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

Categories of Agents

 Induction 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    1 ST 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 0-6 m Low risk 150-250 ng/ml Mod Risk 175-325 ng/ml High risk 200-350 ng/ml 6-12 m > 12 m 100-200 ng/ml 125-225 ng/ml 150-250 ng/ml 50-150 ng/ml 75-175 ng/ml 100-200 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

0-6 m 6-12 m > 12 m

Tacrolimus (Prograf): Monitoring

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

CNI Side Effects

Event

Hepatotoxicity Cardiovascular  Hypertension  Hypercholesterolemia Glucose intolerance Neurotoxicity  Tremor    Headache Insomnia Paresthesia

Comments

 Liver function should be monitored at regular intervals   Fewer tacrolimus-treated patients require antihypertensive medications Tacrolimus’ impact on lipid levels is less than that seen with cyclosporine  Recent studies indicate little differences between tacrolimus and cyclosporine  Seen more often with tacrolimus and generally improve with dose reduction

CNI Side Effects

Event

Cosmetic side effects  Gingival hypertrophy   Hirsutism Alopecia Malignancy  Skin cancers   Cervical cancer Lymphoproliferative disorders

Comments

    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  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

More with Tacrolimus Neurologic SE GI side effects PTDM Alopecia Hypertrophic cardimyopathy in children

CNI

More with Cyclosprin Hypertension Hyperlipidemia Hirsutism 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

 Nephrotoxic agents    NSAIDs Vancomycin Ganciclovir  Aminoglycosides  Potassium-sparing diuretics

Comments

  Monitor renal function NSAIDs may have increased nephrotoxicity with hepatic impairment  Hyperkalemia has been reported  Antacids  HMG-CoA reductase inhibitors (statins)   Magnesium and aluminum antacids may inhibit absorption of CNIs If necessary, should be taken 2 hours after CNI dose  Increased risk of rhabdomyolysis, bone marrow suppression

CNI

 Tacrolimus v. Sandimmune   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

Agent

Azathioprine MMF (Cellcept) Sirolimus Corticosteroids

Daily Dose

1-3 mg/kg qd 750 mg-1.5 g bid 2-5 mg qd 5-10 mg qd

Monitoring

None available MPA:1.6 – 2.75 mg/L* 5-15 ng/mL (whole blood trough level) None available *Borrows R, et al. Am J Transplant 2006(6):12-128

Antiproliferative Agents

Agent Daily Dose Azathioprine (Imuran) 1-3 mg/kg qd Mycophenolate mofetil (MMF, Cellcept ) 750 mg-1.5 g bid Monitoring None available 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

 Azathioprine    Leukopenia Anemia Thrombocytopenia    Hepatitis Cholestasis Pancreatitis  MMF   Leukopenia Anemia       Thrombocytopenia Diarrhea Nausea Bloating dyspepsia Vomiting Esophagitis  Gastritis

Clinical Implications

 Complete blood counts should be performed regularly to monitor for hematologic side effects   Complete blood counts should be performed regularly to monitor for hematologic side effects 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

Azathioprine MMF

Drug Interactions With Antiproliferative Agents

Interactions

 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   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

 Sirolimus             Hypercholesterolemia Hypertriglyceridemia Hypertension Rash Leukopenia Anemia Thrombocytopenia Interstitial pneumonitis Delayed wound healing Mouth ulcers Proteinuria Edema

Clinical Implications

 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

 Corticosteroids  Acne         Cushingoid facial appearance Hirsutism Mood disorders Hypertension Glucose intolerance Cataracts Osteoporosis Growth retardation in children

Clinical Implications

 May potentiate adverse events of CNIs

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