Transplantations

Question 1

Organs: explain which organs can be transplanted and why

Answer 1

Transplantation is done to save life or to enhance life.

• 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.
• Kidney transplants increase survival chances against dialysis past 106 days.
• Organs fail for a variety of reasons (metabolic, viral, etc.) – BE AWARE OF THIS.
  
  • Cornea, skin, bone marrow, kidneys, liver, heart, lungs, pancreas, small bowel – all can be transplanted.

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.

Total organ transplant numbers have increased (just pancreas and intestinal have fallen) with majority kidneys.

~50,000 people have a functional transplant in the UK as of march 2016.

Question 2

Outline the donours where the transplanted organs come from

Answer 2

Types of donors:

1: 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.

2. Living donor.

Deceased Donors:

• For deceased donors, you must exclude:
  
  • Viral infection, malignancy, drug abuse/overdose/poison, disease of the transplanted organ.
• Removed organs must be rapidly cooled and perfused:
  
  • Max cold ischaemia for kidneys is 60 hours (ideally <24h) – much shorter for other organs.
  • Cornea is an exception at 96 hours’ cold ischaemia time.

Question 3

Ethical issues: summarise the ethical and structural/organisational issues surrounding organ transplantation

Answer 3

– Organisation:

Transplant selection – for access to the waiting list:

• Referral for assessment à MDT assess eligibility à NHS transplant list AND inspect contraindications (too early to be placed on list, co-morbidities, patient wishes).
• Transplant numbers have been dropping and available organs rising but there is still a disconnect.

Transplant allocation – for access to an organ:

• NHSBT (NHS Blood and Transplant) monitors allocation – using national guidelines and algorithms.
• Organ allocation: equity (fairness) and efficiency (waiting + matching ability) – Kidney:
  
  • 5 tiers of patient – paediatric/adult, sensitised/not-sensitised.
  • 7 elements:

1. Waiting time.
2. HLA-matching + age.
3. Donor-recipient age difference.
4. Location.
5. HLA-DR homozygosity.
6. HLA-B homozygosity.
7. ABO blood group matching.

(DBD kidney transplant patients are assessed nationally.

DCD kidney transplant patients are assessed locally.

This is so the kidneys can be implanted with less warn ischaemia.)

50% of potential donors after brain death donate organs – mainly due to declined consent by the family.

• This is aiming to be raised by:
  
  1. UK Gov. Dept. of Health initiatives.
  2. Public engagement.
  3. Improved quality of organ retrieval and transplantation.
  4. 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.
• Half-life of a kidney transplant is approx. 10 years.

Question 4

Summarise the immunological issues in transplantation and describe the effects of ABO blood group

Answer 4

The immune system recognises someone else’s organ as foreign

• The most important variations in clinical transplantation is:
  
  • ABO blood group.
  • HLA coded on Chr6 by the MHC.
    ​

A and B proteins are found on RBCs and the endothelial lining on blood vessels in the transplanted organ.

• ABO blood groups:

1. O+ = 1x fructose, 1x n-acetyl-glucosamine, 2x galactose.
2. A+ = 1x fructose, 1x n-acetyl-glucosamine, 2x galactose, 1x n-acetyl-galactosamine.
3. B+ = 1x fructose, 1x n-acetyl-glucosamine, 3x galactose.

• Circulating pre-formed anti-antibodies will bind to the donor endothelium antigens -> antibody mediated rejection.
• Antibodies activate complement classical pathways.
  
  • They also activate macrophages.
• ABO-incompatible transplantation can occur but:
  
  • Remove ABs in recipient plasma.
  • There is often a GOOD outcome.
  • Done for – kidneys, liver & heart.

Question 5

Summarize the function of HLA

Answer 5

HLA:

• These are highly variable cell surface markers of self.

HLA types:

• Class 1 – A, B, C – expressed on ALL cells.
• Class 2 – DR, DQ, DP – expressed by APCs.

Function:

• APC digests foreign protein and depicts it on cell surface within an HLA molecule located on the cell surface
• T cells sees the foreign peptide within the context of HLA – it becomes activated and initiates an immune reaction against It

HLA molecules are highly polymorphic with lots of alleles for each to be encoded with and individuals most often have 2 types of each HLA molecule due to 2 chromosomes (mum and dad).

• The highly polymorphic MHC molecules are most likely to provoke an immune response.
• HLA matching is done in transplantation and can be seen in notation forms – MM 1: 2: 0 = 3 miss-matches.
• 0-6 is acceptable – more miss-match equals more chance of death later down the road.
• MHC Class 1 and Class 2 about the same area of antigen binding
• HLA A B and DR are the most important ones in terms of matching

Sibling -> sibling transplant = 25% chance of 0MM, 6MM, 50% chance of 3MM.

The immune reaction can cause immune graft damage and failure – rejection = most common cause of graft failure.

• Diagnosis = histological examination
• treatment = immunosuppressive drugs.

Question 6

Outlinethe main types of graft rejection

Answer 6

Rejection

HOW: Rejection can be T-cell mediated or anti-body mediated.

WHEN: Rejection can be hyper-acute, acute or chronic.

T-Cell Mediated Rejection:

• Lymphocytes infiltrate the interstitial area.
• Lymphocytes rupture the tubular Basement Membrane and cause tubulitis and local organ damage.
• The graft can be infiltrated by allo-reactive CD4+ cells.
• Cytotoxic T lymphocytes can:
  
  • –Release of toxins to kill target • Granzyme
  • –Punch holes in target cells •Perforin
  • –Apoptotic cell death •Fas Ligand
• Macrophages can – phagocytose, release proteases, produce cytokines and oxygen/nitrogen radicals.

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’.
• You may see features of both forms of rejection in graft rejected patients.

Question 7

Complications: explain the risks and complications associated with transplantation and transplant immunosuppression

Answer 7

– Monitoring:

• Watch for deteriorating graft function – i.e. kidneys (reduced GFR, increased creatinine), liver (rise in LFTs).
• To prevent rejection:

1. Maximise HLA compatibility.
2. Give life-long immunosuppressive drugs.

• To treat rejection, give more immunosuppressive drugs than baseline ones
• Immunosuppressive drugs:
  
  • Target T-cell activation and proliferation.
    
    • Anti-CD3 ABs, JAK3 inhibitors, Azathioprine, cyclosporine.
  • Target B-cell activation, proliferation and antibody production – (remove cells that make antibody aka B).
    
    • Splenectomy, anti-CD20 ABs, Bortezomib (proteasome inhibitor), anti-C5, intravenous immunoglobulin plasma exchange (IVIG).

Regime of 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.

Infections

• Post-transplant on Immunosuppressives gives you a higher chance of conventional infections.
  
  • Opportunistic infections – cytomegalovirus, BK virus, Pneumocytis carinii, Murcormycosis, CMV.
• Post-transplantation malignancy: Typical tumour driven by immunosuppression
  
  • Skin cancer.
  • Post-transplant lymphoproliferative disorder – EBV driven.
  • Other – i.e. Kaposi’s Sarcoma.