Kidney Transplant Therapeutics (Tran/Won)

In the immunologic risk assessment step, who are considered low risk for rejection?

1st transplant, low panel reactive antibodies (PRA), no donor specific antibodies (DSA), negative human leukocyte antigen (HLA) crossmatch

In the immunologic risk assessment step, who are considered high risk for rejection?

previous transplant, high PRA, positive DSA, positive HLA, crossmatch, african-american, pregnant (?)

What are the induction meds?

ATG [Rabbit] (Thymoglobulin), Basiliximab (Simulcet), Alemtuzumab (Campath)

Who are CI for ATG (Thymoglobulin)?

Rabbit allergy

What type of biopharmaceutical is ATG (Thymoglobulin)?

polyclonal antibody (from rabbits)

MOA of ATG

binds to T-cell surface antigens and depletes T-cells

Indication of ATG

Patients at HIGH immunologic risk

What are the premedications that you have to give to the patient before you give Thymoglobulin? How long prior to ATG administration?

methylprednisolone or prednisone, APAP, and diphenhydramine (helps with initial allergic/histamine reaction), 30-60 minutes

What is the route of administration for ATG (and what is its benefits)?

central line preferred, avoid phlebitis and thrombosis

If the patient only has peripheral line available, what is the procedure to administer Thymoglobulin?

heparin and hydrocortisone

When administering peripheral line Thymoglobulin, heparin and hydrocortisone are in addition to which premedication?

methylprednisolone or prednisone, APAP, and diphenhydramine

When administering Thymoglobulin through central line, is heparin and hydrocortisone required?

No, there is less risk of thrombosis and phlebitis through central

what are the monitoring parameters with AGT [Rabbit] (Thymoglobulin)?

Infusion reaction, Serum Sickness, Cytokine release syndrome

What biopharmaceutical is Basiliximab (Simulect)?

chimeric monoclonal antibody

MOA of Basiliximab (Simulect)

blocks a-subunit of IL-2 receptor (and IL-2 binding), preventing T cell activation from IL-2 cytokine

Is Basiliximab (Simulect) a maintenance drug?

no

Who are indicated for Basiliximab (Simulect)?

patients at LOW immunologic risk, high risk of infection (can’t take thymoglobulin), or renal dysfunction that affect CNI fxn

(don’t focus on dosing) When should basiliximab (Simulect) be taken after surgery?

20 mg day of transplant, 20 mg on POD (post-op day) 3 or POD 4 (2 doses total)

Basiliximab (Simulect) is infused 20-30 min through which line?

peripheral or central line

Does Basiliximab (Simulcet) require premedication?

no (another difference from Thymo)

What monitoring parameters should be followed with basiliximab?

Gi upset, infusion reaction

What is the first-line for post-transplant therapy?

calcineurin inhibitors + mycophenolic acid/antimetabolite + coricosteroids PO

What are the CNIs?

tacrolimus (Prograf, Astagraf, Envarsus XR), cyclosporine (Gengraf, neoral, sandimmune)

What are the CS?

Methylprednisolone, prednisone

Which Tacrolimus brand names are once daily dosing?

ER-TAC (Astagraf) and LCP-TAC (Envarsus EX)

When managing tacrolimus-induced nephrotoxicity, what are the options?

DECREASE dose of tacrolimus and add sirolimus/everolimus OR d/c tacrolimus and add sirolimus/everolimus

Are dosage forms interhchangeable (PO and IV)?

NO

What are the IV:PO conversion for Tacrolimus? (ON EXAM)

1:4

What are the PO:SL conversion for Tacrolimus?

2:1

What are the IR-TAC:LCP=TAC conversion for Tacrolimus?

1: 0.8 (TDD)

What are the IR-TAC:ER-TAC conversion for Tacrolimus?

1:1 (TDD)

What are the IV:PO conversion for cyclosporine?

1:3

What are the modified (Neoral or Gengraf) : Non-modified (Sandimmune) conversion for cyclosporine?

variable (non-modified/Sandimmune has higher bioavailability and absorption can depend on bile production)

How long after administration is steady state reached after cyclosporine administration?

2 days

How long after administration is steady state reached after IR-TAC (Prograf) administration?

2-3 days

How long after administration is steady state reached after LPC-TAC (Envarsus XR) and ER-TAC (Astagraf) administration?

5-7 days

What are major DDIs with CNIs?

CNIs are CYP3A4 and P-gp substrates → interact with CYP3A4 inhibitors and inducers

What are major CYP3A4 inhibitors that interact with CNIs?

Antifungals (-azoles), CCBs (Verapamil, diltiazem, -dipine), Macrolide Antibiotics (clarithromycin), and others (grapefruit, protease inhibitors…)

What are major CYP3A4 inducers that interact with CNIs?

Antibiotics (rifampin), antiepileptics (phenytoin, phenobarbital, carbamazepine), and others (St. John’s Wort…)

Which adverse effects are more prominent with higher peak levels or exposure with cyclosporine and tacrolimus?

nephrotoxicity, neurotoxicity (HA, tremor), hypomagnesemia, hyperkalemia

Which side effects are more prevalent with cyclosporine than tacrolimus?

hyperlipidemia, hypertension, hirsutism, gingival hyperplasia

Which side effects are more prevalent with tacrolimus than cyclosporine?

neurotoxicity (HA, tremor), hyperglycemia, alopecia

Which medications require therapeutic drug monitoring?

sirolimus, everolimus, cyclosporine, tacrolimus

MT is currently taking tacrolimus 2 mg SL BID. The team wants to convert him to IR capsules. What is the equivalent dose via oral route?

Key: PO:SL = 2:1 → 4mg PO BID

Which are the antimetabolites/antiproliferatives?

mycophenolate mofetil, MMF (Cellcept), mycophenolic acid, EC-MPA (Myfortic), azathioprine (Imuran)

What is the main administration rule with Mycophenolate (especially for Myfortic) and Azathioprine (Imuran)

do NOT open, chew, crush, or split oral capsules or tablets (enteric coated)

What is the conversion between IV:PO for Mycophenolate? (ON EXAM)

1:1

What is the conversion between MMF:EC-MPA for Mycophenolate? (ON EXAM)

250mg MMF : 180mg EC-MPA

What are the side effects with mycophenolate?

GI (diarrhea, nausea, pain, dyspepsia), leukopenia, thrombocytopenia (low count of platelets), anemia

What are the common reasons for dose adjustments with mycophenolate?

(typically halve the current dose) when GI intolerance, leukopenia, infection

What are the requirements for men and women when taking mycophenolates due to it being in the REMS Program?

women of child-bearing age → 2 contraception, men → 1 contraception

What are the DDIs with mycophenolate?

Iron, Ca, Al, or Mg antacids, cholestyramine, and sucralfate decrease absorptions

How to mitigate DDIs between mycophenolate and Fe, Ca, Al, Mg antacids?

separate admin by 2 hours before/after

What genetic testing is required for azathioprine?

TPMT activity (Thyoprine methyltransferase affects metabolism/toxicity; if low/absent → increase risk of toxicity)

What are the common reasons for dose adjustment with azathioprine? (sim to mycophenolate)?

leukopenia, alopecia, myelosuppression

What are the side effects with azathioprine?

bone marrow suppression (myelosuppression), alopecia, stomatitis, mucositis, N/V, Hepatotoxicity, arthralgias/myalgias

What medications can cause myelosuppression?

Mycophenolate, azathioprine

What medications can cause hepatotoxicity?

azathioprine

What is the conversion between methylprednisolone and prednisone? (ON EXAM)

4 mg IV methylprednisolone : 5 mg PO prednisone

What is a key administration rule with CS?

ALWAYS TAPER

What are the short-term side effects with CS?

increase BP, blood glucose, appetite; fluid retention; GI upset; mood changes; insomnia

What are the long-term side effects with CS?

moon face, cataracts, HTN, diabetes, dyslipidemia, muscle weakness, osteoporosis, striae/thin skin, impaired wound healing

What are the mTOR inhibitors (mechanistic target of Rapamycin)

sirolimus (Rapamune), everolimus (Zotress)

What are the benefits of sirolimus and everolimus compared to CNIs?

decreased nephrotoxicity

What are the differences between sirolimus and everolimus?

less hyperlipidemia risk with everolimus, sirolimus (QD) and everolimus (BID)

What are the side effects with sirolimus and everolimus?

impaired wound healing, hyperlipidemia (TGs), mucositis, pneumonitis, thrombocytopenia (anemia → fatigue), rash, arthralgia

What is the reason why sirolimus and everolimus are not taken right after transplant?

impaired wound healing (mainly), thrombocytopenia, pneumonitis

What are the DDIs with mTOR inhibitors?

CYP3A4 inducers/inhibitors

Who are indicated for Belatacept?

CNI-sparing regimens (no cyclosporine or tacrolimus)

What is belatacept usually taken with?

mycophenolate mofetil (MMF) or everolimus, and CS

What is the boxed warning with belatacept?

CI in EBV IgG negative patients due to disproportionate rates of PTLD (post-transplant lymphoproliferative disorder - WBC multiple uncontrollably)

Dosing of belatacept is rounded to the nearest ______ increment?

12.5 mg

What is the BENEFIT Trial?

prospective, multicenter, phase III, randomized controlled trials

What are the interventions listed in the BENEFIT Trial?

less intense (LI) Belatacept, more intense (MI) Belatacept, and cyclosporine

What are the primary outcomes of the BENEFIT Trial?

Pts surviving with functioning graft, GFR < 60 ml/min/1.73m2 or GFR decrease month 3-12 ≥ 10ml/min/1.73m2, incidence of acute rejection

What was found with belatacept compared to cyclosporine within the first year in the BENEFIT Trial?

improved renal fxn at 12 months compared to cyclosporine

What was found with belatacept in the 7 year follow-up of the BENEFIT Trial?

improved renal function compared to cyclosporine at 84 months

What are the CNI-sparing medications?

sirolimus, everolimus, belatacept

Opportunistic infections can appear how soon after transplant?

1-12 months after (when max immune suppression occurs)

What are the opportunistic infections?

cytomegalovirus (CMV), Pneumocystis Jirovecii Pneumonia, Fungal infections (Candida and Aspergillus), Thrush

What is the preferred agent for Thrush Prophylaxis?

fluconazole

What are the agents that can be used for Thrush Prophylaxis?

Fluconazole, Clotrimazole, Nystatin

When using any of the Thrush prophylaxis agents for thoracic/lung infections, what do they also cover?

Aspergillus prophylaxis

How long should a patient be on thrush prophylaxis for kidneys?

1 months (3 months if HIV+)

How long should a patient be on thrush prophylaxis for lungs?

lifeling (thrush or Aspergillus prophylaxis)