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New Developments in the Management of Kidney Transplant Patients

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Title: New Developments in the Management of Kidney Transplant Patients


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

3
Cause of End Stage Renal Disease Among New
Patients on Hemodialysis in 1997
18
3
13
28
4
Factors Determining Transplantation Outcomes
  • Type of donor (cadaveric vs. living)
  • Matching and sensitization
  • HLA match (0 antigen mismatch gt 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
  • 1950s
  • First successful kidney transplant
  • Total body irradiation for immunosuppression
  • Steroids
  • 1960s
  • Azathioprine
  • 1970s
  • Polyclonal anitbodies anti-lymphocyte globulin
    (now Atgam?, Thymoglobulin?)
  • 1980s
  • 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) CDcluster 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. 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 CDs)
  • 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
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