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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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slide1

IVIg in renal transplantation

Marcus Säemann

Internal Medicine III

Clin. Div. of Nephrology & Dialysis

AKH Wien/MedUni Vienna, Austria

slide2

non-infectious

infectious

highly sensitized

ASR

immunodeficiency

TMA

HHS

virus

Immunodeficiency

ASR

novel indications…

complications

AGENDA

IVIG Indications

slide3

antigen

Complement (C1q)

light chains

heavy chains

IgG, IgM, IgA, IgD

Fc receptor

macrophage, granulocyte, NK cell, B cell

IMMUNGLOBULINs

Fab part

Fc part

slide4

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
slide5

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
slide6

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

slide7

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
slide8

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

slide9

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

slide10

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

slide11

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

slide12

anti-idiotypic Ab

Molecular Mechanisms of IVIg

anti-idiotypic antibodies: block(anti-HLA) Ab – antigen binding

Idiotypes

anti-HLA Ab

slide13

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

slide14

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

slide15

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

slide16

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)

slide17

BK virus nephropathy (BKVN)

Current treatment algorithms

Reduction of immunosuppression

Leflunomid

Zidofovir

?!

no prospective 1A trials exist !

literature full of case series !

slide18

% 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
slide19

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
slide20

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

slide21

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

slide22

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

slide23

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

slide24

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

slide25

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
slide26

IVIg in alloimmunity

PRE-TRANSPLANT:

Sensititized patients

- IVIG alone

- IVIG plus plasmapheresis (PP)

POST-TRANSPLANT:

Steroid-resistent ASR

- IVIG plus plasmapheresis (PP)

- IVIG alone

slide27

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!

slide28

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

slide29

Rituximab and human disease

B-CLL (NHL)

PcP

various autoimmune diseases

membranous nephropathy, …

  • NTX
  • highly sensititzed patients
  • humoral rejection
  • ABO incompatible TX
slide30

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

slide31

. . .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

slide32

Plasmapheresis:

plasma exchange and immunoadsorption

slide33

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

slide34

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

slide35

IVIg + anti-CD 20 + plasmapheresis, preformed DSA

Loupy A et al., Transplantation. 2010;89(11):1403

slide36

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

slide37

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

slide38

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

slide39

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

slide40

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

slide41

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

slide42

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

slide43

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
slide44

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?