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Researchers report that donor-recipient tissue typing had nosignificant long-term effect on the success of corneal transplantationin a nationwide clinical study of over 400 patients at high risk forrejection. The results of this National Eye Institute-supportedresearch were published today in the Archives of Ophthalmology.
The Collaborative Corneal Transplantation Studies (CCTS) suggestedinstead that matching patient and donor blood types (ABOcompatibility), a test which is not currently standard practice incorneal transplantation, might be effective in improving patientoutcome. CCTS investigators also believe that treating patients withhigh-dose topical steroid therapy for several months after surgery mayhave improved transplant survival in this study.
These findings, based on three years of extensive patient followup,indicate that these two inexpensive strategies may potentially be moreeffective in improving high-risk corneal transplantation than the moreexpensive 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 inthe United States. But about one in 10 patients receiving a cornealtransplant 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 theeye that may later recognize the graft as foreign and attack it.
The CCTS was designed to evaluate whether donor-recipient tissuetyping, transplanting a donor cornea that has cell-surface proteins(HLA, or human leukocyte antigens) which closely resemble those on therecipient’s natural cornea, helps to prevent transplant rejection.
These antigens serve as molecular “fingerprints” on everycell in the body and allow a person’s immune system to distinguishone’s own cells from those belonging to another person. Previousstudies had suggested that closely matching the donor’s HLA with thoseof the recipient may increase the likelihood that a person’s immunesystem would accept, rather than reject, the donor tissue.
If donor-recipient tissue typing were to become standard practice incorneal transplantation, it would greatly increase the cost andwaiting period for this operation. The process of matching antigens islabor intensive and would add at least $1,000 to the cost of a cornealtransplant operation, now about $5,000. Moreover, since there isalready a national shortage of donor corneas, high-risk patients wouldlikely have to wait even longer for a suitably matched donor cornea.
After three years of patient followup, CCTS researchers found thatpeople who received corneal transplants with well-matched antigens didnot fare significantly better than those with a poor match. Eachpatient group had similar rates of initial immune reactions, graftrejection, and graft failure due to infection or other causes.According to the investigators, these findings indicate that tissuetyping was not an important factor in transplant survival.
The researchers also noted that CCTS patients who matched thedonor’s blood type had a better outcome than unmatched patients. Thisfinding was particularly interesting because ABO compatibility hasbeen shown in several other organ transplantation studies to enhancegraft survival, but it had never been reported in cornealtransplantation 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 itsthree-year mark–higher than the usual average of about 50 percent inhigh-risk patients. The CCTS researchers note that the study’s highsuccess rate might owe to rigorous high-dose steroid therapy tocontrol the patients’ immune reaction to the donor cornea severalmonths after surgery. All CCTS patients received more intensivepostoperative topical steroid therapy than did patients in two recentinvestigations that showed HLA matching positively influencedtransplant survival.
Dr. Walter Stark, chairman of the study and professor ofophthalmology at The Johns Hopkins University Medical Institutions,said that although the CCTS found HLA matching had no effect on graftsurvival, high-dose topical steroid therapy proved so effective in thestudy that it could have actually masked any beneficial effect ofantigen matching. He stated that whenever patients showed initialsigns of an immune response against the graft, their steroid dosagewas 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 (boththe patient and clinician did not know to which treatment group thepatient had been assigned) clinical study. It was designed to assessthe effectiveness of matching on two general types of HLA–HLA-A, -B,and HLA-DR–on corneal graft survival in patients who were at highrisk for rejection. Specifically, CCTS investigators sought todetermine the effect of various degrees of donor-recipient match forsix antigens on graft survival.
For HLA-A, -B, 0 to 1 antigens mismatched was considered a highmatch, while 2 to 4 mismatched antigens was a low match. For HLA-DR, 0antigens mismatched was a low match, and 1 or 2 antigens mismatchedwas 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 inthe HLA-DR High Match group. The remaining patients were assigned toLow Match groups. Two-hundred and ninety-four patients (70%) receivedcorneas from ABO compatible donors.
Following surgery, all patients were treated with a topical steroidregimen consisting of various dosages of prednisolone acetate 1%,dexamethasone ointment, and fluoromethalone 0.1%. Dosages wereincreased if an immune response against the graft occurred.
After three years of follow-up, the CCTS found in 313 patients:
- In the HLA-A, -B group, 37 percent of grafts in the low-matchgroup and 33 percent in the high-match group had failed.
- In the HLA-DR group, 24 percent of grafts in the low- matchgroup 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 incompatiblegroup.
The CCTS was a multicenter and an ongoing, National Eye Institute(NEI) clinical research project that investigates the effect ofantigen-matching in high-risk corneal transplantation.
The NEI, part of the National Institutes of Health, is theFederal government’s lead agency in the study of the human visualsystem 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