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Transplant Flashcards

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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
**Monoclonal Antibodies**
**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)
26
**Polyclonal Antibodies**
**Antithymocyte Globulin** (RATG or ATGAM) SE - Increased PTLD and CMV **IVIG** (pooled human IgG) **Desensitization** and treatment of **Acute AMR**
27
What does **UNOS** stand for?
**U**nited **N**etwork of **O**rgan **S**haring
28
**Etiologies** of **ESHF** prompting heart transplant
1. **Ischemic** - **90**% 2. **Valvular** - 2% 3. Adult **Congenital** - 2% 4. **Retransplant** - 2%
29
**Indications** for **Heart** Transplant
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
**Absolute Contraindications** to **Heart** Transplant
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
**Relative Contraindications** for **Heart** Transplant
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
Calculate **P**umonary **V**ascular **R**esistance
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
Determination of **Fixed** vs. Reversible **PHTN**
**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
**REMATCH Trial**
29 Patients VAD vs. OMT **Survival** at **1-year** **52**% vs. **28**% Survival at **2-years** **29**% vs. **13**%
35
Determinants of **Recipient Priority**/Organ Allocation
1. **Blood Type** 2. Body **Size** 3. Duration of **Time** at a particular status level 4. Geographic **Distance**
36
UNOS **Status 1A**
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
UNOS **Status 1B**
1. **VAD \> 30-days** 2. Continuous IV **Inotropes**
38
What is Autonomic/**Cytokine Storm**?
1. Norepinepherine release causes **endocardial ischemic** 2. Cytokine release causes **myocardial depression** 3. **Vasodilitation** 4. Loss of **temperature** regulation
39
**Autonomic** Response to **Brain Stem Death**
1. Loss of **Sympathetic Tone** 2. **Hypovolemia** 3. **Hypotension** 4. **Hypothermia** 5. **Dysrrhythmias** 6. **DM Insipidus**
40
**Brain Death** Criteria
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
**Contraindications** for Heart **Donoation**
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
Prinicples of **Stabilzation** of the Heart **Donor**
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
Steps of Heart **Procurement**
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
Principles of Organ **Preservation**
1. Static **Hypothermia** (4-10°C) 2. Diastolic **Arrest** 3. Safe ischemic **Time** (\<6-hours)
45
**Cardioplegia Solutions** for Heart Procurement
**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
Describe the **5** Different **Techniques** for **Heart** **Transplantation**
1. **Orthotopic** 2. **Heterotopic** 3. **Bicaval** 4. **Shumway** (RA and Septum) 5. **Biatrial** (RA and LA cuffs)
47
**Advantages** of **Bicaval** Approach to Heart Transplant
1. Increased **Survival** 2. Less **Arrhythmias** (earlier return to NSR) 3. Improved **RV Function** 4. Decreased Early **RA Pressure** 5. Decreased **TR**
48
Special **Surgical Considerations** when performing Heart **Transplant** post-**LVAD**
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
Consequences of **Autonomic Denervation**
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
Etiologies of **Early Allograft Failure**
1. **Donor** Instability 2. **PHTN** 3. **Ischemic** injury during preservation 4. Acute **Rejection** (rare)
51
Management of **PHTN** and **RV Failure** Post-Transplant
1. **Inhaled NO** 2. **Nitroglycerine** 3. **Nitroprusside** 4. **PGE1** 5. **Prostacyclin** 6. **IABP** 7. **VAD** 8. **ECMO**
52
Common **Arrhythmias** Post-Transplant and their **Treatment**
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
**Alterations** to **Medication Responses** Post-Transplant
**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
**Hyper-Acute Rejection** (RF, MOA, Timeline, Histology, Treatment)
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
**ISHLT** Grading of **ACR** (Acute Cellular Rejection)
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
**ISHLT** Grading of Acute **AMR** (Antibody-Mediated Rejection)
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
**CMR** (Cell Mediated Rejection) **Treatment**
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
**AMR** (Antibody Mediated Rejection) **Treatment**
1. High Dose **Corticosteroids** 2. **Thymoglobulin** 3. **Plasmaphoresis** 4. **IVIG** 5. **Cyclophosphamide, MMF** 6. **Heparin**
59
**Indications** for **Re**transplantation
Early Allograft **Failure** Chronic Allograft Vasculopathy (**CAV**) Refractory Acute **Rejection**
60
**1yr Survival** for **Re**transplantation
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
**Survival** following Heart **Transplantation**
**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
Common **COD** post-heart transplant
**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
**Lung Allocution Score**
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
Serum **titers** to be measure prior to listing specifically for **lung transplantation**
1. **Histoplasma** 2. **Coccidioides** 3. **Toxoplasma**
65
HLA donor-recipient matching at the following loci improves graft survival
Heart 1. **HLA-DR** Lung 1. **HLA-B** 2. **HLA-DR**
66
**PRA \> 25** in a **lung** transplant recipient...
...Necessitates a **prospective crossmatch** for **lung** transplantation
67
**PRA \> 10** in a **heart** transplant recipient...
...Necessitates a **prospective crossmatch** for **heart** transplantation
68
**Indications** for **Lung** Transplant
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
**Contraindications** for **Lung** Transplant
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
**Post-Transplant Lymphoproliferative Disorder** Diagnosis/Histology/Treatment/Prognosis
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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