Introduction to Transplantation Immunosuppression

History 1909 - The first kidney transplant experiments were performed in humans in France using animal kidneys (rabbit). 1933 - The first human-to-human kidney transplant was performed. 1954 - The first successful human-to-human transplant from one twin to another by Dr. Joseph E. Murray and his colleagues at Peter Bent Brigham Hospital in Boston. 1962 – The first cadaveric donor kidney transplant at Peter Bent Brigham Hospital (now Brigham & Women's Hospital) in Boston.

General Principle of Immunosuppression Primary immune responses are more easily repressed than secondary (memory) Suppression is more likely to be achieved if therapy is begun before exposure to the immunogen Different immunosuppressants have different effects on different immune reactions and mediators

Introduction Advances in transplant immunosuppression have contributed to the decrease in the frequency of acute rejection increase in graft survival longevity for renal allograft recipients Proliferation of agents means more options different mechanisms of action more complicated management schemes increase potential for drug-drug interactions and complex side effect profiles 6

Categories of Agents Induction agents Maintenance agents Monoclonal or polyclonal antibodies Administered intravenously immediately following surgery Maintenance agents Prednisone CNIs form the cornerstone of immunosuppressive therapy Antiproliferative agents: Cellcept, Imuran, Rapamune Triple agents / withdrawal / avoidance / conversion

Immunologic History Sensitization First or re-transplant Rejection Infection HLA-matching

Induction Agents Muromonab (OKT3) Equine polyclonal ATG (ATGAM) Rabbit polyclonal ATG (Thymoglobulin) Basiliximab (Simulect) Daclizumab (Zenapax) Alemtuzumab (Campath-1H) FTY 720

Induction Thymoglobulin 1ST dose given in OR Dose: 1.5 mg/kg Total dose: usually 6 mg/kg Adverse effects: cytokine release syndrome (fever, chills, arthralgia), leucopenia, thrombocytopenia Premedication: Tylenaol, Benadryl, Hydrocortisone Also effective in treating rejection

Induction Anti-IL-2 Receptor Antibodies Basiliximab (Simulect) Daclizumab (Zenapax)

Anti-IL-2 Receptor Antibodies Basiliximab (Simulect) Chimeric antibody (75% human, 25% mouse) Dosing: 20 mg i.v. pre-op and POD# 4 Daclizumab (Zenapax) Humanized (95% human, 5% mouse) Dosing: 1 mg/kg pre-op and q 2 w for total 6 doses Not effective for treating rejection

Calcineurin Inhibitors Cyclosporine Different preparation are not equivalent Sandimmune (cyclosporine, USP) Gengraf (cyclosporine, USP – Modified) Neoral (cyclosporine, USP – Microemulsion) Tacrolimus (FK 506, Prograf)

Advantages of CsA Microemulsion formulation Twice the bioavailability Less intraindividual and interindividual variability Reduced time (more than 30 percent) to maximal concentration (Tmax) Absorption and drug levels are less susceptible to the effects of food (particularly fatty foods), Not dependent upon bile salts for absorption.

CNI: Dosing Cyclosprine (Neoral, Gengraf, Sandimmune) Initial dosing: 8-10 mg/kg/day Maintenance: 2-6 mg/kg/day Tacrolimus (Prograf) Initial dosing: 0.15 mg/kg/day Maintenance:0.05-0.15 mg/kg/day

Cyclosporin: Monitoring Trough or C0 level Low risk Mod Risk High risk 0-6 m 150-250 ng/ml 175-325 ng/ml 200-350 ng/ml 6-12 m 100-200 ng/ml 125-225 ng/ml > 12 m 50-150 ng/ml 75-175 ng/ml S Hariharan. Am J Kidney Dis. 2006. 47(S2):S22-S36.

Monitoring

Cyclosporin: Monitoring Cyclosporin: C2 Level < 6 months: 1000-1500 ng/ml > 6 months: 800-900 ng/ml Little evidence from prospective studies to support the theoretical benefits of C2 monitoring. Potential dose reductions in stable patients may reduce costs, but no short-term clinical benefit is seen.* *Knight, S R. et al. Transplantation 2007 Jun; 83(12):1525-1535

Tacrolimus (Prograf): Monitoring Low risk Mod Risk High risk 0-6 m 6-12 ng/ml 8-12 ng/ml 8-15 ng/ml 6-12 m 5-8 ng/ml 5-10 ng/ml > 12 m 4-8 ng/ml S Hariharan. Am J Kidney Dis. 2006. 47(S2):S22-S36.

CNI Side Effects Event Comments Hepatotoxicity Liver function should be monitored at regular intervals Cardiovascular Hypertension Hypercholesterolemia Fewer tacrolimus-treated patients require antihypertensive medications Tacrolimus’ impact on lipid levels is less than that seen with cyclosporine Glucose intolerance Recent studies indicate little differences between tacrolimus and cyclosporine Neurotoxicity Tremor Headache Insomnia Paresthesia Seen more often with tacrolimus and generally improve with dose reduction

CNI Side Effects Event Comments Cosmetic side effects Gingival hypertrophy Hirsutism Alopecia Use of steroids may exaggerate development Gingival hypertrophy and hirsutism are associated with cyclosporine Calcium channel blockers can exacerbate gingival hypertrophy Alopecia can occur with tacrolimus Malignancy Skin cancers Cervical cancer Lymphoproliferative disorders Incidence appears to be a function of overall amount and duration of immunosuppression rather than any specific agent

CNI Side Effects Nephrotoxicity (Striped fibrosis) TMA Type IV RTA

CNI More with Tacrolimus More with Cyclosprin Neurologic SE Hypertension GI side effects Hyperlipidemia PTDM Alopecia Hirsutism Hypertrophic cardimyopathy in children Gingival hyperplasia

Metabolic Interactions That Increase CNI Levels Calcium channel blockers Verapamil Diltiazem Amlodipine Nicardipine Antifungal agents Ketoconazole Fluconazole Itraconazole Clotrimazole Metronidazole Immunosuppressants Sirolimus Glucocorticoids Methylprednisolone Antibiotics Erythromycin Clarithromycin Josamycin Ponsinomycin Azithromycin Protease Inhibitors Saquinavir Indinavir Nelfinavir Ritonavir Foods Grapefruit Grapefruit juice

Metabolic Interactions That Decrease CNI Levels Antituberculosis drugs Rifampin Rifabutin Isoniazid Anticonvulsants Barbiturates Phenytoin Carbamazepine Herbal preparations Saint John’s wort Antibiotics Nafcillin IV trimethoprim IV sulfadimidine Imipenem Cephalosporines Terbinafine Ciprofloxacin Other drugs Ticlopidine Octreotide Nefazodone

Nonmetabolic Interactions With CNIs Drug Type Comments Nephrotoxic agents NSAIDs Vancomycin Ganciclovir Aminoglycosides Monitor renal function NSAIDs may have increased nephrotoxicity with hepatic impairment Potassium-sparing diuretics Hyperkalemia has been reported Antacids Magnesium and aluminum antacids may inhibit absorption of CNIs If necessary, should be taken 2 hours after CNI dose HMG-CoA reductase inhibitors (statins) Increased risk of rhabdomyolysis, bone marrow suppression 29

CNI Tacrolimus v. Sandimmune Tacrolimus v. Neoral acute rejection may be less with tacrolimus. similar graft survival Tacrolimus v. Neoral In some studies, tacrolimus has reportedly had lower acute rejection rates. Despite this, both agents are associated with similarly excellent allograft survival rates, although some studies report an advantage of one agent over the other.

CNI In a meta-analysis and meta-regression study of 123 reports from 30 trials (4102 patients), the followings were found. At six months, graft loss was significantly reduced in tacrolimus treated recipients and this effect persisted up to three years. At one year, tacrolimus treated patients had less acute rejection. Treating 100 recipients with tacrolimus instead of cyclosporin for the first year after transplantation avoids 12 patients having acute rejection and two losing their graft but causes an extra five patients to develop insulin dependent diabetes. Webster AC. Et al. BMJ 2005 Oct 8;331(7520):810

Dosing of Adjuvant Agents Daily Dose Monitoring Azathioprine 1-3 mg/kg qd None available MMF (Cellcept) 750 mg-1.5 g bid MPA:1.6 – 2.75 mg/L* Sirolimus 2-5 mg qd 5-15 ng/mL (whole blood trough level) Corticosteroids 5-10 mg qd *Borrows R, et al. Am J Transplant 2006(6):12-128 32

Antiproliferative Agents Daily Dose Monitoring Azathioprine (Imuran) 1-3 mg/kg qd None available Mycophenolate mofetil (MMF, Cellcept) 750 mg-1.5 g bid Not required MPA:1.6 – 2.75 mg/L* *Borrows R, et al. Am J Transplant 2006(6):12-128

Side Effects of Antiproliferative Agents Drug and Side Effects Clinical Implications Azathioprine Leukopenia Anemia Thrombocytopenia Hepatitis Cholestasis Pancreatitis Complete blood counts should be performed regularly to monitor for hematologic side effects MMF Diarrhea Nausea Bloating dyspepsia Vomiting Esophagitis Gastritis GI side effects are more common when dose exceeds 1 g bid and respond to dose reduction or more frequent administration of smaller doses

Drug Interactions With Antiproliferative Agents Azathioprine Coadministration with ganciclovir, ACE inhibitors, carbamazepine, clozapine, or cotrimoxazole can lead to the exacerbation of hematologic toxicity Allopurinol is contraindicated, as concomitant administration can lead to life-threatening myelosuppression MMF Coadministration with ganciclovir, ACE inhibitors, carbamazepine, clozapine, or co-trimoxazole can lead to the exacerbation of hematologic toxicity Administration with tacrolimus may potentiate GI side effects

Myfortic Enteric-coated MMF Intended to reduce GI side effects but has not been proved in clinical trials Dose equivalent 180 mg Myfortic = 500 mg MMF

Mycophenolate v. Azathioprine Several studies, particularly some initial pivotal reports, found that acute rejection rates were lower with mycophenolate. However, these studies may be flawed. Given current evidence, azathioprine and mycophenolate mofetil appear to be similar in terms of acute rejection rates and long-term allograft survival rates.

Mycophenolate v. Azathioprine MYSS Trial 336 patients undergoing a deceased donor renal transplant randomly assigned to mycophenolate mofetil or azathioprine both groups also receiving cyclosporine microemulsion and corticosteroids. Corticosteroids were continued for the first six months (phase A), after which they were slowly withdrawn and patients were followed for another 15 or more months (phase B). Remuzzi G. et al. Lancet 2004 Aug 7;364(9433):503-12.

Mycophenolate v. Azathioprine MYSS Trial The incidence of clinical rejection was the same for both mycophenolate and azathioprine in phase A (34 and 35 percent, respectively) and phase B (16 and 12 percent, respectively). Rates of allograft loss, and serum creatinine concentration were the same in both groups. However, mycophenolate was approximately 15 times more expensive than azathioprine Remuzzi G. et al. Lancet 2004 Aug 7;364(9433):503-12.

Mycophenolate v. Azathioprine MYSS Follow-up Study Remuzzi G. et al. J Am Soc Nephrol. 2007 June; 18: 1973–1985.

Mycophenolate v. Azathioprine the long-term risk/benefit profile of MMF and azathioprine therapy in combination with cyclosporine Neoral is similar. In view of the cost, standard immunosuppression regimens for kidney transplantation should perhaps include azathioprine rather than MMF.

mTOR Inhibitor Sirolimus (Rapamune / Rapamycin) Dosage: 2-5 mg qd Level: 5-15 ng/mL (whole blood trough level)

Side Effects of Sirolimus Drug and Side Effects Clinical Implications Sirolimus Hypercholesterolemia Hypertriglyceridemia Hypertension Rash Leukopenia Anemia Thrombocytopenia Interstitial pneumonitis Delayed wound healing Mouth ulcers Proteinuria Edema Pneumonitis occasionally resolved in discontinuation of sirolimus

Drug Interactions With Sirolimus As sirolimus is metabolized by the same pathway as the CNIs (P-450 3A4), interactions are the same Sirolimus has been shown to raise blood levels of cyclosporine and MMF Sirolimus should be administered 4 hours after cyclosporine or tacrolimus Sirolimus blood levels are raised by cyclosporine Proper monitoring is advised

Steroids Prednisone Methylprednisone Decreased activity with anti-TB and anti-seizure medications Increased activity with estrogen, OCP, erythromycin

Steroids

Side Effects of Corticosteroids Drug and Side Effects Clinical Implications Corticosteroids Acne Cushingoid facial appearance Hirsutism Mood disorders Hypertension Glucose intolerance Cataracts Osteoporosis Growth retardation in children May potentiate adverse events of CNIs 50

Tailoring Drug Regimens Refractory rejection Changing from cyclosporine to tacrolimus has proven successful in reversing rejection Cardiovascular disease High blood pressure and high cholesterol may be lowered with changes from cyclosporine to tacrolimus High cholesterol may also be lowered by replacing sirolimus with MMF Diabetes De novo presentation of diabetes may improve with lowering of steroid dose Rarely, patients switched from tacrolimus to cyclosporine may see improvements of glucose metabolism

Tailoring Drug Regimens Hirsutism Changing from cyclosporine to tacrolimus generally reverses hirsutism Gingival hyperplasia Replacing cyclosporine with tacrolimus can alleviate gingival hyperplasia Withdrawing calcium channel blockers may also lead to improvements in gingival tissue Tremor If dose reduction of the CNI does not stop tremor, consider switching to the alternate therapy Gout Convert azathioprine to MMF if allopurinol must be used

Deficiencies with Immunosuppressive Therapy Patient’s compliance and adherence Side effects of long-term exposure Long-term comorbidities induced by these agents Need to continue these agents for life Inability to induce tolerance

Conclusion Proper immunosuppression is critical to the survival of the renal allograft Understanding proper dosing and monitoring becomes especially critical when comorbid conditions are involved Some side effects are inherent with a suppressed immune system; others occur as the result of specific agents Experimental drug protocols that eliminate or withdraw steroids and CNIs remain untested in the long term and must be eyed with caution Patient education regarding compliance should be ongoing throughout the life of the transplant