EXPERIMENTAL AND CLINICAL TRANSPLANTATION

The cornea is the transparent structure in the front of the eye and consists of 5 layers.¹ The epithelial layer, which is the outermost layer of the cornea, constitutes 10% of the total corneal thickness. The Bowman membrane, located between the epithelial layer and the stroma, is the structure just below the basement membrane and is the acellular zone of the anterior stroma. The stroma layer, which is the thickest corneal layer and is 90% of the entire corneal thickness, is under the Bowman membrane. The stroma is an avascular structure mainly composed of water and collagen fibers. The Descemet membrane, located below the stroma, is the basement membrane of the endothelium. On the other hand, the endothelial layer is the innermost layer of the cornea and consists of endothelial cells and is the structure that maintains corneal transparency by pumping water out of the stroma.² Opacification of the cornea causes corneal blind-ness, which affects approximately 10 million people worldwide.³ The treatment for corneal blindness is corneal transplant surgery, which includes the replacement of corneal tissue.⁴ The main indications for corneal transplant include keratoconus, corneal edema after cataract surgery, corneal opacities due to infectious causes such as herpetic keratitis, corneal dystrophies, and corneal opacities due to trauma or injury.⁵ The surgical approach in corneal transplant con-sists of 3 main types: penetrating transplant, anterior lamellar transplant, and posterior lamellar/endothelial transplant, according to the characteristics of the transplanted corneal layer. The decision of which corneal layer to transplant depends on which corneal layer is affected by the disease. All corneal layers are transplanted in penetrating corneal transplant; only the superficial corneal layer is transplanted in anterior lamellar corneal transplant; and the endothelial layer with or without posterior stroma is transplanted in posterior lamella/endothelial corneal transplant.⁴ The first full-thickness corneal transplant was performed in 1905 by the Austrian ophthalmologist Eduard Zirm.⁶ Significant advances have been made in this regard since the first application of corneal transplant, such as use of immunosuppressive treatment, development of corneal storage solution, and establishment of eye banks, all of which aim to increase the number of corneal transplants.^7-12 According to the global survey by Gain and colleagues,¹³ an average of 185?000 corneal transplants are performed annually. Although corneal transplant is the most-performed tissue transplant worldwide, approximately 70 candidates are expected per donor corneal tissue. The estimated number of people awaiting transplants is 12.7 million worldwide. With this high ratio of wait list candidates versus available donor tissue, it is not surprising that the average wait time is 6.5 months.¹³ There is a similar urgency (and scarcity) in other solid-organ donation programs, most of which have an established set of selection parameters (such as blood enzyme levels) that are easily defined and measurable.^14-16 In contrast, there is still no worldwide consensus on such selection criteria for corneal transplant. The wait list for corneal transplants from eye banks is long, and the selection of appropriate recipients from the wait list is managed by a designated authority (the authorized recipient selection operator) informed by the literature and the characteristics of the recipient within a framework of generally accepted, but variable, guidelines. The authorized recipient selection operator manually evaluates a variable number of parameters among hundreds of candidates on the wait list. Eye banks for corneal transplant have been established at the national level in some countries, whereas local eye banks have proved successful in other countries, such as Turkey.¹³ National eye banks are preferred because they are more systematic, but organization at the national level is more difficult because management is more comprehensive. While wait lists are more prominent in national eye banks, the wait list of corneal recipients for both types of eye banks long, making the process difficult to select a corneal transplant candidate from the recipient list. Particular priority scoring systems have been tested but have been judged to be of limited importance.¹⁷ Most of these systems have attempted to simulate surgeon selections with few criteria, but such systems have not always yielded consistent results.¹⁸ Courtright and colleagues¹⁷ tested a priority assignment system for selection of corneal transplant recipients based on the following considerations: one-eyed, progressive corneal disease, legal blindness, potential good outcome, ocular pain, and wait list times. These parameters were subjected to regression analysis after 10 months. Analysis of the priority score showed that of the 6 criteria, ocular pain and one-eyed contributed significantly to selection priority. Of the other criteria, potential good clinical outcome and wait time were not contributory factors; also, legal blindness and progressive disease were only minor contributory factors. Based on these results, 2 models were created. The first model revealed that ocular pain, vision in a single eye, and progressive eye disease were the only independent predictors of surgery in the priority scheme. Inclusion of other factors in the model, such as the respective surgeon, recipient sex, vision in a single eye, ocular pain, and progressive eye disease, improved the prediction of who would have surgery. The fact that the respective surgeon was a strong predictive factor suggested that there were significant differences of implementation of the priority system by individual surgeons. Another study of the same priority system was published in 2002 by Saunders and colleagues.¹⁹ According to the criteria, a good outcome was defined as improvement in 3 parameters: visual acuity (operated eye), ocular pain, and visual function (person). According to these criteria, 88.2% of the recipients showed improvement in at least 1 of these parameters. The recipients with the best recovery had aphakic or pseudophakic bullous keratopathy, whereas the worst recovery was in recipients with a history of Fuchs dystrophy. Overall, there was a significant correlation between outcome and preoperative priority scores. However, it is not helpful to generalize scoring systems for recipient selection for corneal transplant. Also, this scoring system is characterized by a manual selection process and is therefore affected by human subjectivity and thus prone to bias. In 2017, Rosenfeld and Varssano¹⁸ proposed a calculation method for candidate selection. In their report, current best corrected visual acuities in both eyes, potential best corrected visual acuity in the operated eye, preoperative ocular pain level, preoperative risk of infection, time since current disease onset, and estimated success rate were the priority parameters. They excluded age, sex, socioeconomic status, and general health from the system. They stated that these parameters were not included when deciding which candidate would benefit most from the transplant because it could not be decided what effect they should have. Their simple system was a close predictor of their human decision for their selected criteria. With this review, we focus on the preferred solution options and criteria for selection of corneal recipients from the worldwide transplant wait list. As mentioned above, there are a limited number of studies of recipient selection criteria in the literature. At this point, we will discuss some prominent issues one by one.

Age may be the most controversial criterion for recipient selection. Some researchers have argued that recipient age is important for transplant success, while others have reported that recipient age is unimportant. In a study of 2385 corneal transplant recipients, Vail and colleagues²⁰ found that older age is not a risk factor for graft survival but does affect the recipient’s visual outcome. Similarly, Dandona and colleagues²¹ reported that there was no difference in graft survival between age groups in 1725 corneal transplant recipients. In yet another similar study from 2003, Price and colleagues²² evaluated a cohort of 3992 corneal transplant recipients and observed no increased risk of graft failure in older recipients. Contrary results have also been reported. Maguire and colleagues²³ reported that graft failure increased in recipients younger than 40 years in their study with 457 participants. In a retrospective study conducted by Marisa and colleagues²⁴ in 2001, data from 468 participants were analyzed, and it was shown that graft failure was associated with the age of the recipient. According to the retrospective cohort study conducted by Reinprayoon and colleagues²⁵ with 704 participants in 2021, the risk of graft failure was higher in corneal transplant recipients aged 41 to 60 years compared with those aged 21 to 40 years.

Sex is another controversial issue in corneal transplant. Maguire and colleagues²³reported that male sex is a risk factor for graft failure. Similarly, Marisa and colleagues²⁴ showed that graft failure is associated with male sex. On the contrary, Omar and colleagues²⁶ reported that sex is not statistically associated with corneal transplant failure.

Age Match and Sex Match

Evaluation of the age match and sex match between donor and recipient may provide more meaningful insight versus consideration of only the recipient’s age and sex. Again, there are conflicting results on this subject in the literature. Achiron and colleagues²⁷ examined this matching problem with Descemet stripping endothelial keratoplasty and penetrating keratoplasty in 2 patient groups (high-risk patients and low-risk patients) and found that (1) sex mismatch was statistically associated with graft failure in high-risk patients and (2) male-to-female transplants were a risk factor for failure. However, age mismatch was not a risk factor for transplant failure. Ong and colleagues²⁸ showed that sex mismatch and age mismatch were not risk factors for graft failure for deep anterior lamellar corneal transplant. Hopkinson and colleagues²⁹ conducted an important study on this subject with 18?171 participants and reported that sex matching is necessary for graft success in corneal transplant recipients with Fuchs endothelial dystrophy. Compared with the sex-inconsistent group, the success rate was 40% lower in female-to-female transplants and 20% higher in male-to-male transplants. In addition, the probability of failure of sex-matched transplant in keratoconus was 30% higher than that of male-to-male transplant. For other diseases that had been treated with penetrating corneal transplants, the probability of sex mismatch rejection was 30% higher than for female-to-female transplants.

Socioeconomic Status

Socioeconomic status may be an important predictor of transplant success. With regard to recipient socioeconomic status and graft survival, Chua and colleagues³⁰ conducted a study with 13?644 participants in 2013 and reported no statistically significant difference between low socioeconomic status and graft failure. In contrast, Dandona and colleagues²¹ identified low socioeconomic status as a risk factor for graft failure.

Unlike the aforementioned issues, there is a consensus in the literature about the effect of regraft on graft success. Studies have shown that as the number of transplants increases, the risk of graft failure increases. Although the graft failure rate differs between surgical techniques, it remains high compared with previous transplant.^31-36

The primary disease indication for corneal transplant may be an important factor for the success of transplant and for graft survival. Reinprayoon and colleagues²⁵ reported that some primary diseases (active keratitis, peripheral bullous keratopathy, pre-existing glaucoma, pseudophakic/aphakic bullous keratopathy) are associated with higher failure rates in corneal transplant. In support of this, Sibley and colleagues³⁷ reported that corneal vascularization is significantly higher in infected patients (65%) versus patients with keratoconus (10%) or pseudopathic bullous keratopathy (25%). In addition, pseudopathic bullous keratopathy has been associated with a higher risk of rejection when vascularization is present in more than 2 quadrants. Price and colleagues²² examined 5-year graft survival rates according to primary diseases (keratoconus, 97.4%; Fuchs endothelial dystrophy, 96.9%; pseudophakic bullous keratopathy, 88.1%; aphakic bullous keratopathy, 83.2%; corneal scars and ulcers, 80.2%). Again, in terms of long-term prognosis, Thompson and colleagues³⁸ reported that the 5-year graft survival rate was 97% and the 10-year graft survival rate was 92% in keratoconus, whereas the 5-year and 10-year graft survival rates for Fuchs endothelial dystrophy were 97% and 90%, respectively. However, the 5-year graft survival rate for aphakic bullous keratopathy was significantly lower at 70%.

Visual Prognosis

The expectation of an increase in visual acuity is an important parameter for corneal transplant. A graft may survive, but if blindness remains, then the success of the transplant should be reconsidered. Dandona and colleagues²¹ reported that cases of keratoconus and corneal dystrophies are more likely to have a visual acuity of greater than 6/18 versus cases with other diagnoses. Similarly, Claesson and colleagues³⁹ reported that visual acuity improved in 86% of keratoconus cases and 54% of Fuchs endothelial dystrophy cases. However, visual acuity improved in only 31% of patients with bullous keratopathy and 35% of patients who were assigned “other diagnosis.” Saunders and colleagues¹⁹ also reported that old trauma and Fuchs endothelial dystrophy are associated with worse visual prognosis.

Ocular pain is an important factor for evaluation of recipients for corneal transplant. Patients may remain on the corneal transplant wait list for prolonged periods (months), and many may experience ocular pain during the wait period, so this pain should be considered in the recipient selection process. Whether the pain is continuous or intermittent is an important detail, as well. Saunders and colleagues¹⁹ reported that post-transplant ocular pain relief was observed in 77.6% of recipients who had experienced pretransplant ocular pain while awaiting transplant. They also showed that ocular pain relief was evident in aphakic and pseudophakic bullous keratopathy.

Time on the Wait List

Wait time for corneal transplant is an important factor that can affect the recipient selection process, and wait time has been included as a parameter in some previously reported corneal recipient selection systems. Presently, the average wait period is 6 months, but there are significant differences between countries. In a study where wait time was chosen as a selection parameter, the highest score was attributed to wait times of 36 months or more.¹⁸ In contrast, Courtright and colleagues¹⁷ analyzed the components of the priority score and showed that of the 6 priority criteria, the time on the wait list was not a contributory factor for selection.

Primary Disease Progression

The progression of the primary disease may be an important influential factor for recipient selection, but the relevant data are scarce. The most important contribution to the literature in this sense is from Courtright and colleagues,¹⁷ who reported that progressive disease is one of the independent predictors of surgery and is a valuable predictor of corneal transplant recipient selection.

Status of the Fellow Eye

The condition of the fellow eye may also be a valuable parameter in corneal recipient selection. A candidate with low vision in both eyes may be assigned higher priority in terms of ethical decisions versus a candidate with similar characteristics in need of a single-eye corneal transplant. In this sense, Rosenfeld and Varssano¹⁸ defined the condition of the fellow eye as 1 of 7 important parameters for their calculation. In another study, single-eye vision was included in the scoring system at the beginning of the study with no consideration of the fellow eye. Its scoring was increased in the reconstructed scoring system considering the data in the rest of the study.¹⁷ This study reported that the condition of the fellow eye, such as progressive disease, is an independent predictor of surgery and is a valuable predictor for corneal transplant selection.¹⁷

Although corneal transplant is the most-performed transplant worldwide, the gap between the number of donors and recipients remains a problem for the corneal transplant community.¹³ Due to this gap, which is also present for other solid-organ transplants, there are advanced parameters for recipient selection. Unfortunately, there are no universally accepted selection criteria for corneal transplant. The authorized recipient selection operator conducts a manual selection process on the basis of information from the literature. The difficulty of this process is proportionate to the length of the wait and becomes progressively more susceptible to human bias. In this respect, when the relevant literature is reviewed, although some factors are examined in detail with regard to graft survival, there remain insufficient data for other factors. Age and sex are among the first parameters evaluated in this sense. Older grafts have lower graft survival,^24,25 especially in posterior lamella and full-thickness corneal transplants, and male sex of the donor has a higher risk to cause rejection by stimulation of the immune system.^23,24 Again, a recipient’s previous transplant surgery is among the factors known to reduce the success of the graft.^31-36 The nature of the primary disease indicator for corneal transplant can also affect the success of the graft by acting on the immune system. In addition, the visual prognosis is expected to be higher after corneal transplant in some corneal diseases.^22,25,37,38 The presence and level of ocular pain is also an important parameter in corneal recipient selection. There may be a tendency to assign priority to candidates with ocular pain, especially in cases of prolonged wait time.¹⁹ The importance of time spent on the wait list is controversial. Some studies have reported that long wait periods can influence priority, whereas other studies have reported that long wait periods did not have a significant effect on candidate selection. There are very few published data on the relationship between the progression of the primary disease and the condition of the fellow eye, which may be important factors in the recipient selection process. Courtright and colleagues¹⁷ reported that both the condition of the fellow eye and the presence of progressive disease are independent predictors of surgery and are valuable for prediction of who will undergo corneal transplant surgery. The effect the risk of graft failure on prioritization for transplant is an important factor in all tissue and organ transplant decisions. Accurate pretransplant predictors of transplant success are important for both the patient and the surgeon in the follow-up. However, with regard to corneal transplant, this factor is variable, as corneal transplant remains the most successful type of transplant among all transplants. The question arises whether candidates at high risk of graft failure should wait longer than candidates with a better prognosis, and there is presently no simple answer for corneal transplant. In the selection decision, ethical factors such as legal blindness, the visual function of the fellow eye, and presence of ocular pain may affect the choice. Therefore, there is a need for artificial intelligence-based systems to evaluate multiple factors, perform systematic analyses, and provide a simple user interface and long-term results of these analyses. All of these above-mentioned features are effective in the recipient selection process by the authorized recipient selection operator for donor corneas. Apart from these issues, there are also items such as vision in the fellow eye and discomfort in the eye of the candidate that may affect the selection process of the authorized recipient selection operator, but the published data on these details are scarce and presently insufficient. There are scarce data in the literature on corneal recipient selection criteria, and it is not possible to reach a definite conclusion about the comparative contribution of each specific criterion. Therefore, quantification of the corneal selection procedure as a ranking problem remains difficult and challenging. Unlike other solid organ transplants, there are no defined numerical values for corneal transplants; some criteria are subjective and therefore the selection process can be variable. Prospective randomized controlled studies are needed to better define and, if possible, quantify the factors that may affect success in corneal transplant. In this respect, artificial intelligence systems are needed to simulate operator selection. A flexible selection method would be appropriate, in which the agents responsible for candidate selection would decide which parameters should be included and how these should be weighted, based on ethical beliefs and clinical judgment.¹⁸ This selection method would also enable the quantification of the above-mentioned factors, which could contribute substantially to reduction of the workload of the authorized recipient selection operator and minimize the subjectivity and margin of human error. Evaluation of the results of these systems in the long-term will facilitate establishment of a universal priority scoring system, which will reduce donor-recipient mismatch.

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