Week 10- Solid organ transplant Flashcards
14:27 what are the different types of transplants?
- Heart
- Lung
- Liver*
- Simultaneous Pancreas and Kidney transplant (SPK)*
- Pancreas*
- Kidney*
- Bowel*
- Multi-visceral*
where are the organs from?
• Deceased donor • Living donor (altruistic= anyone or directed=to someone you know) - Liver section - Kidney •Exclusion
what patients can’t be a donor?
- ebola
- active cancer
- HIV patients
what is the process for a transplant?
- transplant assessment= must have something wrong that cant be cured any other way, reviewed by a MDT (multidisciplinary team to see if they are appropriate for the waiting list)
- waiting list= exclusion criteria e.g. patient had other diseases life expectancy less than 2 years, donor-recipients blood groups,
- wait for a phone call
- the recipents immune system is the biggest barrier, immunosuppression
what are the aims for solid organ transplant?
- Increased life expectancy
* Increased QoL
what is the biggest problem for solid organ transplant?
-recipents immune system
what is the solution for the biggest problem for solid organ transplant?
using immunosuppression
what are the aims for immunosuppression?
-prevent graft rejection
-induction of tolerance for the organ
-reduce risk like
• Side effects
• Infections
• Malignancy
• Post Transplant
Lymphoproliferative Disease
what is a graft?
a surgical procedure to move tissues from one site to another on the body, or another creature without bringing its own blood supply
what are the different types of grafts?
- xenografts
- autografts
- isografts
- allografts
what is a xenografts?
between different species = greatest immune response = Rejection
what is an autograft?
from one part of the body to another on the same individual = No rejection
what is an isograft?
grafts between genetically identical individuals = no rejection
what is an allograft?
between members of the same species = varied response dependent on degree of histocompatibility of donor and recipient (but
also type of organ)
what are the antigens responsible for rejection of the organ called?
histocompatibility antigens and are prodcuts of the hstocompatibility genes
what is the loci of the genes that cause the most vigour rejection ?
major histocompatibility complex MHC AND IN HUMANS ITS CALLED HUMAN LEUKOCYTE ANTIGEN HLA
what are the 2 classes of MHC split into?
MHC I and MHC II
What are MHC I?
normally expressed on all nucleated cells and present antigenic peptides from inside the cell to CD8 T cells
what are MHC II ?
are only expressed on professional antigen presenting cells, activated
macrophages and B cells and present extracellular antigens to CD4 T cells
why are MHC molecules important?
part of a physiological function where presents antigens to T cells as they are only recognised when in complex with MHC molecules
what immune systems are involved in transplants?
adaptive (both cellular and
humoral response) and innate mechanisms
what cells are important and involved in rejections of grafts?
T cells
what do T cells do?
T cells become activated,
undergo clonal expansion and differentiate to express effector functions.
what are the 2 ways to minimise/control the host immune resposne to a transplant?
- HLA compatibility
- immunosuppression
how are genes in the MHC I and MHC II complex affecting rejection?
-genes at certain loci of the MHC I and MHC II COMPLEX PLAY a stronger or lesser of a role causing rejection. Strongest determinants is the HLA-DR for matching between donor and recipient , decrease chance of rejection
what are the benefits of good HLA-compatibiltiy?
• Better graft function
• Fewer episodes of rejection
• Longer graft survival
• Possibility of reduced immunosuppression (potential for reduced infection and
malignancy risk)
• Decreased risk of sensitisation increasing issues with further transplants if
required
what are the two phases of immunosuppression?
induction and maintaence
what is the induction phase?
the start immunosupression needed for as long as the graft is occuring for transplant. high dose due to transplant being a foreign molecule being introduced
what is the maintencence immunosuppression?
a lower dose of IS after the transplant
what are medication used for indcution immunosuppressant?
- corticorsteriod
- basiliximab
- alemtuzumab
- antithymocyte glbulin (ATG)
11:06 what are the medication used for maintanence?
- Ciclosporin / Tacrolimus
- Azathioprine / Mycophenolate
- Corticosteroids
- Balatacept
what is basilizimab?
-for induction
it is a monoclonal antibody acts against IL-2 receptror(CD25 T cells must be activated for this to be expressed)
• Inhibits differentiation and proliferation but is minimally T cell depleting
• Minimal adverse effects (no pre-med/specialist monitoring required)
• Given at induction and 3-4 days post surgery
what is alemtuzumab?
-for induction
• Humanised, rat IgG monoclonal antibody directed against CD52 cell surface
antigen causing cell lysis and prolonged depletion (also inhibits most monocytes, macrophages and natural killer cells)
• Associated with first dose reaction, neutropenia, anaemia, pancytopenia
(rare) and autoimmunity (haemolytic anaemia, thrombocytopenia and
hyperthyroidism)
• Used to treat episodes of rejection
what is Antithymocyte globulin?
-for induction
-IgG from horse or rabbits
-Blocks a large number of T cell membrane proteins (including CD2, CD3, CD45), causing
altered function, lysis and prolonged T cell depletion
• Cell lysis can be responsible for cytokine release syndrome – fever, chills, hypotension
• Associated with thrombocytopenia, leukopenia, occasional serum sickness and allergic reactions
• Pre-medication – paracetamol, chlorphenamine and corticosteroid
• Close monitoring required
• Used to treat episodes of rejection
what is corticosteriods?
-for induction
• Also used in maintenance therapy
• S/E: adrenal suppression, HTN, diabetes, osteoporosis, Cushing’s syndrome, GI, Wt gain,
hyperlipidaemia, infection, etc….
how long do patients take these maintenance drugs for?
theyll take one for a least the rest of thier life
what ciclosporin?
-for maintenance
-its a Calcineurin inhibitor
-• Is a metabolite of fungal, Tolypocladium inflatum
• Binds to cyclophilin (an immunophilin) to form a complex. Complex inhibits
calcineurin phosphatase suppressing T cell activation by inhibiting cytokine
production, primarily IL-2
• Concentration related adverse effects: nephrotoxicity, hypertension,
hyperlipidaemia, gingival hyperplasia, hirsutism, tremor
• May also induce: haemolytic uraemic syndrome, diabetes mellitis
• Twice daily dosing regime (adjusted to levels)
• Therapeutic drug monitoring
• Brand prescribing required – Neoral / generics
• Metabolised by the CYP 450 enzymes = NUMEROUS interactions
• Major positive impact on rejection and survival following transplant
what is tacrolimus?
-for maintence
-its a Calcineurin inhibitor
• Macrolide antibiotic derived from Streptomyces tsukubaensis
• Binds to FK506-binding protein 12 (an immunophilin) to inhibit calcineurin and T cell
activation (binds a different intracellular protein to ciclosporin but has subsequent
same mechanism of action)
• More potent than ciclosporin
• Similar S/E to ciclosporin (nephrotoxicity and haemolytic uremic syndrome) but
lower incidence of hypertension, hyperlipidaemia, hirsutism and gum hyperplasia
and higher incidence of diabetes mellitus and neurotoxicity
• Once or twice daily dependent on brand and transplant
• Brand prescribing required – Prograf, Advagraf, Adoport
• Best absorption on an empty stomach (food decreases bioavailability)
• Therapeutic drug monitoring – trough level
• Metabolised by the CYP 450 enzymes = NUMEROUS interactions
what are some improtanct considerations for the calcineurin inhibitor?
• Brand prescribing
• Difference in bioavailability with different formulations
• Oral cyclosporin dose approximately 3 times the IV dose
• Oral dose of tacrolimus approximately 3-5 times the IV dose
• Ciclosporin has specific information regarding the dilution of the solution
• S/E more likely to occur above the therapeutic range but can be
idiosyncratic and occur at normal concentrations
• Therapeutic drug monitoring
what is azathioprine?
-for maintenance
-its a antiproliferative drugs
-Summary – 6-MP is converted to thioguanine nucleotides which interfere
with DNA synthesis. Another metabolite can also inhibit purine synthesis.
• Inhibiting proliferation of T and B cells
• Main S/E – Haematological (dose dependent myelosuppression can occur
with over 50% of patients developing leukopenia – reversed by
reducing/stopping the drug), thrombocytopenia (reversed by
reducing/stopping the drug); N&V (alleviated when given with food or in
divided doses)
• Close FBC monitoring required
• Once daily dosing
• Interaction – ALLOPURINOL (reduce the azathioprine dose to ¼)
what is Mycophenolic acid (MPA)?
-for maintenance
-its a antiproliferative drugs
• MPA blocks inosine monophosphate dehydrogenase, the enzyme required
for de novo synthesis of guanosine monophosphate nucleotides. This
blocks purine synthesis preventing B and T cell proliferation
• More potent than azathioprine with greater reduction in acute rejection
• Main S/E: Haematological – neutropenia, leukopenia, mild anaemia;
gastrointestinal – diarrhoea can be dose limiting (EC MPA (Myfortic)may
improve this)
• Monitor FBC
• Twice daily dosing
• Important drug interactions
what is sirolimus?
-for maintenance
-is a mTOR inhibitor
• Used as an alternative to calcineurin inhibitors and antiproliferatives or
in combination with calcineurin inhibitors
• Formally known as rapamycin, sirolimus is a drug that inhibits the
mammalian target of rapamycin (mTOR)
• Sirolimus firstly binds the immunophilin FKBP12 forming a complex that
inhibits mTOR
• mTOR is a serine/threonine protein kinase involved in regulation of cell
growth, proliferation and of protein synthesis and ribosome biogenesis
• Blockade of mTOR inhibits the cellular proliferation response to a variety
of cytokines including IL-2
• Therapeutic drug monitoring required
• S/E:
• Less nephrotoxic than CNI
• Less likely to cause diabetes
• Risk of life threatening pneumonitis (resolves after treatment withdrawal)
• Impair wound healing (mTOR inhibition of fibroblast response to fibroblast growth factor) – not
used immediately post transplant
• Hyperlipidaemia,thrombocytopenia
• Metabolised by the CYP 450 enzymes = NUMEROUS interactions
• Administer consistently (with or without food)
what is balatacept?
-for maintenace
-its a Selective T cell co-stimulation
blocker
• Binds CD80 and CD86 receptors on the antigen presenting cell
preventing CD28 on the T cell from binding
• Dosing divided into two phases:
• Initial phase, IV day1 and 5 and at the end of weeks 2, 4, 8 and 12
• Maintenance phase, IV end of week 16 and every 4 weeks thereafter
• Risk of post transplant lymphoproliferative disease
• Used as an alternative to CNI
• Comparison studies have shown equivalent patient and graft survival but a higher incidence of
acute rejection
what is combination therapy and the beneift for maintence ?
• As more therapy has become available the use of combination therapy with action at different sites has been shown to have better outcomes
• Reduced steroid dose
• Better patient outcomes – reduced rejection
• Dependent on type of transplant and perceived immunosuppressive
challenge
• Initiated at the time of surgery
• Generally will have at least one continued life-long
what are some complications for immunospression?
- individual side effects
- high chance of infection
- malignancy is higher espeically those caused by viral aetiology
