KIDNEY TRANSPLANTATION

AYESHA FAREED

PHARM D

Topic overview

IntroductionTypes of donorsRejectionTypes of rejectionInduction therapyMaintenance therapy

• Kidney transplantation or renal transplantation is the organ transplant of a kidney into a patient with end-stage renal disease.

• It is a surgical procedure to remove a healthy, functioning kidney from a donor and implant it into a patient with non-functioning kidneys.

Types of kidney donors1.Living donors2.Deceased donors(formerly known as cadaveric) LIVING DONORS3.Genetically related(living-related)4.Non-related(living-unrelated

DECEASED DONOR

• A deceased donor transplant is a transplant where the donated kidney comes from a person who has died

There are several classifications of kidneys that come from deceased donors:

• Standard criteria donor (SCD)• Extended criteria donor kidneys (ECD)• Donation after cardiac death donors (DCD)• High social risk donors

PREPARING FOR A KIDNEY TRANSPLANT

DONOR AND RECIPIENT MATCHING Donor and recipient matching can be divided into three distinct

areas: 1)blood group matching2) tissue type matching 3) cross matching.It applies to living kidney donation and deceased kidne donation.Blood Typing

There are 4 different blood types. The most common blood type in the population is type O. The next most common is blood type A, then B, and the rarest is blood type AB. The blood type of the donor must be compatible with the recipient.

The chart below shows which blood type can donate to which.

If your blood type is: You can donate to these blood type:TYPE O TYPE O, A, B, ABTYPE A TYPE A, ABTYPE B TYPE B, ABTYPE AB TYPE AB

HLA TypingHLA typing is also called “tissue typing”. HLA stands for human leukocyte antigen. Antigens are proteins on the cells in the body. Out of over 100 different antigens that have been identified, there are six that have been shown to be the most important in organ transplantation. Of these six antigens, we inherit three from each parent.Except in cases of identical twins and some siblings, it is rare to get a six-antigen match between two people, especially if they are unrelated. The chance of a perfect or six-antigen match between two unrelated people is about one in 100,000. Kidneys are commonly transplanted between two people with no matching antigens without a rejection episode. In other cases where all six antigens matched, recipients have suffered from rejection. There is no way to predict who will experience a rejection episode. Living donors with a 6 antigen match do allow the opportunity for decreased immunosuppression.

Cross-Match TestingThe crossmatch test is a very important part of the living donor work-up and is repeated again just before the transplant surgery. Blood from the donor and recipient are mixed. If the recipient’s cells attack and kill the donor cells, the crossmatch is considered positive. This means the recipient has antibodies “against” the donor’s cells. If the crossmatch is negative, the pair is considered compatible.

RejectionThe body resists the presence of foreign cells or tissue of a donor kidney in much the same way that it fights off bacteria and viruses which cause illness. The rejection process occurs when the patient’s white blood cells reduce or stop the function of the transplanted kidney. Some patients experience a rejection episode in the first few weeks after their operation. Symptoms of rejection may include fever, decreased urine output, fluid retention and increase in weight, tenderness over the kidney and elevated blood pressure. Most rejection episodes can be reversed with drug treatment.

TYPES OF REJECTION

Hyperacute Rejection • Can occur minutes or hours after the transplant. • This type of rejection is very rare. It is untreatable and the kidney

is removed immediatelyAcute rejection • Acute rejection can happen any time after a kidney transplant.

During acute rejection, the serum (blood) creatinine rises. • Acute rejection can usually be treated with a higher dose or a

different type of immunosuppressive medicine until the creatinine returns to baseline.

Chronic rejectionThis is a process that may happen after a kidney transplant. It can develop over months or even years. There is no known treatment

DRUGS USED IN KIDNEY TRANSPLANT

INDUCTION THERAPY

1)monoclonal antibodies: muromonab-CD3, basiliximabDaclizumaBAlemtuzumab2) polyclonal antibodies:Antithymocyte globulin [equine] Antithymocyte globulin [rabbit])

MAINTENANENCE THERAPY 1)Calcineurin inhibitors– Cyclosporine– Tacrolimus

2)Purine synthesis inhibitors/APA– Azathioprine– Mycophenolate mofetil

3)steroids– prednisone

4)mTOR inhibitors– Sirolimus

INDUCTION AGENTSMonoclonal Daclizumab, Basiliximab, Alemtuzumab,muromonab(OKT3) Polyclonal Thymoglobulin, Atgam

DEPLETING AGENTS Thymoglobulin, Alemtuzumab, OKT3

NON DEPLETING AGENTS Daclizumab, Basiliximab

ANTITHYMOCYTE GLOBULIN(EQUINE) MOA:T cell destructionDOSE:10–30 mg/kg i.v. for 4–14 days and is typically infused over four to six hours per dose.

ANTITHYMOCYTE GLOBULINE(RABBIT)MOA:T cell suppressionDOSE: 1 to 4 mg/kg/day for 3–10 days after transplantation. The most common dosage strategy is 1.5 mg/kg/day for 3–5 days. platelet count: 50,000–75,000 platelets/mm3 OR WBC count: 2,000-3,000cells/mm3

then doses may be halved or administered at less frequent intervalsDiscontinuation of the drug should be considered if these values drop below 50,000 platelets/mm3 or to <2,000 white blood cells/mm

SIDE EFFECTS: • Fever , chills, headache , nausea , diarrhea , malaise ,

dizziness , and pain • Myelosuppression, specifically leukopenia and

thrombocytopenia, may occur in up to 30% of patients treated with either preparation.

• Anaphylactic reactions

MUROMONAB- CD3(OKT3)• OKT3 is a murine monoclonal antibody directed against

the CD3 receptor. • When OKT3 is bound to CD3, the TCR undergoes

endocytosis resulting in an inert T-cell. T cells are then removed via opsonization and ultimately, phagocytosis.

• A substantial T-cell loss could occur within the first few hours after an initial dose.

• As the T-cell counts begin to fall, several T-cell-derived cytokines (eg,TNF, IL-2, and IFN-γ) are released into the circulation.

Dosage: 5mg iv bolus, daily for 10 days

Side Effects:• “Cytokine release syndrome”, typically 45

minutes after the injection.• Non-cardiogenic pulmonary edema• Neurologic complications (mild headache,

aseptic meningitis to severe encephalopathy)• Infections and lymphoma• Develpoment of neutralizing antibodies (anti-

OKT3 response) seen in 50% of treatments.

ALEMTUZUMAB• It is a humanized monoclonal antibody directed

against CD52.• CD52 is present on virtually all B- and T-cells as well

as macrophages, NK cells, and some granulocytes.

• When the alemtuzumab antibody binds to CD52, it is thought to trigger an antibody-dependent lysis of the cell.

• The depletion of lymphocytes is so marked that it takes several months to a year post administration for the immune system of a patient to be fully reconstituted.

Dosing: • 20-30 mg on the day of transplantation. A second

dose on POD 1 or 4 can also be given.

Side Effects: • The depleting efficiency of alemtuzumab is so

profound that it is invariably associated with side effects viz. neutropenia (70%), thrombocytopenia (52%), anemia (47%), nausea (54%), vomiting (41%), diarrhea (22%), headache (24%), dysthesias (15%), dizziness (12%), and AIHA(<5%).

NON DEPLETING AGENTS (ANTI CD25 ANTIBODIES)

Daclizumab• 1 mg/kg within 24 hours of transplantation plus an

additional four doses of 1 mg/kg at a schedule of every two weeks after surgery.

• Causes receptor saturation that lasts up to 120 days• reduced dosing schedule with an initial dose of 1

mg/kg on the day of transplant and POD 4 is equally efficacious and safe compared with the 5-dose regimen.

Basiliximab• 20 mg IV given two hours prior to the transplant,

followed by a second 20 mg dose on POD 4. • causes a complete saturation of the CD25 receptor

for 5-8 weeks

SIDE EFFECTS• Extremely safe agents.• Hypersensitivity reactions is the only

significant side effect (<1%) with both the agents.

• There is no increased risk of CMV infections and malignancies.

MAINTENANCE THERAPYCalcineurin inhibitors: CYCLOSPORINSandimmune-immediate release capsule starting dose:10-14 mg/kg/dayNeoral-microemulsion formulation 9 mg/kg/day

TACROLIMUS 0.2 mg/kg/day

ADVERSE EFFECTSSide Effect Cyclosporine FK506Nephrotoxicity ++ +Hypertension ++ +Hypercholesterolemia ++ +

Gingival hyperplasia ++ ?

Hyperglycemia + ++Tremor, neuropathy, convulsion

+ ++

Susceptibility to malignancy

++ +

Susceptibility to viral infection

+ +

Hypomagnesemia + +Hyperkalemia ++ +Hyperuricemia ++ +Hepatotoxicity (cholestatic)

+ +

Nausea, vomiting, diarrhea

+ +

Anaphylaxis + +

PURINE SYNTHESIS INHIBITORSProphylaxis of organ rejection in patients receiving allogeneic renal transplants; use concomitantly with cyclosporine and corticosteroids Mycophenolate mofetil (MMF) 1 g PO/IV q12hr, infused over ≥2 hours• Mycophenolic acid (MPA): 720 mg PO q12hr MOA• Inhibits T- and B-cell proliferation, as well as antibody

production• Acts as noncompetitive, selective, and reversible

inhibitor of inosine monophosphate dehydrogenase (IMPDH)

Adverse Effects >10% Hyperglycemia (44%), Hypercholesterolemia (41%),Hypomagnesemia(39%), Dyspnea (37%),Back pain (35%),Increased blood urea nitrogen (BUN) (35%), Leukopenia (34%),Pleural effusion (34%),Urinary tract infection (34%), Increasing frequency of cough (31%),Hypocalcemia (30%),Hypertension (28%) Abdominal pain (27%),Peripheral edema (27%),Anemia (26%),Fever (23%) Nausea (23%),Hyperkalemia (22%),Diarrhea (21%),Infection (21%), Headache(16%) 1-10% Melanoma (1.6-4.2%),Other malignancies (0.7-2.1%),Lymphoma (0.4-1%), Opportunistic infection (including herpes),Neutropenia,GI bleeding, Pulmonary fibrosis,Progressive multifocal leukoencephalopathy

AZATHIOPRIN

DOSE:• 3-5 mg/kg/day IV/PO initially on day of transplant or

3 days before transplant (rare) • Maintenance: 1-3 mg/kg/day IV/PO Mechanism of Action:• Purine antimetabolite, converted to 6-MP; may

inhibit synthesis of DNA, RNA, and proteins; interferes with cellular metabolism; may inhibit mitosis

Adverse Effects

>10%• Leukopenia (28-50%),Infection (20%) <1%• Lymphoma Frequency Not Defined• Abdominal pain, Alopecia, Arthralgia, Bacterial, fungal,

protozoal, viral infections, Bone marrow suppression, Diarrhea, Fever, Hepatotoxicity, Macrocytic anemia, Myalgia, Nausea or vomiting, Rash, Skin cancer, Steatorrhea, Sweet syndrome (acute febrile neutrophilic dermatosis), Thrombocytopenia

mTOR inhibitors: sirolimusDOSE:• loading dose : 6 mg . maintenance dose: 2 mg given OD• In pediatric patients, a loading dose of 3 mg/m2 may be

given, with a maintenance dose of 1 mg/m2/day.• Dosage adjustments should be made to maintain whole

blood sirolimus trough concentrations within the desired range.

• For patients receiving sirolimus with a calcineurin inhibitor and a corticosteroid, a therapeutic range of 5-12 ng/mL is recommended. If the regimen does not include a calcineurin inhibitor, a higher range (12-24 ng/mL) should be used.

Mechanism of Action:• Inhibits T-cell activation and proliferation and inhibits

antibody production that occurs in response to antigenic and cytokine stimulation; inhibits T- cell proliferation by inhibiting progression from the G1 to the S phase of the cell cycle.

Side effects: • Increased serum lipids, decreased hemoglobin, arthralgia,

peripheral edema, gastrointestinal complaints, skin disorders, stomatitis, electrolyte disturbances (e.g. hypokalemia and hypophosphatemia), dyspnea, cough, infectious diseases and a higher incidence of lymphoceles.

• One of the more serious side effects is the development of SRL-induced interstitial pneumonitis.

STEROIDS: PREDNISONEDOSE:• 5-60 mg/day PO in single daily dose or divided q6-12hrMechanism of Action• Glucocorticosteroid; elicits mild mineralocorticoid

activity and moderate anti-inflammatory effects; controls or prevents inflammation by controlling rate of protein synthesis, suppressing migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at cellular level; in physiologic doses, corticosteroids are administered to replace deficient endogenous hormones; in larger (pharmacologic) doses, they decrease inflammation

SIDE EFFECTSIncreased susceptibility to infection, Replication of hepatitis B and C viruses, Weight gain (increased appetite), Cushingoid appearance, Easy bruising, striae, acne, Poor wound healing,Sodium retention, Hypertension, Hypercholesterolemia Accelerated atherosclerosis, Fatal ventricular arrhythmias (rapid bolus), Osteoporosis Avascular necrosis, Arthralgia with rapidly decreasing dose, Myopathy, Diabetes mellitus, Hyperosmotic nonketotic coma, Behavioral changes, psychosis Posterior subcapsular cataracts, Pancreatitis, Peptic ulcer

Kdoqi guidelines

1.1: We recommend starting a combination of immunosuppressive medications before, or at the time of, kidney transplantation. (1A)

1.2: We recommend including induction therapy with a biologic agent as part of the initial immunosuppressive regimen in KTRs. (1A)

1.2.1: We recommend that an IL2-RA be the firstline induction therapy. (1B)

1.2.2: We suggest using a lymphocyte-depleting agent, rather than IL2RA, for KTRs at high immunologic

risk. (2B)

TAKE HOME MESSAGE• Induction therapy in renal transplantation improves short-term

outcomes in terms of improvement in acute cellular rejection after transplantation.

• Antithymocyte globulin (rabbit) is the most commonly used agent, whereas basiliximab appears safer.

• There is no standard immunosuppression regimen that is considered the most effective; therefore, the agent of choice must be determined by individual clinicians and institutions.

• The possible benefits of Alemtuzumab needs to be verified with further trials

References

• http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/renal-transplantation/