Researchers report that donor-recipient tissue typing had no significant long-term effect on the success of corneal transplantation in a nationwide clinical study of over 400 patients at high risk for rejection. The results of this National Eye Institute-supported research were published today in the Archives of Ophthalmology.
The Collaborative Corneal Transplantation Studies (CCTS) suggested instead that matching patient and donor blood types (ABOcompatibility), a test that is not currently standard practice in corneal transplantation, might be effective in improving patient outcome. CCTS investigators also believe that treating patients with high-dose topical steroid therapy for several months after surgery may have improved transplant survival in this study.
These findings, based on three years of extensive patient follow-up, indicate that these two inexpensive strategies may potentially be more effective in improving high-risk corneal transplantation than the more expensive donor-recipient tissue typing.
“The CCTS has produced some excellent data onhigh-risk corneal transplantation,” said Louis W. Sullivan, M.D.,secretary of Health and Human Services. “We now have solidinformation on managing these patients, while keeping health carecosts to a minimum.”
Over 40,000 corneal transplant operations are performed annually in the United States. But about one in 10 patients receiving a corneal transplant is at high risk of rejecting the donor tissue, or graft, because: (1) they have previously rejected a corneal transplant, or(2) new blood vessels have grown into their damaged cornea, introducing immune cells into this normally avascular region of the eye that may later recognize the graft as foreign and attack it.
The CCTS was designed to evaluate whether donor-recipient tissue typing, transplanting a donor cornea that has cell-surface proteins(HLA, or human leukocyte antigens) which closely resemble those on the recipient's natural cornea, helps to prevent transplant rejection.
These antigens serve as molecular “fingerprints” on every cell in the body and allow a person’s immune system to distinguish one's own cells from those belonging to another person. Previous studies had suggested that closely matching the donor’s HLA with those of the recipient may increase the likelihood that a person’s immune system would accept, rather than reject, the donor tissue.
If donor-recipient tissue typing were to become standard practice in corneal transplantation, it would greatly increase the cost and waiting period for this operation. The process of matching antigens is labor-intensive and would add at least $1,000 to the cost of a corneal transplant operation, now about $5,000. Moreover, since there is already a national shortage of donor corneas, high-risk patients would likely have to wait even longer for a suitably matched donor cornea.
After three years of patient follow-up, CCTS researchers found that people who received corneal transplants with well-matched antigens did not fare significantly better than those with a poor match. Each patient group had similar rates of initial immune reactions, graft rejection, and graft failure due to infection or other causes. According to the investigators, these findings indicate that tissue typing was not an important factor in transplant survival.
The researchers also noted that CCTS patients who matched the donor's blood type had a better outcome than unmatched patients. This finding was particularly interesting because ABO compatibility has been shown in several other organ transplantation studies to enhance graft survival, but it had never been reported in corneal transplantation research.
“If future studies prove ABO compatibility has aneffect on corneal transplant survival,” said Carl Kupfer, M.D.,director of the National Eye Institute, “this easily administeredand inexpensive test would improve transplant survival withoutsubstantially increasing the cost of the operation.”
The CCTS also reported a 65 percent rate of graft survival at its three-year mark–higher than the usual average of about 50 percent in high-risk patients. The CCTS researchers note that the study’s high success rate might owe to rigorous high-dose steroid therapy to control the patients’ immune reaction to the donor cornea several months after surgery. All CCTS patients received more intensive postoperative topical steroid therapy than did patients in two recent investigations that showed HLA matching positively influence transplant survival.
Dr. Walter Stark, chairman of the study and professor of ophthalmology at The Johns Hopkins University Medical Institutions, said that although the CCTS found HLA matching had no effect on graft survival, high-dose topical steroid therapy proved so effective in the study that it could have actually masked any beneficial effect of antigen matching. He stated that whenever patients showed initial signs of an immune response against the graft, their steroid dosage was increased and the attack generally soon subsided.
“Given the inadequate state of knowledge of the causesof corneal transplant failure,” he said, “one might arguethat the most important conclusion to be drawn from the CCTS is thathigh-dose, postoperative topical steroids, good patient compliancewith a self-administered steroid regimen, and close patient followupare the keys to successful corneal transplantation in high-riskindividuals.”
Background Information on the Study
Launched in 1986, the CCTS was a prospective, double-masked (both the patient and clinician did not know to which treatment group the patient had been assigned) clinical study. It was designed to assess the effectiveness of matching on two general types of HLA–HLA-A, -B, and HLA-DR–on corneal graft survival in patients who were at high risk for rejection. Specifically, CCTS investigators sought to determine the effect of various degrees of the donor-recipient match for six antigens on graft survival.
For HLA-A, -B, 0 to 1 antigens mismatched was considered a high match, while 2 to 4 mismatched antigens was a low match. For HLA-DR, 0antigens mismatched was a low match, and 1 or 2 antigens mismatched was a high match.
A total of 419 patients were enrolled in the study. Of this number,137 (33%) were in the HLA-A, -B High Match group and 199 (47%) were in the HLA-DR High Match group. The remaining patients were assigned to Low Match groups. Two-hundred and ninety-four patients (70%) received corneas from ABO compatible donors.
Following surgery, all patients were treated with a topical steroid regimen consisting of various dosages of prednisolone acetate 1%, dexamethasone ointment, and fluorometholone 0.1%. Dosages were increased if an immune response against the graft occurred.
After three years of follow-up, the CCTS was found in 313 patients:
- In the HLA-A, -B group, 37 percent of grafts in the low-match group and 33 percent in the high-match group had failed.
- In the HLA-DR group, 24 percent of grafts in the low-match group and 25 percent of those in the high-match group had failed.
- Patients in the ABO compatible group had a failure rate of 31percent compared to 41 percent for those in the ABO-incompatible group.
The CCTS was a multicenter and ongoing, National Eye Institute(NEI) clinical research project that investigates the effect of antigen-matching in high-risk corneal transplantation.
The NEI, part of the National Institutes of Health, is the federal government’s lead agency in the study of the human visual system in health and disease.
- The Collaborative Corneal Transplantation Studies (CCTS). Effectiveness of Histocompatibility Matching in High-Risk Corneal Transplantation. The Collaborative Corneal Transplantation Studies Research Group. Arch Ophthalmol. 1992 Oct. PubMed