Transplantation medicine Flashcards
Immunosuppresion after transplantation is a matter of balance between rejection & complications. What are the dangers of each? (2x2)
Rejection:
1. Graft failure
2. Graft dysfunction
Complication:
1. Malignancies
2. Infections
What was an important factor allowing for a strong decrease in acute organ rejection over the past decades?
Introduction of calcineurin inhibitors
Which drugs are calcineurin inhibitors? (2)
- Cyclosporine
- Tacrolimus
What is the effect of the introduction of calcineurin inhibitors on long-time graft survival?
No significant improvement -> beneficial effect of calcineurin inhibitors disappears after 1 year, after that, surival curves run parallel to old immunosuppressive regimen curves
What is the most common cause of graft loss?
Death with functioning graft
What are the causes of death with functioning graft? How many % do they each comprise? (5)
- Cardiovascular: 34%
- Infection: 16%
- Malignancy: 15%
- GI/liver complications: 6%
- Other: 29%
True or false: immunosuppression after transplantation increases the risk of some malignancies
False; (virtually) all malignancies are increased
What is the most prevalent type of tumour in transplantation patients?
Skin cancer
How much is the risk of skin cancer elevated in Tx-recipients compared to normal population?
125x
Which types of skin cancer are increased in Tx-recipients? (5)
- Melanoma
- Squamous cell carcinoma (SCC)
- Basal cell carcinoma (BCC)
- Kaposi sarcoma
- Merkel cell tumours
What are the risk factors for skin cancer in Tx-recipients? Are they different from non Tx-recipients?
- UV radiation
- Fair phenotypic features
- Geographic location
- History of SCC/BCC
- Viral infection: HHV8, HPV
- Genetic factors
Which genetic polymorphisms especially predispose for skin cancer?
Polymorphims in folate pathways
What are Tx-specific risk factors for skin cancer (and cancer more generally)? (3)
- Age at transplantation
- Type of transplant
- Type, duration & intensity of immunosuppression
What is the cumulative incidence of non-melanoma skin cancer (NMSC) in Tx-recipients after 5 and 20 years?
<5 years: 29%
>20 years: 82%
Which skin cancer type behaves significantly different in skin cancer patients?
Squamous cell carcinoma -> more aggressive & invasive
Incidences of solid tumours post-Tx are not equal in every country and even differ between transplantation centres. What differentiates them? (4)
- Genetics
- Environmental conditions
- Patient population accepted for Tx
- Immunosuppressive regimens used
How much increased are the odds of invasive solid tumours in Tx-recipients compared to the general population?
15,7x increased
Which types of cancer don’t have an increased incidence in Tx-recipients? (3) Why?
- Mamma
- Prostate
- Lung
These cancers already have a high incidence -> immunosuppression doesn’t excessively increase epidemiological risk
How many years post-Tx do solid tumours typically occur?
~15 years
Through which mechanisms do anti-T-cell therapies in Tx-patients contribute to malignancy?
Specific increase of virus-associated tumours
What is an example of a tumour that can occur due to decreased T-cell surveillance due to immunosuppression in transplant patients?
EBV-related post-transplant lymphoproliferative disease (PTLD)
How does EBV-related post-transplant lymphoproliferative disease (PTLD) develop? (3)
- EBV-infected cells are normally held in check by CD8+
- Immunosuppression reduced CD8+ surveillance, allowing expansion of EBV-infected B-cells
- PTLD
How can the risk of EBV-related post-transplant lymphoproliferative disease (PTLD) be lowered?
Addition of rituximab if anti-T-cell therapy is used
How is EBV-related post-transplant lymphoproliferative disease (PTLD) treated?
Rituximab
What determines the risk of EBV-related post-transplant lymphoproliferative disease (PTLD)?
EBV infection status pre-Tx:
EBV+ pre-Tx = no increased risk
EBV- post-Tx = increased risk upon EBV infection
In which instances are anti-T-cell therapies used in transplantation settings? (2)
- Induction therapy
- Acute T-cell mediated rejection
Which anti-T-cell therapies are used in transplantation settings? (2)
- Alemtuzumab
- Anti-thymocyte globulin (ATG)
How can the risk of EBV-related post-transplant lymphoproliferative disease (PTLD) due to induction therapy be lowered?
Using a non-T-cell suppressive induction therapy such as basiliximab in EBV- patients
Why is it difficult to observe the risk of malignancy due to immunosuppressive therapies in clinical trials?
Malignancies take a long time to develop -> require extremely long follow-up times
What are the pro-malignant effects of calcineurin inhibitors?
- Increased levels of TGF-β: promotes tumour growth & invasive behaviour
- Elevated VEGF-expression: pro-angiogenic effects
- Increased levels of IL-6: predisposition to EBV-induced B-cell expansion
Calcineurin inhibitors give a stronger increase in [non-melanoma skin cancer/melanoma] than in [non-melanoma skin cancer/melamoma]
Non-melanoma skin cancer = stronger increase than melanoma
Which strategy is employed to reduce malignancy risks due to calcineurin inhibitors?
Measure through levels & taper immunosuppression as much as possible
Azathoprine was frequently used in post-Tx immunosuppression, but has largely been phased out. Why?
Replaced by calcineurin inhibitors
What is the mechanism of action of azathoprine?
Purine antagonist: inhibits DNA, RNA & protein synthesis & metabolism
What are the oncogenic effects of azathioprine?
- Impaired DNA repair mechanisms
- Photosensitization
- Accumulation of 6-thioguanine in DNA -> produces ROS when exposed to UV-A
Which type of cancer is particularly increased by azathioprine?
Squamous cell carcinoma
What is the mechanism of action of mycophenolate mofetil?
Inhibition of inosine monophosphate dehydrogenase (IMDPH) in the de novo purine synthesis pathway -> suppression of T- and B-cell proliferation
What is the effect of mycophenolate mofetil on malignancy risk?
No additional risk of malignancy observed
True or false: patients with grafts from a DCD donor have a higher risk of malignancy than from DBD donors
False: DBD and DCD have equal risk
What is the general effect of post-Tx immunosuppression on malignancy prognosis?
Severely worse than age-matched peers
Why are patients receiving organ transplantation today more at risk of developing malignancy than patients from the 1990s?
More aggressive immunosuppressive regimens
Which drug was used before the introduction of calcineurin inhibitors?
Cyclosporine
Which 3 drugs form the standard immunosuppressive regimen after kidney transplantation? (3)
- Tacrolimus
- Mycophenolate mofetil (MMF)
- Steroids (prednisone)
What are the side effects of prednisone (5)? How strong are these effects (-/+/++/+++)?
- Hypertension: +
- Hair growth: +
- Increased cholsterol: +
- Muscle weakness: +
- Obesity/facial fat: ++
What are the side effects of tacrolimus? (6) How strong are these effects (-/+/++/+++)?
- Hypertension: +
- Hair growth: -
- Diabetes mellitus/worsening: ++
- Nephrotoxicity: ++
- Neurotoxicity: +
- Increased cholsterol: +
What are the side effects of cyclosporine? (6) How strong are these effects (-/+/++/+++)?
- Hypertension: ++
- Hair growth: +
- Diabetes mellitus/worsening: +
- Nephrotoxicity: ++
- Neurotoxicity: +
- Increased cholsterol
What are the side effects of azathioprine? (3) How strong are these effects (-/+/++/+++)?
- Hepatotoxicity: ++
- Bone marrow toxicity: +++
- Abdominal complaints/diarrhoea: +
What are the side effects of mycophenolate mofetil? (2)How strong are these effects (-/+/++/+++)?
- Bone marrow toxicity: ++
- Abdominal complaints/diarrhoea: +++
What are the side effects of sirolimus/everolimus? (6) How strong are these effects (-/+/++/+++)?
- Nephrotoxicity: +
- Ulcerations in the mouth: +
- Increased cholsterol: ++
- Hepatotoxicity: +
- Bone marrow toxicity: ++
- Abdominal complaints/diarrhoea: +
Which three groups of complications of kidney transplantation can occur? (3)
- Complications around surgery
- Side effects of immunosuppressive medication
- Negative effects of immunosuppression
What are surgery-related complications of kidney transplantation? (4)
- Thrombosis
- Bleeding
- Infection
- Ureter obstruction/leakage
What are approaches to prevent post-Tx cancer?
- Increased screening
- Preventative strategies
- Reactive strategies
Which adaptations are made in cancer screening post-Tx?
More frequent screening for cervival cancer (HPV test every year instead of every 5 years)
Which adaptations to cancer screening post-Tx are being considered? (2)
- Yearly faecal occult blood test for CRC-screening (instead of every 2 years)
- Starting CRC screening earlier (45 or 50 years instead or 55)
Which preventative strategy for post-Tx malignancies is being explored? Is this succesful?
Tapering of immunosuppression; database research of tapering of immunosuppression shows no survival benefit -> patients experience more graft loss
What are reactive strategies post-Tx malignancies? (2)
- Tapering immunosuppression after cancer diagnosis
- Switching to sirolimus/everolimus (for skin cancer)
For which cancer types is tapering of immunosuppression in Tx-recipients currently recommended? (2)
- Lymphoma
- Kaposi sarcoma
What is the benefit of switching to sirolimus/everolimus upon diagnosis of skin cancer in Tx-recipients?
Sirolimus/everolimus appears to reduce the risk of formation of new skin cancers to a (small) degree
What is the benefit of switching to sirolimus/everolimus upon diagnosis of skin cancer in Tx-recipients?
25% of patients do not tolerate this treatment
