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DoH IVIG Workshop Update on usage in Transplantation and outcomes measurement. Haifa Lyster Consultant Pharmacist – Transplant & VADs Royal Brompton & Harefield NHS Foundation Trust. Overview. Changes in Transplant indications in 2 nd edition Previously mostly grey indications

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doh ivig workshop update on usage in transplantation and outcomes measurement

DoH IVIG WorkshopUpdate on usage in Transplantation and outcomes measurement

Haifa Lyster

Consultant Pharmacist – Transplant & VADs

Royal Brompton & Harefield NHS Foundation Trust

overview
Overview

Changes in Transplant indications in 2nd edition

Previously mostly grey indications

Agreed outomes

updated blue indications for transplantation
Updated ‘blue’ INDICATIONS FOR TRANSPLANTATION

Antibody Incompatible Transplants

Antibody Mediated Rejection (AMR)

Viral pneumonitis (eg varicella, RSV, adenovirus)

T cell mediated rejection (TCR)

Steroid resistant, or

where steroids are not appropriate

slide5
There are no reports of the chronic use of IVIg to treat any of these indications (although patients may have repeated episodes of AMR), so IVIg is not used as a chronic or maintenance therapy in these conditions
antibody incompatible transplants
Antibody Incompatible Transplants

As adjunctive therapy in conjunction with immunoadsorption/plasmapheresis +/- rituximab

Dosage is variable:

upto 2g/kg to be repeated as per DSA measurements,

in renal desensitisation 100mg/kg (8-12 courses)

slide7

Jordan SC et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol. 2004 Dec;15(12):3256-62.

Conclude that IVIG is better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized patients with ESRD. Transplant rates for highly sensitized patients with ESRD awaiting kidney transplants are improved with IVIG therapy

slide8

Glotz D et al. Desensitization and subsequent kidney transplantation of patients using intravenous immunoglobulins (IVIg). Am J Transplant. 2002 Sep;2(8):758-60.

IVIg therapy allows safe and prompt kidney transplantation of immunized patients

These protocols thus demonstrate that the presence of anti-donor antibody, once an absolute contra-indication to transplantation, can, nowadays, be considered as an immunological hurdle that can be managed through appropriate immunological manipulation

slide9

Jordan et al. Desensitization therapy with intravenous gammaglobulin (IVIG): applications in solid organ transplantation. Trans Am Clin Climatol Assoc. 2006;117:199-211

These advancements have enabled transplantation of patients previously considered untransplantable and in concert with new diagnostic techniques has resulted in new approaches to management of AMR

slide10

N Engl J Med. 2008 Jul 17;359(3):242-51.Rituximab and intravenous immune globulin for desensitization during renal transplantation.Vo AA et al.

These findings suggest that the combination of intravenous immune globulin and rituximab may prove effective as a desensitization regimen for patients awaiting a transplant from either a living donor or a deceased donor. Larger and longer trials are needed to evaluate the clinical efficacy and safety of this approach

slide11

Tyan DB, Li VA, Czer et al 1994, Intravenous immunoglobulin suppression of HLA alloantibody in highly sensitised transplant candidates and transplantation with a histoincompatible organ. Transplantation 57(4) 553-562.

More impressively, successive in vivo administration of IVIG to a sensitized (anti-HLA-A2, A68, A69; B57, B58) heart transplant candidate resulted in successful transplantation with an A2+ histoincompatible heart

slide12

Danskine AJ, Smith JD, Pottle A, Lyster H, Carby M, Banner NR, Rose ML, The effect of immunadsorption therapy on HLA antibody levels and clinical response after thoracic organ transplantation. 2006 Human Immunology, 67(suppl 1):S27

Antibody Incompatible Transplantation, British Transplantation Society 2006. www.bts.org.uk

antibody incompatible transplants agreed outcome measures
Antibody Incompatible Transplants – agreed outcome measures

Thoracic

Measuring Donor Specific Antibodies (DSA) and correlating to clinical outcomes

Patient survival

Length of stay (ITU & hosp)

Graft function (EF/spirometry)

Renal

Type of renal transplant

HLA class DSA

Rejection episodes

Patient survival

Allograft survival

Renal function eg eGFR (MDRD)

antibody mediated rejection amr
Antibody Mediated Rejection (AMR)

Antibody mediated rejection (AMR) of solid organ transplants leads to inevitable failure of the transplanted organ if it is not reversed. There are no reports of spontaneous recovery from AMR, and graft failure leads to death in the recipients of life-sustaining grafts (heart, lung, liver) and return to dialysis with associated significant decrease in life expectancy and quality in kidney transplant recipients

As adjunctive therapy in conjunction with immunoadsorption/plasmapheresis +/- rituximab

Dosage is variable:

upto 2g/kg to be repeated for 2-3 cycles

slide15

Jordan SC, Quartel AW, Czer LS et al, 1998 Post-transplant therapy using high-dose immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action. Transplantation 66(6) 800-805.

IVIG appears to be an effective therapy to control posttransplant AR episodes in heart and kidney transplant recipients, including patients who have had no success with conventional therapies. Vascular rejection episodes associated with development of donor-specific cytotoxic antibodies appears to be particularly responsive to IVIG therapy.

slide16

Montgomery RA, Zachary AA, Racusen LC, et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation 2000; 70: 887-95

In this study, seven patients for whom the combined therapies of PP/IVIG were successful in reversing AHR mediated by Ab specific for donor HLA antigens. Furthermore, this protocol shows promise for eliminating DSA preemptively among patients with low-titer positive antihuman globulin-enhanced, complement-dependent cytotoxicity (AHG-CDC) cross-matches, allowing the successful transplantation of these patients using a live donor without any cases of HAR

slide17

Pottle A, Lyster H, Danskine AJ, Rose ML, Banner NR, The Management of Acute Antibody-Mediated Rejection after heart Transplantation. 2007 British journal of Transplantation 2(1):10-15

Case report illustrating the many challenges posed by acute AMR after heart transplantation. Treatment included IVIG.

A number of different therapeutic options are available and a combination of these is often required.

antibody mediated rejection amr agreed outcome measures
Antibody Mediated Rejection (AMR) – agreed outcome measures

Thoracic

Measuring Donor Specific Antibodies (DSA) and correlating to clinical outcomes

Patient survival

Length of stay (ITU & hosp)

Graft function (EF / Spirometry)

Renal

C4d staining, HLA class DSA, rejection episodes

Patient survival

Allograft survival

Renal function eg eGFR (MDRD)

viral pneumonitis eg varicella rsv adenovirus
Viral pneumonitis (eg varicella, RSV, adenovirus)

Adjunctive therapy (antiviral eg aciclovir, ribavirin as appropriate)

Dose: 0.5g/kg for 5 days

Champlin RE, Whimbey E, Community respiratory virus infections in bone marrow transplant recipients: The MD Anderson Cancer Center Experience, Biology of Blood and Marrow Transplantation 2001, 7 suppl, 8S-10S

For BMT recipients with respiratory syncytial virus URTIs, treatment with ribavirin and intravenous immunoglobulin may be helpful in preventing progression to pneumonia and thus in reducing mortality, but this approach requires confirmation in controlled clinical trial

slide20

Carby M, Jones A, Burke M, Hall A, Banner NR, Varicella infection after heart and lung transplantation: A single-center experience, Journal of Heart and Lung Transplantation 2007; 26(4):399-402.

Disseminated varicella-zoster virus infection after organ transplantation in adults is a rare but serious event causing significant morbidity and mortality. We describe our 10-year experience of 13 cases in a single center, including risk factors for infection, lack of protection from pre-existing anti-varicella-zoster virus antibodies, and unusual modes of presentation, including disseminated intravascular coagulation. We also report our preliminary observation of resolution of infection without sequelae in 4 patients with severe disseminated varicella-zoster virus infection who were treated with the combination of intravenous acyclovir and polyspecific intravenous immunoglobulin

viral pneumonitis eg varicella rsv adenovirus agreed outcome measures
Viral pneumonitis (eg varicella, RSV, adenovirus)– agreed outcome measures

Virus type

Reversal of radiological change

Length of stay

Survival (30 and 90 days, 1 year)

Lung function - return to baseline? (RFTs, spirometry)

Need for respiratory support inc ABGs (CPAP, NIV, Invasive ventilation)

t cell m e diated rejection tcr renal
T cell mediated rejection (TCR) - Renal

Conventional approach involves the use of corticosteroids and antiproliferative agents (mycophenolate). Occasionally we may encounter a patient in which the rejection episode is resistant to steroids or there is a desire to avoid steroid therapy due to patient co-morbidities.

There is one randomized controlled trial comparing steroid resistant TCR with a more conventional therapy – the anti-T cell antibody muromonab, OKT3, [Casadei et al. Transplantation 2001]. It showed identical graft survival in both groups [11/15 in IVIG receiving vs 13/15 in OKT3 receiving; p0.79] with no difference in creatinine or patient survival. IVIG was better tolerated in this study, and although not reported has not been associated with infections or increased long term malignancy risk as with polyclonal antibodies [Bustami RT, Ojo AO et al. AJT 2004; 4(1): 87].

IVIG has been shown to be useful when high dose steroids are contraindicated [Moger V et al. Transplantation 2004. 77(9): 1455] due to co-morbidities

t cell m e diated rejection tcr renal dosage outcomes measures
T cell mediated rejection (TCR) – Renal Dosage & outcomes measures

Dosage: 2 doses of 1g/kg administered post plasma exchange

Outcomes:

Patient survival

Allograft survival

Renal function eg eGFR (MDRD)

slide28

MDSAS IVIG Support

How to contact MDSAS about the IVIG Database

0161 277 7917

support@mdsas.com

slide29

Thank you for listening and have a great Christmas!

Rob.Hollingsworth@MDSAS.com

0161 277 7917

In need of IT Services? Contact us - support@mdsas.com or visit our website www.mdsas.com