Final: Transplants Flashcards by TheOneandOnly Ash

What is an AUTOtransplantation?

Transplant of tissue from one part of the body to another

-same person

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What is an ALLOtransplantation?

Transplant of tissue from one person to another person

-different person

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What is a XENOtransplantation?

Transplant of tissue from a different species

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What does orthotopic mean?

Transplanted into the recipient in the same place it came from

(ex: heart, lung transplant)

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What does heterotopic mean?

Transplanted into the recipient un a different place than it came from

***ex: kidney where we do not remove the old kidneys and just add a new one in

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What are the 2 types of deceased organ donors?

Deceased by brain death (DBD)

Decreased by circulatory death (DCD)

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What does “deceased by brain death” mean?

Primary brain death with intact cardiac and respiratory function

*Organs are perfused until the time of procurement

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What does “deceased by circulatory death” mean?

Does not meet the brain death criteria

*Non-beating heart donation

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Group AB blood is considered the “universal” what?

Recipient

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Group O blood is considered the “universal” what?

Donor

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What is the Major Histocompatibility Complex (MHC)/ Human Leukocyte Antigen (HLA) Complex?

-An association of genes found on the short arm of chromosome 6
-These play an important role in immune recognition and response

-Used to determine compatibility for transplants

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How are HLA antibodies formed?

-Do not form naturally
-Form in response to non-self HLA exposure (sensitizing events)

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What does the presence of pre-transplant HLA donor-specific antibodies (DSA) indicate?

Contraindication in deceased donor transplants

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What does the presence of post-transplant donor-specific antibodies (DSA) indicate?

Failure of immunosuppression

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What are Panel Reactive Antibodies (PRA)?

Amount of pre-formed HLA antibodies in a recipient compared to the general population

% of the panel to which the patient has developed antibody

*Higher the PRA = increased sensitization to MHC antigens (bad)

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What percent is considered sensitized (high risk) for a Panel Reactive Antibody study (PRA)?

20-30%

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What is a crossmatch?

Must obtain negative results before a transplant

-Test the recipient’s serum (lymphocytes) against donor T cells to determine if there is preformed anti-HLA Class I antibody

-A positive test indicates the presence of pre-formed donor-specific antigens and has a high risk of rejection
**Transplant is typically cancelled if this comes back positive

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What are the 2 types of donor-specific HLA antibody testing (Crossmatch)?

Standard: Qualitative (positive or negative)

Flow: Quantitative (measures degree of antibody activity)

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What 3 things do we want to balance out with immunosuppressive therapy?

Rejection
Infection
Toxicity

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African Americans tend to be rapid metabolizers of what drug?

Tacrolimus

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African Americans may benefit from what drug?

Envarsus

-a prolonged-release tacrolimus

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What is a hyperacute rejection?

OCCURS INSTANTLY -within minutes to hours after transplant

-Mediated by preformed circulating antibodies

-Not common anymore due to pre-testing

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What is an acute rejection?

Highest risk of occurrence in the first year

-Occurs within days to months after transplant

-T-cell mediated

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What is a chronic rejection?

Occurs months to years after transplant

-Both cellular-mediated and antibody mediated

Appears as a progressive decline in organ function

-all organs are at risk for this due to organ expiration

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Under-immunosuppressing a transplant patient creates a risk of what?

Rejection

Over-immunosuppressing a transplant patient creates a risk of what?

Infection Toxicity Malignancy

What are the 3 types of immunosuppressive regimens?

Induction therapy Maintenance therapy Rejection therapy

What is induction therapy?

Intense prophylactic therapy given AT THE TIME OF THE TRANSPLANT

What is maintenance therapy?

Long-term, chronic immunosuppression given after transplant *lifelong

What is rejection therapy?

Most intense form of therapy used in response to a rejection episode

What are the agents that can be used in induction therapy?

Polyclonal Antibodies -Rabbit Antithymocyte Globulin (Thymoglobulin) -Horse Antithymocyte Globulin (ATGAM) Monoclonal Antibodies -Alemtuzumab IL-2a Receptor Antagonists -Basiliximab

How does Rabbit Antithymocyte Globulin work?

Contains polyclonal IgG against human T-lymphocytes derived from rabbits Reduces the number of circulating T-lymphocytes which alters T-cell activation, homing, and cytotoxic function

**What is the main thing to remember about the action of rabbit antithymocyte globulin?

Lymphocyte depletion

**What are the main adverse effects of rabbit antithymocyte globulin?

Leukopenia + Thrombocytopenia --dose limiting Fever + Chills --premedicate with diphenhydramine and acetaminophen

What is the indication for alemtuzumab?

Off-label use in solid organ transplant for induction

**How does Alemtuzumab work?

Humanized *anti-CD52* monoclonal antibody

**What is the main function of Alemtuzumab?

Profound depletion of T cells

What is a benefit to Alemtuzumab's dosing?

1 dose intraoperatively -shorter hospital stay -get maintenance therapy the next day

What are the adverse effects of Alemtuzumab?

Infusion-related reactions: Chills, Rigors, Fever *pre-medicate with diphenhydramine and acetaminophen

How does Basiliximab work?

Recombinant, chimeric, monoclonal antibody against *CD25* Competitively inhibits IL-2-mediated activation of lymphocytes

**What is the main consideration with Basiliximab?

Non-lymphodepleting (competitively inhibits their activity at the receptor but does not knock out the B and T cells)

What are the depleting induction agents?

Alemtuzumab Thymoglobulin

What is the non-depleting induction agent?

Basiliximab

What are the monoclonal induction agents?

Alemtuzumab Basiliximab

What is the polyclonal induction agent?

Thymoglobulin

What type of induction therapy is more commonly used? Lymphocyte depleting or non-depleting?

Lymphocyte depleting *especially for high-risk patients

When would we use Basiliximab?

Only if one of these patient factors is present: -History of malignancy -High infection risk, immunocompromised -HIV, untreated HCV -Advanced age (>65)

What are the drug classes used for maintenance therapy?

Calcineurin Inhibitors Antimetabolites mTOR Inhibitors Corticosteroids T-cell Co-stimulation Blocker

What are the calcineurin inhibitors?

Cyclosporine Tacrolimus

What are the antimetabolites?

Azathioprine Mycophenolate mofetil Mycophenolate sodium

What are the mTOR inhibitors?

Sirolimus Everolimus

What are the corticosteroids?

Methylprednisolone Prednisone Dexamethasone

What is the T-cell Co-stimulation Blocker?

Belatacept

**Which drug class is the cornerstone of immunosuppression and the most commonly used?

Calcineurin Inhibitors (Tacrolimus, Cyclosporine)

What is the moa of the calcineurin inhibitors?

Induce immunosuppression by inhibiting signal-1 of T-cell activation Inhibit calcineurin phosphatase enzyme within the T cell (prevents T cell activation)

What formulation of cyclosporine is non-modified and should never be used?

Sandimmune -has poor and erratic bioavailability

What is an important thing to remember about the different brands of cyclosporine?

The modified and non-modified forms are NOT interchangeable

What is the immediate-release form of tacrolimus?

Prograf

What are the extended-release forms of tacrolimus?

Astagraf XL Envarsus XR

**What are the benefits to using extended-release tacrolimus?

-Lower overall dose -Improved adherence -Less peak effects (reduced adverse effects) -Less swings/variability in trough concentration

What form of Tacrolimus do we never want to use in solid organ transplant?

IV -increased risk of nephrotoxicity -you are harming the new kidney

**What considerations do we make with Therapeutic Drug Monitoring (TDM) of Tacrolimus?

50x more potent than cyclosporine Goal 12-hr trough ranges: about 5-15 ng/mL *Different conversions for IR vs ER

What is the conversion between Prograf (immediate release tacrolimus) and Envarsus (extended release)?

1mg Prograf = 0.8mg Envarsus

**How is cyclosporine metabolized?

Cytochrome P450 (CYP) 3A4 *P-glycoprotein (unique to this drug)

**How is Tacrolimus metabolized?

Cytochrome P450 (CYP) 3A4

What is important to know about cyclosporine elimination?

Highly variable! T 1/2 is 10-40hr

**What are Cyclosporine's adverse effects?

Hypertension Hypercholesterolemia Hypertriglyceridemia *Gingival hyperplasia *Hirsutism

What are Tacrolimus's adverse effects?

Neurotoxicity -headache -insomnia -*tremor* -dizziness Hyperglycemia/ post-transplant diabetes Alopecia

**What are the CYP 450 inducers that will decrease tacrolimus/ cephalosporin concentrations?

Phenytoin Carbamazepine Phenobarbital Rifampin

**What are the CYP 450 inhibitors that will increase tacrolimus/cephalosporin concentrations?

Erythromycin + Clarithromycin Azole Antifungals (fluconazole) Diltiazem + Verapamil Ritonavir Grapefruit juice

**How does liver dysfunction affect tacrolimus?

Tacrolimus is predominantly eliminated through the liver, half life is prolonged

**How does renal dysfunction affect the calcineurin inhibitors?

Dose adjustments are not needed

What is the moa of azathioprine?

Antimetabolite -Purine analog

What are the adverse effects of Azathioprine?

GI: Abdominal Pain, N/V, Diarrhea, Dyspepsia Bone Marrow Suppression: Agranulocytosis, Macrocytic Anemia, Leukopenia, Neutropenia, Thrombocytopenia

What drugs does Azathioprine interact with?

Allopurinol + Febuxostat -these reduce AZA concentrations by 50-75%

Which drug is the most commonly used adjunct agent with calcineurin inhibitors?

Mycophenolic Acid

What is the moa of mycophenolic acid?

Inhibits de novo synthesis of purines (selective for lymphocytes) Limits progression of activated T and B cells

What is the immediate release form of mycophenolic acid and where is it released?

Mycophenolate mofetil -released in the stomach

What is the delayed release form of mycophenolic acid and where is it released?

Mycophenolate sodium -small intestine

**What is the conversion factor between the 2 forms of Mycophenolic acid?

Mofetil 250mg = Sodium 180mg IV:PO = 1:1

**What is the adverse effect to know for Mycophenolic Acid?

FDA pregnancy category D (teratogenic) -formal consent required for women of childbearing potential (REMS program) -2 forms of birth control required

**What drug interactions occur with mycophenolic acid?

Other myelosuppressive drugs -Valganciclovir -Sirolimus (increases myelosuppression)

What is the most common place in therapy for the mTOR inhibitors (Sirolimus, Everolimus)?

Most commonly used to replace mycophenolate

**How are the mTOR inhibitors metabolized?

CYP 3A4 + P-glycoprotein *same mechanism as the calcineurin inhibitors*

**What is Sirolimus approved for?

Kidney transplant

**What Everolimus approved for?

Kidney + Liver transplant

**What are the adverse effects of the mTOR inhibitors? (sirolimus, everolimus)

Edema *Hyperlipidemia *Hypertriglyceridemia *Impaired wound healing Mouth ulcers Proteinuria

When would we NOT want to give an mTOR inhibitor?

If they have had recent surgery or are going to have surgery Avoid immediately post-transplantation -impaired wound healing

**What drugs were the original cornerstone of immunosuppression?

Corticosteroids

**How are corticosteroids dosed for transplants?

Tapered to low dose or completely off post- transplant Some centers use early steroid withdrawal or steroid-free regimens

What are important points to know about corticosteroid adverse effects and what are the main adverse events to watch?

*The adverse events are related to both average and cumulative duration doses* -Hyperglycemia -Hypertension

**When is Belatacept contraindicated?

Liver transplants EBV seronegative patients (must be positive to receive)

**What is the dosing of Belatacept?

IV only -Given every 4 weeks at an infusion clinic

**What is a benefit to Belatacept dosing?

Guaranteed adherence

**What is the place of Belatacept in transplant therapy?

Replacement or adjunct to CNI

What is the preferred regimen for Maintenance Immunosuppression?

Tacrolimus + Mycophenolate + Prednisone

What is the typical regimen for Acute Cellular Rejection?

Mild-Moderate: High-dose corticosteroid Moderate-Severe: Rabbit antithymocyte globulin Refractory: alemtuzumab

What is the typical regimen for Antibody Mediated Rejection (AMR)?

Steroids +/- Rituximab +/- IVIG

What infection are transplant patients at the biggest risk for?

PCP/ PJP

**What do we use to treat a PCP/PJP infection in transplant patients?

Sulfamethoxazole-Trimethoprim (Bactrim)

**What do we use to treat an HSV, VZV, or Cytomegalovirus infection in transplant patients?

Valganciclovir

**What do we use to treat a fungal infection in transplant patients (aspergillus spp.)?

Posaconazole

What pathogen are we most concerned about in lung transplants?

Aspergillus

Final: Transplants Flashcards

(103 cards)