Introduction immunosuppression akl_isneap2017

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


ADAPTIVE - INNATE LINK


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


ACTIVATION

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


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


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 [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


INDUCTION AGENTS


INDUCTION AGENTS

• Muromonab (OKT3)

• Equine polyclonal ATG (ATGAM)

• Rabbit polyclonal ATG (Thymoglobulin)

• Basiliximab (Simulect)

• Daclizumab (Zenapax)

• Alemtuzumab (Campath-1H)

• FTY 720 (Psoriasis)


• 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


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


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)


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

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


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 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.


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


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

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


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


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 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


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


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


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.



• 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.



• 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.



MYSS Follow-up Study

Remuzzi G. et al. J Am Soc Nephrol. 2007 June; 18: 1973–1985.



•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.


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


Mycophenolate:

mTOR Inhibitor

•Dosage: 2-5 mg qd

•Level: 5-15 ng/mL (whole blood trough level)


Sirolimus (Rapamune / Rapamycin)

SIDE EFFECTS OF SIROLIMUS


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


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


Side Effects of Corticosteroids


Corticosteroids Acne

Cushingoid facial appearance

Hirsutism

Mood disorders

Hypertension

Glucose intolerance

Cataracts

Osteoporosis

Growth retardation in children

May potentiate adverse

events of CNIs


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


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


• 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


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


PROTOCOLS


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


ISN EDUCATION AMBASSADORS PROGRAM MINYATE EL NASR PROJECT 2017

شكرا جزيال

Introduction immunosuppression akl_isneap2017

Investor Relations

Transcript of Introduction immunosuppression akl_isneap2017