TRANSPLANTATION - Comprehensive Exam Notes
1. APNEA TEST FOR DIAGNOSING BRAIN DEATH [5 marks]
Definition of Brain Death
Brain death is defined as the irreversible cessation of all functions of the entire brain, including the brainstem. It is a clinical diagnosis and represents legal death in most jurisdictions.
Prerequisites Before Apnea Testing
The following conditions MUST be excluded first (Royal Colleges / Harvard criteria):
- Depressant drugs - narcotics, hypnotics, benzodiazepines must have been excluded
- Primary hypothermia must be excluded (core temperature >36°C)
- Metabolic/endocrine disturbances - no profound abnormality of electrolytes, acid-base, blood glucose
- Neuromuscular blocking drugs - excluded by eliciting spinal reflexes or nerve stimulator
- The condition must be due to irremediable structural brain damage
Clinical Tests for Brainstem Death (all must be absent)
- Pupils fixed and non-reactive to light
- No corneal reflex
- Vestibulo-ocular reflexes absent (no eye movement with 20 mL ice-cold water in each external meatus - caloric test)
- No motor response within cranial nerve distribution to somatic stimulation
- No gag reflex or response to bronchial suction
- No respiratory effort on ventilator disconnect = the Apnea Test
Apnea Test - Step by Step
- Pre-oxygenate with 100% O2 for 10 minutes
- Ensure baseline PaCO2 is 40-45 mmHg (normocarbia); adjust ventilator to target PaCO2 of 5.3-6.0 kPa (40-45 mmHg) as starting point
- Disconnect ventilator - deliver 100% O2 via catheter at 6 L/min to prevent hypoxia
- Observe closely for any respiratory effort (diaphragmatic or chest movements) for 8-10 minutes
- Draw ABG at end of test
- Apnea confirmed if no respiratory effort with PaCO2 ≥ 6.7 kPa (50 mmHg) - above the threshold that should stimulate respiration
- CO2 rises at ~0.3-0.4 kPa/min (2-3 mmHg/min) during apnea
Stopping the Test
- Stop if cardiovascular instability occurs (SpO2 <85%, arrhythmia, hypotension)
- In such cases, use ancillary/confirmatory tests
Ancillary Confirmatory Tests (optional)
- EEG: isoelectric (electrocerebral silence)
- Radionuclide brain scanning: absence of cerebral blood flow
- Cerebral angiography: no intracranial filling
- Transcranial Doppler: absence of flow
Who Performs and How Many Times
- Two doctors (consultants) must independently confirm brain death
- At least one must be a neurologist/neurosurgeon; neither should be part of a transplant team
- Tests repeated after an appropriate interval
Sources: Pye's Surgical Handicraft; Harrison's Principles of Internal Medicine 22E; Bradley and Daroff's Neurology; Plum and Posner's Coma
2. TYPES OF ORGAN TRANSPLANT
By Source of Graft (Type of Donor)
| Type | Definition | Example |
|---|
| Autograft | Tissue transplanted within same individual | Skin graft, vein graft (CABG) |
| Isograft / Syngraft | Transplant between genetically identical individuals | Identical twin transplant |
| Allograft | Transplant between genetically non-identical members of same species | Most organ transplants |
| Xenograft | Transplant between different species | Pig valve, pig kidney (experimental) |
By Type of Donor
- Living donor: Related (living related donor - LRD) or unrelated (living unrelated donor - LURD)
- Deceased donor (Brain Death Donor / DBD): Donation after Brain Death
- Donation after Circulatory Death (DCD): formerly called non-heart-beating donor
By Anatomical Position of Graft
- Orthotopic: Graft placed in same anatomical site (liver transplant - native liver removed and replaced)
- Heterotopic: Graft placed in a different site (kidney transplant in iliac fossa)
- Auxiliary: Native organ kept, graft added alongside (auxiliary liver transplant)
By Organ
Kidney, liver, heart, lung, pancreas, small intestine, combined organs (e.g. heart-lung, liver-kidney), composite tissue allografts (hand, face), and islet cell transplantation.
3. WARM AND COLD ISCHEMIC TIME [5 marks]
Between Donor Nephrectomy and Reperfusion - Three Time Periods
(A) First Warm Ischemia Time (Donor WIT / Extraction Time)
- Period from aortic cross-clamping or cardiac arrest to establishment of cold preservation
- This is the most damaging period
- For DBD donors: begins at cross-clamp
- For DCD donors: begins at cardiac arrest (withdrawal of life support)
- Acceptable: < 30 minutes for DBD; < 15-20 minutes for DCD kidneys
(B) Cold Ischemia Time (CIT)
- Period the organ spends in cold preservation solution (0-4°C); sandwiched between the two warm ischemia periods
- Begins when cold flush is established (organ flushed with cold preservative - e.g., UW solution, HTK solution)
- Ends when organ is removed from cold storage
- Organs slow down all metabolic activity at low temperature (reducing but not eliminating ischemic injury)
- Acceptable CIT limits (approximate):
- Kidney: up to 24-36 hours (optimal <12 hours)
- Liver: 8-12 hours (optimal <8 hours; >8 hours is associated with decreased graft survival)
- Heart: 4-6 hours
- Lung: 6-8 hours
- Pancreas: 12-18 hours
(C) Second Warm Ischemia Time (Graft WIT / Implantation WIT)
- Period from removal of organ from cold storage to reperfusion in the recipient
- Begins when organ removed from ice at back-table (or disconnected from machine perfusion)
- Ends when arterial clamp released and reperfusion occurs
- Implantation WIT in kidney transplant should be < 30-45 minutes
Consequences of Prolonged Ischemia
- Delayed Graft Function (DGF): need for dialysis in first post-transplant week - commonest consequence of prolonged ischemia
- Primary Non-Function (PNF): irreversible graft non-function
- Ischemia-reperfusion injury: cell swelling, free radical generation, complement activation
- Increased risk of acute rejection (due to increased immunogenicity)
- Reduced long-term graft survival
Organ Preservation Solutions
- University of Wisconsin (UW) Solution: gold standard - contains lactobionate, raffinose, hydroxyethyl starch
- Histidine-Tryptophan-Ketoglutarate (HTK): low viscosity, used for flush
- Custodiol: another HTK-based solution
Sources: Brenner and Rector's The Kidney; Miller's Anesthesia; Sabiston Textbook of Surgery
4. RENAL TRANSPLANTATION - Indications, Patient Selection, Donor and Recipient Surgery [3+2+5]
Indications for Renal Transplantation
End-stage renal disease (ESRD) from any cause, GFR <15 mL/min/1.73m2
Common causes:
- Diabetic nephropathy (most common in Western countries)
- Hypertensive nephrosclerosis
- Chronic glomerulonephritis (IgA nephropathy, FSGS, membranous GN)
- Polycystic kidney disease (ADPKD)
- Reflux nephropathy / chronic pyelonephritis
- Lupus nephritis / SLE
- Alport syndrome
- Renal tubular disorders
Pre-emptive transplant (before dialysis) is preferred when possible.
Absolute Contraindications
- Active malignancy (except non-melanoma skin cancer, adequately treated cancer with appropriate disease-free interval)
- Active untreated infection (tuberculosis, HIV not well controlled)
- Active substance abuse
- Severe uncontrollable psychiatric disease
- Irreversible major organ dysfunction (severe cardiac disease, severe COPD)
- Patient non-compliance
- Short life expectancy (<1-2 years from non-renal cause)
- Active vasculitis or recent MI (relative)
Patient Selection / Pre-Transplant Evaluation
Medical evaluation:
- Full history, examination
- Cardiac: ECG, echocardiography, stress testing (especially diabetics)
- Pulmonary: PFTs if indicated
- Malignancy screening: colonoscopy, mammography, PAP smear, PSA
- Infection screening: HIV, hepatitis B/C, CMV, EBV, TB (Mantoux), syphilis
- Urological: bladder capacity and voiding dynamics (urodynamics), voiding cystourethrogram if lower urinary tract abnormality suspected; ensure bladder is adequate for anastomosis
Immunological evaluation:
- Blood group (ABO compatibility mandatory)
- HLA typing (A, B, DR)
- Panel Reactive Antibody (PRA) - measures pre-formed antibodies
- Cross-match (donor-specific - mix recipient serum with donor lymphocytes)
- A negative cross-match is essential before transplant
Surgical evaluation:
- Peripheral vascular assessment (iliac vessels - Doppler, CT angiography)
- Exclude severe aorto-iliac disease that would preclude anastomosis
Surgery - Living Donor Nephrectomy
Laparoscopic donor nephrectomy is now the standard approach (hand-assisted laparoscopic or pure laparoscopic/robotic):
- Left kidney preferred (longer renal vein) unless right kidney needed for special reasons
- Hand-port in iliac fossa; ports in flank
- Vascular control: renal artery and vein clipped; ureter divided with surrounding periureteral fat preserved (to protect blood supply)
- Kidney extracted intact, immediately flushed with cold UW or HTK solution on back-table
- Donor stays one night; low morbidity
Open donor nephrectomy (flank/loin incision) - older approach, now rarely used.
Surgery - Recipient (Heterotopic Renal Transplant)
Position: Kidney placed in the right or left iliac fossa (right preferred - iliac vein is longer and more accessible)
Incision: Gibson's (curvilinear) iliac fossa incision (retroperitoneal approach)
Steps:
- Expose external iliac artery and vein (retroperitoneal dissection)
- Venous anastomosis first: End-to-side anastomosis of renal vein to external iliac vein (or IVC if needed)
- Arterial anastomosis: End-to-side anastomosis of renal artery (on Carrel patch if deceased donor) to external iliac artery; or end-to-end to internal iliac artery
- Reperfusion: Release clamps - kidney reperfuses and usually turns pink immediately; brisk urine output expected
- Ureteric anastomosis (ureteroneocystostomy): Modified Lich-Gregoir extravesical technique; double-J ureteric stent placed routinely
- Native kidneys are NOT removed unless they cause problems (hypertension, recurrent UTI, polycythemia)
- Wound closure in layers
Post-operative monitoring:
- Hourly urine output
- CVP monitoring (keep well hydrated)
- Renal function (serum creatinine, urea) - should halve each day in well-functioning graft
- Doppler ultrasound on day 1 (assess blood flow)
- Immunosuppression: calcineurin inhibitor (tacrolimus/cyclosporine) + mycophenolate + prednisolone ± induction agent
Sources: Sabiston Textbook of Surgery; Brenner and Rector's The Kidney
5. LIVER TRANSPLANTATION - Indications, Contraindications, Extended Donor Criteria [3+3+4]
Indications for Liver Transplantation
A. Chronic End-Stage Liver Disease (most common)
- Noncholestatic cirrhosis:
- Alcoholic liver disease (~39% of all listings in USA) - requires sobriety criterion
- Metabolic-associated steatohepatitis (MASH/NASH cirrhosis) - growing rapidly
- Hepatitis C cirrhosis (reduced by DAA therapy, still listed)
- Hepatitis B cirrhosis
- Autoimmune hepatitis cirrhosis
- Cryptogenic cirrhosis
- Drug-induced cirrhosis
- Cholestatic cirrhosis:
- Primary biliary cholangitis (PBC)
- Primary sclerosing cholangitis (PSC) - complications of portal hypertension, recurrent cholangitis
- Caroli disease, biliary atresia (pediatric)
- Choledochal cyst
B. Acute Liver Failure (ALF)
- Acetaminophen overdose (most common cause of ALF)
- Hepatitis B (fulminant)
- Drug-induced (non-acetaminophen)
- Wilson disease (acute decompensation)
- Autoimmune hepatitis
- Indeterminate ALF
- King's College Criteria used for listing:
- Acetaminophen: arterial pH <7.3 after resuscitation; OR all three: PT >100 seconds + creatinine >300 umol/L + grade III-IV encephalopathy
- Non-acetaminophen: PT >100 seconds alone; OR any three of: age <10 or >40 years, etiology (non-A non-B hepatitis, drug), jaundice >7 days before encephalopathy, PT >50 seconds, bilirubin >300 umol/L
C. Hepatocellular Carcinoma (HCC) - ~16% of US transplants
- Milan Criteria (standard): 1 lesion ≤5 cm; or up to 3 lesions each ≤3 cm; no vascular invasion; no extrahepatic disease
- UCSF Criteria (extended): 1 lesion ≤6.5 cm; or up to 3 lesions largest ≤4.5 cm, total ≤8 cm
- Neoadjuvant therapy (TACE, ablation) used as bridge to transplant
D. Metabolic/Genetic Liver Diseases
- Wilson disease
- Hemochromatosis
- Alpha-1 antitrypsin deficiency
- Glycogen storage disease
- Familial amyloid polyneuropathy (neurological disease, liver is source of abnormal TTR protein)
- Primary hyperoxaluria type 1
E. Other
- Hepatopulmonary syndrome (exception points for MELD)
- Portopulmonary hypertension (if mean PAP <35 mmHg with treatment)
- Budd-Chiari syndrome
- Hilar cholangiocarcinoma (selected cases, with neoadjuvant chemoradiation)
Contraindications to Liver Transplantation
Absolute Contraindications:
- Active extrahepatic malignancy (cancer outside liver not amenable to curative treatment)
- Cholangiocarcinoma outside accepted protocols (intrahepatic CCA, perihilar CCA without neoadjuvant protocol)
- Active uncontrolled sepsis or systemic infection
- Active substance abuse (active alcohol/drug use without commitment to sobriety)
- Severe cardiopulmonary disease incompatible with surgery (severe COPD, severe irreversible pulmonary hypertension mPAP >50 mmHg)
- AIDS (not HIV alone - AIDS-defining illness with poor prognosis)
- Anatomical impossibility of transplant (complete portal/hepatic vein thrombosis without options for reconstruction)
- Non-compliance/inability to comply with post-transplant management
Relative Contraindications:
- Age >70 years (case by case)
- Portal vein thrombosis (technical challenge, not absolute)
- Prior complex hepatobiliary surgery
- Obesity (BMI >40)
- Renal failure requiring dialysis (combined liver-kidney transplant now considered)
- HIV infection (HIV alone - now successfully transplanted in many centers)
- HCC outside Milan criteria (can be bridged, downsized)
- Psychiatric illness (if treatable)
- Marginal cardiac/pulmonary reserve
- Portopulmonary hypertension if mPAP 35-50 mmHg (medically manage first)
Extended Donor Criteria (EDC) for Liver Transplant
The gap between organ supply and demand has led to use of marginal/extended criteria donors (ECD). These carry higher risk of primary non-function and graft dysfunction but can be acceptable in selected recipients.
Standard Criteria Donors (SCD) vs Extended Criteria:
| Parameter | Standard | Extended |
|---|
| Age | <50 years | >60 years (elderly donors) |
| BMI | <30 | >30 (fatty liver) |
| ICU stay | <5 days | Prolonged |
| Hemodynamic stability | Stable | Unstable, high-dose vasopressors |
| Na | <155 | >155 mmol/L (hypernatremia) |
| AST/ALT | Normal | Elevated (>3x normal) |
| Bilirubin | Normal | Elevated |
| Steatosis on biopsy | <10% | >30% (macrovesicular) |
| DCD | No | Yes (donation after circulatory death) |
| Split liver | No | Yes |
| CIT | <8 hours | >12 hours |
Specific ECD criteria:
- Age > 60-65 years: Higher rates of PNF and initial poor function; acceptable in stable non-urgent recipients
- Donation after Circulatory Death (DCD): Additional warm ischemia time incurred; higher rates of ischemic cholangiopathy ("biliary cast syndrome"), PNF, and DGF; used selectively
- Macrovesicular steatosis:
- <30%: acceptable
- 30-60%: relative contraindication, selective use
-
60%: near-absolute contraindication (high PNF risk); biopsy assessment mandatory
- Prolonged cold ischemia time (>12 hours): Avoid in DCD, elderly, or fatty livers
- Hypernatremia (Na >155 mmol/L): Correct before procurement; associated with worse outcome
- Split liver grafts: Left lateral segment (segments II/III) for pediatric recipient; right lobe (segments V-VIII) for adult; requires expert hepatobiliary team
- Living donor liver transplant (LDLT): Right lobe (65% of liver volume) for adult-to-adult; requires donor remnant >30% estimated liver volume; donor risk of major complications 0.5%, mortality 0.1-0.5%
- Hepatitis C positive donor: Previously contraindicated; now successfully transplanted with post-transplant DAA therapy
- Hepatitis B core antibody positive (anti-HBc+): Acceptable with prophylaxis (HBIG + antiviral); risk of de novo HBV in recipient
- Marginal hemodynamics: Liver from donor with cardiac arrest history or prolonged hypotension - assess by functional tests, perfusion
MELD Score: Used to prioritize recipients. MELD = 10 × [0.957 × ln(creatinine) + 0.378 × ln(bilirubin) + 1.120 × ln(INR)] + 6.43. Patients with MELD ≥15 benefit from transplant (survival benefit). Status 1A = fulminant hepatic failure, highest priority.
Sources: Sabiston Textbook of Surgery; Current Surgical Therapy 14e; Yamada's Gastroenterology
6. GRAFT VERSUS HOST DISEASE (GvHD) [5 marks]
Definition
GvHD occurs when immunocompetent donor T lymphocytes (in the graft) recognize and mount an immune attack against host/recipient tissues. It is the REVERSE of rejection (where the host attacks the graft).
Conditions Required (Billingham's Criteria, 1966)
- Graft must contain immunologically competent cells (T lymphocytes)
- Recipient must be immunologically unable to reject the graft (immunocompromised)
- Recipient must express antigens absent from the donor (HLA mismatch)
Occurs in
- Bone marrow / hematopoietic stem cell transplant (HSCT) - most common and important
- Transfusion of non-irradiated blood products to immunocompromised patients
- Solid organ transplants containing significant lymphoid tissue (liver, small bowel)
- Thymus transplantation
Classification
Acute GvHD (within 100 days of transplant)
- Target organs: Skin, liver, gastrointestinal tract
- Clinical features:
- Skin: maculopapular rash (palms, soles, ears), erythroderma, blistering
- GI: watery/bloody diarrhea (>1 L/day), nausea, vomiting, abdominal cramping
- Liver: cholestatic jaundice, elevated bilirubin and alkaline phosphatase
Grading (Glucksberg Criteria):
- Grade I: Skin only, mild
- Grade II: Skin + mild liver/gut involvement
- Grade III: Severe skin + moderate gut/liver
- Grade IV: Life-threatening, severe multiorgan
Chronic GvHD (after 100 days)
- Resembles autoimmune disorders (Sjogren syndrome, scleroderma, lichen planus)
- Organs: Skin (lichenoid changes, sclerosis), eyes (keratoconjunctivitis sicca), mouth (sicca syndrome, ulceration), liver (cholestasis), lungs (bronchiolitis obliterans), musculoskeletal (fasciitis, myositis)
- Can occur de novo or evolve from acute GvHD
Pathophysiology
- Donor T cells recognize recipient MHC + peptides via direct or indirect allorecognition
- IL-2, IFN-gamma, TNF-alpha drive inflammatory cascade
- Cytokine storm damages epithelial targets
Prevention
- HLA-matched donor selection (10/10 HLA match)
- T-cell depletion of graft (ex vivo purging)
- Immunosuppressive prophylaxis: Methotrexate + cyclosporine (or tacrolimus); mycophenolate
- Irradiation of blood products (to prevent transfusion-associated GvHD)
Treatment
- Acute GvHD: High-dose methylprednisolone (1-2 mg/kg/day) is first-line; second-line: anti-TNF (infliximab), extracorporeal photopheresis, ruxolitinib (JAK inhibitor - now approved)
- Chronic GvHD: Prolonged immunosuppression (steroids ± sirolimus); supportive care; ruxolitinib for steroid-refractory cGvHD
Sources: Sabiston Textbook of Surgery; standard hematology-transplant references
7. GRAFT REJECTION - Types and Immunological Basis [5+5 marks]
Immunological Basis of Allograft Rejection
Key concept: The transplanted organ carries donor MHC (HLA) antigens that the recipient immune system does not recognize as "self."
Two Pathways of T-cell Allorecognition:
-
Direct pathway: Recipient T cells recognize intact donor MHC on donor APCs (dendritic cells)
- Major mechanism for acute rejection
- Very potent; many T-cell clones involved
-
Indirect pathway: Recipient T cells recognize processed donor peptides presented on SELF MHC by recipient APCs
- More important in chronic rejection
- Slower, more sustained
3-Signal Model of T-cell Activation:
- Signal 1: TCR + Antigen (MHC-peptide) - recognized by tacrolimus/cyclosporine
- Signal 2: Costimulatory signal (B7-CD28 interaction) - recognized by belatacept (CTLA4-Ig)
- Signal 3: Cytokine-driven proliferation (IL-2) - recognized by mTOR inhibitors (sirolimus, everolimus) and anti-IL-2R (basiliximab)
B cells and Antibodies:
- B cells produce donor-specific antibodies (DSA) against HLA antigens
- Antibody-mediated rejection (AMR) is increasingly recognized as distinct entity
- Complement activation (C4d deposition) is marker of AMR
Types of Graft Rejection
| Type | Time | Mechanism | Clinical | Treatment |
|---|
| Hyperacute | Minutes to hours after reperfusion | Pre-formed anti-donor antibodies (ABO mismatch or pre-existing HLA antibodies) activate complement; type III hypersensitivity | Graft immediately turns blue/flaccid, no urine; diagnosed on table | Irreversible - graft must be removed; prevented by cross-match |
| Accelerated acute | 2-5 days | Sensitized T cells (prior sensitization) | Rapid graft swelling, oliguria, fever, pain | High-dose steroids; often graft loss |
| Acute | Days to weeks (most common 1st week to 3 months) | Cell-mediated (T-cell CD4/CD8); also antibody-mediated | Rising creatinine, fever, graft tenderness, oliguria; diagnosed on biopsy | Pulse methylprednisolone (500 mg IV × 3 days); ATG for steroid-resistant; IVIG + plasmapheresis for AMR |
| Chronic | Months to years | Chronic fibrosis, arteriopathy; indirect T-cell pathway + antibody-mediated | Gradual decline in graft function; proteinuria; biopsy shows interstitial fibrosis, tubular atrophy, arterial intimal hyperplasia | Optimize immunosuppression; no reliable treatment; leads to graft loss |
Biopsy Banff Classification is used for standardized grading of rejection.
Acute rejection Banff grades:
- Grade I: Tubulitis ± interstitial infiltrate
- Grade II: Arteritis (intimal)
- Grade III: Transmural arteritis/fibrinoid necrosis
8. IMMUNOSUPPRESSION IN TRANSPLANTATION [5 marks]
Goals
- Prevent rejection
- Minimize drug toxicity
- Avoid over-immunosuppression (infection, malignancy)
Classification and Drugs
A. Induction Agents (peri-operative)
- Anti-thymocyte globulin (ATG, Thymoglobulin): Polyclonal antibody depleting T cells; potent, non-specific; risk = cytokine release syndrome, over-immunosuppression
- Basiliximab (Simulect): Monoclonal anti-IL-2 receptor (CD25) antibody; blocks T-cell proliferation; less immunosuppressive; fewer side effects
- Alemtuzumab (Campath): Anti-CD52; depletes all lymphocytes; very potent
B. Maintenance Immunosuppression (triple therapy standard)
1. Calcineurin Inhibitors (CNI) - Backbone
- Cyclosporine: Binds cyclophilin → inhibits calcineurin → blocks IL-2 gene transcription → prevents T-cell activation. Side effects: nephrotoxicity (dose-dependent), hypertension, hirsutism, gingival hyperplasia, neurotoxicity, PTDM (post-transplant diabetes mellitus). Narrow therapeutic window; trough levels monitored.
- Tacrolimus (FK506): Binds FKBP12 → same mechanism; 100x more potent. Preferred over cyclosporine (>90% liver transplants). Side effects: nephrotoxicity, neurotoxicity, PTDM (more than CSA), alopecia, GI upset. No gingival hyperplasia/hirsutism.
2. Antiproliferative Agents
- Mycophenolate Mofetil (MMF): Inhibits inosine monophosphate dehydrogenase → blocks de novo purine synthesis → prevents lymphocyte proliferation. Side effects: GI (diarrhea, nausea), leukopenia, teratogenic.
- Azathioprine (older, still used): Pro-drug of 6-mercaptopurine; inhibits purine synthesis. Side effects: myelosuppression, hepatotoxicity.
3. mTOR Inhibitors
- Sirolimus (Rapamycin): Binds FKBP12 → inhibits mTOR → blocks IL-2-driven lymphocyte proliferation (Signal 3). Side effects: hyperlipidemia, impaired wound healing, proteinuria, interstitial pneumonitis. CNI-sparing. Anti-tumor properties useful in HCC recipients.
- Everolimus: Similar to sirolimus; shorter half-life.
4. Corticosteroids
- Prednisolone/Methylprednisolone: Inhibit cytokine gene transcription (IL-1, IL-2, TNF-alpha), reduce T-cell migration, anti-inflammatory. Used for maintenance and treatment of acute rejection (pulse therapy). Side effects: DM, hypertension, osteoporosis, Cushingoid, cataracts, peptic ulcer, growth retardation in children.
5. Costimulation Blockade
- Belatacept: CTLA4-Ig fusion protein; blocks B7-CD28 signal 2; IV monthly; approved for kidney transplant; better renal function but higher acute rejection risk vs CNIs.
C. Treatment of Acute Rejection
- Cellular: IV methylprednisolone pulse (3 days); ATG for steroid-resistant
- Antibody-mediated: Plasmapheresis + IVIG + rituximab (anti-CD20) + eculizumab
Triple Therapy Standard Regimen
Tacrolimus + Mycophenolate + Prednisolone (± induction agent)
9. DONATION AFTER CIRCULATORY DEATH (DCD) [5 marks]
Definition
DCD donors are individuals in whom death is declared based on cessation of circulatory function (cardiac arrest) rather than brain death. Formerly called "non-heart-beating donors."
Maastricht Classification
| Category | Description |
|---|
| I | Dead on arrival (uncontrolled) |
| II | Unsuccessful resuscitation (uncontrolled) |
| III | Awaiting cardiac arrest after withdrawal of life support (controlled) - MOST COMMON |
| IV | Cardiac arrest in brain-dead donor |
| V | In-hospital cardiac arrest (unexpected) |
Controlled DCD (Category III): Life support withdrawn in ICU/OR; team stands by; death declared after circulatory cessation (5-minute no-touch period); rapid organ procurement proceeds.
Warm Ischemia Time in DCD
- Functional warm ischemia begins when systolic BP drops <50 mmHg or SpO2 <70% (functional agonal phase)
- Total warm ischemia = agonal phase + no-touch period (5 min) + time to cold perfusion
- Acceptable total functional WIT for DCD: kidney <30 min, liver <15 min
Considerations
- Higher rates of Delayed Graft Function (DGF) in kidneys (2-3x vs DBD)
- Higher risk of ischemic cholangiopathy (biliary cast syndrome) in DCD liver grafts due to dual blood supply damage
- DCD kidneys: excellent long-term outcomes; preferred over dialysis
- Normothermic regional perfusion (NRP): re-perfuse abdominal organs in situ after death declaration to reduce ischemic injury - increasingly used
- Machine perfusion (hypothermic or normothermic) used to assess and recondition DCD organs
10. LIVING DONOR vs DECEASED DONOR KIDNEY TRANSPLANTATION [5 marks]
| Feature | Living Donor | Deceased Donor |
|---|
| Source | Related or unrelated living person | Brain-dead or DCD |
| Cold ischemia time | Very short (<1-2 hours) | 12-24 hours |
| Graft function | Immediate function (almost always) | DGF in 20-30% |
| HLA match | Better (related donors) | Variable |
| 5-year graft survival | ~85-90% | ~75-80% |
| 10-year graft survival | Better | Lower |
| Pre-emptive transplant | Possible (before dialysis) | Less predictable |
| Donor risk | Nephrectomy morbidity; 0.03% mortality | None |
| Waiting time | Bypass waiting list | Average 3-5 years (USA) |
| Evaluation | Full medical, psychological, functional renal assessment | KDPI score, biopsy |
Absolute Contraindications to Living Donation:
- Single kidney
- Significant proteinuria (>500 mg/day)
- GFR <80 mL/min (or reduced eGFR)
- Diabetes mellitus
- Hypertension requiring >1 medication (or uncontrolled)
- Active malignancy
- Active systemic illness (autoimmune, HIV)
- Obesity (BMI >35)
- Urological abnormalities in remaining kidney
- Pregnancy (absolute at time of donation)
Relative Contraindications to Living Donation:
- Young age (long residual lifetime at increased risk)
- Mild hypertension on single agent
- Borderline GFR
- Nephrolithiasis (solitary stone, metabolic risk)
- History of psychiatric illness
- Moderate obesity (BMI 30-35)
- Family history of renal disease
- Abnormal anatomy requiring complex surgery
11. EVALUATION OF POTENTIAL RECIPIENTS FOR ORGAN TRANSPLANTATION [5 marks]
The evaluation aims to: confirm benefit from transplant, identify and treat modifiable risk factors, exclude contraindications, and optimize peri-operative risk.
Components:
1. Confirm Diagnosis and Need
- Establish etiology and irreversibility of organ failure
- Confirm ESRD, ESLD, or other indication
- Assess severity: MELD (liver), GFR/dialysis status (kidney), cardiac index (heart)
2. Cardiovascular Assessment
- ECG, 2D echocardiography
- Stress testing (nuclear/dobutamine echo) in diabetics, older patients
- Coronary angiography if indicated
- Peripheral vascular assessment (for kidney - iliac vessels)
- Cardiology clearance
3. Pulmonary Assessment
- Chest X-ray
- PFTs (for lung recipients; for liver: exclude hepatopulmonary syndrome/portopulmonary HTN)
- CT chest if abnormal
4. Malignancy Screening
- Age-appropriate cancer screening
- Colonoscopy (>50 years)
- Mammography, pap smear (women)
- PSA (men >50)
- Skin check (dermatology)
- CT chest/abdomen/pelvis if history of malignancy
- Cancer-free period required (typically 2-5 years depending on tumor type)
5. Infection Screening
- Serology: HIV, Hepatitis B (HBsAg, anti-HBc, anti-HBs), Hepatitis C, CMV, EBV, HSV, VZV, HTLV I/II, Toxoplasma
- TB: Mantoux / IGRA
- Urinalysis and urine culture
- Dental evaluation
6. Immunological Workup
- ABO blood group
- HLA typing (A, B, C, DR, DQ, DP)
- Panel Reactive Antibody (PRA) - screen for pre-formed antibodies
- Donor-specific antibody (DSA) testing
7. Psychosocial Assessment
- Psychiatric evaluation
- Substance use history (alcohol, drugs)
- Compliance assessment
- Social support (caregiver available post-transplant)
- Financial/insurance planning
8. Nutritional Assessment
- BMI, albumin, nutritional status
- Obesity (BMI >35 relative contraindication)
- Malnutrition treatment pre-transplant
9. Other
- Urological evaluation (kidney): voiding history, urodynamics if lower tract dysfunction
- Native liver assessment (hepatology): coagulation, portal HTN complications
- Ophthalmology (diabetes)
- Bone density (liver - osteoporosis common in cholestatic disease)
12. CRITERIA FOR DECLARING BRAIN STEM DEATH (for organ donation) [5 marks]
Who Performs
- Two registered medical practitioners, each of appropriate experience
- At least one a consultant; neither may be part of the transplant team
- Both must independently confirm; tests may be done simultaneously or serially
Preconditions (Must ALL be fulfilled)
- Cause established: Irremediable structural brain damage - head injury, intracerebral hemorrhage, post-cardiac arrest hypoxic injury
- Deeply comatose: GCS 3, on ventilator
- Drug exclusion: No depressant drugs (narcotics, benzodiazepines, barbiturates); adequate time elapsed
- Hypothermia excluded: Core temperature >35°C
- Metabolic causes excluded: No severe electrolyte/acid-base/glucose disturbances; no endocrine crisis
Seven Brainstem Reflex Tests (all must be ABSENT):
- Pupillary light reflex: Fixed, dilated pupils; no response to bright light
- Corneal reflex: No blink to cotton wool touching cornea
- Oculo-cephalic reflex (Doll's eyes): No eye movement when head rotated (not applicable in C-spine injury)
- Vestibulo-ocular reflex (Caloric test): No eye movement after 20 mL ice-cold water instilled into each ear (with confirmed intact tympanic membrane)
- Response to pain in cranial nerve territory: No grimacing or response to supraorbital pressure
- Gag reflex: No response to pharyngeal stimulation
- Cough reflex: No response to tracheal suction
Apnea Test (as above - 8th test):
- PaCO2 must rise to ≥ 50 mmHg (6.7 kPa) with NO respiratory effort
13. ISLET (PANCREATIC) TRANSPLANTATION [5 marks]
Background
- Insulin-producing beta cells from the islets of Langerhans of a deceased pancreas are isolated and transplanted into the portal vein of the recipient
- Settles in the liver sinusoids and produces insulin
- Aim: insulin independence and prevention of hypoglycemic unawareness in Type 1 DM
Types of Pancreatic Transplant
- Simultaneous Pancreas-Kidney (SPK): Most common; pancreas + kidney transplanted simultaneously in ESRD diabetic patient. Best outcomes.
- Pancreas After Kidney (PAK): Pancreas transplant after prior successful kidney transplant
- Pancreas Transplant Alone (PTA): For brittle Type 1 DM without ESRD; controversial (requires lifelong immunosuppression)
- Islet cell transplantation: Less invasive; multiple donors usually needed; Edmonton protocol (2000)
Edmonton Protocol (Islet Transplant)
- Steroid-free immunosuppression: sirolimus + tacrolimus + daclizumab
-
70% achieved insulin independence at 1 year
- At 5 years, only ~10-20% maintain insulin independence (progressive islet loss)
- Improved results with better islet isolation and immunosuppression protocols
Indications for Islet Transplant
- Type 1 DM with severe hypoglycemic unawareness
- Brittle DM with life-threatening hypoglycemia
- Progressive diabetic complications despite optimal insulin therapy
- Prior/concurrent kidney transplant (already requires immunosuppression)
Limitations
- Need 2-3 donors per recipient
- Progressive function loss over years
- Risk of portal hypertension (from infusion), bleeding
- Lifelong immunosuppression required
- Shortage of suitable donors
Current Status
- Whole pancreas transplant (SPK) remains gold standard for combined type 1 DM + ESRD (insulin independence rates >80% at 1 year)
- Islet transplant is still considered investigational in many countries but increasingly accepted for selected indications
14. COMPLICATIONS OF RENAL TRANSPLANT
Surgical Complications
- Vascular: Renal artery/vein thrombosis (early graft loss), renal artery stenosis (late hypertension, graft dysfunction)
- Urological: Urinary leak (early, from anastomosis), ureteral stenosis (late), lymphocele (most common perigraft fluid collection)
- Wound: Hematoma, seroma, infection, hernia
Medical Complications
- Delayed Graft Function (DGF): Temporary requirement for dialysis; managed with fluid balance, avoidance of nephrotoxic drugs
- Acute Rejection: Rising creatinine, treated with steroids/ATG
- Chronic Rejection (Chronic Allograft Nephropathy): Gradual decline, managed by optimizing immunosuppression
- Calcineurin inhibitor toxicity: Nephrotoxicity, hypertension
- Infections: Bacterial (UTI, pneumonia); viral (CMV - months 1-6, BK virus nephropathy, EBV-related PTLD); fungal (Aspergillus, Candida, PCP)
- Metabolic: PTDM, hyperlipidemia, hypertension, gout
- Malignancy: PTLD (post-transplant lymphoproliferative disease - EBV-related), skin cancers (50x increased risk), Kaposi sarcoma
SUMMARY TABLE: Ischemia Time Limits
| Organ | Warm Ischemia (max) | Cold Ischemia (max) |
|---|
| Kidney | 30-45 min | 24-36 hours |
| Liver | 15-20 min | 8-12 hours |
| Heart | 5-10 min | 4-6 hours |
| Lung | 10-15 min | 6-8 hours |
| Pancreas | 30 min | 12-18 hours |
Sources: Sabiston Textbook of Surgery (The Biological Basis of Modern Surgical Practice); Brenner and Rector's The Kidney; Current Surgical Therapy 14e; Harrison's Principles of Internal Medicine 22E; Pye's Surgical Handicraft 22nd Edition; Bradley and Daroff's Neurology in Clinical Practice; Plum and Posner's Diagnosis and Treatment of Stupor and Coma.
