All right, thanks, Dr. [INAUDIBLE] We'll move now into the medical grand rounds portion of the day. And we're really excited to have Dr. Jonathan Hogan with us here today. Dr. Hogan is currently an assistant professor at the University of Pennsylvania. And in terms of some background, Dr. Hogan was born and raised in Queens, New York, and started his career and earning his MD and doing his internal medicine residency there. He then moved on to Columbia to pursue a fellowship in nephrology as well as glomerular disease, and stayed on as faculty there before returning to Penn in 2014. Then he also serves as the clinical director for the Glomerular Disease Center and the director of the Lupus Clinic as well. 

And really, through his early career, he has become a national expert and in a wide range of areas, including nephritic and nephrotic syndromes, onco-nephrology, as well glomerular diseases, teaching widely nationally on the issue-- on these issues-- as well as becoming a favorite clinical teacher at Penn amongst residents and Fellows there. He's also developed as leading researcher in the area, serving as a site investigator for numerous trials, and lead investigator for the Penn Kidney [INAUDIBLE] Project. 

And so with that background, we're very, again, honored, and excited, and grateful for Dr. Hogan to be here today to join us for a medical grand rounds and to walk us through the complexities of glomerular diseases, and bring some clarity to this often confusing range of pathology. So with that, please join me in welcoming Dr. Hogan. 

[APPLAUSE] 

Can everybody hear me or no? Better? Move it up. It's OK? Higher? Warmer? Is this better? OK, good. Well, thank you so much for the introduction. And thank you, I want to thank Karen for advocating for the invitation. As we know, these things do go a long way, particularly for junior faculty. And Karen's always been a role model for advocating for junior faculty, and actually was my residency-- our little pod of people, and she would take us out to dinner. So if you ever want someone to take you out to dinner, Karen is apparently the person. And so but she's-- but really a role model with regards to medical education. So I really appreciate this opportunity. So thank you. 

And I know that when you woke up today, the first thing on your mind is, what's going on with glomerular disease? And I think that's fire that burns and all of us. And so what I'm going to do is I'm going to go well past 3:10 PM today because nothing's going on at 3:10 PM, to go right into the basketball game, to go over all of the glomerular diseases that have ever existed and have no cures. No. 

But I'm going to be talking about glomerular disease because I do think that there is a paradigm shift, the way that we kind of taught and learned these diseases is completely shifting from this histology-based, confusing paradigm to more of a paradigm based on biology. So it's a really exciting time for our field. And so I'm hoping to impart that a little bit today. 

So here are my disclosures. So the agenda today is first to review the kidney biopsy, which is needed to diagnose most glomerular diseases. To then go over some case-based examples of the evolution from histology to biology-based approaches to glomerular diseases. And that's because, again, I only have a few jokes and moves-- so for those of us who saw my talk yesterday, I'm sorry. But this is the way that people respond to glomerular diseases in many cases, right? If you've seen the movie, you know what I'm talking about. 

But there are some things in life that just shut you down, right? You start talking about interstitial lung disease, and UIP, and whatever letters you want to use-- just go ahead, because I am not listening, because I just can't-- I can't handle it. But I think where we're going to be going now is from more of a-- and I think the same thing is happening in interstitial lung disease, where we're going from things based on these descriptive patterns more to biology-based diagnoses and treatments, which is very exciting. 

In nephrology and in medicine, we kind of have a love-hate relationship with glomerular disease. We love them because they're challenging, they're interesting, the names are cool, right? You start throwing around acronyms, MPGN, and just say it-- say glomerular five times fast. That's how you get the clinical director position at Penn, you need to say it five times fast because it's not an easy thing to say. 

You become comfortable using immunosuppression, right? So whenever a patient was admitted on even like 1 milligram of tacrolimus to my service in residency, I was like, please don't die on my service. And somebody call and tell me what to do with the tacrolimus, I just-- but when I become comfortable with it, it's a very empowering experience. 

We have good acronyms. We have like the CYCLOPS trial. Cyclops, very good, very cool. Cardiologists have the TIMI trial, we have a CYCLOPS trial. It's very cool. And the experts sound cool when they talk about this, right? And that's because anytime somebody is talking about something that you don't know about, they sound like an expert, and that sounds cool. 

But they also make us feel dumb. They're rare. So it's very difficult to gain experience and expertise in them because we don't see a lot of them unless they're concentrated. The names are generally not helpful historically. MPGN is not a helpful name for disease. The side effects of immunosuppression can be dangerous and severe. The data quality historically has been poor, although much better recently. And experts historically-- and I'll put myself into that category, I guess, because I'm at the podium today-- have not understood much about these diseases. 

And so it's kind of turned it into deal with a situation like minimal change disease. So when biopsies were first done, they were patients with the nephrotic syndrome, and something is clearly wrong with them. Like they've gained 30 pounds in a week. And you do a biopsy and the light microscopy is normal. It's like a mill disease, or light point nephrosis, or minimal change disease, and you give steroids. And then, the thinking '70s, electron microscopy. And there's foot process effacement. So when you saw minimal changes, you thought foot process effacement, because that's always on your medical school tests. And we can test medical students, and we gave them-- we give them steroids. 

And then in 2019-- right-- we're trying to go to Mars. We have CRISPR, we have CAR T cells. But we're still giving steroids for minimal change disease. So I think that we have to get to a better place. And I think that what this talks about, is that we are getting to a better place with regards to this disease. And then you do this. So you go-- you make make your index card-- well, I used to make index cards, back when people wrote index cards. 

And so it would be nephritic, nephrotic, nephritic-- whoops, sorry-- it's both. We have nephritic, nephrotic, nephritic, nephrotic, nephritic-- and then you learn it for the test. And then you're just like, I-- I'm done, right? I'm going to move on to my next subject matter. And that's OK. But again, I'm hoping to impart a bit more about biology-based approach to these diseases. 

So the first thing is that we need the kidney biopsy to make almost all of these diagnoses. And the first thing is a philosophical approach to recommending a kidney biopsy, or really any invasive procedure. I think people try to memorize these things about, what are indications or not indications? But we should not be so specific to the kidney. Just think like a logical person and you will be led in the right direction, right? So we need this test-- any test-- if it's required to make a diagnosis or provide information that will guide treatment decisions. 

The natural history of the diseases has to be bad, right? And so I think what we always have to remind people is that kidney disease is very bad. And mortality for patients on dialysis is astronomical. When I speak to my oncology colleagues who I collaborated closely with, they're always astounded that our mortality exceeds most of their cancers. And we don't get that message out enough clearly to the community, that that's why we do need to make better efforts at diagnosing and treating these diseases. 

The natural history of diseases can be altered, right? So if we couldn't alter it, we're not going to do the test. The treatment of diseases differ, right? So we don't use one hammer for all nails. So in the past, it was always steroids, Cytoxan, and maybe pheresis, right? So if you ever quizzed on rounds about a glomerular disease, if you say steroids, cyclophosphamide, and maybe pheresis, you're almost always right, right? Because that's what's been available historically. And that's what we're getting away from, actually, with regards to the differences in treatments. That the treatments adverse event profiles are acceptable, and that the risk of the procedure is acceptable. 

So again, you don't need to think like a nephrologist, you just need to think like any other test that you're ordering for your patients, and you'll be led in the right direction. We also do kidney biopsies because we are not that great at predicting the future. This was a study that was done out of North Shore-LIJ in 2009, where they looked at 196 biopsies. And then they looked back at the charts to figure out how good nephrologists were at predicting the diagnosis. And as you can see here-- do we have the mouse here or no? I was told not to use this because people don't like it in the room but anyway-- 

[INAUDIBLE] 

Oh, it's the sun? Ah, there we go. Excellent. Good. Yeah. So you can see here that-- thank you. So the predicted diagnosis was 29% of the time. The diagnosis was on the differential 14% of the time. And it was an unexpected diagnosis 15% of the time. The rest of them done were done for disease severity, or were non-diagnostic. But if I'm going to my patient and say, you know, I'm thinking about giving you cyclophosphamide for six months, and I'm like 29% right-- I'm like 29% sure that this is the diagnosis. That's not going to be good enough, right? So that's why we do the-- that's why we do the kidney bias. 

We do need to know a bit about the risk of the kidney biopsy, briefly. If we look at large studies, this is just a summary. Or you can see here that with regards to major risks, that the percentage of patients requiring a blood transfusion is on average around 1%. This is the sickest of the sick, and the healthiest of the healthy. And that about one in 1,000 need an intervention to stop the bleeding after the procedure. 

Subsequent studies and other studies show much higher risks in inpatients. And obviously, that's true. So we always have to weigh the risks. But we-- again, I want to reinforce that the morbidity and mortality of these conditions is significant. So this should be taken into consideration. I basically need to be convinced not to biopsy patients. It's not that I'm just like sneaking up on them with a needle. But you know what I mean. Like I go into every patient saying, I should be thinking about biopsying this patient because I think it will yield important information. 

So to summarize the approaches, we can sit there, and I can go out there and give you a different-- ask you to generate a differential diagnosis. And by the time you've gone through your differential diagnosis, I've already snuck up and biopsied the patient, and I can get the answer usually within about 24 hours with regards to the diagnosis, right? 

So I think that the exercise of generating a differential is important on some level, and certainly for people in nephrology, but if you're practicing outside of nephrology, just recognizing that the kidney function is abnormal, that unexplained renal failure is a good enough indication for biopsy. You don't need to know anything else about proteinuria, just unexplained renal failure is a good enough reason for biopsy, that we should just move forward with more biopsies. 

All right, so now we're going to demystify the kidney biopsy a little bit. So this is the brief sort of tutorial on the kidney biopsy. So we look at the kidney biopsy with three methods, light microscopy, immunofluorescence microscopy, and electron microscopy. So here is a biopsy. These are the cores under a dissecting scope. So these are the glomeruli, these little circles. You see those? Yeah. They're the glomeruli. Hi, glomeruli, good to see you. So that's what we like to see-- right-- because we'd like to get mostly cortex for the diagnosis of glomerular disease. 

So light microscopy, again, very simple. So if you're not-- because I don't know about you guys, but I said this yesterday, but if you try to pull up a kidney biopsy report, it just keeps on going, and going, and then there's sections, and you're like, where is it going to stop? Just tell me what the diagnosis is, right? But it's actually not that complicated. We just have to-- I remember the first time when I was a nephrology fellow, the renal pathologist called me and was like, there's segmental sclerosis and the capillary proliferation, and this, and that. I said, I have no idea what you're talking about. Please call somebody who speaks the language that you're speaking to me right now, because I'm going to hurt someone. 

But it's really not that complicated, because when you think about it, and when I talk to patients, light microscopy is just how a disease has manifested when you take a piece of tissue out and look at it under a microscope, right? This is not rocket science. If it was rocket science, I would not be doing it. The glomerulus-- just to give you a little bit of post-traumatic stress from your medical school course-- here is the structure of the glomerulus. 

And so to orient you as I go through things, is that we go through the major structures of the glomerular capillary loop, which is the endothelial cell layer and the blood side, the glomerular basement membrane here, and the all-important podocytes on the outside of the glomerular capillary loop. And then there's the mesangial cell. And essentially, when you talk about the mesangial cell, if you're not a mesangial cell expert, you're just like, don't ask me about the mesangial cell. Please, just don't ask me, because I can't tell you much about it. But I'm being a little facetious because most of the action that we're talking about is in this entire structure, and we'll be describing all of these structures. 

Here's a schematic. So this would be a normal glomerulus. So if you're lost as we go through some of the pictures, just look for the capillary loops to orient yourself. Here they are on the periphery, nice capillary loops. If you see a nucleus on the outside of the capillary loop, it may be a podocyte nucleus. If you see a nucleus on the inside, it may be an endothelial cell nucleus. Some different diseases manifest with different patterns of injury in the glomerulus. They can be inflammation with more proliferation in the mesangium, in the endocapillary space, or the extracapillary space. And the extracapillary proliferation is forming a certain shape that we always test people on which is a-- 

Crescent. 

Yeah. So now I'm just getting-- we're getting the greatest hits here, right? We've got foot process effacement, we've got crescent. But crescent does not a diagnosis. Crescent is not a diagnosis. crescent is an observation. I had a patient sent to me with IgA nephropathy. They had 40 glomeruli on the biopsy. They had one crescent. And the UpToDate article says that for patients with crescentic IgA nephropathy, you should consider them for Cytoxan and steroids. This patient's creatinine was 0.5. They had 500 milligrams of proteinuria. And they had microscopic hematuria for 30 years. And she was 60. And I told her, go away. You don't need me. And that's when patients love you, right? 

So observations of structural change are not disease, right? So it's just descriptions, so you're off the hook. You don't to make a diagnosis based on [INAUDIBLE]. So this is where the fun begins with all of these things that give you PTSD, or if you love memorizing, then this is kind of where you love it. So you're getting into the patterns of injury. But these are all just patterns of injury. They're not telling you anything about the disease process itself. Of course, we do care about the interstitium in the vessels, too. I'm not going to get into that too much more. But these are all descriptive phenomenon of disease manifestations. And this is where it becomes difficult to understand it if it's not biology-based. 

Electron microscopy in a very simplistic way just looks at this on really high power. You cannot make any disease diagnoses with electron microscopy. It's just a high-powered view of how the architecture of the kidney looks. And in many ways, it just may confuse you if, you're not used to that. So again, if you look at glomerular capillary loop, again, here's your endothelial cell layer here. Your glomerular basement membrane here. And the nice podocyte foot processes here. 

But the money is in the immunofluorescence. So the immunofluorescence is where we-- is where we stain for certain proteins, and antibodies, and other things that are deposited or present in the kidney. And this is where it could help you to understand pathogenesis. It's very simple. What do we stain for? We stain for immunoglobulin heavy chains, IgG, IgA, IgM. So a patient with IgA dominant staining, the diagnosis is-- right-- exact-- I'm telling you, if it was rocket science, I wouldn't be doing it. 

So it doesn't matter if they have mesangial proliferative glomerulonephritis in light microscopy. It doesn't matter if they have endocapillary proliferative. If it's IgA dominant, it is IgA nephropathy. And that's because the biology of the disease is related to abnormal IgA molecule that deposits in the kidney. 

We also look at light chains. So if you're looking for things that are restricted to a monoclonal plasma cell population, like in the setting of multiple myeloma, then you may see evidence of a monoclonal light chain that's causing kidney damage, like cast nephropathy. If you have something like lupus, where there's lots of things going on, polyclonal stimulation, lots of clones, you get lots of stuff going on. IgG, IgA, IgM, and that's-- what they call that full house staining, which you may remember. But again, that doesn't matter that it's full house, it just matters that you're thinking about it in the context of biology. 

And then there's the thing that everybody loves to think about in addition to glomerular disease. And that's drawing out the complement system, right? So at 3:10 PM, we will go over the complement system one piece at a time. The doors are going to be locked. It's going to be a great time. But again, the reason people are excited about this is because there is representation of biology with complement deposition. And there are really expensive medicines that can be used to block complement. But it does reflect biology that may be important in these patients. 

Just bring you back briefly to-- in the patterns of injury, again, I'm not going to belabor the point. But the pattern of injury may be associated with certain types of glomerular diseases. So you're immune complex diseases have the granular staining, because those deposits are happening all over the complement, and the antibodies are depositing sort of scattered throughout the glomerulus. And when you take a step back, you can see them in discrete areas. 

Anti-glomerular basement membrane disease, the antibody deposits all along the glomerular basement membrane as its antigen. And so it's a very confluent staining. And then you have no staining in the case of ANCA-associated vasculitis, which is the so-called pauci-immune. Now why is it that if this is antibody mediated, why is there no staining on the biopsy? What's the deal with pauci-immune glomerular-- this is my Seinfeld. No? No? Nobody. No. 

So why isn't stained? I'm telling you it's antibody mediated, but why isn't it staining like the other two? Because what are the antibodies binding to? What's the name say? Anti-- neutrophil, right? So they're binding to the neutrophil-- I'm telling you, I'm not trying to trick you. I'm really-- I'm very simple-minded. So binding to the neutrophil, the neutrophil goes into the microvasculature, degranulates, and breaks through the capillary loop. And when it breaks through the capillary loop, you get inflammation outside of the capillary loop. And that is a crescent, right? So again, this is all putting it together now. 

So that's how we make the diagnosis. So if it's OK with you guys, what I'm going to do is I'm going to move on to some representative cases of diseases that I think can-- that can exhibit some of the advances that have occurred in our field. So this is the case of a 77-year-old man with nephrotic syndrome. So he's a 77-year-old man with a history of hypertension who presented in December 2014 with lower extremity edema and fatigue. And he was detected to have 3+ proteinuria by dipstick. His past medical history was remarkable for-- only for essential hypertension, which was first diagnosed about 20 years prior. He had been on quinapril for many years. And he had been checking his home blood pressures, which were usually at goal. 

His social and family histories were really unremarkable, as were his additional medication prescriptions. And on exam, when he was presenting, he was hypertensive, he had gained about 20 pounds compared to his baseline. And he was-- exam was really only notable for having 3+ bilateral lower extremity edema. These were his labs. So his creatinine was 1.1, which was at his baseline. His serum albumin was 2.4, which is low. He had evidence of proteinuria on both UA and on 24 hour urine of 14.2 grams. 

He had-- you know, if you're an intern-- right-- you get this patient in the middle of the night at the hospital, and you're like, do I need to send off all the serologies so that the renal fellow will not yell at me in the morning for not sending up the serologies? And so these serologies were sent initially. And everything was negative or normal as of that time. 

So you get a kidney biopsy, right? Because that's always the right answer-- almost always. So the kidney biopsy showed-- and this takes a little bit of a trained eye, and you got to get used to these things-- but the-- these capillary loops are mildly thickened compared to the normal. So if you look out here, the loops are just thickened. There's not a lot more cells in the glomerulus. There's not a lot more blue, but they're mildly thickened. So the membranes of the glomerulus are thickened. So if the membranes are thickened, then we make the diagnosis of membranous nephropathy, right? So again, not very complex. So that's the light microscopy diagnosis. 

If you look here, it's hard to see-- if you're ever giving a presentation and you're not sure what you're looking at, especially a pathologist slide, you just say, oh, the lighting is off, right? You just say the lighting is off. If you turn the lights down-- but you can see the sort of spikes and holes that are occurring here. You see areas of light and dark, light and dark here. And that's evidence that there are immune complexes that are present in the glomerular basement membrane. And these stained for IgG, and kappa, and lambda. 

We have an IgG mediated, a polyclonal IgG mediated glomerular disease. And we have the classic subepithelial deposits. So again, here's your-- you're looking at the glomerular capillary loop here. And these dark areas here, these are all the deposits that should not be here. Here's a dark area, here is dark area. So these are the subepithelial deposits. And I'll come back to this there in a second. And so the diagnosis is membranous glomerulonephritis. 

And then you're like, OK, please, please get through this. I'm really uncomfortable with glomerular histology. I'm having post-traumatic stress from my index cards or whatever people do in the post-paper era. And so what do we do with patients? You put them on immunosuppression. So one of the first-line agents was tacrolimus. So he got started on tacrolimus. It's an immune-mediated disease. It's totally empiric. And he developed acute kidney injury and actually also had hyperkalemia and unilateral hearing loss. So that was stopped. Then he was put on this crazy first-line regimen called the Ponticelli regimen, which was oral cyclophosphamide and prednisone. And he developed shingles, and then neutropenic sepsis. 

So he was admitted to the hospital with neutropenic sepsis. And at that point is, creatinine was rock-solid stable. But he'd still had severe proteinuria at 7.3 grams. And he had a serum albumin, which was still low at 2.8 grams. And what the guidelines would say-- and this is when I got the call from a nephrologist, is what is the next immunosuppression I should give to this patient? So in the good old days, you would say, well, this is-- patient is at high risk for renal damage and progression. So the guidelines would say that this patient needs treatment. But that doesn't really help. It doesn't help us to make an evidence-based opinion. 

And so the thing that just makes sense is that we have an antibody that is responsible for this disease. And this was a discovery about 10 years ago now, by Larry Beck and David Salant at Boston University, where they found out that this PLA2R antibody was the antibody that was responsible for the disease in 70% to 80% of patients with what used to be called idiopathic membranous nephropathy. It's kind of a similar story to the ANCA story, where before the 1980s or so, everybody just had pauci-immune glomerulonephritis, right? And then the ANCAs were discovered and we found out that 90% of them are ANCA-positive, anti- [INAUDIBLE], anti-PR3 positive. 

So similarly, we have idiopathic membranous nephropathy. And now we know 70% to 80% of them have this pathogenesis. And it just makes sense. It makes sense that there's an antibody that's traversing and binding to the antigen. So the antigen for this antibody is on the podocyte. So when you learned subepithelial deposits, that's because the epithelial cell is the podocyte. So now it's all making sense. The deposits are right on the podocyte. And therefore, leading to these classic subepithelial deposits. So this is now making more sense. Now you don't even need to make an index card. You just understand it and it makes sense. 

Turns out that-- this is an early slide, but-- oop-- about 70% to 80% of patients with membranous nephropathy have this antibody. And it's-- the specificity is bordering on 100%. It's like 98% to 100% specific for membranous nephropathy. You couldn't ask for anything better. After not having any biomarker for so long, you could not ask for better test characteristics with regards to specificity. You couldn't ask for anything better. The higher the antibody level on the y-axis here, the more proteinuria the patient has. So it correlates with the degree of proteinuria. You couldn't ask for much more and a biomarker. 

As the patient goes from nephrotic syndrome into remission, the antibody goes down. And then when they relapse, the antibody goes back up again. I mean, you couldn't plan it any better for our first major biomarker in glomerular disease. Even more importantly-- and this is the really fun part-- fun because I'm easily amused-- but it's fun because when the antibody titer goes down, all you have to do is wait for the proteinuria to go away. 

So if you have a patient that comes in with PLA2R-positive membranous, and you check the antibody, because you can stain for PLA2R on the biopsy. You can do that stain to see if that's the disease that they have. You can check the antibody, and if the antibody is negative, you just wait. You do nothing. You say, I got this one. I'm going to do nothing. And it's amazing, because you just wait. But it can take months to actually-- even over the course of years for the proteinuria to go away. 

And the test is that good that the paradigm is actually, I think, going to change soon, that instead of me sneaking up on people and biopsying them before you can even generate your differential diagnosis, that you're actually just going to check the PLA2R antibody, which is FDA approved since 2014. So there's good enough studies showing that this is probably going to be the future. That patients who have this antibody-- in most patients are not going to need a biopsy, in the future, where our field-- nephrologists are very slow to adapt. So it's going to take a little bit of time. But this-- the characteristics are undeniable. 

If you remembered about cancer-associated membranous nephropathy from medical school, that some patients have cancer and membranous nephropathy, that is true. That's based on observations that patients with membranous nephropathy have higher rates of diagnoses of cancer compared to the general population in age-matched populations. But this is so much more satisfying. So there's another antigen-- it's not PLA2R. It's this thrombospondin thingy that I'm not even going to pronounce for you. 

But essentially, what we've found out is that this is probably the antigen in about 3% to 5% of patients with membranous nephropathy. And there was a case-- and there's actually two cases now-- of a patient. This patient had a gallbladder carcinoma. They also had membranous nephropathy that stained for this antigen. And what they did was they found this antigen in the kidney, and they found it in the gallbladder. So now you're thinking, mechanism. That now you have an antigenic stimulation of an autoimmune response. And that autoimmune response is affecting the kidney. 

So what'd they do? They took out the tumor. The antibodies went down to zero. And the proteinuria went down to zero. So now we have kind of the entire picture. We're not just saying this is an association because we observe it. We're having biological associations with things that we can actually test for. So I actually have a few cases now that I'm trying to juggle with, of patients with cancer and with kidney-- and with membranous nephropathy. And I need to get the tissue and stain for these antigens, and to see if they are actually related. 

So what do we do? We had the PLA2R staining on the biopsy for this patient. And this type of staining pattern is positive. It's in the exact same distribution as the IgG staining that was done previously. And I checked the antibody and it was negative. So like I said before, you just sit there and you wait. We kind of went back to the future-- so I had the stain added on to the biopsy from like a year before-- I got what was going on before. It was PLA2R-positive. Now this antibody status is negative. So now I can see the future. And in the future, everything gets better by doing nothing. 

So his proteinuria went down to a basically normal. His albumin normalized, and his kidney function remained normal. And the patients love you the most if they are expecting you to hammer them with immunosuppression when they walk into your office, and they walk out of the office and you say, I am not going to do anything to you, except for wait. And this is evidence-based. It's very satisfying. So I like this story. So if you're thinking about patients with the nephrotic syndrome, call your favorite nephrologist, say, should we order this test? You don't need nephrology referral to do it, but they can help you to interpret it. And we can make these diagnoses and treat these patients appropriately. 

The next paradigm I'd like to talk about is this case that I saw of a 24-year-old woman with hepatitis C virus infection and glomerulonephritis. So she's a 24-year-old white female who has a history of hepatitis C virus infection, who is referred for a second opinion for glomerular disease. Her hepatitis C history when I first saw her is listed here. She was actually diagnosed during pregnancy when she was noted to have abnormal liver function tests. She subsequently had a elective abortion. 

And about two years later, she developed hives that she described on her bilateral low extremities. And then she experienced some urinary frequency and urgency. And she was treated for a urinary tract infection. But the urinary color got progressively darker and she had episodes of gross hematuria with a negative urologic workup, including a cystoscopy. And here are her labs when she was presenting with this. So her creatinine was 1.4. There is no normal creatinine-- right-- for those non-nephrologists. There is no normal creatinine-- no normal creatinine, OK? 

So 1.4, even though it's just mildly normal, you guys see this all the time. It's like, oh it's just a creatinine of 2.5. No, their kidney function is 15%. So let's-- so 1.4 is not normal in a young, healthy woman. You can see her creatinine was going up to 1.8. She had evidence of proteinuria and hematuria. And she had significant proteinuria on urinary protein to creatinine ratio. And when originally checked, both her complements, her C3 and her C4 were both normal. 

Her kidney biopsy showed what essentially is going to show MPGN. And I'm not going to bore you with all the-- the findings, but what you see here is you see a lot more blue than in the previous case, right? There's a lot more nuclei. This is a proliferative glomerulonephritis compared to the other case. It stained mostly for IgM and kappa, although it also stained for IgG and lambda. And I'm going to get into why that's important in a little bit. 

And the reason why this is important is because when you went to medical school and you learned about hepatitis C and glomerular disease, or you look on UpToDate and it generates a differential for hepatitis C being associated with any autoimmune condition. We have to remind ourselves about the biology. It's not that there is hep C and there's a cryo, but how does that happen? What is a cryoglobulin? What are these pathogenic immunoglobulins? 

It turns out that there's very good evidence that suggests that the hepatitis C virus itself, or an antigen from the hepatitis C, directly or indirectly stimulates B cells, but does not actually infect them. So it stimulates B cells and it preferentially stimulates the B cell clones that make things like the rheumatoid factor, which is IgM kappa. So this is all why you check a rheumatoid factor. It's not that you just check it because you want to check it off the list on your test. It's because it is the B cell that the hepatitis C preferentially stimulates. 

And multiple studies have shown that clonal B cell expansion in the peripheral blood and the liver of patients with hepatitis C and mixed cryoglobulinemia. So if you're going to go after treating patients, then you don't need to talk about steroids, Cytoxan, and maybe pheresis. You don't need to be empiric. It's not as empiric is going after lupus, because lupus is a multifaceted disease. In this case, we know that this is B cell mediated. And so the obvious choice was to go for rituximab type treatments. 

This is a randomized controlled trial in Italy from a few years ago. And as you can see here, patients with cryoglobulinemic vasculitis with hepatitis C-- and the majority of them. The majority of patients who got rituximab did much better than those who had gotten conventional therapy with steroids and Cytoxan. And you can see here, the survival of treatment at six months was 64% versus 3.5% in the conventional group. So rituximab had targeted B cell approach. So again, taking-- my analogy from yesterday is the chicken and the egg-- so you're not going after the glomerulonephritis. You're not necessarily treating the immunoglobulins. You're treating what's causing those bad immunoglobulins to be-- to be produced. 

So you say, well, we learned about this in medical school, why am I showing you this case? What is so interesting about this? Well, it turns out that she had already been treated for hepatitis C before she presented glomerulonephritis. And her hep C PCR was completely negative, as we're going to talk about. So how is this possible? What's the deal with hepatitis C-associated GN in a patient who is cure for hepatitis C? How is this possible? And actually, the diagnostic line on the renal pathologist said hepatitis C-associated GN because the history said the patient had a history of hepatitis C virus infection. 

And so in the landmark case series published by Ghosn and Hogan as the senior author-- the landmark, I'm sure you saw it, it was all over the news. We have observed these two patients that this has happened, where they developed hepatitis C-associated kidney disease after they were treated with direct-acting antiviral therapy. And you go back to the literature, and there actually is some literature from the rheumatology literature that describes in the interferon era, that in four and eight patients respectively, in the previous publications, that patients developed cryoglobulinemic vasculitis after they were already treated with interferon-based therapies. 

So there's already precedent in the literature that this is happening in spite of the fact that the hep C is no longer detectable in the blood. And some of those patients actually got kidney involvement as well. So you say, how is this possible? Well, it kind of makes sense that when we have antigenic stimulation, or we have stimulation of the immune system, sometimes the horse is out of the barn, right? We always talk about the first hit, second hit. But once that hit happens with ANCA-associated vasculitis, it just goes. We don't know if that antigenic stimulation is still required. The immune system is turned on and there's proliferation. 

So there could be that they're still an occult hep C persistence or infection with antigenic stimulation of the B cell clone. It could be that the B cell clone is just there. It's just revved up and it's not turning off, despite going into a sustained virologic response. And actually, if you go back-- so if you look at-- just as a side note, and I don't want to veer into something that I'm not truly an expert on-- but even in patients who are quote-unquote "cured" for their hepatitis C after getting direct-acting antivirals, I think that there's a fair amount of data showing that if you biopsy certain organs, the hep C is still there. And some of these patients do relapse, right? So I don't think it's completely closed door, although it's clearly amazing phenomenon with these direct-acting antivirals. 

So she got rituximab and then she kind of got lost to follow-up. But if you can see her-- she got rituximab and steroids, and her disease essentially resolved. No proteinuria, complements normalized. Then she developed a rash. She essentially relapsed. We did a bone marrow biopsy to see if we characterize her clone. We did not find anything on the bone marrow biopsy. So we empirically treated her again with prednisone and rituximab and she's essentially-- we don't know how long we're going to need to treat her for. 

But this is a reminder that the biology is fairly well worked out. It's not hep C GN. Go through the intermediary, right? Where's the chicken? Where's-- the I guess, in this case, the chicken. You got your egg. There's your GN, right? And then your B cells and your hepatitis. And so then you kill-- kill the chicken-- sorry, for the renal folks who had to see this slide yesterday. I told you, I'm kind of a one-trick nephrologist. 

OK. So that's the paradigm, is treating the causality and the biology informing us. So the last case I'm going to-- I'm going to go through fairly quickly because it's a bit obscure. But it talks about this-- this MPGN. So I got this case of this patient that came to see me. So he was first diagnosed with kidney disease at age 11, in the great year of 1978, which is the year of my birth, when he had a kidney biopsy in our children's hospital, which is unfortunately named CHOP, if you weren't-- if you weren't aware, that showed MPGN. 

And patients with MPGN, they get steroids, right? Any he developed end-stage kidney disease at age 19. He underwent the living-- living related kidney transplant in 1987, which is a good year. It was one year after the Mets won the World Series, I remember it fondly. He then had recurrent MPGN in the allograft and developed ESRD in 1993. He then underwent a second transplant from his dad in 1994, and again had recurrent MPGN-- lasted four years. He underwent a third transplant in 2000. Had recurrent MPGN. The allograft lasted seven years and-- you see where this is going, right? 

And underwent fourth transplant from the sister-- I mean, just going down the family, [INAUDIBLE] family-- nobody wants to go to family reunions anymore with this guy, right? Because they're just like-- getting them drunk and having them sign some paperwork. It's a very dangerous situation. So again had MPGN. And he came to see-- the amazing part about this is that every-- all the way through this is MPGN, MPGN, MPGN. 

And actually, the other amazing part was that the reason that this patient got referred to me is because I gave a talk on the disease I'm going to talk about in a second at a-- at a children's nephrology division in Delaware at Nemours. And this patient's wife is one of the dialysis nurses there. And she heard me talk about this disease and was like, I think this may be what my husband has. So when I saw the patient, his creatinine was 3. He had 12 grams of proteinuria and he was making plans for dialysis again. 

So remember-- remember this? The, fool me once, shame on you-- and then-- and then whatever George Bush said after that-- some butcher-- but you know what I mean. It's just like, how many times are we going to do this? Because MPGN is just not a disease. And of course, I'm not blaming the people in 19-- in the sentinel year of 1978 for not knowing that MPGN was not a disease. We didn't know. 

But now we know better. And that's because we have now partitioned some of these MPGNs based on that immunofluorescence findings into different disease categories. And one of them is the C3 glomerulopathies. These are diseases where you see MPGN on the light microscopy, but you only see C3 staining. The only thing that stains on the immunofluorescence is C3. So that led some people to say, well, maybe complement is the problem here. 

And so the hypothesis is that the alternative complement pathway is dysregulated in these patients and is causing the disease. But they're all under the MPGN umbrella. And this has been shown to be definitive. In some cases, we have genetic mutations that are driving this, similar to atypical HUS or complement-mediated HUS. And in other cases, they're acquired autoantibodies. And they're all on this pathway. So let's buckle up and let's start with the-- no, I'm just kidding. I'm not going to do it to you. I'm not going to do it to you, because you'll do this. 

I actually was-- there was a fellow who wanted to give a job talk at an academic institution. And he's like, I want to give a job talk and I want to talk about C3 glomerulopathy. And I said, do not do that. You will not get the job. And the reason is because your second slide, you're going to put this up, and it's all over. Nobody will listen to you after this. So suffice to say that there are lots of people who are interested in this for academic reasons, and because, as I said, there are-- this is one extraordinarily expensive medicine, eculizumab, that's on the market for complement-mediated HUS and PNH. 

But there are people who have devoted their lives to profiling the complement systems in these patients. So you can send off all of these tests. You can send off genetics, you can send up a whole profile that looks at the complement activation in these patients. The treatments are not really well-defined yet. There's been some case reports and case series of using eculizumab, very difficult to get, insurance companies do not approve it, the majority of patients. In transplant, sometimes we can get it. 

And then there's really empiric immunosuppressions with, again, steroids, Cytoxan, and maybe pheresis, and then whatever else you want to throw at people. But this is sort of where we're now at the precipice of defining the different abnormalities. And you can see this because the companies are circling, right? There's been all these complement compounds out there for-- for a long time. Are there any complement experts in the audience? 

OK. So complement experts are kind of like-- their world meetings were like 400 people in the entire world going to these meetings. And now everybody is interested in complements. It's kind of like the person that maybe it wasn't that-- wasn't that popular in high school, and then they went to work for like Google and Apple, and now they're in NASA. And then they go back to the high school reunion, and everybody wants to talk to them, right? Because they're just-- they're getting bombarded with-- because they people need their expertise. 

So these are the-- if you look at the ClinicalTrials.gov, these are the studies are currently recruiting with inhibitors of various parts of the complement system, except for this one, daratumumab is not involved in complement, it's another story, which I will bore you with afterwards, if you would like. 

So what do we do? We actually went back. I went-- because that's the problem, is that all of the biopsies that I got initially just said MPGN. It was just carried forward, carried forward. So actually, when I got the biopsy from Penn and from Jefferson, which is another institution in Philadelphia, and I had the pathologist look, he was actually very excited. And all of them showed C3 only. That's the only thing it showed. So since 1978, so 40 years, he's been given the diagnosis of MPGN, and now we have a potential etiology. 

So we sent off the testing to the University of Iowa. And he was positive for this C3 nephritic factor, which is an antibody that binds and stabilizes to the C3 convertase, which leads to over-activation activation of the alternative complement-- the complement pathway. So he has an autoantibody that's causing this condition. So now we have a biology-based diagnosis for the patient. You don't need to remember complement. You just need to know to call somebody who knows what to do with a kidney biopsy when something is amiss. 

So at that point, he was on PD, and they were basically trying to figure out what to do with him. Should we give eculizumab? These drugs are not available for patients with transplants yet. And so what are we going to do if it recurs? So I thought that was a little more satisfying. To briefly mention a few other things-- so if you think about genetics and kidney disease, so what is that show, Best Year Ever? Isn't there a show on like VH1, Best Year--? OK, I was trying to find that icon. 

So if you think about other diseases, if you think about the characterization that genetics must be involved in many aspects of kidney disease, look at this in the last year. Now for those who are not nephrology-oriented, you may not know about see Jason and Jason in Kidney International, which is a real journal. I'm not making it up. High impact factor in our field. But New England Journal, Annals of Internal Medicine are looking at genetic diagnostic rates with whole exome sequencing for various types of populations of patients with kidney disease. 

And as you can see here, the yield of making a-- of finding a genetic mutation that is associated with a mono-genetic kidney disease is somewhere in, depending on the population of 10% to 40-something percent. There's a lot that could be discussed, but clearly, I think what we're finding is that this is-- you know, I guess everybody's got to put a tip of the iceberg in there, right? That's like one of a stock photos. So this is the tip of the iceberg with regards to, again, another component of understanding the biology. There's clearly genetics involved. There's always nature and nurture. 

But this is a glimpse into what we're going to be finding. And of course, I have not even spoken about APOL1, 1 which is probably one of the biggest stories ever in nephrology, because we've known for a long time that patients of-- as we term, recent African ancestry are at much higher risk of developing kidney disease. So I think the-- going to the dialysis unit, or you're seeing patients on the wards, that you see of a predominance of African-Americans who have hypertension and are called hypertensive nephropathy. 

Just say it out loud. Say hypertensive nephropathy out loud. It's so unsatisfying, right? Because in residency clinic, we had tons of hypertensive patients. And they did not have kidney disease. And so it's not hypertensive nephropathy. There there's lots of things going on that we are now-- diabetic nephropathy is not a thing. Diabetic nephropathy is not one thing. My dad's had diabetes for 35 years. He takes-- he does things with his insulin that would not be recommended by any human. I love my dad. I love my dad. But he does stuff with his insulin-- I have no idea. And he's trucking along with a creatinine of 1.1 and 30 milligrams of proteinuria. And he has diabetic foot, he's got the whole thing, no kidney disease. So it's very complex. 

But APOL1 is now found to be a risk allele that seems to account for a large-- a large proportion of the risk that we're seeing in patients-- in African-Americans who have kidney disease. And this is-- has massive implications on public health, on kidney donation strategies, et cetera. So this is a major, major public health discovery that everybody in our field was interested in. 

What do we do next? We're trying to get better at organizing, right? So there is large cohort studies that are studying different types of glomerular diseases as well as the acute kidney injury, Kidney Precision Medicine Project. We have 700, 2,400 patients with glomerular diseases. This is a study that's actually run out of Penn for patients with diabetic kidney disease that we're doing biopsies on. So clearly, the writing's on the wall that even five years from now, our entire understanding of kidney disease is going to be transformed. 

So to summarize, the historical nomenclature of many glomerular diseases is purely descriptive and may not add it to understanding of the treatment or pathophysiology. But that these recent advances are really transformative. So if you are an early trainee, if you're a resident, if you're the-- if you're the head of the residency program at the University of Virginia, you want to rethink your decision of not having gone into nephrology because that was your true passion. We are open arms of people that are interested. And you can see that there are only upsides to what we're learning about nephrology, currently. 

And that really, if you're not thinking in depth-- if you don't wake up thinking about these diseases like I do, that really, that exercise that you went through in medical school of generating your differential is not nearly as important as identifying which patients need referral and a kidney biopsy. So if you don't know-- we all need phone-a-friends, right? If I have a compliment question, I am not-- I'm not looking at that chart. I will pass out. So I call my friend who is a competent expert and I ask them. So find your phone-a-friend, ask them what to do with your patient, get them into your adrenal clinic. 

And that's because we want to go from this understanding of glomerular disease to more of a-- it's like the end of the first movie, when he just gets it. And then he's like unstoppable, right? So that's sort of-- that's what we hope to be in the future, is this sort of much better insight into what's going on in our diseases. So again, thank you so much for this invitation to speak about glomerular disease. And I'm happy to take any questions. 

[APPLAUSE]