The major histocompatibility (MHC) antigens are
the most antigenic proteins on donor organs, meaning that they cause the
most intense immune responses when the donor and recipient do not share
the same antigens. The MHC genes are coded by a single chromosomal
complex of closely linked genes on the short arm of the sixth chromosome.
This complex consists of at least seven loci that code for genes
involved with histocompatibility: human lymphocyte antigen (HLA)-A,
HLA-B, HLA-C, HLA-D, HLA-DR, HLA-DQ, and HLA-DP. Each HLA gene locus
is highly polymorphic, so that as many as 50 or more discrete antigens
are controlled by each locus. The collection of HLA genes in an MHC
complex is termed a haplotype.
Histocompatibility antigens are grouped into class I (A, B, and
C) and class II (DR, DQ, DP) antigens. Class I antigens are composed
of a 45-kDa heavy chain with three globular extracellular domains (α1, α2, α3)
that confers HLA specificity, a transmembrane portion, and an intracellular
domain. Class I antigens are stabilized by β2-microglobulin,
a 12-kDa protein that is not encoded in the MHC complex. Class I
antigens are expressed on all nucleated cells and interact primarily
with CD8+ T cells. Class II antigens are composed of two
noncovalently linked chains: a 33-kDa α chain and
a 28-kDa β chain. Each chain has two extracellular domains
that confer HLA specificities. Class II antigens are only constitutively expressed
on B cells and antigen-presenting cells (macrophages, monocytes, dendritic
cells) but can be induced on activated T cells and endothelial cells. Class
II antigens interact primarily with CD4+ T cells. The three
most important antigens clinically in solid organ transplantation
are A, B, and DR. Since each person has two MHC complexes, one on each
copy of chromosome 6, everyone has a total of six HLA antigens that
are relevant to organ transplantation.
The 3D structures of both class I and II molecules are similar.
The extracellular domains form a β-pleated sheet
with two looping α-helices that creates a groove facing
away from the cell. Following ribosomal synthesis, during assembly
of the HLA antigens, peptides are added to this groove. Intracellularly
derived peptides are added to class I antigens in the endoplasmic
reticulum, while extracellularly derived proteins are added to class
II antigens. The end of the groove on class II antigens is open,
allowing class II antigens to accommodate longer peptides. Antigenic
determinants are found predominantly on the α1
and α2 chains of the class I molecule and on the β chain of
the class II molecule. Some antigenic determinants are shared by
many different HLA allotypes. These common determinants are called public
specificities. Antigenic determinants that are only found
on a unique HLA antigen are termed private specificities.
Lymphocytes are categorized as either B or T cells. B cells are
responsible for antibody production. T cells are categorized into
two functional subsets: helper cells that are CD4+ and
cytotoxic T cells that are CD8+. Helper T cells preferentially recognize
peptides displayed in the groove of class II antigens, while cytotoxic
T cells preferentially recognize peptides displayed by class I antigens.
A third type of T cell called regulatory T cells has recently been
identified and may be either CD4+ or CD8+. Helper
T cells direct both the formation of cytotoxic T cells, which are
able to cause graft destruction directly, and the maturation of
B cells. Helper T cells can be further subdivided based on their
cytokine secretion profile into type 1 and type 2 cells. Type 1
helper T cells secrete interleukin (IL)-2, interferon (IFN)-γ,
IL-12, and TNF-α. These cytokines stimulate delayed-type hypersensitivity,
cytolytic activity, and the development of complement-fixing IgG antibodies.
Type 2 helper T cells secrete IL-4, IL-5, IL-10, and IL-13. These
cytokines activate eosinophils and cause the production of IgE antibodies.
Allograft rejection begins when foreign antigen is taken up by
an antigen-presenting cell, processed, and presented to helper T
cells. The T cell is activated in response to properly presented
antigen and secretes cytokines that in turn recruit and activate
additional lymphocytes and cause them to begin to clonally proliferate.
Cytokines released in the allograft milieu by other cells, including
macrophages, contribute to the generation of the immune response
as well. Helper T cells also stimulate the differentiation and proliferation
of cytotoxic T cells and B cells.
B-cell activation induces the production of specific antibodies
directed against donor antigens. This response is important, especially
for class I antigens. Recipients who develop a primary immunological
response to a particular antigen and produce cytotoxic antibodies
directed against the donor HLA will often retain memory B cells
and maintain the ability to produce antibodies that are directed
against that particular HLA allotype. Upon reexposure to the same antigens,
an immediate destructive reaction to the graft—called hyperacute
rejection—occurs. Antibody directed against the donor vascular
endothelium triggers fixation of complement, direct cellular damage,
and the formation of platelet and fibrin plugs, leading to microvascular
thrombosis and ischemic necrosis of the organ. Transplantation in
the presence of cytotoxic anti-HLA antibody directed against a donor
organ is prevented in practice by performing a complement-mediated
cytotoxic crossmatch with pretransplant recipient sera against lymphocytes
from the potential donor.
Testing, Crossmatching, & Blood Group Compatibility
Grafts between identical twins are rare but very successful because
immunosuppressive therapy is not required when there is no antigenic
difference between the donor and recipient. Grafts between HLA-identical
siblings who share two HLA haplotypes give the next best results.
One fourth of any given sibling pair will share both HLA haplotypes
and thus share all of the same HLA antigens. Despite sharing HLA, immunosuppression
is still required because of incompatibilities at minor histocompatibility
loci. Parents, offspring, and half of siblings share one HLA haplotype.
One fourth of siblings will not share an HLA haplotype and will
therefore share antigens only by chance. The same is true for genetically unrelated
donor/recipient pairs such as spouses and friends. At one
time, HLA compatibility was considered to be crucial because there
were large differences between graft survival depending on the degree
of histocompatibility. Transplants between individuals who shared
many HLA antigens were much more likely to avoid graft loss compared
to donor/recipient pairs who did not share HLA antigens.
This has changed due to the ability of modern immunosuppression
to provide for excellent immunological outcome even in the setting
of complete HLA mismatch. HLA testing is now of much lesser value
than it once was. HLA histocompatibility testing is now primarily
of value in determining which of several donors has the best histologic
match to the intended recipient. Kidney allocation from deceased
donors was once heavily influenced by HLA matching. This has now
changed because of the realization that the degree of HLA match
has a relatively unimportant effect on the odds of successful outcome.
The newest allocation strategy relies more on waiting time and less
on the degree of HLA match. Kidneys from donors who share all six
HLA antigens with a recipient on the waiting list are still allocated
first to any recipient who happens to be a “perfect match.” This
situation is uncommon, affecting fewer than 10% of the
kidneys from deceased donors.
Regardless of the results of tissue typing and antigen matching,
it is essential to determine whether a recipient has preformed antibodies
against donor antigens, since their presence would result in a hyperacute
rejection of the graft as described previously. Preexisting antibodies
may develop because of prior exposure to foreign histocompatibility antigens
in the form of blood transfusion, pregnancy, or previous organ transplants.
These antibodies are identified by performing a crossmatch between
the patient’s serum against the donor’s lymphocytes.
Multiple methods of performing the crossmatch are available with varying
degrees of sensitivity and specificity. It is difficult to find
an appropriate donor with a negative crossmatch for patients who
have antibodies directed against multiple HLA specificities. Some of
these patients can be treated with desensitization strategies to
reduce their burden of circulating antibodies. Methods being currently
investigated include plasmapheresis, infusion of random donor immune
globulin, and anti–B cell monoclonal antibodies. Experience
is accumulating with desensitization protocols suggesting that donor/recipient
pairs with positive crossmatches can sometimes be successfully transplanted.
The long-term outcome for these kidneys is unclear.
The ABO blood group antigens behave as strong histocompatibility
antigens for kidney transplantation; therefore, ABO-incompatible
kidney transplants have generally been considered an absolute impossibility.
It is certainly true that ABO-incompatible kidneys will fail rapidly
if nothing is done to reduce the amount of antibody directed against
the incompatible antigen in the recipient’s serum. Success
is now being reported for AB-incompatible kidney transplants using
combinations of anti–B cell therapy and plasmapheresis.
Klein J, Sato A: The HLA system. (Two parts.)
N Engl J Med 2000; 343:702.
Multiple immunosuppressive strategies are effective at preventing
acute allograft rejection. Most strategies involve the use of more
than one agent. Conceptually, using multiple immunosuppressive agents
has the effect of blocking multiple targets in the immune response
cascade, which allows relatively low doses of each drug to be used,
thus avoiding toxicity associated with high doses of these powerful
drugs. Thus, many patients are treated with “triple therapy” using
corticosteroids, a calcineurin inhibitor, and either an antimetabolite
or a TOR (target of rapamycin) inhibitor. A variant of this strategy,
termed “quadruple therapy,” involves the initial
use of a very potent antilymphocyte agent and chronic administration
of the same drugs used for triple therapy. The antibody treatment
has two effects: It decreases the likelihood of rejection in the
critical first few months after the transplant, and it allows there
to be a delay before the introduction of the calcineurin inhibitor.
This is advantageous because of the associated nephrotoxicity of
calcineurin inhibitors. Since the risk of rejection is highest immediately
after the transplant, it is typical to begin with relatively high
doses of each agent and gradually taper down to a maintenance level
over several weeks to months.
Rejection is diagnosed by biopsy. Patients are followed up with
serial measurements of renal function in the form of serum creatinine.
When a transplanted kidney begins to function, the serum creatinine
will fall gradually over several days to reach a nadir level that
becomes a new baseline for the patient. Any significant elevation
above the baseline should prompt evaluation as to the cause, and
once obstruction, dehydration, and infection have been ruled out,
it is usually appropriate to biopsy the kidney graft. Rejection
may be treated with high-dose “pulse” corticosteroid
therapy over several days or with antilymphocyte antibodies. Rejection
therapy is effective in more than 90% of cases.
Many drugs are available today for immunosuppression. All of
these drugs share the common side effect of increasing susceptibility
to infectious diseases. This is an intrinsic feature of currently
available therapy, which aims to suppress natural immune responses
against all foreign antigens. When the transplant recipient develops
an infection, it is vital that a physician with experience prescribing
immunosuppression is involved with the patient’s care.
In many cases, it is appropriate to temporarily reduce the degree
of immunosuppression in order to allow recovery from the infection.
Precisely how this is accomplished varies widely among practitioners,
but it generally involves lowering the dosage or withholding one
or more of the agents being used for maintenance immunosuppression.
When the infection has resolved, immunosuppression is restored to
an acceptable maintenance regimen. It is appropriate to individualize
therapy because different individuals have different propensities
to develop both rejection and infection.
Many long-term immunosuppressive therapies are associated with
the development of malignancy, especially skin cancer and lymphomas.
Patients receiving chronic immunosuppression should pay particular
attention to minimizing direct exposure to ultraviolet radiation. Since
many skin cancers are treatable with simple resection, it is also
important that transplant physicians are careful to monitor for
and treat skin lesions that develop in transplant recipients.
In the future, it may be possible either to modify the graft
so that it is not viewed as foreign to the recipient’s
immune system or to modify the recipient’s immune system
so that it will not reject the graft without altering the immune
response to other foreign antigens.
The antimetabolite drugs include azathioprine,
cyclophosphamide, mycophenolate, and leflunomide. These drugs inhibit nucleic
acid synthesis, which in turn limits the ability of activated lymphocytes
to rapidly clonally expand. In general, these drugs are used to
prevent rejection but are not effective at reversing active acute rejection.
Azathioprine, a purine analog, is the original member of this
family. The effects of this drug are not specific to lymphocytes; therefore,
the drug also frequently causes decreased levels of circulating neutrophils
and platelets. This side effect is dose dependent.
Cyclophosphamide is an alkylating agent that is a common component
of chemotherapy protocols. It is an effective immunosuppressant
when given in high doses, but it has been used only very infrequently
in clinical transplantation.
Mycophenolate is an inhibitor of inosine monophosphate dehydrogenase,
a critical enzyme in the de novo synthesis pathway of purines. Lymphocytes uniquely
depend on the de novo pathway to synthesize purines, while other
cells are able to utilize a salvage pathway for synthesis. Mycophenolate
is therefore more specific for lymphocytes than the other antimetabolites.
It has largely replaced azathioprine for use in combination with
a calcineurin inhibitor and corticosteroids since well-designed
studies have shown it to have a superior ability to prevent rejection.
Side effects are primarily gastrointestinal in nature.
Leflunomide is a selective inhibitor of de novo pyrimidine synthesis.
It is thought to work by inhibiting the enzyme dihydroorotate dehydrogenase.
It is used widely for treatment of rheumatoid arthritis. Clinical
trials have demonstrated it to be efficacious in terms of preventing
rejection, but it is difficult to use clinically because of its
long half-life (15–18 days).
Corticosteroids used in combination with azathioprine was the first
combination of immunosuppressants with the ability to prevent the
development of allograft rejection, and high doses of corticosteroids
was the first practical and effective means of reversing established
rejection. Hence, over the past 40 years, corticosteroids have been
a component of most successful immunosuppressive protocols. Typically,
a high dose of intravenous corticosteroids is given at the time
of engraftment, and the dose is tapered over weeks to months down
to a maintenance dosage of 0.1–0.2 mg/kg of oral
prednisone. In the recent past, there has been strong interest in
discontinuation of corticosteroids—and even more recently,
in developing protocols that do not require the administration of
any corticosteroids. The evidence is accumulating that this treatment
is appropriate and effective for some low-risk renal transplant recipients,
but the use of corticosteroid-free protocols for higher-risk candidates—including
those with known sensitization to HLA and patients undergoing second
renal transplants—is more controversial.
Corticosteroid therapy is associated with many different side
effects, including infection, weight gain, cushingoid features,
hypertension, increased bruisability, hyperlipidemia, hyperglycemia,
and acne. Daily corticosteroid therapy in children may inhibit somatic
growth. This may be circumvented to some degree by alternate-day
treatment, administering the drug once in the morning every other day.
Corticosteroids are standard therapy for a rejection episode, typically
consisting of three or more daily doses of between 100 mg and 500
mg of intravenous methylprednisolone (“steroid pulses”).
Depending on the severity of the rejection, steroid pulses will
resolve 50–80% of allograft rejection episodes.
Transplantation was revolutionized by the introduction of the first
calcineurin inhibitor, cyclosporine, into clinical practice in the
early 1980s. Cyclosporine is a cyclic undecapeptide isolated from
a fungus. It is a potent immunosuppressant and the first compound
identified that can inhibit immunocompetent lymphocytes specifically
and reversibly. Cyclosporine was followed by the introduction of
tacrolimus, another compound derived from a fungus that also inhibits
calcineurin. The primary mechanism of these agents appears to be
inhibition of the production and release of IL-2 by helper T cells.
They also interfere with the release of IL-1 by macrophages as well
as with proliferation of B lymphocytes. Blood levels must be carefully
monitored because both drugs are nephrotoxic and neurotoxic at higher
levels. They also both have chronic effects on renal function and
lead to significant long-term renal dysfunction in many patients
who take them chronically. Both cyclosporine and tacrolimus are
also associated with an increased incidence of neoplasms, particularly lymphomas.
of Mammalian Target of Rapamycin
Sirolimus is a macrocyclic triene antibiotic produced by a species
of Streptomyces. It was originally developed as
an antifungal and antitumor agent but was found to have significant
immunosuppressive properties. The effect of sirolimus is believed
to relate to inhibition of lymphocyte transduction pathways through
binding to the mammalian target of rapamycin. It functions as an
antiproliferative and prevents not only expansion of lymphocyte
clones but also smooth muscle proliferation. It is known to effectively
prevent rejection in combination with a calcineurin inhibitor. The
major advantages of this drug are that it does not cause renal dysfunction
and its antiproliferative properties suggest that it will not be
associated with the same risk of developing long-term malignancy.
Side effects, in addition to the infections associated with immunosuppression,
include oral ulcerations, wound healing problems associated with
its ability to inhibit smooth muscle proliferation, and significant
hyperlipidemias. An association with hepatic artery thrombosis has
also been noted in patients receiving sirolimus therapy as part
of their initial immunosuppression regimen following liver transplantation.
Everolimus is a derivative of sirolimus that also acts as a mammalian
target of rapamycin inhibitor. It has a side effect profile similar
to that of sirolimus but a shorter serum half-life.
Antithymoblast or Antilymphocyte Globulin and Antithymocyte Globulin
Antilymphoblast globulin and antithymocyte globulin are polyclonal
antibody preparations derived by immunizing animals against some
type of human lymphocytes and collecting and purifying the antibodies
that animals develop in response to the foreign antigenic proteins.
They are potent drugs that deplete circulating lymphocytes, an effect
that can be measured and followed by flow cytometry or by simply
following the complete blood count with differential. Because they
are polyclonal, they not only are effective against T cells but
also may have important effects against circulating B cells and
natural killer cells.
These agents are particularly effective in induction of immunosuppressive
therapy and in the treatment of established rejection that is either
severe or resistant to pulse corticosteroid therapy. Therapy is
typically given daily for 5–7 days. The effect of these
agents is profound immunosuppression that lasts for weeks to months.
They are associated with increased incidence of viral infections
because of their effects on cellular immunity and also with a higher
lifetime risk of developing malignancy, particularly B-cell lymphoma.
Side effects are many and include fevers and chills, neutropenia,
and thrombocytopenia. Fever, chills, and malaise occur because of
mediator release by T cells and circulating mononuclear cells, especially
TNF-α, IL-1, and IL-6, that occurs when the antibody
is bound to certain cell surface receptors. The symptoms are very
similar to those associated with an acute viral infection. These
effects are usually transient, often lasting less than 12 hours. They
occur primarily following the first or second dose of the treatment
and can be attenuated markedly by pretreatment with corticosteroids,
acetaminophen, and diphenhydramine. Neutropenia and thrombocytopenia
occur because of direct antibody binding to these cell types, causing
depletion. This effect is also transient and tends to resolve in
24–48 hours. It is necessary to monitor neutrophil and
platelet counts during therapy and withhold doses of the treatment
if the counts drop to dangerously low levels.
The knowledge that the T cell is central to the development of
allograft rejection led to the development of agents that selectively
inhibit or deplete T cells, or both. The first example of such an
agent is the monoclonal antibody OKT3 (muromonab-CD3), which is
secreted by a hybridoma in culture. This agent may have some advantages
over antilymphoblast globulin and antithymocyte globulin preparations
in management of rejection because it specifically blocks T-cell
generation and function. Because it is a monoclonal antibody and
reacts with a defined antigen, it can be consistently produced with
a defined activity and without unwanted reactivities against other cells
like neutrophils and platelets. OKT3 is most effective in the treatment
of steroid-resistant rejection, where more than 90% of
rejection episodes are reversed, thus obviating further high-dose
steroids. The downside of this antibody treatment is that since
it is a murine monoclonal antibody, it may induce recipient antibody directed
against the murine antibody molecule. This effect occurs in 5–10% of patients
treated with OKT3 and may decrease the efficacy of the treatment
if given a second or third time. Like the polyclonal antilymphocyte
preparations, treatment is usually given daily for 5–7 days.
Side effects due to cytokine release are typically more severe than those
seen with polyclonal agents but may also be attenuated with appropriate pretreatment.
Since the antibody does not bind to epitopes other than the CD3 molecule,
which is found only on T cells, it does not cause cytopenias.
The success of OKT3 led to the development of a new generation
of monoclonal antibodies that are “humanized.” The monoclonal
antibody molecule has been modified by genetic engineering to avoid the
side effects seen with OKT3. The genetic code directing the production
of the antibody molecule by the hybridoma has been altered by replacing
most of the murine portion of the sequence with human antibody sequence.
The antibody is thus chimeric, or “humanized” since only
the highly variable portion of the antibody that binds to the antigenic epitope
is foreign to the human recipient. Cytokine release therefore does
not occur when the antibody is administered, nor is it likely that
the recipient will develop neutralizing antibodies against the monoclonal
preparation. Because the antibodies so closely resemble human immunoglobulin,
they also have a long circulating half-life.
The first of these agents, daclizumab and basiliximab, bind to
CD25, the high-affinity subunit of the T-cell receptor for IL-2. Since
IL-2 is necessary for T-cell activation and proliferation, these
agents have the ability to selectively inhibit the expansion of
T-cell clones that are activated at the time of transplantation,
without effecting existing T-cell immunity to other antigens. Existing
cellular immunity to viruses, for example, is left intact. Induction
treatment with anti-CD25 antibodies at the time of engraftment has
been shown to reduce the incidence of future rejection episodes.
A more recent agent, alemtuzumab (Campath-1H), is a depleting
humanized monoclonal antibody that binds to CD52, an antigen found
on all peripheral blood mononuclear cells. Alemtuzumab administration
causes a profound and sustained depletion of T cells from peripheral
blood that lasts for many months. It similarly depletes B cells,
natural killer cells, and monocyte, but to a lesser degree. Alemtuzumab
is currently approved for treatment of patients with some forms
of chronic lymphocytic leukemia. It is being used by some transplant
centers for initial induction immunosuppression and for treatment
Carpenter CB: Immunosuppression in organ transplantation.
N Engl J Med 1990;322:1224.
Krieger NR, Emre S: Novel immunosuppressants. Pediatr Transpl
Levy G et al: Safety, tolerability, and efficacy of everolimus
in de novo liver transplant recipients: 12- and 36-month results. [Erratum
appears in Liver Transpl 2006;12:1726]. Liver Transpl 2006;12:1640.
Mourad G et al: Induction versus noninduction in renal transplant
recipients with tacrolimus-based immunosuppression. Transplantation
The two sources of kidneys for renal transplantation are living
donors and deceased donors. Approximately one third of patients
who are acceptable candidates for transplantation will have a willing
and medically suitable living donor. ABO-compatible donors are not absolutely
required today because of the availability of treatments that can
reduce the amount of antidonor antibody in the recipient. However,
ABO-compatible donors are greatly preferred, because antibody reduction
treatments are expensive and associated with infectious risk due
to the depletion of protective antibodies.
At one time, only related living donors were acceptable because
it was necessary to have closely matched HLA antigens between the
donor and recipient in order to achieve acceptable graft survival rates.
The graft survival rate for donor/recipient pairs who do
not share any HLA antigens is now greater than 90%, leading
transplant programs to accept increasing numbers of donors who are not
genetically related to the recipients. It is now common practice
to accept volunteer donors who are spouses, in-laws, friends, coworkers,
and even members of the same community who may be only acquaintances.
More controversial is a recent trend for patients and donors to meet
through Internet web sites. Despite initial hesitancy to condone
this method of finding a living donor, it has been difficult for
the transplant community to make value judgements about the relationship between
living donors and recipients as long as both parties are fully informed and
Recently, programs have begun arranging transplants between two
or more pairs of living donors and recipients who participate in
a paired exchange. Recipients with willing but incompatible donors are
paired with another donor/recipient pair who have the same
problem. The outcome from paired donation transplants has been similar
to that seen with other living donor transplants.
Living donors should be in good health both physically and psychologically. Above
all, the living donor should be a volunteer and must clearly understand the
nature of the procedure so that informed consent to the operation
can be given. Donors should generally be of legal age, but reasonable
exceptions have been made in extenuating circumstances, particularly
when an identical twin donor is available. In these circumstances,
it is wise for the program to assign to the donor an outside advocate who
has no relationship with either the recipient or the remainder of
the family to ensure that the minor is not coerced into proceeding.
Live kidney donors are now as common as deceased donors, although
since each deceased donor can donate two kidneys, the total number
of kidneys from deceased donors still far exceeds that obtained
from living donors. Because of the biological ability of the body
to compensate for the loss of one kidney, renal function tends to
stabilize at approximately 75–80% of the original
renal function a few months following donation. Follow-up studies
on donors show that they have good renal function and do not appear
to suffer ill effects from the procedure, either physically or psychologically. Women
with one kidney do not have an increased incidence of urinary infections during
There are at least two methods of performing donor nephrectomy
in common practice: open nephrectomy and laparoscopic nephrectomy.
Open nephrectomy, long the standard method, involves a flank incision
about 15 cm long below the 12th rib. The peritoneum is retracted
medially, and the kidney is removed along with its vessels and ureter without
disturbing the intra-abdominal contents. More recently, laparoscopic
techniques have been developed to allow the removal of a kidney
for transplantation. The donor is placed under general anesthesia,
and the abdomen is insufflated with carbon dioxide to allow visualization
of the abdominal structures. Some surgeons use a large port in the midline,
just above the umbilicus, to insert their hand into the abdomen.
The kidney is then withdrawn through the hand port once it has been
dissected free from surrounding tissues and the vessels and ureter
have been divided. It is also possible to remove the kidney using
purely laparoscopic techniques without inserting a hand port. The
kidney is removed by placing it in a bag inside the abdomen and
withdrawing the bag through a low transverse incision. Laparoscopic
nephrectomy tends to take longer than a nephrectomy through an open
approach, but it is associated with somewhat less postoperative
pain and a briefer period of convalescence. Prospective donors should
be informed about the options for nephrectomy and the advantages
and disadvantages of each technique as well as the associated risk
and the known complications.
The main risk to a donor is the anesthesia and the operation
itself. The mortality rate is estimated to be 0.03%, and
most deaths are not judged to be preventable but appear to be intrinsic
risks of having a major operation. The most common significant complications
following nephrectomy are wound related, including infection and
hernia formation. These complications occur in less than 1–3% of cases.
Wound infections typically respond to dressing changes, and hernias
require operative repair.
The evaluation of a living donor must be thorough and complete.
It is first necessary to make sure that the donor is truly a volunteer
and is not being coerced or unfairly influenced by the recipient
or other family members. This often involves a careful evaluation
by an individual with excellent understanding of the transplant
process as well as excellent communication skills. It is advisable
that this portion of the interview be conducted in private so that
donors can be honest about their feelings. Transplant social workers,
psychologists, and psychiatrists are typically involved with this aspect
of donor selection. Once it is clear that the donor is genuinely
seeking to donate of his or her own accord, a detailed history is
taken, and a physical examination is performed. Factors that may
affect operative risk as well as future risk of renal failure are
carefully sought out. The routine workup includes chest x-ray, electrocardiography, urinalysis,
complete blood count, fasting blood glucose, serum bilirubin, hepatic
transaminases, serum creatinine, and blood urea nitrogen. If these
are normal, the kidneys are imaged radiographically to make sure
that two kidneys are present, to rule out intrinsic or structural
renal disease, and to evaluate the vasculature of the kidneys. Angiography,
CT, and MRI are all methods that can be used. Kidneys with multiple
renal arteries may be transplanted, but care must be taken in the
anastomosis of small accessory vessels, particularly when they come
from the lower pole and may therefore provide the sole vascular
supply to the ureter. When there are multiple renal veins, the smaller
veins can often be ligated, since there is free communication of
the veins within the kidney.
Two thirds of eligible kidney recipients do not have a suitable
living donor. These patients are placed on a waiting list for a kidney
from a deceased donor. Since more patients are added to the list
each year, the number of patients waiting for a kidney from a deceased
donor grows longer each year and will exceed 100,000 in the United
States by 2010.
Kidneys can be successfully transplanted from donors who are
declared dead on the basis of brain death or from donors who die
of cessation of spontaneous cardiovascular activity.
Brain death is now widely accepted in principle in the United
States, and all hospitals have protocols to be followed to ensure
that the diagnosis of brain death is confirmed without any doubt.
Consent for donation should always be obtained by individuals
with training in how to approach the family of the donors. In this
way, the family can be given time to grieve and express the inevitable
sorrow and anger that accompanies the death of a loved one. Individuals
who are not part of the team caring for the patient are best able
to provide the emotional support that families need during this
time. The discussion regarding donation can then occur separate
from the discussion in which the family learns that their loved
one has died.
Kidneys from brain-dead donors are removed operatively. The excision
of the kidneys occurs operatively following in situ cold perfusion
and exsanguination of the kidneys, often in concert with the removal
of other transplantable abdominal and thoracic organs. The kidneys
are perfused with specially designed preservative solutions and
kept cold. Successful transplantation has been reported following
cold storage of more than 72 hours, but optimal results are achieved
if the kidney is transplanted as soon as possible following removal from
the donor, preferable within 24 hours.
Kidneys may also be transplanted from deceased donors following
cardiopulmonary death, a practice termed “donation following
cardiac death.” The most common circumstance under which
this occurs in the United States is when medical therapy that is
judged to be futile is withdrawn from an individual. Typically,
patients have suffered profound, irreversible brain injury and have
essentially no conscious awareness and no potential for meaningful
recovery. Standard medical practice in this circumstance is to recommend
withdrawal of life-sustaining support such as mechanical respiration
and intravenous infusions, since the vast majority of people state
that they would not want to be kept alive in such a hopeless state.
Withdrawal of support always occurs with the consent and understanding
of the family. The decision to donate organs should be made separate
from the decision to withdraw medical therapy. Once consent is obtained
and preparation for donation is completed, support is withdrawn by
the primary care team. When cardiopulmonary activity ceases, the
primary physician team declares death, and the organs are then excised
as with brain-dead donors.
Patients with chronic renal failure should be considered for
transplantation. Acute renal failure on the basis of acute tubular necrosis
can usually be managed with temporary dialysis, and therefore kidney transplantation
is not appropriate in this setting. It is not necessary for patients
to be on dialysis at the time of transplantation. In fact, results
for patients who receive kidney transplants prior to beginning dialysis
have the best chance of graft survival, while patients who had long-term
dialysis prior to transplantation have poorer success rates. It
is therefore important to begin consideration for renal transplantation
as soon as dialysis appears to be inevitable and imminent within
the next year.
During the early years of renal transplantation, most of the
patients accepted for transplantation were between 15 and 45 years
old. In recent years, the age range has been extended in both directions—children
younger than age 1 and adults who are over 70 years old have received transplants.
For many years, the success rates for transplanting in young children was
inferior to that achieved with adults, but this problem has now
been corrected. Even children younger than 1 year of age at the
time of transplantation can be expected to have an excellent chance
of graft survival.
Historically, there has been reluctance to perform renal transplants
in the elderly. However, as the practice of renal transplantation
continues to improve, with less toxic and more effective immunosuppression
and more effective methods of preventing posttransplant infections,
this unwillingness appears less justified. Elderly individuals naturally
have a shorter life span, but to date, patients over 60 years old
who receive transplants appear to enjoy approximately the same degree of
improvement in life expectancy as do younger patients.
This benefit has been quantified by comparing the mortality rate
of suitable candidates awaiting kidney transplantation with the
mortality rate following transplantation. Life expectancy appears
to be approximately doubled by kidney transplantation in all age
ranges that have been studied to date. The improved life expectancy
following kidney transplantation is particularly dramatic for diabetic patients.
Today, patients tend to be judged on the basis of their physiologic functional
status rather than on their chronological age. It is nevertheless
true that elderly patients are more commonly found to be poor candidates
for transplantation because of either coexisting disease or poor
Candidates must be free of active infections at the time of transplantation. Chronically
infected tissues such as chronic pyelonephritis or chronic osteomyelitis
should be definitively treated prior to consideration for transplantation. Patients
with active viral or bacterial infection at the time an organ is
available for transplantation should usually be deferred until the
infection has resolved. This is because it is unwise to initiate immunosuppression
during an active infection, particularly given that the highest
doses of immunosuppression are given around the time of the procedure.
Recipients with almost all types of primary renal disease have
been successfully transplanted: glomerulonephritis, hypertensive
nephropathy, chronic pyelonephritis, polycystic kidney disease, reflux
pyelonephritis, Goodpasture syndrome, congenital renal hypoplasia, renal
cortical necrosis, Fabry syndrome, and Alport syndrome. Successful
transplants have been achieved in patients with certain systemic
diseases in which the kidney is one of the end organs affected (cystinosis,
systemic lupus erythematosus, and diabetic nephropathy). Renal transplantation
is generally inadvisable in patients with oxalosis if high serum
levels of oxalate are present because the disease recurs in the
transplant quickly. However, liver transplantation corrects the
enzymatic defect that leads to excessive oxalate accumulation. Therefore,
combined liver-kidney transplantation may be an acceptable treatment
option for these patients.
Patients who do not have normal bladder function may be acceptable
kidney transplant candidates, but a plan for ureteral drainage should
be made before transplantation occurs. Many patients with long-term
defunctionalized bladders can still undergo ureteral reimplantation
and then be treated with intermittent catheterization if necessary
posttransplant. If the bladder is congenitally or surgically absent,
a defunctionalized loop of small bowel can be created, brought out
as a stoma, and used for a urinary conduit. Care must be taken in
planning the positioning of the conduit so that the ureter from
a transplanted kidney will reach it.
Transplant patients must be compliant with posttransplant care
to achieve successful outcome. Patients with a history of poor compliance
may be candidates for transplantation if they are regretful of past
behavior and have established a compliant pattern. In some cases,
especially in the adolescent age group, it is wise for the patient
to experience dialysis prior to receiving a kidney transplant in order
to foster a complete understanding of the differences in lifestyle
that are afforded by a successful kidney transplant. It is also
necessary that patients have a support network to help them manage
following the transplant. They will need a way to reliably obtain
immunosuppressive therapy as well as transportation to and from
the transplant center that is continuously and reliably available.
Fortunately, support services are often available to patients who
lack social support, and it is rare to deny transplantation solely
on the basis of inadequate social support.
In the early years of kidney transplantation, it was common to
perform bilateral nephrectomy prior to transplantation, but this
has recently become very uncommon. Most patients who have native nephrectomy
have polycystic kidney disease with profound pain, recurrent infections,
or recurrent hemorrhage. Other indications for native nephrectomy include
recurrent infection, especially when associated with ureteral reflux,
and occasionally profound hypertension attributable to an ischemic
Wolfe RA et al: Comparison of mortality in all
patients on dialysis, patients on dialysis awaiting transplantation,
and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725.
The surgical technique of renal transplantation involves anastomoses
of the renal artery and vein and ureter (Figure
transplant kidney is placed in the iliac
fossa through an oblique lower abdominal incision. The dissection
is carried out by retracting the peritoneum medially so the kidney
will lie in an extraperitoneal position. The iliac arteries and
veins are mobilized as indicated for the proposed specific anastomoses.
An end-to-side anastomosis is performed between renal vein and iliac vein;
an end-to-side anastomosis is then performed between the renal artery
and the iliac artery. An alternative technique is to connect the
renal artery end-to-end to the internal iliac artery, but this technique
is more difficult in most patients. When multiple arteries are present,
there are several options. If the artery is very small (less than
2 mm), it can often be ligated, especially if it is an upper pole branch.
If the kidney is from a deceased donor, it is often possible to
use a large Carrell patch of donor aorta that encompasses all of
the arteries. Other options include reimplanting multiple renal
arteries into the iliac artery using multiple anastomoses; reimplanting
a smaller artery into the side of the dominant renal artery and
then using the larger artery for anastomoses to the iliac; and spatulating the
ends of the two arteries together to form a single lumen for anastomosis.
Technique of renal transplantation.
In small children and infants, the kidney transplant can be performed
either through a midline abdominal incision or by making a very
large flank-type incision extending from the pubic symphysis to the
costal margin and exposing the aorta and vena cava by reflecting
the peritoneal contents medially and superiorly. End-to-side anastomoses
of the renal vessels may be made to the iliac vessels if they are
large enough, but often it is necessary to use the infrarenal vena cava
and aorta for the anastomotic site.
Kidneys from small pediatric deceased kidneys function poorly
when transplanted into small pediatric recipients. However, many
pediatric kidneys have often been transplanted en bloc with the donor
aorta and vena cava anastomosed to the recipient’s iliac
vessels along with double ureteral anastomoses. The exact age at
which it is best to transplant kidneys as a single unit is unclear,
but certainly kidneys from children as young as 6 will function
well and last a long time when transplanted into adults.
Urinary tract continuity can be established by pyeloureterostomy,
ureteroureterostomy, or ureteroneocystostomy. The most common technique
is ureteroneocystostomy. This technique can be performed by bringing
the ureter into the bladder through a submucosal tunnel and suturing
the mucosa of the ureter to the mucosa of the bladder from the inside
of the bladder through a large cystotomy (Politano-Leadbetter method).
Other techniques include an external neocystostomy, which avoids
the need for a large cystotomy, and the “one stitch” technique,
whereby the mucosa of the ureter is not directly sutured to the
bladder mucosa, but rather the ureter is fixed into place in the
interior of the bladder with a suture that traverses the full thickness
of the bladder wall. A ureteral stent may be placed with any of the
techniques discussed above. A 6Fr pediatric ureteral stent with
a J shape at each end fits nicely across the anastomosis
and goes from the interior of the renal pelvis into the bladder
or other urinary conduit. The stent should be removed in the first
month or two following the transplant to prevent stone formation
and bladder infection.
Management & Complications
Recipients who have received a kidney transplant usually produce
urine immediately, and the serum creatinine falls over the next
3–7 days. The magnitude of urine output is related to how
hydrated the patient was before transplantation and to how much
fluid is administered during the procedure. It is important that
the patient is fully hydrated at the time the kidney is revascularized
in order to achieve the best chance of immediate transplant kidney
function. Transplanted kidneys frequently will have an obligate
diuresis for a period of hours to days after they begin to function.
During this phase, it may be necessary to replace urinary output
in order to prevent the development of hypovolemia as a result of
excess urinary output. Once this phase has passed, intravenous fluid
can be discontinued. However, patients are encouraged to maintain generous
fluid intake to prevent dehydration in the future, as transplanted
kidneys appear to have a greater susceptibility to hypovolemia than
native kidneys. Patients are usually able to eat the morning following
the transplant procedure and should be encouraged to get out of
bed with assistance. The urinary catheter can be removed as early
as 2 days following the procedure, depending on the technique used
for ureteral anastomosis. Some programs prefer to leave the urinary catheter
in place for a longer period of time to allow sufficient healing
of the anastomosis. Most recipients are able to be discharged from
the hospital on the second or third postoperative day if there are
no complications in their postoperative course once they are able
to maintain oral hydration, have learned how to properly take their
medications, and have received training about what to do, what not
to do, and what to watch out for in the next few weeks.
Kidney transplantation can be followed by a variety of postoperative
complications that must be recognized and treated early for optimal
results. The most frequent complications are infection and rejection,
reflecting the natural tension between too much and too little immunosuppression.
Urinary infection is one of the most common complications and usually
responds to antibiotic therapy. Bacterial pneumonia is the most
common pulmonary complication and may be very serious if not promptly
diagnosed and treated. Current immunosuppression protocols that
focus on the T lymphocyte are associated with unusual, opportunistic
types of infections including herpesviruses, the parasite Pneumocystis
carinii, and fungal infections. These infections are seen
much less often than previously because it is standard to prescribe
prophylactic anti-infective therapy aimed at preventing the common
types of infection. In particular, the availability of agents that
are effective against cytomegalovirus (CMV) infection has almost eliminated
clinical CMV infections. At one time, CMV infections were a frequent,
expensive, and exceedingly unpleasant occurrence after many transplants.
In approximately 20% of kidney transplants from deceased
donors, the kidney will fail to function immediately. This complication
is termed delayed graft function and is due to acute tubular necrosis
of the kidney. In some cases, there is a modest urinary output,
but the serum creatinine does not fall. In other cases, there is
profound oliguria. Delayed graft function can also occur following
living donor transplantation, but it is much less common (less than
3%). Delayed graft function is associated with older donors
and donors who had a rising creatinine at the time of donation.
Long ischemic times are also known to increase the chance of delayed
graft function. In most cases, the acute tubular necrosis will resolve and
the renal function will recover. Most recovery happens within a
week, but in some cases, the kidney will require several weeks before
renal function is sufficient to support the patient without dialysis.
Treatment is supportive with dialysis as necessary. If recovery
takes more than a week, it may be wise to biopsy the kidney to rule
out silent rejection.
Vascular complications of kidney transplants are uncommon, affecting
1–2% of renal transplants. Either renal artery
or venous thrombosis of the kidney is devastating and almost uniformly
results in graft loss. The incidence of acute graft thrombosis is
higher in patients with high levels of circulating anti-HLA antibodies, suggesting
that some of these cases are related to accelerated acute rejection. The
incidence of graft thrombosis is also higher in patients with factor
V Leiden and other physiologic derangements that cause a hypercoagulable
state. Patients should be screened for factor V Leiden if they have
a history of unusual thrombotic events and receive anticoagulation
perioperatively when it or other known hypercoagulable states are
known. Renal artery stenosis, which may be associated with rejection
involving the renal artery, is also a rare complication. It can
present with severe hypertension. It may be treated surgically or
in some cases by percutaneous transluminal balloon angioplasty.
Urologic complications occur in about 4% of patients,
most often urinary extravasation from the cystotomy closure or ureteral
obstruction. These complications can almost always be managed with
percutaneous placement of a nephrostomy tube by an interventional
radiologist and are not associated with a higher risk of graft loss.
A complication relatively unique to kidney transplantation is
formation of a pelvic lymphocele in the transplant bed. Lymphatic
fluid may come from either lymphatics in the hilum of the kidney
or from lymphatics disrupted during exposure of the iliac vessels.
Careful ligation of the adjacent lymphatics during preparation of
the recipient blood vessels may decrease the incidence of this complication.
Large lymphoceles may obstruct the ureter or the vasculature of
the transplanted kidney, and they occasionally become infected. Sterile
lymphoceles may be drained into the peritoneal cavity, while infected
lymphoceles need to be drained externally.
Gastrointestinal complications may affect all levels of the intestine,
but upper gastrointestinal symptoms, including nausea and abdominal
pain, are most common. In many cases, the culprit is the large number
of medications that the patient must take. Peptic ulceration was once
a major problem for transplant recipients, but this complication
has virtually disappeared because of routine use of medications
like H2-blockers and proton pump inhibitors to inhibit
the production of gastric acid.
Despite advances in immunosuppressive management, rejection is
still a major hazard for the postoperative allograft recipient.
Most episodes of rejection occur within the first 3 months. There
are three basic kinds of rejection:
(1) Hyperacute rejection is due to preformed cytotoxic
antibodies against donor antigens. Pretransplant crossmatch testing
is designed to prevent this type of rejection. This reaction begins
soon after completion of the anastomosis, and complete graft destruction
occurs in 24–48 hours. Initially, the graft is pink and
firm, but it then becomes blue and soft, with evidence of diminished
blood flow. There is often no effective method of treating hyperacute rejection,
but treatment with plasmapheresis and immunoglobulin infusion may be
effective if the diagnosis is made immediately.
(2) Acute rejection is the most common type of rejection episode
during the first 3 months after transplantation. It is primarily
an immune cellular reaction against foreign antigens. The reaction
may be predominantly cellular, or there may be a component of antibody-mediated
inflammation. Typically, the patient is asymptomatic and the diagnosis
of rejection is suspected on the basis of serial measurement of
serum creatinine levels. In severe cases, symptoms may include oliguria,
weight gain, and worsened hypertension. Fever and tenderness and
enlargement of the graft are uncommon with modern immunosuppressive
protocols but used to be seen when only azathioprine and corticosteroids
were available. This type of rejection process is usually treated
with pulse steroid therapy. If this is unsuccessful, or in very
severe cases of acute rejection, either a polyclonal or monoclonal
depleting antilymphocyte preparation is used. The vast majority
of acute rejection episodes are successfully reversed. Currently,
grafts are only lost to rejection when patients are noncompliant
or when rejection occurs together with a life-threatening infection,
since it is unsafe to enhance the degree of immunosuppression in
(3) Chronic rejection is a late cause of renal deterioration.
It is unclear precisely what causes chronic rejection, but the absence
of cellular elements on biopsy and the association of antidonor
antibodies with chronic graft loss have led to the assumption that
it is mediated by humoral factors. It is most often diagnosed on
the basis of slowly decreasing renal function in association with
proteinuria and hypertension. Chronic rejection is resistant to
all known methods of therapy and graft loss will eventually occur,
though perhaps not for several years after renal function begins to
deteriorate. It is unclear what the relationship is between this
pathologic process and the damage produced by chronic calcineurin
inhibitor use, which is seen in nonrenal transplant recipients as well.
It has recently been uncovered that chronic graft loss is accelerated
in patients who experienced rejection in the first year after a
transplant, in patients who had delayed graft function, and in patients
who received kidneys from marginal donors.
Diagnosis of Renal Allograft Dysfunction
An unexpected elevation in serum creatinine above baseline levels
in a renal transplant recipient has a broad differential diagnosis
list. Dehydration should be ruled out by history and physical examination.
The medication the patient is taking should be reviewed, paying
attention to over-the-counter medications, especially nonsteroidal
anti-inflammatory drugs and herbal remedies. These drugs can cause
renal dysfunction or can alter the metabolism of immunosuppressant medications
and result in blood levels that are either too high or too low.
Urinary infection should be ruled out with a urinalysis. If these
simple evaluations do not disclose the cause of renal dysfunction,
the next step is usually a renal ultrasound to rule out ureteral
obstruction, followed by a renal allograft biopsy. This last step
is crucial to arriving at the correct diagnosis. A biopsy may disclose acute
rejection, or it may show calcineurin inhibitor toxicity. Since
the treatment for these conditions is opposite, a biopsy is very
important to guide appropriate therapy.