New Developments in the New Developments in the Management of Kidney Management of Kidney

Transplant PatientsTransplant Patients

Christine E. Chamberlain, Pharm.D., BCPS

Clinical Center Pharmacy Department

10/23/01

Am J Kidney Dis 1999;34(Suppl 1)

End Stage Renal DiseaseEnd 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(Suppl1)

Cause of End Stage Renal Disease Cause of End Stage Renal Disease Among New Patients on Among New Patients on

Hemodialysis in 1997Hemodialysis in 1997

Diabeticnephropathy

Hypertension

Glomerulo-nephritis

Cystic KidneyDz

Other

38%

28%

13%

3%

18%

Factors Determining Factors Determining Transplantation OutcomesTransplantation 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 TransplantationHistory of Kidney Transplantation1950’s 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 ImmunosuppressionBasics 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 ImmunosuppressionBasics 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 ActivationT- Lymphocyte Activation

Three signals involved in T-cell activationCalcineurin is activated and induces

cytokine genes and T-cell activation genesIL-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 Management of a Transplant RecipientRecipient

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?What is Tolerance?

Immunologic unresponsiveness by the recipient to the kidney graft in the absence of maintenance immunosuppression.

Goals of Transplant ResearchGoals 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 Immunosuppressant Discoveries 1990-20001990-2000

Tacrolimus (Prograf)

Mycophenolate Mofetil (Cellcept )

Basiliximab (Simulect )

Cyclosporine Microemulsion (Neoral )

Daclizumab (Zenapax )

Rabbit Antithymocyte globulin (Thymoglobulin )Sirolimus (Rapamune )

NEJM 2000;342:605-12

How are we doing?How are we doing?One Year Survival Rate Percentage One Year Survival Rate Percentage

Living vs. CadavericLiving vs. Cadaveric

0102030405060708090

100

Living CAD

Prior to 1988

1988-1996

Modes of Action of Currently Modes of Action of Currently Available ImmunosuppressantsAvailable 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)

NEJM 2000;342:605-12

Graft Half-life in YearsGraft Half-life in Years

0

5

10

15

20

25

30

35

40

Living CAD

Half-life prior to1988

Half-life 1988-1996

censored half-lifeprior to 1988

censored half-life1988-1996

Trends in ImmunosuppressionTrends in Immunosuppression

Steroid sparing regimens, and steroid avoidance

Reducing calcineurin inhibitor dose after critical post transplant period

Calcineurin inhibitor avoidanceSingle drug regimens

Agents on the HorizonAgents 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 Other New Developments in Kidney TransplantationKidney 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 NIHCurrent 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 PharmacistRole 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 TransplantKidney Transplant

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