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
How do steroids act as immunosuppressants?
Steroids are used in renal transplant if more than one steroid responsive rejection episode has occured.
Steroids inhibit clonal proliferation of T and B cells and macrophage activation. Interact with intracellular receptors to inhibit transcription of specific genes that code for various cytokines, esp IL-2
Given orally, i.v. - main effects occur after 2-8 hours because protein synthesis of mediators and enzymes is required
Operative factors related to renal transplantation success
MC complication is related to ureteric anastomosis
Warm ischaemic time is important, graft survival is directly related to this
- long warm ischaemic times increase the risk of acute tubular necrosis which may occur in all types of renal transplantation, provided other insults are minimal will recover
Types of organ rejection
1) Hyperacute - occurs immediately through presence of preformed antibody (e.g. ABO incompatibility)
2) Acute - occurs during the first 6 months and is usually T cell mediated
- tissue infiltrates and vascular lesions
3) Chronic - occurs after the first 6 months, vascular changes predominate
Hyperacute graft rejection
Renal transplants most susceptible to this process
Risk factors - major HLA mismatch and ABO incompatibility
Rejection occurs almost immediately and macroscopic features may become manifest following completion of vascular anastomosis and removal of clamps
- kidney becomes mottled, dusky and the vessels will thrombose
Only treatment is graft removal - if left it will produce and abscess
Acute graft rejection
All organs may undergo acute rejection
Mononuclear cell infiltrates predominate
All types of transplanted organs are susceptible - occurs in 50% of cases
Most can be managed medically
Chronic graft rejection
All transplants with HLA mismatch
- previous acute rejections and immunosensitising events all increase risk
Vascular changes are most prominent with myointimal proliferations leading to organ ischaemia
How can graft rejection be detected post operatively following renal transplant
Post operative urine output is the most readily available and easily measured indicator of graft rejection. Patients divided into 3 groups following renal transplantation regarding graft function:
1) Immediate graft function - brisk diuresis and falling serum creatinine
2) Slow graft function - modest urine output and slowly falling creatinine levels
3) Delayed graft function - need for dialysis post transplant
Early complications of renal transplantation
Poor renal function - may indicate acute graft rejection, ciclosporin toxicity or acute tubular necrosis caused by ischaemia before the kidney was revascularised. Pre and post renal problems can also arise
Cellular rejection (acute graft rejection) is a cell mediated process and occurs in the first 6 months following transplantation
Vascular rejection is more chronic, aggressive and often antibody mediated. Usually vessel damage and plasma exchange is used to remove antibodies.
CMV infection is the most important infection to consider in solid organ transplant - fever, retinopathy, hepatitis, enteritis, pneumonitis, and thrombocytopaenia. Treatment is with ganciclovir, foscarnet and cidofovir
Vascular - renal artery thrombosis, renal vein thrombosis
What early vascular complications can follow renal transplant?
May involve donor vessels, recipient vessels or both
Renal artery thrombosis usually occurs early post transplant, but is uncommon (incidence around 1%), typically results in graft loss
- normally happens because of technical complication
- sudden cessation of urine output most common feature
- investigate with duplex scanning
- Rx = immediate surgical re-exploration, but graft most often lost by this point –> graft nephrectomy
Renal vein thrombosis not as common cf. arterial graft thrombosis
- discomfort at the graft site with swelling and loss of urine output is usual PC
- duplex scanning is implicated but graft loss is high
Chronic complications of transplantation
Loss of renal function - from immune and non immune mechanisms
- contributing factors: hypertension, ciclosporin nephrotoxicity, recurrent disease (esp focal segmental glomerulosclerosis, membranoproliferative nephropathy, and IgA nephropathy)
Hypertension - steroid use, ciclosporin induced vasoconstriction, renin secretion by native kidney or renal artery stenosis of transplanted organ
Hyperlipidaemia - esp steroid or ciclosporin therapy
Osteoporosis of femoral head - steroid use
Skin cancer
Post transplant lymphoproliferative disease
BK virus
What is post transplant lymphoproliferative disease?
A lymphoma like disease caused by EBV. Can occur early or late after transplantation, usually responds to a reduction in immunosuppression
BK virus
Polyoma virus that infects most children, can be reactivated in immunosuppressed patients causing renal impairment
- virus can be detectable in the urine and can also cause cytological changes in urinary cells
Biopsy may show polyoma virus associated nephropathy (PVAN) with inflammatory interstitial changes, and tubular nephropathy
Rx - reduction in immunosuppressoin
