Solid Organ Transplantation

Indications for Kidney Transplant

• Diabetes

• Hypertension

• Lupus

• Polycystic kidney disease

• Drug toxicities

Indications for Liver Transplant

• Hepatitis B

• Hepatitis C

• Alcohol/Drug Toxicity

• Hepatocellular carcinoma

• Fatty liver disease

• Autoimmune

• Biliary disease

Indication for Pancrease transplant

• Diabetes

Indication for Lung Transplant

• COPD

• Idiopathic pulmonary fibrosis

• Cystic fibrosis

• Idiopathic pulmonary arterial hypetension

Indication of Heart Transplant

• CHF

• CAD

• Arrhythmias

• Congenital disease

Ultimate goal of Transplantation Immunology

Permanent acceptance or tolerance

Components of the Immune System

• MHC/HLA

• Antigen-presenting cells

• T-lymphocytes

• B-lymphocytes

Types of antigen-presenting cells

• B-cells

• Macrophages

• Dendritic cells

Mechanism of APC

Display HLA to host T-cells to cause antigen-specific T-cell activation

Function of CD4

• Recognize MHC Class 2

• Stimulate B- and T-cells

Function of CD8

• Recognize MHC Class 1

• Kill infected cells

Function of B-lymphocyte

• Antibody formation against antigen

Signal 1 T-cell Activation

APC presents MHC class II antigen to T_H through the T-cell receptor (TCR)-CD3 complex

Signal 2 T-cell Activation

Co-stimulatory protein binding of CD80 and CD86 on the APC to CD28 of the T_H occurs

Signal 3 T-cell Activation

IL-2 is released and binds to IL-2 receptor on the T-cell, activating target of rapamycin necessary for cell proliferation

Goals of Immunosuppression

• Promote the acceptance of donor graft, prolonging patient and graft survival

• Prevent acute rejection while minimizing risk of infection and toxicity

Immunosuppression is achieved by

• Depletion of lymphocytes

• Diversion of lymphocyte traffic

• Blocking of lymphocyte proliferation and response

Triple regimen for immunosuppression

• 3 maintenance drugs

• Ab induction + 2 maintenance drugs

Donor factors for immunosuppression

• Age

• Organ quality

• Living vs deceased donor

• Cold ischaemia time

• HLA matching, cross-matching results

• Organ type

• Organ cold ischaemia time

Recipient factors for immunosuppression

• Age

• Ethnicity

• Panel reactive antibodies

• Previous transplants

• Blood transfusion

• Pregnancy

• Infection and/or malignancy history

Desensitization strategies

• Proteasome inhibitor (Bortezomib, carfilzomib)

• Belatacept

Induction Immunosuppression

• Monoclonal, non-depleting (Basiliximab)

• Monoclonal, depleting (Alemtuzumab)

• Polyclonal, depleting (Rabbit anti-thymocyte globulin)

• Corticosteroids (Methylprednisolone)

Basiliximab (MOA)

Bind to CD25 (subunit of IL-2 receptor on activated T-cells), inhibiting IL-2 mediated effects

Alemtuzumab (MOA)

Bind to CD52

Alemtuzumab (Adverse Reactions)

• Infusion reactions

• Hematologic infections

Alemtuzumab (HL)

12 days

Rabbit anti-thymocyte globulin (MOA)

Induce T-cell depletion

Rabbit anti-thymocyte globulin (Indication)

• High immunologic risk patients

• Acute rejection

Rabbit anti-thymocyte globulin (HL)

30 days

Rabbit anti-thymocyte globulin (Dosage Reduction Criteria)

• Leukopenia (WBC < 3000)

• Thrombocytopenia (Platelets < 75000)

Rabbit anti-thymocyte globulin (Pre-medications)

• Acetaminophen

• Diphenhydramine

• And/or steroids

Rabbit anti-thymocyte globulin (Administration)

Central line OR peripherally inserted central catheter

Maintenance Immunosuppression Pharmacotherapy

• Calcineurin Inhibitors (Cyclosporine, Tacrolimus)

• Antimetabolites (Azathioprine, Mycophenolate)

• Target of Rapamycin inhibitors (Sirolimus, Everolimus)

• Corticosteroids (Methylprednisolone, Prednisone)

• Belatecept

Tacrolimus (MOA)

Bind to FKBP-12

Cyclosporine (MOA)

Bind to cyclophilin

CNI IV Formulation (Indication)

Bone marrow transplant patients with severe mucositis

CNI Adverse Effects

• Neurotoxicity

• Nephrotoxicity

• Diabetes

Higher diabetes risk

Tacrolimus

More potent CNI

Tacrolimus

CNI for patient less than 5 years old

Cyclosporine

CNI to switch to if hair growth

Tacrolimus

CNI to switch to if hair loss

Cyclosporine

CNI to switch to if gingival hyperplasia

Tacrolimus

CNI to switch to if Tremors/Falls

Cyclosporine

CNI to switch to if rejection

Tacrolimus

Antimetabolite: Azathioprine (MOA)

Inhibit DNA and RNA synthesis via 6-mercaptopurine

Antimetabolite: Mycophenolate mofetil (MOA)

Inhibit inosine monophosphate dehydrogenase via mycophenolic acid metabolite

Antimetabolite: more specific?

Mycophenolate mofetil

Screening before Azathioprine administration

Test for TPMT enzyme activity or TPMT genotype

Antimetabolites: Azathioprine precaution

Avoidance of xanthin oxidase inhibitors

Antimetabolite: Azathioprine (Adverse Effects)

• Myelosuppression

• Alopecia

• Pancreatitis

• Hepatotoxicity

• Squamous cell CA

Antimetabolite: Mycophenolate (Adverse Effects)

• Myelosuppression

• GI Upset

Mycophenolate ADR Amelioration

• Take with food

• Use anti-motility agents

• Use anti-emetics

• Change formulation to EC formulation

mTOR Inhibitor MOA

Blocks IL-2 signal transduction, specifically signal 3

mTORi Pharmacotherapy

• Sirolimus

• Everolimus

mTORi: Sirolimus (Half-life)

60 hours

mTORi: Everolimus (Half-life)

30 hours

Duration when to administer Sirolimus after cyclosporine

4 hours

mTORi Adverse Effects

• Hyperlipidemia

• Nausea, diarrhea, gastritis

• Myelosuppression

• Nephrotoxicity

• Mouth ulcers

• Pulmonary toxicity

• Wound healing complications

Corticosteroids (MOA)

• Decrease immune cell proliferation by reducing APC secretion of IL-1 and IL-6

• Reduction of phagocytosis by decreasing IL-2, IL-3, IL-4, TNF, and Interferon response

Drug combination for good outcome in maintenance regimen

Calcineurin Inhibitors + MMF

Indications of corticosteroids

• Patients with multiple rejections on steroid-free regimen

• Very high risk transplant patients or positive crossmatch

• No induction (the 3 drug regimen)

• Patients on chronic steroids for autoimmune disorders

Short-term effects of Corticosteroids

• Impaired glucose tolerance

• Increase BP/fluid retention

• Increase appetite

• Mood disturbance

• Leukocytosis

• Impaired wound healing

Long-term effects of Corticosteroids

• Diabetes

• Osteoporosis

• Acne

• Cataracts

• Infection

• Steroid-dependence

• Weight gain

• Hyperlipidemia

Benefits of Belatacept

• Preserve renal function

• Improve long-term outcomes

Belatacept MOA

Signal 2 blocker that promotes T-cell anergy and apoptosis

Contraindication of Belatacept

Liver transplant patient due to increased risk of graft loss and death

Indication of Belatacept

Additional immunosuppression in patient with significant rejection burden

ADRs of Belatacept

• Myelosuppression

• GI Upset

• Neuropathy

Risk factors for post-transplant lymphoproliferative disorder

• Recipient EBV negative serostatus

• Lymphocyte depleting therapy

• Co-infection with CMV

Manifestation of Post-transplant lymphoproliferative disorder

• Uncomplicated mononucleosis

• Lymphoma

• CNS Involvement

Triple Regiment

CNI + Steroids + Antimetabolites

Induction Choice for Kidney

1. Thymoglobulin

2. Alemtuzumab

3. Basiliximab

Bela pros over CNI

• Avoids CNI nephrotoxicity

• Superior in long-term renal function endpoint

Adjust Agent: If patient is steroid free

Use Ab induction

When to use mTORi

• Alternative for MPA intolerant patient

• Patients at risk for tumor recurrence

• Patients with skin cancer

Risk for IMS Non-adherence

• High cosr of IMS

• Young age

• Living related donor

• Perception that IMS not needed

• Pill burden

• Drug toxicities

• Depression

Rejection RIsk per Organ Type

Lung/Small bowel > Heart > Kidney/Pancrease > Liver

1st Line Treatment of Rejection

Corticosteroids

2nd Line rejection treatment for Cellular Rejection

Anti-thymocyte globulin

2nd Line rejection treatment for Antibody mediated rejection

• Plasmapheresis

• Rituximab

• IVIG

• Bortezomib

• Eculizumab

• Tociluzumab

Indication of Rituximab

• Desensitization

• AMR Treatment

• PTLD

Indication of IVIG

• Desensitization

• AMR Treatment

• Hypogammaglobulinemia

AMR Therapies ADRs on infusion-related reactions

• Rituximab

• IV IG

Bortezomib Indication

• Desensitization

• AMR

Bortezomib Adverse Effect

• Peripheral neuropathy

• Diarrhea

• Nausea

• Thrombocytopenia

• Neutropenia

• Anemia

Eculuzimab Indication

• AMR

• Prevention of AMR

Eculuzimab Risk

Meningococcal infection

Viral (CMV) 3-Drug Prophylaxis

• Valganciclovir

• Ganciclovir

• Acyclovir

Bacterial (PCP Pneumonia or Toxoplasmosis) 3-Drug Prophylaxis

• sulfamethoxazole and trimethoprim

• Dapsone

• Atovaquone

• Petamidine INH

Fungal (Candidiasis/Aspergillus) 3-Drug Prophylaxis

• Voriconazole

• Itraconazole

Infection prophylaxis for 3 months for rejection therapies

• Anti-thymocyte, Rituximab, Bortezomib

• Patient treated for > 2R rejection 3 or more times within 3 months

Antibody-mediated therapy that inhibits C5 complement proteins

Eculizimab

Adverse effect of Tacrolimus

• Alopecia

• GI Problems

Adverse effects of Cyclosporine

• Hirsutism

• Gingival hyperplasia