Transplantation Flashcards
Why do we do transplantations?
(1) Save life
• other life-support methods not fully developed
• other methods at the end of their lives
(2) Enhance life
• other methods less good e.g. dialysis
• organ is nor vital but enhances life e.g. cornea
Why do organs fail?
For variety of reasons:
• cornea - degenerative disease/infection/trauma
• skin/composite - burn/trauma/infection/trauma
- kidney - diabetes/HBP/glomerulonephritis
- liver - cirrhosis/ acute LF
- heart - etc.
What organs can be transplated?
Cornea Skin Bone marrow Kidney Liver Heart Lungs Pancreas Small bowel
Types of transplantations?
- Autografts
• within same individual
• e.g. coronary artery bypass - Isografts
• between genetically identical individuals of same species - Allografts
• between diff. individuals of the same species - Xenografts
• betw. individuals of diff. species
• e.g. heart valves & skin - Prosthetic graft
• plastic, metal
Types of donors for allografts?
Deceased donor
vs.
Living donor
Explain deceased donors
DBD - Deceased Brain-Death
• heart is beating
• COOL DOWN to minimise ischaemic damage
DCD - Deceased Cardiac-Death
• heart NOT beating
• longer period of warm ischaemia time
• suitable for kidney transplant
What needs to excluded for deceased donors before they can be used?
Viral infection (HIV, HBV, HCV)
Malignancy
Drug abuse, OD, poison
Disease of the transplated organ
What happens to the organs after they are removed?
Rapidly cooled & perfused
• max. cold ischaemia for kidneys if 60hr (shorter for other organs)
• cornea exception @ 96hrs
Transplant selection?
For access to WAITING LIST
x Refer for assessment
x MDT asses eligibility
x NHS transplant list
x Inspect contraindications
Transplant allocation?
For ACCESS to an ORGAN
NHSBT montiors allocation
• uses national guidelines & algorithms
Explain organ allocation using kidneys as an example
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
Difference in DBD vs. DCD kidney transplant?
DBD transplant
• patient assessed NATIONALLY
DCD transplant
• patient assessed LOCALLY
This is so the kidneys can be implanted with less warm ischaemia
Strategies to increase transplantation activity?
- Increased deceased donation
- Increased living donation
- Xenotransplantation & stem cell research opportunities
Half-life for kidney transplant?
10 YEARS
The I.S recognises someone else’s organ as foreign - what are the most important variations in clinical transplanation?
Most relevant PROTEIN variations in clinical transplantation:
(1) ABO blood group
(2) HLA coded on Chr6 by the MHC
Explain how the ABO blood groups poses an issue for transplation
A and B proteins are found on:
• RBCs & endothelial lining on blood vessels in the transplanted organ
Circulating pre-formed anti-antibodies will bind to the donor endothelium and = antibody mediated rejection
What makes up the ABO blood groups?
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
How can the ABO blood group issue be tackled?
ABO-imcompatible transplantation can occur but:
- remove Abs in recipient blood
- often = good outcomes for KIDNEY, HEART, LIVER
Explain why HLA can cause an issue with transplantations
These are highly variable cell surface markers of self
HLA types: o Class 1 – A, B, C – expressed on ALL cells o Class 2 – DR, DQ, DP – expressed by APCs
HLA molecules are highly pleomorphic with lots of alleles for each to be encoded with
• individuals most often have 2 types of each HLA molecule due to 2 chromosomes (mum and dad)
Explain what is meant by MM
Number of mismatches!
• compared between HLA-A, B & DR
o 0-6 is acceptable
– more miss-match equals more chance of death later down the road
o Sibling –> sibling transplant = 25% chance of 0MM 6MM 50% chance of 3MM
(Onenote!!)
What can an I.R cause due to the highly pleomorphic MHC molecules
Exposure to foreign HLA can result in I.R to the FOREIGN EPITOPES
Can cause:
• Immune graft damage & failure i.e. rejection
Diagnosis - histological examination
Treatment - immunosuppresive drugs
Define Rejection
Can be either
• T-cell mediated
OR
• Ab-mediated
It can also either be:
• hyperacute / acute / chronic
Explain T-cell mediated rejection
Lymphocytes infiltrate the interstitial area
• they rupture the tubular BM = cause tublitis = local organ damage
The graft can be infiltrate by allo-reactive CD4+ cells
• CTLs can release granzyme B, perforin & FasL
• Macrophages can phagocytose, release proteases, produce cytokines & radicals
Explain Ab-mediated rejection
Abs against:
• graft HLA & AB antigens
Abs arise:
• pre-transplantation (‘sensitised’) - patient already exposes in pregnancy or previous transplantation
• post-transplantation (‘de novo’)
May see features of BOTH forms of rejection in graft rejected patients
How to monitor transplantation?
Watch for deteriorating graft function
E.g.
• Kidney, - reduced GFR, rise if creatinine, fluid retention
- Liver - rise if LFTs, coagulopathy
- Lungs - breathlessness, pulmonary infiltrate
How to prevent rejection?
- Maximise HLA compatibility
2. Life-ling immunosuppressive drugs
Treatment for rejection?
Immunosuppressive drugs!!
How do immunosuppressive drugs work?
(1) Target T-cell activation and proliferation
• Anti-CD3 ABs, JAK3 inhibitors, Azathioprine, cyclosporine
(1) 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 standard immunosuppressive regime?
(1) Pre-transplantation
– Induction agent (T-cell depletion or cytokine blockade)
(2) From implantation
– base-line immunosuppression:
Signal transduction blockade – CNI inhibitors – e.g. Cyclosporine.
Anti-proliferative agents – Azathioprine
Corticosteroids
(3) If needed
– treatment of acute rejection.
T-cell mediated – steroids, anti-T agents.
Antibody dependant – IVIG, plasma exchange, anti-CD20, anti-complement
Post-transplant infections?
Post-transplant on Immunosuppressives gives you a higher chance of conventional infections
o Opportunistic infections
– cytomegalovirus, BK virus, Pneumocytis carinii, Murcormycosis, CMV
What are the post-transplantation malignancy?
o Skin cancer
o Post-transplant lymphoproliferative disorder (EBV driven)
o Other i.e. Kaposi’s Sarcoma
