3 - Transplantation Flashcards
When are organs transplanted?
Organs are transplanted when they are failing or have failed, or for reconstruction
What is live-saving organ transplantation and in what situations do they occur?
LIFE SAVING
Other life-supportive methods have reached end of their use
- liver
- heart (LVAD – left ventricular assist device)
- small bowel (TPN - total parenteral nutrition)
What is life-enhancing organ transplantation and in what situations does it occur?
LIFE-ENHANCING
Other life-supportive methods less good
- Kidney – dialysis
- Pancreas – in selected cases, txbetter than insulin injections
Organ not vital but improved quality of life: cornea, reconstructive surgery
Why do skin/composite tranplants fail?
Burns
Trauma
Infections
Tumours
Why do cornea transplants fail?
Degenerative disease
Infections
Trauma
Why do bone marrow transplants fail?
Tumours
Hereditary Disease
Why do kidney transplants fail?
Diabetes
Hypertension
Glomerulonephritis
Hereditary Conditions
Why do liver transplants fail?
Cirrhosis
- viral hepatitis
- alcohol
- auto-immune
- hereditary conditions
Acute Liver Failure
- paracetomol
Why do heart transplants fail?
Coronary artery or valve disease
Cardiomyopathy
- viral
- alcohol
Congenital defects
Why do lung transplants fail?
COPD/Emphysema
- smoking
- environmental
Interstitial Fibrosis/Interstitial Lung Disease
- idiopathic
- autoimmune
- environmental
Cystic Fibrosis
- hereditary
Pulmonary Hypertension
Why do pancreas transplants fail?
Type I Diabetes
Why do small bowel transplants fail?
IN CHILDREN - “SHORT GUT”
Volvulus Gastroschisis
Necrotising Enteritis related to prematurity
IN ADULTS
Crohn’s
Vascular Disease
Cancer
List the different types of transplantation
AUTOGRAFTS
- within the same individual
- e.g. reconstructive surgery
ISOGRAFTS
- between genetically identical individuals of the same species
- this is only really relevant to identical twins
ALLOGRAFTS
- between different individuals of the same species
- most common form
XENOGRAFTS
- between individuals of different species
PROSTHETIC GRAFT
- plastic, metal
What are autografts?
WITHIN THE SAME INDIVIDUAL
e. g. coronary bypass
e. g. reconstructive surgery
In the future, this may be the way to construct organs for transplant from stem cells
What are xenografts?
BETWEEN INDIVIDUALS OF DIFFERENT SPECIES
- Heart Vales (pig/cow)
- Skin
What are allografts?
BETWEEN DIFFERENT INDIVIDUALS OF THE SAME SPECIES
- Solid organs (kidney, liver, heart, lung, pancreas)
- Small bowel
- Free cells (bone marrow, pancreas islets)
- Temporary: blood, skin (burns)
- Privileged sites: cornea
- Framework: bone, cartilage, tendons, nerves
- Composite: hands, face, larynx
How many transplants are peformed in the UK?
Just over 5000 in 2017-18
Increases per decade
How many transplants are reported as functioning?
50,000 people living with transplants in the UK
What types of donor are used for allografts?
ALLOGRAFT - types of donor
Deceased Donor
- biggest source of organs
Living Donor
- bone marrow, kidney, liver
- genetically related or unrelated (spouse; altruistic)
List the different forms of deceased donor
DECEASED DONORS
DBD = donor after brain stem death
DCD = donor after circulatory death
What are DBD donors?
DBD: DONORS AFTER BRAIN STEM DEATH
Use neurological criteria of death.
- majority of organ donors
- brain injury has caused death before terminal apnoea has resulted in cardiac arrest and circulatory standstill
- e.g. Intracranial haemorrhage; road traffic accident
- circulation established through resuscitation
- confirm death using neurological criteria
- harvest organs and cool to minimise ischaemic damage
- organs can be retrieved in a very good condition
What are DCD donors?
DCD: DONORS AFTER CIRCULATORY DEATH
Use circulatory criteria of death.
- death is diagnosed and confirmed using cardio-respiratory criteria; 5 minutes observation of irreversible cardiorespiratory arrest
- Controlled: generally patients with catastrophic brain injuries who while not fulfilling the neurological criteria for death have injuries of such severity as to justify withdrawal of life-sustaining cardiorespiratory treatments on the grounds of best interests
- [Uncontrolled: no or unsuccessful resuscitation]
- Longer period of warm ischaemia time
Outline the neurological criteria of death
Irremediable structural brain damage of KNOWN cause
Apnoeic coma NOT due to
- cardiovascular instability
- depressant drugs
- metabolic or endocrine disturbance
- hypothermia
- neuromuscular blockers
Demonstrate absence of brain stem reflexes
- pupillary reflex absent (light)
- corneal reflex absent (touch)
- ocular vestibular reflex (no eye movements with cold caloric test)
- motor response cranial nerves (to orbital pressure)
- cough and gag reflex
- lastly - Apnoea test: no respiratory movements on disconnection from ventilator (with PaCO2>50 mmHg)
What cases are excluded from being deceased donors?
EXCLUDE:
Viral infection (HIV, HBV, HCV)
Malignancy
Drug abuse, overdose or poison
Disease of the transplanted organ
- USS potential donor
What happens when someone becomes a deceased donor?
Removed organs rapidly cooled and perfused
Absolute Maximum Cold Ischaemia Time
- for kidney 60h (ideally <24h)
- much shorter for other organs
How many deceased donor transplants occur in the UK?
There is a disparity between people on waiting lists and the number of donors/transplants
The gap is shrinking over time but it remains a problem
Overall, how is transplant allocation decided?
National Guidelines
- NHSBT (NHS Blood and Transplant)
- Provision of reliable, efficient supply of blood, organs and associated services to the NHS
Evidence based compute algorithm
EQUITY - what is fair?
- time on waiting list
- super-urgent transplant (imminent death: heart, liver)
- what else?
EFFICIENCY - what is the best use for the organ in terms of patient survival and graft survival?
Outline the tiers of patients waiting for kidney transplants
5 tiers of patients depending on:
- paediatric or adult
- highly sensitised or not
What are the 7 elements used to decided kidney allocation?
Waiting time
HLA match and age combined
Donor-recipient age difference
Location of patient relative to donor
HLA-DR homozygosity
HLA-B homozygosity
Blood group match
How many people die per year in circumstances making them eligible for donation?
6000 people die
How many die on average per day in need of an organ?
3 people per day
How many transplants occur annually?
5000
How many people are on the active transplant list?
6000
What is the Organ Donation Taskforce (ODT)?
Governmental scheme to identify barriers to organ donation and recommend actions needed to increase organ donation
Closing gap between number of organs needed and number of donors
What other strategies could be used to increase transplantation activity?
- DECREASED DONATION
* marginal donors (DCD, elderly, co-morbidities) - LIVING DONATION
- transplantation across tissue compatibility barriers
- exchange programmes (organ swaps for better tissue matching)
- THE FUTURE?
- xenotransplantation
- stem cell research
What is the half-life for adult kidney transplant recipients?
Depending on whether you get a kidney from a living donor or a deceased donor, the half-life of the kidney will be between 9-12 years (so organ will last around 20-30 years)
Outline the immunology of transplantation
The immune system recognises someone else’s organ as foreign
Most relevant protein variations in clinical transplantation
- ABO blood group
- HLA (human leukocyte antigens) coded on chromosome 6 by Major Histocompatibility complex (MHC)
What are ABO blood groups?
ABO BLOOD GROUP
A and B proteins with carbohydrate chains on red blood cells
Not just on RBCs, but also on endothelial lining of blood vessels in transplanted organ
Naturally occurring antibodies against the proteins we don’t have
What would occur if a patient with blood group A received a heart transplant from someone with blood group B?
PATIENT - blood group A
- red cells express A
- patient serum contains naturally occuring anti-B antibodies
DONOR - blood group B
- cells express blood group B
Circulating, pre-formed recipient anti-B antibody binds to B blood group antigens on donor endothelium.
= antibody-mediated rejection
How do you treat an ABO-incompatible transplantation?
Remove the antibodies in the recipient (plasma exchange)
- if the recipient doesn’t have the same blood group as the donor, can get rid of the recipient’s antibodies using plasma exchange
Good outcomes, even if the antibody comes back
Kidney, Heart, Liver
What is HLA?
HLA = HUMAN LEUKOCYTE ANTIGEN
Discovered after first failed attempts at human transplantation
HLA are cell surface proteins (mainly on WBCs)
While ABO may not be an issue anymore due to plasma exchange, HLA is still a problem
Highly variable portion
Variability of HLA molecules important in defense against infections and neoplasia
They are really important in recognising foreign antigens by T-lymphocytes
T-cells have to see the antigen on the surface of an HLA in order to mount an immune reaction against to it
Foreign proteins are presented to immune cells in the context of HLA molecules recognised by the immune cells as “self”
Our cells present foreign antigens (which are fragments of foreign HLA) on our own HLA molecules
- delayed hypersensitivity response
What are the different classes of HLA?
CLASS I - A, B, C
- expressed on all cells
- alpha chain and beta-2 microglobulin chain
- peptide-binding groove = all alpha
CLASS II - DR, DQ, DP
- expressed on antigen-presenting cells
- but also can be upregulated on other cells
- alpha and beta chain
- peptide-binding groove = half alpha,half beta
How many types of HLA molecule does each individual tend to have?
Highly polymorphic
- lots of different types of each HLA molecule
- lots of alleles for each locus
- for example, A1, A2…A341…etc
Each individual often has 2 types for each HLA molecule
- for example, A3 and A21
- each person has two different types of HLA molecule, one from mother and one from father
Outline the different HLA isotypes
HLA A, B, C and DR are very polymorphic
How does HLA matching for transplantation occur?
Mismatching in HLA-types in simplified into mismatches in HLA-A, B and DR
What does minimising HLA differences do for transplant outcomes?
Minimising HLA differences between donor and recipient improves transplant outcome
The more mismatches you have, the worse the transplant outcome
Why is donation from related donors encouraged?
Likely to have less HLA mismatches between close relatives
Would be sharing 50% of HLA with one of your parents
What can exposure to foreign HLA molecules result in?
Exposure to foreign HLA molecules results in an immune reaction to the foreign epitopes
- There are also, however, other molecules which are minor histocompatability molecules that can cause a degree of mismatch
The immune reaction can cause immune graft damage and failure = rejection
What is rejection?
Most common cause of graft failure
Diagnosis = histological examination of a graft biopsy
Treatment = immunosuppressive drugs
Outline T-cell mediated rejection
T-CELL MEDIATED REJECTION
Antigens of the kidney get taken up by AP cells in local secondary lymphoid organs. This is where the antigens meet T-cells.
They they re-circulate to the graft.
Encounter the HLA molecules on the endothelium of the graft that are capable of stimulating
Tether, roll, arrest
Go through the lining into interstitial
Form an lymphocytic-interstitial inflammatory infiltrate
Also attack tubules with epitopes (antigens) that they recognise (tubulitis)
OTHER CELLS THAT HELP T-CELLS:
Graft infiltration by alloreactive CD4+ cells
Cytotoxic T Cells
- Release of toxins to kill target (Granzyme B)
- Punch holes in target cells (Perforin)
- Apoptotic cell death (Fas-Ligand)
Macrophages
- Phagocytosis
- Release of proteolytic enzymes
- Production of cytokines
- Production of oxygen radicals and nitrogen radicals
Outline Antibody-Mediated Rejection
When you form antibodies against the graft
Antibody against graft HLA and AB antigen
Antibodies arise
- pre-transplantation = ‘sensitised’
- A and B
- or if you have had transfusions or pregnancies
- post-transplantation = ‘de novo’
Normally, antibodies fix to antigens on endothelial cells of blood vessels of donated organ
Antibodies then recruit complement which triggers damage.
Inflammatory cells can also be directly attracted to the endothelial cells by the antibodies.
Often get mixed rejection, with antibodies and T-cells
What is checked in post-transplant monitoring for rejection?
DETERIORATING GRAFT FUNCTION
- KIDNEY TRANSPLANT
- rise in creatinine
- fluid retention
- hypertension
- LIVER TRANSPLANT
- rise in LFTs
- coagulopathy
- LUNG TRANSPLANT
- breathlessness
- pulmonary infiltrate
SUBCLINICAL
- KIDNEY
- HEART
- no good test for dysfunction
- regular biopsies
How is prevention of rejection mainly managed?
Maximise HLA compatibility
Life-long immunosuppressive drugs
What do immunosuppressive drugs for transplant patients target?
Target:
- T-cell activation and proliferation
- B-cell activation and proliferation
- Antibody production
How do drugs that target T-cell activation work?
Want to stop the interaction between AP cell and the T-cell that is going to mount a reaction against graft
- receptors
- co-stimulatory molecules
- cytokine signals that amplify T-cell activation
Common drugs used:
- calcium ion inhibitors
- cell-cyle and nucleotide synthesis inhibitors
- steroids
How do drugs that target antibodies/b-cells (in the context of rejection) work?
Only used when antibodies against the graft are found before/after transplant
Outline the standard immunosuppressive regime
PRE-TRANSPLANTATION - induction agent
- T-cell depletion or cytokine blockade
FROM TIME OF IMPLANTATION - base-line immunosuppression for whole life/life of organ
- Signal transduction blockade
- usually a CNI inhibitor like Tacrolimus or Cyclosporin
- sometimes mTOR inhibitor like Rapamycin
- Corticosteroids
IF NEEDED - treatment of episodes of acute rejection
- T-cell mediated
- steroids
- anti-T-cell agents
- Antibody-mediated
- IVIG
- plasma exchange
- anti-CD20
- anti-complement
What are the positives and negatives of immunosuppression in the context of transplantation?
POSITIVES
- avoid transplant rejection
NEGATIVES
- infection
- tumours
- drug toxicity
Outline what the risks are regarding post-transplantation infection
INCREASED RISK FOR CONVENTIONAL INFECTIONS
- bacterial
- viral
- fungal
OPPORTUNISTIC INFECTIONS
Normally relatively harmless infectious agents give severe infections because of immune compromise
- cytomegalovirus
- BK virus
- pneumocytis carinii (jirovecii)
Outline what the risks are regarding post-transplantation malignancies
Skin cancer (but can be any cancer
Post-transplant lymphoproliferative disorder
- EBV driven (virus driven)
Others
At what stage do most potential organ donors lose the opportunity to become actual donors?
What are the rates of living organ donation in Europe and the USA?
What is the advantage of kidney transplant compared to dialysis?
Dialysis is associated with a lot of long-term complications which can lead to higher rates of mortality
Transplants are associated with increased life-expectancy
What is the main reason for transplanted organs not lasting a lifetime in the recipient?
- Immunological Disparity and Rejection
* main reason - Warm Ischaemia Time
* certain amount of function is lost due to time taken between harvesting and transplanting - Infections
- Drug Toxicities
- Recurrence of Disease that caused you to lose kidney in the first place
