1. Introduction to Transplantation Immunosuppression

2. History
The first kidney transplant experiments were performed in humans in France using animal kidneys (rabbit).
The first human-to-human kidney transplant was performed.
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.

5. 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

6. 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

7. 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

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

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

11. 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

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

13. 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

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

17. 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.

18. CNI: Dosing Cyclosprine (Neoral, Gengraf, Sandimmune)
Initial dosing: mg/kg/day
Maintenance: 2-6 mg/kg/day
Tacrolimus (Prograf)
Initial dosing: mg/kg/day
Maintenance: mg/kg/day

19. Cyclosporin: Monitoring
Trough or C0 level
Low risk
Mod Risk
High risk
0-6 m
ng/ml
ng/ml
ng/ml
6-12 m
ng/ml
ng/ml
> 12 m
ng/ml
ng/ml
S Hariharan. Am J Kidney Dis (S2):S22-S36.

20. Monitoring

21. Cyclosporin: Monitoring
Cyclosporin: C2 Level
< 6 months: ng/ml
> 6 months: 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):

22. 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 (S2):S22-S36.

23. 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

24. 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

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

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

27. 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

28. 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

29. 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

30. 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.

31. 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

32. 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

34. 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

35. 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

36. 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

37. 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

38. 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.

39. 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):

40. 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):

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

42. 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.

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

45. 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

46. 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

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

48. Steroids

50. 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

51. 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

52. 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

53. 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

54. 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