Pathophysiologie des glomérulonéphrites extra-membraneuses

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1 Pathophysiologie des glomérulonéphrites extra-membraneuses Pierre Ronco Unité INSERM 1155 Service de Néphrologie Hôpital Tenon 43 ème Séminaire d'enseignement du CUEN 6 Juin 2016 Outline of the lecture Background and review of recent pathophysiological advances Fromthe benchto the bedside - diagnostic tests - predictive value of antibodies - treatment monitoring Exogenous antigens Perspectives 1

2 Membranous Nephropathy Major cause of nephrotic syndrome and chronic renal failure Aetiologies of membranous nephropathy 30% associated with - infections -cancers - autoimmune diseases - drugs 70% «idiopathic forms» : Treatmentiscontroversialbecauseof unpredictableoutcomevs side-effects and lack of pathophysiology-driven therapy Proteinuria as the only biomarker for disease follow-up! 2

3 30/07/2016 Walter Heymann, Cleveland, 1959 Heymann nephritis Renal BB IgG deposits Megalin, the target antigen of HN Podocytes Activation of complement Rat: megalin Human? GBM Proteinuria Endothelium In situ formation of immune deposits Kerjaschki and Farquhar PNAS 1982, 79:5557 ; Ronco et al J Immunol 1986, 136:125 3

4 The case : Hugo D. (male gender) 34 Wks of gestation : oligohydramnios and enlarged kidneys 38 Wks: birth 1st Daysof life : respiratorydistressand oligoanuria, followed by nephrotic range proteinuria and increased blood pressure 4 Wks: CT-guidedkidneybiopsy Negative tests for syphilis, toxoplasmosis, cytomegalovirus and hepatitis-b virus infections Negative Coombs test. Normal levels of complement components at day 35 Debiec et al. N Engl J Med 2002, 346:2053 Antigenidentification froman extremephenotype: Neonatal membranous nephropathy NEP : neutral endopeptidase MOTHER Asymptomatic anti-nep IgG NEP NEP NEP FETUS Transient nephrotic syndrome mother 1 2 control 1 2 IgG C5b Blot: anti-nep mab PLACENTA Infant born with MN and nephrotic syndrome Debiecet al. N EnglJ Med. 2002, 346:2053 4

5 Membranous nephropathy: a monogenic disease All mothers have truncating mutations in MME gene Wild-type Heterozygote MME cdna 15 exon A T C C G A G A A T C C G A G A 7 Wild-type A T C T G A G A III Heterozygote Homozygote ATG 466delC P156fsX C T R448X TGA AA CC TC TAC A A C C T C T A C A A C T C T A C T A A C T C TAC T Portugal Netherlands, Morocco, Germany, Italy Fromantigenidentification to genetic defect MOTHER Genetic defect PLACENTA NEP FETUS NEP deficient NEP IgG GBM anti-nep IgG Y Five families Morocco Netherlands Portugal Germany Italy Debiecet al. N EnglJ Med 2002 and Lancet

6 Auto-immune «idiopathic» MN in adults Principle of pangenomic(gwas) studies 6

7 From polygenic disease to rare association of common variants 556 Patients ; 2338 controls (Euro MN Consortium = F+UK+NL) Risk of MN x 80 HLA-DQA1 No mutation in PLA2R1 coding sequence PLA2R1 Stanescuet al, New EnglJ Med, 2011, 364: 616 ; Coenenet al, J Am Soc Nephrol, 2013,24:677 Are anti-pla2r antibodies pathogenic? Transfer experimentsimpossible becauseof lackof expression of PLA2R in mouse, rat and rabbit podocytes Lackof experimentalmodel Strong predictive value of anti-pla2r antibody Recurrence aftertransplantation : «The humanmodel» of passive Heymann nephritis Exceptional case of recurrence related to PLA2R IgG3k mab (Debiec et al, JASN 2012, 23:1949) 7

8 Direct effectof autoantibodies: The example of PLA2R M292V H300D G1106S N CRD FN2D Extracellular domain Conformation-dependent epitopes CTLD Putative PLA2 binding domain TMD CD Positive regulator MAPK activation Lipid mediator production ROS production and activation of DNAdamage pathways C Negative regulator Internalization Degradation Debiec et al, Semin Immunopathol 2014, 36:381 A new podocyte antigen in adult patients with MN : THSD7A PLA2R A CRD FN2D CTLD N N 1 Putative PLA2 binding domain TMD CD Kao et al, JASN 2014, Sept 9 ; Fresquetet al, JASN 2014, Oct6 Conformational epitope is located in this region 31 mer peptide from this domain Thrombospondin type-1 domain containing 7A (THSD7A) B N RGD motif CD Trombospondin type-1 domains TSDs TMD 10 % of PLA2R-negative patients with MN Tomas et al, NEJM 2014, 371:

9 Outline of the lecture Background and review of recent pathophysiological advances Fromthe benchto the bedside - diagnostic tests - predictive value of antibodies - treatment monitoring Exogenous antigens Perspectives HoxhaE et al, NDT 2011, 26:2526 9

10 Specificity and sensitivity of PLA2R antibody 100 N=689 70% N=71 2% N=21 19% N=19 15% N=17 12% N=90 0% N=153 0% Meta-analysis(2014) Positive for anti-pla2r (%) studies, 2212 patients -Specificity= 99% (95% CI : %) -Sensitivity= 78% (95% CI :66-87%) Du et al, PLoSOne 2014, 9:e imn SLE Cancer HBV GvH DC HC «Secondary» MN Debiec,Tesar and Ronco; HofstraJASN 2012 ; Hoxha et al, NDT 2011, KI 2012; Qin et al, JASN 2011 Antigen detection in biopsy is more sensitive than serology Tenon cohort n = 106 (84 imn ; 22 smn) -sensitivity PLA2R -Ag : 86% - apla2r-ab : 76% Pourcine et al, unpublished Retrospective diagnosis Debiecand Ronco, New EnglJ Med, 2011, 364 :689 ; Svobodovaet al, NDT, 2013, 28:1839 ; Hofstraet al, J Am Soc Nephrol, 2012, 23:1735 ; Ruggenentiet al, J Am Soc Nephrol, 2015, March 24 10

11 There are exceptions.. SecondaryMN and PLA2R Lupus MN HepB Sarcoidosis Coincidence of imn with the associated disease? StehléT et al, NDT 2015, 30:1047 IgG subclass distribution according to underlying disease IgG 1 IgG 2 IgG 3 IgG 4 Idiopathic + to Lupus ± Neoplasia to ++ Recurrent MN in the allograft De novo MN in the allograft Noël LH et al, Clin ImmunolImmunopathol1988, 46:186 ; Ohtaniet al, NDT, 2004, 19:574 ; Quet al, NDT 2012, 27:1931 ; Debiec, personaldata ; Markowitz, personal data 11

12 Management of newly diagnosed MN Newly diagnosed Membranous nephropathy 1. Anti-PLA2R & PLA2R Antigen in kidney biopsy 2. IgG subclasses in biopsy 3. N inflam. cells per glomeruli CambierJ and RoncoP, Clin JASN, :1701 Antibody/Ag (+) AND IgG4 predominance AND inflammatory cellsper glomeruli 8 Antibody/Ag (-) OR IgG1-2 predominanceor > 8 inflammatory cells per glomeruli Idiopathic MN Stop investigation exceptif personal and hereditary cancer risk factors Secondary MN Search for cancer High levels of PLA2R-Ab are correlated with: A lowerrate of remission, eitherspontaneousor induced by IS treatment A higherrisk: - of occurrence of nephrotic syndrome in nonnephrotic patients - of renal function deterioration A longer time to remission under IS treatment KanigicherlaD et al, Kidney Int : 940; HofstraJM et al, JASN : 1735 ; HoxhaE et al, JASN :1357 ; RuggenentiP et al, JASN 2015, March 14; HoxhaE et al, PLoSOne :e

13 Percent changes in proteinuria, serum albumin and anti-pla2r antibody levels 100 Serum Albumin Y = *(ln(X) )+0.179*(X^ ) Time to 50% increase = 11.4 months Mean percent change vs baseline h Proteinuria Y = *(X^ ) *(X ) Time to 50% decrease = 10.5 months -100 Y =mean percent change vs baseline X = (time+1)/10 Anti PLA 2 R autoantibody Y = *(X^ )-0.404*(X^ ) Time to 50% decrease = 0.65 months months Ruggenenti, Debiec,, Ronco, Remuzzi, J Am Soc Nephrol :2545 PLA2R Ab titer increase or antibody re-emergence is associated with a high risk of relapse Proportion of patients with relapse of the nephrotic syndrome Increase YES Increase NO Unadjusted HR (95%CI): 7.68 ( ); p=0.003 Adjusted HR (95%CI): 6.70 ( ); p=0.007 Proportion of patients with relapse of the nephrotic syndrome Re-emergence YES Re-emergence NO Unadjusted HR (95%CI): 7.03 ( ); p=0.00 Adjusted HR (95%CI): 6.54 ( ); p=0.010 Patients at risk months Patients at risk months Increase NO Increase YES Emergence NO Emergence YES Ruggenenti, Debiec,, Ronco, Remuzzi, J Am Soc Nephrol :

14 Anti-PLA2R antibodies predict relapse rate after IS therapy Bechet al, Clin JASN 2014, 9:1386 Can anti-pla2r be useful for the diagnosis and monitoring of patients with recurrent and de novomn? Recurrent : about 50% anti-pla2r De novo : 0 In patients with a positive test at the time of TP there is ~80% chance of recurrence but 20% have not recurred for up to 9 years (PPV=83%) If the test is negative there is still a 50% chance of recurrence (NPV=42%) Debiecet al, Am J Transplant 2011, 11:2144 ; Debiecet al, JASN 2012, 23:1949 ; Larsen and Walker, Transplantation 2013 ; KattahA et al, Am J Transplant, :

15 Whatshouldwedo in 2016? Assess anti-pla2r antibody in all adult patients with a suspected diagnosisof MN, startingwiththe IF test (specificity, 100% ; sensitivity, 70 to 80%), and anti-thsd7a antibody in PLA2Rnegative patients Search for PLA2R antigen in kidney biopsies from all patients with MN, and for THSD7A in PLA2R-negative biopsies Determine Ig subclass in kidney biopsies from all patients with MN Monitor anti-pla2r antibody titer during follow-up and in grafted patients with MN Outline of the lecture Background and review of recent pathophysiological advances Fromthe benchto the bedside - diagnostic tests - predictive value of antibodies - treatment monitoring Exogenous antigens Perspectives 15

16 Antibodies and their targets A Endogenous antigen and allo- or autoantibodies B Exogenousantigenand allo-or xenoantibodies NEP PLA2R/THSD7A Food Therapeutic proteins Viruses Y Y Placenta Autoantibodies Y Y Y Maternal alloantibodies α-enolase SOD2 Aldose reductase Y Planted antigen cbsa Y Y Y Y Arylsulfatase, α-glucosidase Immunization Pathogenic antibodies Hep B Debiec et al, Semin Immunopathol 2014, 36:381 What s next? Understand the genetic bases of disease triggering, spontaneousremissionand progression by next generation sequencing Identifyadditionalantigensand T cellpopulations involved in triggering and progression Design new therapeutic strategies 16

17 From the podocyte to new therapeutic approaches of autoimmune diseases IgG Debiec et al, Lancet, 2015, 385:1983 Eliminating environmental factors: diet, toxin Reducing autoantibodies Depletion of B-cells (non specific) Depletion of B-cells producing pathogenic antibodies Development of antibody traps or decoys B. Iorga, CNRS Gif C5b-9 complex ER stress Inhibiting complement activation Drug design Ubiquitin proteasome system Protecting the podocyte Inhibitors of ER stress Quantum Rattle Humbury, PNAS 2015 D. Bazin & C. Sanchez, Collège de France The expanding spectrum of human membranous nephropathies Neonatal, alloimmune: NEP Early childhood MN : cationic BSA Enzymotherapy-induced MN in patients treated with ERT - a-glucosidase - arylsulfatase «Idiopathic» MN %: PLA 2 R (+ otherspecificities: AR, SOD2, enolase?) - <10 %: THSD7A (10% of PLA2R negative MN), associated with cancer? Secondary MN : Hep B antigens, other antigens to be identified GraftMN : -Recurrent: PLA2R (> 50%) -De novo : allo-immune 17

18 Substitute molecularsignatures for uniform histological definition: Towards new ontology.and personalizedmedicine, diagnostic and therapy(specific immunoadsorption) 18

19 Acknowledgments Bergamo(I) G. Remuzzi P. Ruggenenti Nijmegen(NL) J. Wetzels J. Hofstra UK R. Kleta(London) P. Brenchley(Manchester) CNG (Evry) D. Bacq-Daian Paediatricians V. Guigonis(Limoges, F) A. Bensman(Paris, F) G. Deschênes(Paris, F) P. Niaudet(Paris, F) T. Ulinski(Paris, F) J. Nauta(Rotterdam, NL) F. Janssen (Brussels, B) J. Nortier(Brussels, B) D. Bockenhauer(London, UK) M. Kemper(Hamburg, D) F. Emma, M. Vivarelli(Rome, I) B. Stengel(Paris, F) 19