Introduction to Transplantation
Immunosuppression
History

1909 - The first kidney transplant experiments were performed in
humans in France using animal kidneys (rabbit).
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1933 - The first human-to-human kidney transplant was performed.
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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.
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1962 – The first cadaveric donor kidney transplant at Peter Bent
Brigham Hospital (now Brigham & Women's Hospital) in Boston.
General Principle of Immunosuppression
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Primary immune responses are more easily repressed than secondary
(memory)
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Suppression is more likely to be achieved if therapy is begun before
exposure to the immunogen
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Different immunosuppressants have different effects on different
immune reactions and mediators
Introduction
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Advances in transplant immunosuppression have contributed to
the
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decrease in the frequency of acute rejection
increase in graft survival
longevity for renal allograft recipients
Proliferation of agents means
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more options
different mechanisms of action
more complicated management schemes
increase potential for drug-drug interactions and complex side effect
profiles
Categories of Agents
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Induction agents
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Monoclonal or polyclonal antibodies
Administered intravenously immediately following surgery
Maintenance agents
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Prednisone
CNIs form the cornerstone of immunosuppressive therapy
Antiproliferative agents: Cellcept, Imuran, Rapamune
Triple agents / withdrawal / avoidance / conversion
Immunologic History
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Sensitization
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First or re-transplant
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Rejection
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Infection
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HLA-matching
Induction Agents
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Muromonab (OKT3)
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Equine polyclonal ATG (ATGAM)
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Rabbit polyclonal ATG (Thymoglobulin)
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Basiliximab (Simulect)
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Daclizumab (Zenapax)
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Alemtuzumab (Campath-1H)
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FTY 720
Induction
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Thymoglobulin
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1ST dose given in OR
Dose: 1.5 mg/kg
Total dose: usually 6 mg/kg
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Adverse effects: cytokine release syndrome (fever, chills, arthralgia),
leucopenia, thrombocytopenia
Premedication: Tylenaol, Benadryl, Hydrocortisone

Also effective in treating rejection
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Induction
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Anti-IL-2 Receptor Antibodies
Basiliximab (Simulect)
 Daclizumab (Zenapax)
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Anti-IL-2 Receptor Antibodies
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Basiliximab (Simulect)
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Daclizumab (Zenapax)
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Chimeric antibody (75% human, 25% mouse)
Dosing: 20 mg i.v. pre-op and POD# 4
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
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Cyclosporine
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Different preparation are not equivalent
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Sandimmune (cyclosporine, USP)
Gengraf (cyclosporine, USP – Modified)
Neoral (cyclosporine, USP – Microemulsion)
Tacrolimus (FK 506, Prograf)
Advantages of CsA Microemulsion
formulation
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Twice the bioavailability
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Less intraindividual and interindividual variability
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Reduced time (more than 30 percent) to maximal concentration (Tmax)
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Absorption and drug levels are less susceptible to the effects of food
(particularly fatty foods),
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Not dependent upon bile salts for absorption.
CNI: Dosing
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Cyclosprine (Neoral, Gengraf, Sandimmune)
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Initial dosing: 8-10 mg/kg/day
Maintenance: 2-6 mg/kg/day
Tacrolimus (Prograf)
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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
150-250 ng/ml
> 12 m
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
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Cyclosporin: C2 Level
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< 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
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
ng/ml
S Hariharan. Am J Kidney Dis. 2006. 47(S2):S22-S36.
CNI Side Effects
Event
Comments
Hepatotoxicity
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Liver function should be monitored at
regular intervals
Cardiovascular
 Hypertension
 Hypercholesterolemia
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Fewer tacrolimus-treated patients require
antihypertensive medications
Tacrolimus’ impact on lipid levels is less than
that seen with cyclosporine
Glucose intolerance
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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
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CNI Side Effects
Event
Cosmetic side effects
 Gingival hypertrophy
 Hirsutism
 Alopecia
Comments
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Malignancy
 Skin cancers
 Cervical cancer
 Lymphoproliferative
disorders
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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
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Nephrotoxicity (Striped fibrosis)
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TMA
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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
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Calcium channel blockers
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Immunosuppressants
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Ketoconazole
Fluconazole
Itraconazole
Clotrimazole
Metronidazole
Sirolimus
Glucocorticoids
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Methylprednisolone
Antibiotics
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Antifungal agents
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Verapamil
Diltiazem
Amlodipine
Nicardipine
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Protease Inhibitors
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Erythromycin
Clarithromycin
Josamycin
Ponsinomycin
Azithromycin
Saquinavir
Indinavir
Nelfinavir
Ritonavir
Foods
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Grapefruit
Grapefruit juice
Metabolic Interactions That
Decrease CNI Levels
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Antituberculosis drugs
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Barbiturates
Phenytoin
Carbamazepine
Herbal preparations
Saint John’s wort
Antibiotics
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Anticonvulsants
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Rifampin
Rifabutin
Isoniazid
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Nafcillin
IV trimethoprim
IV sulfadimidine
Imipenem
Cephalosporines
Terbinafine
Ciprofloxacin
Other drugs
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Ticlopidine
Octreotide
Nefazodone
Nonmetabolic Interactions With CNIs
Drug Type
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Comments
Nephrotoxic agents
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NSAIDs
Vancomycin
Ganciclovir
Aminoglycosides
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Monitor renal function
NSAIDs may have increased
nephrotoxicity with hepatic impairment
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Potassium-sparing diuretics
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Hyperkalemia has been reported
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Antacids
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Magnesium and aluminum antacids may
inhibit absorption of CNIs
If necessary, should be taken 2 hours after
CNI dose
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HMG-CoA reductase
inhibitors (statins)
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Increased risk of rhabdomyolysis, bone
marrow suppression
CNI
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Tacrolimus v. Sandimmune
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acute rejection may be less with tacrolimus.
similar graft survival
Tacrolimus v. Neoral
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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
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In a meta-analysis and meta-regression study of 123 reports from 30
trials (4102 patients), the followings were found.
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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):12-128
Antiproliferative Agents
Agent
Daily Dose
Monitoring
Azathioprine (Imuran)
1-3 mg/kg qd
None available
Not required
Mycophenolate mofetil
(MMF, Cellcept)
750 mg-1.5 g bid
*Borrows R, et al. Am J Transplant 2006(6):12-128
MPA:1.6 – 2.75 mg/L*
Side Effects of Antiproliferative Agents
Drug and Side Effects
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Azathioprine
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Complete blood counts should be
performed regularly to monitor for
hematologic side effects
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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
Leukopenia
Anemia
Thrombocytopenia
Hepatitis
Cholestasis
Pancreatitis
MMF
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Clinical Implications
Leukopenia
Anemia
Thrombocytopenia
Diarrhea
Nausea
Bloating dyspepsia
Vomiting
Esophagitis
Gastritis
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Drug Interactions With
Antiproliferative Agents
Drug
Azathioprine
Interactions
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MMF
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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
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Enteric-coated MMF
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Intended to reduce GI side effects but has not been proved in clinical trials
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Dose equivalent
 180 mg Myfortic = 500 mg MMF
Mycophenolate v. Azathioprine
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Several studies, particularly some initial pivotal reports, found that acute
rejection rates were lower with mycophenolate. However, these studies may
be flawed.
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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
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MYSS Trial
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336 patients undergoing a deceased donor renal transplant
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randomly assigned to mycophenolate mofetil or azathioprine
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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
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MYSS Trial
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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).
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Rates of allograft loss, and serum creatinine concentration were the
same in both groups.
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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
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the long-term risk/benefit profile of MMF and azathioprine therapy in
combination with cyclosporine Neoral is similar.
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In view of the cost, standard immunosuppression regimens for kidney
transplantation should perhaps include azathioprine rather than MMF.
mTOR Inhibitor
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Sirolimus (Rapamune / Rapamycin)
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Dosage: 2-5 mg qd
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Level: 5-15 ng/mL (whole blood trough level)
Side Effects of Sirolimus
Drug and Side Effects
Clinical Implications
 Sirolimus
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Hypercholesterolemia
Hypertriglyceridemia
Hypertension
Rash
Leukopenia
Anemia
Thrombocytopenia
Interstitial pneumonitis
Delayed wound healing
Mouth ulcers
Proteinuria
Edema
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Pneumonitis occasionally resolved
in discontinuation of sirolimus
Drug Interactions With Sirolimus
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As sirolimus is metabolized by the same pathway as the CNIs (P-450
3A4), interactions are the same
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Sirolimus has been shown to raise blood levels of cyclosporine and MMF
 Sirolimus should be administered 4 hours after cyclosporine or
tacrolimus
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Sirolimus blood levels are raised by cyclosporine
 Proper monitoring is advised
Steroids
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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
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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
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Refractory rejection
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Cardiovascular disease
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Changing from cyclosporine to tacrolimus has proven successful in
reversing rejection
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
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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
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Hirsutism
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Gingival hyperplasia
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Replacing cyclosporine with tacrolimus can alleviate gingival hyperplasia
Withdrawing calcium channel blockers may also lead to improvements in
gingival tissue
Tremor

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Changing from cyclosporine to tacrolimus generally reverses hirsutism
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
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Side effects of long-term exposure
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Long-term comorbidities induced by these agents
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Need to continue these agents for life
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Inability to induce tolerance
Conclusion
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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