Renal Transplantation

Authored by Dixon Kaufman, MD, Director of Pancreas Transplantation, Associate Professor, Department of Surgery, Division of Transplantation, Northwestern University Medical School

Coauthored by Alan Koffron, MD, Director, Living-Donor Transplantation, Assistant Professor of Surgery, Department of Surgery, Division of Transplantation, Northwestern University Medical School

Dixon Kaufman, MD, is a member of the following medical societies: American Association for the Study of Liver Diseases, American Association of Immunologists, American College of Surgeons, American Diabetes Association, American Medical Association, American Society of Transplant Surgeons, Association for Academic Surgery, Central Surgical Association, Illinois State Medical Society, National Kidney Foundation, Phi Beta Kappa, Society for Surgery of the Alimentary Tract, and Society of University Surgeons

Edited by Laura Lyngby Mulloy, DO, Chair, Associate Professor, Department of Internal Medicine, Division of Nephrology, Hypertension and Transplantation, Medical College of Georgia; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; George R Aronoff, MD, Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine; Michael E Zevitz, MD, Consulting Faculty, Clinical Assistant Professor, Department of Medicine, Finch University of Health Science, Chicago Medical School; and Vecihi Batuman, MD, FACP, Chief of Renal-Hypertension, New Orleans VA Medical Center, Professor, Department of Internal Medicine, Section of Nephrology, Tulane University School of Medicine

eMedicine Journal, December 26 2001, Volume 2, Number 12

INTRODUCTION

 

Background: Kidney transplantation should be strongly considered for all patients who are medically suitable with chronic and end-stage renal disease (ESRD). A successful kidney transplant offers enhanced quality and duration of life and is more effective (medically and economically) than chronic dialysis therapy. Transplantation is the renal replacement modality of choice for patients with diabetic nephropathy and pediatric patients.

Currently in the US, more than 80,000 persons are living with a functioning kidney transplant. This number represents 27% of the nearly 300,000 persons enrolled in the US ESRD program.

In 1973, Congress enacted Medicare entitlement for ESRD treatment to provide equal access to dialysis and transplantation for all patients with ESRD in the Social Security system by removing the financial barrier to care. Currently, the main obstacle is donor organ shortage.

Pathophysiology: An increasing rise in ESRD coupled with a lack of donor organs has resulted in an average waiting time of more than 2 years for a cadaveric renal transplant.

Frequency:

Mortality/Morbidity: The 1-year life expectancy after kidney transplantation is 95-98%. The standardized mortality rate for patients on dialysis who are awaiting kidney transplantation is 6.3/100 patient-years. The standardized mortality rate with each treatment per 100 patient-years is as follows:

Age: The proportion of patients either waiting for a kidney transplant or receiving a kidney transplant according to age is as follows:

Age (Years)

Wait List (%)

Transplant (%)

0-19

2.8

3.7

20-39

31.2

33.6

40-59

15.0

13.0

60-70

39.5

37.2

(From Wolfe et al, NEJM 341: 1725, 1999.)

CLINICAL

 

History: Candidates for renal transplantation undergo an extensive evaluation to identify factors that may have an adverse effect on outcome. Virtually all transplant programs have a formal committee that meets regularly to discuss the results of evaluation and select medically suitable candidates to place on the waiting list. Most programs perform the evaluation in the outpatient setting and possess a relatively uniform approach to the diagnosis and treatment of the pertinent medical and psychosocial issues affecting candidacy.

Causes:

WORKUP

 

Lab Studies:

Imaging Studies:

Other Tests:

Procedures:

TREATMENT

 

Medical Care: The primary goal of short-term and long-term medical follow-up is enabling surveillance for signs and symptoms of renal allograft dysfunction.

Renal parenchymal dysfunction has many etiologies. The clinical manifestation is typically an increase in serum creatinine. Causes are numerous, and the differential diagnosis must be approached systematically.

The greatest considerations are rejection, nephrotoxicity of calcineurin inhibitors, and recurrence of native kidney disease. The time interval between transplantation and the rise in serum creatinine often is helpful to determine the etiology graft dysfunction.

Surgical Care:

MEDICATION

 

Medications are used in renal transplantation for immunosuppression.

All kidney transplant recipients require life-long immunosuppression to prevent a T-cell, alloimmune rejection response. Several new immunosuppressive agents have been approved by the Federal Drug Administration (FDA), and several others currently are in clinical trials.

There are 2 broad classifications of immunosuppressive agents, intravenous induction of antirejection agents and maintenance immunotherapy agents. No consensus exists about which is the single best immunosuppressive protocol, and each transplant program utilizes various combinations of agents slightly differently.

The goals are to prevent acute and chronic rejection, to minimize drug toxicity and rates of infection and malignancy, and to achieve the highest possible rates of patient and graft survival.

Drug Category: Antirejection induction agents -- Induction immunotherapy consists of a short course of intensive treatment with intravenous agents. Antilymphocyte antibody induction therapeutics are varied and include polyclonal antisera, mouse monoclonals, and so-called humanized monoclonals. Polyclonal antisera, such as antilymphocyte globulin (ALG), antilymphocyte serum (ALS), and antithymocyte globulin (ATG), are equine, goat, or rabbit antisera directed against human lymphoid cells. The effect is to significantly lower and almost abolish the circulating lymphoid cells that are critical to the rejection response.

The agents are very effective at prophylaxis against early acute rejection, which is especially beneficial in managing the recipient with delayed graft function. The agents provide an effective immunologic cover during a period in which the calcineurin inhibitors are either delayed or given in subtherapeutic doses until graft function improves. Induction agents are used less often if immediate graft function occurs, such as in recipients of living kidney donors, especially HLA-ID grafts.

Drug Name

Antithymocyte globulin, equine (ATGAM) -- Only polyclonal preparation approved by the FDA for prophylaxis of rejection as an induction agent. Primarily IgG from horse hyperimmune serum.

Adult Dose

10-20 mg/kg/d IV for 7-14 d

Pediatric Dose

Administer as in adults

Contraindications

Documented hypersensitivity; hypersensitivity to horse proteins

Interactions

None reported

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Infection, leukopenia, and thrombocytopenia may occur; adverse reactions include fever, chills, malaise; to reduce the risk of phlebitis, only administer via IV; medical emergency resources should be immediately available to manage the rash, dyspnea, hypotension, or anaphylaxis if necessary

 

Drug Name

Muromonab-CD3 (Orthoclone OKT3) -- A mouse, antihuman, monospecific antibody directed against CD3 antigen on T lymphocytes. Binding of OKT3 to CD3 molecule causes T-cell modulation or results in elimination of circulating T cells. Agent is extremely effective at reversing acute rejection episodes.

Adult Dose

5 mg/d IV for 7-14 d

Pediatric Dose

2.5-5 mg/d IV for 7-14 d

Contraindications

Documented hypersensitivity; hypersensitivity to mouse proteins

Interactions

None reported

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Congestive heart failure, pulmonary edema, fever, and infections may occur; adverse reactions include fever, chills, malaise, headache, and cytokine release syndrome

 

Drug Name

Daclizumab (Zenapax) -- Humanized monoclonal antibody that specifically binds to and blocks IL-2 receptor on surface of activated T cells.

Adult Dose

1 mg/kg/dose for 5 doses, beginning at time of transplant, then q14d

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

Interactions

None reported

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Manage patients receiving the drug in facilities with adequate supportive medical resources

 

Drug Name

Basiliximab (Simulect) -- Chimeric monoclonal antibody that specifically binds to and blocks IL-2 receptor on the surface of activated T cells.

Adult Dose

20 mg IV at time of transplant and repeated 4 d posttransplant

Pediatric Dose

2-15 years: 12 mg/m2; not to exceed 20 mg

Contraindications

Documented hypersensitivity

Interactions

None reported

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Long-term effect on ability of immune system to respond to antigens is unknown

 

Drug Name

Antithymocyte globulin, rabbit (Thymoglobulin) -- A purified immunoglobulin solution produced by the immunization of rabbits with human thymocytes that is used to treat acute rejection.

Adult Dose

1.25-1.5 mg/kg/d IV for 7-14 d

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity; hypersensitivity to rabbit proteins

Interactions

None reported

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Infection, leukopenia, and thrombocytopenia may occur; adverse reactions include fever, chills, malaise, headache

 

Drug Name

Methylprednisolone (Solu-Medrol, Adlone, Medrol, Depo-Medrol) -- Steroids ameliorate delayed effects of immune reactions.

Adult Dose

250-1000 mg at time of transplant; taper for next 2-3 doses

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

Interactions

None reported

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in active infection, diabetes, heart failure

Drug Category: Maintenance Immunosuppression -- There are several immunosuppressive agents currently in use for maintenance immunotherapy in kidney transplant recipients. Optimal maintenance immunosuppressive protocol has not been developed. Maintenance immunosuppressive agents are required for the patient's entire life.

Drug Name

Prednisone (Deltasone, Orasone, Meticorten) -- Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Adult Dose

Administered as a taper beginning with approximately 60-20 mg/d over first month posttransplant; taper to approximately 5 mg/d PO qd over next y

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease

Interactions

Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

 

Drug Name

Azathioprine (Imuran) -- Active component of azathioprine is 6-mercaptopurine. Acts as purine analog that interacts with DNA and inhibits lymphocyte cell division.

Adult Dose

1-3 mg/kg/d PO qd; not to exceed 150 mg/d

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity; significant leukopenia

Interactions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Risk of leukopenia and (rarely) liver dysfunction; caution with liver disease and renal impairment; hematologic toxicities may occur

 

Drug Name

Mycophenolate mofetil (CellCept) -- Inhibitor of enzyme IMPDH. Results in inhibition of lymphocyte proliferation. Used for prophylaxis of organ rejection in patients receiving allogeneic renal allografts

Adult Dose

1-1.5 g PO qd administered in divided doses, usually bid

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

Interactions

May elevate levels of acyclovir and ganciclovir; antacids and cholestyramine decreases absorption, reducing levels (do not administer together); probenecid may increase levels of mycophenolate; salicylates may increase toxicity of mycophenolate

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Do not use with azathioprine; avoid if significant leukopenia develops

 

Drug Name

Cyclosporine (Sandimmune, Neoral, Gengraf, Eon) -- Calcineurin inhibitors that diminish IL-2 production in activated T cells. These agents bind to the intracellular immunophilin cyclophilin, interfering with the action of calcineurin, which inhibits nuclear translocation of the NFAT.

Adult Dose

Dosed according to blood concentrations, typically the 12 h trough concentration range is: 150±50 ng/mL by TDx immunoassay; common starting doses are: 9±3 mg/kg/d PO administered in divided doses, usually 12 h apart

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

Interactions

Drugs that increase cyclosporine levels include diltiazem, nicardipine, verapamil, ketoconazole, fluconazole, itraconazole, erythromycin, clarithromycin, allopurinol, danazol, HIV protease inhibitors, and drugs that inhibit cytochrome P450IIIA; drugs that reduce cyclosporine levels include phenytoin, phenobarbital, rifampin, and drugs that induce cytochrome P450IIIA

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

 

Drug Name

Tacrolimus (Prograf) -- Calcineurin inhibitor that diminishes IL-2 production in activated T cells. Binds to intracellular immunophilin and FKBP, interfering with the action of calcineurin, which inhibits nuclear translocation of the NFAT. FDA approved for prophylaxis of organ rejection in patients receiving allogeneic renal allografts.

Adult Dose

Dosed according to blood concentrations, typically the 12-h trough concentration range is 9±3 ng/mL by IMx immunoassay
Common starting doses are 0.125±0.05 mg/kg/d PO administered in divided doses usually, 12 h apart; IV dosing approximately 1/3 that of PO; administered as continuous infusion over 24 h

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

Interactions

Tacrolimus levels may increase with diltiazem, nicardipine, clotrimazole, verapamil, erythromycin, ketoconazole, itraconazole, fluconazole, bromocriptine, grapefruit juice, metoclopramide, methylprednisolone, danazol, cyclosporine, cimetidine, and clarithromycin; tacrolimus levels may reduce with rifabutin, rifampin, phenobarbital, phenytoin, and carbamazepine

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Has nephrotoxic effects; do not administer simultaneously with cyclosporine; tonic clonic seizures may occur

 

Drug Name

Sirolimus (Rapamune) -- Inhibits lymphocyte proliferation by interfering with signal transduction pathways. Binds to immunophilin FKBP to block action of mTOR. FDA approved for prophylaxis of organ rejection in patients receiving allogeneic renal allografts.

Adult Dose

Loading dose of 6 mg PO, followed by 2 mg/d PO as single dose; trough blood concentrations >8 ng/mL correlated with immunosuppressive activity

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

Interactions

Levels may increase with diltiazem, nicardipine, clotrimazole, verapamil, erythromycin, ketoconazole, itraconazole, fluconazole, bromocriptine, grapefruit juice, metoclopramide, methylprednisolone, danazol, cyclosporine, cimetidine, and clarithromycin; levels may reduce with rifabutin, rifampin, phenobarbital, phenytoin, and carbamazepine

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

May exacerbate hyperlipidemia and thrombocytopenia

 

FOLLOW-UP

 

Further Outpatient Care:

Complications:

Prognosis:

MISCELLANEOUS

 

Special Concerns:

BIBLIOGRAPHY

 

eMedicine Journal, December 26 2001, Volume 2, Number 12