Transplant Pharmacotherapy

Panel Reactive Antibody (PRA)

How likely the patient is to react against donor organs

Higher PRA = more preformed antibodies → higher rejection risk

Factors that contribute to higher PRA: prior transplant, blood transfusions, pregnancy

Kidney Donor Profile Index (KDPI)

How “good” the donor kidney is and how long it’s expected to last

Higher KDPI = higher risk of graft failure

Factors that may contribute to higher KDPI: older donor, donor comorbidities (HTN, DM, hepatitis, CVA, donation after cardiac death)

Induction Choice: Basiliximab

Low risk level

Key Factors: Low PRA, living donor, good match

Induction Choice: Antithymocyte globulin (ATG)

High risk level

Key Factors: High PRA, prior transplant, deceased donor

Kidney Disease Improving Global Outcomes (KDIGO) Guidelines For Induction

Use combination therapy - Induction agent + antiproliferative + corticosteroids

Start meds before or at the time of transplant

KDIGO Induction Agent Selection: Interleukin-2 receptor antagonists (IL2-RA)

first line for patients with low to moderate immunologic risk

KDIGO Induction Agent Selection: Lymphocyte depleting agents

for patients with high immunologic risk

Low risk: Agent examples

Basiliximab induction

steroids

mycophenolic acid

Calcineurin inhibitor (day 1-2)

High risk: Example agents

Antithymocyte globulin induction

Steroids

Mycophenolic acid

Calineurin inhibitors (a few days later)

Rabbit Antithymocyte Globulin (Thymoglobulin)

Requires premedication to reduce infusion related reactions

Give acetaminophen, diphenhydramine, corticosteroid

Give premeds ~60 minutes before Thymoglobulin infusion

Rabbit Antithymocyte Globulin Dose

1.5 mg/kg IV q24hrs

~3-5 days

Administer through an in-line 0.22 micron filter

1st dose: infuse over at least 6 hours through a high flow vein (i.e. central line). Increased risk for thrombosis and phlebitis if administered via a peripheral IV line

Subsequent doses: infuse over at least 4 hours via a dedicated line

Rabbit Antithymocyte Globulin Adverse Effects

Thrombocytopenia, neutropenia cytokine release syndrome, serum sickness, allergic reaction

Basiliximab

Lower non-immune toxicity compared to lymphocyte depleting agents

Typically does not require premedications

1st dose given within 2 hours before kidney transplant surgery

2nd dose given 4 days after surgery

Give over 20-30 minutes

Giving the drug too fast can cause nausea, vomiting, and pain at the injection site

Corticosteroids

Methylprednisolone (Solu Medrol), Prednisone (Deltasone), Predisolone (Orapred), etc.

Note: some patients with underlying autoimmune disease may require indefinite therapy with steroids

Corticosteroids ADEs

Hyperglycemia

Hypertension

Mood swings, and personality changes

GI upset, GI hemorrhage

Adrenal suppression

Impaired wound healing

Cushing’s syndrome

Increased bone loss, growth suppression in children

Steroid Avoidance

Steroids are used initially

Steroids withdrawn during the 1st week post-transplant

Steroid Free

no steroids

Steroid Withdrawal

Steroids used initially

Steroids withdrawn later in therapy (after the 1st week post-transplant)

Typical Induction Immunosuppression Regimen For a Kidney Transplant Patient

1. Antiproliferative agent, given 1st dose on admission to hospital for transplant surgery, continued as maintenance immunosuppression post transplant surgery (Example: Cellcept or Myfortic; Azathioprine for patients who cannot tolerate)

2. Induction agent selected based on immunologic risk (Example: Basilximab [Simulect] for low to moderate risk or Rabbit antithymocyte globulin (Thymoglobulin) for patients with high immunologic risk

3. Corticosteroid (example: Methylprednisolone AKA Solu Medrol

KDIGO Recommendations For Maintenance Therapy

Use combination therapy

Calcineurin inhibitor (CNI) + antiproliferative agent +/- corticosteroids

First line CNI: tacrolimus (Prograf)

First line antiproliferative agent: mycophenolate (Cellcept or Myfortic)

DC steroids during first week post transplant for low immunologic risk patients

Tacrolimus (Prograf)

Calcineurin inhibitor of choice for maintenance therapy

Typically not started until patient’s renal function shows adequate improvement due to risk for nephrotoxicity

Tacrolimus (Prograf) ADEs

Higher incidence of post transplant diabetes compared to CSA

Neurotoxicity (tremors) and nephrotoxicity

Magnesium wasting

Increased risk for anaphylaxis with IV formulation

Increased risk of toxicity in patients who have acute diarrhea

Drug-drug interactions (e.g. fluconazole + tacrolimus) and drug-food interactions (e.g. grapefruit juice)

Cyclosporine (CSA)

Used for patients when tacrolimus is not appropriate (e.g. patients who are at increased risk for diabetes)

Cyclosporine (CSA) ADEs

Higher incidence of hypertension, hyperlipidemia, hirsutism, and gingival hyperplasia compared to tacrolimus

Neurotoxicity and nephrotoxicity

Lower incidence if new onset diabetes compared to tacrolimus

Drug-drug interactions (e.g. fluconazole + cyclosporine) and drug-food interactions (e.g. grapefruit juice)

Mycophenolate

Is the preferred antiproliferative agent

Cellcept, Myfortic

Mycophenolate Adverse Effects

GI upset and diarrhea (common)

The drug absorbs best when given on an empty stomach but may be given with food for patients who experiences GI effects when taken on an empty stomach

Less GI effects with delayed release formulation Myfortic (mycophenolic acid)

Neutropenia & anemia

Embryofetal toxicity - Prescribers and pharmacies must perform Risk Evaluation and Mitigation Strategy (REMS) for all female patients of child bearing age

Azathioprine

2nd line antiproliferative agent

For patients who cannot tolerate mycophenolate due to adverse effects

Adverse effects of concern: leukopenia and bone marrow depression

Sirolimus (Rapamune)

For patients who cannot tolerate calcineurin inhibitors

Typically not started until graft function is established and surgical wounds are healed

Sirolimus (Rapamune) ADEs

Not frequently used due to adverse effect profile

Delayed wound healing, delayed graft function, increased risk of lymphocele

Proteinuria

Hyperlipidemia

Thrombocytopenia

Avoid concomitant use with CNI due to increased risk for nephrotoxicity. If concomitant therapy is needed then use low dose of cyclosporine to reduce risk of nephrotoxicity

Everolimus (Zortress)

Alternative to sirolimus

Adverse effect profile similar to sirolimus

Belatacept (i.e. LEA29Y)

Labeled indication: Epstein-Barr virus sero-positive kidney transplant recipients

Use with basiliximab induction, mycophenolate, and corticosteroids

Risk Evaluation and Mitigation Strategies (REMS) due to increased risk for post-transplant lymphoproliferative disease (PTLD) in EBV negative patients

A Typical Maintenance Immunosuppression Regimen For a Kidney Transplant Patient

1. Mycophenolate (either Cellcept or Myfortic) - Antiproliferative agent; Azathioprine is an alternative agent

2. Tacrolimus (Prograf) - CNI; cyclosporine is alternate agent for patients who cannot tolerate

3. ± prednisone or prednisolone (Orapred)

Vaccinations

Avoid live vaccines post-transplant

Only give inactivated vaccines according to the recommended schedules

Hold routine vaccinations within the first 6 months after transplant except for influenza vaccine

Give influenza vaccine prior to onset of flu season to patients who are at least 1-month post-transplant

3 doses of mRNA COVID-19 vaccine + “updated vaccines” based on current CDC recommendations

Cytomegalovirus (CMV) prophylaxis

D+/R- carries the highest risk for CMV disease

Prophylaxis therapy recommended for all patients except when both the donor & recipient have negative serologies (D-/R-)

Incidence of CMV disease in D-/R- is < 5%

Valganciclovir PO for at least 3 months after transplant

Valganciclovir PO for at least 6 months after treatment with a T-cell depleting antibody

Pneumocystis jirovecii Pneumonia

Referred to as PCP or PJP

Prophylaxis with SMX/TMP (sulfamethoxazole/Trimethoprim) for 3 to 6 months post-transplant

Efficacy for PCP prophylaxis is similar for once daily vs three times weekly dosing

Once daily dosing may have added benefit for UTI prophylaxis

Alternative Agents for PCP

Dapsone – test patients for Glucose-6-phosphate dehydrogenase deficiency (G6PD)

Atovaquone – PO given once daily for prophylaxis

Pentamidine – inhalation given monthly

Candida

Prophylaxis therapy against oral and esophageal Candida infections for 1 to 3 months post-transplant with antithymocyte antibody

Oral clotrimazole lozenges

Nystatin suspension swish and swallow

Fluconazole orally