CASE PRESENTATION MINA BESHARA PRECEPTOR : DR.GHAZVINI KIDNEY TRANSPLANT.

C A S E P R E S E N T A T I O N M I N A B E S H A R A

P R E C E P T O R : D R . G H A Z V I N I

KIDNEY TRANSPLANT

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 non-bloody 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

13

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 3.5-5.5 m/mm3

Hgb 11.9 g/dl 12-16 g/dl

14

LABORATORY VALUES(2-14-2013)



K 4.2mEq/L 3.5-5.5 mEq/L

CL 104 mEq/L 96-106 mEq/L




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

15

LABORATORY VALUES(2-15-2013)



K 4.1 mEq/L 3.5-5.5 mEq/L

CL 111 mEq/L 96-106 mEq/L




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

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 pre-

formed antibodies, which are results of previous transplants or blood transfusion which leads to • Tissue damage can be mediated through antibody-

dependent, 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

• 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

• 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

• 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

• 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 .

• Imuran• Leukopenia• Hepatotoxicity • Anemia• Thrombocytopenia• Hepatitis• Cholestasis• Pancreatitis

• 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 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

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 CNISide 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

• Antifungal agents • Immunosuppressant

• Sirolimus

• Glucocorticoids • Antibiotics

• Erythromycin• Clarithromycin• Josamycin• Azithromycin

• Proteases inhibitors• Foods

• Grapefruit• Grapefruit juice

• Drugs that decrease the CNI level • Anti-tuberculosis

• Rifampin • Rifabutin • Isoniazid

• Anticonvulsants• Barbiturates • Phenytoin• Carbamazepine

• Herbal• Saint John’s wort

• Antibiotics• Nafcillin• IV trimethoprim• IV sulfadimidine• Imipenem• Cephalosporins• Terbinafine• Ciprofloxacin

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 T-lymphocyte 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 T-lymphocyte 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


• 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 Short-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

• Fluid retention • Stomach upset• Emotional instability • Insomnia • Increase appetite • Weigh gain• Possible high blood pressur3

• Monitoring parameter • BP• Glucose • CBC • Renal weight • Sign of infection bone density

POLYCLONAL ANTIBODIES

ANTI-THYMOCYTE GLOBULIN (ATGAM) EQUINE

• Mechanism of action:• Reverse rejection by

binding to antigens on T-lymphocytes 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 T-lymphocytes 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



• Dose • 1.5 mg/kg/day 7-

14 days

• Clinical pearls:• May need to

premedicate (diphenhydramine), acetaminophen and steroid

SIDE EFFECTS Side effects Monitoring parameters

• 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

• 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 10-14 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


• 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



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



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, Double-Blinded 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 Meta-Regression 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.

CASE PRESENTATION MINA BESHARA PRECEPTOR : DR.GHAZVINI KIDNEY TRANSPLANT.

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Transcript of CASE PRESENTATION MINA BESHARA PRECEPTOR : DR.GHAZVINI KIDNEY TRANSPLANT.