Organ Transplantation

Clinical Background

Organ transplantation is the strategy of choice for end-stage organ disease. Immunosuppressive therapies have allowed patients to extend the life of the organ but require careful monitoring to prevent toxicity and rejection. Therapeutic ranges and toxic thresholds should be carefully considered based on the clinical setting. Important factors include the organ transplanted, time post-transplant, age and clinical status of the patient, as well as concomitant medications.

Epidemiology

Prevalence - >60,000 patients in 2005 were living in the U.S. with functioning organ transplants
1-year graft survival rate approximates 80-90%

Immunosuppressive Drug Regimens for Organ Transplants
Available Immunosuppressives (immunosuppressive regimen depends on organ transplanted; most common combination is steroid plus calcineurin)	Mechanism of Action	Toxicity	Therapeutic Ranges
Biological Agents
Antithymocyte globulin (ATG®, Atgam®, Thymoglobulin®)	Lymphocyte depletion	Increases risk of infection
Corticosteroids	Proapoptic effect on lymphoid cells	Increase risk of infection; increased risk of malignancy (nonmelanoma skin cancers [NMSC])
IL-2 antibodies Daclizumab (Zenapax®), Basiliximab (Simulect®)	Selectively blocks IL-2 receptors on T helper cells, preventing T-cell proliferation	Increased risk of malignancy (NMSC and lymphomas)
OKT3 (Muromonab CD3®)	Lymphocyte depletion	Increases risk of infection	500-1,500 ng/mL during steady state treatment
Immunosuppressants
Azathioprine (Imuran®) 6-mercaptopurine (Puinethol®)	Inhibits purine nucleotide synthesis, which interferes with DNA synthesis	Infection and increased risk of malignancy (acute myelogenous leukemia [AML] and myelodysplastic syndromes [MDS])
Cyclosporin A (CSA - Sandimmune®, Neoral®)	Inhibit calcineurin and reduce IL-2 expression	Increased risk of malignancy, nephrotoxicity, cardiotoxicity, hyperlipidemia	Cyclosporine therapeutic ranges for the kidney and heart are: Up to 3 months post-transplant: 350-525 ng/mL 4 months and older: 145-350 ng/mL Cyclosporine therapeutic ranges for the liver are: 290-525 ng/mL Toxic: greater than 700 ng/mL
Mycophenolic acid (CellCept®, MMF®)	Selective inhibition of inosine monophosphate dehydrogenase - interferes with DNA synthesis	Infection	Therapeutic range not well established
Sirolimus (Rapamune®, Rapamycin®) Everolimus (Certican™)	Blocks B- and T-cell proliferation by blocking pathway between IL-2 receptor and nucleus; does not block calcineurin pathway; synergistic with cyclosporine	Hyperlipidemia and infection	Sirolimus: 4.0-12.0 ng/mL
Tacrolimus (Prograt®)	Inhibit calcineurin and reduce IL-2 expression	Increased risk of malignancy, nephrotoxicity, cardiotoxicity, hyperlipidemia	Tacrolimus therapeutic ranges for the kidney and liver are: 0-2 months post-transplant: 10.0-15.0 ng/mL 3 months and older: 5.0-10.0 ng/mL Tacrolimus therapeutic ranges for the heart are: 0-2 months post-transplant: 10.0-18.0 ng/mL 3 months and older: 8.0-15.0 ng/mL Toxic: 26 ng/mL or greater

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Cyclosporine A by Tandem Mass Spectrometry

ARUP #: 0070035

Methodology: Liquid Chromatography/Tandem Mass Spectrometry

Use:

Dose optimization, compliance monitoring

Limitations:

Concentrations determined by mass spectrometry may be 10-50% lower than observed by immunoassay methods due to greater specificity of the assay for the parent drug

Test name: Everolimus (Certican™)

ARUP #: 0092118

Methodology: Tandem Mass Spectrometry

Use:

Dose optimization, compliance monitoring

Limitations:

Therapeutic ranges and toxic thresholds are not well established, but are anticipated to be similar to sirolimus

Test name: Mercaptopurine Quantitation, Serum or Plasma

ARUP #: 0091084

Methodology: High Performance Liquid Chromatography

Use:

Compliance monitoring

Limitations:

This test measures concentration of parent drug only. Risk of toxicity associated with TPMT deficiency should be evaluated by thiopurine methyltransferase, RBC

Test name: Mycophenolic Acid

ARUP #: 0090213

Methodology: High Performance Liquid Chromatography

Use:

Dose optimization, compliance monitoring

Limitations:

In vitro conversion of parent drug to mycophenolic acid can occur if specimens are collected shortly after iv administration, and could contribute to falsely elevated concentrations of mycophenolic acid. Therapeutic ranges and toxic thresholds are not well established

Test name: OKT3, Circulating Drug Level

ARUP #: 0095895

Methodology: Flow Cytometry

Use:

Dose optimization

Test name: Sirolimus

ARUP #: 0098467

Methodology: Tandem Mass Spectrometry

Use:

Dose optimization, compliance monitoring

Limitations:

Concentrations determined by mass spectrometry may be 10-50% lower than observed by immunoassay methods due to greater specificity of the assay for the parent drug

Test name: Tacrolimus by Tandem Mass Spectrometry

ARUP #: 0090612

Methodology: Liquid Chromatography/Tandem Mass Spectrometry

Use:

Dose optimization, compliance monitoring

Limitations:

Concentrations determined by mass spectrometry may be 10-20% lower than observed by immunoassay methods due to greater specificity of the assay for the parent drug

Test name: Thiopurine Methyltransferase Genotyping (TPMT)

ARUP #:

Methodology:

Use:

Identify patients at risk for severe toxicity with azathioprine or 6-mercaptopurine

Test name: Lymphocyte Transplantation CD3

ARUP #: 0095949

Methodology: Flow Cytometry

Use:

Monitor immunosuppressive therapy with OKT3 test verifies CD3 antigen removal

Follow-up:

For immunocompromised patients, order lymphocyte subset panel 4 -T-cell subsets percent and absolute test

Test name: Lymphocyte Transplantation Profile

ARUP #: 0095798

Methodology: Flow Cytometry

Use:

Monitor immunosuppressive therapy with anti-lymphocyte drugs, such as OKT3 or ATG (anti-thymocyte globulin)

Additional Tests Available

Test name: Chimerism, Post-Transplant

ARUP #: 0050760

Methodology: Polymerase Chain Reaction/Fragment Analysis

Comments:

Test name: Transplantation (ImmuKnow®) Immune Cell Function Assay

ARUP #: 0051272

Methodology: Cell Culture/Chemiluminescence

Comments:

References

General References

Anglicheau D, Legendre C, Thervet E. Pharmacogenetics in solid organ transplantation: present knowledge and future perspectives. Transplantation. 2004;78(3):311-315.

Augustine JJ, Bodziak KA, Hricik DE. Use of sirolimus in solid organ transplantation. Drugs. 2007;67(3):369-391.

Bradley BA. Prognostic assays for rejection and tolerance in organ transplantation. Transpl Immunol. 2005;14(3-4):193-201.

Braun F, Behrend M. Basic immunosuppressive drugs outside solid organ transplantation. Expert Opin Investig Drugs. 2006;15(3):267-291.

Chan M, Pearson GJ. New advances in antirejection therapy. Curr Opin Cardiol. 2007;22(2):117-122.

Ciancio G, Burke GW, Miller J. Current treatment practice in immunosuppression. Expert Opin Pharmacother. 2000;1(7):1307-1330.

Creput C, Durrbach A, Deroure B, Charpentier B. New therapeutic targets for antibodies and recombinant proteins in organ transplantation. Curr Opin Mol Ther. 2007;9(2):153-159.

Duncan MD, Wilkes DS. Transplant-related immunosuppression: a review of immunosuppression and pulmonary infections. Proc Am Thorac Soc. 2005;2(5):449-455.

El-Wahsh M. Liver graft preservation: an overview. Hepatobiliary Pancreat Dis Int. 2007;6(1):12-16.

Gareri J, Klein J, Koren G. Drugs of abuse testing in meconium. Clin Chim Acta. 2006;366(1-2):101-111.

Golshayan D, Buhler L, Lechler RI, Pascual M. From current immunosuppressive strategies to clinical tolerance of allografts. Transpl Int. 2007;20(1):12-24.

Gutierrez-Dalmau A, Campistol JM. Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review. Drugs. 2007;67(8):1167-1198.

Haberal M, Dalgic A. New concepts in organ transplantation. Transplant Proc. 2004;36(5):1219-1224.

Kelly DA. Current issues in pediatric transplantation. Pediatr Transplant. 2006;10(6):712-720.

Ostrea EM Jr. Understanding drug testing in the neonate and the role of meconium analysis. J Perinat Neonatal Nurs. 2001;14(4):61-82.

Scherer MN, Banas B, Mantouvalou K, Schnitzbauer A, Obed A, Kramer BK, Schlitt HJ. Current concepts and perspectives of immunosuppression in organ transplantation. Langenbecks Arch Surg. 2007;392(5):511-523.

Srinivas TR, Meier-Kriesche HU, Kaplan B. Pharmacokinetic principles of immunosuppressive drugs. Am J Transplant. 2005;5(2):207-217.

Ting LS, Villeneuve E, Ensom MH. Beyond cyclosporine: a systematic review of limited sampling strategies for other immunosuppressants. Ther Drug Monit. 2006;28(3):419-430.

References from the ARUP Institute for Clinical and Experimental Pathology Research®

Lundell R, Elenitoba-Johnson KS, Lim MS. T-cell posttransplant lymphoproliferative disorder occurring in a pediatric solid-organ transplant patient. Am J Surg Pathol. 2004;28(7):967-973.

Medical Reviewers

McMillin, Gwen, Ph.D. Medical Director of Clinical Drug Abuse Testing, Clinical Toxicology and Trace Elements, Co-Medical Director for Pharmacogenomics at ARUP Laboratories; Assistant Professor, Pathology, University of Utah

Wittwer, Carl T., M.D., Ph.D. Medical Director, Flow Cytometry and New Technologies at ARUP Laboratories; Professor, Clinical Pathology, University of Utah

Comprehensive Review: July 2008
Last Update: September 2008