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INTRODUCTION TO TRANSPLANTATIONIMMUNOSUPPRESSION
DR. AHMED AKL, MD, PhD, FISN
CONSULTANT OF NEPHROLOGY & TRANSPLANTATION,
UROLOGY&NEPHROLOGY CENTER,
MANSOURA, EGYPT
ISN EDUCATIONAL AMBASSADOR
ISN EDUCATION AMBASSADORS PROGRAM MONDAY 20TH FEB 2017
• Background
• Induction agents
• Overview of Immunosuppressants• Calcineurin inhibitors• Antiproliferative agents• Proliferation signal inhibitors (mTOR inhibitors)• Glucocorticoids
• Practical use• Protocols• Monitoring• Side effect management
• Recent trials and “the future”
OUTLINE
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
History of Immunosuppression
• 1954: First successful renal transplant
• Identical twin donor w/o immunosuppression
• 1959: First successful allograft
• Non-identical twin
• Sublethal total body irradiation
• 1962: First successful unrelated allograft
• Azathioprine
• >1 yr survival
• 1963: Reversal of rejection with steroids
• 1967: First Heart Transplant—
died of rejection in several days
Adapted from AST Fellows Conference
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
ADAPTIVE - INNATE LINK
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
TRANSPLANTATION IMUUNOLOGY
Semi Direct allogeneic presentation
T cell recognizes
unprocessed allogenic
MHC molecule bound to
self MHC molecule
c
Direct allogeneic presentation
T cell recognizes
unprocessed
allogeneic MHC
molecule on graft
APC
Presentation of
processed peptide of
allogeneic MHC
molecule bound to self
MHC molecule
Indirect allogeneic presentation
Early Post Transplant
Late Post Transplant
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
ACTIVATION
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
Goals of Immunosuppression
•Challenges for post-transplant recipients…• To provide adequate immunosuppression
• Minimize adverse effects
• Treat adverse effects and chronic, drug-related problems
• Screening for drug-related complications
•Our drugs are good for preventing acute rejections but not chronic, Ab mediated rejection• Recent improvement in short-term outcomes
• Less improvement in long-term outcomes
•No recent, promising agents so focus is on different combinations, reduced dosing to improve outcomes
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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.
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
CATEGORIES OF AGENTS
• INDUCTION AGENTS [PROTEIN DRUGS]
• Monoclonal or polyclonal antibodies
• Administered intravenously immediately following surgery
• MAINTENANCE AGENTS [SMALL-MOLECULE DRUGS]
• Prednisone
• CNIs form the cornerstone of immunosuppressive therapy
• Antiproliferative agents: Cellcept, Imuran, Rapamune
• Triple agents / withdrawal / avoidance / conversion
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
INDUCTION AGENTS
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
INDUCTION AGENTS
• Muromonab (OKT3)
• Equine polyclonal ATG (ATGAM)
• Rabbit polyclonal ATG (Thymoglobulin)
• Basiliximab (Simulect)
• Daclizumab (Zenapax)
• Alemtuzumab (Campath-1H)
• FTY 720 (Psoriasis)
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
• 1ST dose given in OR
• Dose: 1.5 mg/kg
• Adverse effects: cytokine release syndrome (fever, chills, arthralgia), leucopenia, thrombocytopenia
• Premedication: Tylenaol, Benadryl, Hydrocortisone
• Also effective in treating rejection
THYMOGLOBULIN
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
MAINTENANCE
IMMUNOSUPPRESSION
CALCINEURIN INHIBITORS
• CYCLOSPORINE
• Different preparation are not equivalent• Sandimmune (cyclosporine, USP)
• Gengraf (cyclosporine, USP – Modified)
• Neoral (cyclosporine, USP – Microemulsion)
• TACROLIMUS (FK 506, PROGRAF)
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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.
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
CYCLOSPORIN: MONITORING
Low risk Mod Risk
0-6 m 150-250 ng/ml 175-325 ng/ml
6-12 m 100-200 ng/ml 125-225 ng/ml
> 12 m 60-150 ng/ml 75-175 ng/ml
S Hariharan. Am J Kidney Dis. 2006. 47(S2):S22-S36.
Trough or C0 level
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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 6-12 ng/ml
> 12 m 4-8 ng/ml 5-10 ng/ml 6-12 ng/ml
S Hariharan. Am J Kidney Dis. 2006. 47(S2):S22-S36.
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
PRACTICAL CONSIDERATIONS
• TACROLIMUS• Slow up-titration
• Rapid metabolizers?
• May not need to have level 10-15 for immunosuppressive effect
• Draw as trough level
• If level supertherapeutic, ask pt if he took drug before level drawn—don’t assume either way
• Use 1 mg capsules
• IV formulation difficult to titrate
• Generic ok
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
CNI
More with Tacrolimus More with Cyclosprin
Neurologic SE Hypertension
GI side effects Hyperlipidemia
PTDM
Alopecia Hirsutism
Hypertrophic cardimyopathy
in children
Gingival hyperplasia
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
Non-metabolic 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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
Dosing of Adjuvant Agents
Agent 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 None available
*Borrows R, et al. Am J Transplant 2006(6):12-128UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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 Leukopenia
Anemia
Thrombocytopenia
Diarrhea
Nausea
Bloating dyspepsia
Vomiting
Esophagitis
Gastritis
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
Drug Interactions With Antiproliferative Agents
Drug Interactions
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 Co-administration 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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
Myfortic
•Enteric-coated MMF
• Intended to reduce GI side effects but has not been proved in clinical trials
•Dose equivalent• 180 mg Myfortic = 250 mg MMF
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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.
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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.
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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.
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
Mycophenolate v. Azathioprine
MYSS Follow-up Study
Remuzzi G. et al. J Am Soc Nephrol. 2007 June; 18: 1973–1985.
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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.
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
Practical Considerations
• Can take with food/meds
• GI symptoms responsive to change in dose
• Switch to AZA if not tolerated
• Suspend/change dose for WBC<3.5
• Generic ok
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
Mycophenolate:
mTOR Inhibitor
•Dosage: 2-5 mg qd
•Level: 5-15 ng/mL (whole blood trough level)
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
Sirolimus (Rapamune / Rapamycin)
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
AZOOSPERMIA
Pneumonitis occasionally resolved
in discontinuation of sirolimus
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
Steroids
• Prednisone
• Methylprednisone
• Decreased activity with anti-TB and anti-seizure medications
• Increased activity with estrogen, OCP, erythromycin
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
Practical Considerations
• Wean as quickly as condition allows
• Divide dose when >20mg daily
• Infection prophylaxis when >10mg daily
• Give with food
• Not all weight gain is steroid-induced
• Encourage weight bearing exercise for bone health
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
STEROIDS
Tailoring Drug Regimens
• REFRACTORY TRANSPLANTED GRAFT 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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
• 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
Tailoring Drug Regimens
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
PROTOCOLS
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
CONCLUSION
• 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
UROLOGY&NEPHROLOGY CENTER MONDAY 20TH FEB 2017
ISN EDUCATION AMBASSADORS PROGRAM MINYATE EL NASR PROJECT 2017
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