Alemtuzumab is a humanized monoclonal antibody against CD52 proteins on the
surface of T cells and B cells, natural killer cells, macrophages, and granulocytes.
Binding of CD52 elicits antibody-dependent lysis of these cells. It is approved for
use in certain types of leukemias, but not in organ transplant. Because it causes a
profound reduction or depletion in lymphocytes, especially TH lymphocytes, a
number of studies have evaluated its effect as induction therapy to prevent acute
rejection after kidney transplant. Several studies have investigated its use in low and
high immunologic risk transplants and in steroid avoidance or withdrawal regimens
and CNI avoidance or withdrawal regimens. Short-term studies have indicated a role
for this agent in these situations. It is rarely used in liver transplantation. Most
protocols with this agent give a single IV or subcutaneous (SC) dose in the operating
room. With this dose, significant neutropenia and lymphopenia can occur, lasting for
months to years in some patients. This single-dose regimen has been successful in
reducing the incidence of fungal and viral infections as compared with multiple-dose
regimens although infection is still a concern with single dose.
These agents, although not indicated for kidney transplantation, are being used and
studied primarily in kidney transplantation. Intravenous immunoglobulin and
sensitized. Eculizumab, a C5 complement inhibitor, and bortezomib, a proteasome
inhibitor, are also being used and studied in these situations, as well as for the
treatment of antibody-mediated acute cellular rejection.
All patients with ESRD are potential candidates for kidney transplantation unless
contraindicated. The contraindications (absolute or relative) are determined by the
individual transplant center. Absolute contraindications include current malignancy,
active infection, active liver disease, HbsAg-positive, severe or symptomatic
cardiac or pulmonary disease, specific renal diseases with an accelerated recurrence
rate, substance abuse, and abnormal psychosocial and noncompliant behavior.
Relative contraindications for the recipient of a kidney transplant include chronic
liver disease, active infection, positive for hepatitis C, human immunodeficiency
virus (HIV) positive, morbid obesity, current positive cross-match, and age greater
than 70 years. The relative contraindication for the elderly with ESRD is
controversial because approximately 40% of the ESRD population is older than 65
years and an increasing number of these patients are undergoing kidney
transplantation. Patients with ESRD need not wait until they are receiving dialysis
before being considered for a kidney transplant because early transplantation is
associated with lower cost, better quality of life, and longer survival than patients on
dialysis awaiting transplantation. The primary diseases leading to ESRD and
transplant are diabetes, hypertension, glomerulonephritis, and polycystic kidney
Diabetes and hypertension are the most likely causes of ESRD. A kidney transplant
should return renal function to near normal (i.e., a glomerular filtration rate between
50 and 80 mL/minute), improve quality of life, and correct the complications of
ESRD such as anemia, hypocalcemia, and hyperphosphatemia, but not diabetes,
hypertension, or hyperlipidemia.
The risk–benefit ratio must be considered when evaluating a patient for any organ
transplantation. In general, kidney transplants are performed to improve the quality of
life and avoid the complications and outcomes associated with dialysis and renal
failure. It is also more cost effective than dialysis. On the other hand, patients who
are candidates for liver transplantation will die if the transplanted liver fails.
Therefore, the criteria established for organ transplantation must be evaluated
carefully before it is offered to any patient.
HLA matching of donor and recipient at the HLA-A, HLA-B, and HLA-DR loci is
associated with better graft survival and longer half-lives for both living-related and
deceased donor kidney transplants. A six-antigen match is ideal, whereas a zero
antigen match is less favorable. The half-life refers to the time it takes for half of the
grafts that survive the first year to fail. Organ half-lives are longer with living donors
(average 15.9 years) compared with deceased donors (average 11.9 years).
kidney recipients, the 1- and 3-year graft survival for a first deceased donor
transplant is greater than 90% and greater than 80%, respectively. These
positive factors may be offset, however, by ethnicity. Patient and graft survival after
kidney transplantation is reduced in the African-American population compared with
others because of immunologic, medical, pharmacologic, pharmacokinetic,
pharmacogenomic, and socioeconomic reasons. Along with African-American race,
other risk factors associated with decreased survival include advanced donor age,
recipient age less than 15 years and greater than 50 years, retransplantation, a high
PRA (>20%–50%), and delayed graft function. Recipients who fall into these
categories are referred to as high-risk patients.
Because of a limited number of donors, the organ transplant community has
devised methods to increase the donor pool by attempting to safely utilize marginal
donors. In its most current form, this allocation system has incorporated the use of a
predictive tool that determines the degree of marginality, termed the Kidney Donor
Profile Index (KDPI). The KDPI uses donor information, including age, height,
weight, ethnicity, hypertension, diabetes, cause of death, serum creatinine, hepatitis C
status, and circulatory death status to rate kidneys from 0% to 100%. Those in the
higher percentile are more likely to fail, as compared to kidneys with lower KDPIs.
In the current allocation system, donors with a high KDPI (85% or higher) are
reserved for older recipients.
QUESTION 1: G.P. is a 52-year-old, 72-kg African-American man with end-stage renal disease (ESRD)
Blood urea nitrogen (BUN), 44 mg/dL
Serum creatinine (SCr), 13.9 mg/dL
globulin 100 mg IV. He is also given furosemide 100 mg IV after the kidney has been transplanted.
surgery. Why is G.P. being treated with this immunosuppressive regimen?
The major goal of immunosuppressive therapy is to prevent rejection and infection
with minimal adverse effects and to ensure long-term patient and graft survival as
well as improved quality of life. Overall acute rejection rates are <15% during the
first year after kidney transplantation. Most of these episodes respond to acute
No consensus exists on the best induction and maintenance immunosuppressive
regimen, and selection primarily depends on the program and the specific organ to be
transplanted. Although studies have evaluated the various regimens, comparisons are
influenced by differences in donor selection and condition, organ preservation and
procurement, organ ischemic (cold and warm) time, recipient’s pretransplant
conditions, comorbid and high-risk or low-risk immunologic factors, surgical
procedures, postoperative management and monitoring, and length of follow-up.
Another important consideration is that many of the these agents show significant
effects during the first year, but fail to show a significant impact on long-term effects
such as chronic rejection and graft survival
3 The choice of a particular regimen
generally depends on the risk factors present at the time of transplantation. During
this early time period, because the risk of acute rejection is highest in the first few
weeks to months, the number of agents, doses, and target drug concentrations are
higher than later on after transplantation.
Most initial combination immunosuppressive drug regimens rely on two to three
maintenance agents, although in some cases monotherapy has been used, depending
on organ type and risk factors. Common combination regimens include a CNI
(tacrolimus and cyclosporine) with MPA or sirolimus/everolimus, and prednisone.
The most common regimen is tacrolimus, mycophenolate, and prednisone along with
short-term administration of a monoclonal antibody (alemtuzumab, basiliximab) or a
polyclonal antibody (rabbit antithymocyte globulin). Regimens that avoid steroids
and CNIs, or use a short course, in the early transplantation period, or are withdrawn
some time (usually several months) after transplantation in an attempt to avoid the
prednisone) gives excellent results; however, acute rejection may still occur, as well
as with other regimens. Combination therapy is used to take advantage of different
mechanisms of action and to reduce drug toxicity by using sequential therapy and
smaller doses of multiple agents rather than larger doses of any agent used alone.
These multidrug combinations can lead, however, to increased drug costs,
compliance issues, a higher incidence of infection and malignancy, and difficulty in
assessing and managing adverse effects.
Because G.P. is receiving a deceased donor transplant and is considered an
immunologically high-risk recipient (he is African-American),
an antibody plus several maintenance agents would be appropriate. He is started
on tacrolimus, mycophenolate, and prednisone. This combination based on the
literature is the most effective.
After the first 6 months, drug dosages are reduced over time and maintained at a
stable dose for 6 months to 1 year. In G.P., tacrolimus cyclosporine, sirolimus, and
everolimus doses are adjusted based on target trough concentration ranges, which are
reduced over time as well. MMF may be discontinued later. Although the
discontinuation of a drug may reduce adverse effects, it must be counterbalanced
against the risk of rejection and potential graft loss. Monotherapy, generally with
tacrolimus or cyclosporine, may be achieved in low-risk kidney, liver, transplant
recipients at some time after transplantation. Most patients require lifetime
CASE 34-1, QUESTION 2: What is induction therapy and which is the preferred agent for G.P?
Induction therapy after transplantation refers to the use of an antibody, typically at
time of transplant and during the first few days after transplant. rATG, alemtuzumab,
and basiliximab are induction agents. Acute rejection and delayed graft function
(need for dialysis during first 7 days after transplant) can occur in the early transplant
period. Both of these have a negative impact on graft survival. Antibody induction
reduces the incidence of early acute rejection, delayed graft function, and has
typically been used in immunologically high-risk patients. They allow the use of
lower doses, or slower introduction or sequential use of maintenance
immunosuppression. They are a major component of early therapy in high-risk
patients. Their use in patients at low-to-moderate risk has increased, often as a means
of reducing or avoiding the use of CNI and steroids. Currently, approximately 80% of
all kidney transplants receive induction therapy, with rabbit antithymocyte globulin
rATG was chosen as induction because G.P. is African-American and is at higher
risk for acute rejection. In general, rATG appears to be more effective than ATGAM
(horse ATG) and is the antibody of choice. rATG, when used for induction, results in
reduced acute rejection, improved survival, and manageable side effect profile. In
kidney transplants, this agent is effective in reducing acute rejection and improving
short- and long-term graft survival compared to horse ATG and especially in highrisk patients.
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