ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΝΕΟΤΕΡΑ ΔΕΔΟΜΕΝΑ

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1 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΝΕΟΤΕΡΑ ΔΕΔΟΜΕΝΑ ΤΣΟΥΧΝΙΚΑΣ ΙΩΑΝΝΗΣ ΝΕΦΡΟΛΟΓΟΣ Γ. Ν. Θ. ΙΠΠΟΚΡΑΤΕΙΟ

2 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΕΠΙΔΗΜΙΟΛΟΓΙΚΑ ΔΕΔΟΜΕΝΑ Συχνότερο αίτιο νεφρωσικού συνδρόμου σε μη διαβητικούς ενήλικες περιπτώσεις (ιδιοπαθούς) / εκατομμύριο πληθυσμού το έτος 15-33% των διαγνώσεων σε βιοψίες νεφρού Συχνότερη στους άνδρες (~ 2:1) Συχνότερα τη 5 η δεκαετία

3 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΙΣΤΟΛΟΓΙΚΗ ΒΛΑΒΗ Υποεπιθηλιακές εναποθέσεις ανοσοσυμπλεγμάτων με επακόλουθη πάχυνση της ΒΜ Διάχυτες κοκκώδεις IgG και C3 εναποθέσεις κατά μήκος της ΒΜ Πιθανή συνύπαρξη μεσαγγειακών ανοσοεναποθέσεων (δευτεροπαθείς μορφές)

4 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΠΑΘΟΛΟΓΟΑΝΑΤΟΜΙΚΗ ΕΙΚΟΝΑ Οπτικό: Διάχυτη πάχυνση ΒΜ Οπτικό: Φυσιολογικό σπείραμα Ανοσοφθορισμός Διάχυτες κοκκώδεις IgG ΗΜ: Μικρές υποεπιθηλιακές εναποθέσεις

5 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ Ιδιοπαθής (75%) - παρουσία αυτοαντισωμάτων Δευτεροπαθής Αυτοάνοσα (Συστηματικός Ερυθηματώδης Λύκος) Λοιμώξεις (ηπατίτιδα Β, ηπατίτιδα C και άλλες) Φάρμακα (χρυσός, πενικιλαμίνη και άλλα) Κακοήθειες (κυρίως συμπαγείς όγκοι)

6 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΑΙΤΙΑ ΔΕΥΤΕΡΟΠΑΘΟΥΣ

7 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΔΕΥΤΕΡΟΠΑΘΗΣ Συστηματική νόσος Δημογραφικά στοιχεία ΔΙΑΓΝΩΣΤΙΚΑ ΣΤΟΙΧΕΙΑ Απουσία PLA2R (υποδοχέας της φωσφολιπάσης 2 ) αντισωμάτων Ιστολογικά 1. Μεσαγγειακές ή/και υπενδοθηλιακές εναποθέσεις 2. Μη IgG4 ανοσοσφαιρίνες 3. Σωληναριακή μεμβράνη θετική στον IF στην ΙgG 4. Απουσία PLA2R χρώσης??

8 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ IgG Subclass Distribution IgG 1 IgG 2 IgG 3 IgG 4 Idiopathic + + ± ++++ Lupus ± Neoplasia Ohtani et al, Nephrol Dial Transplant 2004; 19: 574

9 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΔΕΥΤΕΡΟΠΑΘΗΣ ΚΑΚΟΗΘΕΙΕΣ Η συχνότητα κακοήθειας αυξάνει με την ηλικία Κακοήθεια στο 20-30% των ασθενών με ΜΣ άνω των 60 ετών Συχνότερες προστάτη και πνευμόνων ΕΛΕΓΧΟΣ ΓΙΑ ΚΑΚΟΗΘΕΙΑ Επανάληψη κλινικής εξέτασης Α/α θώρακος CT Μαστογραφία Γυναικολογική εξέταση - ΠΑΠ-test PSA Κόπρανα για Hb (γαστροσκόπηση κολονοσκόπηση >50 ετών) Εξέταση θυρεοειδούς CT ΑΚΟ??

10 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΙΣΤΟΛΟΓΙΚΗ ΕΙΚΟΝΑ ΣΤΑΔΙΑ Stage 1: Μικρές υποεπιθηλιακές εναποθέσεις απουσία spikes στη χρώση αργύρου. Χωρίς πάχυνση της ΒΜ Stage 2: Νέα Βασική Μεμβράνη γύρω από τις εναποθέσεις «ακίδες spikes» φαίνονται στη χρώση αργύρου. Πάχυνση ΒΜ. Stage 3: Συσσωμάτωση των εναποθέσεων (ενδομεμβρανικές εναποθέσεις). Σποραδική λύση των εναποθέσεων και νέα μεμβράνη μεταξύ εναποθέσεων και ποδοκυττάρων Stage 4: Ανώμαλη πάχυνση της ΒΜ στο οπτικό. Σπειραματοσκλήρυνση

11 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΙΣΤΟΛΟΓΙΚΗ ΕΙΚΟΝΑ SPIKES Οι ακίδες (spikes) της (νέας) β.μ. που αναπτύσσεται μεταξύ των υποεπιθηλιακών εναποθέσεων

12 ΦΥΣΙΟΛΟΓΙΚΟ ΣΠΕΙΡΑΜΑ ΗΛΕΚΤΡΟΝΙΚΟ ΜΙΚΡΟΣΚΟΠΙΟ

13 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΣΤΑΔΙΑ ΗΛΕΚΤΡΟΝΙΚΟ ΜΙΚΡΟΣΚΟΠΙΟ ΣΤΑΔΙΟ 1 ΣΤΑΔΙΟ 2 Moderate numbers of small subepithelial deposits (IgG C3) New basement membrane between subepithelial deposits forming spikes ΣΤΑΔΙΟ 3 ΣΤΑΔΙΟ 4 Deposit lysis Deposits undergoing incorporation Fresh deposit Lysis of deposits

14 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΠΑΘΟΓΕΝΕΙΑ Possible Mechanisms of the Formation of Subepithelial Deposits in Experimental Models of, and Patients with, Membranous Nephropathy Glassock RJ, NEJM 2009; 361: 81-83

15 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΠΑΘΟΓΕΝΕΙΑ Υπεύθυνα αντιγόνα στον άνθρωπο 1959: Active Heymann nephritis model 1973: Passive Heymann nephritis model 1980s: Megalin identified as Heymann antigen in rats 2002 Neutral endopeptidase Alloimune MN Debiec H, NEJM 2009 PLA2R1 Idiopathic Beck, NEJM 2010 Aldose reductase and SOD2 Idiopathic Prunotto M, JASN 2011 Cationic bovine serum albumin Early childhood Debiec H, NEJM 2014 Thrombospondin Type 1 Domaincontaining 7A Idiopathic Tomas N, NEJM

16 extract of human glomerular proteins with serum samples SERUM

17 Expression of the M-Type Phospholipase A2 Receptor (PLA2R) in Normal Kidney Tissue and Glomeruli.

18

19 Anti-PLA2R-associated membranous nephropathy membranous lupus nephritis Idiopathic membranous Immunohistochemical staining for PLA2R. The image in panel A is a glomerulus from a biopsy with membranous lupus nephritis. The podocyte cytoplasm is positive for PLA2R antigen, but the subepithelial deposits are PLA2R-negative. This pattern is seen in secondary MN and in normal glomeruli. Image B shows a glomerulus from a patient with PLA2R-positive primary MN. The subepithelial deposits are strongly positive for PLA2R, and there is diminished to absent staining in podocyte cytoplasm. Original magnification 400 (both panels).

20 Anti-Phospholipase A2 Receptor Antibody in Membranous Nephropathy Anti-PLA2R is detected infrequently in secondary MN. The dark bars represent the prevalence of anti-pla2r detected in patients with idiopathic (IMN), lupus-associated (LMN), hepatitis B associated (HBV-MN), and cancer-associated (Ca-MN) membranous nephropathy, using the standard Western blot assay Qin W, J Am Soc Nephrol 2011; 22:

21 Serial monitoring of anti-pla2rin initial PLA2R-negative patients with primary membranous nephropathy Serial assessment for circulating apla2r should be made in gpla2r-positive and apla2r-negative cases with persistent NS, and might increase the proportion of cases with apla 2 R-positive PMN. Ramachadran R, KI 2015; 88:

22 Η εξαφάνιση των Anti-PLA2R προηγείται της μείωσης της λευκωματουρίας Rituximab-Induced Depletion of Anti-PLA2R Autoantibodies Predicts Response in MN Beck LH, JASN 2011; 22:

23 Η εξαφάνιση των Anti-PLA2R προηγείται της μείωσης της λευκωματουρίας Phospholipase A2 Receptor Autoantibodies and Clinical Outcome in Patients with Primary Membranous Nephropathy Hoxha LH, JASN 2014; 25:

24 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΠΑΘΟΓΕΝΕΙΑ

25 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΠΑΘΟΓΕΝΕΙΑ THSD7A is expressed on glomerular podocytes rather than on the glomerular basement membrane

26 Prevalence of Enhanced Granular Expression of Thrombospondin Type-1 Domain Containing 7A in the Glomeruli of Japanese Patients with Idiopathic Membranous Nephropathy Prevalence of enhanced granular expression of THSD7A and M-type PLA2R in the glomeruli of pts with IMN and secondary MN. Numbers of patients with enhanced granular expression of IgG4 among thrombospondin type-1 domaincontaining 7A (THSD7A)-positive, M-type phospholipase A2 receptor (PLA2R)-positive, and THSD7A/PLA2R-negative patients with idiopathic MN and secondary membranous nephropathy. PLOS ONE 2015; 10(9): e

27 A risk HLA-DQA1 allele is associated with imn and may interact with PLA2R alleles French (n=75 ; c=157) Dutch (n=146 ; c=1832) British (n=335 ; c=349) All patients (n=556; c=2338) Stanescu et al, New Engl J Med, 2011, 364:

28 Odds Ratios for Idiopathic Membranous Nephropathy, According to Single- Nucleotide Polymorphism (SNP) and Genotype Combinations Persons who were homozygous for the low-risk allele (GG) constituted the reference category. Numbers of cases and total numbers of subjects are from the joint analysis. OR denotes odds ratio.

29 ΑΝΑΓΝΩΡΙΣΗ ΒΑΣΙΚΟΥ ΕΠΙΤΟΠΟΥ ΤΩΝ PLA2R ΑΥΤΟΑΝΤΙΣΩΜΑΤΩΝ ΣΤΗ ΜΕΜΒΡΑΝΩΔΗ ΝΕΦΡΟΠΑΘΕΙΑ Identification of the Immunodominant Epitope Region in PLA2 Receptor-Mediating Autoantibody Binding in Idiopathic Membranous Nephropathy Kao L, JASN 2015; 26: In this study, we showed, for the first time, that the immunodominant antigenic epitope in PLA2R responsible for autoantibody binding is exclusively formed by a region encompassing the CysR, FnII, and CTLD1 domains. Our conclusion is supported by the following evidence. (1) Autoantibody did not recognize the CysR, CysR-FnII, or FnII-CTLD1 domain but strongly recognized the CysR-FnII-CTLD1 domain complex (1 3 construct). (2) Autoantibody only recognized the nonreduced 1 3 construct but not the reduced form. (3) When the 1 3 construct was absent, autoantibody did not recognize any of the remaining domains. (4) The 1 3 construct in its native conformation completely blocked the reactivity of 10 patient sera containing high levels of autoantibodies with the full-length PLA2R. (5) The 1 3 construct was recognized as effectively as the full-length PLA2R by autoantibodies from various serum samples from patients with IMN.

30 ΑΝΑΓΝΩΡΙΣΗ ΒΑΣΙΚΟΥ ΕΠΙΤΟΠΟΥ ΤΩΝ PLA2R ΑΥΤΟΑΝΤΙΣΩΜΑΤΩΝ ΣΤΗ ΜΕΜΒΡΑΝΩΔΗ ΝΕΦΡΟΠΑΘΕΙΑ Identification of a Major Epitope Recognized by PLA2R Autoantibodies in Primary MN Fresquet M, JASN 2015; 26: recognized by 90% of human anti-pla2r autoantibodies Located in the N-terminal CysR ricin domain, the b2-b3 strands of the trefoil structure involve the peptide WQDKGIFVIQSESLKKCIQAGKSVLTLENCK, which forms the focus of this epitope. The crystal structure of this CysR domain is reported as a b-trefoil form also seen in ricin B17 and is composed of 12 antiparallel b strands: 4 in each part of the 3-lobed -structure. Three disulfide bonds hold these lobes in place, highlighting the structural importance of the disulfide bond present in the 31-mer peptide connecting b2 and b3 strands. Our data show that this epitope in the PLA2R fragments (N-C8, N-C3, N-C2, and ricin domains) in nondenaturing conditions is available to react with human anti PLA2R autoantibodies. Importantly, the epitope structure is resistant to reduction in the larger species N-C8 and N-C3 but is sensitive to reduction in N-C2, ricin, and the 31-mer peptide.

31 ΑΝΑΓΝΩΡΙΣΗ ΕΠΙΤΟΠΩΝ ΤΩΝ PLA2R ΑΥΤΟΑΝΤΙΣΩΜΑΤΩΝ ΣΤΗ ΜΕΜΒΡΑΝΩΔΗ ΝΕΦΡΟΠΑΘΕΙΑ Η ΣΗΜΑΣΙΑ ΤΟΥΣ ΣΤΗΝ ΚΛΙΝΙΚΗ ΕΚΔΗΛΩΣΗ Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy Switz-Polski B, J Am Soc Nephrol 27: ccc ccc, doi: /ASN

32 ΑΝΑΓΝΩΡΙΣΗ ΕΠΙΤΟΠΩΝ ΤΩΝ PLA2R ΑΥΤΟΑΝΤΙΣΩΜΑΤΩΝ ΣΤΗ ΜΕΜΒΡΑΝΩΔΗ ΝΕΦΡΟΠΑΘΕΙΑ Η ΣΗΜΑΣΙΑ ΤΟΥΣ ΣΤΗΝ ΚΛΙΝΙΚΗ ΕΚΔΗΛΩΣΗ Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy Switz-Polski B, J Am Soc Nephrol 27: ccc ccc, doi: /ASN

33 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΚΛΙΝΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ Νεφρωσικό σύνδρομο (70-80%) Φυσιολογική αρτηριακή πίεση (70%) Φυσιολογική νεφρική λειτουργία (70%) ΟΝΑ (θρόμβωση νεφρικών φλεβών, crescentic σπειραματονεφρίτιδα, φάρμακα, προνεφρική ιατρογενής)

34 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΚΛΙΝΙΚΕΣ ΕΚΔΗΛΩΣΕΙΣ Σε συνδυασμό με άλλες σπειραματοπάθειες Διαβητική Νεφροπάθεια FSGS ΤΕΣΝ (ANCA Anti-GBM) IgA νεφροπάθεια

35 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΦΥΣΙΚΗ ΙΣΤΟΡΙΑ ΤΗΣ ΝΟΣΟΥ The course of primary (idiopathic) MN asestimated from literature reports. Note that slightly over 20% of patients with MN initially present with nonnephrotic proteinuria and slightly less than 80% present with the nephrotic syndrome. Evolution to ESRD or death usually is slow, and predominantly occurs among patients who do not experience a remission of nephrotic range proteinuria. It is estimated that about 50% of patients will have a sustained remission or have persistent nonnephrotic proteinuria 15 years after discovery of MN. (Reprinted with permission from Parikh C, Teitelbaum I, Cameron JS: The long term outcome of glomerular diseases, in SchrierRW, ed: Diseases of the Kidney (ed 7). Philadelphia,Lippincott, Williams Wilkins, 2001,pp ) Glassock RJ, Seminars in Nephrology, 2003; 23(4) :

36 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΠΟΡΕΙΑ ΤΗΣ ΝΟΣΟΥ ΜΕ Η ΚΑΙ ΧΩΡΙΣ ΘΕΡΑΠΕΙΑ ΜΕΤΑΝΑΛΥΣΗ Probability of renal survival from the pooled analysis of all studies 86% στα 5 έτη 65% στα 10 έτη 59% στα 15 έτη Hogan SL, AJKD 1995; 25(6):

37 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΠΟΡΕΙΑ ΤΗΣ ΝΟΣΟΥ ΛΕΥΚΩΜΑΤΟΥΡΙΑ ΜΗ ΝΕΦΡΩΣΙΚΟΥ ΕΠΙΠΕΔΟΥ Metropolitan Toronto Glomerulonephritis Registry Group 1: never nephrotic ml/min/y Group 2: nephrotic post-presentation ml/min/y Group 3: nephrotic at presentation The majority of Group 2 and 3 pts received immunosupression treatment while 19% of Group 1 pts received mainly corticosteroids Hladunewich MA, CJASN 2009; 4:

38 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΠΟΡΕΙΑ ΤΗΣ ΝΟΣΟΥ ΝΕΦΡΩΣΙΚΟ ΣΥΝΔΡΟΜΟ DIALYSIS FREE SURVIVAL Immunotherapy Ν=53 SURVIVAL WITHOUT REACHING EITHER END POINT Immunotherapy Ν=53 Supportive Ν=51 Supportive Ν=51 Jha V, JASN 2007; 18:

39 KDIGO Guidelines, KI 2012; 2: Definitions of complete and partial remission in IMN Complete Remission: Urinary protein excretion <0.3 g/d (upcr <300 mg/ g or <30 mg/mmol), confirmed by two values at least 1 week apart, accompanied by a normal serum albumin concentration, and a normal SCr. Partial Remission: Urinary protein excretion <3.5 g/d (upcr <3500 mg/g or <350 mg/mmol) and a 50% or greater reduction from peak values; confirmed by two values at least 1 week apart, accompanied by an improvement or normalization of the serum albumin concentration and stable SCr.

40 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ Ο ΡΟΛΟΣ ΤΗΣ ΛΕΥΚΩΜΑΤΟΥΡΙΑΣ ΣΤΗΝ ΕΞΕΛΙΞΗ ΤΗΣ ΝΕΦΡΙΚΗΣ ΒΛΑΒΗΣ Cattran DC, The impact of sex in primary glomerulonephritis. NDT 2008; 23: Relation between time-average proteinuria and the rate of renal function decline in MN, FSGS, and IgA nephropathy. Declines in renal function are associated with higher levels of sustained proteinuria in patients with MN (where a decline is observed at levels of sustained proteinuria >5 g/d) than in patients with FSGS (where a decline in renal function is observed with sustained proteinuria around 2 3 g/d) or patients with IgA nephropathy (where a decline in renal function is observed with sustained proteinuria >1 g/d). The severity of proteinuria alone does not fully explain the rate of loss of renal function, and other disease specific factors likely play a role.

41 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ Ο ΡΟΛΟΣ ΤΟΥ ΦΥΛΟΥ ΣΤΗΝ ΕΞΕΛΙΞΗ ΤΗΣ ΝΕΦΡΙΚΗΣ ΒΛΑΒΗΣ Cattran DC, The impact of sex in primary glomerulonephritis NDT 2008; 23:

42 Ο ΤΙΤΛΟΣ ΤΩΝ ANTI-PL2R ΑΥΤΟΑΝΤΙΣΩΜΑΤΩΝ ΕΧΕΙ ΠΡΟΓΝΩΣΤΙΚΗ ΣΗΜΑΣΙΑ ΓΙΑ ΤΗΝ ΠΛΗΡΗ Ή ΜΕΡΙΚΗ ΥΦΕΣΗ ΤΟΥ ΝΕΦΡΩΣΙΚΟΥ COMPLETE AND PARTIAL REMISSION COMPLETE REMISSION Kaplan Meier curves for the proportion of participants with primary MN and detectable antibodies at baseline who achieved the combined end point of complete or partial remission (left panel) or complete remission considered as a single end point (right panel) in three tertiles of baseline anti- PLA2R autoantibody titer. The probability of achieving both end points progressively decreased from the lowest to the middle and the highest tertile (reference). The upper and lower HRs refer to lowest and middle tertiles versus high Ruggenenti P, JASN 2015; 26:

43 Ο ΤΙΤΛΟΣ ΤΩΝ ANTI-PL2R ΑΥΤΟΑΝΤΙΣΩΜΑΤΩΝ ΕΧΕΙ ΠΡΟΓΝΩΣΤΙΚΗ ΣΗΜΑΣΙΑ Η αύξηση ή η επανεμφάνιση των αυτοαντισωμάτων προβλέπουν την υποτροπή της νόσου Kaplan Meier curves for the proportion of participants with primary MN with a relapse of the NS after initial C or P remission considered according to previous anti-pla2r autoantibody titer increase/re-emergence after initial rituximab-induced reduction/depletion (left panel) or reemergence only into circulation after initial depletion (right panel). In both cases, titer increase or antibody reemergence are associated with a significant excess risk of subsequent disease relapse, even after adjusting for other risk factors (age). 95% CI, 95% confidence interval; HR, hazard ratio. Ruggenenti P, JASN 2015; 26:

44 Ο ΤΙΤΛΟΣ ΤΩΝ ANTI-PL2R ΑΥΤΟΑΝΤΙΣΩΜΑΤΩΝ ΕΧΕΙ ΠΡΟΓΝΩΣΤΙΚΗ ΣΗΜΑΣΙΑ PLA2R Antibody Levels and Clinical Outcome in Patients with Membranous Nephropathy and Non-Nephrotic Range Proteinuria under Treatment with I-RAS N=33 FU=25.3 ± 8.8 months Hoxha E, PLOS ONE 2014; 9 (10): e110681

45 Ο ΤΙΤΛΟΣ ΤΩΝ ANTI-PL2R ΑΥΤΟΑΝΤΙΣΩΜΑΤΩΝ ΕΧΕΙ ΠΡΟΓΝΩΣΤΙΚΗ ΣΗΜΑΣΙΑ Anti-PLA2R antibodies measured by ELISA predict long-term outcome Kanigicherla D, KI 2013; 83: Survival from Doubling of Serum Creatinine according to tertiles of A-PLA2R levels Survival analysis of time to doubling of serum creatinine (DSC) for all patients (who had not reached DSC at time of sample, n ¼ 82). A-PLA2R levels are shown as tertiles (high, medium, and low) for the whole group. Numbers of patients at risk at selected time points (0, 2.5, and 5 years) are indicated below the plot. Cox regression adjusted for treatment shows Po0.001.

46 Η ΠΑΡΟΥΣΙΑ ΤΩΝ ΑΥΤΟΑΝΤΙΣΩΜΑΤΩΝ ΕΧΕΙ ΣΗΜΑΣΙΑ ΓΙΑ ΤΟ ΕΙΔΟΣ ΤΗΣ ΘΕΡΑΠΕΙΑΣ N=28 pts negative for Phospholipase A2 receptor antibodies (PLA2R-Ab) and thrombospondin type-1 domain-containing 7A antibodies (THSD7A-Ab) in the serum IMMUNOSUPRESSION 1 10 CONSERVATIVE A univariate Cox regression analysis indicated that the use of immunosuppression did not alter the chance to reach a remission of proteinuria. REMISSION NO REMISSION Hoxha E, NDT 2015; 30:

47 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ Ο ΡΟΛΟΣ ΤΗΣ ΥΦΕΣΗΣ ΤΟΥ ΝΕΦΡΩΣΙΚΟΥ ΑΝΕΞΑΡΤΗΤΑ ΑΠΟ ΤΗ ΘΕΡΑΠΕΙΑ McQuarrie EP, NDT 2012; 27: pts with IMN and Nephrotic Syndrome

48 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ Δυσμενείς προγνωστικοί παράγοντες Ηλικία > 50 έτη Άρρεν φύλο Έκπτωση νεφρικής λειτουργίας κατά τη διάγνωση Σοβαρού βαθμού λευκωματουρία (> 8-10 g/24h) Εμμένουσα λευκωματουρία Σημαντικού βαθμού σπειραματική σκλήρυνση, σωληναριακή ατροφία και ίνωση του διάμεσου χώρου Τίτλος των anti-pl2r κατά τη διάγνωση

49 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ Διαστρωμάτωση Κινδύνου ΧΝΝ κατά τη διάγνωση Χαμηλού κινδύνου Λευκωματουρία < 4 gr/24h Φυσιολογική GFR Σταθερή νεφρική λειτουργία σε περίοδο παρακολούθησης 6 μηνών Μέτριου κινδύνου Λευκωματουρία 4-8 gr/24h Φυσιολογική GFR Σταθερή νεφρική λειτουργία σε περίοδο παρακολούθησης 6 μηνών Υψηλού κινδύνου Λευκωματουρία > 8 gr/24h Οποιαδήποτε GFR

50 Μεμβρανώδης Νεφροπάθεια ΘΕΡΑΠΕΙΑ Ποιοι θα λάβουν θεραπεία?? Πότε θα ξεκινήσει η θεραπεία?? Ποια θεραπεία?? Πως θα προσαρμόζεται η θεραπεία?? Πότε θα σταματήσει??

51 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ ΜΗ ΑΝΟΣΟΚΑΤΑΣΤΑΛΤΙΚΗ ACEi η ARBs Ρύθμιση ΑΠ (130/80mmHg) Περιορισμός πρόσληψης άλατος Περιορισμός προσλαμβανόμενης πρωτεΐνης (0,8g/kg BW) Υπολιπιδαιμική αγωγή Αντιπηκτική αγωγή

52 Ιδιοπαθής Μεμβρανώδης Νεφροπάθεια KDIGO Guidelines, KI 2012; 2: Selection of adult pts with IMN to be considered for treatment with immunosuppressive agents 7.2.1: We recommend that initial therapy be started only in patients with nephrotic syndrome AND when at least one of the following conditions is met: urinary protein excretion persistently exceeds 4 g/d AND remains at over 50% of the baseline value, AND does not show progressive decline, during antihypertensive and antiproteinuric therapy during an observation period of at least 6 months; (1B) the presence of severe, disabling, or life threatening symptoms related to the nephrotic syndrome; (1C) SCr has risen by 30% or more within 6 to 12 months from the time of diagnosis but the egfr is not less than ml/min per 1.73 m2 AND this change is not explained by superimposed complications. (2C) 7.2.2: Do not use immunosuppressive therapy in patients with a SCr persistently >3.5 mg/dl (or an egfr <30 ml/min per 1.73 m2) AND reduction of kidney size on ultrasound (e.g., <8 cm in length) OR those with concomitant severe or potentially life threatening infections. (Not Graded)

53 ΙΔΙΟΠΑΘΗΣ ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ ΑΝΟΣΟΚΑΤΑΣΤΑΛΤΙΚΗ Κορτικοστεροειδή Αλκυλιωτικοί παράγοντες (κυκλοφωσφαμίδη, χλωραμβουκίλη) CNIs (κυκλοσπορίνη, tacrolimus) Rituximab (μονοκλωνικό αντίσωμα έναντι του CD20 των Β λεμφοκυττάρων) Mucophenolate mofetil (MMF) ACTH Shengi particles tripterygium wilfordii multiglycosides

54 ΙΔΙΟΠΑΘΗΣ ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ ΑΝΟΣΟΚΑΤΑΣΤΑΛΤΙΚΗ Donadio JV, KI 1974; 6: N=22(11-11) FU=12m We conclude that treatment with cyclophosphamide for one year did not have a favorable effect on proteinuria, renal function or morphologic aspects of the glomerular lesion.

55 ΙΔΙΟΠΑΘΗΣ ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ KDIGO Guidelines, KI 2012; 2: Cyclical corticosteroid/alkylating-agent therapy for IMN (the Ponticelli Regimen ) Month 1: i.v. methylprednisolone (1 g) daily for three doses, then oral methyprednisolone (0.5 mg/kg/d) for 27 days Month 2: Oral chlorambucil ( mg/kg/d) or oral cyclophosphamide (2.0 mg/kg/d) for 30 days Month 3: Repeat Month 1 Month 4: Repeat Month 2 Month 5: Repeat Month 1 Month 6: Repeat Month 2 IMN, idiopathic membranous nephropathy. Monitor every 2 weeks for 2 months, then every month for 6 months, with serum creatinine, urinary protein excretion, serum albumin, and white blood cell count. If total leukocyte count falls to <3500/mm3, then hold chlorambucil or cyclophosphamide until recovery to 4000/mm3.

56 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ A 10-year follow-up of a randomized study with methyiprednisolone and chlorambucil in membranous nephropathy Ponticelli C, KI 1995;48 :

57 ΜΕΜΒΡΑΝΩΔΗΣ ΣΠΕΙΡΑΜΑΤΟΝΕΦΡΙΤΙΔΑ ΠΟΡΕΙΑ ΤΗΣ ΝΟΣΟΥ ΝΕΦΡΩΣΙΚΟ ΣΥΝΔΡΟΜΟ Τροποποιημένο Ponticelli με κυκλοφωσφαμίδη COMPLETE REMISION PARTIAL REMISSION Immunotherapy Ν=53 Immunotherapy Ν=53 Supportive Ν=51 Supportive Ν=51 Jha V, JASN 2007; 18:

58 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ KDIGO Guidelines, KI 2012; 2: : Initial therapy of IMN 7.3.1: We recommend that initial therapy consist of a 6-month course of alternating monthly cycles of oral and i.v. corticosteroids, and oral alkylating agents (see Table 15). (1B) 7.3.2: We suggest using cyclophosphamide rather than chlorambucil for initial therapy. (2B) 7.3.3: We recommend patients be managed conservatively for at least 6 months following the completion of this regimen before being considered a treatment failure if there is no remission, unless kidney function is deteriorating or severe, disabling, or potentially life threatening symptoms related to the nephrotic syndrome are present (see also Recommendation 7.2.1). (1C) 7.3.4: Perform a repeat kidney biopsy only if the patient has rapidly deteriorating kidney function (doubling of SCr over 1 2 month of observation), in the absence of massive proteinuria (415 g/d). (Not Graded) 7.3.5: Adjust the dose of cyclophosphamide or chlorambucil according to the age of the patient and egfr. (Not Graded) 7.3.6: We suggest that continuous daily (noncyclical) use of oral alkylating agents may also be effective, but can be associated with greater risk of toxicity, particularly when administered for >6 months. (2C)

59 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ KDIGO Guidelines, KI 2012; 2:

60 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ KDIGO Guidelines, KI 2012; 2: ΚΟΡΤΙΚΟΣΤΕΡΟΕΙΔΗ Η MMF

61 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ CNIs CYCLOSPORINE Cyclosporine in patients with steroid-resistant membranous nephropathy: A randomized trial. Failed to achieve remission of proteinuria after a minimum of 8 wk of prednisone at 1 mg/kg/d Dose Cy of 3.5 mg/kg/day in the group and ml/kg/day in the placebo group REMISSION Complete and Partial 26 wk Complete and Partial 78 wk Pred + Cy N=28 Pred+Placebo N=23 75% 22% 39% 13% Cattran D, KI 2001; 59:

62 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ CNIs TACROLIMUS Pts with nephrotic syndrome 12m treatment and 6m tapering whole blood 12-h trough level between 3 and 5 ng/ml TACROLIMUS N=25 CONTROL N=23 Probability of remission (either CR or PR) in tacrolimus-treated group (solid line) and control group (dashed line) Praga M, KI 2007; 71:

63 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ CYCLOSPORIN - ΜΟΝΟΘΕΡΑΠΕΙΑ CyA and predn n=31 CyA n=20 CyA dose 2-3 mg/kgbw CyA trough levels 100 and 200 ng/ml Alexopoulos E, NDT 2006; 21:

64 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ CHLORAMBUCIL OR CYCLOSPORIN

65 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ RITUXIMAB Ν=100 4 weekly rituximab doses (375mg/m 2 ) Ruggenenti P, JASN 2012; 23:

66 SA-OR011 ASN, KIDNEY WEEK 3-8 NOV 2015 A Randomized Controlled Trial of Rituximab for Severe Idiopathic Membranous Nephropathy (IMN) Pierre M. Ronco,1,2,8 Karine Dahan,1 Hanna Debiec,2,8 Emmanuelle M. Plaisier,1,2,8 Marine Cachanado,3 Alexandra Rousseau,3 Laura Wakselman,3 Pierre-Antoine Michel,1 Fabrice Mihout,1 Bertrand Dussol,4 Marie Matignon,5 Christiane I. Mousson,6 Tabassome Simon.3,7,8 1Nephrology and Dialysis, AP-HP, Hôpital Tenon, Paris, France; 2UMR_S 1155, INSERM, Paris, France; 3Clinical Pharmacology and Unité de Recherche Clinique (URCEST), AP-HP, Hôpital Saint Antoine, Paris, France; 4Nephrology and Transplantation, AP-HM, Hôpital de la Timone, Marseille, France; 5Nephrology and Transplantation, AP-HP, Hôpital Henri Mondor, Créteil, France; 6Nephrology and Transplantation, Centre Hospitalier Univ, Dijon, France; 7UMR_S1148, INSERM, Paris, France; 8UPMC, Sorbonne Univs, UPMC Univ Paris 06, Paris, France. Background: IMN is a common cause of nephrotic syndrome. Anti-PLA2R antibodies occur in 70% of patients. No randomized controlled trial has evaluated rituximab efficacy and safety. Methods: Patients with biopsy proven IMN and persistent nephrotic syndrome after 6 months despite Non Immunosuppressive Antiproteinuric Treatment (NIAT) were randomly assigned to 6-month therapy with NIAT and 375 mg/m2 of rituximab on days 1 and 8, or NIAT alone. At month 6, the primary end point was the rate of remission; the composite end point was defined as reduction of proteinuria > 50% and increase of serum albumin > 30%; secondary end points were proteinuria, serum albumin, serum creatinine, and PLA2R-Ab. Results: 37 and 38 patients received NIAT with rituximab and NIAT alone. At month 3, rituximab decreased PLA2R-Ab rate and titer (P<0.001), and induced PLA2R-Ab depletion in 56 % of patients (P<0.001). At month 6, 13 (35 %) patients in the NIAT-rituximab group and 8 (21 %) in the NIAT group reached the primary end point (P=0.17); 15 (41 %) patients in the NIAT-rituximab group and 5 (13 %) in the NIAT group reached the composite end point (OR=0.22, 95% CI= [0.07; 0.70]; P=0.007). Serum albumin increased more with rituximab (P=0.029), without difference in proteinuria. Number of SAEs was comparable in both groups. Conclusions: Rituximab induced immunological and clinical remission defined by a composite end point with a high safety profile (GEMRITUX ClinicalTrials.gov number). Funding: Pharmaceutical Company Support - Hoffmann La Roche, Private Foundation Support, Government Support - Non-U.S.

67 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ ACTH A Randomized Pilot Trial Comparing Methylprednisolone Plus a Cytotoxic Agent Versus Synthetic Adrenocorticotropic Hormone in IMN CP or CHL + PRED N=16 ACTH N=16 COMPLETE REMISSION PARTIAL REMISSION REMISSION TOTAL (%) % 87% Ponticelli C, AJKD 2006; 47:

68 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ CYCLOPHOSPHAMIDE OR ACTH Synthetic ACTH in High Risk Patients with IMN: A Prospective, Open Label Cohort Study nephrotic syndrome despite conservative treatment, an egfr > 60 ml/min/1.73m2, a high risk for ESRD, and a (relative) contraindication to our standard treatment with CP and steroids. High risk for ESRD was defined as an urinary βeta-2-microglobulin (β2m) excretion of >500 ng/min ACTH 1mg twice a wk IM Van de Logt A, PLoS One Nov 12;10(11):e

69 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ Shengi particles Prospective, multicenter, RCT, efficacy and safety of Shenqi particle in adult pts with IMN 9.3 g Shengi particles vs prednisolone and cyclophosphamide Chen Y, AJKD 2013; 62:

70 ΜΕΜΒΡΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ Comparison of tripterygium wilfordii multiglycosides and tacrolimus in the treatment of idiopathic membranous nephropathy: a prospective cohort study Liu S, BMC Nephrology 2015; 16: 200 TWG +Predn N=23 TAC +Predn N=30 Tripterygium wilfordii Hook F (TwHF) one of the most widely studied Chinese medicinal plants is a member of the Celastraceae family of perennial vine-like plants. Tripterygium wilfordii multiglycosides is a preparation that is extracted and purified from the root xylem of TwHF [10], and is commercially available as tablets.

71 ASN, KIDNEY WEEK 3-8 NOV 2015 Belimumab in Idiopathic Membranous Nephropathy: An Interim Analysis of Exploratory Biomarkers Including Anti-PLA2R Autoantibodies Christine Barrett,1 Shaun Flint,1 Robert Brian Henderson,1 Tim Sebastian Schmidt,1 Sophie I. Gisbert,1 Gengqian Cai,2 Caroline O.S. Savage.1 1GlaxoSmithKline plc, United Kingdom; 2GlaxoSmithKline plc. Background: Belimumab, a B-lymphocyte stimulator (BLyS)-specific inhibitor has been shown to reduce anti-phospholipase A2 receptor (PLA2R) autoantibodies and proteinuria in a mechanistic study (BEL116472) in idiopathic (primary) membranous nephropathy (IMN). Here we report an interim analysis of individual patient responses and analysis of exploratory pharmacodynamic (PD) biomarkers. Methods: 14 anti-pla2r autoantibody positive IMN patients with nephrotic range proteinuria received 10mg/kg iv belimumab every 4 wks (or 2 wks if >10g/24h) for up to 100 wks. 11 of these completed at least 28 wks treatment, with 3 withdrawals before wk 16. Assessment of proteinuria, anti-pla2r antibody levels, belimumab kinetics, BLyS levels and B cell immunophenotypes was performed. Results: There was a significant reduction in anti-pla2r antibodies by wk 12 (-46%, p=0.025) and in upcr by wk 36 (-38%, p=0.022). 9 of 11 subjects showed a reduction of >50% in anti-pla2r levels at the primary endpoint (wk 28). 6 of 11 achieved at least partial remission of proteinuria and negative or borderline anti-pla2r levels by last follow-up to date ( wks). Lack of remission was linked to a smaller fall in anti-pla2r levels, or anti-pla2r at wk 28 >100 RU/ml, or a shorter follow-up ( 36 wks). Week 2 belimumab trough levels showed strong negative correlation with baseline upcr (rs=-0.94 p<0.0001). The correlation of baseline BLyS level with proteinuria response was weak. Exploratory belimumab PD effects included a reduction in naive B cells and expanded memory B cells. Conclusions: This mechanistic trial of belimumab in IMN has enabled a novel analysis of PD and PK endpoints, confirming but also extending the PD effects previously reported in studies of SLE. Further analysis of anti-pla2r antibody kinetics as a predictor of remission may also be informative. Funding: Pharmaceutical Company Support - GlaxoSmithKline plc

72 ΜΕΜΒΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ ΘΕΡΑΠΕΙΑ ΠΡΟΟΠΤΙΚΕΣ A new rescue regimen with plasma exchange and rituximab in high-risk membranous glomerulonephritis Eur J Clin Invest 2015 Oct 7. doi: /eci [Epub ahead of print] We evaluated a new rescue protocol including: plasma exchanges (PE) against albumin intravenous immunoglobulins (IVIGs) and rituximab for 10 patients with a biopsy-proven diagnosis of imgn who were therapy-resistant to all conventional regimens and had a urinary protein to creatinine ratio of more than mg/g Crea achieved partial remission in 90% of patients who had been refractory to therapy. The mean time to partial remission was 2 1 months.

73 ΜΕΜΒΑΝΩΔΗΣ ΝΕΦΡΟΠΑΘΕΙΑ STARMEN STUDY Sequential TACROLIMUS RITUXIMAB VS ΘΕΡΑΠΕΙΑ ΠΡΟΟΠΤΙΚΕΣ STEROIDS + CYCLOPHOSPHAMIDE A European multicentre and open-label controlled randomized trial to evaluate the efficacy of Sequential treatment with TAcrolimus Rituximab versus steroids plus cyclophosphamide in patients with primary MEmbranous Nephropathy: the STARMEN study Clinical Kidney Journal, 2015; 8(5): MTAC STUDY Mycophenolate Mofetil and Tacrolimus VS Tacrolimus for the Treatment of Idiopathic Membranous Glomerulonephritis (MTAC) MENTOR STUDY RITUXIMAB VS CYCLOSPORIN A Multicenter Randomized Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR) Nephron 2015; 130:

74 ΑΝΤΙΠΗΚΤΙΚΗ ΘΕΡΑΠΕΙΑ ΣΤΗΝ ΙΔΙΟΠΑΘΗ ΜΕΜΒΡΑΝΩΔΗ Venous Thromboembolism in Patients with Membranous Nephropathy Lionaki S, CJASN 2012; 7: Adjusted risk of VTE by the level of serum albumin in 732 patients with available data

75 ΑΝΤΙΠΗΚΤΙΚΗ ΘΕΡΑΠΕΙΑ ΣΤΗΝ ΙΔΙΟΠΑΘΗ ΜΕΜΒΡΑΝΩΔΗ Personalized prophylactic anticoagulation decision analysis in pts with membranous nephropathy Lee T, Kidney International 2014; 85: Base case analysis: the ratio of benefit-to-risk according to risk categories for VTE and major bleeding choose the preferred benefit-to-risk ratio Decision approach for prophylactic anticoagulation

76 ΣΥΜΠΕΡΑΣΜΑΤΑ Η ανακάλυψη νέων αντιγόνων και αυτοαντισωμάτων και ο καθορισμός του ρόλου τους (anti-pla2r) μάλλον θα βοηθήσουν σημαντικό ποσοστό ασθενών, αλλά χρειάζονται και άλλες μελέτες Η αναγνώριση επιτόπων και ο ρόλος τους πιθανώς θα βοηθήσουν στην πιο εξειδικευμένη αγωγή Η ονοματοδοσία πιθανώς θα αλλάξει σε πιο ανοσολογικά συγκεκριμένους όρους Η κυκλοφωσφαμίδη και τα κορτικοστεροειδή παραμένουν στην πρώτη γραμμή Η θεραπεία με Rituximab υπόσχεται αρκετά, πιθανώς και ως θεραπεία πρώτης γραμμής

77 ΕΥΧΑΡΙΣΤΩ