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
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INTRODUCTION
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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:
- In the US: The overall rate of ESRD is approximately
735/1,000,000. As the end-stage population continues to increase,
projections estimate that the current population of 372,407 will exceed
660,000 by the year 2010.
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:
- Cadaveric transplant - 3.8
- Living donor transplant - 2.0
Age: The proportion of
patients either waiting for a kidney transplant or receiving a kidney
transplant according to age is as follows:
|
Age (Years)
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Wait List (%)
|
Transplant (%)
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|
0-19
|
2.8
|
3.7
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20-39
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31.2
|
33.6
|
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40-59
|
15.0
|
13.0
|
|
60-70
|
39.5
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37.2
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(From
Wolfe et al, NEJM 341: 1725, 1999.)
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CLINICAL
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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.
- Preexisting morbidities of the transplant candidate with renal
disease
- Hematologic abnormalities, such as anemia and
platelet-hemostatic dysfunction
- Upper and lower gastrointestinal track
abnormalities, such as gastritis, peptic ulcer disease, diverticulosis, diverticulitis,
spontaneous colonic perforation, and prolonged adynamic ileus
(pseudoobstruction)
- Hepatic abnormalities, such as viral hepatitis
B and C
- The cardiovascular system is profoundly
affected in patients with chronic or end-stage renal failure. The
increased mortality is related to hypertension, atherosclerotic heart
disease with myocardial infarction, congestive heart failure, and left
ventricular hypertrophy.
- Bone and joint disease is common because of low
calcium levels, high phosphorus concentrations, and elevated serum
parathyroid hormone (PTH) levels.
Causes:
- A diverse array of diseases destroys renal function in all age
groups. The most common etiologies of renal disease leading to kidney
transplantation are the following:
- Chronic glomerulonephritis – 28%
- Polycystic kidney disease – 12%
- Nephrosclerosis (hypertensive) – 9%
- Systemic lupus erythematosus (SLE) – 3%
- Interstitial nephritis – 3%
- Understanding the etiology of renal disease is important because the
primary renal pathology may influence the outcome based on the propensity
for recurrence of disease and the association of comorbidities.
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WORKUP
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Lab Studies:
- Pretransplant recipient laboratory evaluation: Emphasize
identifying and treating all coexisting medical problems that may increase
the morbidity and mortality rates of the surgical procedure and adversely
impact the posttransplant course. In addition to a thorough medical
evaluation, evaluate the social issues of the patient to determine
conditions that may jeopardize the outcome of transplantation, such as
financial and travel restraints and a pattern of noncompliance.
- Pertinent components include the following:
- Hepatitis B and C serologies
- Epstein-Barr virus serologies (immunoglobulin M
[IgM] and immunoglobulin G [IgG])
- Cytomegalovirus (CMV) serologies (IgM and IgG)
- Varicella-zoster serologies (IgM and IgG)
- Rapid plasma reagin (RPR) test for syphilis
- Purified protein derivative (PPD) -
Tuberculosis skin test with anergy panel, when indicated
- Urinalysis, urine culture, and cytospin (when indicated)
Imaging Studies:
- A complete cardiac workup including angiography is unnecessary in
all patients. However, individuals with a significant history, symptoms,
type I diabetes, or hypertensive renal disease should undergo a thorough
evaluation to rule out significant coronary artery disease.
- Chest x-ray (posteroanterior [PA] and lateral)
- Exercise and dipyridamole thallium scintigraphy
- Two-dimensional echocardiography with Doppler
(+/- dobutamine)
- Coronary arteriogram (if indicated)
- Special procedures in selected patients dictated by findings on
history and physical examination
- Ultrasound of native kidneys
- Peripheral arterial Doppler studies
- Urodynamic pressure-flow studies
Other Tests:
- Recipients of kidney transplants undergo an extensive immunological
evaluation that primarily serves to avoid transplants that are at risk for
antibody-mediated hyperacute rejection. There are 4 components of the
immunologic evaluation.
- ABO blood group determination: This test is used to determine if
the patient is a potential target of recipient circulating preformed
cytotoxic anti-ABO antibody. Transplantation across incompatible blood
groups may result in humoral-mediated hyperacute rejection.
- Human leukocyte antigen (HLA) typing: All transplant recipients are
tissue typed to determine the HLA class I and class II loci. Six HLA antigens
are determined. The kidney donors also are HLA typed, and the degree of
incompatibility between the donor and recipient is defined by the number
of antigens that are mismatched at each of the HLA loci.
- Serum screening for antibody to HLA phenotypes
- Sensitization to histocompatibility antigens is
of great concern in certain populations of transplant candidates. This
occurs when the recipient is sensitized because of receiving multiple
blood transfusions, a previous kidney transplant, or from pregnancy.
- Transplantation of a kidney into a recipient
that is sensitized against donor class I HLA antigens puts the recipient
at high risk of developing hyperacute antibody-mediated rejection. All
transplant candidates are screened to determine the degree of humoral
sensitization to HLA antigens.
- Crossmatching: This is an in vitro assay method that determines
whether a potential transplant recipient has preformed anti-HLA class I
antibodies against those of the kidney donor. This immunologic test is
conducted prior to transplantation. A negative crossmatch must be obtained
prior to accepting a kidney for transplantation.
Procedures:
- The medical workup may reveal circumstances requiring surgical
intervention to prepare the patient for kidney transplantation.
- Pretransplant native kidney nephrectomy/nephroureterectomy: This no
longer is a routine pretransplant procedure. The native kidneys are left
in place because they still may produce significant volumes of urine,
secrete erythropoietin, and activate vitamin D.
Nephrectomy/nephroureterectomy is reserved for specific indications, such
as large polycystic kidneys, significant proteinuria, and chronic reflux
disease.
- Pretransplant cholecystectomy: Ultrasound evidence of symptomatic
or asymptomatic gallstones is an indication. The mortality and morbidity
of acute cholecystitis is significant in the transplant recipients that
are immunosuppressed.
- Splenectomy: This no longer is a requisite pretransplant surgical
procedure. However, splenectomy may be indicated as part of a protocol for
ABO-incompatible kidney transplants.
- Multiple random blood transfusions: Once, this was associated with
improved, kidney transplant, graft survival in the precyclosporine era.
Currently, there is no clinical benefit to transfusion, and the risk of
sensitization is significant. In the setting of living kidney
transplantation, donor-specific transfusion therapy also has been almost
completely eliminated.
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TREATMENT
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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.
- Delayed graft function immediately posttransplantation usually is
due to acute tubular necrosis (ATN). Frequency is variable among the
different transplant centers and approximates roughly 20-30% of cadaver
transplants.
- The nephrotoxicity of calcineurin inhibitors, cyclosporine and
tacrolimus, is dose related. Occasionally, performing a renal allograft
biopsy is necessary if the serum creatinine does not respond to a
reduction in dose.
- Hemolytic uremic syndrome (HUS) has an unknown etiology, but it
seems to be associated with endothelial injury associated with calcineurin
inhibitors and the occurrence of CMV. Laboratory evaluation showing
diminished platelet count, anemia, reduced haptoglobin levels, rising
lactic dehydrogenase (LDH) levels, and a peripheral blood smear with
schistocytes is consistent with the diagnosis. The definitive diagnosis is
made with the aid of renal allograft biopsy showing glomerular
microthrombi.
- Recurrent renal disease in patients who have had kidney transplants
accounts for less than 2% of all graft losses, though it affects as many
as 10% of transplant recipients. A few diseases have a high risk of renal
allograft loss, such as focal segmental glomerulosclerosis, HUS oxalosis,
and membranoproliferative glomerulonephritis. Diabetic nephropathy can
recur in renal allografts, but the time to onset is similar to that seen
in native kidneys and is an uncommon cause of graft loss.
- Hyperacute rejection of the renal allograft
happens within hours of the transplant, and it occurs when circulating,
preformed, cytotoxic, antidonor antibodies directed to the ABO blood
group antigens or to the donor HLA class I antigens are present. No
treatment exists, and nephrectomy is indicated.
- Accelerated acute rejection is a very early,
rapidly progressive, aggressive rejection reaction. It can occur within
the first week of transplantation. Immediate therapy with anti–T-cell
antibodies and pulse corticosteroids may reverse the process.
Approximately 50% of cases can be salvaged.
- Acute tubular interstitial cellular rejection
is the most common type of rejection reaction with an incidence of
approximately 20-25%. Typically, it occurs between 1-3 months
posttransplant. It is T-cell mediated, and injury is directed to the
renal tubules. The criterion standard for diagnosis is renal allograft
biopsy. Mild rejections may be successfully reversed with corticosteroids
alone, whereas moderate or severe rejections may require the use of
anti–T-cell antibodies, either polyclonal or monoclonal.
- Chronic rejection is a slow and progressive
deterioration in renal function characterized by histologic changes
involving the renal tubules, capillaries, and interstitium. The precise
mechanism of this disease is poorly defined and is an area of intense
study. Application of conventional antirejection agents, such as
corticosteroids or anti–T-cell antibodies, does not appear to alter the
progressive course. Unfortunately, this is a major cause of kidney
allograft loss, occurring later than 2 years posttransplant.
Surgical Care:
- Wound complications: In patients who have had transplants, risk
factors for and the morbidity of wound complications are significant.
- Bleeding: Kidney transplantation is a vascular surgery procedure;
however, it is not an operation associated with much blood loss. Postoperatively,
a life-threatening bleeding complication is very rare but could result
from rupture of the arterial anastomosis from a mycotic aneurysm.
- Vascular thrombosis: Acute arterial thrombosis occurs in 1% of all
kidney transplants. Salvage of the renal allograft is possible if
diagnosed within the first one half hour of occurrence (during recovery in
the postanesthesia recovery room). Rarely, venous thrombosis occurs. If it
occurs, the kidney usually is unsalvageable. The cause often is never
satisfactorily identified.
- Urine leak: Leaks occur at the ureterovesical junction or through a
ruptured calyx secondary to acute ureteral obstruction. Often, the
etiology of early urine leak is due to necrosis of the tip of the ureter.
Urine leaks manifest as diminished urine output, an increase in
creatinine, and lower abdominal or suprapubic discomfort. Repair employing
minimal intervention may be attempted with either a percutaneous
nephrostomy and drainage with internal stenting or through a cystoscopic
retrograde approach. More aggressive treatment involves operative
intervention with reimplantation of the ureter or a ureteroureterostomy,
utilizing the ipsilateral native ureter.
- Ureteral stenosis and obstruction: This is a relatively late
complication, occurring months or years posttransplant, that could result
from ischemia of the ureter or a tight ureteroneocystostomy. Ureteral
stenosis is manifested by elevated creatinine and hydronephrosis.
- Lymphocele: This is a circumscribed collection of retroperitoneal lymph
that originates from lymphatic vessels about the iliac vasculature and the
hilum of the kidney. Significant secondary problems may arise if external
compression of the iliac vein (causing leg swelling and discomfort) or
compression of the transplant ureter (causing hydronephrosis and renal
dysfunction) occurs. The standard principal is that intraperitoneal
drainage of the lymphocele should be accomplished with either a
laparoscopic or an open surgical approach, with marsupialization of the
edges of the lymphocele.
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MEDICATION
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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.
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Drug Name
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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.
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Adult Dose
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10-20 mg/kg/d
IV for 7-14 d
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Pediatric Dose
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Administer as
in adults
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Contraindications
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Documented hypersensitivity;
hypersensitivity to horse proteins
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Interactions
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None reported
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Pregnancy
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C - Safety for
use during pregnancy has not been established.
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Precautions
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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
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Drug Name
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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.
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Adult Dose
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5 mg/d IV for
7-14 d
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Pediatric Dose
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2.5-5 mg/d IV
for 7-14 d
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Contraindications
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Documented hypersensitivity;
hypersensitivity to mouse proteins
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Interactions
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None reported
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Pregnancy
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C - Safety for
use during pregnancy has not been established.
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Precautions
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Congestive heart
failure, pulmonary edema, fever, and infections may occur; adverse reactions
include fever, chills, malaise, headache, and cytokine release syndrome
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Drug Name
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Daclizumab (Zenapax)
-- Humanized monoclonal antibody that specifically binds to and blocks IL-2
receptor on surface of activated T cells.
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Adult Dose
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1 mg/kg/dose
for 5 doses, beginning at time of transplant, then q14d
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Pediatric Dose
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Not
established
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Contraindications
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Documented
hypersensitivity
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Interactions
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None reported
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Pregnancy
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C - Safety for
use during pregnancy has not been established.
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Precautions
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Manage patients
receiving the drug in facilities with adequate supportive medical resources
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Drug Name
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Basiliximab
(Simulect) -- Chimeric monoclonal antibody that specifically binds to and
blocks IL-2 receptor on the surface of activated T cells.
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Adult Dose
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20 mg IV at
time of transplant and repeated 4 d posttransplant
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Pediatric Dose
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2-15 years: 12
mg/m2; not to exceed 20 mg
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Contraindications
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Documented
hypersensitivity
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Interactions
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None reported
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Pregnancy
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B - Usually safe
but benefits must outweigh the risks.
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Precautions
|
Long-term
effect on ability of immune system to respond to antigens is unknown
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Drug Name
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Antithymocyte globulin,
rabbit (Thymoglobulin) -- A purified immunoglobulin solution produced by the
immunization of rabbits with human thymocytes that is used to treat acute
rejection.
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Adult Dose
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1.25-1.5
mg/kg/d IV for 7-14 d
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Pediatric Dose
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Not
established
|
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Contraindications
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Documented
hypersensitivity; hypersensitivity to rabbit proteins
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Interactions
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None reported
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Pregnancy
|
C - Safety for
use during pregnancy has not been established. |