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Transplant Flashcards

1
Q

Class I Human Leukocyte Antigens (HLA)

A
  1. HLA-A
  2. HLA-B
  3. HLA-C

Expressed on all cells types

ID cells as “self”

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2
Q

Class II Human Leukocyte Antigens (HLA)

A
  1. HLA-DR
  2. HLA-DRw
  3. HLA-DQ
  4. HLA-DP

Expressed on APCs

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3
Q

Mechanisms of Hyper-Acute Rejection

A
  1. IgM antibodies to donor HLA antigens
    1. blood group mismatching
  2. IgG antibodies to donor HLA antigens
    1. Acquired from previous transfusions (especially multidonor platelets)
    2. Previous pregnancy
    3. Previous transplant
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4
Q

Direct vs. In-direct Antigen Presentation

A

Direct Antigen Presentation

Donor cell presentation of donor antigen

In-direct Antigen Presentation

Donor antigens presented by host APC

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5
Q

Signal 1 Pathway of T-cell Activation

A

Signal 1 Pathway (direct T-cell activation)

  1. Direct antigen presentation by donor (passenger) APCs
    1. CD8+ T-cell activation
    2. Early CMR
  2. In-direct antigen presentation by host APCs
    1. CD4+ T-cell activation
    2. Later AMR
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6
Q

Signal 2 Pathway of T-cell Activation

A

Signal 2 Pathway (T-cell Co-stimulation)

  1. Augmented T-cell activation via co-stimulatory receptors that recognize APC or donor cell antigens
  2. T-cell augmentation of B-cell activation
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7
Q

Cell Mediated Rejection Mechanisms

A

T-cell Mediated

  1. Direct Effector Pathway
    1. Activation of CD8+ T-cells
    2. Cytotoxic T-cells induce apoptosis of graft cells bearing the HLA of their activating APC
  2. In-direct Effector Pathway
    1. Activation of CD4+ T-cells
    2. Release of cyotkines that increase cytotoxic CD8+ T-cell mediated apoptosis

B-cell Mediated

APC activated CD4+ T-helper cells activate B-cells to produce antibodies that

  1. Destroy donor endothelial cells
  2. Induce Antibody-Dependant Cytotoxicity
  3. Activate the Classical Complement Pathway
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8
Q

ISHLT Criteria for Antibody Mediated Rejection

A
  1. Clinical evidence of donor-specific antibodies in the recipient
  2. Endomyocardial Bx evidence of immunopathologic complement (C4d and C3d) staining
  3. Endomyocardial Bx evidence of endothelial cell and macrophage activation (CD68 staining positive)

Can be assoc. with HLA or non-HLA antibodies

Usually occurs early (weeks-months)

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9
Q

Histologic Criteria for the Dx of AMR

A
  1. Endothelial swelling
  2. Activated macrophages in the graft
  3. Immunoglobulin (IgG or IgM) staining positive
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10
Q

Clinical Presentation of AMR

A
  1. Decreased LVEF (>25% reduction)
  2. Increased LV Mass
  3. Decreased R-wave Voltage
  4. New RBBB or LBBB
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11
Q

What is Desensitization Therpay and when is it Indicated?

A
  1. IVIG
  2. Plasmaphoresis
  3. Rituximab (anti-CD20)
  4. Cyclophosphamide

Indicated pretransplant if calculated PRA predicts <50% chance of donor match

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12
Q

Maintenance Immunosuppression

A
  1. Tacrolimus
  2. MMF
  3. Prednisone
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13
Q

Treatment of Acute AMR

A
  1. IVIG
  2. Rituximab (anti-CD20)
  3. Alemtuzumab (anti-CD52)
  4. Plasmaphoresis
  5. Thymoglobulin
  6. Other
    1. Belatacept (CTLA4-Ig)
    2. Bortezomib (proteozome inhibitor)
    3. Eculizimab (anti-C5i complement inhibitor)
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14
Q

Chronic Allograft Vasculopathy (CAV) and Treatment

A

Definition

Diffuse (epicardial and small vessel) arterial wall thickening and stenosis

  1. Stage O - Not significant
  2. Stage 1 - Mild
  3. Stage 2 - Severe
  4. Stage 3 - Severe with Graft Dysfunction

Treatment

  1. Sirolimus (mammalian target of rapomycin (mTOR) inhibitor)
  2. Statins

​Outcomes

Accounts for 45% of SCD

Mortality 25% at 5-years; 50% at 10-years

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15
Q

Central vs. Peripheral Tolerance

A

Central Tolerance

Deletion of “self”-reactive T-cells in the thymus

Peripheral Tolerance

  1. Deletion (T-cell apoptosis)
  2. Anergy/Ignorance (induced functional nonresponsiveness; no co-stimulation)
  3. Regulation (active alloimmunity via CD4+ Tregs)
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16
Q

CDC Screening Assay

A

Recipient serum mixed with cells expressing known HLA antigens and complement

Disadvantages

  1. Dependent on the affinity of the antibodies present (countered by preheating serum to inactivate IgM or add humanglobluin (CDC-AHG assay) to increase sensitivity of low titer IgGs)
  2. Clouded by other serum proteins
  3. Not all antibody isotypes bind complement
  4. Does not determine titer
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17
Q

Panel Reactive Antibody (PRA) Screening Test

A

Recipient serum is exposed to panel of cells expressing known HLA antigents. PRA “titer” represents the percentage of the donor pool that would be killed by the patients serum.

PRA > 10% or > 25% have incrementally poorer outcomes

Poor for low titer antibodies or MCH class II antibodies

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18
Q

Risk Factors for High PRA

A
  1. Pregnancy (multiparity)
  2. Multiple Blood Product Transfusions
  3. MCS
  4. Congenital Heart Disease
  5. Previous Transplant
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19
Q

Solid Phase Flow Cytometry (SPA)

A

Reactivity to HLA antigens characterized by mean fluorescence intensity

Advantages

  1. Provides titer
  2. Provides individual donor-recipient compatibility
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20
Q

Virtual Crossmatch

A

Comparison of donor HLA genotype and recipient SPA antibodies

PPV 80%

True cross-match confirmed by CDC-AHG assay

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21
Q

Glucocorticoids

A

MOA

Inhibition of intracellular NF-kB

  1. decreases proinflammatory Th1 cytokines
  2. increases antinflammatory Th2 IL-10
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22
Q

Purine Analogs

A

MOA

Incorporates into DNA/RNA disrupting cell cycling

Azathioprine (Imuran)

SE - bone marrow susppression

Mycophenolate Mofetil (mmF/Cellcept)

More specific to immune cells types

SE - GI upset

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23
Q

Calcineurin Inhibitors

A

MOA

Inhibits caclineurin binding of calmodulin which activates TCRs and NFAT induced proinflammatory gene activation

Cyclosporin A

Tacrolimus (FK506)

SE - renal dysfunction, DMII, DLP, cholestasis, neuologic, non-Hodgkins lymphoma

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24
Q

mTOR Inhibitors

A

MOA

Inhibit serine/threonine protein kinase inhibiting immune cell activation and proliferation and VEGF production

Sirolimus (Rapamycin)

Everolimus

SE - impaired wound healing, cancer

Can be used to lower the dose/SE of calcineurin inhibitors

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25
Q

Monoclonal Antibodies

A

Basiliximab (Simulect; anti-CD25)

Rituximab (anti-CD20)

B-cell depletion

Desensitization and treatment of AMR

Bortezomib (Velcade; anti-CD265 proteosome)

Treats persistant AMR

Alemtuzumab (Campath; anti-CD52)

Treats Acute Rejection

Belatacept (Nulojix; CTLA4-Ig protetypic immunoglobulin fusion protein)

Inhibits Signal 2 Pathway (co-stimulation)

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26
Q

Polyclonal Antibodies

A

Antithymocyte Globulin (RATG or ATGAM)

SE - Increased PTLD and CMV

IVIG (pooled human IgG)

Desensitization and treatment of Acute AMR

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27
Q

What does UNOS stand for?

A

United Network of Organ Sharing

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28
Q

Etiologies of ESHF prompting heart transplant

A
  1. Ischemic - 90%
  2. Valvular - 2%
  3. Adult Congenital - 2%
  4. Retransplant - 2%
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29
Q

Indications for Heart Transplant

A
  1. Systolic HF (EF 35%)
  2. Intractable Angina
  3. Intractable Arrhythmias
  4. Hypertrophic Cardiomyopathy (NYHC IV despite all therapies)
  5. Congenital HD withOUT fixed PHTN
  6. Cardiac Tumor (without invasion or metastasis)
  7. Restrictive Cardiomyopathy (NYHC IV despite all therapies)
30
Q

Absolute Contraindications to Heart Transplant

A
  1. Age > 65-75
  2. Fixed PHTN (PVR > 6 woods units; PV gradient > 15mmHg)
  3. Systemic illness limiting survival
    1. Cancer (<2-5y survival)
    2. HIV/Aids
    3. Systemic Lupus
    4. Sarcoidosis with multisystem involvement
    5. Systemic process with high risk of involvement of the donor heart
    6. Irreversable other organ failure
31
Q

Relative Contraindications for Heart Transplant

A
  1. Recent Malignancy
  2. COPD
  3. Unresolved PE or Pulmonary Infarct
  4. DM with end-organ damage
  5. PVD
  6. Cerebral VD
  7. Acute PUD
  8. Current or recurrent diverticulitis
  9. Systemic illness likely to limit survival or rehab
  10. BMI < 20 or > 35
  11. Severe osteoporosis
  12. Active Smoking/EtOH/Drugs
  13. Hx of non-compliance
  14. Psychiatric illness likley to interfere with compliance
  15. Absence of psychosocial supports
32
Q

Calculate Pumonary Vascular Resistance

A

TPG (mmHg) = MPAP (mmHg) - PCWP (mmHg)

PVR (woods units) = MPAP (mmHg) - PCWP (mmHg)

CO (L/min)

PVRI = PVR

BSA

TPG > 15mmHg or PVR > 6 woods units indicative of PHTN

33
Q

Determination of Fixed vs. Reversible PHTN

A

PVR > 6 woods units without evidence of reversibility

Reversibility on right heart cath…

  1. Nitroprusside (0.5ug/kg/min)
  2. Adenosine
  3. Prostaglandin E1
  4. Milrinone
  5. Inhaled NO
  6. Prostacyclin

Decrease in PVR of > 2.5 woods units or 50%

34
Q

REMATCH Trial

A

29 Patients

VAD vs. OMT

Survival at 1-year 52% vs. 28%

Survival at 2-years 29% vs. 13%

35
Q

Determinants of Recipient Priority/Organ Allocation

A
  1. Blood Type
  2. Body Size
  3. Duration of Time at a particular status level
  4. Geographic Distance
36
Q

UNOS Status 1A

A
  1. MCS (IABP, VAD, TAH, ECMO)
  2. MCS > 30-days with complications
  3. Mechanical Ventilation
  4. Continuous Inotropes or invasive hemodynamic monitoring
  5. Life Expectancy < 7-days
37
Q

UNOS Status 1B

A
  1. VAD > 30-days
  2. Continuous IV Inotropes
38
Q

What is Autonomic/Cytokine Storm?

A
  1. Norepinepherine release causes endocardial ischemic
  2. Cytokine release causes myocardial depression
  3. Vasodilitation
  4. Loss of temperature regulation
39
Q

Autonomic Response to Brain Stem Death

A
  1. Loss of Sympathetic Tone
  2. Hypovolemia
  3. Hypotension
  4. Hypothermia
  5. Dysrrhythmias
  6. DM Insipidus
40
Q

Brain Death Criteria

A

Clinical

  1. Etiology consistent clinical picture
  2. Exclude metabolic or drugs
  3. Core temperature > 36°C
  4. No reversible paralysis
  5. SBP > 100mmHg
  6. No spontaneous respiration

Comatous

  1. No motor response
  2. No brainstem reflexes
  3. Outside standoff period 6-24hrs
  4. Confirmed by 2 qualified people
  5. Apnea test (patient resp-optimized pre, no spont resp off vent, ABG at 8-10min shows PCO2>60 or rise>20)

Ancillary

  1. EEG consistent with brain death
  2. No cerebral blood flow by doppler or MRI
41
Q

Contraindications for Heart Donoation

A
  1. Malignancy (non-cerebral)
  2. Severe CAD
  3. Contusion
  4. Prolonged HoTN
  5. Prolonged Arrest
  6. Septicemia
  7. Intracardiac drug injection
  8. HIV/HBV/HCV
42
Q

Prinicples of Stabilzation of the Heart Donor

A
  1. Swan
  2. Minimize Volume
  3. Inotropic Support (MAP>60, CVP6-10)
  4. DDAVP for DM Insipidus
  5. Maintain Normothermia
  6. Maintain Acid/Base
  7. Treat Thyroid (triiodothronine 4ug + 3ug/h)
  8. Steroids (methylpred 15mg/kg)
  9. Maintain blood sugars
43
Q

Steps of Heart Procurement

A
  1. Mobilize and encirle the…
    1. IVC
    2. SVC
    3. Azygous
    4. Aorta
    5. PA(s)
  2. Heparinize (30 000U)
  3. Ligate the SVC and Azygous
  4. Transect IVC
  5. Vent the LV (LAA or RUPV)
  6. X-clamp Ao and administer cardioplegia
  7. Cold saline and slush
  8. Apicalize the heart and transect…
    1. Pulmonary vv. or LA cuff
    2. Aorta
    3. MPA or RPA/LPA
  9. Check for PFO
  10. Pack on ice
44
Q

Principles of Organ Preservation

A
  1. Static Hypothermia (4-10°C)
  2. Diastolic Arrest
  3. Safe ischemic Time (<6-hours)
45
Q

Cardioplegia Solutions for Heart Procurement

A

Intracellular Solutions

Mod-High K / Low Na

Decrease hypothermia induced cellular edema

  1. University of Wisconsin
  2. Euro-Collins
  3. Bretschnieders (HTK)
  4. Intracellular Stanford

​Extracellular Solutions

Low-Mod K / High NA

Avoid intracellular damage and increased SVR caused by high K

  1. Hopkins
  2. Celsior
  3. Krebs
  4. St. Thomas Hospital
46
Q

Describe the 5 Different Techniques for Heart Transplantation

A
  1. Orthotopic
  2. Heterotopic
  3. Bicaval
  4. Shumway (RA and Septum)
  5. Biatrial (RA and LA cuffs)
47
Q

Advantages of Bicaval Approach to Heart Transplant

A
  1. Increased Survival
  2. Less Arrhythmias (earlier return to NSR)
  3. Improved RV Function
  4. Decreased Early RA Pressure
  5. Decreased TR
48
Q

Special Surgical Considerations when performing Heart Transplant post-LVAD

A
  1. Minimize manipulation of the LAA and LVApex to avoid entraining air
  2. Clamp outflow graft before initiating CPB to avoid backward flow through device
  3. More likely to be vasolplegic post with the reintroduction of pulsitile flow
49
Q

Consequences of Autonomic Denervation

A
  1. Increased intrinsic SA node rate (90-110bpm)
  2. Decreased rate response to hypovolemia/hypoxia/anemia
  3. Orthostatic hypotension
  4. Absence of response to treatments with MOA through autonomic nervous system
    1. Carotid message
    2. Valsalva
    3. Atropine
    4. Digoxin
50
Q

Etiologies of Early Allograft Failure

A
  1. Donor Instability
  2. PHTN
  3. Ischemic injury during preservation
  4. Acute Rejection (rare)
51
Q

Management of PHTN and RV Failure Post-Transplant

A
  1. Inhaled NO
  2. Nitroglycerine
  3. Nitroprusside
  4. PGE1
  5. Prostacyclin
  6. IABP
  7. VAD
  8. ECMO
52
Q

Common Arrhythmias Post-Transplant and their Treatment

A

Sinus/Junctional Bradycardia (50%)

Treat with Theophylline

RFs - prolonged organ ischemic time; abnormal nodal artery; biatrial anastomoses, preop amiodarone, rejection

AFib/Flutter/SVT (30%)

53
Q

Alterations to Medication Responses Post-Transplant

A

No Effect

  1. Atropine
  2. Digoxin
  3. Class Ia antiarrhythmics (procainamide)

Attenuated Effect

  1. Dopamine
  2. Ephedrin

Exagerated Effect

  1. Beta-blockers
  2. Calcium channel blockers
  3. Adenosine
  4. Epi/Norepinephrine
54
Q

Hyper-Acute Rejection

(RF, MOA, Timeline, Histology, Treatment)

A

RF - Young Female Donor

MOA - Donor-specific antibodies (ABO or PRA)

Occurs in Minutes to Hours

Histology - global interstitial hemorrhage and edema with immunoglobulin and complement deposition

Treatment

  1. Plasmaphoresis
  2. IVIG
  3. Mechanical support
  4. Retransplant
55
Q

ISHLT Grading of ACR (Acute Cellular Rejection)

A
  1. Interstitial or Perivascular Infiltrate and
  2. Myocyte Damage

Grade 0R - No Rejection

Grade 1R - (Mild) 1 Focus

Grade 2R - (Moderate) 2 or more Foci

Grade 3R - (Severe) Diffuse with hemorrhage, edema and/or vasculitis

56
Q

ISHLT Grading of Acute AMR (Antibody-Mediated Rejection)

A
  1. Histologic Features
  2. Immunologic Features (CD68 or C4D staining)

AMR 0 - No Rejection

AMR 1(H) - Histologic only

AMR 1(I) - Immunologic only

AMR 2 - Both

AMR 3 - Severe histologic features (hemorrhage, edema, capillary fragmentation, multi cell infiltrates, endothelial cell pyknosis/karyorrhexis)

57
Q

CMR (Cell Mediated Rejection) Treatment

A

High Dose Prednisone 100mg/d

Change

  1. Tacrolimus → Cyclosporine
  2. Sirolimus → MMF or Azathioprine

If severe or in the first 3 months

  1. IV methelprednisolone 1000mg/d
  2. OKT3
  3. Thymoglobulin
  4. Antithymocyte Globulin
58
Q

AMR (Antibody Mediated Rejection) Treatment

A
  1. High Dose Corticosteroids
  2. Thymoglobulin
  3. Plasmaphoresis
  4. IVIG
  5. Cyclophosphamide, MMF
  6. Heparin
59
Q

Indications for Retransplantation

A

Early Allograft Failure

Chronic Allograft Vasculopathy (CAV)

Refractory Acute Rejection

60
Q

1yr Survival for Retransplantation

A

Within 6 month - 50%

After 2 years - 85% (comparable to initial Tx)

Risk Factors

  1. Older recipient age
  2. Elevated creatinine
  3. Preop mechanical ventilation
  4. Bridge to Tx with ECMO or VAD
61
Q

Survival following Heart Transplantation

A

30 day - 5-10%

1 year - 85%

Annual risk of death - 3.5%

Better

  1. age < 55
  2. young donor
  3. shorter ischemic time
  4. caucasian
  5. centre volume > 9/yr

Worse

  1. diabetes
  2. mechanical ventilation
62
Q

Common COD post-heart transplant

A

Early (30d)

  1. Graft Failure
  2. MSOF
  3. Infection

1 Year

  1. Infection
  2. Graft Failure
  3. Acute Rejection

Late

  1. CAV (chronic allograft vasculopathy)
  2. Malignancy
63
Q

Lung Allocution Score

A

Days on the wait list subtracted from predicted 1 year post-transplant survival using the following criteria:

Age, height, weight, lung Dx code, functional status, 6 min walk test, ventalitory support, oxygen requirements, FVC, systemic PAP, mean PAP, PCWP, current pCO2, lowest pCO2, highest pCO2, change in pCO2, diabetes, creatinine

64
Q

Serum titers to be measure prior to listing specifically for lung transplantation

A
  1. Histoplasma
  2. Coccidioides
  3. Toxoplasma
65
Q

HLA donor-recipient matching at the following loci improves graft survival

A

Heart

  1. HLA-DR

Lung

  1. HLA-B
  2. HLA-DR
66
Q

PRA > 25 in a lung transplant recipient…

A

…Necessitates a prospective crossmatch for lung transplantation

67
Q

PRA > 10 in a heart transplant recipient…

A

…Necessitates a prospective crossmatch for heart transplantation

68
Q

Indications for Lung Transplant

A
  1. COPD/Emphysema
  2. Interstitial Pulmonary Fibrosis
  3. Cystic Fibrosis
  4. A1 Anti-trypsin Deficiency
  5. Idiopathic Pulmonary Artery Hypertension
  6. Bronchiectasis
  7. Congenital Heart Disease
  8. Obliterative Bronchiolitis
  9. Sarcoidosis
  10. Interstitial Pneumonitis
  11. Cancer
  12. Allograft Failure
69
Q

Contraindications for Lung Transplant

A
  1. Age > 65
  2. Systemic or MSOD
  3. Irreversible Liver or Renal Dysfunction
  4. Active malignancy (other than non melanoma skin)
  5. Corticosteroids
  6. Cachexia or Obesity
  7. Pan-resistant Pulmonary Flora
  8. Active Smoking
  9. EtOH or drug abuse
  10. Psychiatric illness with noncompliance
  11. Previous Cardiothoracic Surgery (relative)
  12. Osteoporosis
  13. Prolonged mechanical ventilation
  14. HIV
  15. HCV/HBV with Bx proven liver disease
70
Q

Post-Transplant Lymphoproliferative Disorder

Diagnosis/Histology/Treatment/Prognosis

A

Diagnosis/Histology

High index of suspicion and Bx

Presence of lymphoproliferation and EBV DNA/RNA/protein

Treatment

d/c Immunosuppression

Treat malignancy (surgery/rad/chemo/inerferon/immunoglobulin)

Outcomes

Mortality 60-100%

Cardiac Surgery (shared) (14 decks)

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