Transplantation Flashcards
Why is transplantation done?
Save life:
- Other life-support methods not fully developed
- Other methods at the end of their lives
Enhance life:
- Other methods are less good – e.g. kidney dialysis
- Organ is nor vital but enhances life – e.g. cornea
What are the different types of transplantation?
- Autograft - within the same individual – e.g. coronary artery bypass
- Isografts - between genetically identical individuals of the same species.
- Allografts - between different individuals of the same species
> Solid organs – kidney into the RIF
> Small bowel
> Free cells – bone marrow transplant
> Temporary – blood
> Privileged sites – cornea
> Framework – tendons
> Composite – face - Xenografts - between individuals of different species – e.g. heart valves and skin
- Prosthetic graft plastic, metal
What are the types of donors for allografts?
Deceased donor:
- DBD – Deceased Brain-Death (heart is beating):
> Cool to minimise ischaemic damage.
> There is irremediable structural brain damage of a KNOWN cause
> The apnoeic coma is NOT due to – depressant drugs, hypothermia, NM-blockers, metabolic or endocrine disturbances
> There is a demonstrateable lack of brain-stem function – e.g. no gag reflex
- DCD – Deceased Cardiac-Death (heart not beating):
> Long period of warn ischaemic time
> Suitable for kidney transplants
Living donor
What must be excluded from deceased donors?
- Viral infection
- malignancy
- drug abuse/overdose/poison
- disease of the transplanted organ
What is the max cold ischaemia for organs?
- for kidneys is 60 hours (ideally <24h) – much shorter for other organs
- Cornea is an exception at 96 hours’ cold ischaemia time
How do patients access the transplant waiting list?
Referral for assessment -> MDT assess eligibility -> NHS transplant list AND inspect contraindications (too early to be placed on list, co-morbidities, patient wishes)
How is transplantation allocated?
NHSBT (NHS Blood and Transplant) monitors allocation – using national guidelines and algorithms.
Organ allocation – Kidney: - 5 tiers of patient – paediatric/adult, sensitised/not-sensitised. - 7 elements: > Waiting time > HLA-matching + age > Donor-recipient age difference > Location > HLA-DR homozygosity > HLA-B homozygosity > ABO blood group matching
How can the number of donors be raised?
- UK Gov. Dept. of Health initiatives
- Public engagement
- Improved quality of organ retrieval and transplantation
- Donor transplant co-ordinators – critical care nurses and carry out family interviews to gain consent
Other strategies to increase transplantation activity:
- Increased deceased donation – from marginal donors including the elderly
- Increased living donation – the UK has a VERY GOOD living donator record
- Xenotransplantation and stem cell research opportunities
What are the most important variations in clinical transplantation?
- ABO blood group
- HLA coded on Chr6 by MHC
What are the ABO blood groups made of?
O+ = 1x fructose, 1x n-acetyl-glucosamine, 2x galactose
A+ = 1x fructose, 1x n-acetyl-glucosamine, 2x galactose, 1x n-acetyl-galactosamine
B+ = 1x fructose, 1x n-acetyl-glucosamine, 3x galactose
What causes antibody mediated rejection?
Circulating pre-formed anti-antibodies will bind to the donor endothelium
What do antibodies activate?
complement classical pathway
macrophages
What are the classes of HLA?
Class 1 – A, B, C – expressed on ALL cells
Class 2 – DR, DQ, DP – expressed by APCs
- individuals most often have 2 types of each HLA molecule due to 2 chromosomes (mum and dad)
How is HLA matching done in transplantation?
MM 1: 2: 0 = 3 miss-matches
- 0-6 is acceptable – more miss-match equals more chance of death later down the road
- Sibling -> sibling transplant = 25% chance of 0MM, 6MM, 50% chance of 3MM
What happens in T-cell mediated rejection?
- Lymphocytes infiltrate the interstitial area
- Lymphocytes rupture the tubular BM and cause tubulitis and local organ damage
- The graft can be infiltrated by allo-reactive CD4+ cells
- CTL lymphocytes can release – granzyme B, perforin and FasL
- Macrophages can – phagocytose, release proteases, produce cytokines and oxygen/nitrogen radicals
What happens in antibody-mediated rejection?
Antibodies are made against graft HLA and AB antigens
Antibodies arise:
- Pre-transplantation – ‘sensitised’ – patient already been exposed in pregnancy or previous transplants
- Post-transplantation – ‘de novo’
What can be done to prevent rejection?
- maximise HLA compatibility
- give life lone immunosuppressive drugs
- to treat rejection - give more immunosuppressive drugs
What are some immunosuppressive drugs?
Target T-cell activation and proliferation:
- Anti-CD3 ABs
- JAK3 inhibitors
- Azathioprine
- cyclosporine
Target B-cell activation, proliferation and antibody production:
- Splenectomy
- anti-CD20 ABs
- Bortezomib (proteasome inhibitor)
- anti-C5
- intravenous immunoglobulin plasma exchange (IVIG)
What is the regime of immunosuppressive drugs?
Pre-transplantation – Induction agent (T-cell depletion or cytokine blockade)
From implantation – base-line immunosuppression:
- Signal transduction blockade – CNI inhibitors – e.g. Cyclosporine
- Anti-proliferative agents – Azathioprine
- Corticosteroids
If needed – treatment of acute rejection
- T-cell mediated – steroids, anti-T agents
- Antibody dependant – IVIG, plasma exchange, anti-CD20, anti-complement
What are some examples of post- transplant infections?
Opportunistic infections:
- cytomegalovirus
- BK virus
- Pneumocytis carinii
- Murcormycosis
- CMV
What are examples of post-transplantation malignancy?
- Skin cancer
- Post-transplant lymphoproliferative disorder – EBV driven
- Other – i.e. Kaposi’s Sarcoma
