New Developments in the Management of Kidney Transplant Patients Christine E. Chamberlain, Pharm.D., BCPS Clinical Center Pharmacy Department 10/23/01

End Stage Renal Disease Options for patients with renal disease: Peritoneal dialysis Hemodialysis Kidney transplantation Living Donor (related and unrelated) Cadaveric Donor Approximately 222,000 patients were receiving hemodialysis (1999 US Renal Data System Report) Only 9000 cadaveric kidney transplants performed in 1999 Approximately 4000 living donor transplantations per year In the year 2000, more than 45,000 patients receiving dialysis were awaiting cadaveric kidney transplantation Am J Kidney Dis 1999;34(Suppl 1)

Am J Kidney Dis 1999;34(Suppl1) Cause of End Stage Renal Disease Among New Patients on Hemodialysis in 1997 18% 3% 13% 28% Am J Kidney Dis 1999;34(Suppl1)

Factors Determining Transplantation Outcomes Type of donor (cadaveric vs. living) Matching and sensitization HLA match (0 antigen mismatch > 6 antigen mismatch) Negative crossmatch Racial Differences Recipient Age Donor Age Other Factors (delayed graft function, cold ischemia time, acute rejection, chronic rejection, years on dialysis, diseases leading to ESRD)

History of Kidney Transplantation First successful kidney transplant Total body irradiation for immunosuppression Steroids 1960’s Azathioprine 1970’s Polyclonal anitbodies – anti-lymphocyte globulin (now Atgam, Thymoglobulin) 1980’s Cyclosporine (Sandimmune ), “triple drug therapy” Monoclonal antibody, OKT3 (Orthoclone ) in 1985

Basics of Immunosuppression Immune system distinguishes self from non-self Antigen: anything that can trigger an immune response B-cell (lymphocyte) – secretes antibodies, presents antigen to T-cell T-cell (lymphocyte), secretes cytokines (ex. IL-2), directs and regulates immune responses, also attacks infected, cancerous or foreign cells

Basics of Immunosuppression Cytokines are chemical messengers – bind to target cells, encourage cell growth, trigger cell activity, direct cell traffic, destroy target cells, and activate phagocytes (“cell eaters”) IL-2 activates T-cells and causes proliferation T-cell surface markers (CD3, CD25, CD52 and T-cell receptor) CD=cluster of differentiation of T-cells

T- Lymphocyte Activation Three signals involved in T-cell activation Calcineurin is activated and induces cytokine genes and T-cell activation genes IL-2 binds to IL-2 receptor which in turn activates Target of Rapamycin (TOR) and promotes T-cell proliferation De novo synthesis of purines is necessary for B and T cell proliferation

Management of a Transplant Recipient Induction Therapy: administer medications that provide marked suppression prior to and during the first week post transplantation, some agents can also block B-cell mediated rejection Maintenance Therapy: administer immunosuppressive agents continuously to prevent acute rejection Administer medications to induce Tolerance?

What is Tolerance? Immunologic unresponsiveness by the recipient to the kidney graft in the absence of maintenance immunosuppression.

Goals of Transplant Research Prevent rejection and kidney graft loss Reduce the amount of immunosuppression Decrease side effects Decrease toxicity and long term effects Enhance long term patient and graft survival Provide reasonable cost effective therapy Improve patient adherence and quality of life Induce Tolerance (no long term medications, reduces adverse effects, improves quality of life)

Immunosuppressant Discoveries 1990-2000 Tacrolimus (Prograf) Mycophenolate Mofetil (Cellcept ) Basiliximab (Simulect ) Cyclosporine Microemulsion (Neoral ) Daclizumab (Zenapax ) Rabbit Antithymocyte globulin (Thymoglobulin ) Sirolimus (Rapamune )

How are we doing. One Year Survival Rate Percentage Living vs How are we doing? One Year Survival Rate Percentage Living vs. Cadaveric

Modes of Action of Currently Available Immunosuppressants Calcineurin inhibitors Cyclosporine Tacrolimus Purine synthesis inhibitors Azathioprine Mycophenolate mofetil Nonspecific prednisone Target of Rapamycin inhibitor Sirolimus Polyclonal antibodies (bind several CD’s) Thymoglobulin  Atgam  Monoclonal Antibodies Blocks Il-2 receptor Daclizumab Basilixmab OKT3 (anti-CD3)

Graft Half-life in Years

Trends in Immunosuppression Steroid sparing regimens, and steroid avoidance Reducing calcineurin inhibitor dose after critical post transplant period Calcineurin inhibitor avoidance Single drug regimens

Agents on the Horizon Campath 1H (anti-CD52) – lymphocyte and monocyte depleting agent Deoxyspergualin – blocks maturation of T and B cells Everolimus – TOR inhibitor like sirolimus FTY-720 – reversible depletion of lymphocytes from peripheral blood (migration to spleen) CTLA4-Ig – blocks T-cell activation

Other New Developments in Kidney Transplantation Laparoscopic kidney donation Advantages: less post operative pain, shorter hospital stay, minimal scarring Disadvantages: impaired early graft function, graft loss or damage, longer operative time Improved surgical techniques and storage of the kidney graft New antibiotics to treat and prevent opportunistic infections (new antifungals, oral ganciclovir and valganciclovir)

Current Trials at NIH Sirolimus Monotherapy to Optimize Activation Induced Cell Death (AICD) in Renal Transplants Following Lymphocyte Depletion Induction with Thymoglobulin Tolerance Induction Following Human Renal Transplantation Using Treatment with a Humanized Monoclonal Antibody Against CD52 Campath1-H Renal Allotransplantation for the Treatment of End Stage Renal Disease in the Setting of Human Immunodeficiency Virus (HIV) Infection

Role of the Transplant Pharmacist Disease state management Hypertension Diabetes Mellitus Osteoporosis Hyperlipidemia Electrolyte abnormalities Patient understanding and adherence to the drug regimen Pharmacokinetic drug level monitoring Drug interactions (esp. with immunosuppressants) Adverse drug reaction monitoring

Kidney Transplant View a kidney transplant at: www.vesalius.com Click on clinical folios Click on abdomen Click on kidney transplant