Jonathan Barratt, PhD, FRCP: Turning now to Sanjeev and the kidney biopsy, would you be able to walk us through how the kidney biopsy makes the diagnosis of IgA nephropathy? When you're looking at a biopsy, what are you looking for? And why is it important for us as nephrologists to understand that?

Sanjeev Sethi, MD: For most glomerular disease, I would say you need a diagnostic kidney biopsy. You may have a few markers for lupus, and you may have a few markers for ANCA or membranous, PLA2R, you mentioned. At the end of the day, you do need a diagnostic kidney biopsy for almost all glomerular diseases. Very few glomerular diseases can you diagnose in the absence of a kidney biopsy. Let's just go straight to IgA nephropathy. For those who are not into the kidney biopsy story, we start our day, most renal pathologists start a day by looking at immunofluorescence. There is a panel that we stain for IgA, IgG, IgM, C1q, C3, kappa and lambda. There's a panel that we stain the antibodies and IgA really is one of the easiest diagnoses that most renal pathologists will make because when you look at the immunofluorescence under the microscope, immunofluorescence microscope, the IgA lights up. As soon as you see bright IgA sitting inside a glomerulus, typically in the missense location, very few things look like that. Once you look under the immunofluorescence, it's a straightforward diagnosis. This is IgA nephropathy. Along with that, as you were just talking, very often you will get some complement activation. We also stain for C1q and C3. Typically, C3 goes along with IgA. Sometimes you can get less, sometimes you can get a fair amount. Typically, C1q is absent. So, you get bright IgA, you get bright C3 variable, and then just to make sure that this indeed is polyclonal, we also look at kappa and lambda. Lambda tends to be a little stronger than kappa for reasons most people don't know. But usually it's lambda, kappa, IgA, C3. So, the diagnosis really clinched on immunofluorescence microscopy. A few other things will give you that picture and we can discuss that later. But really, it's bright IgA on immunofluorescence microscopy and you know you're dealing with IgA. Then you come to light microscopy is next. Like any other kidney biopsy, almost every glomerular disease, we look for 2 things. We look for glomerular activity, how active is the lesion? And the second thing we look for chronicity, how chronic is the lesion? You were just talking about it. Was a biopsy done earlier? Was the biopsy done later? How active is the disease? And that's not just IgA nephropathy. We can talk about C3G later. We can talk about any glomerular disease. You look for 2 things. How active is the lesion, how chronic is the lesion? Activity in terms of IgA nephropathy, once you've seen the immunofluorescence, there's IgA 3 plus. Now, you go to the light microscopy, and you start looking at the glomerulus to see how active is the lesion. The activity is marked by classically what's called mesangial proliferation. These IgA deposits are located predominantly in the mesangial of that part of the glomerulus, which supports the glomerular capillary loops. And that's where all the action is. That leads to mesangial proliferation. Sometimes when the lesion is extremely active, you also get what's called endocapillary hypercellularity. That means there are cells within the capillary loops, in addition to the mesangial. And when the lesion becomes super active, you can also get necrosis in what terminology we use as crescents. These are the active parts of the IgA nephropathy. But as the lesion progresses, you get the chronic indices start coming into play and then the glomerulus gets sclerosed. This glomerulus is pretty much given up. It's scarred now. The terminology glomerulosclerosis is used for that. Even though this is a glomerular lesion, almost all glomerular lesions end up in tubular atrophy and interstitial fibrosis. That means it's not just the glomerulus that's damaged, the interstitium, the other parts of the parenchyma of the kidney also undergo scarring. This could be from hematuria. This could be from proteinuria. The various mechanisms. But that also leads to a lot of tubular interstitial scarring, as we call it. So, all of this was put together in what's called the Oxford score. And it's sometimes we call it in short, we call it the MEST-C score. M stands for exactly what I said, mesangial hypercellularity. And we give it a score of 0 or 1. E, stands for endocapillary hypercellularity. And we give it a score of 0 or 1, to pretty much absent or not or present. So, 0 and 1. So endocapillary hypercellularity is a little tough to diagnose, but basically, you're looking for cells within the capillary loops. So M, E, then comes S. S stands for segmental sclerosis. I said there's global and there's segmental sclerosis. Segmental sclerosis, when you see a glomerulus is now being sort of destroyed or is on its way of giving up. And so, we scored S1 or S0 if it's there. T is when you move out of the glomerulus now. You've gone into the interstitium and so you want to see how much scarring there is. And we give it a score of T0, if there is no scarring or less than 25%, 25% to 50%, we give it a T1, more than 50, we give it a T2 score. This was called the MEST score. And then some folks said, "Hey listen, there's also sometimes you see crescent." Crescents are the severest form of glomerular injury and occasionally you do see it in IgA nephropathy. Does that have any role? And they found that indeed once you see crescents, they're more active. Now we give it a C score. Crescents present or not. And we do categorize it less than 25% or more than 25% of the glomerular line wall by crescents. So, we've come up with what's called the Oxford score and with its designate called MEST-C score, M-E-S-T-C. So, we make the diagnosis based on the IF, immunofluorescence. That means you see 3 plus IgA or 2 plus IgA. Typically, trace amount of IgA is maybe seen in another disease. But IgA nephropathy is characterized by at least 2 to 3 plus IgA out of 3. Very often there's C3. Then we come to the light microscopy and we look for the activity indices, mesangial proliferation, endocapillary hypercellularity, crescents. The next step is to look for chronicity so you get an idea of the entire kidneys already sclerosed. So, we give you an S score and a T score. Typically, when you get very high activity scores, the chronicity scores are low. So, you get an M1, E1, C1. On the other hand, you may biopsy the patient 10 years out into an IgA nephropathy. You may get an M1, maybe, maybe M0, E0 for sure, C0 for sure, but you'll get an S1 and a T2. These patients have gone too far along. In general, that's the IgA story.

Transcript Edited for Clarity