SOLID ORGAN TRANSPLANT Limitations: Limited Donors REJECTION Infection Medication Side Effects Malignancy Death w/a functioning

oning graft Rejection risk: Rejection: Recognition of histocompatibility difference Mediated by activation of T-cells & APC such as B lymphocytes, macrophages, dendritic cells T-cells infiltrate the transplanted organ/tissue Triggers inflammation and cytotoxic effects Classes Class I and II antigens of the major histocompatibility complex (MHC) Class I most nucleated cells Class II B and T-helper cells T-helper cells which direct immune response require Class II for antigen recognition Cytotoxic cells require Class I for antigen recognition T-cell activation requires receptors, MHC, adhesion molecules and costimulatory molecules Acute Rejection: Most common In kidney rejections similar S/Sx to CSA/TAC nephrotoxicity (see chart) Primarily in first 3 months (<4 weeks**) T-Cell mediated immunity Cytotoxic cells cause direct cellular destruction Usually reversible when identified early - Emperic- Treat with high dose pulse steroids (500-1000 mg methylpred IV x 1-3 doses) African Americans are often resistant ATG a better 10 agent for this population -If it clears up w/empiric TX or biopsy (+) Increase dose of current immunosuppressant drug Addition of another immunosuppressive drug indefinitely -Short term treatment with a polyclonal or monoclonal antibody reserved for moderate to severe rejection Acute Rejection Often < 4 weeks post op ** Fever Hypertention Weight gain Graft swelling/ tenderness daily urine output Rapid rise in SCr (0.3 mg/dl/day) Normal CSA or TAC levels Interstitial lymphocytic infiltrates TCR signaling IL-2 gene transcription (cyclosporine, tacro, steroids) IL-2 secretion IL-2 receptor binding (daclizumab, basiliximab) IL-2 receptor signaling (sirolimus, everolimus) Proliferation (mycophenolate, azathioprine) CNI nephrotoxicity Often < 6 weeks post op No Fever Hypertention Graft not tender Good urine ouput Gradual rise in SCr (>0.15 mg/dl/day) Elevated CSA or TAC levels Interstitial fibroids, glomular thrombosis, arterial inflammation

Hyperacute rejection Occurs within minutes of revascularization Preformed anti-donor antibodies (ABO, MHC class I) - less common due to cross matching Activation of complement system, platelet aggregation, microvascular obstruction Thrombotic occlusions and/or hemorrhage Irreversible tissue necrosis Uncommon in kidney & . Can happen w/liver Humural rejection B-cell mediated Ab mediated process against human leukocyte antigens (HLA) on donor vascular endothelium Less common Primarily first 3 months More difficult to treat

Matching ABO blood type Tissue (T and B cell) Sensitization Prior transplant Blood transfusion Pregnancy Panel Reactive Antibody (PRA) Race- A.A & Hispanic > risk Age > 50-60 Donor source Live Deceased (brain vs. death) Delayed graft function Cold/warm ischemia time- travel time Chronic rejection

DDX HX

Slow, progressive decline in function Both B and T-cell mediated Months to years following transplant Difficult to separate from long term medication side effects Currently no treatment

S/SX

LABS Other Risks: Infection Highest immediately following transplant Bacterial, Viral and Fungal Prophylxis is key Hepatitis B and C recurrence and HIV reactivation Malignancy

Four fold increased risk Increase prevalence of PTLD, Kaposi sarcoma, renal, uterine and liver cancers Skin cancers are most common Usually occur many years from transplant

Immunosupressive agents
INDUCTION AGENTS Antithymocyte Globulin - ATGAM: equine - Thymoglobulin (RATG): rabbit Basiliximab - Simulect Daclizumab MAINTINANCE Corticosteroids -Methylprednisone Mycophenolate - Mofetil/Sodium Cyclosporine Tacrolimus Sirolimus,Everolimus Azathioprine Belatacept

Specific considerations- Maintenance CNI: Cornerstone of regimen; Tacro > CSA - BOTH ARE VERY NEPHRO-TOXIC -Neurologic (tremors, HA, peripheral neuropathy & seizures) Tacro > Cyclo - Hypertension: Cyclo > Tacro - Hyperlipidemia: Cyclo > Tacro - Hyperglycemia: Tacro > Cyclo - Cosmetic Cyclo= hirsuism & gingival hyperplasia (good hygene or switch to tacro) Tacro= alopecia Antimetabolites: Great add-on immunosuppressives -MMF = MPA(mycophenolate mofetil /acid) >> AZA -Myco: no nephro, neuro or hypertensice effects + cyclo = lower cyclosporine levels + acyclovir = higher levels of both -AZA: Big time hematologic issues Sirolimus: used to prevent kidney rejection. Use w/ CCS & cyclosporine or after DC of cyclo in patients w/ low or med. rejection risk May want to avoid for 1st 3 months to allow wound healing Better for the kidney / lipids will be a problem Lipids peak w/in 3 mos Can start a statin or fibrate Steroids: Are they so bad?? A new approach is to withdraw or eliminate CI after the early post-transplant period (> 3 months), but before the development of CI-induced nephrotoxicity or evidence of CAN MONITORING: 1-2 wks BUN/SCr Chem 7 LFT tests Kidney/ Liver Drug Levels CBC Lipid panels HbA Once Daily Daily Daily Once Once Once 1-3x week 1-2x week 1-2x week Q 3 mos Q 3 mos Monthly Q 1-2 wks Q 1-2 wks Q 1-2 wks Q 3 mos Q 3 mos Q 1-3 mos Monthly Monthly Monthly Q 3 mos Q 3 mos Q 1-3 mos Q 1-2 mos Q 1-2 mos Q 1-2 mos Q 3 mos Q 3 mos Daily Daily 1 month 1-2x week 1-2x week 2-4 months Q 1-2 wks Q 1-2 wks 4-12 months Monthly Monthly >12 months Q 1-2 mos Q 1-2 mos

Induction: Summary Potency: Thymocyte gobulin (ATG) >> Simulect ATG pro: Its preferred when there is a high risk of rejection ATG con: It increases the risk of infections, opportunistic infections, and malignancies Induction options: None; Simulect; ATG No induction may be suitable for very low risk recipients Patients who have a low reactive body panel Consider Simulect for recipients at low/moderate risk of rejection OR when there is concern about infections/malignancies Consider ATG for recipients at moderate/high risk of rejection OR when you plan to use minimizing maintenance regimens Maintenance: Summary Use 2-3 immunosuppressive with unique MOAs Med #1 is nearly always a calcineurin inhibitor (CNI) Tacrolimus, Cyclosporine Med #2 is often an antimetabolite Mycophenolate (Modafi/Acid), AZA, Depends on many factors: Organ (type, number, transport time) Donor (deceased, living) Recipient (age, underlying disease, PRA) Degree of match/mismatch Tolerance of immunosuppressive agents Rejection episodes (number, severity) A new approach is to withdraw or eliminate CI after the early post-transplant period (> 3 months), but before the development of CI-induced nephrotoxicity or evidence of CAN

Problem Infection

Pharmacotherapy
Herpes/ Zoster- acyclovir 10 mg/kg Q 8h CMV- Ganiciclovir 5mg/kg Q 12h P. carinii- Bactrim 400/80mg TIW Prophalaxis- Fungal (Candida) - nystatin 100,000 units every 6 h Treatment- Fungal (Candida)- azoles

Special Consideration
P. carinii prophalaxis for patients receiving acute rejection TXsulfa allergies: dapsone 100 mg daily + trimethoprim 1520 mg/ kg/day Q 6 h Caution- kidney issues: monitor CSA & TAC levels- decrease doses Adjust doses of acyclovir, Bactrim, valgancyclovir May be exacerbated by CSA, TAC, ACE-Is or Renal insufficiency CCS, TAC, & CSA increase glucose levels Caution w/metformin & renal insufficiency As perfusion improves, insulin demands will increase Decreased TAC absorption, adjust dose w/ renal fail CSA > TAC; consider switch to TAC; discontinue or hold SRL CSA/TAC may increase statin levels; start at lowest dose Monitor LFTs Diltiazem, verapamil inhibit CSA/TAC metabolism Dihydropyridines may potentiate CSA-gingival hyperplasia ACEIs; angiotensin II receptor antagonists May exacerbate hyperkalemia Monitor K+, Scr to assess for renal allograft vascular disease; may be useful in posttransplant erythrocytosis (HCT >55%)

Hyperkalemia Hyperglycemia

Restrict dietary intake, dialysis Fludrocortisone 0.1 mg PO for refractory hyperkalemia Pretransplant- Insulin, oral hypoglycemics Post transplant- Insulin, oral hypoglycemic, metformin

Ulcer Prophalaxis Hyperlipidemia

PPIs & H2 inhibitors Diet HMG-CoA reductase inhibitors (statins) Gemfibrozil

Hypertention
Calcium channel blockers - amlodapine

Osteoporosis

Oral calcium supplementation (1,0001,500mg/day) Oral vitamin D Calcifediol (1,000 international units/day)- If kidney functioning Calcitriol (0.5 mcg/day)- If kidney not functioning Calcitonin or oral bisphosphonates Documented loss in bone mineral density >3% Minimize immunosuppressant doses; Avoid sun exposure (sun block, hats, clothing); Routine self-examinations (skin, lymphnodes); Yearly gynecologic/prostate exams

If daily intake <1,000 mg elemental calcium Data lacking for bisphosphonates in patients with RI

Malignancy

AZA particularly associated with skin cancers CSA/TAC may be associated with lymphoproliferative disorders (lymphomas)

Tacrolimus- Prograf
Macrolide antibiotic compound Mechanism of Action- Binds to FK-binding protein (FKBP)

Cyclosporine- Sandimmune, Neoral, Gengraft, Generics

Cyclic polypeptide of fungal origin Mechanism of action- Binds to cyclophilin (cytoplasmic receptor protein)

Inhibits calcineurin phosphatase Prevents nuclear factor of activated T-cells (NF-AT) from entering the nucleus Inhibits production of IL-2 early in the T-cell activation pathway Inhibits expression of IL-2 surface receptors Minimal effects on B-cells DOSING IV: 1/3 PO dose, 20-100 ml D5 or PSS (non-PVC) over 2-6 hours Oral: mix with orange or apple juice, water Dosing Based on trough concentrations Initial range 5 - 10 mg/kg/day Maintenance range varies rejection, tox., and other immunodrugs used Therapeutic Range Whole blood: 100 - 400 mcg/L Plasma: 50 - 200 mcg/L TOXICITIES Renal - nephrotoxicity (dose dependent) Decrease Mg, increase K Hirsutism, gingival hyperplasia CNS - fine tremors Hyperlipidemia Infection Hypertension

DOSING IV infusion: 1/3 - 1/5 PO dose (0.03 - 0.1 mg/kg/day) Oral: 0.1 - 0.30 mg/kg/day in 2 divided doses Based on trough concentrations Maintenance range varies rejection, tox., and other immunodrugs used Therapeutic Range Early post-transplant: 10 - 20 ng/mL Late post-transplant: 3 - 10 ng/mL

TOXICITIES Nephrotoxicity GI complaints Hypertension Tremor Headache Absorption -Erratic (13-38%) - Does not require bile

Insomnia Hyperkalemia Higher risk for infection & lymphomas Hyperglycemia Pancreatitis Alopecia

Absorption -30-45% - Sandimmune - erratic and incomplete (requires bile) - Neoral-more complete (does not require bile) Half-life-About 8 hours-Varies in children, adults, ethnic groups Metabolism CYP3A4 enzyme system P-glycoprotein Excretion Primarily in bile Minimal renal excretion

Half-life- About 12 hours Varies in children, adults, ethnic groups Metabolism CYP3A4 enzyme system P-glycoprotein Excretion- Primarily in bile Minimal renal excretion

DDIs- BOTH CYCLOSPORINE AND TACROLIMUS

Decrease Levels Enzyme inducers Phenytoin Phenobarbital Rifampin Octreotide Carbamazepine Increase Levels - Enzyme inhibitors Diltiazem Ketoconazole Erythromycin Fluconazole Grapefruit juice Metoclopramide

Prednisone
Mechanism of Action
Affects both cellular and humoral immunity Interfere with macrophage function Inhibit synthesis and release of IL-1 & IL-2 secretion from T-cells Nonspecific immunosuppressive effects (IL-3, IL-6, interferon-gamma, TNF-) Anti-inflammation actions

Mycophenolate- CellCept, Myfortic

Mechanism of Action
Inhibits inosine monophosphate dehydrogenase (IMPDH) Inhibits de novo pathway of purine synthesis in B and T-cells (salvage pathway unaffected) Does not affect IL-1 or IL-2 production Inhibits arterial smooth muscle, fibroblast, and endothelial cell proliferation

Dosing: varies according to each center

Induction: Highest doses at time of transplant or as Treatment of an acute rejection episode (250-1000 mg of Methylprednisolone) Maintenance: Slow taper over days to years - down to low maintenance levels (Prednisone 5 mg Daily) Some centers may choose to stop steroids completely after only a few weeks

Dosing in Transplantation
IV, oral solution, pills and capsules Majority of patients Cellcept 1 gm (Myforic 720 mg) po bid High-risk patients 1.5 gm po bid Patients with rejection when given lower dosing African-American / Hispanicrecipients Reduce SE: 500 mg po qid (360 qid) IV: 1g in 150 ml D5W, 1.5g in 250 ml D5W; infuse over no less then 2 hours

ADVERSE EFFECTS:
Acne CNS effects Hypertension Myopathy Hyperlipidemia Osteoporosis Impaired growth Cataracts GI ulcerations Steroid-induced diabetes Impaired wound healing Sodium and water retention Increased risk for infection Increased appetite

ADVERSE EFFECTS:
Gastrointestinal (N, V, D) Infection Hematologic Teratogenic Headache Chills

DDIs
Interactions: CYP - 450 inducer and substrate Often times interactions are not identified

DDIs
Acyclovir Probenecid Cholestyramine Antacids Cyclosporine

Belatacept: alternative to CNI- data in kidney paients only

Costimulation blocker that inhibits T-cell activation Mechanism of Action - Binds to CD80/86 on antigen presenting cells - Blocks CD28 mediated costimulation of T cells - Inhibits production of IL-2, IL-4, interferon-, TNF-

Basiliximab : Induction only - No effect on Acute Rejection

Humanized monoclonal antibody Mechanism of Action - Targets IL-2 receptor-alpha (CD25, Tac) CD25 is induced on activated T-cells Used only as Induction Therapy

Dosing and administration- INFUSE OVER 30 minutes

10 mg/kg (Actual BW) on days 1, 5 and week 2, 4, 8 and 12 5 mg/kg starting at week 16 and every 4 weeks thereafter IV

Dosing and Administration

- 20 mg IV infusion over 30 minutes x 2 doses on day 0 and day 4

ADVERSE EFFECTS:
Malignancies & Infections (polyoma virus, TB) Anemia, diarrhea, constipation, UTIs, edema, pyrexia, HTN Higher rejection rates but better renal function

ADVERSE EFFECTS:
No Evidence of Cytokine Release Syndrome Generally free of Adverse Effects

Sirolimus/Everolimus
Mechanism of Action Binds intracellularly to FK506 binding protein DOES NOT inhibit calcineurin phosphatase Binds later in T-cell activation pathway than CSA or tacrolimus (mTOR) Markedly suppresses IL-2 T-cell proliferation Halts cell cycle

Antithymocyte Globulin (ATG/ALG, ATGAM, Thymoglobulin)

ATGAM: equine polyclonal antibody Thymoglobulin (RATG): rabbit polyclonal antibody Mechanism of Action? Bind to multiple receptors CD2, 3, 4, 8, 25, 45 among others Antibodies against human T-cells T-cell depletion and modulation CD4 subset may be suppressed for years?

Dosing-Sirolimus
Loading Dose: 6 or 15 mg Maintenance Dose: 2 to 5 mg Separate dose with CSA/Tac atleast 4 hours

Dosing and Administration

ATGAM - 10 - 15 mg/kg IV infusion over 4-6 hrs x 14 days Thymoglobulin - 1-1.5 mg/kg IV infusion over 4-6 hrs for 3-14 days Monitor CD2, CD3, CD4 T-cells CBC w/differential, Platelets Premedication recommended o Methylprednisolone o Acetaminophen o Diphenhydramine o No NSAIDS

Dosing-Everolimus

0.75 mg BID Same time as CSA/TAC Maintenance range varies ( rejection, tox., and other immunodrugs used) Therapeutic Range Early post-transplant: 5 - 15 ng/mL Late post-transplant: 3 - 10 ng/mL Everolimus: 3 8 ng/ml

ADVERSE EFFECTS:
Increase cholesterol and triglycerides Decrease platelets and WBCs, anemia Mouth ulcers

Decreased wound healing Decreased renal function ( SCr GFR) Interstitial pneumonitis

ADVERSE EFFECTS:
Toxicity: infusion reactions, hematologic, infections Leukopenia Thrombocytopenia

Fever Chills Erythema Pruritis

Rituximab (Rituxan) -Pre-treatment for ABO-Incompatible Transplantation

Humanized monoclonal antibody directed against CD20 Primary used for non-Hodgkins lymphoma Treatment of CMV based B cell lymphoma in transplant patients Treatment of B cell (Humoral) rejection Dosing and Administration 375 mg/m2 IV infusion weekly for 4-8 doses 375 mg/m2 IV infusion x 1 dose pre-transplant 375 mg/m2 IV infusion (intermittent dosing) Premedicate (at least 1 hour prior to dose) Diphenhydramine (50 mg IV/PO) Acetaminophen (650 mg)

Azathioprine
Mechanism of Action Metabolized to 6-mercaptopurine Inhibits purine nucleotide synthesis Inhibits DNA and RNA synthesis Prevents both B and T-cell formation Dosing in Transplantation IV and oral dosage forms Varies greatly (0.5 - 3 mg/kg/day) Adjust dose based on WBC and PLT counts Reduce dose in combination with allopurinol Toxicity Bone marrow suppression GI intolerance Alopecia, Pancreatitis, Cancers