2 - Transplantation (13.02.2020) Flashcards

Question

What are the 2 types of deceased donors?

Answer 1

- DBD – donor after brain stem death | - DCD – donor after circulatory death

Answer 2

- 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

Answer 3

- 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 -> BAD FOR THE ORGANS

Answer 4

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)

Answer 5

- viral infection (HIV, HBV, HCV) - malignancy - drug abuse, overdose or poison - disease of the transplanted organ - > USS potential donor

Answer 6

- Removed organs rapidly cooled and perfused absolute maximum cold ischaemia time for kidney 60h (ideally <24h) - much shorter for other organs

Answer 7

- listing (waiting list) at a transplant centre after multidisciplinary assessment - is the patient healthy/stable enough for a transplant? Is the patient eligible? not the same as transplant allocation

Answer 8

- how organs are allocated as they become available - when the organ becomes available, how is it allocated to all the patients on the waiting list not the same as transplant selection

Answer 9

NHS Blood and Transplant - Provision of a reliable, efficient supply of blood, organs and associated services to the NHS - Establishes rules for organ allocation and monitors allocation - algorithms

Answer 10

- use organs that may not have been used before (e.g. older people, DCDonors) - the use of elderly organs has increased, increasing the number of transplants that took place. 1. deceased donation - Marginal donors – DCD, elderly, co-morbidities 2. living donation - transplantation across tissue compatibility barriers - Exchange programmes: organ swaps for better tissue matching 3. The future? - Xenotransplantation - Stem cell research

Answer 11

It has to be fair and efficient! - > National guidelines - > Evidence based computer algorithm - Equity – what is fair? - Time on waiting list - Super-urgent transplant - imminent death (liver, heart) - What else? - rare group/how difficult are they to match? How long will they have to wait for the next compatible donor? - Efficiency – what is the best use for the organ in terms of patients survival and graft survival?

Answer 12

5 tiers of patients (ABCDE) depending on - paediatric or adult - Highly sensitised or not

Answer 13

- 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 - Some people have to be given some extra points (e.g. if they have genes that are hard to match) because otherwise they will be waiting for an organ for way too long.

Answer 14

- The immune system recognises someone else’s organ as foreign - Most relevant protein variations in clinical transplantation 1. ABO blood group 2. HLA (human leukocyte antigens) coded on chromosome 6 by Major Histocompatibility complex (MHC) 3. also some others but rarely, the first two are the most important.

Answer 15

- A and B proteins with carbohydrate chains on red blood cells but also endothelial lining of blood vessels in transplanted organ - Naturally occurring anti-AB antibodies - A and B antigens are also present on the endothelium - Can lead to organ rejection - As soon as blood starts going through the kidney becomes purple and does not function

Answer 16

- Remove the antibodies in the recipient (plasma exchange) - Good outcomes (even if the antibody comes back) - Kidney, heart, liver

Answer 17

- human leukocyte antigens - Discovered after first failed attempts at human transplantation - Cell surface proteins - Highly variable portion - Variability of HLA molecules important in defense against infections and neoplasia - Foreign proteins are presented to immune cells in the context of HLA molecules recognised by the immune cells as “self” (i.e. the cells won't eat the sandwich by itself, it has to be presented on a plate) - Class I (A,B,C)– expressed on all cells - Class II (DR, DQ, DP) – expressed antigen-presenting cells but also can be upregulated on other cells - Highly polymorphic – lots of alleles for each locus (for example: A1, A2, …, A341… etc.) - Each individual has most often 2 types for each HLA molecule (for example: A3 and A21) Donor cells shed HLA molecules -> Uptake and presentation in recipient APC -> Recognised by T-cells

Answer 18

- Class I (A,B,C)– expressed on all cells - Class II (DR, DQ, DP) – expressed antigen-presenting cells but also can be upregulated on other cells Both have peptide binding groove

Answer 19

- you look at the alleles that both recipient and donor have (2 alleles for each, one from mom, one from dad) - Look at HLA-A, HLA-B, HLA-DR (e.g. MM 1:2:0 = 3/6 mm) -> because those are the polymorphic ones - Number of mismatches : 0 to 6 - Minimising HLA differences between donor and recipient improves transplant outcome!! - The better the match, the better the outcome

Answer 20

≥3/6 matched

Answer 21

25% - 6MM 50% - 3MM 25% - 0MM

Answer 22

- Exposure to foreign HLA molecules results in an immune reaction to the foreign epitopes - The immune reaction can cause immune graft damage and failure = rejection

Answer 23

- Most common cause of graft failure - Diagnosis = histological examination of a graft biopsy - Treatment = immunosuppressive drugs

Answer 24

- T-cell mediated vs. AB mediated vs. mixed | - hyper-acute vs. acute vs chronic (when it occurs after transplantation)

Answer 25

- donated cell shed HLA antigens - APCs carry the donor antigens to local lymph nodes - T-cells (CD4+) are activated - recirculation, get to the site of the foreign HLA molecules, attach and infiltrate organs - start attacking the tissues (e.g. tubular epithelium in kidney) - T-cells also recruit other cells (CD8+ cytotoxic cells, macrophages) -> AMPLIFICATION OF INJURY - Inflammation and tissue damage -> rejection -> damage to e.g. tubules (in AB mediated the damage tends to be intravascular)

Answer 26

- Antibody against graft HLA and AB antigen - Antibodies arise - Pre-transplantation (“sensitised”) - Post-transplantation (“de novo”)

Answer 27

- CD8+ T-cells - CD4+ T-cells - macrophages

Answer 28

- sensitised refers to already having antibodies against foreign HLA - patients that had a previous transplant, patients that had many blood transfusions, women that were pregnant -> difficult to transplant because of an immediate and vigorous rejection

Answer 29

- antibodies bind to the foreign (HLA or ABO) molecules - complement activation (via C1q -> classic complement pathway) and recruitment of inflammatory cells (which have an Fc-Receptor) - endothelial necrosis and coagulation - membrane attack, complement activation -> intravascular damage

Answer 30

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)

Answer 31

- maximise HLA compatibility - Life-long immunosuppressive drugs But unfortunately transplants don't last forever, this is mainly due to immunological reactions.

Answer 32

- more drugs | - e.g. steroids, azathioprine, mABs, calcineurin inhibitors

Answer 33

- Targeting T cell activation and proliferation - Targeting B cell activation and proliferation, and antibody production - azathioprine targets the cell cycle - drugs that target cd52 and deplete t-cells (mAB)

Answer 34

- you have to remove the ABs or B-cells making them - Anti CD-20 (Rituximab) to deplete B-cells - proteasome inhibitors (bortezomib) to deplete plasma cells - anti-C5 to target complement activation - plasma exchange and IVIg dampen the AB production

Answer 35

Rejection vs cancer+infections+drug toxicity

Answer 36

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)

Answer 37

- Skin cancer - Post transplant lymphoproliferative disorder – Epstein Barr virus driven - Kaposi's sarcoma? - others

Answer 38

- inflammation in interstituum - ruptured tubular basement membrane - tubulitis (immune cells infiltrating the tubular epithelium) Cd4+ cells also recruit cytotoxic T cells as well as macrophages.

Answer 39

CD3: T-cell antigen (there would be a mixture of 4 and 8) CD68: macrophages

Answer 40

- complement marker | - look for presence of complement in tissues

Answer 41

- anti-t-cell activation drug - targeting the APC and T-cell communication - e.g. target co-stimulation - e.g. target signal 3

Answer 42

- target the antibodies - target the cells producing the antibodies (anti-CD20 e.g. rituximab; bortezomib is a protease inhibitor that depletes plasma cells) - plasma excange or IVIG will dampen the AB production - drugs targeting complement activation => give drugs based on the pathophysiology of rejection.

Answer 43

Pre-transplantation - Induction agent (T-cell depletion or cytokine blockade) From time of implantation - Base-line immunosuppression from the moment the transplant goes in. Signal transduction blockade, usually a CNI inhibitor: Tacrolimus or Cyclosporin; sometimes mTOR inhibitor (Rapamycin) Antiproliferative agent: MMF or Azathioprine 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

Answer 44

Ortho: in which the previous liver is removed and the transplant is placed at that location in the body Hetero: e.g. the kidney is usually placed in a location different from the original kidney because the non-functioning kidneys are generally not removed.