Clinical Transplantation
Clinical Transplantation
Organ transplants are in widespread use. Limitations
include the scarcity of donor organs and expense. Failure to achieve successful
grafts is primarily due to histoincompatibility and lack of safe and effective
immunosuppressive regimens to halt rejection. Avoiding transmission of
infectious agents (eg, HIV, hepatitis B virus, hepatitis C virus,
cytomegalovirus) from donor to recipient requires extensive pretransplant
serologic testing.
Kidney Transplantation
End-stage renal disease is the indication for kidney
transplantation. Factors that determine outcome include antigenic disparity (ABO
blood groups and major histocompatibility or HLA) between donor and recipient,
the type of immunologic response mounted by the host, and the immunosuppressive
regimen used to prevent graft rejection. Nonimmunologic factors that affect the
risk of chronic rejection include age and race of recipient; donor age; length
of time on dialysis; and coexisting hyperlipidemia, hypertension, or
cytomegalovirus infection.
Kidneys from living related donors who are HLA-identical
and also red cell ABO-matched grafts have 90% survival at 1 year; grafts from
less-well matched relatives and from living unrelated donors have lower rates.
Antigens are matched for HLA-A, -B and -DR loci, with -DR compatibility most
important for long-term graft survival. Grafts from cadaver donors with zero HLA
mismatches have a half-life of 11.3 years. Those with six mismatches have a
half-life of 6.8 years, compared with those from HLA-identical siblings, which
have a half-life of 23.6 years.
Some donors are highly sensitized to HLA antigens from
previous transfusions, ie, possess high panel reactive antibody levels. It may
be difficult to find a suitable donor, since a positive cross-match by
cytotoxicity testing is likely and would be a contraindication to transplant.
Donor screening is performed in all cases to assess suitability, rule out
hypertension or anatomic anomalies, and avoid transmission of hepatitis viruses,
HIV, and other infectious agents. Owing to the scarcity of related donors,
living unrelated donors may be used in certain circumstances. Pretreatment of
recipients with blood transfusions from the donor appears to extend graft
survival even longer.
Delayed allograft function can be due to hyperacute graft
rejection, postischemic acute tubular necrosis, cyclosporine toxicity, or
obstructive nephropathy. If conservative measures do not improve function or
patients are at high risk for allograft rejection, renal biopsy should be
performed for definitive diagnostic purposes. Renal allograft rejection may be
due to hyperacute rejection from binding of cytotoxic antibodies and complement
activation, acute rejection from cellular immune responses, or chronic
rejection. A form of interstitial nephritis secondary to polyomavirus infection
is associated with aggressive immunosuppression. Noninvasive methods to diagnose
rejection are being developed. To replace the need for renal biopsy, studies of
mRNA reveal that the levels of FOXP3 in urinary cells may serve as a
mechanistically informative biomarker of acute rejection.
Chronic allograft nephropathy is characterized by
vasculopathy and immune-mediated graft obliteration. Previous acute rejection is
strongly linked with later chronic rejection, and severity of those episodes has
prognostic implications. Cyclosporine-induced nephrotoxicity and recurrent or de
novo renal disease are also significant factors affecting long-term
survival.
Induction immunosuppressive regimens have been used to
suppress acute rejection during the high-risk period, immediately following
transplantation. High doses of combined corticosteroids, calcineurins and
antiproliferative agents or sirolimus may be used during the induction phase, or
alternatively, T cell-depleting polyclonal or monoclonal antibodies may be used.
Maintenance immunosuppressive regimens are characterized by lower doses of
immunosuppressive agents with the aim of preventing recurrent rejection and
chronic nephropathy, prolonging graft survival, and minimizing potentially
serious medication side effects.
High-Dose Chemotherapy With Hematopoietic Progenitor Cell (Stem Cell) Transplantation
Transient myelosuppression after cancer chemotherapy is a
well-established adverse effect of such treatments. For most regimens, it is
rapidly reversible and requires no intervention. Some malignancies (eg, many
leukemias, lymphomas, and chemotherapy-sensitive breast and small-cell lung
carcinomas) may demonstrate a higher cure rate with higher-dose therapy;
however, associated with this approach is an increase in hematologic toxicity.
Administering the maximal tolerated chemotherapy dose and restoring all
hematopoietic functions as rapidly as possible has led to evolution of the
concept of hematopoietic progenitor cell (HPC) or "stem cell" transplant. HPC
transplants have also expanded somewhat into the therapy of certain nonmalignant
disorders of hematopoiesis and hematologic function; examples are aplastic
anemia, sickle cell anemia, thalassemia, myelodysplasia, amyloidosis, and
paroxysmal nocturnal hemoglobinuria.
The sources of HPC are the bone marrow, peripheral blood,
and cord blood. They comprise less than 0.5–1% of all nucleated bone marrow
cells. Although HPCs are "rare" cells, they can be obtained from the peripheral
blood by apheresis. As the peripheral blood has approximately one-fortieth the
number of circulating HPCs as the bone marrow, these cells must be "mobilized"
by the administration of cytotoxic chemotherapy (with the harvest being
performed during the recovery phase) or enriched by the administration of
hematopoietic growth factors. The cells are frozen and administered at a later
date. Transplantation of HPC from umbilical cord blood can be used in unrelated
donors, with a potentially lower rate of graft-versus-host disease, or may be
autologous, from frozen stored blood.
Because syngeneic transplants between identical
(monozygotic) twins are rare, the two predominant transplants are autologous,
where the HPCs are harvested from and returned to the patient; or allogeneic,
where the source is an HLA-matched donor, ideally a sibling. The goals of the
two procedures—and their associated adverse effects—are frequently different.
Allogeneic transplants are most commonly offered to patients with malignant and
nonmalignant disorders involving the bone marrow. Chemotherapy is given to
ablate the marrow, resulting in maximal suppression or eradication of the
recipient's native immune system. The bone marrow is repopulated by infusion of
donor cells containing not only HPCs but also functional donor T lymphocytes.
These T cells can cause graft-versus-host disease, in which the recipient's
tissues are recognized as nonself. While this is occasionally desirable, as in
the "graft-versus-leukemia" effect, it is the cause of considerable morbidity
and can be fatal. There are two separate phases of graft-versus-host disease:
acute, secondary to cytokine-mediated cytotoxicity against the cells of the
liver, the mucosa of the gastrointestinal tract, and skin; and chronic,
characterized by fibrosis and collagen deposition and resembling autoimmune
disease such as scleroderma. The incidence of graft-versus-host disease can be
decreased by depleting the donor marrow of T cells, but this is associated with
a higher incidence of graft failure and, in the case of leukemia, a higher
relapse rate. Allogeneic peripheral HPC transplants have been attempted, and
graft-versus-host disease in such cases does not appear to be as severe.
Autologous HPC transplants are performed solely for the
treatment of malignancies. In these cases the chemotherapy is intensively
myelosuppressive although not necessarily myeloablative. One prominent exception
is patients with chronic myelogenous leukemia in blast crisis, who receive their
autologous HPC in an effort to return their disease to the chronic phase. Since
patients usually have some residual immune function and are receiving their own
HPC—and thus do not require posttransplant immunosuppression—the risk of
opportunistic infections and immunosuppression-related neoplasia is markedly
reduced.
The success rates of HPC transplantation depend mostly on
the underlying disease and the associated risk of relapse (in cases of
leukemia), the level of matching between donor and recipient (and thus the
likelihood of graft-versus-host disease), the age of the recipient, and the
complications associated with conditioning (veno-occlusive liver disease and
infection). Chronic graft-versus-host disease can lead to scleroderma-like or
sicca-type syndromes.
Overall, the survival rates at 1 year are about 60–70% in
aplastic anemia and 40–75% in various forms of leukemia and other neoplasms such
as non-Hodgkin's lymphomas; results in breast carcinoma are less well defined
Recources:Current Medical Diagnosis & Treatment 2008 Stephen J. McPhee, Maxine A. Papadakis, and Lawrence M. Tierney, Jr., Eds. Ralph Gonzales, Roni Zeiger, Online Eds.