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

Transcription

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 John Feehally, Leicester, UK Prof. Rosanna Coppo Director of the Nephrology, Dialysis and Transplantation Department Regina Margherita Hospital Turin, Italy Slide 1 Slide 2

2 Thank you. Slide 3 As you remember, the Oxford classification detected 4 histological features: mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy and interstitial fibrosis as risk factors for progression, which were independent from clinical data at renal biopsy and during follow-up. Slide 4

3 However, the cohort investigated was quite small, 265 cases from four continents, so there was the need of a validation. Slide 5 That's why the ERA-EDTA approved this application by the ERA-EDTA working group of immunonephrology on first research call in This was a validation study FOR the Oxford classification on a European cohort.

4 Slide 6 The Steering Committee was the same as the group who performed the first original Oxford study. Slide 7

5 In this retrospective cohort patients with primary IgAN were enrolled, children and adults, with any kind of proteinuria, any treatment, long follow-up longer than 1 year but also shorter follow-up if a patient progressed to ESRD. There should have been a sufficient amount of renal biopsy material available for review and suitable clinical data. So as you can appreciate, also patients with low proteinuria, lower than 0.5g and patients with short follow-up who were excluded from the initial Oxford study were enrolled in this cohort. Slide 8

6 Thanks to a fantastic European collaboration, 55 centres from 13 European countries got 1252 patients from all over Europe. Slide 9 The clinical data Slide 10

7 were gathered from the nephrologists at renal biopsy during follow-up. The local renal pathologist reviewed the renal biopsies according to the MEST criteria. Data were sent to the coordinated centre in Turin Slide 11 and slides were sent to Oxford Slide 12

8 for the centre pathology review. Then all the data were sent Slide 13 to the statistical centre in Canada for statistical analysis. Slide 14

9 Of the original 1200 cases, Slide 15

10 1147 were confirmed for both pathology and clinical data. Slide 16 So we have a large databank accounting for records, what a treasure! Slide 17 The patients enrolled cover all ages, the mean age was % were paediatrics at first assessment. Slide 18

11 In comparison to the original Oxford cohort, the blood pressure was similar whilst the GFR at renal biopsy Slide 19 was 75 ml/min, a little bit less than in Oxford. Slide 20

12 Proteinuria median was 1.2 g, a little less than in the Oxford cohort. Slide 21 This large number of patients included more than 300 patients Slide 22

13 in CKD1, more than 300 Slide 23 in CKD2, 300 Slide 24

14 in CKD 3 and 100 patients in the other stages of CKD 4 and 5. Slide 25 As I mentioned before,

15 Slide 26 we had more than 200 patients with a lower proteinuria, lower than 0.5 g Slide 27 but a huge number of patients Slide 28

16 with higher levels of proteinuria, Slide 29 which allowed different examinations. Slide 30

17 The follow-up was in median Slide 31

18 5 years Slide 32 and most of the patients were treated, as expected, with RAS-blockers, 82% of the cases. Some 40% received oral steroids, 10% methylprednisolone pulses but in general only a minority received in addition immunosuppressive drugs and all together we had 46% of patients who received or steroids or immunosuppressive drugs. Slide 33

19 The rate of renal function decline was ml/min/year, which was much better than the original Oxford cohort. So was the original endpoint. As you can see, a 50%, decrease in renal function was reached in 15% of the cases instead of 22%, ESRD in 12% and the combined event end stage renal failure a 50% decrease in renal function was reached in 16% of the cases. Slide 34 The survival from the combined endpoint Slide 35

20 at 10 years was 74%. Slide 36 The survival from the combined endpoint was slightly different according to the quartile of proteinuria. There was a significant difference between the first quartiles, the second, the third and the fourth. At renal biopsy as well Slide 37

21 as when we consider by quartiles the time average for proteinuria values. There was a significant difference between each quartile. Slide 38 When we calculated the ROC curve for the initial proteinuria to the combined event. We observed a proteinuria of 1.9 g at the best cut-off. Slide 39

22 When we considered time average proteinuria, the cut-off was 1.4 g. Slide 40 For what concerns blood pressure Slide 41

23 the ROC curve showed a best cut-off MAP of 100 both at the moment of renal biopsy or during follow-up. Slide 42

24 If you look at the univariate linear regression analysis, the egfr slope was significantly correlated as expected with proteinuria and blood pressure. The β coefficient increased as the length of the observation increased from renal biopsy to 1 year, to two years or if we consider the time average period. This is for proteinuria as well as for blood pressure. Slide 43 It was the same when we considered at univariate analysis the survival to ESRD of 50% reduction of GFR and the association with proteinuria and blood pressure. Again the association was very strong and again, the hazard ratio increased as the length of observation increased. Slide 44

25 So we assessed four multivariate linear regression models the --- variable was the egfr slope. Slide 45 We obtained Slide 46

26 four formulas according to whether we considered the value of proteinuria or MAP at renal biopsy or after one year of observation or 2 years or over the entire follow-up. Slide 47 We observed that the performance of this multivariate linear regression models increased from renal biopsy to 1 year or 2 years increasing the time of observation. Slide 49

27 So the VALIGA formulas help predict the functional decline in patients with IgAN at renal biopsy or even better if we consider data after 1 year of follow-up independently from pathology data. Slide 50 However, VALIGA was most aimed at investigating the opposite, the predictive value of pathology findings Slide 51

28 independently from clinical data. Slide 52 So let me show you the results of the centre review of 1147 renal biopsies which were performed by Shubha Bellur and Ian Roberts in Oxford.

29 Slide 53 Again, compared to the Oxford cohort you can see that these chronic lesions were about the same: segmental glomerulosclerosis, tubular interstitial injury and artery score were about the same as in the Oxford cohort. However, VALIGA patients showed less mesangial proliferation, less endocapillary hypercellularity and even less crescents. Slide 54

30 In red you can see the MEST scores according to clinical data in the whole population but the group was so big that we could consider also different subgroups. For instance, in green the group of 100 patients with GFR lower than 30 ml/min. As expected the amount of segmental sclerosis or tubular interstitial injury was high but also mesangial proliferation was high. In blue from pale blue to dark blue the different amount of proteinuria and the MEST score nicely increased as the amount of proteinuria increased. Slide 55 So we looked at the correlation between MEST score and clinical data at renal biopsy. We found a very strict correlation between S1 or T1 lesions and egfr, proteinuria, and blood pressure. The same was true for mesangial proliferation, a very nice correlation. However, for endocapillary hypercellularity the association was found only with the level of proteinuria at renal biopsy. Slide 56

31 Then we looked at the true core of validation. The correlation between MEST score and outcome and we found that mesangial profileration, segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis were significantly associated with renal function decline and the survival from renal failure or a 50% decrease in GFR. As you can appreciate, we cannot validate endocapillary proliferation in the whole casistics. Slide 57 However, we looked at a subgroup of more than 200 patients with initial proteinuria lower than 0.5 g/day. Slide 58

32 In this group we observed that endocapillary hypercellularity was associated with lower survival to 50% loss of GFR and renal disease. The hazard ratio was quite high, 8. Slide 59

33 Moreover, we looked at a surrogate endpoint. In this group of patients with low proteinuria we looked at development of higher level of proteinuria which obviously worsened the prognosis. M1 and E1 mesangial proliferation and endocapillary hypercellularity resulted to be significantly predictive factors for progression. This was confirmed also when data were adjusted from MAP and RAS-blockers. The hazard ratio was 2.3. Slide 60

34 Then due to the huge number of patients we had the possibility to perform some subanalyses. For instance, more than 500 patients received immunosuppressive steroids or immunosuppressive drugs, immunosuppressive drugs in a minority but anyway the combination of the two while another relevant group received no steroids or immunosuppressive drugs. Slide 61 So we compared the data of this group of patients without immunosuppression or with immunosuppression and we observed that there was no difference in baseline data. Slide 62

35 However, this is a retrospective cohort and so this reflected the choice made by the doctors. The doctors adopted steroids or immunosuppressive treatment in patients with higher proteinuria at renal biopsy and tendency with a lower GFR at renal biopsy, as expected, if you want. Slide 63 It is nice to note that the doctors made the choice also on the basis of a higher mesangial proliferation, higher endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis. This was done before the publication of the Oxford classification. So the patients who were treated had a more severe disease from a clinical and histological point of view. Slide 64

36 But in spite of that Slide 65 when we considered the rate of renal function decline, it was significantly better in the group of patients who received steroids or immunosuppressive drugs in comparison to those who did not receive these drugs. Slide 66

37 As far as both is concerned the renal function declined as well as the slope of proteinuria. This is quite striking. Slide 67 So we looked at the predictive value of MEST in these two subgroups: receiving or not steroids or immunosuppressive therapy. We checked the three risk factors which were detected in the whole cohort mesangial proliferation, segmental glomerulosclerosis, tubular atrophy and interstitial fibrosis. Slide 68

38 We observed that the rate of renal function decline was associated with these three risk factors only when Slide 69 we considered patients who did not receive a following treatment with steroids or immunosuppressive therapy. Slide 70

39 So this observational registry showed that steroids or immunosuppressive treatment blunted the risk factors associated with MEST score. Slide 71

40 It was confirmed by Stefan Troianov who built up this ROC curve. The added value of pathology score in predicting the rate of GFR loss in patients was observed, was statistically significant only in the subgroup of patients who did not receive immunosuppressive drugs or steroids because in the others the treatment blunted the prognostic value of the pathology features. Slide 72 So to conclude, this VALIGA paneuropean validation study showed a full validation of most Oxford criteria: mesangial hypercellularity, segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis which are risk factors independently of baseline follow-up clinical data. However, endocapillary hypercellularity is a risk factor for early low proteinuric stages. Slide 73

41 So I think that Slide 74 this study adds some significant data on the role of pathological and clinical features in predicting progression of IgAN Slide 75

42 but what was extremely of interest is the value of this large multicentre European collaboration. Slide 76 I have to thank all the many centres, the 55 centres who performed this study. Slide 77

43 I have to thank the clinicians, the pathologists, the trainees, fellows who did a huge work in reviewing all those cases, the steering committee of VALIGA people who took care of the database and the ERA-EDTA and the scientific advisory board and the council for support. Slide 78 Thank you for your attention. Slide 79

44 Chairman: OK this paper is open for discussion. Go ahead. Question: Yesterday it was mentioned that the presence of complement in the mesangium also expressed worst outcome. What do you think about that? It was mentioned yesterday in one of the sessions. Prof. Coppo: The mesangium proliferation resulted to be a significant risk factor for progression and this is highly confirmed. It was confirmed in the whole cohort, it was confirmed in patients with low levels of proteinuria and it was confirmed as well in the subgroup I didn't show for sake of time, of about 100 patients who had a renal biopsy when they had a GFR lower than 30 ml/min. Those patients had a significant mesangial proliferation apart from segmental glomerulosclerosis and tubular interstitial lesions and we found that mesangial proliferation was a risk factor even for these patients. So in our European cohort we are closer, more similar to the Chinese cohort where mesangial proliferation is a relevant risk factor so we have to consider it. So when you treat patients. Question: So going with the complement? Because they're talking about the presence of complement in the biopsy. More complement staining and worse outcome. Prof. Coppo: We didn't look at the complement staining. Question: I think it was a nice cohort, so I don't know but I'm going to try that. Prof. Coppo: No this is nice but anyway even in the first study we didn't take into consideration immunofluorescence because it was so difficult to get sufficiently homogeneous data. So we didn't consider the immunofluorescence. So we don't have data. Question: I think it was presented in ASN. So it was a good idea. Question: Thank you for this very interesting data. Do you think from this data that you should treat patients with low proteinuria and endocapillary proliferation? Prof. Coppo: Well, you know it's difficult, this is an observational study, it's a retrospective study. So it gives only inside the programme and anyway that can be the basis for a future trial. But since according to this data we have quite relevant elements to think that steroids and immunosuppressive therapy are relevant particularly when there is mesangial proliferation and even in cases with segmental glomerulosclerosis or initial tubular interstitial fibrosis. For the initial cases, it's difficult because we look at our endpoint and the endpoint was so far away that we had to move to a 30% reduction in GFR instead of a 50% reduction in GFR. Again, it was seen that indeed endocapillary proliferation and mesangial proliferation were predictive factors and treatment in some way modified these risk factors, that's all. But anyway it's already something. Question: Thank you very much. I would like to ask professor Feeley, you have stated before for many years that you don't believe that corticosteroids will be of any help for these patients. How would you speak now about this? Are you convinced we should use them?

45 Prof. Coppo: What I have said for many years is that I did not think we had sufficient evidence as to whether we should use steroids or not and I think that this is interesting additional evidence to encourage to use of steroids but I think we still want to wait for the randomised controlled trials. Could I ask Rosanna from these data how do you think we should now design the next clinical trials? Should we use the pathological features to decide which patients to recruit into trials? Question: John according to this VALIGA study I think that of the four three are very strong: mesangial proliferation, glomerulosclerosis and tubular interstitial injury. So I would suggest using these three for design of new trials. Chairman: Ok so I think it's time to proceed to the next speaker, chairman. Chairman: I'm sorry we have to move on.