Renal - Transplantation Flashcards
What patients should be considered for renal transplantation?
ALL patients should be considered unless there are specific contraindications.
Absolute:
- active malignancy - period of 2 years complete remission
- active vasculitis or anti-GBM disease, with positive serology - 1 year of remission recommended
- severe heart disease
- severe occlusive aorto-iliac vascular disease
Relative:
- age - transplants are not routinely offered to young children (<1 yr) or older people (>75 yr)
- high risk of disease recurrence in transplant kidney
- disease of lower urinary tract
- significant comorbidity
Location of transplanted kidney
Kidneys come from live donors or cadavers
Implanted in right or left iliac fossa
Renal artery is sutured to the external or internal iliac artery and the renal vein to the external iliac vein, and the ureter is implanted into the bladder wall
Donor recipient matching
Donor and recipient must have compatible blood types
HLA haplotypes also used
- 4 most important alleles are HLA-A, HLA-B, HLA-C and HLA-DR
Ideal organ match is one in which all 8 alleles (remember 2 from each parent, 4 genes in total = 8). HLA molecules bind peptide fragments of protein antigens in a groove for recognition by T cells. Peptides from self proteins are bound and recognised as self by T cells. Unmatched transplantation, T cells see foreign HLA molecules and regardless of the bound peptide trigger an immune attack. Matched HLA molecules in a transplant organ can bind peptides from other unmatched polymorphic molecules –> immune attack
Immunosuppresive regimes minimise acute graft rejection, but the more alleles unmatched –> increased risk of graft rejection.
Immunosuppressive regime for renal transplantation
Initial - ciclosporin/ tacrolimus + monoclonal antibody
Maintenance - ciclosporin/ tacrolimus + MMF or serolimus
Add steroids if more than one steroid responsive acute rejection episode
Actions of ciclosporin
Reduces cell mediated immune responses - lesser effect on antibody mediated responses.
Interferes with antigen induced T cell differentiation and the clonal proliferation of T cells and thus the development and activation of cytotoxic T cells and other T cells responsible for CMI responses (e.g. Th2)
Complexes with cyclophilin t inhibit calcineurin which normally activates the transcription of IL-2
What are the important pharmacokinetics of ciclosporin?
Can be given orally or i.v.
Tissue concentration is 3 x plasma
Metabolised in the liver by P450 3A enzyme system (liver inducers lower ciclosporin activity)
Adverse effects associated with ciclosporin
Nephrotoxicity - renal vasoconstriction (acute and chronic) Hypertension and hepatotoxicity GIT disturbances Tremor Hirsuitism Gum hypertrophy Hyperkalaemia
What is tacrolimus?
Similar drug to ciclosporin (i.e. IL-2 inhibitor)
Indirectly inhibits calcineurin; more potent that ciclosporin with similar adverse effects - myelosuppression but greater nephrotoxicity
Higher incidences of impaired glucose intolerance and diabetes
Mechanism of action of azothioprine
Reduces clonal proliferation of T and B cells during the induction phase of the immune response. Interferes with purine synthesis and has cytotoxic action on dividing cells.
Given orally or by i.v. infusion. Metabolised to mercaptopurine which is the cytotoxic moiety acting by interfering with purine nucleotide metabolism. MCP is inactivated by xanthine oxidase
Adverse effects of azothioprine
Myelotoxicity (dose related) ---> monitor bloods GIT disturbances Hypersensitivity reactions (skin, rashes, arthralgia)
Mycophenolate mofetil
Selectively restrains the clonal proliferation of T and B cells and reduces the production of cytotoxic T cells.
Inhibits de novo purine synthesis specifically in T and B lmyphocytes (other cells can generate purines by another pathway)
Given orally or by i.v. infusion. Metabolised to mycophenolic acid which is the active moiety which interferes with purine nucleotide metabolism
Adverse effects of mycophenolate mofetil
GIT, CVS, and respiratory system disturbances Hepatitis Pancreatitis Tremor Dizziness Flulike syndrome
What is sirolimus
Antiproliferative immunosuppressant antibiotic (aka rapamycin)
Inhibits clonal proliferation of T and more particularly - B cells; decreases immunoglobulin production
Blocks response of precursor cells to IL-2 (by binding a cytosolic protein - FK binding protein 12 which inhibits mTOR) and thus preventing activation of T and B cells
Given ORALLY - metabolised by P450 3A (so many drug interactions)
Adverse effects of sirolimus
Myelosuppression (important), hyperlidiaemia, venous thromboembolism, diarrhoea, rash, osteonecrosis
Drug concentrations in the blood need monitoring
What monoclonal antibodies are used as immunosuppressants in renal transplant?
Selective IL-2 inhibitors - daclizumab, basiliximab
Anti-CD20 antibodies - rituximab –> B cell depletion, reduces antibody mediated rejection
