II. PRETRANSPLANT EVALUATION OF THE RECIPIENT
III. GRAFT OUTCOME AFTER RENAL TRANSPLANTATION
IV. TRANSPLANT REJECTION- AN UNRESOLVED PROBLEM
V. SUMMARY AND CONCLUSIONS
KEY CONCEPTS
Although reports of tissue transplantation date back to antiquity, the modern era of transplantation began in 1954 when Murray at the Peter Bent Brigham Hospital in Boston successfully transplanted a kidney from one identical twin to another. The success of this procedure culminated a half century of investigation, proving that the technical aspects of solid organ transplantation did not pose an insurmountable barrier. Rather, it was immune factors and tissue rejection that constrained progress in transplantation for nearly a decade. The discovery of HLA antigens by Dausset in 1953 and the introduction of azathioprine and Prednisone as oral immunosuppressive drugs in 1964 set the stage for a remarkable expansion of organ transplant programs. Currently, the results of over 100,000 renal transplants are recorded in the UCLA Transplant Registry, reflecting the transplant experience in the U.S. and Canada. Annually, about 10,000 kidney transplants are performed in the United States, limited substantially by the shortage of donor organs. This essay is intended as an overview of the field of renal transplantation with an emphasis on factors that have lead to improved graft survival as well as problems that are currently unresolved.
Although several medical factors must be considered prior to transplantation,
this section will focus only on the immunological evaluation of the recipient.
First, kidneys, like blood, must be compatible for ABO blood group antigens.
ABO incompatible transplants (e.g. A kidneys into O recipients) are generally
rejected in a hyperacute fashion. Accordingly, all donors and recipients
are typed for blood group antigens to insure compatibility.
Another absolute requirement for transplantation is that the recipient must
not have HLA antibodies directed against donor antigens. Hence, a crossmatch
is performed just prior to transplantation, testing patient's serum against
donor lymphocytes, a convenient source of cells bearing HLA antigens. Hyperacute
rejection may occur if transplants are performed in the face of a positive
crossmatch.
The most important targets for the rejection response are HLA antigens and,
in general, graft survival correlates with the extent of HLA matching. Therefore,
donors and recipients are HLA typed prior to transplantation and every attempt
is made to minimize HLA incompatibility. This represents a formidable problem,
however, since the HLA loci are extremely polymorphic. The HLA region contains
four loci, HLA-A, -B, -C and -DR, which are important with regard to transplantation.
Each locus has multiple alleles such that the likelihood is small that any
two unrelated individuals will share HLA antigens. Since the HLA region
is inherited as a unit, however, first degree relatives are much more likely
than unrelated individuals to share some or all of their HLA antigens. By
creating organ sharing networks or by choosing healthy relatives as donors,
donor:recipient HLA matching can be maximized. Since immunosuppressive drugs
can reduce the frequency of rejection episodes, even when grafts are totally
mismatched, HLA differences between the donor and recipient do not constitute
an absolute contraindication to transplantation.
Back to Top
Once the problems of surgical technique were resolved, the importance
of immune factors in transplant survival became obvious. Both patient mortality
and graft loss were excessive prior to 1970, reflecting the limitations
of immunosuppressive therapy available at the time. As immunosuppressive
therapy was refined, patient survival improved strikingly between 1970-1980,
owing largely to a decrease in the frequency of life-threatening infections.
Currently, a 6-month patient survival of 95% is achievable at most centers,
despite the fact that criteria for recipient selection have been liberalized
to include older individuals and patients with systemic illnesses such as
diabetes mellitus.
Paradoxically, during the 1970's, 1 year graft survival remained virtually
constant, despite advances in HLA typing and crossmatching. Since 1980 graft
survival has steadily improved, however, for reasons that will be explained
shortly. In the data compiled by the UCLA Registry, kidneys transplanted
between HLA-identical siblings enjoyed the most favorable outcome, with
1 year graft survivals of 90% and 5 year survivals of 70%. Furthermore,
these patients require less immunosuppression, have fewer rejection episodes,
and are discharged from the hospital sooner than other transplant patients.
At the other extreme, recipients of cadaveric grafts had a 1 year graft
survival ranging from 77%-83%, depending upon the extent of HLA matching.
In spite of these favorable outcomes, grafts continued to be lost after
1 year. Overall 5 year survivals of cadaveric kidneys transplanted in 1982
were 41%, a figure not remarkably different from those observed between
1970 and 1980.
Several factors have been identified that are responsible for the improvements
in 1 year graft survival observed during the past decade. First, cyclosporin,
a potent inhibitor of IL-2 production, was introduced during this time as
a first-line immunosuppressive drug. Improvements in graft outcome of 10%-15%
have been attributed to cyclosporin alone. An important drawback of cyclosporin
therapy is that this drug is nephrotoxic, causing interstitial fibrosis
and tubular atrophy in most recipients. Furthermore, cyclosporin therapy
has been associated with a small, but measurable increase in the frequency
of malignancies involving the lymphoid system (malignant lymphoma). To avoid
these long term complications, patients receive lower doses of cyclosporin
in addition to other immunosuppressive agents such as azathioprine and prednisone
post-transplant ("triple therapy").
A second factor resulting in improved graft survival in the 1980's was that
during the past decade HLA typing techniques have improved. In particular,
since 1980, most tissue typing laboratories have been able to type for the
gene products of the HLA-D region (DR antigens), as well as HLA -A, -B,
and -C, using serological or, more recently, DNA-based techniques. This
advance allows recipients to be matched with cadaveric kidneys for these
important loci in the time frame during which organ preservation is possible
(24-48 hours). A 10%-15% difference in graft outcome has been documented
when DR-matched and mismatched kidneys are compared. Furthermore, the benefits
of HLA -A, -B, and -DR matching persist beyond 1 year and, in fact, become
increasingly important determinants of graft outcome 5 years and 10 years
after transplantation. Recently, national organ sharing of HLA matched kidneys
has been promoted by the development of the United Network for Organ Sharing
(UNOS). As a result of this program several hundred HLA matched grafts have
been transplanted with half-lives approaching those observed with HLA identical,
living-related grafts.
Finally, new tools for the treatment of cellular rejection have been introduced,
notably the murine monoclonal antibody OKT3 (anti-CD-3.) Although other
anti-lymphocyte globulins prepared in horses, sheep, or rabbits have been
available for several years, the potency of these sera varies from batch
to batch, and the specificity of these antibodies includes hematopoietic
cells other than lymphocytes. In contrast, OKT3 antibodies are uniquely
specific for an invariant component of the T cell receptor (CD3), the glycoprotein
on T cells that confers specificity. Essentially, the ability of T lymphocytes
to react with foreign antigens, including histocompatibility antigens, is
blocked by OKT3 antibodies. In clinical trials, these antibodies rapidly
reverse cellular rejection. When rejection is diagnosed early, it is possible
with appropriate therapy to re-establish normal renal function. It is likely
that other monoclonal antibodies will be available in the future that will
react with T cells directed specifically against histocompatibility antigens,
while T cells reactive with other foreign antigens, such as those present
on bacteria and viruses, remain functional.
Back to Top
A variety of medical and surgical catastrophes can occur following
renal transplantation which compromise graft outcome. Technical failures,
infections, and recurrence of the disease for which the transplant was performed
are among the problems occasionally encountered in these patients. However,
except for transplants performed between identical twins, transplant rejection
continues to be the most important contributor to graft loss.
Historically, rejection has been subdivided into 3 categories, based on
the rapidity with which rejection occurs after transplantation. Hyperacute
rejection occurs within minutes to hours after transplantation and is caused
by circulating antibodies in the recipient directed against antigens expressed
on graft endothelial cells. Complement activation and neutrophil-mediated
cytotoxicity lead to destruction of the vascular endothelium. Ultimately,
the coagulation system is activated, resulting in fibrin thrombi occluding
the renal vasculature and renal failure. No therapy is effective, but this
form of rejection is largely preventable by avoiding blood group incompatibilities
and performing lymphocyte crossmatches prior to transplantation.
Acute cellular rejection occurs 10 days to 3 months after engraftment and
is mediated mainly by cytotoxic lymphocytes. This form of rejection is extremely
common and is amenable to antirejection therapy. Morphologically, lymphocytes
are observed infiltrating the interstitium and blood vessels of the graft.
Many of these cells are activated T lymphocytes, producing lymphokines such
as IL-2, B cell growth factor, and gamma-interferon. As a consequence of
T lymphocyte activation, cells in the graft replicate, nonspecific effector
cells are recruited and functionally activated, and HLA antigen expression
as well as enhanced expression of adhesion molecules in target cells such
as endothelial cells and tubular epithelium is induced. Untreated, acute
rejection results in the loss of renal allografts due to vascular and tubular
injury.
The third form of rejection, chronic rejection, is insidious in onset and
of uncertain pathogenesis. The principal lesion is vascular, particularly
involving the small and medium-sized arteries in the kidney. These blood
vessels show marked intimal fibrosis, resulting in compromised renal blood
flow. Interstitial fibrosis, tubular atrophy, and glomerular sclerosis are
common associated findings. It is likely that chronic rejection is a consequence
of persistent or smoldering acute rejection. However, chronic rejection
occurs in some patients with no clinical evidence of acute rejection. Interestingly
enough, a similar lesion is found in chronically rejected cardiac allografts.
It is important to point out that many of the advances in the management
of renal transplant patients have improved the short term outcome of these
grafts, but have produced little change in long term graft survival, i.e.,
survival greater than 1 year. Although patients who have lost their grafts
can return to dialysis and receive second or even third transplants, this
is not an acceptable solution to the problem of chronic rejection.
Renal transplantation offers a realistic therapeutic option to patients
with end-stage renal disease, in many cases restoring these patients to
near normal health. Postoperative mortality is acceptably low and the short-term
survival of these grafts is approximately 80%. HLA-identical, living-related
transplants have the best outcomes with 1 year graft survivals of 90% or
better. It is worth noting, however, that 10% of HLA-identical grafts are
lost because of rejection during the first year after transplantation and
that all patients, with the exception of transplants between monozygotic
twins, must receive immunosuppressive drugs permanently.
With the introduction of cyclosporin, improved HLA matching, and new tools
for treating rejection, 1 year graft survivals have improved significantly
in the past decade. However, graft loss over longer periods of time, due
largely to chronic rejection, represents an unresolved problem. Research
effort in the future will be necessary to unravel the pathogenesis of chronic
rejection, in order to provide a rational basis for prevention or therapy.
REFERENCES
1. Kahan BD; Ghobrial R. Immunosuppressive agents. Surgical clinics of North
America 74:1029, 1994.
2. Gjertson DW, et al. National allocation of cadaveric kidneys by HLA matching.
New Eng J Med 324:1032, 1991.
3. Port FK, et al: Comparison of survival probabilities for dialysis patients
vs. cadaveric renal transplant recipients. JAMA 270:1339-1343, 1993.
4. Solez K, et al. International standardization of criteria for the histologic
diagnosis of renal allograft rejection. Kidney Int. 44:411, 1993.
5. Sathanthiran M, Strom T. Renal transplantation. NEJM 331: 365, 1994.
6. Sathanthiran M, Strom T. Immunobiology and immunopharmacology of organ
graft rejection. J Clin Immunology 15:161, 1995. 324:1032, 1991.
Back to Top
Immunopathology I
Immunopathology II
Questions?
Comments? Send a message to the CATS guru: jkessler@salus.uvm.edu
Go Back to Immunopathology