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Exam 2 (and 3) - CNS, mental health, renal and liver > Organ transplant > Flashcards

Organ transplant Flashcards

1
Q

What is the biggest barrier to transplants?

A

The immune system

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2
Q

What need to be assessed if a patient is put on a donor waiting list?

A
  • Exclusion criteria- e.g. has other diseases so life expectance is less than 2 years
  • Donor-recipient blood group compatability
  • HLA- compatibility
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3
Q

What are the aims of immunosuppression in organ transplants?

A

Prevent graft rejection- acute or chronic
Induction of tolerance to transplant organ
Risk of immunosuppression: side effects, infections, malignancy, post-transplant lymphoproliferative disease (Lymphoma)

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4
Q

What are they different types of grafts?

A
  • Xenografts: Between different species. propose the greatest immune response = rejection
  • Autograft- From one part of the body to another on the same individual= no rejections
  • Isografts- between genetically identical individuals = no rejections
  • Allografts- most often seen- between members of the same species- varied response dependent on the histocompatibility of donor and recipient and also the organ transplanted.
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5
Q

Discuss the antigens responsible for rejection of a graft?

A

Histocompatibility antigens produced by histocompatibility genes.
Major histocompatability complex (MHC) produces human leukocyte antigens (HLA).

MHC I : On all nucleated cells, present anitgenic peptides from inside the cel to CD8+ t-cells
MHC II: Only expressed on professional antigen-presenting cells, activated macrophages and b-cells and present the EC antigens to CD4+ t-cells.

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6
Q

Discuss the role of t-cells in recognition of a foreign graft.

A

T-cells are central in the rejection of grafts= t-cells become activates, undergo colonial expansion and differentiate to express effects functions. This leads to injury and cell death in the transplanted organ and rejection.

Signal 1: Interaction between the t-cell receptor and the antigen presented by the MHC.
Signal 2: Co-stimulatory receptor/ligand interaction between t-cell and antigen presenting cell (APC) e.g. CD8 of t-cell and APC cell surface ligand e.g. B7-1 or B7-2 (aka CD80 & CD86). This leads to activation of 3 signalling pathways:
- Calcium-calcinuerin pathway
- Mitogen activated protein (MAP) kinase pathway
- Protein kinase-C- nuclear factor kappa beta
these are responsible for transcription factor activation
Signal 3: Growth signal activating the cell cycle. Activation. of phosphoinositide-3 kinase (PI-3K) Pathway and molecular target of Rapamycin (mTOR)

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7
Q

What does it mean if there is a low HLA-compatability?

A

Increased risk of rejection.
Want the closest match as possible

MHC class 1 is encoded by genes at HLA-A, B and C loci
MHC Class 2 is encoded by genes in HLA-DP, DQ or DR regions

The strongest determinant in rejection (strongest match between donor and recipient): HLA-DR
Most important that HLA-DR is matched

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8
Q

What are the benefits of good HLA-compatability?

A
  • Better graft function
  • Fewer episodes of rejection
  • Longer graft survival- due to less damage caused via rejection
  • Possibility of decreasing doses of immunosuppression which can decrease infection and malignancy risk and side effects
  • Decreased risk of sensitisation increasing issues with further transplants if required.
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9
Q

What are the 2 parts of immunosuppression required with an organ transplant?

A

INDUCTION: Higher levels are needed initially as this is the time with highest risk of ejection:
Corticosteroids
Basiliximab
Alemtuzumab
Antithymocyte globulin (ATG)
Is enhanced by monoclonal antibodies given inter-operatively

MAINTENANCE
Ciclosporin/tacrolimus - calcineurin inhibitors
Azathioprine/ Mycophenolate
Corticosteroids
Balatacept
Sirolimus- mTOR inhibitor
doses decrease overtime

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10
Q

Discuss when basiliximab is used and how it works and the side effects?

A

This is a chimeric monoclonal antibody against the IL-2 receptor (CD25) which is only expressed on activated t-cells.
Therefore, it inhibits the differentiation and proliferation of t-cells (not the ones that already exist though).
- Has monimal ADRs = no pre-medication or specialist monitoring required
- Given at induction, during transplant and 3-4 days post surgery

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11
Q

Discuss when Alemtuzumab is used and how it works and the side effects ?

A

This is a humanised IgG monoclonal antibody against CD25 cell surface antigen - causes cell lysis and depletion. It inhibits most monocytes, macrophages and NK cells.
- S/Es: Neutropenia, anemia, pancytopenia, auto-immunity (can develop haemolytic anaemia, thrombocytopenia, hyperthyroidism)
- Used to treat episodes of rejection
- is so immunosupressing that it may decrease the need to immediately start maintenance therapy straight after surgery = beneficial

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12
Q

Discuss when Antithymocyte globulin (ATG) is used and how it works and the side effects ?

A

This is an IgG antibody from horses or rabbits immunised with humanised thymocytes.
Blocks t-cell membrane proteins including CD2, CD3 CD45= altered function, lysis and prolonged t-cell depletion.
- Cell lysis can cause cytokine release syndrome- as cell bursts, its contents is released and can cause fever, chills, hypotension, rash, dyspnoea. If this occurs, stop the drug!
- S/Es: Thrombocytopenia, leukopenia, serum sickness, allergies
- Give pre-medication: Paracetamol, IV corticosteroids and Chlorphenamine
- Can be used to treat epidosed of rejections and monitor svery 15 minutes. Is used less at induction nowadays
-Have to dose via IBW if obese to prevent overdosing.

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13
Q

Discuss when corticosteroids are used and how it works and the side effects ?

A

Used in maintenance therapy and induction
- S/Es: adrenal suppression, HTN, DM, Osteoporosis, Cushing’s syndrome, GI, weight gain, hyperlipidemia, infections

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14
Q

What are the drugs used for maintenance filling a transplant?

A

Usually remain on at least one of the following for life:
- Calcineurin inhibitors- Ciclosporin, Tacrolimus
- Anti-proliferative drugs- azathioprine, mycophenolic acid
- mTOR drugs - sirolimus
- selective t-cell co-stimulation blockers- Balatacept

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15
Q

What are examples of calcineurin inhibitors?

A

ciclosporin
Tacrolimus

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16
Q

How does ciclosporin work?

A

Ciclosporin is a calcineurin inhibitor that binds to cyclophillin to form a complex. This complex inhibits calcineurin phosphatase, suppressing t-cell activation by inhibiting cytokine production especially IL-2

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17
Q

What are the possible side effects of Ciclosporin?

A

Nephrotoxicity- monitor creatinine and urea
HTN
Hyperlipidaemia
Gingival hyperplasia (overgrowth of gums)
Hirtuism- excess hair growth
Tremor

In up to 5% of patient t may induce diabetes or haemolytic uraemiac syndrome

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18
Q

What is the dosing frequency of cyclosporin?

A

Twice daily

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19
Q

What is the recommended trough level for ciclosporin?

A

Monitor and adjust dose to around 100-300 ng/mL (trough level)

20
Q

What is important when prescribing Ciclosporin or Tacrolimus?

A

They must be prescribed by brand

21
Q

What must a patient on ciclosporin or Tacrolimus not consume?

A

Grapefruit juice- ciclosporin and tacrolimus is metabolised by cyp-p450 enzymes so can cause interactions.

Grapefruit juice- inhibits CYP P450 3A4 so this prevents the metabolism of cyclosporin and tacrolimus = accumulates

22
Q

How does Tacrolimus work?

A

Tacrolimus is a macrolide antibiotic that binds to FK506-Binding protein 12 (an imunophillin) which inhibits calcineurin and t-cell activation.
- Is more potent than cyclosporin
- Similar S/Es to cyclosporin: neurotoxicity and haemolytic ureic syndrome but decreased risk of incidence of HTN, Hyperlipidaemia, hirtsuism, gum hyperplasia
BUT INCREASED risk of diabetes and neurotoxicity.

23
Q

What is the dosing regime for tacrolimus?

A

Once or twice daily doses
e.g. in renal transplant: Once daily Advagraf MR
in liver transplant: Twice daily Adopt

24
Q

How should tacrolimus be taken?

A

On an empty stomach as food decreases bioavailability and absorption.

25
Q

What is the recommended trough level for tacrolimus?

A

5-15 ng/mL

26
Q

Is the dosing of different cyclosporin and tacrolimus formulations the same?

A

NO- they must be prescribed by brand.
Additionally, there is different bioavailablities with different formulations e.g. Oral cyclosporin dose is approx 3x that of the IV dose
and tacrolimus is 3-5 x

27
Q

What are the examples of anti-proliferative drugs used post transplant?

A

Azathioprine
Mycophenolic acid

28
Q

How does Azathioprine work?

A

Azathioprine is metabolised to mercaptopurine and then thioguanine nucleotides which interfere with DNA synthesis.
- inhibits proliferation of t and b cells
- Is a OD dose

29
Q

What are the side effects of azathioprine?

A

Mainly haematological side-effects that are dose-dependent e.g. myelosuppression can occur with over 50% of patients developing leukopenia. This can be reversed by stopping the drug.
- N+V- give with food or in divided doses
- Thromboytopenia requires
- Requires FBC monitoring
-

30
Q

What is an important interaction of azathioprine?

A

Azthoprine interacts with allopurinol = decrease the azathioprine dose to 1/4 because allopurinol inhibits xanthine oxidase which metabolises azathioprine.

31
Q

How does mycophenolic acid work?

A
  • Mycophenolic acid Acid is the active ingredient of mycophenolate motefil - MPA blocks inosine monophosphate dehydrogenase- which is the enzyme required for de novo synthesis of guanosine monophosphate nucleotides = blocks Purine synthesis = prevents t and B-cell proliferation - mycophenolic acid is more potent than azathioprine so has an increased reduction in rejection.
  • BD dose
32
Q

What are the side effects of mycophenolate acid (mycophenolate Motefil)?

A
  • Haemological: leukopenia, neutropenia, mild anemia
  • GI e.g. diarrhoea- can be dose limiting = decrease dose
  • Enteric coated MPA may help with gI effects (Myfortic)
33
Q

What are possible interactions with Mycophenolic acid (mycophenolate motefil)?

A
  • Iron, antacids, rifampicin- decrease mycophenolate motefil levels
  • Aciclovir, ganciclovir = increase mycophenolate motefil levels
34
Q

What is an example of an mTOR drug?

A

Sirolimus

35
Q

How does sirolimus work?

A
  • It inhibits mTOR by binding to the immunophillin, FKBP12 which forms a complex that inhibits mTOR.
  • mTOR is a serine/threonine protein kinase involved in regulation of cell growth, proliferation, protein synthesis and ribosome biogenesis.
  • Blocking mTOR, inhibits cell proliferation in response to cytokines e.g. IL-2
  • Can be used in combination with calcineurin inhibitors
36
Q

What is the maintenance trough level for Sirolimus?

A

12-20 ng/mL

37
Q

What are the potential side effects of sirolimus?

A
  • Is less nephrotoxic than calcineurins- but some glomerular effects and can cause proteinuria.
  • less likely to cause DM
  • Risk of pneumonitis- stop drug
  • Impaired wound healing- as doesn’t just act on lymphocytes but also other praise dividing cells e.g. fibroblasts. Therfore, don’t start drug immediately post-transplant to allow wound to heal.
  • Hyperlipidemia
  • Thrombocytopenia
  • HTN

Note, is CYP P450 metabolised

38
Q

Why don’t you start Sirolimus immediately post transplant?

A

Impaired wound healing- as doesn’t just act on lymphocytes but also other praise dividing cells e.g. fibroblasts. Therfore, don’t start drug immediately post-transplant to allow wound to heal.

39
Q

What is an examples of selective t-cell co-stimulation blockers used in post organ transplants?

A

Balatacept
- Can be used as an alternative to calcineuring inhibitors- but found to have increased incidence of acute rejection.

40
Q

How does balatacept work?

A

Binds to CD80 & CD86 receptors on antigen-presenting cells, preventing CD28 on the t-cell from binding = no activation.

41
Q

What is a risk that may occur when using Balatacept?

A

Balatacept can lead to post-transplant lymphoproliferative disease- associated with b-cells that have been infected by Epstein-Barr virus = increased proliferation of infected cells, and as the patients immunosupressed, there is no t-cell control like there normally wild be.

42
Q

What is the unusual dosing of Balatacept?

A

Has 2 phases (not everyday):
Initial:
Day 1
Day 5
Ends of weeks 2, 4, 8 and 12
Maintenance:
End of week 16 and then every 4 weeks thereafter

43
Q

What is the typical immunosuppression used in an intestinal transplant?

A

Induction:
- Alemtuzumab SC- has risk of cytokine release ( Flu symptoms, HTN, tachycardia)- Give pre-medication:
Chlorphenamine
Paracetamol
Methylprednisolone
- Also at induction: Methylprednisolone IV- then switch to oral and decrease to stop
- Calcineurin inhibitor = immediate release Tacrolimus e.g. Prgograf

  • After transplant = azathioprine or mycophenolate

= 3 immunosuppressive agents are continued post transplant.

44
Q

What is the typical immunosuppression used in a Renal transplant?

A

Pre-med and induction:
- Mycophenolate
- IV Methylprednisolone
- IV Basaliximab (OR Aletuzumab if increased immunologic risk r.g. previous transplant, previous rejection)
Need 2nd dose of Basiliximab 4 days later

From day 1 post-transplant:
- Prednisolone 20mg OD- decrease overtime
- Advagraf (calcineurin I- prolonged release tacrolimus) - 0.15mg/kg OD
- Mycophenolate motefil (after basiliximab)- 750mg BD

after transplant, drugs perviously needed for dialysis will be stopped e.g, eponymous, renavit, iron, phosphate binders

45
Q

What other considerations must be managed in immunosupressed patients post transplant?

A

Patients have an increased risk of infection:
- Pneumocystic Jiroveci (PCP): A fungal infection that symptoms are fever, chills, cough, fatigue.
This can cause a loss of graft and can be fatal.
THEREFORE, ALL kidney transplant patients are given 6 month prophylaxis with co-trimoxazole

  • Fungal infections e.g. Candida
    Prophylaxis: give all patients Nystatin solution for 4 weeks post-transplant
  • Tuberculosis- patient risk is reviewed: where are they from? have they been exposed to TB? Are they a carrier of latent TB? If there is a risk, give prophylactic Isoniazid and Pyridoxine
  • Cytomegalovirus:
    Can be asymptomatic, may have flu like symptoms but can lead to end-organ damage.
    Is passed on by contact of bodily fluids when virus is active- often people are infected as a child, so has zero-positive antibodies against CMV. BUT, transplanting organs = risk of passing on infection- if patient has CMV and was latent, the immunosuppression now suppresses the immune system and the infection becomes active.
    Give Valganciclovir prophylaxis to anyone who is at risk. Dose is dependent on renal function for 3-6 months.

Not infection but still important:
- Risk of transplant renal vein thrombosis and DVT:
Give patients LMWH prophylaxis while in hospital (is weight and renal function dependent). Note the renal function won’t be the best post renal transplant but will increase so dose may need to increase top.
- Use of steroids and surgery- need gastric mucosal protection e.g. PPI, omeprazole 20mg OD
- pain relief- paracetamol, Fnetanyl PCA

Exam 2 (and 3) - CNS, mental health, renal and liver (23 decks)

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