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IVIg in renal transplantation

IVIg in renal transplantation. Marcus Säemann Internal Medicine III Clin. Div. of Nephrology & Dialysis AKH Wien/MedUni Vienna, Austria. non-infectious. infectious. highly sensitized ASR immunodeficiency TMA HHS. virus Immunodeficiency ASR novel indications…. complications.

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IVIg in renal transplantation

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  1. IVIg in renal transplantation Marcus Säemann Internal Medicine III Clin. Div. of Nephrology & Dialysis AKH Wien/MedUni Vienna, Austria

  2. non-infectious infectious highly sensitized ASR immunodeficiency TMA HHS virus Immunodeficiency ASR novel indications… complications AGENDA IVIG Indications

  3. antigen Complement (C1q) light chains heavy chains IgG, IgM, IgA, IgD Fc receptor macrophage, granulocyte, NK cell, B cell IMMUNGLOBULINs Fab part Fc part

  4. Physiological Functions of Antibodies • neutralizationof toxins, bacteria, viruses • opsonization of microbes  phagocytosis (macrophages, neutrophils, basophils) • ADCC (antibody-dependent cellular cytotoxicity): CD8, NK • complement activation  lysis, opsonization • neutralization of activated complement • physiologicalAuto-Abs Immunoregulation

  5. IVIg • = pooled antibodies from healthy donors • pooled from >>1000 donors spectrum of all “physiological” Abs • predominantlyIgG (little IgA) • small amounts of CD4, CD8, HLA • natural Abs = without immunization • especially auto-Abs, anti-idiotypic Abs • auto-Absblock autoreactive B cell-clones • vs. cytokines: neutralizing or prolonging t1/2 • block Fas: agonistic or block

  6. Indications • IVIg over 25 years clinically used • idiopathic thrombocytopenic purpura (ITP) • Guillain-Barré syndrome • myasthenia gravis • Kawasaki syndrome • dermatomyositis • GVHD prophylaxis • autoimmune uveitis • multiple sclerosis • AIHA • results from prospective, randomized trials Kazatchkine und Kaveri; NEJM 2001; 345:747

  7. Side effects • <5%, <1% • headache, malaise, hypertension • acute aseptic meningitis: <72 h after admin. durch NSAID verhinderbar, • anaphylaxis: sehr selten • AKI/ARF • thrombosis • infection risk: NO report about HIV-transmission; cases of Hep C >15 yrs ago • no specific long-term sequelae • contraindications: hypersensitivity (especially anti-IgA Ab) • interactions: false-positive results after serological testing, vaccinations

  8. 71% of patients display isometric tubular vacuolization: no CNI toxicityHaas M et al., Transplantation 2004 IVIg lots differ in salt and sugar content, pH, and osmolality! (cave: sucrose-based products !) Vo AA et al., Clin J Am Soc Nephrol. 2006;1(4):844 Renal effects

  9. tubular macrovacuoles lysosomal accumulation of sugar Increased osmotic load accompanying IVIg infusion with adequate parenteral hydration !!! Renal effects age-related tubular impairment in donor grafts more vulnerability to IVIg-related toxicity ? Bollee G et al., Clin J Am Soc Nephrol. 2008;3(5):1461

  10. Molecular Mechanisms of IVIg • Fc receptors: • blockade of Fc receptors on macrophages and effector cells • inhibition of antibody-dependent cellular cytotoxicity • induction of inhibitory Fc receptor IIB • Inflammation: • attenuation of complement-mediated damage • decrease in immune-complex-mediated inflammation • induction of anti-inflammatory cytokines • inhibition of activation of endothelial cells • neutralization of microbial toxins • B cells and antibodies: • control of emergent bone marrow B cell repertoires • negative signaling through Fc receptors • selective down-regulation and up-regulation of antibody production • T cells: • regulation of the production of helper T cell cytokines • neutralization of T cell superantigens • inhibition of lymphocyte proliferation • regulation of apoptosiss Kazatchkine und Kaveri; NEJM 2001; 345:747

  11. Y Y Y Y Y Y Y= (patholog.) Antikörper Y Y Y Y Y Y Y Y Y Y Plasma Y Y Y= IVIG Y Y Y Y Y Y Y Y Y Y Pinozytose Y Y Y Y Y Y Y Y FcRn Y Y Y Y Y Y Y Y X Y X X Y Y X Y Y Y X Y Y X X Y Y X X Y X Lysosome Endothelial cell Molecular Mechanisms of IVIg Increased decay of IgG  also pathological IgGs (saturated protective FcRn-r) Yu und Lennon, NEJM 1999; 340:227

  12. anti-idiotypic Ab Molecular Mechanisms of IVIg anti-idiotypic antibodies: block(anti-HLA) Ab – antigen binding Idiotypes anti-HLA Ab

  13. Anti-inflammatory activity of IVIG through inhibitory Fc receptor(Samuelsson A et al., Science 2001) Molecular Triggering Activation of FOXp3+ T-cells(Tha-Inn T et al., Transplantation 2010) IVIg Novel molecular Mechanisms of IVIg

  14. IVIg preparations • Pentaglobin® (Biotest): IgG, IgA, IgM • Intraglobin® F (Biotest): IgG, IgA • Sandoglobulin® (Novartis) • Kiovig® (Baxter) • Gammagard S/D® (Baxter) • Octagam® (Octapharma) • Venimmun N® (Aventis) • Gamma-Venin P® (Aventis) US: 85-100$ per gram IVIg62-88 EUR/g2g/kg für 70kg Pat. (=140g):; 10.000 EUR

  15. Immunodeficiency - Hypogammaglobulinemia Wieneke H et al., Clin Nephrol. 1996;45(1):22 Predictive value of IgG subclass levels for infectious complications in KTX recipients HGG in stable KTX: up to 45% !!! Combined hypo-Ig (G+A)/(G+M): frequent infections (respiratory !) IVIg ?!?! < 500 mg/dl ? Broeders EN et al., Transpl Int. 2008;21(1):57

  16. Distinct infections in the KTX patient CNS vasculitis due to parvovirus B19 infection (Ilmay B. et al. Ped Nephrol 2005) Refractory adenovirus infection after SPK (Emovon O. et al., NDT 2003) Hemophagocytic Syndrome (HHS) in KTX Tuberculosis + CMV E. coli (Asci G. et al., J Nephrol 2006)

  17. BK virus nephropathy (BKVN) Current treatment algorithms Reduction of immunosuppression Leflunomid Zidofovir ?! no prospective 1A trials exist ! literature full of case series !

  18. % DNA inhibition . . . BKVN Sener et al., Transplantation et al. 2006 n=8 stable KTX patients with declining GFR IVIg plus IS reduction (2g/kg 2-5 days): In 7/8 patients: GFR stabilization & in 4 complete histological resolution • Randhawa et al., Transplantation 2010 • IVIg have significant anti-BKV activity • 2 IVIg preparations tested • direct neutralization (wide-spread prevalence!) • 5g can neutralize 9.5E*09 BKV genome eqivalents or 1.9E*06 circulating copies/ml • 0.2g/kg IVIg should suffice

  19. CMV & KTX • most important pathogen affecting Tx recipients • associated with increased risk of • acute viral syndromes • opportunistic superinfection • acute & chronic allograft dysfunction • CMV prophylaxis • currently ganciclovir/valganciclovir • Problems: resistance • inefficiency: late CMV infection • side-effects

  20. Clinical Trials: Hyperimmune globulin • 11 randomized clinical trials (N=698)1 compared •  CMVIg vs. control, placebo or antivirals • Study endpoints: • CMV antigenemia: pp65 antigen • CMV viremia: PCR • CMV disease: leukopenia, thrombocytopenia, elevated transaminases Bonaros N, Clin Transplant [2008] 22:89-97

  21. CMV ELISA  Cytotect vs IVIg • significant higher antibody content 140 *** 120 p<0.0001 ** 100 SEM [PEI U/mL] p=0.0035 80 CMV ELISA 60 40 Mean 20 0 Cytotect EU IVIG US IVIG + + + + mean SEM 89 5 54 1 57 0 n 3 52 376 GPS – unpublished data IVIg released 2009

  22. CMV neutralization  Cytotect vs IVIG • Significant higher functional antibody titers in  standard IVIG* vs. Hyperimmune •  US vs. EU IVIG 140 * 120 p=0.0328 * * 100 SEM p=0.0029 80 [PEI U/mL] 60 Mean 40 * * 20 p=0.0040 0 Cytotect EU IVIG US IVIG 66 3 82 6 4 mean SEM 40 10 11 N 3 GPS – unpublished data * IVIG released between 2006 and 2009

  23. CMV neutralization  differences? • IVIG1&Cytotect 2 produced from pooled human plasma •  Cytotect selects for high CMV ELISA titers • Differences in plasma origin? •  IVIG/Kiovig®: Germany, Austria, USA  Cytotect®: Belgium, Germany, Austria, USA • Differences in manufacturing process?  Kiovig®/Cytotect®: Cohn ethanol fractionation • Differences in IgG subclasses distribution… 1Kiovig ® monograph, Baxter International Inc., 20062 Cytotect® Biotest, Product Information., 2004

  24. CMV neutralization  IgG subclasses? • Differences in IgG subclasses distribution •  neutralizingantibodies1 IgG3>>IgG1 •  “… enrichment of IgG3 antibodies may be useful…“ Cytotect [%] IVIG [%] IgG1 62 > 56.9 IgG2 34 > 26.6 IgG3 0.5 > 3.4 IgG4 3.5 > 1.7 1Gupta CK & Siber GR: IgG subclass Abs to human CMV in normal human plasma samples and immune globulins and their neutralizing activities. Biologicals [1996] 24:117

  25. CMV opportunity IVIg • IVIG has considerable advantages… • better functional / neutralizing titers • better supply • better pharmacoeconomics • Proposal • head-to-head comparison of CMV Hyperimmune versus IVIg • Study endpoint: CMV viremia /PCR

  26. IVIg in alloimmunity PRE-TRANSPLANT: Sensititized patients - IVIG alone - IVIG plus plasmapheresis (PP) POST-TRANSPLANT: Steroid-resistent ASR - IVIG plus plasmapheresis (PP) - IVIG alone

  27. n=15; pilot study • PRA>50% or positive CXM (live donor) • 85% re-KTX • 3x 2g/kg IVIGevery month pre-KTX • Immunsuppression: • IVIG (2g/kg): d0-1; d20-21; d40-41 (cumulative dose: 12g/kg IVIG) • Tacrolimus • MMF: 2g/Tag • Steroide • Thymoglobulin for 10 days • Anticoagulation: heparin, LMWH; aspirin Glotz et al. AJT 2002; 2:758 IVIg pre-Tx 87% were effectively desensitized ! 11/13 patients: successful TX!

  28. IVIg reduces HLA-antibodies: NIH-IG02 Trial “Mount Sinai Protocol“: IVIg 2 g/kg monthly for 4 mo then 12 + 24 mo IVIg to PRA serum: extent of cytotoxicity inhibition Cumulative time to transplantation Crea-2-yrs: 1.68 for IVIG vs 1.28 for placebo S. Jordan et al., JASN 2004

  29. Rituximab and human disease B-CLL (NHL) PcP various autoimmune diseases membranous nephropathy, … • NTX • highly sensititzed patients • humoral rejection • ABO incompatible TX

  30. Rituximab and IVIg for Desensitization during KTX Ashley A. Vo, et al., N Engl J Med 2008; 359:242, 2008 IVIg 2g/kg days 1+30 Rituximab day 15

  31. . . .Rituximab and IVIg for Desensitization during KTX 76 CXM+ patients ! ASR: 37% (29% C4d+) Wait list: 95 months to 4.2 months Most difficult: high DSA (>100,000 SFI units) Ashley A. Vo, et al., Transplantation 2010

  32. Plasmapheresis: plasma exchange and immunoadsorption

  33. PP/IVIg/anti-CD20 vs high-dose IVIg for AMR Gruppe A: IVIG Gruppe B: PP + anti-CD 20 + IVIg Lefaucheur C, et al., Am J Transplant. 2009;9(5):1099

  34. Log Rank P=0.65 Group 2 Group 1- IVIG IVIg + anti-CD 20 + plasmapheresis, preformed DSA XM-positive 78% 71% XM-negative Loupy A et al. Transplantation 2010;89:1403

  35. IVIg + anti-CD 20 + plasmapheresis, preformed DSA Loupy A et al., Transplantation. 2010;89(11):1403

  36. Single prä-Tx IA session Only +ve CDC-XM convertible after 8l treatment accepted Vienna protocol (since 1999)Peri-transplant IA in sensitized +ve CDC-XM cadaveric transplants Post-Tx IA sessions Prevention of antibody rebound IA Every 1-3 days IA (Protein A) ALS/a-IL-2R Ab KTX offer: Re-Tx >40%PRA CyA/tacrolimus + MMF + corticosteroids KTX

  37. Uncensored allograft survival: Vienna (deaths included) XM-positive 78% 71% XM-negative % Survival Log Rank P=0.65 Months Lorenz M et al. Transplantation 2005;79:696

  38. ABO: Protocol Vienna Tacrolimus (target level: 12-15ng/ml, for 3 mo) MMF (2g/day) Steroids (20 mg/d) Bactrim/Valgancyclovir - 4 wk -8d -4d day 0 BGA monitoring IVIG (0.5 g/KG) IA IA IA IA IA IA IA Rituximab (375mg/m2) KTX Target titer before last IA ≤1:8 Haidinger M et al., Wien Klin Wochenschr. 2009;121(7-8):247

  39. IVIg and ACUTE REJECTION • 17 KTX patients with steroid- (n=13) or Ab-resistant rejection (n=4); 76% Banff I, 24% Banff II; m17.5 Mo. post-KTX • IVIG 2g/kg (total) 2-10 days; 4x2; 3x≥3 courses; mfollow-up: 21.5 Mo. • 82% better (29%) or complete resolution resolution (53%) • graft survival: 71% (12/17) • Crea: 2.8mg/dl (3.3mg/dl during IVIg therapy) • 7 pat. solely IVIg: 6/7 (86%) response; 10 pat. plus steroids: 8/10 (80%) 4 patwithsteroid-resistant rejection: response 75% (3/4) • 1x CMV infection 5 mo post-IVIG (and ATG) Shapiro et al. Transplantation 2001; 72:419

  40. IVIg & PE for AHR • 5 pat. with akuter humorale rejection (AMR) • histologal+serological verified; steroid- und Ab-resistant • 6-20 days post-NTX • 3/5 with PRA>90% pre-NTX • PP plus IVIG (400mg/kg): 4-7 x; plus FK, MMF • successful in 5/5 • Crea 1.2±0.3, mFollow-up 19.6±5.6 Pascual et al. Transplantation 1998; 66:1460

  41. IVIg for plasma cell-rich rejection in KTX mature plasma cells peritubular C4d+ interstitial inflammation 0.5 g/kg/d – 4x additional Thymo/Steroids/PP Stable renal function Adrogue EH et al., Transplantation. 2006;82(4):567

  42. IVIg for acute cellular rejection: Vienna Protocol BANFF BL BANFF I BANFF IIa BANFF IIb/III Fortecortin Thymoglobulin Severe infection Multimorbidity (e.g. wound healing problems) Sepsis BANFF IIb/III or steroid-resistant ASR + IVIg (2g/kg/d x 2 days) + steroid reduction

  43. Summary & Open Questions • IVIg has a solid place in transplant medicine • is well tolerated and has few side-effects in renal insufficiency • HGG is highly prevalent after solid organ transplant patients and is associated with more infectious diseases • IVIg has potent anti-infectious effects • IVIg is efficient against BKVN • IVIg is promising against CMV infection • IVIg enables successful transplantation of highly sensitized patients • IVIg given in multiple doses plus PP may be the most efficient • IVIg is also effective during ASR, steroid-/antibody-resistant ASR • IVIg is ideal against ASR and coexisting infection • is also effective during plasma cell-rich ASR

  44. Prospective multicenter trials Future Tasks Defining the mechanism of action in the individual clinical setting? Assessment of the depth and breadth of sensitization! Developing safe trigger points for transplantation: fine tuning of protocols Role during humoral immunodeficiency: impact on incidence of infection? BKVN and CMV: Dosing? Frequency? Duration? Concomitant therapy?

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