Fellows Conference 01/21/2016

Transcription

1 Fellows Conference 01/21/2016

2 Outline Basics of transplantation Benefits of transplantation Immunosuppressive medications

3 Anatomy of Renal Transplantation

4 Recipient Selection General medical condition. Cardiovascular screening. Age-appropriate routine cancer screening (pap smear, mammography, colonoscopy, PSA). Infection (HIV, Hepatitis, TB). Presence of preformed antibody (PRA). Pregnancy, prior transplant, blood transfusion Psychosocial evaluation, including compliance.

5 Benefits of Transplantation Life expectancy Cardiovascular benefits Quality of life Socioeconomic benefits

6 Life Expectancy Ojo, J Am Soc Neph, 2001;12:589

7 Cardiovascular Benefits Foley, Am J Kidney Dis, 1998;32(S1):8 Slide courtesy of Dr. Robert Gaston

8 Quality of Life Numerous studies have detailed improved quality of life. Life satisfaction, physical and emotional well-being and ability to return to work higher in transplant recipients. Uremic complications more fully reversed. Fertility returns.

9 Socioeconomic Benefits Increased rates of return to work. Cost to society: First year after transplantation: > Annual cost of hemodialysis Thereafter: $10,000 per year.

10 Immunosuppressive Medications Slide courtesy of Dr. Meier-Kriesche

11 Immunosuppression use USRDS Patients age 18 & older receiving a first-time, kidney-only transplant. IL2-RA: interleukin-2 receptor antagonist.

12 Three-Signal Model Halloran, N Eng J Med, 2004;351:3715

13 Immunosuppressive Medications Induction: Corticosteroids Anti-thymocyte globulin (ATG) Alemtuzumab (Campath) IL-2 receptor antagonists Maintenance: Corticosteroids Calcineurin inhibitors (CNIs) mtor inhibitors Antimetabolites Belatacept

14 Immunosuppressive Medications Treatment of Rejection: Corticosteroids Anti-thymocyte globulin Intravenous Immunoglobulin (IVIG) Rituximab Bortezomib Plasmapheresis

15 Induction Agents Monoclonal (Daclizumab, Basiliximab, Alemtuzumab, OKT3) Polyclonal (Thymoglobulin, atgam) Depleting agents (Thymoglobulin, Alemtuzumab, OKT3) Non-depleting agents (Daclizumab, Basiliximab)

16 Corticosteroids Used for induction, maintenance and treatment of rejection. Mechanism of action: Inhibit function of dendritic cells. Inhibit translocation to nucleus of NF-κB. Suppress production of IL-1, IL-2, IL-3, IL-6, TNF-α, and γ-ifn. Adverse effects numerous and well-known.

17 Halloran, N Eng J Med, 2004;351:3715

18 Corticosteroids Component of >80% of transplant protocols. Given IV at high doses ( mg/day) for induction or treatment of rejection. Tapered to maintenance dose of 5-10 mg/day in early post-transplant phase. Should NOT be tapered off: increased risk of rejection and graft loss! Steroid free regimen: overall some benefits but graft survival likely worse.

19 Anti-thymocyte Globulin (Thymoglobulin) Used for induction and treatment of rejection. Prepared by immunization of rabbits with human lymphoid tissue. Causes depletion of peripheral blood lymphocytes. The optimal dose - 6 mg/kg Typical regimen of Thymoglobulin for induction consists of 1.5 mg/kg for 3 to 5 days Administered generally via central line for 3-10 days. Premedication required: acetaminophen, corticosteroids and antihistamine.

20 Anti-thymocyte Globulin: Adverse Effects Infusion-related reactions: chills, fevers, arthralgias. Lymphopenia. Thrombocytopenia. Prolonged immunosuppression: increased risk of opportunistic infections (PCP, CMV, fungal). Possibly increased risk of BK virus nephropathy.

21 Alemtuzumab (Campath) It is a humanized monoclonal antibody directed against CD52. CD52 is present on virtually all B- and T-cells as well as macrophages, NK cells, and some granulocytes. When the alemtuzumab antibody binds to CD52, it is thought to trigger an antibody-dependent lysis of the cell. The depletion of lymphocytes is so marked that it takes several months to a year post administration for the immune system of a patient to be fully reconstituted

22 Halloran, N Eng J Med, 2004;351:3715

23 Alemtuzumab: Adverse Effects Dosing: mg on the day of transplantation. A second dose on POD 1 or 4 can also be given. Side Effects: The depleting efficiency of alemtuzumab is so profound that it is invariably associated with side effects viz. neutropenia (70%), thrombocytopenia (52%), anemia (47%), nausea (54%), vomiting (41%), diarrhea (22%), headache (24%), dysthesias (15%), dizziness (12%), and AIHA(<5%).

24 IL-2 Receptor Blockers Basiliximab (Simulect ) and Daclizumab (Xenapax ). Block CD25 (IL-2 receptor) on activated T cells. Used for induction only. Almost no side effects, but also much less potent.

25 Halloran, N Eng J Med, 2004;351:3715

26 Calcineurin Inhibitors Used for maintenance immunosuppression. Two agents in clinical practice: Cyclosporine (Sandimmune, Gengraf, Neoral, generic; CysA) Tacrolimus (Prograf, generic; FK506). Generics NOT clinically therapeutically equivalent. At present are key to maintenance immunosuppression and a component of the majority of transplant protocols.

27 Calcineurin Inhibitors: Mechanism of Action CsA: Cyclosporine FK506: Tacrolimus FKBP: FK Binding Protein CpN: Cyclophilin NF-AT: Nuclear Factor of Activated T-cells (ccytosolic component; n- nuclear component). Stepkowski, Expert Rev Mol Med, 2000;2(4):1

28 Halloran, N Eng J Med, 2004;351:3715

29 Calcineurin Inhibitors: Dosing and Monitoring Both medications are generally dosed twice per day, 12 hrs apart. Trough levels monitored: check approximately 12 hrs after last dose. In some cases C2 levels might be checked 2 hrs after administration. Cyclosporine is 35-40% bioavailable, tacrolimus approximately 25%. Oral to IV conversion 3-4:1. Both are metabolized by cytochrome P450 3A4 & 3A5.

30 Calcineurin Inhibitors: Interactions Halloran, from Johnson (ed.), Comprehensive Clinical Nephrology, Mosby Elsevier, 2003.

31 Calcineurin Inhibitors: Interactions Drugs to use with caution: NSAIDs avoid. Amphotericin B & Aminoglycosides worsened nephrotoxicity. ACEi & ARBs use with caution. Statins avoid lovastatin, start others at lowest possible dose.

32 Calcineurin Inhibitors: P-Glycoprotein P-Glycoprotein (P-gp, also known as MDR1) is an ABC-transporter found among other places, in the intestine. It is thought to have evolved as a defense mechanism against harmful substances. It acts as an efflux pump for many substances including drugs (CNIs, colchicine, some cancer chemotherapeutic agents, digoxin, corticosteroids, antiretrovirals). Decreased P-gp expression, such as in diarrhea, leads to elevated drug levels.

33 Calcineurin Inhibitors: Adverse Effects Nephrotoxicity: Functional decrease in blood flow from afferent arteriolar vasoconstriction. Thrombotic microangiopathy (rare). Chronic interstitial fibrosis. Hyperkalemia, hypomagnesemia and type IV renal tubular acidosis. Cyclosporine thought to be more nephrotoxic.

34 Calcineurin Inhibitors: Adverse Effects Cyclosporine Tacrolimus Hypertension ++ + Pancreatic islet toxicity + ++ Neurotoxicity + ++ Hirsutism + - Hair loss - + Gum hypertrophy + - GI side effects - + Gastric motility - + Dyslipidemia + - Hyperuricemia ++ + K + / Mg Adapted from Danovitch, Handbook of Kidney Transplantation, Lippincott Williams & Wilkins, 2005

35 mtor Inhibitors Target site is the mammalian target of rapamycin (mtor), a key regulatory kinase in cell division. Sirolimus (Rapamune ) only available mtor inhibitor in the US. Administered once daily, 24-hour trough levels monitored. Also metabolized by P450 3A system, with interactions similar to the CNIs.

36 Sirolimus: Mechanism of Action SRL: Sirolimus FKBP: FK Binding Protein mtor: Mammalian target of rapamycin Cdk: cyclin-dependent kinase Stepkowski, Expert Rev Mol Med, 2000;2(4):1

37 Halloran, N Eng J Med, 2004;351:3715

38 Sirolimus: Adverse Effects Nephrotoxicity: Delays recovery from ATN. Potentiates cyclosporine nephrotoxicity. Induces proteinuria. Tubulotoxic. Impairment of wound healing. Dyslipidemia (increased LDL and TGs). Pneumonitis. Cytopenias and anemia.

39 Antimetabolites Azathioprine (Imuran, generic) is a purine analogue that is incorporated into RNA and inhibits cell replication. A mainstay of transplantation for 30 years, it has largely been replaced by the below drugs. Mycophenolate mofetil (Cellcept ) and enteric-coated mycophenolate sodium (Myfortic ) are prodrugs of mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (IMPDH).

40 Mechanism of Action: MPA Prodrugs Stepkowski, Expert Rev Mol Med, 2000;2(4):1

41 Halloran, N Eng J Med, 2004;351:3715

42 Antimetabolites: Adverse Effects Azathioprine: Bone marrow suppression. Hepatitis. Azathioprine is inactivated by xanthine oxidase, therefore should not be used in combination with allopurinol. MPA prodrugs: GI toxicity: diarrhea, nausea, esophagitis. Leukopenia and anemia. Not different between formulations.

43 Antimetabolites: Interactions Azathioprine: Allopurinol Other marrow suppressive drugs MPA prodrugs: Cyclosporine Antacids Cholestyramine Ferrous sulfate OK to use with allopurinol

44 Belatacept: 1st Biological drug to get FDA approval for kidney transplant

45 Halloran, N Eng J Med, 2004;351:3715

46 Belatacept: Mechanism of Action This monoclonal antibody fusion protein is designed to act as a selective costimulation blocker. It binds to CD80/86 on antigen-presenting cells (APCs), blocking CD28-mediated costimulation of T cells. Costimulation blockade inhibits cell division, cytokine production, anergy, and apoptosis.

47 T-Cells Require Costimulation for Full Activation Signal 2 Costimulation between ligands Signal 1 Antigen triggers T-cell receptor Cytokine production T-cell proliferation APC=antigen-presenting cell

48 T-Cells Require Costimulation for Full Activation TCR signal only=no activation No Signal 2 Signal 1 only No cytokine production No cell division Becomes anergic Undergoes apoptosis APC=antigen-presenting cell; TCR=T-cell receptor; MHC=major histocompatibility complex

49 CTLA4 Negatively Regulates T-cell Activation CTLA4 (CD152) expression is induced by T-cell activation CTLA4 is structurally similar to CD28 CTLA4 binds CD80/86 with greater avidity than CD28 CTLA4 negatively regulates T-cell activation

50 Belatacept Potently and Selectively Blocks T-Cell Activation Belatacept Selective costimulation blocker No cell division No cytokine production Anergy Apoptosis

51 Belatacept: Potential Benefits When compared with CNI-based therapy, belatacept use is associated with significant advantages that seem to translate into better long-term allograft survival, including: Preservation of the GFR A favorable metabolic profile Fewer late rejections An impact on de novo donor-specific antibody (DSA) formation

52 Intravenous Immune Globulin Used primarily for treatment of antibody-mediated rejection. Mechanism of action: Reduction of alloantibodies through suppression of antibody formation. Increased catabolism of circulating antibodies. Adverse effects: Infusion-related reactions (myalgias, headaches). Severe headache & aseptic meningitis. Autoimmine hemolytic anemia. Sucrose-based IVIG can cause ARF.

53 Rituximab Used in the treatment of antibody-mediated rejection. Monoclonal antibody directed at CD20 antigen on B lymphocytes. Causes rapid and sustained depletion of B lymphocytes. Does not have direct activity against plasma cells and memory B cells, which do not express CD20. Adverse events: infusion reactions, and increased susceptibility to infection.

54 Bortezomib Mechanism of action Inhibits proteosome formation, thus interfering with protein degradation and leading to programmed cell death (apoptosis). Targets mature rapidly proliferating antibody-producing plasma cells. Also interferes with T-cell function, IL-1, IL-6 and TNF-α production.

55 Bortezomib Dosing 1.3 mg/m 2 (usual starting dose). In case of side effects, dose is reduced to 1.0 mg/m 2, then to 0.9 mg/m 2, then to 0.7 mg/m 2 (if needed). Metabolized by the liver and thus no need to adjust dose by renal function. Partially removed by dialysis (administer after dialysis). Cleared by plasmapheresis (administer after plasmapheresis).

56 Bortezomib Contraindications Moderate to severe pre-existing peripheral neuropathy Platelet count < 30,000/mm 3 ANC < 500/ mm 3 Hgb < 8 g/dl Uncontrolled hypotension

57 Bortezomib Adverse reactions Neurologic: peripheral neuropathy (mostly sensory: pain and paresthesias), fatigue, malaise, weakness, headache, insomnia Hematologic: leukopenia (especially days 1-11), neutropenia, anemia, thrombocytopenia GI: nausea, vomiting, anorexia, constipation CV: hypotension, edema ID: Herpes zoster infection

58 Other Agents OKT3 Used for induction and treatment of rejection, now largely replaced by anti-thymocyte globulin. Monoclonal antibody against CD3 Severe infusion reactions (pulmonary edema & capillary leak syndrome). Leflunomide (Arava ) Dihyroorotate dehydrogenase (DHODH) inhibitor. Used in certain clinical settings as an adjunct immunosuppressive.