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
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
Diabetic
nephropathy
18% Hypertension
3%
38% Glomerulo-
13% nephritis
Cystic Kidney
28% Dz
Other
Am J Kidney Dis 1999;34(Suppl1)
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
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
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 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
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
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?
Immunologic unresponsiveness by the
recipient to the kidney graft in the absence of
maintenance immunosuppression.
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
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
100
90
80
70
60
50 Prior to 1988
40
1988-1996
30
20
10
0
Living CAD
Modes of Action of Currently
Available Immunosuppressants
Calcineurin inhibitors Target of Rapamycin inhibitor
– Cyclosporine – Sirolimus
Polyclonal antibodies (bind
– Tacrolimus several CD’s)
Purine synthesis inhibitors – Thymoglobulin
– Azathioprine – Atgam
– Mycophenolate mofetil Monoclonal Antibodies
– Blocks Il-2 receptor
Nonspecific Daclizumab
– prednisone Basilixmab
– OKT3 (anti-CD3)
Graft Half-life in Years
40
35
30
25
20 Half-life prior to
1988
15
Half-life 1988-1996
10
5 censored half-life
prior to 1988
0
Living CAD censored half-life
1988-1996
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
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
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
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
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
View a kidney transplant at:
– www.vesalius.com
– Click on clinical folios
– Click on abdomen
– Click on kidney transplant