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Stage 2: Inflammation > Kidney Transplantation > Flashcards

Kidney Transplantation Flashcards

1
Q

What are the benefits of kidney transplantation?

A

1) Prolongs life (if on dialysis with ESRF, not if > 75)

2) Improves QoL compared to dialysis and medication

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2
Q

What are the risks of kidney transplantation?

A

1) Surgery risks
2) Infection
3) Malignancy (from medication)

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3
Q

Describe kidney transplantation

A
  • Not a cure of kidney disease
  • Can last up to 20-40 years (majority no)
  • Just another type of RRT to replace kidney function
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4
Q

Why does transplantation lead to rejection without immunosuppressive medication?

A

APC presents foreign antigens to T cell activating rejection cascade

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5
Q

What medication stops the cell going into the cycle that would lead to rejection?

A

Sirolimus/everolimus

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6
Q

Describe the immune system in transplant rejection

A
  • HLA antigens on the transplanted organ are the main target
  • Involves both innate and adaptive
  • T cells orchestrate the alloimmune response after transplantation and are essential for graft rejection
  • Effector mechanisms = CD8 mediated cytotoxicity, CD4 mediated delayed type hypersensitivity, antibody mediated injury
  • Without lymphoid organs, can’t have immune response against transplanted organ
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7
Q

What triggers innate immunity?

A

Tissue injury e.g. ischaemia or infection

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8
Q

What is the adaptive immune system in rejection?

A

Antigen specific response driven by the recognition of alloantigens (non self antigen of same species) by specific cell receptors

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9
Q

Why has there been a significant decrease in rates of early acute rejection?

A

1) Better medication

2) Better methods of monitoring e.g. identifying potential antigens that can cause problems which can lead to rejection

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10
Q

What are the challenges in transplantation?

A

1) Little substantial improvement in long-term allograft (although donors have gotten worse) and patient survival
2) Requirement for use of more marginal grafts, older donors, and immunologically sensitised recipients with higher co-morbidity esp. diabetes

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11
Q

Why are transplantations nowadays more challenging?

A

Bc the donors are less perfect, used to be stricter criteria

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12
Q

What do optimal outcomes of transplantation require?

A

1) Optimal care of the donated organ
2) Optimal care of the transplanted organ after transplantation - preventing allograft injury and minimising risk of infection
3) Optimal care of the recipient - minimising co-morbidity and maximising longevity
So need to balance between too much and too little immunosuppression

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13
Q

Why are older decreased donors being accepted?

A
  • So more patients get the benefits of transplantation
  • Prognosis of ESRD on dialysis is so poor that it is probably better to get a sub-optimal donor than stay on dialysis forever
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14
Q

What is the main influence on outcome of kidney?

A

Age of donor (rather than DBD vs DCD - survival is the same unlike liver)

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15
Q

What are the 4 types of organ donor?

A

1) Donation after brain death (DBD)
2) Donation after circulatory death (DCD) - not much different from DBD for kidney, doesn’t fulfill criteria for DBD, stop treatment and act quickly
3) Living donation
4) Expanded criteria (EC) donors - older, stroke, HTN, more likely to use in older patients, about half now

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16
Q

What is the impact of putting the kidney on ice from someone who has died?

A

It increases inflammation, activating the innate immune system increasing the risk of rejection

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17
Q

Why is elective living donation the best?

A

1) Can optimise recipient
2) Can plan in advance and do it daytime
3) Can minimise cold ischaemia time (time spent on ice)
4) Can have recipient and donor next to each other

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18
Q

Why does it not really matter if after 10 years the extended criteria donor organ starts to be worse than others?

A

Still better bc e.g. if 65 with ESRF on haemodialysis without a transplant prognosis is max 5-6 years

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19
Q

What are the barriers for transplantation?

A

1) ABO antigens (expressed on donor kidneys)
2) HLA antigens (used to present foreign peptides to T cells)
3) Preformed anti-HLA antibodies

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20
Q

What are contra-indications for transplant bc they will cause hyperacute rejection?

A
  • ABO incompatibility
  • Preformed anti-donor HLA antibodies (positive cross match)
  • Can do HLA/ABO incompatible transplant in some situations
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21
Q

Why do you want to get the best HLA match (even though matching is not required)?

A

1) Reduces risk of acute rejection
2) Improves graft survival (less likely to form de novo donor specific antibodies)
3) Prevents allo-sensitisation i.e. formation of anti-HLA antibodies - important if young recipient bc would make second transplantation more challenging bc if really bad match will make antibodies against potential donors

22
Q

What blood type are the universal donors?

A

O

23
Q

What blood type are the universal recipients?

A

AB

24
Q

What is slightly different about ABO compatibility in kidney transplants vs blood transfusions?

A

A2 kidney donors can be transplanted into O or B recipients if anti-A2 antibodies are low < 1:8

25
Q

How do anti-HLA antibodies develop?

A

After exposure to blood products, pregnancies or prior transplants

26
Q

What is a crossmatch?

A

Mixing blood from recipient and donor

27
Q

What is an absolute contraindication for renal transplantation?

A

A positive CDC T cell crossmatch

28
Q

Describe HLA mismatches

A
  • There are 3 types of HLA antigens (A, B, DR)
  • 6 potential mismatches bc 2 of each antigens
  • Best match = 0,0,0 mismatch
  • Worst = 2,2,2 which means don’t have any of the antigens in common between recipient and donor, more likely to form anti-HLA antibodies
  • Less important for living donor grafts
29
Q

What does graft survival/half life over time decrease with?

A

Increasing HLA mismatch

30
Q

What is the effect of pre-formed HLA antibodies?

A
  • Increases risk of antibody mediated rejection
  • Reduces graft survival even if negative cross match and not donor specific
  • Ideally no anti HLA antibodies at all
31
Q

Why is child to mother transplantation a bit more immunologically risky?

A

During pregnancy, the mother is sensitised towards the child and therefore the risk of rejection is slightly higher

32
Q

What is a paired kidney donation?

A
  • When two people willing to donate to a specific person swap recipients
  • Exchange donor transplants to improve compatibility
  • Good solution when donor/recipient pairs are ABO or HLA incompatible
  • Can even have three pair exchange
33
Q

When is the risk of acute rejection and graft loss highest and therefore immunosuppression highest?

A

First 3 months

34
Q

Why is immunosuppression tapered slowly to maintenance levels by 6-12 months?

A

Bc risk of rejection goes down but risk of infection and cancer is always there

35
Q

Are younger or older patients at greater risk of rejection?

A

Younger

36
Q

What else increases your risk of rejection?

A

If you have autoimmune disease or African American

37
Q

Describe induction immunosuppression

A
  • Given just before transplantation instead of steroids
  • Immunosuppression infusions
  • Reduces the number of certain cells
  • Reduces risk of rejection until the maintenance starts working
38
Q

What drugs are used in induction immunosuppression?

A

1) Mabs e.g. basiliximab (anti-IL2 receptor, most common), alemtuzumab (anti-CD52)
2) Polyclonal antibodies e.g. antithymocyte globulin

39
Q

What drugs are used in maintenance immunosuppression?

A

1) Calcineurin inhibitors e.g. tacrolimus (can be used also to treat proteinuria), cyclosporin
2) Purine syntheses inhibitors e.g. mycophenolate mofetil (most common), azathioprine, mycophenolate sodium
3) Corticosteroids
4) mTOR inhibitors (if want to avoid calcineurin inhibitors0 e.g. sirolimus, everolimus
5) Fusion proteins e.g. belatacept (CTLA4-Ig) - not used v often

40
Q

What is the most common combination of drugs used in maintenance immunosuppression?

A

Tacrolimus + mycophenolate + steroids

41
Q

Describe the problems with some of the immunosuppression drugs?

A

1) Tacrolimus - hypomagnesaemia, tremor, hyperkalaemia, hyperglycaemia (toxic to pancreas), hair loss
2) Mycophenolate mofetil - teratogenic in pregnancy, stop and use azathioprine
3) Cyclosporin - nephrotoxic, gum hyperplasia
4) Azathioprine - can’t give with allopurinol, leads to bone marrow suppression

42
Q

How do you prevent drug toxicity post transplant?

A

1) Steroid sparing regimens and steroid avoidance - give lots of immunosuppression in beginning so can try and stop steroids, slightly increases risk of rejection (may be acceptable if have v well matched kidney)
2) Reduce calcineurin inhibitor dose post transplant period
3) Calcineurin inhibitor avoidance - if reason to avoid them completely, use belatacept infusion
4) Single drug regimens have higher rates of acute rejection

43
Q

Describe the features of post-transplant infections

A
  • Patients will have fewer symptoms and muted clinical findings, delayed presentation e.g. low to no fever
  • Potential drug interactions with anti-rejection drugs
  • Drug resistance more common bc often patients have been in hospital a lot
  • Drug levels only crudely estimate immunosuppressive burden
  • Focus on infectious disease prevention e.g. prophylaxis and vaccination
  • After 6 months-1 year more likely to be community acquired or persistent rather than rare opportunistic
44
Q

Describe virus infections post transplant

A
  • Community acquired e.g. common respiratory viruses
  • Latent viruses e.g. HSV, CMV, VZV, Hep B/C, papillomavirus, polyomavirus
  • Infections from donor (donor derived) e.g. CMV, EBV (if were CMV/EBV naive), Hep B/C, HIV, rabies
45
Q

Describe risk of cancer in transplant patients?

A
  • Higher risk of cancer post-transplantation especially skin cancer
  • 70% of cancers occur in first 10 years of transplantation
  • Non-melanoma skin cancer has 25x increased risk
  • Breast cancer only 1.1x increased risk
46
Q

What are the causes of acute allograft dysfunction (AKI)?

A

1) Immunological e.g. rejection
2) Vascular e.g. perfusion of kidney may be compromised already
3) Obstructive e.g. non-functioning bladder blocking urine flow
4) Infection of kidney

47
Q

Describe acute antibody mediated rejection

A
  • Mediated by all antibodies against the transplanted organ
  • Direct antibody mediated injury, complement activation, Fc mediated toxicity
  • Endothelium in peritubular capillaries and glomeruli is the primary target of alloantibodies
  • Treatment includes removal of alloantibodies, decreased production of alloantibodies and attenuation of the immune response to antibodies
48
Q

What are the stages of antibody-mediated rejection?

A

1) Complement activation
2) Direct endothelial activation e.g. mTOR
3) Antibody-mediated cytotoxicity via Fc receptor on macrophage/NK cells

49
Q

Describe the complement cascade in acute antibody mediated rejection

A
  • Proteolytic cascade present in the plasma
  • Cytotoxicity, chemotaxis and enhancer of APC response
  • Cascade leads to membrane attack complex that causes the damage
50
Q

Describe acute cellular rejection

A
  • Mediated by lymphocytes and macrophages
  • Elicited by CD8 mediated cytotoxicity and CD4 mediated cytokine secretion and macrophage recruitment
  • The tubulointerstitium is the main kidney compartment affected
  • Treatment includes high dose steroid or thymoglobulin/ATG
51
Q

What should you do/encourage in transplant patients?

A

1) Strictly manage CV risk factors
2) Encourage self examination and attendance at national screening programmes e.g. cervical smear tests
3) Encourage avoidance of sun exposure
4) Vaccinate against influenza and pneumococcus
5) Refer to transplant unit for preconception management
6) Promptly refer to transplant unit in context of febrile episode

52
Q

What should you not do in transplant patients?

A

1) Administer live vaccines
2) Prescribe drugs that induce or inhibit cytochrome P450 activity if the patient is taking sirolimus, tacrolimus or cyclosporin
3) Prescribe nephrotoxic drugs e.g. NSAIDS

Stage 2: Inflammation (39 decks)

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