# Presentation: 230208

## 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

- <date/time>

- 28%

- 13%

- 3%

- 18%

## 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

- <date/time>

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

## 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 CD’s)
- Thymoglobulin 
- Atgam 
- Monoclonal Antibodies
- Blocks Il-2 receptor
- Daclizumab
- Basilixmab
- OKT3 (anti-CD3)

## Graft Half-life in Years

- <date/time>

## 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](http://www.vesalius.com/)_
- Click on clinical folios
- Click on abdomen
- Click on kidney transplant