New Immunosuppressive therapies in Idiopathic Nephrotic Syndrome (INS)

Transcription

1 New Immunosuppressive therapies in Idiopathic Nephrotic Syndrome (INS) Actualités Jean Hamburger 2008 Philippe Grimbert CHU Henri Mondor

2 Idiopathic Nephrotic Syndrome: MCNS and FSGS Not a disease but histological lesions Obscur pathophysiology Mechanism of action of drugs is poorly understood Meyrier A, NDT 2004

3 Glomerular nephropathy incidence Swaminathan S et al Clin JASN 2006

4 Idiopathic Nephrotic Syndrome IS sensitivity IS resistance Immune genetic Mutations /deletions (Podocine, nephrine, ACTN-4 WT1, ADNmt,...) Mechanisms? podocyte dysfunction Cytoskeleton desorganisation

5 Immune hypothesis Antigenic stimulation (virus, vaccination, insect bite, atopy, ) Activation of cytokinesregulation pathway (voie NFχB, voie du protéasome) T lymphocyte activation Th2 shift Increase cytokines production : TNFα, IL-8, IL-13, IL-5, IL-6, Glomerular permeability factor Interaction with podocytes Podocytes cytoskleton reorganization and functional activity of filtration barrier disruption

6 Glomerular Permeability Factor Koyama A., Kidney international 1991

7 INS AND IMMATURE CELLS CD34+ CD34- Sellier-Leclerc AL JASN 2007

8 INS and IL-13 IL-13+ IL-13+ B7-1 IL-13- Il-13 - IL-13 + Lai KW, JASN 2007

9 Evidence based recommandations? IS are used in INS since 1940 Empiric therapy based on inhibition of T cells, B cells mediators of inflammation and fibrosis What is the evidence base for therapy

10 The conviction with which many nephrologists hold an opinion varies inversely with the evidence UTI Transplant HD No. of RCTs DN PD Calcul Acid-base ARF GN CRF No. of citations E Lewis JASN 2006

11 MCNS: Conventional therapies 1 Corticosteroids Response to steroids Steroid-dependent Or Frequent relapse 2 Ciclosporine Alkylants agents Levamisole Rémission 70% 85 à 90 % 40 à 50 % 10 à 15 % Steroid-resistant Failure: 50-60% cas FSGS

12 Cyclosporine: tolerance Side effects SDNS (n = 74) SRNS (n = 43) P b Gum hyperplasia 25 (33.8%) 13 (30.2%) Hypertrichosis 51 (68.9%) %) Hypertension 4 (5.4%) 8 (18.6%) Renal dysfunction 2 (2.7%) 5 (11.6%) El Husseini H, N DT 2005;

13 FSGS: conventional therapies 1 Steroids 2 Cyclosporine 50 à 60 % Response to steroids ~ 50 % Frequent relapse or Steroid-dependent 40 à 50 % Steroid-resistant * Même après un traitement prolongé de plus de 6 mois

14 FSGS: Remission is the best pronostic factor Remission: facteur pronostic Thomas et al Kidney Int 2006

15 FSGS: remission is the best pronostic factor Korbet S Kidney Int (2002) 62: 2301

16 2. FSGS: conventional therapies Korbet et al Sem Nephrol 2003

17 FSGS: time to remission % remission 50% EBR: GRADE A Median (months) Rydel: 3.7 Cattran: 4 Ponticelli: Length of therapy

18 Response to cyclosporine Initial response N Complete R Partial R Failure Steroid S 15 73% 7% 20% Steroid R % 22% 49% Relapse after CyA withdrawal: 50-90% Korbet S Kidney Int (2002) 62: 2301

19 Alkylant agents and FSGS Initial response to steroids N Complete R Partial R Failure Steroid S 43 51% 23% 26% Steroid R % 15% 69% Korbet S Kidney Int (2002) 62: 2301

20 Rational for the use of new IS drugs: Steroid-dependent Side effects using conventional IS Dependency to IS Steroid-resistant Failure using conventional IS 50%: ESRF First purpose therapy? Save in steroid

21 New IS drugs IL-2 Signal 1 Signal 2 Signal 3 Signal 4 G1 S Signal 1 Signal 2 Signal 3 Signal 4 Ciclosporine Anti CD 40-L Sirolimus Azathioprine Tacrolimus CTLA4-Ig Anti IL-2R MMF Stéroïdes Dérivés du leflunomide

22 Mycophenolate Mofetil and INS De novo pathway Ribose-5P + ATP PRPP synthetase RNA PRPP RNA Salvage pathway Inosine MP Guanosine MP Adenosine MP Adenosine desaminase IMP deshydrogenase HPGRTase (ADA) (Lesch-Nyhan) (IMPDH) Guanine DNA Mycophenolic Acid DNA

23 MMF and MCNS (Sepe V et al, Kidney Int 2008)

24 MMF and FSGS

25 MMF and INS (Mendibazal et al Pediatric Nephrol 2005) 26 patients: MCNS (12) - FSGS (16) D R Steroid-dependent: n = 20 Steroid-resistant n = 6 MMF: 6 months 1200mg/m 2 /24h --- -Save in steroid: (50%): n = 15-9 patients with complete remission - Relapse in 50% after MMF withdrawal RP: n= 1

26 MMF and steroid-dependent INS 42 children: MMF (25mg/kg/d) + Cs Relapse rate (6 months): 50% Complete remission: 25% Decrease in cumulative steroid dose : 50% in 80% of patients Hematological tolerance+++ Afzal K et al Pediatric Nephrol 2007

27 MMF et SNI : conclusion Preliminary results: D2 et D3 Dose ( mg/m 2 ) and length (1-39 months) are heterogeneous Steroid-dependant and not steroid-resistant INS Lack of «de novo» study (PHRC national) Azathioprine? (Cade R, Arch Int Med 1986)

28 SNI et Tacrolimus T cells immunosuppressive drug FK506 Higher in vitro NFAT inhibition Lower incidence of acute rejection in transplantation GPF synthesis inhibition? Hemodynamic effects

29 Tacrolimus and SNI : D2 D3 Westhoff T, Drug Evaluation 2008

30 Tacrolimus and INS 83 Patients EBR: D2 Segarra & al NDT 2002 Tacrolimus (0.1mg/kg/d) + stéroïds 25 adults with FSGS after failure or dependency to CYA At 6 months: 10 complète remissions (40%), PR: n = 2 (8%). Failure: 50% Renal toxicity 40%. FK dependency (76% relapse) Loeffler & al, Ped Nephrol childrens with steroid-resistant FSGS FK (0.1mg/kg/d)+ stéroïds At 6 months: Complete remission :81%. Bhimma & al, Am J Nephrol children with steroid-resistant resistant FSGS treated with Tacrolimus (0.1mg/kg/d) for 1 year CR: 40%, PR: 45%, Failure 15%, Relapse: 40% Gulati & al, NDT children with steroid-resistant resistant INS (9 MCNS et 11 FSGS) FK (0.1mg/kg/d) + stéroïds At 9 Months: complete remission : 84% and partial remission: 10% GFR stable

31 SNI: Tacrolimus/ciclosporine (1) (Sinha M, NDT 2005) 10 children with SD INS (MCNS=9) 2 periods: CyA (5mg/kg/j) and FK (0.1mg/kg/d) Follow up: 9 years

32 SNI: Tacrolimus/ciclosporine (2) (Li X et al NDT 2007)

33 Tacrolimus as «First line therapy» (Duncan et al NDT 2004) -6 adults with FSGS -Tacrolimus: 4mg/d (To: 4-7 ng/ml) -Length of therapy: 13 months At presentation At follow-up t-test Serum albumin (g/l) 26.8 (±4.6) 37.7 (±1.9) P = Urinary protein excretion (g/24 h) 11.0 (±4.5) 2.8 (±2.5) P = MDRD GFR (ml/min/1.73 m 2 ) 71.7 (±22.4) 55.9 (±9.7) P = 0.07

34 Tacrolimus and SNI No clear benefit in steroid-dependent SNI compared with Cyclosporine Rational for Tacrolimus in steroid-resistant SNI remains to be determined First line therapy?

35 mtor inhibitors Sirolimus-Everolimus Activation (ou PKB) G1 S

36 Tumlin JA, Miller D, Near M & al. A prospective open trial of sirolimus in the treatment of FSGS Clinical Journal of the ASN, 1: ; patients with FSGS FSGS steroid-resistant (7 ciclo R) Sirolimus: 6 months and one year-follow up

37 Sirolimus and proteinuria? Letavernier E Clin JASN 2007 Diekman F JASN 2007

38 Rituximab

39 CD20 and B cell development

40 Anti CD20: mechanisms of action Rituximab : chimérique murin 1 Cytotoxicité dépendante du complément 2 Cytotoxicité dépendante des anticorps 3 Apoptose

41 Rituximab and INS

42 Rituximab and ISN

43 Rituximab in INS: Pediatric experience (1)

44 Rituximab in INS: Pediatric experience (2) Mean follow up: 9 months Réduction IS 1: 85% without relapse 100% if CR and 50% (n=7) if nephrotic Complete IS withdrawal: n = 5 Relapse: 4 in 3 patients: CD19: /mm 3 Side effects: 45% (1 pneumocystis, 1 gastroenteritis, 1 bronchospasm, 5 hypogammaglobulinemia)

45 Rituximab in steroid-resistant SNI Bagga et al New England J Med 2007

46 Rituximab and INS IS saving in steroiddependent INS Preliminary results in steroid-resistant INS Role of humoral immunity?

47 Role of B lymphocytes in INS Immunoadsorption effectiveness (Dantal J et al, New Engl J Med 1994, JASN 1998) Th2 activation (Sahali D et al JASN 2001, Grimbert P, NDT 2003) Ig deposits in MCNS (Habbib R, Pediatr Nephrol 1988) CD23 expression during relapse (Cho BL, Pediatr Nephrol 1999) IgG1-2 expression (Lin CY, Pediatr Nephrol 1990)

48 CD20 and T lymphocytes Hultin L Cytometry 1993 Glennie M Mol Immunol 2007

49 New immunosupressive drugs in MCNS?

50 New immunosuppresssive drugs in FSGS HSF Sirolimus? Corticoïdes? Tacrolimus? Cortico-sensitivity Cortico-resistance MMF Cyclosporine? Remission Cortico-dépendence Remission Failure Cyclosporine- Alkylating agents? Rituximab Remission Failure

51 In the future? Targeting podocyte signaling pathway and links between podocyte and immune system Co-stimulatory blockade (Belatacept)? B7-1 Peter Mundel JCI 2005 TLR-4 Banas M JASN 2008