New developments in the management of kidney transplant patients
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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

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New developments in the management of kidney transplant patients

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

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)


Cause of end stage renal disease among new patients on hemodialysis in 1997

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

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

History of Kidney Transplantation

1950’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 immunosuppression

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 immunosuppression1

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

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

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

What is Tolerance?

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


Goals of transplant research

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

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 cadaveric

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)

Modes of Action of Currently Available Immunosuppressants


Graft half life in years

Graft Half-life in Years


Trends in immunosuppression

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

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

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

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

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

Kidney Transplant

  • View a kidney transplant at:

    • www.vesalius.com

    • Click on clinical folios

    • Click on abdomen

    • Click on kidney transplant


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