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

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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

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Cause of End Stage Renal Disease Among New
Patients on Hemodialysis in 1997
18
3
13
28
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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)

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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

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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

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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

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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

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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?

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What is Tolerance?

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

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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)

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Immunosuppressant Discoveries 1990-2000

• Tacrolimus (Prograf?)
• Mycophenolate Mofetil (Cellcept ?)
• Basiliximab (Simulect ?)
• Cyclosporine Microemulsion (Neoral ?)
• Daclizumab (Zenapax ?)
• Rabbit Antithymocyte globulin (Thymoglobulin ?)
• Sirolimus (Rapamune ?)

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

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Graft Half-life in Years
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Trends in Immunosuppression

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

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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

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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)

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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

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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

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Kidney Transplant

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