaveri: What about cryo? Isn't that also a fibril...

Koyal Jain: cryos can be around closer to 30 ish.

Kenar Jhaveri: And just a reminder to everybody what Koyal mentioned very quickly, because she's so confident about it, is they're randomly arranged fibrils. So these are just randomly stacked and small size. Whereas if you look at immunotactoid, they're stack-like, they're not randomly arranged.

And the other thing is the structure of cryo is more curve like, so the pathologist will tell you. But if you wanna be smart and also question the pathologists, do that because sometimes these diagnoses [00:09:00] are important. If you miss an amyloid and you call it something else. Or if you miss a fibrillary and it's immunotactoid, it's a big difference.

So I think pathology is the most likely asked questions with these type of disorders.

Koyal Jain: A hundred percent. And I think also clinically it becomes really important once you get this light microscopy and you get your EM back and you have your amyloid. Trying to figure out what type of amyloid through your immunofluorescence or mass spec really helps you determine what's your treatment for your patient.

So to go into immunofluorescence when you're looking at these patients who have, let's say, AL amyloidosis, so L stands for light chain and the A stands for the amyloidosis. When you have the AL Amyloidosis, you really have lighting up of a certain light chain. If it's a heavy chain amyloidosis, it'll not light up for Kappa or Lambda.

Now typically immunofluorescence is pretty good at picking up your AL amyloidosis. However, it's not great at picking up some of the other amyloidosis that Dr. Jhaveri just mentioned, all the detailed amyloidosis. [00:10:00] We can stain for AA and ALEC2, but we can't really stain for everything and we can't stain for it in all the different institutions that exist out there. Even for us, we actually don't do mass spec ourselves. We will send them to an outside place, somewhere to get a mass spec done, to figure out what type of amyloidosis exists because that will then determine how do I treat my patients?

Kenar Jhaveri: Just for everybody. Mass spectometry is a detailed chemistry. If you remember from organic chemistry, it'll detect the type of protein that is in the deposits. So it'll actually tell you the exact protein that is, elevated in that patient that's depositing there. But what about genetic testing?

Would that help you Koyal along with the path?

Koyal Jain: I think so. I think if you have some patients who have the hereditary renal amyloidosis that you mentioned, then you could do genetic testing. I will say generally, path is really needed because what if you have a genetic test that's positive, but you really don't have amyloidosis present, [00:11:00] right?

Or amyloid fibers getting deposited, causing kidney damage, for example. You really can't just follow the genetic testing.

Kenar Jhaveri: And the other thing is in terms of the mass spec is so important - there's actually an illustrative case in the New England Journal where a patient had MGUS with Lambda light chains and the patient had a kidney biopsy as everybody's assuming that it's gonna be AL Lambda based amyloid and the IF was not a great sample, so the IF was unable to be done, , because of sampling issues.

But given the fact that there was bone marrow showed AL and MGUS, they thought this most likely is AL Amyloidosis, and the patient decided to get chemotherapy. Turns out genetic testing was done and Mass spec was sent. It ended up being one of those genetic amyloidosis. So just because you have MGUS in the bone marrow doesn't mean you automatically will have light chain or heavy chain amyloid, you still might have 10%, 15% hereditary amyloid. So it's very important what Koyal mentioned here, that a mass [00:12:00] spec is so key. And if you're not sure of the diagnosis, the best is send for a mass spec.

Koyal Jain: I will add to this that it's not just for kidney biopsies. We send cardiac tissue also for mass spec. We are lucky in the kidney world that we do immunofluorescence on all our patients, and that gives us some data. But that doesn't necessarily happen in the other biopsies outside of the kidneys, and so people routinely have to send for mass spec, especially myocardial tissue.

So, we know the different types of amyloidosis. We kind of know how to diagnose these amyloidosis. And I think the last thing that we should focus on is how do you really manage these patients? Like, what do you do for patients with AL amyloidosis and what is something you should do for all patients with amyloidosis?

So let me ask you, Dr. Jhaveri, and then I will tell you whether you're correct or incorrect,

what do you do? For patients with AL specific amyloidosis, how do you treat those?

Kenar Jhaveri: Hematology consult. Because it's not my forte, right? It's not a nephrologist's forte. AL amyloidosis is a malignancy and [00:13:00] they should be treated with therapy like plasma, anti plasma cell therapy like bortezomib, daratumumab, and the whole CyBorD with a stem cell transplant.

Yeah, you can do supportive therapy. But I would be careful putting these patients on ACEs and ARBs because they do drop their blood pressures. So I don't aggressively treat the proteinuria if the hematologist is quickly gonna treat the hematologic component of it.

There's no other role here in terms of pheresis or anything like that. It's really treating the underlying hematologic component.

Am I correct?

Koyal Jain: I forgot my job as the interviewer. Yes, you're correct. I wanna highlight something you said about the RAAS inhibition. I often see patients with amyloidosis being placed on RAAS inhibition. I place them on RAAS inhibition as well, as long as blood pressure's high.

There's actually a study in the cardiac literature which came out and said If you had AL amyloidosis of the heart and you were on RAAS inhibitors, you actually had higher mortality then patients who are not on RAAS inhibitors, which is opposite to [00:14:00] what we would think is true. And the reason for this is because a lot of patients with cardiac involvement also have vascular involvement and run low blood pressures.

And in those patients, when you give them RAAS blockade, they drop their blood pressures like you said and obviously mortality is higher. However, if you have a patient who's not having autonomic dysfunction, who is not having low blood pressures, blood pressure's running in the one forties, one fifties, and you're having to give them some medication for blood pressure, then in that case I prefer the RAAS inhibition to reduce the proteinuria. Okay, so finally what do you do for other forms of amyloidosis treatment?

Kenar Jhaveri: So the AA, which is the inflammatory - again treat the underlying inflammatory condition, right? So if it's rheumatoid arthritis, you need to talk to the rheumatologist. If it's renal cell cancer causing AA amyloid, talk to the oncologist. Sometimes, you can yourself approach and give an anti-IL-6 agent or some of those anti-inflammatory agents, but you have to work with the disease, modifying doctor there.

[00:15:00] Really, it's whatever the disease that's triggering the AA amyloid. And then with the genetic amyloids, the only treatment available right now is for TTR Amyloid. There is , inotersen, vutrisiran, patisiran and all these drugs for ATTR amyloid. Most of these are prescribed in the cardiac world, and cardiologists usually are managing these because 90% of TTR amyloid is cardiac, but we are seeing some patients of proteinuria and renal involvement.

So this might become something that might be useful. And for the genetic amyloids really not much out there in terms of treatment. It's mostly supportive care and transplantation, and some of them need both liver and kidney transplantation, depending when that protein is produced.

Koyal Jain: And I will also say that there are some trials that are happening out there. If you have a patient and there is a trial that is available close by, please consider enrolling them. Going over the conservative management, just remember anytime you have [00:16:00] proteinuria, and especially in a patient who's oftentimes nephrotic and swollen and has volume overload, cutting down the sodium in the diet is really helpful in controlling some of their protein excretion, but also in controlling their blood pressure and their volume. Apart from the RAAS inhibition that we've already talked about, we'll start them on lipid lowering therapy because their cholesterol levels are really high, and then diuretic therapy. I typically prefer to use some longer acting diuretics over furosemide, which doesn't last as long.

Plus with a low albumin level, it may not get secreted and may not be as effective as some other loop diuretics, which are longer acting. So I prefer non furosemide based loop diuretics in these patients.

Kenar Jhaveri: Oh, I agree. The other big issue is when they start dialysis, you have to be very careful. They do get hypotensive because of vascular involvement and fluid removal, so dialysis with some of the advanced amyloid patients is very challenging. We're not gonna go in detail about transplant, but the recurrence after transplant in some of [00:17:00] these, especially the genetic amyloid, is reasonably high. Especially the AFib amyloid has a pretty high recurrence rate. And some of these, like AA amyloid, AL amyloid in the current literature do very well post kidney transplants, if anything better than on dialysis. So, counter to the prior thoughts we used to have that they didn't do that well with kidney transplant.

So if the clone has been treated and the underlying inflammation has been treated, then these patients do fairly well post kidney transplant.

Oh, just one more thing, Koyal, about the biopsy. I always tell this to my trainees. Always biopsy the organ with the tissue with the issue. If there's no proteinuria, don't go biopsying the kidney.

If the patient's presenting with heart failure and AKI, biopsy the heart, the patient has eight grams of protein, biopsy the kidney because that's where the amyloid is being deposited.

If you're gonna go around biopsying the wrong organ, you're not gonna get a diagnosis and that's where the things get missed. So always the tissue is the issue here in [00:18:00] amyloidosis.

Koyal Jain: And to be honest this is why we do a lot of myocardial biopsies because there are patients who have not as much kidney involvement, but we can clearly see, that there's potential cardiac involvement. So why not go for something that is easily accessible. People often, like nephrologists, especially worry about cardiac biopsies, they're actually not that difficult and they can be relatively very safe.

And so again, depending on what the outcomes are at your institution, we often prefer cardiac biopsies as well. If there's clear cardiac involvement we'd go for the cardiac biopsy as well.

Kenar Jhaveri: So I think as nephrologists, we are mostly diagnosticians of this disease and not the managers.

Koyal Jain: Ooh. I don't know. I think the co-managers I think we are not the managers of the immunosuppression necessarily, but I think we co-managers of the quality of life because the quality of life depends on the volume status,

Kenar Jhaveri: You can make yourself feel better. Sure,

I think we make good diagnosis. If you can diagnose amyloidosis, you've just saved a patient's life and, gotta get them to the right [00:19:00] type of specialist. Because we don't have those tools to treat these patients.

With that we have to say goodbye. Its Koyal and I signing off on GN in Ten BRB!

Laurel Damashek: This has been GN in 10 from the International Society of Glomerular Disease. You can listen and subscribe wherever podcasts are found and tweet at us at ISGDtweets. Thank you for joining us.

Koyal Jain: I will also like to point out to our listeners that when Dr. Jhaveri asks me a question, , when I give the answer, he's like. Correct. I feel like I'm in an exam. This really sounds like a board.

But this is how I would, pass or fail or know that I'm doing

Kenar Jhaveri: right.

You we can turn that around. take, you take turns

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