Corneal transplantation can restore vision and improve quality of life to those with congenital or acquired corneal opacities (1). Outcomes are typically excellent early after corneal transplantation, but are less satisfactory in the longer term. Registers can provide useful level 4 evidence about the outcomes of surgical procedures (2). The Australian Corneal Graft Registry was established in 1985 to measure graft survival and visual outcome after corneal transplantation, to record changing patterns of practice, and to investigate risk factors for corneal graft failure. It contains records of over 20,000 penetrating (full thickness), lamellar (partial thickness), and limbal (corneal epithelial stem cell) corneal grafts.
Here we show that factors relating to the corneal donor and to practices within eye banks contribute little to overall outcomes after transplantation. However, factors relating to the recipient (many of which cannot be altered) and to a lesser extent to the actual surgery, exert major influences on graft survival and hence on visual outcomes.
PATIENTS AND METHODS
Data Collection
Individual surgeons handled the consent process for each patient, to permit information to be lodged with the register. The institutional Clinical Research Ethics Committee approved the overall operations of the Register, which were carried out in accordance with the Declaration of Helsinki. All information submitted to the Registry was deidentified and amalgamated before analysis.
Records of 18,686 penetrating corneal grafts were examined within a prospective, national database, with annual archival follow-up ranging from less than 1 to 22 years. Information on the graft recipient, donor, eye bank, operative procedure, and postoperative course was collected as previously described (3). Records were submitted by a total of 623 individuals, 345 of whom were ophthalmic surgeons who had carried out the transplant procedure and 278 of whom were practitioners involved in follow-up. Records were submitted to the Registry by the contributing surgeon as soon as possible after the graft and follow-up was requested at intervals of 12 months. Missing data were sought by follow-up letter. Each graft was followed at yearly intervals until graft failure or until the death or loss to follow-up of the patient. At the census date 14,622 penetrating grafts (78%) had been followed on at least one occasion, 875 recipients (5%) were known to have died, and 6107 grafts (33%) had been lost to annual follow-up. Given the age profile of the recipients, (58% aged over 50 years of age at the time of transplantation; peak age between 70 and 80 years), it seems that some recipient deaths have never been reported to the contributing ophthalmologist. Thus for example, 35% eyes grafted for bullous keratopathy (typically older patients) have been lost to follow-up, compared with only 16% for keratoconus (typically younger patients).
Statistical Analyses
Kaplan-Meier survival functions were constructed using SPSS version 15 to provide a graphical record of graft survival (4–6). For surviving grafts, trial time was calculated as the time between the date of graft and the date on which the patient was last seen. For failed grafts, trial time was calculated as the time between the date of graft and the date of failure. No exclusions were applied and each graft was considered as an independent entity. Of 13,879 patients (as distinct from grafts) with follow-up, 19% had had more than one registered penetrating graft in the ipsilateral or contralateral eye. Cox proportional hazards regression analysis was performed using Stata version 9, examining all variables that reached a significance level of P is less than 0.05 in univariate analysis. A model clustered by patient to control for intereye or intergraft dependence was constructed to identify variables best predicting penetrating corneal graft failure (7). Some variables were removed from consideration because of collinearity. The final model was found by a nonautomatic backward elimination process, removing variables not predictive of graft failure. Some variables (graft size and time to graft suture removal) with nonlinear hazard ratios were transformed (square root-transformation and log-transformation, respectively) to improve model fit. The assumption of proportional hazards was reasonable as assessed by Kaplan-Meier plots.
RESULTS
Demography of Corneal Donors and Corneal Transplant Recipients
Sixty-one percent of donors were male, and 55% were aged over 60 years at the time of death. Disease of the cardiac/circulatory system (32%), stroke or hemorrhage (20%), malignancy (17%), traumatic/accidental death (11%), and respiratory system disease (11%) together accounted for over 91% of causes of donor death. Multiorgan, brain-dead–donors comprised only 6% of the donor pool; the remaining 94% of corneas were retrieved from donors after cardiac death. Median death-to-enucleation time was 6 hr (range, 1–35 hr) and median death-to-graft time was 2.6 days (range, <1–≥30 days). Recipient age at graft ranged from 14 days, to 97 years and 8 months, with a median age of 59 years. Major indications for penetrating corneal transplantation were keratoconus (32%), bullous keratopathy (26%), failed previous graft (20%), corneal dystrophy (7%), corneal scars and opacities (7%), corneal ulcers and erosions (3%), active herpetic eye disease (1%), and nonherpetic corneal infection (1%). Only 0.03% of eyes exhibited significant lid or ocular surface disease.
Overall Kaplan-Meier Corneal Graft Survival and Multivariate Analysis
The probability of penetrating corneal graft survival in the whole cohort was 0.87, 0.73, 0.60, and 0.46 at 1, 5, 10, and 15 years, respectively (Fig. 1). Kaplan-Meier survival for the major indications for penetrating keratoplasty is shown in Table 1. Major reasons for graft failure were irreversible rejection (34%), corneal endothelial cell failure including cases of glaucoma (24%), and infection (14%). Primary nonfunctioning grafts, in which the donor cornea never functioned postoperatively, accounted for 4% of all failures and 0.7% of all registered penetrating grafts.
;)
FIGURE 1.:
Kaplan-Meier survival of all penetrating corneal grafts. Of 18,686 records of graft, archival follow-up was available for 14,622. The numbers at risk (n) at 1, 5, 10, and 15 years postgraft are shown above the plot.
TABLE 1: Kaplan-Meier probability of penetrating corneal graft survival, stratified according to major indication for transplantation
Factors which did not influence penetrating graft survival in univariate analysis, and that therefore were not considered for inclusion in the Cox model, or that were significant in univariate analysis and were considered in multivariate analysis, but did not reach significance in the final Cox model, are shown in Table 2. Variables best predicting graft failure in multivariate analysis are shown in Table 3.
TABLE 2: Factors not influencing penetrating corneal graft survival in univariate analysis (log-rank test>0.05), or factors of influence in univariate analysis (log-rank test P<0.05) but not in multivariate analysis (log-rank test P>0.1)
TABLE 3: Final Cox proportional hazards model: independent factors influencing penetrating corneal graft survival (global P<0.1)
TABLE 3: Continued
Visual Outcomes After Corneal Transplantation
The desired outcome after corneal transplantation was visual improvement (72%), visual improvement and relief of pain (14%), pain relief only (4%), structural repair (4%), improved cosmesis (<1%), and a mixture of these outcomes in remaining cases (5%). In the total cohort, best-corrected Snellen acuity (without pinhole) of 6/12 or better was achieved by 45%, of 6/18 or better by 55%, and of less than 6/60 by 26%, of grafted eyes at last follow-up (Fig. 2a). In eyes grafted for keratoconus, best-corrected Snellen acuity of 6/12 or better was achieved by 69%, and of less than 6/60 by 5%. For Fuchs’ dystrophy, the figures were 46 and 14%, respectively. For the relatively high-risk indications of aphakic bullous keratopathy and failed previous graft, visual acuity was less impressive: only 12% of eyes grafted for aphakic bullous keratopathy and 24% grafted for failed previous graft achieved a Snellen acuity of 6/12 or better, whereas 38% and 34%, respectively, of such eyes achieved less than 6/60.
FIGURE 2.:
Visual outcome after penetrating corneal transplantation. (a) Best-corrected Snellen acuity in the grafted eye at the time of the most recent follow-up visit. (b) Best-corrected Snellen acuity in the grafted eye after at least 2 years of follow-up. CF, count fingers at 3 m; HM, perception of hand movements; LP, perception of light only; NPL, no perception of light.
At the time of most recent follow-up, one or more refractive surgical procedures had been performed on 12% of grafts. In instances where one of the desired outcomes of corneal transplantation was improvement in vision, at least one line improvement on the Snellen chart was actually achieved in 57% of grafted eyes. Snellen acuity in grafts followed for at least 2 years is shown in Figure 2(b). At 10 years postoperatively, 65% of grafts were corrected with a spectacle lens and 13% with a contact lens. An intraocular lens was present in 32% of grafted eyes. Comorbidities affecting the visual potential of the grafted eye included unspecified maculopathy in 9%, glaucoma in 7%, anisometropia in 6%, and cystoid macular edema in 6% of grafted eyes. Graft failure exerted the major negative influence on visual outcome after corneal transplantation, but visual potential was also limited by unacceptable astigmatism (>5 dioptres) in 22% of grafts.
DISCUSSION
Corneal donors represent a different pool from those used for vascularized organ grafts. In Australia, 96% of corneas for transplantation are collected from donors after cardiac death, than from brain-dead donors, and malignancy and diseases of the cardiac and respiratory systems are not contra-indications to donation. Furthermore, over half of all corneas are retrieved from donors over the age of 60 years. The median time between donor death and donor cornea retrieval is 6 hr, and depending on the type of corneal preservation medium used, donor corneas can be stored within eye banks for periods of days to weeks.
Neither donor age nor cause of donor death influenced penetrating corneal graft survival significantly in multivariate analysis. Similarly, factors associated with eye banking practices, including retrieval of the donor cornea after brain-death or cardiac-death, death to enucleation time (within standard limits), type of corneal storage medium used within the eye bank, or death to graft time (within approved limits for the preservation medium used), did not influence corneal graft survival significantly. Only 0.7% of transplanted corneas failed to function in the immediate postoperative period, and such failures may reflect recipient-specific or intraoperative problems, rather than eye bank failures. It appears that factors specific to corneal donor demographics or local variations in eye banking practices have no measurable effect on corneal graft survival. Taken together, these findings have implications for donor cornea retrieval services, which do not necessarily need to be linked with those for vascularized organs, and which indeed may operate more effectively at a local level from individual eye banks, given that the demographics of the respective donor pools and the contra-indications for donation are so different.
The major indications for penetrating corneal transplantation have changed little over the past 20 years, with keratoconus, bullous keratopathy and history of a previous failed ipsilateral corneal graft together accounting for approximately 80% of all cases. Some recipient-specific variables affect corneal graft outcome to a profound extent in multivariate analysis, including indication for graft, the extent of corneal neovascularization in the eye to be grafted, the absence of the crystalline lens, and a history of raised intraocular pressure or inflammation in the eye to be grafted. Unfortunately, little can be done to alter these risk factors for failure. Several intraoperative and postoperative variables also appear in the final Cox model but again, the ophthalmologist is unlikely to be able to control most of these factors. Penetrating grafts fail predominantly from the sequelae of irreversible rejection, corneal endothelial cell failure including that associated with glaucoma, and infection.
Most penetrating corneal grafts (85%) were performed to improve vision. Approximately 50% of grafts had achieved good Snellen acuity at the time of most recent follow-up, a time-frame that provides a snap-shot of visual outcome over the whole cohort. By 2 years postoperatively, corneal graft sutures have generally been removed, topical immunosuppression has usually been stopped, and any refractive surgical procedure designed to improve the visual outcome in the grafted eye has been completed. Snellen acuity measured after 24 months was similar to acuity measured at the time of last follow-up.
In conclusion, whereas penetrating corneal graft survival is 87% at 1 year, the survival rate drops to 46% at 15 years postoperatively. The majority of penetrating grafts are performed for vision, but only about half will achieve an excellent visual outcome. However, even a small improvement in visual outcome may be of benefit to the recipient. Novel or improvements in existing interventions designed to reduce the impact of corneal allograft rejection would likely exert a significant effect on both graft survival and visual outcome after penetrating corneal transplantation.
ACKNOWLEDGMENTS
The authors thank all ophthalmologists and eye bank staff who have contributed records to the Registry.
REFERENCES
1. Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: A global perspective.
Bull World Health Organ 2001; 79: 214.
2. Takemoto SK, Arns W, Bunnapradist S, et al. Expanding the evidence base in transplantation: the complementary roles of randomized controlled trials and outcomes research.
Transplantation 2008; 86: 18.
3. Williams KA, Esterman AJ, Bartlett C, et al.; on behalf of all contributors to the Australian Corneal Graft Registry. How effective is corneal transplantation? Factors influencing long-term outcome in
multivariate analysis.
Transplantation 2006; 81: 896.
4. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations.
J Am Stat Assoc 1958; 53: 475.
5. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised clinical trials requiring prolonged observation of each patient. I. Introduction and design.
Br J Cancer 1976; 34: 585.
6. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised clinical trials requiring prolonged observation of each patient. II. Analysis and examples.
Br J Cancer 1977; 35: 1.
7. Williams RL. A note on robust variance estimation for cluster-correlated data.
Biometrics 2000; 56: 645.
