Transplant Flashcards
What is the rationale for kidney transplant?
What factors are considered when evaluating someone for a kidney transplant?
- solid organ transplantation is a well established treatment for end stage organ failure
- (liver, kidney, pancreas, heart, lung, also SB)
- success due to advances in: surgical technique, peri-op care, imunosuppression, infectious diseases
- kidney transplant is more cost-effective than dialysis and improves patient survival and quality of life
General evaluation of potential recipients for organ transplant:
- evaluation by appropriate MDT incl surgeon & physician
- determine presence of comorbid disease
- exclude malignancy & systemic sepsis
- even after curative tx for malignancy, transplant shouldn’t usually be considered for at least 3yrs
- evaluate against organ-specific criteria for transplantation
- evluate need for any preparative surgery to facilitate transplantation
- ?parathyroidectomy
- only when there is intractable renal sepsis or v large polycystic kidneys that intrude into both iliac fossae is native nephrectomy required before transplantation
- optimise recipient condition before transplantation
- determine probable ability to cope psychologically w transplant & comply w immunosuppression
How is tissue rejection classified?
There are three classic histopathological definitions of allograft rejection that are based on not only the predominant mediator, but also the timing of the process.
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Hyper-acute rejection
- Mediated by pre-formed antibodies (ABO blood group incompatible or preformed anti-HLA antibodies)
- After revasc of the graft, antibodies bind immediately to the vasculature, activate the complement system and cause extensive intravascular thrombosis, interstitial haemorrhage and graft destruction within minutes-hours
- Prevented almost universally by lymphocytotoxic crossmatch
- Irreversable
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Acute rejection
- Occurs within first 6months
- Mediated by T-cells - may be cell-mediated, antibody mediated or both
- Reversable if promptly treated (most episodes of acute cellular rejection can be reversed by additional immunosuppressive therapy but antibody-mediated rejection more difficult to treat effectively; may require plasmaphoresis or immunoadsorption)
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Chronic rejection
- ?Term replaced by histological descriptors of long-term damage to transplanted organs
- Occurs after 6months; causes functional deterioration in graft –> complete graft failure after months or years (currently available immunosuppressive therapy has little effect in preventing this)
- most common cause of graft failure
- pathophys not well understood but alloantibodies play a role and non-immune factosr contribute to pathogenesis; risk factors are previous episodes of acute rejection (most important), poor HLA match, long cold ischaemia time, CMV infection, raised blood lipids, inadequate immunosuppression (incl poor compliance)
- characterised by myointimal proliferation in graft arteries leading to ischaemia adn fibrosis; in addition to vasculopathy there are organ-specific features of chronic graft rejection
- kidney: glomerular sclerosis & tubular atrophy
- pancreas: acinar loss & islet destruction
- heart: accelerated coronary artery disease
- liver: vanishing bile duct syndrome
- lungs: obliterative bronchiolitis
The Banff classification is a thorough and widely used method of categorising the type of rejection via terms regarding the driving immune-mediator as well as precise histological criteria for each organ.
How are immunosuppressive medications classified with regard to phase of treatment?
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Induction immunosuppression
- Used for initial conditioning of the hosts immune system
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Maintenance immunosuppression
- Used to prevent minimise rejection following induction
-
Rescue immunosuppression
- Used to reverse an acute rejection episode
- Anti-thymocyte antiglobulins, human, rabbit, or horse dervied antibodies against T cells.
Provide an overview regarding risk of malignant disease in transplant patients.
- The immune system plays a critical role in the identification and destruction of cancer; in particular cancer driven by viral infection
- There is a 10-fold increase in cancer risk in transplant recipients
- 40% of renal TPs get cancer within 20 years
- 25% of TP deaths after 10 years
- Skin cancer are the most common cause of morbidity and mortality
- More aggressive cf non-TP patients
- mostly SCC but BCC & melanoma also more common
- 50% TP pts get skin cancer within 20yrs transplant
- Virally mediated cancers also occur much more frequently
- HPV; Anal, Cervical, Vaginal SCC
- HBV and HCV; HCC
- HHV8; Kaposi sarcoma (300x increased risk but still v uncommon)
- EBV; Post Transplant Lymphoproliferative Disorder
- presents in a variety of ways incl infectious mononucleosis-type illness or oymphadenopathy, or w involvement of extranodal sites eg tonsils, GIT, lung, liver or transplanted organ
- occcurs in 1-3% of kidney & liver transplants, much higher incidence in children
- mortality up to 50%
- if identified early, reduction/cessation of immunosuppressive therapy may cause disease regression & cure; chemo often given and antiviral therapy, surgery and rad may also have a role in treating established disease
- other cancers:
- mild risk (RR2): colon, lung, prostate, gastric, oesophagus, pancreas, ovarian, breast
- mild risk (RR4): testes adn urinary bladder
- mod risk (RR5): melanoma, leukaemia, liver, gynae tumours
- mod-high risk (RR15): kidney
- high risk (RR>20): Kaposi’s sarcoma, PTLD, non-melanoma skin cancer
- aetiology multifactorial
- can be de novo, transmitted or reactivated with immunosuppression/recurrence of pre-existing malignancy
- a combo of impaired immune activity against viruses, impaired immune-surveillance of neoplastic cells, DNA damage and disruption of DNA repair mechanisms, and upregulation of cytokines that can promote tumour progression
- immmunosuppression - increased dose/intensity increases risk
- anti-T-cell treatment particularly increases risk of EBV-associated PTLD
- calcineurin inhibitors increase TGF-beta which ultimately stimulates tumour growth
- exposure to carcinogens
- UV shown to have effect both before & after transplant
- host factors
- genetics play a role
- co-existence of viral infections, EBV, HSV8 for example that may have been dormant
- strategies
- prevention
- avoid carcinogens - espec true for skin cancers & avoidance of UV radiation
- avoid excessive immunosuppression - dose response for all transplant pts & all immunosuppressive therapies
- avoid repeated exposure to depleting anti-lymphocytic antibodies
- screen all donors & recipients for cancer
- screen all donors & recipients for HSV8, EBV to minimise Kaposi’s and PTLD respectively
- if positive recipient, measure EBV titres & adjust immunosuppression if increasing
- early detection - screen recipients regularly for malignancy
- including skin check q6-12mo and good pt education
- if PTLD identified early, reduction/cessation of immunosuppressive therapy may cause disease regression & cure
- management
- prompt and aggressive management of malignancies - eg skin cancer progresses more rapidly if immunosuppressed
- reduce immunosuppression in PTLD
- consider conversion to mTOR inhibitor in Kaposi’s - been shown to induce complete regression
- prevention
Provide an overview regarding risk of infectious disease in transplant patients.
Transplantation medicine is constantly negotiating a balance of risk of rejection against risk of infection from immune-suppression.
- Infections are more common in the immediate post-operative period due to the mandatory immune suppression; early recognition and aggressive treatment is essential
- Donor-derived infections occur but are rare
- These may be missed in the pre-operative screen due to false negative tests, latency of onset, or lack of seropositivity
- CMV, HIV, Hep B, Hep C, TB, Trypanosoma cruzii, West nile virus, and rabies are candidate infections.
- Recipient-derived infections are much more common
- Reactivation of CMV, EBV, Herpes simplex, VZV, PCP, HIV, parasites, and fungi occur much more commonly than transferred infections.
- The risk of reactivation is highest in the first 6-12 weeks post transplant
- Prophylactic regimens may be used, for example CTMX for PCP.
- Bacterial infection - risk highest during first month
- similar to any pt undergoing major surgery - at risk in wound, resp tract, urinary tract - standard to give broad spec abx to cover periop period as prophylaxis against wound ix & poss bacterial contamination of donor organ
- if prev TB, given chemoprophylaxis for 6-12mo post transplant
- Viral infection - risk highest during first 6mo post transplant
- CMV = most common
- may be reactivation of latent infection or primary infection that can be transmitted by an organ from a CMV-pos donor
- w/o prophylaxis, usu presents at 4-8wks with high swinging fever, lethargy, leukopenia
- severity variable; clinical picture depends on organ system most affected; may present as pneumonia, GI disease, hepatitis, encephalitis, retinitis
- severe = potentially fatal
- prophyylaxis = antiviral agents; most common valganciclovir
- dx of active CMV = PCR to detect viral DNA in whole blood & by histo exam of biopsy
- tx = oral valganciclovir or IV ganciclovir
- HSV also common
- usu from reaction of latent infnection
- mucocutaneous lesions round mouth & genitalia
- topical acyclovir or if severe systemic antiviral therapy
- BK virus = important cause of renal graft dysfunction
- almost universal infection during childhood w latent infection in epithelium of urinary tract
- only effective tx = to reduce level of immunosuppression to allow natural immune mechanism to regain control of virus
- Herpes zoster virus common
- reactivation of latent varicella-zoster - systemic antivirals
- primary infection = otentially v serious but rare
- CMV = most common
- Fungal infection - usu within first 3mo, need early dx and aggressive tx
- pneumocystis jiroveci presents w resp sx
- dx on bronchoalveolar lavage or lung biopsy
- chemoprophylaxis highly effective, usu continued for up to 6mo after transplant
- others incl Candida or Aspergillus
- pneumocystis jiroveci presents w resp sx
What are the major groups of immunosuppressive medications?
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Corticosteroids
- Prevents transcription of NF-kß and downstream cytokines, and T-cell activity
- Also inhibits phospholipase A2 (AA cascade)
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Anti-proliferative agents
- Azathiprine and mycophenolate prevent lymphocyte proliferation by blocking purine metabolism/synthesis - mostly T-cell but also bone marrow etc.
- Side effects: leukopenia, thrombocytopenia, HTN, GI symptoms and in azathioprine, hepatotoxicity
-
Calcineurin inhibitors
- Prevent activation of IL-2, which is essential for T-call matruation.
- Calcineurin has a critical role in facilitating transcription of IL-2, the main T cell growth factor and other cytokines after T cell activation
- Cyclosporin and Tacrolimus
- Side effects: nephotoxicity (tacrolimus > cyclosporine), glucose intolerance, neurotoxicity (tacrolimus), hypertension and hyperlipidaemia, and in cyclosporin gingival hypertrophy and hirsutism
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Antibodies
- Anti-CD25
- blocks IL-2 receptor on T lymphocytes
- commonly given at time of transplant to augment effects of calcineurin blockade during early post-transplant period
- side-effects uncommon
- ALG
- polyclonal antibody - antilymphocyte globulin
- infusion reactions, leucopenia, thrombocytopenia
- anti-CD52
- monoclonal antibody against CD52 expressed on T cells & dendritic cells
- infusion reactions, autoimmune disease
- **ALG and anti-CD52 also widely used as more potent & alternative induction agents. These 3 cause temporary depletion in circulating lymphocytes that reduces rejection but may increase infection and malignancy
- as well as use as induction agents, may be used to treat acute rejection episodes that don’t respond to steroids
- anti-CD20 - rituximab
- monoclonal antibody, depletes B lymphocytes
- widely used in protocols to enable ABO & HLA incompatible renal transplants & also may be helpful in antibody-mediated acute rejection
- infusion reactions, pulmonary toxicity
- Monoclonal (OKT3) agents target CD3 antigen and lead to T-cell depletion
- Polyclonal (thymoglobulin) agents causes idespread T-cell inactivation
- Anti-CD25
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Other
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Target of rapamycin (mTOR) inhibitors
- sirolimus and everolimus
- inhibit IL-2 induced T-lymphocyte proliferation (sometimes switch from CNI to these to minimise CNI-induced nephrotoxicity)
- thrombocytopenia, hyperlipidaemia, pneumonitis, impaired wound healing
- CTLA-41g
- prevent full T cell activation (alternative to CNI)
- ?increased risk of PTLD
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Target of rapamycin (mTOR) inhibitors
What are the steps involved in donation after circulatory death?
- Consensus by treating team that withdrawal of intensive therapies (ETT, inotropes etc) not compatible with life
- Discussion with transplant centre about suitability of DCD
- Consensus by treating team that intensive therapies will be withdrawn
- Disucssion of DCD with the family
- Family agreement (coroner also if needed)
- Withdrawal of intensive therapies
- Determination of death
- Organ retrieval after death.
Describe the assessment of a live kidney donor
Comprehensive
Medical, Surgical, Psychosocial assessments including:
- 24 hour ambulatory BP monitoring
- 24 hour urine collect for creatinine
- Nuclear medicine estimation of GFR
- CTA for anatomy.
Traditionally most living-donor transplants were between genetically related individuals, but living-donor kidney tranpslants performed between genetically unrelated individuals also fare better than even well-matched deceased donor grafts
What are the risks of live kidney donation?
- Risks attendant to lap nephrectomy
- 3 in 1000 donors will go onto develop ESKD
- Usually due to systemic disease that affects both kidneys anyway so
- Only ~1 in 10,000 develop ESKD that they otherwise would not have developed.
- 1 in 5000 death
What are the mortality rates for live organ donation?
Kidney donor = 1/5000 (major complication rate <5%)
Left liver lobe donor = 1/1000
Right liver lobe donor = 1/300
(major complication rate for liver donor up to 15%, bile leak one of more common)
What are the side effects of corticosteroids?
- Diabetes
- Cataracts
- Hypertension
- Bruising
- Striae
- Cushingoid appearance (moon face; buffalo hump)
- Psychoses
- GI irritation
Classify the different types of transplant.
- Xenograft
- Transfer of organs from one species to another
- Allograft
- Transfer of organs between members of the same species
- Isograft
- Transfer of organs between identical twins
- Autograft
- Transfer of organs within the same individual
What are the factors affecting success of solid organ transplant?
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Donor factors
- live related > live unrelated > deceased donor
- Younger donor age
- Donor comorbidity affects success rates
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Recipient factors
- Previous rejection is very bad
- Length of time of dialysis is proportional to failure - if transplanted before starting dialysis, graft has 70% survival at 10yrs vs 50% at 10yrs
- Worse comorbidities confer worse prognosis
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Operative/technical factors
- Cold ischaemic time
- Warm ischaemic time
- Preservation method
- Reperfusion injury
- Compromised inflow/outflow
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Post-operative factors
- Immunosuppression
- Compliance
- Secondary malignancies
- Early recognition of rejection - salvage
What are the sources of transplanted organs?
- Deceased donor (multi-organ)
- After brain death (brain-stem dead, heart-beating donors)
- After cardiac death
- Live donor (single organ)
- Risk to donor!
- living donation limited to kidney and to much lesser extent, liver or lung lobe
- DBD provide most of organs for transplant for all other types, though DCD donors provide increasing numbers of kidneys, livers, pancreas glands & lungs
How is brain-death diagnosed?
Brain death occurs when severe brain injury causes irreversible loss of capacity for consciousness combined with irreversible loss of capacity of breathing. In many countries brain death is defined in terms of permanent functional death of the brainstem as neither consciousness nor spontaneous respiration is possible in absence of a functional brain stem.
The medicolegal definition of brain-death varies between states and countries within Australasia, however some principles remain constant;
- The diagnosis must be made by two specialist consultants, neither of whom are members of the transplant team
- The patient must be comatose requiring ventilator support and all reversible physiological causes must have been addressed
- ensure muscle relaxant agents & drugs with known CNS depressant effects aren’t contributing to clinical picture
- hypothermia, profound hypotension & metabolic or hormonal conditions as contributors excluded
- There must be a CNS catastrophe that is compatible with the patient’s state and of known aetiology
Examination must demonstrate absence of:
- cranial nerve reflexes - pupillary reflex, corneal reflex, pharyngeal (gag) and tracheal (cough) reflex, oculovestibular (caloric) reflex
- motor response - to painful stimuli applied to head/face and absence of motor response within cranial nerve distribution to adeqaute stimulation of any somatic area
- spontaneous respiration - disconnected from ventilator for 10 minutes after pre-ventilating with 100% oxygen
(Radiological diagnoses may be made with absent flow on brain CTA.)