55 TRANSPLANT
# 56 TRANSPLANT
Transplantation is heavily examined because it sits at the intersection of immunology, pharmacology and infection. Most MRCS questions hinge on three patterns: matching the timing of rejection to its mechanism, matching the timing of post-transplant infection to its pathogen, and recognising the physiology of the denervated heart.
π©ββοΈ If you remember one thing: Hyperacute = minutes (preformed antibodies). Acute = days to weeks (T cells). Chronic = months to years (fibrosis and vasculopathy).
Types of graft
The terminology defines the immunological relationship between donor and recipient, and therefore the rejection risk.
β‘ Autograft β‘ Donor and recipient are the same individual (e.g. saphenous vein in CABG, split-skin graft). No rejection.
β‘ Isograft (syngeneic graft) β‘ Between genetically identical individuals β monozygotic twins. No rejection, no immunosuppression required.
β‘ Allograft β‘ Between two genetically different individuals of the same species. This is the standard clinical scenario (cadaveric or living donor kidney). Requires HLA matching and lifelong immunosuppression.
β‘ Xenograft β‘ Between different species (e.g. porcine heart valve, experimental porcine kidneys). Hyperacute rejection is the major barrier.
Solid organ transplantation
Kidney
The most commonly transplanted solid organ. Tolerates cold ischaemia up to ~24 hours in preservation solution β the longest window of any organ. Living-donor grafts outperform deceased-donor grafts.
The graft is placed extraperitoneally in the iliac fossa, anastomosed to the external iliac vessels, ureter to bladder. Native kidneys are left in situ.
Matching priority: ABO first, then HLA. Of the HLA loci, HLA-DR > HLA-B > HLA-A by impact on graft survival. HLA-DR is Class II MHC.
Liver
Second most common. Cold ischaemia ~12 h. Immunologically privileged β HLA matching is not routine and hyperacute rejection is rare.
Pancreas
Usually transplanted simultaneously with a kidney (SPK) in type 1 diabetics with end-stage renal failure. Restores insulin independence.
Heart and lung
Short cold ischaemia: 4β6 h heart, 6β8 h lung. Both produce a denervated graft (see below).
Donor types
β‘ Living donor β‘ Best outcomes; kidney and segmental liver.
β‘ DBD β donation after brain death β‘ Heart-beating, perfused organs. Best graft quality.
β‘ DCD β donation after circulatory death β‘ Retrieved after cardiac arrest. More warm ischaemia β higher delayed graft function.
Brain death testing
UK criteria: two doctors, each β₯5 years' post-registration experience, independent of the transplant team and unrelated to the recipient. At least one must be a consultant. Testing is performed on two separate occasions.
Rejection
The single highest-yield table in this lesson.
| Feature | Hyperacute | Acute | Chronic |
|---|---|---|---|
| Onset | Minutes to hours | Days to weeks (up to 6 months) | Months to years |
| Mechanism | Preformed antibodies (anti-ABO or anti-HLA) | T-cell mediated (cellular); may have antibody component | Vascular intimal fibrosis, interstitial fibrosis, multifactorial |
| Trigger | ABO/HLA incompatibility, previous transfusion/pregnancy/transplant | HLA mismatch | Repeated subclinical injury, CNI toxicity, hypertension |
| Appearance | Graft turns dusky/cyanotic on table, swells, thromboses | Rising creatinine, tender graft, fever | Slow decline in function, proteinuria |
| Treatment | None β prevent by crossmatch. Graft must be removed | Pulsed steroids Β± anti-thymocyte globulin (ATG) | Poorly responsive; optimise risk factors |
π©ββοΈ The classic SBA stem is a kidney that turns dusky on reperfusion in theatre β that is hyperacute rejection from preformed antibodies, not surgical thrombosis. The crossmatch should have prevented it.
ββββββββββββββββββββββββββββββ
Immunosuppression
Two-stage strategy: heavy induction at transplant to blunt the initial T-cell response, then lifelong maintenance.
Induction agents
β‘ Basiliximab β‘ Monoclonal antibody against the IL-2 receptor (CD25) on activated T cells. Well-tolerated, no cytokine release.
β‘ Anti-thymocyte globulin (ATG) β‘ Polyclonal antibody that depletes T cells. Used for high-risk grafts and to treat steroid-resistant acute rejection.
Maintenance agents
| Class | Examples | Mechanism | Notable side effects |
|---|---|---|---|
| Calcineurin inhibitors (CNI) | Tacrolimus, ciclosporin | Block calcineurin β no IL-2 transcription β no T-cell activation | Nephrotoxicity (both), gum hypertrophy + hirsutism (ciclosporin), new-onset diabetes (tacrolimus), tremor, hypertension |
| Antimetabolites | Mycophenolate mofetil, azathioprine | Inhibit purine synthesis β block lymphocyte proliferation | Bone marrow suppression, GI upset. Azathioprine + allopurinol = dangerous interaction (xanthine oxidase blocked) |
| mTOR inhibitors | Sirolimus, everolimus | Block mTOR β arrest T-cell cycle | Poor wound healing, hyperlipidaemia, mouth ulcers |
| Corticosteroids | Prednisolone | Broad anti-inflammatory and lymphocyte effects | Diabetes, osteoporosis, weight gain, infection, Cushingoid features |
π©ββοΈ The two CNI side effects examiners love: ciclosporin β gum hypertrophy (think "C for Ciclosporin, C for Chubby gums"); tacrolimus β diabetes.
Post-transplant infections β the timeline
Pathogens follow a predictable schedule because immunosuppression and exposures change over the first year. This timeline is examined repeatedly.
| Period | Most likely pathogens | Notes |
|---|---|---|
| 0β1 month (early) | Conventional bacterial wound/line/UTI infections; HSV reactivation; Candida | Pathogens of any surgical patient β surgical-site, catheter, hospital flora |
| 1β6 months (middle) | CMV (commonest), Pneumocystis jirovecii (PCP), EBV, BK virus, Aspergillus | Peak opportunistic window; prophylaxis with valganciclovir (CMV) and co-trimoxazole (PCP) |
| >6 months (late) | Community-acquired organisms (influenza, Strep pneumoniae); EBV-driven PTLD; chronic viral disease | Patient is now back in the community on lower-dose immunosuppression |
π©ββοΈ Classic SBA: pneumonia at 3 months post-transplant not responding to antibiotics β CMV. Pneumonia at 18 months with lymphadenopathy or a mass β EBV (PTLD).
Malignancy after transplantation
Chronic immunosuppression is oncogenic, mainly through impaired immune surveillance of virally driven tumours.
β‘ Skin cancer β‘ The commonest post-transplant malignancy overall. SCC > BCC (the reverse of the general population), driven by HPV and UV. Counsel on sun protection.
β‘ Post-transplant lymphoproliferative disorder (PTLD) β‘ B-cell proliferation driven by EBV. Highest risk in the first year, particularly in EBV-naive recipients of EBV-positive grafts (paediatric transplants). Treat by reducing immunosuppression Β± rituximab.
β‘ Kaposi's sarcoma β‘ Driven by HHV-8.
β‘ Cervical and anogenital cancer (HPV) are also increased.
The denervated heart β a recurring exam favourite
A transplanted heart is completely denervated β both sympathetic and parasympathetic supply are severed and meaningful reinnervation rarely occurs.
β‘ Resting tachycardia (~90β100 bpm) because the vagal brake is absent.
β‘ No vagal response. Atropine and glycopyrrolate are useless β they block tone that does not exist.
β‘ Indirect sympathomimetics fail. Ephedrine needs intact nerve terminals to release noradrenaline.
β‘ Only direct-acting agents work β isoprenaline (Ξ²1 agonist), adrenaline, dobutamine.
β‘ Exercise cardiac output depends on preload (FrankβStarling) and circulating catecholamines β not on neural drive. Increased venous return stretches the ventricle and stroke volume rises; the rate response is slow.
π©ββοΈ If a transplanted heart goes bradycardic on the table, reach for isoprenaline β not atropine.
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Test yourself
A transplanted kidney turns dusky almost immediately after reperfusion in theatre. What is the most likely diagnosis?
- ((ABO incompatibility (hyperacute rejection)::βοΈ Preformed anti-ABO antibodies trigger immediate complement activation and graft thrombosis.))
- ((Acute T-cell mediated rejection::Days to weeks, not intraoperative; rising creatinine, not table-side cyanosis.))
- ((Chronic allograft nephropathy::Slow decline over months to years with fibrosis.))
- ((Acute antibody-mediated rejection::Develops days to weeks post-op, not within minutes.))
- ((Surgical vascular thrombosis::Possible but would not give the classic immediate immunological pattern; crossmatch failure is the prime suspect.))
π©ββοΈ The crossmatch should have prevented this β once it happens, the graft must be removed.
Intraoperatively a graft swells, becomes cyanotic and thromboses. What is the most likely cause?
- ((ABO incompatibility::βοΈ Preformed antibodies cause hyperacute rejection within minutes of reperfusion.))
- ((HLA mismatch::Drives acute rejection over days to weeks, not on the table.))
- ((Ischaemia-reperfusion injury::Causes dysfunction but not the swellingβcyanosisβthrombosis triad.))
- ((Surgical technical error::Would not produce an immunological pattern across the whole graft.))
A 49-year-old woman is awaiting renal transplant. Aside from ABO, which is the most important antigen match?
- ((HLA-A::Important but lower impact on graft survival than DR.))
- ((HLA-B::Second in importance after HLA-DR.))
- ((HLA-DR::βοΈ Class II MHC; the single most influential locus for graft survival.))
- ((HLA-C::Minor role in solid organ matching.))
- ((Minor histocompatibility antigens::Contribute to chronic rejection but far less important than HLA-DR.))
π©ββοΈ Rank of importance: DR > B > A.
A patient develops pneumonia 3 months after renal transplant, unresponsive to antibiotics. Most likely pathogen?
- ((Cytomegalovirus (CMV)::βοΈ Commonest opportunistic infection 1β6 months post-transplant; treat with ganciclovir/valganciclovir.))
- ((Pneumocystis jirovecii::Possible, but most patients are on co-trimoxazole prophylaxis.))
- ((Aspergillus fumigatus::More typical in lung transplants or profound neutropenia.))
- ((Staphylococcus aureus::Bacterial β would have responded to antibiotics.))
- ((Mycobacterium tuberculosis::Possible but less common than CMV in this window.))
A heart transplant recipient 20 days post-op presents with pneumonia unresponsive to treatment. Most likely pathogen?
- ((Cytomegalovirus (CMV)::βοΈ Peak risk window 1β6 months; classic "antibiotic-refractory" interstitial pneumonia in a transplant recipient.))
- ((Streptococcus pneumoniae::Bacterial β would respond to standard antibiotics.))
- ((Pseudomonas aeruginosa::Associated with ventilator-acquired or nosocomial pneumonia, not the typical post-transplant scenario.))
- ((Influenza virus::Possible but less characteristic of this stem.))
An 18-month post-renal transplant patient presents with infection. Most likely organism?
- ((Epstein-Barr virus (EBV)::βοΈ Late post-transplant infection; drives post-transplant lymphoproliferative disorder (PTLD).))
- ((Cytomegalovirus (CMV)::Typically 1β6 months, not >1 year.))
- ((Human T-cell leukaemia virus (HTLV)::Not a recognised opportunistic post-transplant pathogen.))
- ((Herpes simplex virus (HSV)::Reactivates in the first month post-transplant.))
π©ββοΈ Late infection + lymphadenopathy or mass = think EBV / PTLD.
During cholecystectomy in a heart transplant recipient, extreme bradycardia occurs. Best management?
- ((Atropine::Blocks vagal tone β but the denervated heart has none.))
- ((Glycopyrrolate::Anticholinergic β same failure mode as atropine in this patient.))
- ((Ephedrine::Indirect sympathomimetic; needs intact nerve terminals to release noradrenaline.))
- ((Isoprenaline::βοΈ Direct Ξ²1 agonist; works on cardiac receptors without needing innervation.))
π©ββοΈ Denervated heart = only direct-acting agents work.
A 57-year-old heart transplant recipient exercises in cardiac rehab. What is the main mechanism for increasing cardiac output?
- ((Decreased negative intrathoracic pressure::Would reduce venous return, not increase output.))
- ((Decreased venous tone::Causes venous pooling and reduced preload.))
- ((Decreased ventricular compliance::Impairs filling β reduces stroke volume.))
- ((Increased atrial filling (FrankβStarling)::βοΈ Preload-driven rise in stroke volume; the denervated heart's main response to exercise.))
- ((Increased sympathetic nerve stimulation::Impossible in the early years post-transplant β the heart is denervated.))
π©ββοΈ Output rises mainly via preload and slowly via circulating catecholamines, not neural drive.
Which immunosuppressant is most strongly associated with gum hypertrophy?
- ((Ciclosporin::βοΈ Classic side effect β gum hypertrophy and hirsutism; switch to tacrolimus if troublesome.))
- ((Tacrolimus::Same class (CNI) but causes new-onset diabetes, tremor, alopecia β not gum hypertrophy.))
- ((Mycophenolate mofetil::Causes GI upset and marrow suppression.))
- ((Azathioprine::Marrow suppression; dangerous interaction with allopurinol.))
- ((Sirolimus::Poor wound healing, hyperlipidaemia, mouth ulcers.))
Two doctors are asked to certify brainstem death prior to organ retrieval. Which statement is correct?
- ((Both must have at least 5 years' post-registration experience and be independent of the transplant team::βοΈ UK criteria; at least one must be a consultant; testing repeated on two occasions.))
- ((One doctor is sufficient if a consultant::Two are mandatory under UK code of practice.))
- ((The transplant surgeon may perform one of the assessments::Explicitly excluded to avoid conflict of interest.))
- ((Testing is performed once only::Two sets of tests are required.))
Revision summary
- Graft types: autograft (self), isograft (identical twin), allograft (same species), xenograft (different species).
- Kidney transplant: most common; ABO first, then HLA-DR > B > A; cold ischaemia ~24 h; placed extraperitoneally in iliac fossa.
- Rejection β onset / mechanism: Hyperacute (mins, preformed Ab, prevent with crossmatch); Acute (daysβweeks, T-cell, treat with steroids/ATG); Chronic (monthsβyears, fibrosis, poorly responsive).
- Induction: basiliximab (anti-IL-2R), ATG.
- Maintenance: CNI (tacrolimus/ciclosporin), antimetabolite (MMF/azathioprine), mTOR (sirolimus), steroids.
- Key side effects: ciclosporin β gum hypertrophy; tacrolimus β diabetes; azathioprine β marrow suppression (and avoid allopurinol); CNIs β nephrotoxicity.
- Infection timeline: <1 m bacterial/HSV; 1β6 m CMV, PCP, EBV; >6 m community-acquired and late EBV/PTLD.
- Malignancy: skin SCC > BCC, PTLD (EBV), Kaposi's (HHV-8).
- Denervated heart: resting tachycardia, no vagal response, only direct-acting agents work (isoprenaline), exercise output relies on FrankβStarling and circulating catecholamines.
- Brain death: two doctors, β₯5 years' experience, independent of recipient and transplant team, two sets of tests.