New Developments in New Developments in the Management of the Management of Kidney Transplant Kidney Transplant Patients Patients Christine E. Chamberlain, Pharm.D., BCPS Clinical Center Pharmacy Department 10/23/01
Dec 22, 2015
New Developments in the New Developments in the Management of Kidney Management of Kidney
Transplant PatientsTransplant Patients
Christine E. Chamberlain, Pharm.D., BCPS
Clinical Center Pharmacy Department
10/23/01
Am J Kidney Dis 1999;34(Suppl 1)
End Stage Renal DiseaseEnd 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(Suppl1)
Cause of End Stage Renal Disease Cause of End Stage Renal Disease Among New Patients on Among New Patients on
Hemodialysis in 1997Hemodialysis in 1997
Diabeticnephropathy
Hypertension
Glomerulo-nephritis
Cystic KidneyDz
Other
38%
28%
13%
3%
18%
Factors Determining Factors Determining Transplantation OutcomesTransplantation 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 TransplantationHistory of Kidney Transplantation1950’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 ImmunosuppressionBasics 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 ImmunosuppressionBasics 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 ActivationT- Lymphocyte Activation
Three signals involved in T-cell activationCalcineurin is activated and induces
cytokine genes and T-cell activation genesIL-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 Management of a Transplant RecipientRecipient
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 ResearchGoals 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 Immunosuppressant Discoveries 1990-20001990-2000
Tacrolimus (Prograf)
Mycophenolate Mofetil (Cellcept )
Basiliximab (Simulect )
Cyclosporine Microemulsion (Neoral )
Daclizumab (Zenapax )
Rabbit Antithymocyte globulin (Thymoglobulin )Sirolimus (Rapamune )
NEJM 2000;342:605-12
How are we doing?How are we doing?One Year Survival Rate Percentage One Year Survival Rate Percentage
Living vs. CadavericLiving vs. Cadaveric
0102030405060708090
100
Living CAD
Prior to 1988
1988-1996
Modes of Action of Currently Modes of Action of Currently Available ImmunosuppressantsAvailable 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)
NEJM 2000;342:605-12
Graft Half-life in YearsGraft Half-life in Years
0
5
10
15
20
25
30
35
40
Living CAD
Half-life prior to1988
Half-life 1988-1996
censored half-lifeprior to 1988
censored half-life1988-1996
Trends in ImmunosuppressionTrends in Immunosuppression
Steroid sparing regimens, and steroid avoidance
Reducing calcineurin inhibitor dose after critical post transplant period
Calcineurin inhibitor avoidanceSingle drug regimens
Agents on the HorizonAgents 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 Other New Developments in Kidney TransplantationKidney 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 NIHCurrent 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 PharmacistRole 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