Title: New Developments in the Management of Kidney Transplant Patients
1New Developments in the Management of Kidney
Transplant Patients
- Christine E. Chamberlain, Pharm.D., BCPS
- Clinical Center Pharmacy Department
- 10/23/01
2End 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
3Cause of End Stage Renal Disease Among New
Patients on Hemodialysis in 1997
18
3
13
28
4Factors 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) -
5History 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
6Basics 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
7Basics 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
8T- 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
9Management 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?
10What is Tolerance?
- Immunologic unresponsiveness by the recipient
to the kidney graft in the absence of maintenance
immunosuppression.
11Goals 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)
12Immunosuppressant Discoveries 1990-2000
- Tacrolimus (Prograf?)
- Mycophenolate Mofetil (Cellcept ?)
- Basiliximab (Simulect ?)
- Cyclosporine Microemulsion (Neoral ?)
- Daclizumab (Zenapax ?)
- Rabbit Antithymocyte globulin (Thymoglobulin ?)
- Sirolimus (Rapamune ?)
13How are we doing?One Year Survival Rate
Percentage Living vs. Cadaveric
14Modes 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)
15Graft Half-life in Years
16Trends in Immunosuppression
- Steroid sparing regimens, and steroid avoidance
- Reducing calcineurin inhibitor dose after
critical post transplant period - Calcineurin inhibitor avoidance
- Single drug regimens
17Agents 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
18Other 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)
19Current 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
20Role 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
21Kidney Transplant
- View a kidney transplant at
- www.vesalius.com
- Click on clinical folios
- Click on abdomen
- Click on kidney transplant