Lecture 2: Solid Organ Transplant

Question 1

Indications for Organ Transplant

Answer 1

NOTE: There are 5 main organ transplants! The most common one being kidney! Which is what we will mainly focus on. In NM there is only kidney transplant for now.

Question 2

Organ Transplant Epidemiology (USA)

Answer 2

NOTE: There is an increased in transplant surgery however there are still a large number of ppl who needs transplant organ! and that number is growing! # of ppl waiting on transplant list is growing!

Question 3

Goals of Immunosuppression…a balance

Answer 3

Goal is to
*Prevent rejection
*Avoid complications with high dose immunosuppressants (we can lower the dose by using multiple agents so we can use lower dose of each one! to decrease the chances of side effects)
*Patient and graft survival
*Patient adherence

Question 4

Adaptive immune cell flowchart

Answer 4

Question 5

Phases of Immunosuppression

Answer 5

Question 6

Immunogenicity of Various Organs

Answer 6

NOTE: Liver and kidney may need lower dose/ not as strong of induction/ maintenance agents as transplant!

Question 7

Potency of Immunosuppression

Answer 7

Question 8

Induction Therapy and Goals?

Answer 8

*Goal:
–Prevent early acute allograft rejection using intense, prophylactic immunosuppression therapy
–This produces profound deficiency on T cells and/or B cells that can last months (induction agents can last 1-3months depending. so you can choose maintenance based on this)
.
DRUGS:
*Basiliximab (less immunosupp)
*Antithymocyte globulin
*Alemtuzumab (most immunosupp)

Question 9

Induction Therapy: Basiliximab (Simulect®) MOA and general info

Answer 9

*Mechanism of action:
–Blocks T-cell proliferation via Interleukin-2 (IL-2) reception antagonism (anti-CD25 antibodies)
.
*Used in lowest immunologic risk patients
*Decreased infection rates when compared to other
agents (because it is a weak immunosupp)
*Does not lead to sustained depletion of lymphocytes and related CD4 helper T cells

Question 10

Induction Therapy: Antithymocyte Globulin (Thymoglobulin®)

Answer 10

*Mechanism of Action:
–Binds to T-cell surface antigens leading to the
elimination of T-cells (a stronger immunosupp agent)
*Used in moderate to high immunologic risk
*Increased risk for BK virus (BKV) and Cytomegalovirus
*PJP and other invasive fungal pathogens have been associated with thymoglobulin

Question 11

Induction Therapy: Alemtuzumab (Campath®)

Answer 11

*Mechanism of Action:
–Binds to CD52 on T-cells, B-cells, NK cells, and
monocytes/macrophages causing complement activation
and antibody-dependent cellular toxicity (acts on all parts!!)
* “AIDS” in a bottle, results to pan T-cell depletion
*Used as steroid sparing induction
* CD4/CD8 counts nadir at 4 weeks, 1+ years for recovery
*Associated with many opportunistic infections
.
NOTE: A strong induction therapy! last up to 1 year but some studies have shown it to last up to 3. So if you use a strong induction? you may delay using maintenance or use a weaker maintenance therapy.

Question 12

Maintenance Therapy: Goals and classes of drugs

Answer 12

*Goal:
–Prevent allograft rejection (can happen later on after surgery too! the chances and risks are lower the longer the period of time from surgery)
–Maintain an adequate balance of graft function, adverse effects, and prevention of infection
* Lifelong immunosuppression
.
DRUGS: no gold standard… it’s really patient dependent!
*Corticosteroids
*Calcineurin inhibitors
*Antimetabolites
*mTOR inhibitors

Question 13

Maintenance Therapy: Corticosteroids … MOA, dosing, AE?

Answer 13

*Oldest immunosuppressive agent used in transplantation
.
*Mechanism of Action:
–Inhibition of cytokine gene expression
–Modification of lymphocyte distribution and function
–Anti-inflammatory effects
.
*Dosing:
–Prednisone 5-10 mg/day (maintenance dose… higher doses for stuff like arthritis and induction!)
◦ Higher doses are used for induction & rejection therapy
.
Adverse Effects
SHORT TERM (mainly for the high dose inductions):
–Mood alterations
–Hyperglycemia
–Hypertension
–Increased appetite
–Insomnia
–Mood changes
–Acne
–Leukocytosis
.
LONG TERM (for maintenance use):
–Osteoporosis
–Chronic adrenal
insufficiency
–Ulcerative esophagitis
–Hirsutism
–Pancreatitis
–Amenorrhea
–Diabetes mellitus

Question 14

Maintenance Therapy: Calcineurin Inhibitors (two main meds)

Answer 14

1.) Tacrolimus - prograf, hecoria, astagraf XL
2.) Cyclosporine - neoral, gengraf, sandimmune

NOTE: there are several different brands…these are NOT interchangeable! so pay attention to the medications!

Question 15

Maintenance Therapy: Calcineurin Inhibitors -> Tacrolimus PART 1: products, MOA, PK/PD

Answer 15

1.) Products:
– Prograf® (capsules, IV)
–Generic tacrolimus (capsules, IV)
– Astagraf XL® (extended release capsules)
– Envarsus XR® (extended release capsules)
– Compounded oral suspension
*Also called FK506
.
2.) MOA:
– Inhibits T-cell activity through inhibition of IL-2 production
.
3.) PK & PD
Absorption: Incomplete and variable
–Best absorbed on an empty stomach
–Bioavailability: 7 - 32%
Distribution: highly lipophilic
–99% protein bound (albumin and α1-acid glycoprotein)
Metabolism: extensive CYP3A4, p-glycoprotein
–Half life: ~ 9 hours (immediate release) and ~ 34 hours (extended release)

Question 16

Maintenance Therapy: Calcineurin Inhibitors -> Tacrolimus PART 2: Dosing and therapeutic goals

Answer 16

Dosing:
–Immediate Release: 0.05-0.1mg/kg/day in divided doses
◦ Generally ~1-4 mg BID
–Extended Release: 0.1-0.2 mg/kg/day one time daily
.
Dose adjusted based on trough concentrations and
renal function!
–Goal concentration varies: Time after transplant, type of organ transplanted, infection (NOTE: you will need to aim for a higher trough level right after operation because that’s when you have the highest risk of rejection!)
- Therapeutic range 5 – 15 ng/mL

Question 17

Maintenance Therapy: Calcineurin Inhibitors -> Tacrolimus PART 3: Interactions and AEs

Answer 17

INTERACTION:
1.) Interactions are primarily through hepatic metabolism CYP3A4: inhibition or induction
–Examples: Ketoconazole, fluconazole, diltiazem, and grapefruit juice inhibit CYP3A4 (so increases drug amount) …. Phenytoin and rifampin induce CYP3A4
2.) P-glycoprotein substrate (severe diarrhea can increase tacrolimus levels)
3.) Antacids: Physical interaction by reduced absorption
–Separate by at least 2 hours
.
AEs:
-Hypertension
-Diarrhea
-Nephrotoxicity
-Headache
-Hepatotoxicity
-Neurotoxicity (tremors)
-Hyperglycemia* (*more common in tac than cyclosporine)
-Pruritis
-Hyperkalemia
-Hypomagnesemia
-Infection
-Alopecia

Question 18

Maintenance Therapy: Calcineurin Inhibitors -> Cyclosporine PART 1: products, MOA, PK/PD

Answer 18

1.) Products:
–Modified microemulsion formulation: Neoral® or Gengraf®
–Unmodified formulation: Sandimmune®
–Sandimmune® & Neoral®/Gengraf® are not
equivalent!!! Not interchangeable!
.
2.) MOA:
–Inhibits T-cell proliferation through inhibition of IL-2
production.
.
3.) PK & PD
Absorption: erratic and incomplete
–Non-modified: largely dependent on food, bile acids,
and GI motility
–Modified: up to 30% increase, less dependent on
food, bile acids, and GI motility
Distribution: highly lipophilic
–98% protein bound (lipoproteins)
*Metabolism: CYP3A4 (extensive), p- glycoprotein (similar to tac)

Question 19

Maintenance Therapy: Calcineurin Inhibitors -> Cyclosporine PART 2: Dosing and therapeutic goals/ ranges

Answer 19

Dosing:
– 10-15 mg/kg/day in divided doses to attain target trough levels
.
Dose adjusted based on trough concentrations
and renal function
–Goal concentration varies: Time after transplant, type of organ transplanted, infection (same as tac!)
.
Therapeutic Range: 50-200 ng/mL

Question 20

Maintenance Therapy: Calcineurin Inhibitors -> Cyclosporine PART 3: Interactions and AEs

Answer 20

Primarily through hepatic metabolism CYP3A4: inhibition or induction (just like tac!) * P-glycoprotein substrate! like tac!
.
-Anticipate and manage –> high inter- and intra- patient variability
-Nephrotoxic drugs should be used with caution
- Consistent administration with or without food
.
AEs: in pic

Question 21

Calcineurin Inhibitors Overview/ summary

Answer 21

1.) TACROLIMUS: Binds to FKBP12, Dosing: 0.05-0.1mg/kg/day in divided doses to attain target trough levels, Monitoring: trough levels
.
2.) CYCLOSPORINE: Binds to cyclophilin, Dosing: 10-15 mg/kg/day in divided doses to attain target trough levels, Monitoring: trough and C2 levels

Question 22

Maintenance Therapy: Antiproliferatives -> Mycophenolate PART 1: Products and MOA

Answer 22

next main class of maintenance med that’s
usually used in combo w/calcin (tac.)! will typically use Mycophenolate Mofetil (Cellcept) or Mycophenolate
Sodium (Myfortic) ! NOT INTERCHANG! .
.
PRODUCTS:
–Mycophenolate Mofetil (MMF or Cellcept)
–Mycophenolate Sodium (Myfortic)
THEY ARE ALL Prodrugs for mycophenolic acid (MPA)
.
MOA:
–Inhibition of inosine monophosphate dehydrogenase
(IMPDH) –> inhibits de novo guanosine nucleotide synthesis
–Prevents T and B lymphocytes proliferation

Question 23

Maintenance Therapy: Antiproliferatives -> Mycophenolate PART 2: Dosing and Dosing conversion

Answer 23

Question 24

Maintenance Therapy: Antiproliferatives -> Mycophenolate PART 2: Adverse Effects and interactions

Answer 24

NOTE: An important warning…
Teratogenicity!!!!
–Shown to cause fetal harm
–Negative pregnancy test prior to starting medication
–Women of child-bearing age required to use at least two methods of contraception!

Question 25

Maintenance Therapy: Azathioprine (an antimetabolite) PART 1: MOA, uses, dosing

Answer 25

Question 26

Maintenance Therapy: Azathioprine (an antimetabolite) PART 2: Interactions and AEs

Answer 26

Adverse Effects: –GI Intolerance –Leukopenia, anemia, thrombocytopenia –Increased alkaline phosphatase, total bilirubin & transaminases . Drug interactions: –Mercaptopurine – profound myelosuppression –Allopurinol – inhibits metabolism of azathioprine and 6- MP leading to profound myelosuppression

Question 27

Maintenance Therapy: mTOR Inhibitors (the two drugs) general

Answer 27

1.) Sirolimus (Rapamune®) . 2.) Everolimus (Zortress, Afinitor®)

Question 28

Maintenance Therapy: mTOR Inhibitors --> Sirolimus: MOA, Use, Dosing, AEs, and Interactions

Answer 28

1.) Mechanism of Action: –Binding to FKBP-12 inhibition of mTOR (mammalian target of rapamycin) –Suppresses cytokine mediated T-cell proliferation . 2.) Use: –May be used to replace mycophenolate or a calcineurin inhibitor (tacrolimus or cyclosporine) can also be a 4th add on! . 3.) Dosing: –1-5 mg/day to attain target trough levels . 4.) Adverse Effects: – Edema – Anemia – Impaired wound healing (NOTE: the biggest downfall! because post op pt need faster healing!) – Interstitial lung disease – Proteinuria – Hyperlipidemia . 5.) Interactions: – Metabolized through CYP 3A4 – Similar interactions with cyclosporine and tacrolimus

Question 29

Maintenance Therapy: mTOR Inhibitors --> Everolimus: MOA, Use, Dosing, AEs, and Interactions

Answer 29

THIS IS 3X THE COST OF SIROLIMUS SO THAT'S WHY WE PREFER THAT ONE! . 1.) Mechanism of Action: –Binding to FKBP-12 --> inhibition of mTOR (mammalian target of rapamycin) –Suppresses cytokine mediated T-cell proliferation . 2.) Use: –Renal transplant rejection prophylaxis –Off-label use: heart transplant rejection prophylaxis . 3.) Dosing: –0.75-1 mg PO twice daily to attain target trough levels . 4.) Adverse Effects (similar to siro): – Edema – Anemia – Impaired wound healing – Proteinuria – Hyperlipidemia . 5.) Interactions: – Metabolized by CYP3A4 ◦ Similar drug interactions as cyclosporine and tacrolimus – Consistent administration in regards to food

Question 30

Maintenance Therapy: mTOR Inhibitors --> Everolimus: MOA, Use, Dosing, AEs, and Interactions

Answer 30

THIS IS 3X THE COST OF SIROLIMUS SO THAT'S WHY WE PREFER THAT ONE! . 1.) Mechanism of Action: –Binding to FKBP-12 --> inhibition of mTOR (mammalian target of rapamycin) –Suppresses cytokine mediated T-cell proliferation . 2.) Use: –Renal transplant rejection prophylaxis –Off-label use: heart transplant rejection prophylaxis . 3.) Dosing: –0.75-1 mg PO twice daily to attain target trough levels . 4.) Adverse Effects (similar to siro): – Edema – Anemia – Impaired wound healing – Proteinuria – Hyperlipidemia . 5.) Interactions: – Metabolized by CYP3A4 ◦ Similar drug interactions as cyclosporine and tacrolimus – Consistent administration in regards to food

Question 31

Maintenance Therapy: Belatacept: Indication, MOA, Dosing, AEs

Answer 31

Question 32

Generic Medications Generic immunosuppression availability:

Answer 32

–Tacrolimus –Mycophenolate –Cyclosporine –Sirolimus Patients are encouraged to maintain consistency with the product they use

Question 33

Immunosuppression Considerations: We are always changing regimen based off of...

Answer 33

*Rejection *Toxicity *Adverse Effects *Variability *Infection *Malignancy *Cost *Drug-drug interactions

Question 34

Immunosuppression Complications ... what are the top 3?

Answer 34

*Cardiovascular (the leading cause of mortality in transplant patient!) *Infectious *Malignancy . 1.) Cardiovascular Complications --> Leading cause of mortality in renal transplant recipients! –Hypertension –Hyperlipidemia –Diabetes . 2.) Infectious Complications --> Highest risk immediately following transplant and rejection treatment –Related to degree of immunosuppression -Opportunistic infections -Atypical organisms -Prophylaxis . 3.) Malignancy --> Related to degree of immunosuppression –Increased risk with increased survival - Lung, breast, colon, and prostate cancer are not increased compared to general population - Increased risk of lymphomas and lymphoproliferative disorders, Kaposi’s sarcoma, renal carcinoma, and skin cancers!!! SO WEAR SPF!

Question 35

What are the 2 different types of Rejection?

Answer 35

Question 36

Sensitization & Risk Factors for Rejection

Answer 36

Question 37

Barriers to Adherence

Answer 37

Question 38

Patient Case: MG -HPI: MG is a 40 year old female with a past medical history of ESRD secondary to hypertension and recurrent UTIS – on hemodialysis MWF since April 2019. She is admitted today as a potential kidney transplant recipient. -Donor Info: Donation after Cardiovascular Death (DCD) Kidney Donor Profile Index (KDPI) - 5% -Recipient info: ESRD likely secondary to HTN and recurrent UTIs; Last HD November 021 Panel Reactive Antibodies (PRA) - zero . Step 1: break that down. what does each lab result mean? . Home Medications -Amlodipine 10 mg daily -Hydralazine 25 mg TID -Metoprolol Tartrate 50 mg BID -Norethindrone-ethinyl estradiol 1/35 once a day . Step 2: What Induction Agent would you use??? and why?

Answer 38

Step 1: Donor died by DCD! So that's bad becuase that will increase the risk of rejection! So you may need a stronger immunosupp drug!...The KDPI- the lower the % the better = meaning that kidney will last longer after transplant a score of 5% is so good..prolly from a kid. Panel Reactive Antibodies (PRA) - zero: PRA shows you how likely is it gonna reject! So the lower the score the better so not likely to rej so can use a weaker immunosupp! . Step 2: Induction agent to pick from *Basiliximab (Simulect®): may be considered in lowest immunologic risk patients *Antithymocyte Globulin (Thymoglobulin®): may be considered in moderate to high immunologic risk *Alemtuzumab (Campath®): May be considered to provide steroid sparing induction -ANSWER: Would opt for Antithymocyte Globulin (Thymoglobulin) as the donor is DCD!!!! Main side effect of this med is low WBC! so you must closely monitor the patient WBC and hold med if it gets too low! (NOTE: WBC may be high post op day 1! NOT from infection but from inflammation from surgery, it should go down the following days.)