Transcript Mechanism of action

KIDNEY TRANSPLANT
CASE PRESENTATION
MINA BESHARA
PRECEPTOR : DR.GHAZVINI
CHIEF COMPLAINT
• Patient presents to the ER with complaints of
vomiting and nausea
HISTORY OF PRESENT ILLNESS
• MB is a 64-year-old Caucasian female with a past
medical history significant for a renal transplant in
August 2012 presenting with vomiting and diarrhea
for the last 18 hours with associated abdominal
cramps. The patient stated that she was in her
normal state of health up until last night. The
patient stated that she ate dinner without any
problems, which consisted of a thoroughly cooked
hamburger with lettuce and tomatoes.
Approximately 1-2 hours after ingestion, she started
to feel some nausea and then subsequently nonbloody vomitus, more than ten episodes, with some
mucus.
HISTORY OF PRESENT ILLNESS CONT.
• Shortly after the vomiting started, she developed
diarrhea, more than ten episodes of watery
diarrhea, non-bloody, with some mucus. The
patient stated that eventually the diarrhea turned
to clear yellow liquid. The patient denied any new
foods or any sick contacts. Her husband did eat
the same dinner and he denies any GI symptoms
• While in the emergency room, the patient received
a normal saline bolus of 1 liter x1 and Zofran 4 mg x1
• The only antibiotic the patient has been using is
Bactrim, which she was started on when she had
her renal transplant back in August 2012
PAST MEDICAL HISTORY
• History of polycystic kidney disease that developed
into chronic renal failure, status post bilateral
nephrectomy and right renal transplant.
• History of hypertension that resolved after the
bilateral nephrectomy (related to the polycystic
kidney disease).
• History of rapid heartbeat (per patient, this is
secondary to prolonged beta-blocker use when she
was hypertensive).
• Internal and external hemorrhoids
PAST SURGICAL HISTORY
•
•
•
•
•
Right kidney transplant on August 20, 2012.
Bilateral nephrectomy in 2012.
Hysterectomy.
Bilateral tubal ligation.
Tonsillectomy many years ago.
SOCIAL HISTORY
• The patient is a retired lawyer and currently lives
with her husband who is also a lawyer.
• The patient denies smoking , drinking , and drug
use.
FAMILY HISTORY
• The father has diabetes type 2 and Hypertension
PHYSICAL EXAMINATION
• GENERAL:
• The patient is in no acute distress. She is very pleasant and
cooperative. She is alert and oriented.
• SKIN:
• Warm and dry to the touch.
• HEENT:
• Normocephalic, atraumatic. Extraocular movements intact.
Pupils are bilaterally reactive to light. Tympanic membranes are
normal. Oropharynx is clear. Moist mucous membranes.
• NECK:
• Supple. No lymphadenopathy.
• CARDIAC:
• Regular rate and rhythm. No murmurs, thrills, or rubs. Capillary
refill is less than 2 seconds.
PHYSICAL EXAMINATION CONT.
• RESPIRATORY:
• Clear to auscultation.
• GI:
• Bowel sounds are positive. Soft, nontender, non-distended.
Negative Murphy sign. Negative rebound.
• BREASTS:
• No palpable masses. Negative for any lymphadenopathy in
the axillary regions.
• RECTAL:
• Normal tone. No blood on glove. There are some noticeable
external hemorrhoids.
• EXTREMITIES:
• There is 5/5 strength x4 limbs. Full range of motion x4 limbs.
VITAL SIGNS
•
•
•
•
•
•
Temperature: 97.5 F o
Blood pressure :104/70 mmHg
Pulse rate: 111 bpm
Respiratory rate: 18 breaths/minute
Oxygen saturation 99% on room air
Weight: 63.5 kg.
ALLERGIES
• No known drug allergies
LABORATORY VALUES
(2-13-2013)
Current value
Normal Values
NA
138 mEq/L
135-145mEq/L
K
3.1mEq/L 
3.5-5.5 mEq/L
CL
109mEq/L
96-106 mEq/L
CO2
21 mEq/L
23-29 mEq/L
BUN
20 mg/dL
6-20mg/dL
SrCr
1.4 mg/dL
0.7-1.3 mg/dL
Glucose
101mg/dL 
70-99mg/dL
Total protein
7.2 g/dl
6.0-8.5 g/dl
WBC
3.5 k/mm3
4.5-10.0 K/mm3
RBC
3.52 m/mm3
11.9 g/dl
3.5-5.5 m/mm3
Hgb
12-16 g/dl
13
LABORATORY VALUES
(2-14-2013)
Current value
Normal Values
NA
135 mEq/L
135-145mEq/L
K
4.2mEq/L
3.5-5.5 mEq/L
CL
104 mEq/L
96-106 mEq/L
CO2
21 mEq/L
23-29 mEq/L
BUN
22 mg/dL
6-20mg/dL
SrCr
1.4 mg/dL
0.7-1.3 mg/dL
Glucose
122 mg/dL 
70-99mg/dL
Total protein
L 5.9 g/dl
6.0-8.5 g/dl
WBC
3.5 k/mm3
4-10.5k/mm3
RBC
3.52 m/mm3
3.5-5.5 m/mm3
Hgb
11.9 g/dl
12-16 g/dl
14
LABORATORY VALUES
(2-15-2013)
Current value
Normal Values
NA
140 mEq/L
135-145mEq/L
K
4.1 mEq/L
3.5-5.5 mEq/L
CL
111 mEq/L
96-106 mEq/L
CO2
23 mEq/L
23-29 mEq/L
BUN
13 mg/dL
6-20mg/dL
SrCr
1.4 mg/dL
0.7-1.3 mg/dL
Glucose
100 mg/dL 
70-99mg/dL
Total protein
L 6.0 g/dl
6.0-8.5 g/dl
WBC
3.5 k/mm3
4-10.5k/mm3
RBC
3.52 m/mm3
3.5-5.5 m/mm3
Hgb
11.9 g/dl
12-16 g/dl
15
HOME MEDICATION
Medication
Details
Prednisone ( Deltasone® ) 5 mg daily.
Take one tablet by mouth daily
Mycophenolate mofetil (Cellcept ®) 500mg
Take one tablet by mouth every six hours
Tacrolimus (Prograf ® ) 7mg
Take two capsule b twice daily
Propranolol (Inderal ® ) 80mg
Take one tablet by mouth daily
Valganciclovir (Valcyte ®) 900mg
Take two tablets by mouth daily
Trimethoprim/sulfamethoxazole (Bactrim®)
Take two tablets by mouths daily
Multivitamin
Take one tablet by mouth daily
Ondansetron (Zofran®) 4mg
BID
HOSPITAL MEDICATION ORDER
Medication
Details
MYCOPHENOLATE MOFETIL (Cellcept ®)
500mg
Take one tablets by mouth four time a day
TACROLIMUS (Prograf ®)7mg
Take two tablets by mouth daily
VALGANCICLOVIR (Valcyte ®) 900mg
Take two tablets by mouth daily
PROPRANOLOL (Inderal ® )80mg
take one tablet by mouth daily
PREDNISONE ( Deltasone® ) 5mg
Take one tablet by mouth Daily w/Breakfast
HEPARIN 5,000 Unit / 0.5 mL
Administer Subcutaneous, Inj, Every 8 hours
ESOMPERAZOLE (Nexium®) 40mg
Take one Capsule by mouth Enteric capsule ,
every morning before meal
½ NORAML SALINE +20MEQ 1,000mL
Administer IV, Infuse Over: 13.3 hr, Rate:
75 mL/hr,
PROGRESS NOTES
• 2/13/2013
• Patient was admitted with the current chief complaint
• 2/14/2013
• Nausea, vomiting, and diarrhea possibly secondary to viral
versus bacterial gastroenteritis versus Clostridium difficile
versus other.
• Patient was placed on Zofran 4 mg IV q.6h. scheduled to
control the nausea so that she can tolerate her p.o.
immunosuppressant therapy
• Stools were sent to stool studies includes stool culture, ova
and parasites, adult diarrhea panel, Clostridium difficile
toxin, as well as immunocompromised stool studies.
• Patient was hydrated with IV fluids of half-normal saline with
20 mEq of potassium chloride at 75 cc/hour
PROGRESS NOTES CONT.
• 2/15/2013
• Labs were drawn
• Hypokalemia, due to diarrhea, which also probably is the
cause of mild metabolic acidosis.
• Pancytopenia, most likely due to medications. Differential
diagnoses include Valcyte®, Bactrim and CellCept®
• Patient states that she is doing much better today. She says
that she has had no more bouts of vomiting, has been
tolerating clear liquids, and feels like she can eat and is
requesting a full diet
• Patient would like to walk around instead of the Lovenox®
shots
DISCHARGE MEDICATION
• Patient was discharged on her home medication:
• Prednisone (Deltasone® ) 5 mg Take one tablet by mouth
daily
• Mycophenolate mofetil (Cellcept ®)500 mg take one tablet by
mouth every six hours
• Tacrolimus (Prograf ® ) 7 mg , Take two tablets by mouth daily
• Propranolol (Inderal ® )80 mg, Take one tablets by mouth daily
• Valganciclovir (Valcyte ®) 900 mg , Take two tablets by mouth
daily
• Trimethoprim/sulfamethoxazole (Bactrim®) take two tablets by
mouth daily .
• Multivitamin. Take one tablet by mouth daily
• Ondansetron (Zofran®) 4mg , Take two tablets by mouth daily
CRITIQUE OF THERAPY
• I agree with the current therapy and the home
medications. Patient was controlled on her
transplant medication prior to the admission
• I also suggest counseling patient and the family
regarding to the diagnosis results and treatment
plan
• Patient is to follow up with PCP and return to the ER
if symptoms or pain worsens
KIDNEY TRANSPLANT
OBJECTIVES
• To be familiar with the immunology of transplant
• To be able to differentiate the types of transplant
• To be able to understand the rejection
pathophysiology
• To the differentiate the different type of rejection
• Recommend specific drugs and dosing regimens
for induction therapy
• Recommend specific drugs and dosing regimens
maintenance therapy
INTRODUCTION
• An organ is defined as a unit in the body with a
special function, usually constructed from several
different types of tissue
• Atom Molecules Cell tissue  organs organ system 
individual
• A human being only has one of some organs, and
the organ’s function can be crucial to maintaining
life.
• Transplantation is :
• The Transfer of living cells, tissues and organs from one part of
the body to another or from one individual to another
Woodruff M. Ethical Problems in Organ Transplantation. Br Med J. 1964 6;1(5396):1457–1460.
HLA (HUMAN LEUKOCYTE ANTIGEN )
• HLA are proteins that are located on the surface of the
white blood cells and other tissues in the body , also
known as MHC which is important for histocompatibility
in transplantation.
• Class I antigens present on almost all nucleated cells
in the body
• Cytotoxic T cells specialized to destroy,
• Recognize antigen in the presence of MHC type I antigens
• Class II antigen located primarily on B lymphocytes,
antigen-presenting cells, and vascular endothelium.
• T-helper cell specialized to direct the immune system
• Recognize foreign antigen in the presence of MHC type II.
TYPES OF TRANSPLANT
• Autograft is
• Self-tissue transferred from one body site to another in the same
individual. i.e. skin graft for burn victims.
• Graft is recognized as “self” so there is no immune response
• Isograft is
• Tissue transferred between genetically identical individuals.
• Graft is recognized as “self” so there is no immune response
• Donor and recipient are histocompatible
• Allograft is
• Tissue transferred between genetically different members of the same
species.
• Graft is “foreign” and can get rejected
• Donor and recipient are non-histocompatible
• Xenograft is
• Tissue transferred between different species
http://pathmicro.med.sc.edu/ghaffar/mhc-a.jpg
REJECTIONS
•
•
•
Rejection of any transplanted organ is primarily mediated by
activation of alloreactive T cells and antigen-presenting cells
such as B lymphocytes, macrophages, and dendritic cells.
Acute allograft rejection is caused primarily by the infiltration
of T cells into the allograft which triggers inflammatory and
cytotoxic effects on the graft.
Complex interactions between the allograft and cellular
cytokines, cell-to- cell interactions, CD4+ and CD8+ T cells,
and B cells ultimately lead to chronic rejection and graft loss
if adequate immunosuppression is not maintained
TYPE OF REJECTION
• Hyper acute rejection
• Acute rejection
• Chronic rejection
HYPER-ACUTE REJECTION
• Occurs within a few minutes to a few hours of
transplantation
• Result from the destruction of transplant by preformed antibodies, which are results of previous
transplants or blood transfusion which leads to
• Tissue damage can be mediated through antibodydependent, cell-mediated cytotoxicity or through
activation of the complement cascade.
• Decreased blood flow to the tissue
• Increase leukocytosis and fever
ACUTE REJECTION
• Can begin a few days after transplant
• It is mediated by alloreactive T-lymphocytes that appear
in the circulation and infiltrate the allograft through the
vascular endothelium
• It can be reversed within 1-3 days
• Patient will get complete loss of kidney function within
10-14 days
• It is manifested by :
•
•
•
•
•
Enlargement and tenderness of the grafted kidney
Elevated SrCr
Decreased urine output
Decreased renal blood flow
Immunosuppressant therapy are used to prevent it
CHRONIC REJECTION
• It occurs from months to years after a transplant.
• It is a slow form of acute cellular rejection
• Usually characterized by a slow progressive renal
failure
• unlike acute rejection, chronic rejection is not
reversible with any of the immunosuppressive
agents currently available.
THERAPY
• Induction Drugs
• antibody-based
• Maintenance Drugs :
• CNIs (Calcineurin inhibitors)
• Tacrolimus
• Cyclosporine
• Anti-proliferative agents
• Mycophenolate mofetil (CellCept®)
• Azathioprine (Imuran®
• mTOR kinase Inhibitor
• Sirolimus (Rapamune®)
• Corticosteroids
ANTI-PROLIFERATIVE
AGENT
MYCOPHENOLATE MOFETIL (CELLCEPT®)
• Mechanism of action:
•
•
•
Works by inhibiting the T
lymphocyte proliferation by
altering purine synthesis
Used in conjunction with
cyclosporine and
corticosteroids
Low doses of cyclosporine,
decreases nephrotoxicity
• BBW
• Increase the risk of infection ,
increase the development of
lymphoma and skin
malignancies , and increase
the risk of congenital
malformation and
spontaneous abortion when
used during pregnancy
• Dose : 750 mg-1.5 g bid
• Renal transplant :
• Oral : 1 g twice daily
• IV : 1 g twice daily
• Clinical pearls:
• Should be taking on empty
stomach to avoid variability in
absorption
• Pregnancy category D and
decrease the efficacy of oral
contraceptive
AZATHIOPRINE (IMURAN®)
• Mechanism of action:
•
Works by inhibiting the T
lymphocyte proliferation by
altering purine synthesis
• Dose : 1-3 mg/kg qd
• Renal transplant
• Initial Oral or IV 3-5
mg/kg/day given as a single
daily dose , then 1-3 mg/kg
/day maintenance
• BBW:
• Increase the risk of neoplasia
and serious infection , should
be prescribed by physician
familiar with the risks ,
including the hematologic
toxicities and mutagenic
potential
• Clinical pearls:
•
•
•
Inhibits delayed
hypersensitivity reaction and
cellular toxicity
More useful during the early
period of rejection
Pregnancy category D
SIDE EFFECTS OF ANTI-PROLIFERATIVE
AGENTS
Side effects
•
•
Clinical complication
Cellcept®
• Diarrhea
• GI upset
• Tachycardia
• Leukopenia
• Anemia
• Thrombocytopenia
• Nausea , vomiting
• Bloating dyspepsia
• Esophagitis
•
Imuran
• Leukopenia
• Hepatotoxicity
• Anemia
• Thrombocytopenia
• Hepatitis
• Cholestasis
• Pancreatitis
•
•
•
•
CBC should be performed regularly to
monitor for hematologic side effects
GI side effects are dose dependent when
dose exceeds 1 g bid and respond to dose
reduction or more frequent administration
of smaller doses .
CBC should be performed regularly to
monitor for hematologic side effects
Myelosuppression is a dose dependent
Patient with genetic deficiency of
Thiopurine methyltransferase (TPMT) will
have increase risk of myelosuppressive
effects
DRUG –DRUG INTERACTION
• 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 lifethreatening
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
MYCOPHENOLATE MOFETIL VS
AZATHIOPRINE
• Objective
• Compare both Mycophenolate Mofetil and Azathioprine therapeutic
outcome in a cute rejection cases
• Method:
• Prospective, randomized, parallel-group trial compared acute
rejections and adverse events in recipients of cadaver-kidney
transplants over 6-month treatment with mycophenolate mofetil or
azathioprine along with cyclosporine micro-emulsion (Neoral) and
steroids (phase A), and over 15 more months without steroids (phase
B).
• Result
• 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).
Remuzzi G, lesti M , Gotti E , et al. Mycophenolate Mofetil versus Azathioprine for Prevention of Acute Rejection in
Renal Transplantation (MYSS): a Randomized Trial. Lancet 2004;7;364:503-12.
CNIS (CALCINEURIN INHIBITORS)
TACROLIMUS (PROGRAF ®, HECORIA ®)
• Mechanism of action:
•
Suppress cellular immunity by
inhibiting T lymphocyte
activation
• BBW:
•
Increase susceptibility to
infection and possible
development of lymphoma
• Oral dose:
•
Initial dosing: 0.2 mg/kg/day
Maintenance:0.05-0.15
mg/kg/day
• Iv dose :
•
initial dose 0.03-0.05
mg/kg/day
• Clinical pearls:
•
•
•
•
•
Should be taken on empty
stomach to avoid variability in
absorption
Take exactly as prescribed
Trough 5-10 ng/ml
Dose is decreased due to the
risk of nephrotoxicity
It is a nephrotoxic and
substrates of 3A4
CYCLOSPORINE (NEORAL ®,
GENGRAF®, SANDIMMUNE®)
• Mechanism of action:
• Suppress cellular immunity by
inhibiting T lymphocyte
activation
• BBW:
• Renal impairment (with high
dose)
• Increase the risk of infection ,
may cause hypertension
• Initial dosing:
•
8-10 mg/kg/day
• Maintenance:
•
2-6 mg/kg/day
• Clinical pearls:
• Gengraf®/Neoral® have a
higher bioavailability
compared with cyclosporine
and can not be used
interchangeably
• It is a nephrotoxic and
substrates of 3A4
SIDE EFFECTS OF CNI
Side effects
Monitoring parameter
•
Tacrolimus
• Tremor
• Headache
• Hyperglycemia (including
diabetes)
• Hyperkalemia
• Hypophosphatemia
• Hair loss
• Hypokalemia
• Hypomagnesaemia
• QT prolongation
• Diarrhea
• Hypertension
• Neurotoxicity
•
Closely monitor
• Renal , hepatic , electrolytes (K+) ,
glucose
• CBC , signs of infection
•
Cyclosporine
• Hypertension
• Hirsutism
• Gingival hyperplasia
• Hypertriglyceridemia
• Nephropathy
• Edema
• Hyperkalemia
•
•
•
•
•
CBC should be performed regularly
Lipids
Electrolytes
Uric acid
Signs of infection
DRUG- DRUG INTERACTION
• Drugs that increase the CNI
level
• Calcium channel blockers
•
•
•
•
Verapamil
Diltiazem
Amlodipine
Nicardipine
•
Sirolimus
• Antifungal agents
• Immunosuppressant
• Glucocorticoids
• Antibiotics
•
•
•
•
Erythromycin
Clarithromycin
Josamycin
Azithromycin
• Proteases inhibitors
• Foods
•
•
Grapefruit
Grapefruit juice
• Drugs that decrease the CNI level
• Anti-tuberculosis
•
•
•
Rifampin
Rifabutin
Isoniazid
•
•
•
Barbiturates
Phenytoin
Carbamazepine
•
Saint John’s wort
•
•
•
•
•
•
•
Nafcillin
IV trimethoprim
IV sulfadimidine
Imipenem
Cephalosporins
Terbinafine
Ciprofloxacin
• Anticonvulsants
• Herbal
• Antibiotics
TACROLIMUS VERSUS CYCLOSPORINE AS PRIMARY
IMMUNOSUPPRESSION FOR
KIDNEY TRANSPLANT RECIPIENTS
• Objective:
• To compare the positive and negative effects of Tacrolimus and
cyclosporine as initial treatment for renal transplant recipients.
• Methods
• It included all randomized trials comparing tacrolimus with
cyclosporine solution (Sandimmune) or cyclosporine micro-emulsion
(Neoral) as initial immunosuppressive therapy, with any combination of
additional immunosuppressive treatments in the intervention and
control arms.
• It excluded trials in which participants received another solid organ in
addition to a kidney transplant (such as kidney with pancreas).
• Result:
• Treating 100 recipients with tacrolimus instead of cyclosporine 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. Optimal drug choice may vary
between patients
Webster A , Woodroffe R , Taylor R, et al. Tacrolimus versus Cyclosporine as Primary Immunosuppression for
Kidney Transplant Recipients: Meta-Analysis and Meta-Regression of Randomized Trial Data. BMJ 2005 8;
331(7520):810
MTOR KINASE
INHIBITOR
SIROLIMUS (RAPAMUNE®)
• Mechanism of action:
•
Mammalian target of
rapamycin (mTOR) kinase
inhibitor which inhibit Tlymphocyte activation and
proliferation
• BBW:
• Increase the risk of infection
and development of
lymphoma, not
recommended in lung or liver
transplant patient
• Dose : 2-5 mg qd
• High immunologic risk renal
transplant:
•
LD up to 15mg on day 1 ;
maintenance 5mg /day
• Low – to-moderate
immunologic risk renal
transplant :
• LD 3mg /m2 on day 1 and MD
or 1mg /m2 once daily
• Clinical pearls:
•
Tablets and oral solution are
not bioequivalent due to the
difference in absorption
EVEROLIMUS (ZORTRESS®)
• Mechanism of action :
• Mammalian target of
rapamycin (mTOR) kinase
inhibitor which inhibit Tlymphocyte activation and
proliferation
• BBW:
• Increase the risk of infection
and development of
lymphoma
• Only prescribed by a
physician experienced
• Dose :
• Orally 0.75 mg twice daily
• Clinical pearls:
• Analog of sirolimus: new on
the market
SIDE EFFECTS
Side effects
Clinical complication
• Sirolimus (Rapamune®)
• Delayed wound healing
• Pneumonitis
• Hyperlipidemia
• Thrombocytopenia
• Anemia
• Hypertension
• Peripheral edema
• Pneumonitis occasionally
resolved in discontinuation of
sirolimus
• Everolimus (Zortress®)
• Peripheral edema
• Hypertension
• Fatigue , fever , headache
• Insomnia
• Dizziness
• Dry skin
• Hyperglycemia
• Increase creatinine (12%) in renal
transplant
DRUG- DRUG INTERACTION
• Sirolimus is metabolized by the same pathway as
the CNIs (P-450 3A4), interactions are the same
CORTICOSTEROID
PREDNISONE
• Mechanism of action:
•
Naturally occurring hormones
that prevent or suppress
inflammation and humeral
immune response
• BBW:
• None
• Dose : 5-10 mg qd
• Clinical pearls:
• Must taper slowly to avoid
adrenal crises if used greater
than 7-10 days or more
• Decreased activity with anti-TB
and anti-seizure medications
• Increased activity with
estrogen, OCP, erythromycin
SIDE EFFECTS OF PREDNISONE
Long –term SE
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Adrenal suppression
Impaired wound healing
Hypertension
Hyperglycemia
Acne
Cushing’s syndrome
Hirsutism
Dermal thinning
Mood disorders
Hypertension
Glucose intolerance
Cataracts
Osteoporosis
Growth retardation in children
•
Monitoring parameter
• BP
• Glucose
• CBC
• Renal weight
• Sign of infection bone density
Short-term SE
•
•
•
•
•
•
•
Fluid retention
Stomach upset
Emotional instability
Insomnia
Increase appetite
Weigh gain
Possible high blood pressur3
POLYCLONAL
ANTIBODIES
ANTI-THYMOCYTE GLOBULIN (ATGAM)
EQUINE
• Mechanism of action:
Reverse rejection by binding
to antigens on Tlymphocytes and interfering
wit their function
• Block T-cell membrane
protein (CD2 , CD3 , CD45 ,
and so forth), causing
altered function , lysis , and
prolonged T-cell depletion
• BBW:
• Should be administer under
the supervision of a physician
experienced in
immunosuppressive therapy
•
• Dose :
• Prevention : IV 15 mg/kg/day
for 14 days then give every
other day for 7 more doses for
total of 21 doses in 28 days
• Treatment : IV 10-15
mg/kg/day for 14 days then
give every other day for 7
more doses for total of 21
doses in 28 days
• Clinical pearls:
• May need to premedicate
(diphenhydramine),
acetaminophen and steroid
RABBIT POLYCLONAL ATG
(THYMOGLOBULIN)
• Mechanism of action:
•
•
Reverse rejection by binding
to antigens on Tlymphocytes and interfering
wit their function
Block T-cell membrane
protein (CD2 , CD3 , CD45 ,
and so forth), causing
altered function , lysis , and
prolonged T-cell depletion
• BBW:
• Should be administer under
the supervision of a physician
experienced in
immunosuppressive therapy
• Dose
1.5 mg/kg/day 7-14 days
•
• Clinical pearls:
•
May need to premedicate
(diphenhydramine),
acetaminophen and steroid
SIDE EFFECTS
Side effects
•
Atgam/Thymoglobulin
• Anaphylaxes (intradermal skin
testing is recommended after 1st
dose
• Fever
• Chills
• Pruritus
• Rash
• Leukopenia
• Chest pain
• Hypertension
• Edema
• cytokine release syndrome (fever,
chills, arthralgia)
• Thrombocytopenia
Monitoring parameters
•
•
•
Lymphocyte profile (T-cell count)
CBC
Vital signs during administration
THYMOGLOBULIN VERSUS ATGAM
INDUCTION IMMUNOSUPPRESSIVE
• Objective:
• is to compare the safety and efficacy of thymoglobulin vs
Atgam in induction therapy
• Methods:
• compared the safety and efficacy at 10 years among
patients randomized to Thymoglobulin or Atgam induction
in a single center, randomized, double-blinded trial. Quality
adjusted life years (QALYs) were calculated using utility
weights
• Results:
• This long-term follow up showed that Thymoglobulin was
associated with higher event-free survival and improved
QALYs, without increased PTLD or CMV disease, compared
to Atgam at 10 years
Hardinger K , Rhee S , Buchanan P , et at. A Prospective, Randomized, Double-Blinded Comparison of Thymoglobulin Versus
Atgam for Induction Immunosuppressive Therapy: 10 Year Results. Transplantation. 2008.15; 86: 947–952.
MONOCLONAL
ANTIBODIES
MUROMONAB -CD3 (ORTHOCLONE)
• Mechanism of action:
• Reverse rejection by binding
to antigens on T-lymphocytes
and interfering wit their
function
• Binds to CD3 associated with
T-cell receptor , leading to
initial activation and cytokine
release , followed by
blockade of function , lysis ,
and T-cell depletion
• BBW:
• Anaphylactic reactions may
occur after administration of
any dose. Should be
administer under the
supervision of a physician
experienced in
immunosuppressive therapy
• Dose : 5mg IV once daily for 1014 days
• Clinical pearls:
• CI: patient with seizure history ,
uncompensated CHF ,
uncontrolled HTN , fluid
overload , pregnancy
• May need to premeditate
(diphenhydramine),
acetaminophen and steroid
ALEMTIZUMAB
(COMPATH®)
• Mechanism of action
• Bind to CD52 , a non
modulating antigen that
is present on the surface
of the all B and T
lymphocytes and
monocytes
• BBW
• Serious , including fatal ,
cytopenia infusion
reaction and infection
can occur in patients
taking this agent with a
30mg limit dose
• Dose
• IV 30mg as a single dose a
the time of transplant
(induction)
• Clinical pearl
• Relatively new MAB for this
indication, so it’s not used as
much clinically right now
• Used only for prophylaxis
and not for acute rejection
SIDE EFFECTS
Side Effects
Monitoring Parameters
•
Orthocolone OKT3
• Tachycardia
• Hypertension
• Hypotension
• Edema
• Fever
• Chills
•
•
•
Lymphocyte profile (T-cell count)
CBC
Vital signs during administration
•
Alemtizumab
(compath®)
• Hypotension
• Hypertension
• Dysrhythmia
• Fever , chills , headache
• Anemia , rash
• Dyspnea
•
•
•
•
•
Vital sign ,
Blood pressure
Signs of infection
CMV antigen every 2 months
Infusion reaction including
• Hypotension
• Fever
• Shortness of breath
• Bronchospasm
DRUG- DRUG INTERACTION
• Live virus vaccines can result in immunosuppreive
effect of monoclonal antibodies
• Smallpox vaccine
• Rubella virus vaccine, live
• Mumps virus vaccine, live
• Measles virus vaccine, live
• Varicella virus vaccine
• Rotavirus vaccine, live
INTERLEUKIN 2(IL-2)
RECEPTOR ANTAGONIST
DACILZUMAB (ZENAPAX®)
•
Mechanism of action:
•
•
Binds to block the interleukin
2 – receptor alpha chain
(CD25 antigen ) on
activated T cells , depleting
them and inhibiting
interleukin 2- induced T cell
activation
Humanized (95% human, 5%
mouse)
• Dose :
• 1 mg/kg for 5 dose total , 1
pre-op and 4 more doses
should be given at intervals of
14 days
• BBW:
• Should be administer under
the supervision of a physician
experienced in
immunosuppressive therapy
BASILIXIMAB (SIMULECT ®)
• Mechanism of action:
•
•
Binds to block the interleukin
2 – receptor alpha chain
(CD25 antigen ) on
activated T cells , depleting
them and inhibiting
interleukin 2- induced T cell
activation
Chimeric antibody (75%
human, 25% mouse)
• Dose a cute renal transplant
rejection prophylaxis :
• 20 mg IV. pre-op within 2
hours followed by a second
20 mg dose 4 days after
transplantation
• BBW:
• Should be administer under
the supervision of a physician
experienced in
immunosuppressive therapy
SIDE EFFECTS
Side effects
Monitor parameter
• Daclizumab (Zenapax®) and
Basiliximab (Simulect®)
• Hypertension
• Peripheral edema
• Electrolytes abnormalities
• Sever hypersensitivity
• Fever , headache
• Insomnia , pain
• Tremors
• Respiratory Infection ,
• Anemia
• Signs and symptoms of
hypersensitivity and infection.
ALGORITHM
• Induction therapy (initiation of transplant)
• Use conventional high dose regimen
• Start with CNIs + corticosteroid + Anti-proliferative agents
• Antibodies:
• PABs: Abgam or Thymoglobulin
• MABs: Campath or OKT3
• IL-2 antagonists: Simulect or Zenapax
• Maintenance therapy
CNIs: cyclosporine , Tacrolimus
Antimetabolites: Azathioprine , cellcept
mTOR inhibitors: sirolimus or everolimus
Corticosteroids
Can use cyclosporine + Cellcept+ corticosteroid or aza + Sirolimus
+ Corticosteroids.
• Can combine any of them as long as one of each
• Steroid can be avoid due to long term side effect unless otherwise
indicated
•
•
•
•
•
ROLE OF PHARMACIST
• Recommend specific drugs and dosing regimens for
induction therapy
• Recommend specific drugs and dosing regimens for
maintenance therapy
• Counsel patients and their families on the proper
administration of medication
• Reinsure compliance and improve the patient’s quality
of life
• Identify drug- drug interactions between combination
regimen
• Goal R1.3
• Provide concise and comprehensive drug information
pertaining to the care of transplant patients.
SUMMARY
• HLA (Human Leukocyte Antigen) of both donor and recipient has to match to
minimize rejection
• Kidney transplant is the most common one that occurs. Patients usually die from
infectious complications
• Acute rejection is seen more often then the other two type of rejection
• The goal of maintenance immunosuppression is to prevent acute and chronic
rejection while minimizing drug-related toxicity.
• A common side effect observed in all transplantation recipients who are receiving
maintenance cyclosporine or tacrolimus therapy is nephrotoxicity
• Azathioprine has been considered a part of the “gold standard” regimen with
cyclosporine and corticosteroids, to which all newer regimens have traditionally
been compared.
• (Thymoglobulin) rabbit preparation polyclonal antibody is less immunogenic and
may have other advantages over the equine preparation (Atgam)
• Both ATG and RATG are approved only for the treatment of rejection; however, the
drugs are used often as induction therapy to prevent acute rejection.
• Administration of thymoglubin® and Atgam® can interfere with the immune
response to live vaccines, such as varicella vaccine. If a live vaccine is
administered within 2 months of receiving one of these immunoglobulins,
protection may not be conferred.
SchonderK, Johnson H. Solid Organ Transplantation .In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A
Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill; 2005:761.
REFERENCES
• Woodruff M. Ethical Problems in Organ Transplantation. Br Med J. 1964
6;1(5396):1457–1460.
• Hardinger K , Rhee S , Buchanan P , et at. A Prospective, Randomized, DoubleBlinded Comparison of Thymoglobulin Versus Atgam for Induction
Immunosuppressive Therapy: 10 Year Results. Transplantation. 2008.15; 86: 947–952.
• Webster A , Woodroffe R , Taylor R, et al. Tacrolimus versus Cyclosporine as Primary
Immunosuppression for Kidney Transplant Recipients: Meta-Analysis and MetaRegression of Randomized Trial Data. BMJ 2005 8; 331(7520):810
• Pranav D , Garafal M , Chhabra D , et al. Mycophenolate Mofetil: Safety and
Efficacy in the Prophylaxis of Acute Kidney Transplantation Rejection. Ther Clin Risk
Manag.2009; 5: 139–149.
• Kahan BD. Cyclosporine. N Engl J Med 1989;321:1725–1738.
• SchonderK, Johnson H. Solid Organ Transplantation .In: DiPiro JT, Talbert RL, Yee GC,
Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic
Approach. 7th ed. New York, NY: McGraw-Hill; 2005:761.
• Remuzzi G, lesti M , Gotti E , et al. Mycophenolate Mofetil versus Azathioprine for
Prevention of Acute Rejection in Renal Transplantation (MYSS): a Randomized Trial.
Lancet 2004;7;364:503-12.