Post Transplant Immunosuppression: Consideration for Primary Care Sameh Abul-Ezz, M.D., Dr.P.H.
Objectives Discuss the commonly used immunosuppressive medications and what you need to know to care for patients taking them Describe the risks of prolonged immunosuppressive therapy including the most common infections and malignancies
Outline Evolution of immunosuppression Immunosuppressive drugs: how they work and their potential toxicities Commonly used combination of immunosuppressive drugs If Infections Malignancies
Kidney Transplantation: Earlier Experiences
Overcoming the Barriers
Allorecognition After Kidney Transplantation Halloran P. NEJM.(351)2715, 2004
Targets of Immunosuppressive Therapy Halloran P. NEJM ( 351 ), 2715, 2004
Corticosteroids Inhibit APC/monocyte interaction Inhibit IL-2, IL-1 1, IL-3 3, IL-15 15, IFN, TNF transcription Highly effective Cheap Toxicities: HTN, DM, obesity, AVN osteoporosis, peptic p ulcers, acne, psychosis
Calcineurin Inhibitors The cornerstone of immunosuppression Inhibit the production of many cytokines Cyclosporine: introduced in 1983, Sandimmune and later Neoral, now has many generic competitors; cyclosporine modified, Gengraf, Neon Tacrolimus: known as FK506, Prograf and several generics are being introduced d
Calcineurin Inhibitors Cyclosporine, Tacrolimus Prevent expression of IL-2 Block T cell activation Potential short and long term nephrotoxicity
Beware of Modulators of CYP450-3A4 Inhibitors(increase levels) Diltiazem Verapamil Ketoconazole Itraconzole Voriconazole Fluconazole Erythromycin Clarithromycin Zithromax Grapefruit Juice Inducers(decrease levels) Rifampin Izoniazid id Dilantin Tegretol Phenobarbitol St. John s Wort
Calcineurin Inhibitors Side Effects Profiles Cyclosporine Tacrolimus Hyperkalemia +++ +++ Hyperlipidemia +++ + Tremor + ++ Hyperglycemia + ++ Hirsutism ++ Gingival Hyperplasia ++ Nephrotoxicity ++ ++
Cumulative Incidence of Chronic Renal Failure among 69,321 Persons Who Received Nonrenal Organ Transplants in the United States between January 1, 1990, and December 31, 2000 Ojo, A. et al. N Engl J Med 2003;349:931-940
Anti-Proliferative Agents Azathioprine : Imuran Mycophenolate Mofetil : Cellcept/Myfortic Sirolimus/Evrolimus :Rapamune/Zortress Leflunomide: Arava
Azathioprine Blocks purine metabolism Dose: 1-2 mg/kg PO qd Side effects: Myelosuppression Skin cancer Hepatitis Never use with Allopurinol
Mycophenolate Mofetil (Cellcept/Myfortic) Inhibitor of DNA synthesis by blocking inosine monophosphate p dehydrogenase Selective effect on lymphocytes May block adhesion molecules necessary for lymphocyte homing to allograft
Mycophenolate Mofetil (Cellcept/Myfortic) Available in both IV and PO forms Usual dose is 1g BID/720 mg BID Side effects higher at higher doses Diarrhea Leukopenia Thrombocytopenia Increased CMV severity
Sirolimus /Evrolimus Blocks T and B cell activation Side effects: Increases nephrotxicity of CyA, Tac Hyperlipidemia Leukopenia Thrombocytopenia Delayed wound healing Alters cyclosporine metabolism
Long Term Post-Transplant sp a Complications o Infectious complications Malignancy CKD-T
Infectious Complications After Transplantation
Tissue Diagnosis is Most Important
Principles guiding Management of Post transplant Infections Prevention of life threatening infections is the goal Preclinical diagnosis and preemptive therapy is achievable in some infections Early definitive diagnosis( tissue diagnosis) is extremely important and avoiding drug interactions
Malignancies after Solid Organ Transplantation Skin cancers are greatly increased PTLD/Post transplant lymphoproliferative disorder is increased but remains limited Risk of other solid organ malignancies are increased but not a major cause of morbidity or mortality
Overall Incidence of Malignancy After Transplantation 50 40 % 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 Time After Transplantation (Years) Penn I. Transplant Sci. 1994;4:23-32.
Most Commonly Reported Posttransplant Malignancies* Skin and lip cancer Squamous cell carcinoma (SCC) Basal cell carcinoma (BCC) Merkel cell carcinoma Melanoma PTLD Liver and kidney cancers *Confirmed by different registries, including the Israel Penn International Transplant Tumor Registry (formerly Cincinnati Transplant Tumor Registry), the Australia-New Zealand Dialysis and Transplantation Registry and the United Network for Organ Sharing.
Skin Cancer in Transplant Recipients Differs From the General Population SCC is more common than BCC Merkel cell carcinoma, a neuroendocrine cancer of the skin, is more frequent in the transplant population Lesions develop at a younger age (30 versus 60 years) and occur in multiple sites Tumors are more aggressive and are more likely to recur after resection
Skin Cancers in Transplant and the General Population Transplant General Population SCC/BCC 1.8:1 1:5 Melanoma 5.2% 2.7% Patient age 30 65 Lymph node involved 5.8% Rare Mortality 4.9% 1.5%
Viruses Associated With Certain Types of Cancer EBV with non- Hodgkin s lymphoma and PTLD Ubiquitous virus in >90% of general population 90% overall incidence of EBV+ tumors Higher incidence of PTLD in pediatric population is potentially related to the higher incidence of EBVnaive recipients HPV with cervical Etiologic i factor for cervical cancer in the general cancer population Higher incidence of HPV co-infection in transplant recipients than nontransplant patients with cervical cancer HHV-8 with Kaposi s Sporadic or epidemic occurrence sarcoma Presents as either cutaneous or visceral Often seen in immunocompromised patients Correlated with Mediterranean heritage
PTLD 2nd most common de novo malignancy following renal transplantation More than 93% of lymphoid cancers are non-hodgkin s lymphoma Compare with 65% in nontransplant patients Incidence peaks in the 1st year after surgery Risk is highest during the 1st year, when level of immunosuppression is most intense Sayegh MH, et al. Up to Date Online [serial online]. June 25, 2001; version 10.1.
Management of Solid Tumors Standard Modalities Treatment Regimen Alterations Standard surgery Radiotherapy Chemotherapy Discontinue antimetabolites (azathioprine, mycophenolate mofetil) Decrease calcineurin inhibitors Consider altering maintenance therapy
Immunosuppressive Treatment: The Standard Protocol in 2012 Induction: anti CD-25 or Thymoglobulin Maintenance immunosuppression: Choice of Calcineurin inhibitor: Tacrolimus vs. Cyclosporin Anti-proliferative: Mycophenolate or Sirolimus Steroid withdrawal vs. low dose prednisone
The Goal of Immunosuppression in 2012 Optimize combined regimen to: - Minimize rejection - Minimize toxicity Can optimize therapy for high risk patients Tailor immunosuppressive drug regimen to fit the individual patient s risks and side-effects profile Avoid and monitor for potential drug interactions