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

2. 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)

3. 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)

4. 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)

5. 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

6. 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

7. 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

8. 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

9. 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?

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

11. 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)

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

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

14. 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)

15. Graft Half-life in Years

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

17. 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

18. 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)

19. 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

20. 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

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