Prof. Franco Ferrario Nephropathology Unit Department of Pathology San Gerardo Hospital Università Milan Bicocca Monza, Italy.

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The role of repeated biopsies in the management of Lupus Nephritis Franco Ferrario, Milan, Italy Chairs: David Jayne, Cambridge, UK Vladimir Tesar, Prague, Czech Republic Prof.

1 The role of repeated biopsies in the management of Lupus Nephritis Franco Ferrario, Milan, Italy Chairs: David Jayne, Cambridge, UK Vladimir Tesar, Prague, Czech Republic Prof. Franco Ferrario Nephropathology Unit Department of Pathology San Gerardo Hospital Università Milan Bicocca Monza, Italy Slide 1 Well, I'm a little worried about speaking about these great speakers as a poor nephropathologist Slide 2

but as you can see, EULAR/ERA-EDTA recommendations for the management of lupus nephritis. Indications for the first renal biopsy. Renal biopsy is indispensable.

Renal biopsy is indispensable since in most cases, Fernando before said this concept, clinical, serological or laboratory tests cannot accurately predict renal biopsy findings.

2 but as you can see, EULAR/ERA-EDTA recommendations for the management of lupus nephritis. Indications for the first renal biopsy. Renal biopsy is indispensable. I was present in this but it was not my stimulation. Renal biopsy is indispensable since in most cases, Fernando before said this concept, clinical, serological or laboratory tests cannot accurately predict renal biopsy findings. International recommendations. Slide 3 I'll start immediately with the classification in particular of classes III and IV and not the other classes. All we know, class III focal. Attention, this is the crucial problem. 50%, the cut off. It is generally accepted by all types of pathology that focal is less than 50%, diffuse more than 50% but it's not a problem of percentage in my opinion and in our opinion in classification. Slide 4

inflammatory cells, mainly monocytes, Slide 5 There are mesangial deposits of course, and the

3 As you can see, Class III clearly doesn't present mesangial alteration but a clear welldelineated area of inflammatory processes with necrosis, with infiltration in this area of inflammatory cells, mainly monocytes, Slide 5 There are mesangial deposits of course, and the confirmation that in this limited, delineated area there is fibrinogen so necrosis similar to vasculitis.

Slide 7 Ok, here is a very important topic. Class IV involving more than 50% of glomeruli.

4 Slide 6 This is when there's a progression in Class III in which as you can see, the sclerotic lesion remains well delineated because it is progression of the same active lesion with necrosis. Slide 7 Ok, here is a very important topic. Class IV involving more than 50% of glomeruli. Why did we in the New Classification in New York decide to divide in two classes: IV segmental and IV global? Slide 8

It makes sense that if we have 48% is focal, 52% is diffuse.

5 Class IV segmental presents absolutely the same lesions as Class III. As you can see, not mesangial proliferation very little, this active area with influx of monocytes. It makes sense that if we have 48% is focal, 52% is diffuse. Slide 9 No, because it's a question of the same lesion totally different from the global form, an immune complex form, enormous proliferation, wire loops, monocytes distributed in all the glomerular tufts. Slide 10

6 So independently from the percentage, they are two totally different diseases with enormous deposits, also wire loops by electron microscopy. Slide 11

Before the new classification and probably also now in the trial these two patients were classified with as same disease Class IV not IV segmental or IV global.

7 Ok, Class IV S, IVG. Is there some difference before? I think so, also for who is not an expert in morphological features I think that it's clear that they are two different things: a necrotic form and a membranoproliferative form. Before the new classification and probably also now in the trial these two patients were classified with as same disease Class IV not IV segmental or IV global. I repeat it is only a question of 50% of glomeruli. Slide 12 It is important also clinically. Now, we will see. As you can see, some work after this classification agreed totally that there is a consensus that morphological features, in particular wire loops that mean massive immunocomplex deposition, necrosis means something more similar to vasculitis. Consensus wire loops, capillary thrombi in global, necrosis in segmental. Slide 13 It is important, clinically it is fundamental because as you can see, there is a total consensus after this classification if we divide class IV in segmental and global, there is an enormous

difference, clinically. The global form presents a more severe disease with, more hypertension, more proteinuria usually nephrotic syndrome and more renal insufficiency.

In fact, previous reports and our personal experience suggest that definitive morphologic differences between the segmental and global forms are possible expressions of different pathogenetic and

8 difference, clinically. The global form presents a more severe disease with, more hypertension, more proteinuria usually nephrotic syndrome and more renal insufficiency. So this classification is not something that the pathologist does just because there are some different pictures. Slide 14 No, it's clearly expression of differences. In fact, previous reports and our personal experience suggest that definitive morphologic differences between the segmental and global forms are possible expressions of different pathogenetic and morphogenetic mechanisms with also definitive clinical differences. Otherwise, also if we perform a therapeutical trial, we must know this. know very well this problem from previous Roche trial with Roche now with Belimumab, the new trial with the central pathology review. This is a synthesis of all these not meaningful works but works. Class IV lesion behaves as an immune complex disease while segmental lesions showing necrosis were similar to the lesions of systemic vasculitis suggesting a role of cellular immunity. So what is important? In addition to quantitative, more or less than 50%, is a qualitative change that is very important because it is the expression of two different diseases. Slide 15

9 Repeat biopsy, the importance or not of repeat biopsy. Who performs repeat biopsy in this room please? Hands. One. Ok. As you can see, not my idea. These are the recommendations of international rheumatologic and nephrological societies: EULAR, the American College of Rheumatology, ERA-EDTA, EUVAS also for vasculitis and the use of repeat biopsy strongly correlates with the outcome while serology, creatinine and activity indices show a modest correlation. Fernando Fervenza said this before, ok? Among different clinical and laboratory parameters, ultimately repeat renal biopsy is considered the gold standard for assessing renal activity or chronicity. If you have a flair up, theoretically a flare up, are you sure it is a reactivation or not a chronic evolution of disease? With repeat biopsy you can know. You treat the patient for another year, two other years with a therapy that absolutely is not useful. Slide 16 This is monitoring lupus nephritis, the recommendation of EULAR and ERA-EDTA and consider protocol second biopsy to evaluate treatment efficacy and chronicity. This is another concept that I will explain to you, greater prognostic value of the second biopsy than the diagnostic biopsy. Slide 17

10 Very briefly, these are some work, not much work about repeat biopsy, but this is one from China in lupus flare. In lupus flare, they considered that repeat renal biopsy is necessary to guide treatment Slide 18

Is it more ethical to perform a biopsy that is not such a big intervention or to continue a very toxic therapy?

11 but also in moments in which you are tailoring therapy and repeat biopsy after induction therapy may improve the outcome and also reduce the possible side effects of over immunosuppression. Is it more ethical to perform a biopsy that is not such a big intervention or to continue a very toxic therapy? Is it more ethical or not? That's the problem for everyone. Slide 19 The strategy of second biopsy at the end of the maintenance phase of therapy ok we can go on. Slide 20

This is very important, the concept unfortunately Gary Hill died a few months ago, I'm very sad and performed this study on protocol repeat biopsy and what was the problem?

12 This is very important, the concept unfortunately Gary Hill died a few months ago, I'm very sad and performed this study on protocol repeat biopsy and what was the problem? There is no difference between patients with class IV-S and IV-G lesions at the initial biopsy and at the end of follow up. But at the control biopsy after treatment persistence of class IV-G lesions appear to be associated with a much worse outcome than the patients with class IV- S. So a second biopsy is much more important to evaluate the follow-up and the outcome of the patient. Slide 21 Well, I performed for the Research Committee of the Renal Society in the last three years a big effort because this is in press in NDT and is a collection, unfortunately a retrospective collection, of a large cohort of patients with repeat biopsy. Slide 22

As you can see, 142 patients, cases, so 284 repeat renal biopsies from Italy, Japan, Columbia, Spain, Australia and I hope also now to add some American data. Slide 23 This is a crucial slide.

Because if we have a lot of transformation between class III, class IV-G, global and segmental, of course all this previous discussion is absolutely negative.

13 As you can see, 142 patients, cases, so 284 repeat renal biopsies from Italy, Japan, Columbia, Spain, Australia and I hope also now to add some American data. Slide 23 This is a crucial slide. Well, repeat biopsy could be very important also to validate whether the new classification is valid or not. Because if we have a lot of transformation between class III, class IV-G, global and segmental, of course all this previous discussion is absolutely negative. As you can see, it is very clear first biopsy and second biopsy transformation, the segmental form III and IV-S remain segmental or class III, IV-S or remain II or IV but there is no transformation into global forms and vice versa. As you can see, also very interesting class II mesangial is mesangial and global is mesangial proliferative if you want, in 50% of cases transformed in class IV global. You have a mesangial form, you are very quiet. No, in 50% of cases, there is a transformation in the global form. So it's clear that global and segmental forms are two different diseases. There is not a continuum on the same disease in different stages of disease.

14 Slide 24 Some small examples very rapidly. Segmental class III remained class III. Slide 25 Class III becomes chronic but always well delineated. Slide 26

15 As you can see, segmental IV, more than 50% or less Slide 27

16 but this lesion remains absolutely the same, the same lesion. Slide 28 But it's totally different as you can see, from the global form. The global form is a clear typical membranoproliferative immune complex disease with a lot of proliferation, endocapillary hypercellularity, wire loops and remains in the majority of cases global. Slide 29

But also incredibly global can resolve in mesangial not in sclerotic or segmental sclerotic lesions, I don't know, no, only the mesangium, the capillaries the mesangiocapillaries are involved and

17 But also incredibly global can resolve in mesangial not in sclerotic or segmental sclerotic lesions, I don't know, no, only the mesangium, the capillaries the mesangiocapillaries are involved and resolution is the mesangial form not segmental forms. Slide 30 On the contrary, mesangial form class II if it becomes worse not segmental not a continuum, it becomes global. The other concept, in my opinion this previous work and our big work on an enormous number of cases confirm that the classification is a good classification, it's correct. Slide 31

clinically there is a great difference. Global is a worst disease. Also at the second biopsy.

18 The other concept is the importance clinically. As you can see, we compared the first renal biopsy and the second and we confirmed all previous data that if we divide segmental and global, clinically there is a great difference. Global is a worst disease. Also at the second biopsy. The same problem, renal insufficiency and more proteinuria. Slide 32 So we must divide and in all perspective clinical trials on lupus nephritis if the industry doesn't do a central pathology review, the risk is enormous. Ok, we confirmed also that necrosis is present in segmental and the wire loops in global Slide 33

classes don't present particular differences as those of Gary Hill and the others.

19 also in the second biopsy. Slide 34 I think this is the last slide but it's very important because as you can see, if we take the data from the first biopsy to the last observation, the different classes don't present particular differences as those of Gary Hill and the others. As you can see, mesangial at the end of follow-up the same renal insufficiency as class IV-S or G but if you take data from the second biopsy, you can see that class IV-G global, as also Gary Hill said, is absolutely much, much worse in the outcome. So it's important from a therapeutical point of view and the judgement of evolution of disease. The second biopsy is much more important. Slide 35

Class IV-G is more an immune complex disease and instead the segmental form is with fibrinoid necrosis more similar to systemic vasculitis.

20 So, in conclusion previous reports in our data seem validate the ISN/RPS classification. Segmental class III and IV-S and global Class IV-G lesions present evident morphological differences, possibly the consequence of different pathogenetic mechanisms. Class IV-G is more an immune complex disease and instead the segmental form is with fibrinoid necrosis more similar to systemic vasculitis. These differences in morphological features are very important because they are confirmed by a definite clinical difference at renal biopsy at followup. Slide 36 Previous reports and data our data in large international cohorts of retrospective repeat biopsies demonstrated that transformation from segmental lesions and global lesions and vice versa is very rare. Further suggesting that these two subclasses are actually different clinical pathological entities and not a continuum of different lesions in different stages of disease. Two separate diseases. Previous reports in our data strongly support the value of repeat biopsy in the long-term management of lupus nephritis. At the control biopsy, the presence or persistence of global form lesions appeared to be associated with a much worse outcome.

21 Thank you for your attention. Slide 37

Prof. Rosanna Coppo Director of the Nephrology, Dialysis and Transplantation Department Regina Margherita Hospital Turin, Italy. Slide 1.

Prof. Rosanna Coppo Director of the Nephrology, Dialysis and Transplantation Department Regina Margherita Hospital Turin, Italy. Slide 1. ROLE OF PATHOLOGY AND CLINICAL FEATURES IN PREDICTING PROGRESSION OF IGA NEPHROPATHY: RESULTS FROM THE ERA-EDTA RESEARCH VALIGA Rosanna Coppo, Turin, Italy Chairs: François Berthoux, Saint-Etienne, France