Systematic Meta-Analysis of Impact of Glaucoma, Keratoconus, and Clinical Factors on High-Risk Corneal Transplantation Outcomes

Summary

This meta-analysis of 10,558 cases identifies glaucoma, keratoconus, diabetes, older age, and elevated intraocular pressure as key predictors of poor outcomes in high-risk corneal transplantation, emphasizing individualized preoperative optimization and surgical planning to improve graft survival and visual prognosis.

Abstract

High-risk corneal transplantation in patients with glaucoma, keratoconus, or prior graft failures is frequently associated with suboptimal outcomes. Although individual determinants such as age, gender, diabetes, and intraocular pressure (IOP) are recognized risk factors, their collective impact on graft survival has not been systematically quantified. This meta-analysis aims to clarify the role of glaucoma, keratoconus, and key clinical factors in shaping the prognosis of high-risk corneal transplantation. A systematic search of PubMed, Cochrane, Embase, and Web of Science databases was conducted to identify studies on high-risk corneal transplantation involving glaucoma and keratoconus. Data from 11 observational studies (10,558 cases) were analyzed. Across the included studies, transplant success was generally defined as graft survival with preserved corneal clarity. Subgroup analyses were performed to evaluate the impact of demographic and clinical determinants on transplant success. Glaucoma was found to significantly impact transplant success, with an odds ratio (OR) of 1.43 (95% CI [1.26, 1.63], p < 0.001), while keratoconus also represented a risk factor (OR = 1.22, 95% CI [1.13, 1.31], p < 0.001). Subgroup analysis for glaucoma patients indicated that younger age (<60 years), female gender, absence of diabetes, and preoperative IOP ≤25 mmHg were favorable factors for transplant success. In keratoconus patients, those under 30 years old and female had better transplant outcomes. Sensitivity analysis confirmed the robustness of these results, and minimal publication bias was observed. This study demonstrates that advanced age, male gender, diabetes, and elevated preoperative IOP significantly compromise the success of high-risk corneal transplantation. These findings provide robust evidence to guide patient selection, preoperative optimization, and surgical decision-making in high-risk populations. Incorporating these determinants into clinical practice may enhance graft survival and visual outcomes, while informing the development of tailored management strategies and future clinical guidelines.

Introduction

Corneal transplantation remains the definitive treatment for various corneal diseases, offering significant potential to restore vision and enhance quality of life^1,2. Although generally effective, the outcomes of this procedure are often suboptimal in high-risk patients, defined as individuals with conditions that predispose them to graft failure or postoperative complications³. High-risk corneal transplantation refers to procedures performed in patients with an increased risk of graft failure or postoperative complications, such as those with prior graft failures, glaucoma, or progressive corneal diseases^4,5,6. Despite substantial evidence on the clinical outcomes of high-risk corneal transplantation, a comprehensive meta-analysis systematically addressing the clinical factors influencing success rates across these diverse high-risk categories is lacking.

Several clinical factors, including patient age, gender, comorbid conditions (particularly diabetes), and specific ocular pathologies, are well-established as key determinants of transplant success^1,7,8. The type of corneal transplant performed can also influence postoperative outcomes. However, existing studies often focus on individual transplant techniques or specific risk factors, without offering an integrated understanding of how these factors collectively affect outcomes in high-risk populations^9,10.

High-risk corneal transplantations constitute a significant portion of the global demand for corneal grafts^4,11. Ocular conditions such as glaucoma and keratoconus (especially in cases with severe corneal scarring, previous failed transplants, concurrent eye diseases, and advanced stages) are major risk factors for graft rejection and poor outcomes^3,12,13. Glaucoma, for instance, is associated with elevated intraocular pressure (IOP), which can compromise graft survival by increasing the risk of rejection and corneal edema^14,15. Similarly, keratoconus is a progressive disorder characterized by corneal thinning. In advanced stages, particularly when accompanied by severe corneal scarring, prior graft failure, or coexisting ocular diseases, it may compromise graft stability and refractive outcomes and increase the risk of irregular astigmatism and graft failure^11,16.

The clinical and demographic factors that influence outcomes in high-risk corneal transplantation are not only of medical significance but also carry substantial social and economic implications^7,8,13,16. With the increasing global prevalence of age-related and systemic conditions such as diabetes, the incidence of high-risk corneal transplantation is expected to rise¹¹. Optimizing the management of these patients, through better patient selection and surgical techniques, is of both medical and societal importance. Improving outcomes in high-risk corneal transplantation can reduce healthcare costs, improve patients' quality of life, and ease the burden on transplant registries and donor networks.

Among the various high-risk indications, glaucoma and keratoconus were selected as the primary focus of this analysis because they represent two of the most common and clinically significant conditions associated with compromised graft survival and are relatively consistently reported in the literature. However, despite their clinical importance, few meta-analyses have systematically evaluated the influence of these conditions and related clinical factors on outcomes of high-risk corneal transplantation. Therefore, this meta-analysis aims to evaluate the impact of key clinical factors, including age, gender, diabetes, and high-risk ocular conditions such as glaucoma and keratoconus, on the outcomes of high-risk corneal transplantation. By synthesizing data from existing studies, this analysis seeks to clarify the role these factors play in graft survival, postoperative visual acuity, and complication rates. We hypothesize that clinical factors such as advanced age, male gender, diabetes, and high-risk ocular conditions are significantly associated with poorer graft survival and postoperative outcomes in high-risk corneal transplantation. The findings will provide valuable insights for clinicians, supporting more informed decision-making in the management of high-risk patients and guiding future recommendations for optimizing surgical strategies and postoperative care. To achieve this objective, a systematic review and meta-analysis of available clinical studies was conducted in accordance with PRISMA guidelines to quantitatively evaluate the impact of glaucoma, keratoconus, and related clinical factors on transplantation outcomes.

Protocol

Literature retrieval
A systematic search was conducted to identify studies evaluating factors influencing the efficacy of high-risk corneal transplantation. Relevant studies were retrieved from English-language databases, including PubMed, Cochrane, Embase, Google Scholar, and Web of Science. The search covered the period from the inception of each database through December 31, 2024. The search terms used included high-risk corneal transplantation, glaucoma, keratoconus, graft survival, postoperative visual acuity, and corneal transplant outcomes as detailed in Table 1. The search strategy was executed in accordance with the PRISMA 2020 flow diagram (Figure 1), ensuring a comprehensive and systematic review of available literature. The corresponding PRISMA 2020 checklist is provided in Supplementary File 1. The database search was conducted using combinations of Medical Subject Headings (MeSH) and free-text terms. An example search strategy used in PubMed was as follows: (corneal transplantation OR keratoplasty) AND (high-risk OR graft failure) AND (glaucoma OR keratoconus) AND (graft survival OR transplant outcome). Similar search strategies were adapted for Embase, Web of Science, and Cochrane databases according to database-specific indexing terms. All retrieved records were exported into reference management software. Duplicate records were identified and removed automatically and subsequently verified through manual inspection to ensure accuracy, with 405 duplicate records removed in total. The study selection process followed the PRISMA 2020 reporting guidelines. A PRISMA flow diagram was generated to document the identification, screening, eligibility assessment, and final inclusion of studies (Supplementary File 1).

Inclusion and exclusion criteria
This meta-analysis was conducted based on predefined inclusion and exclusion criteria to ensure the reliability and relevance of the studies included. Studies were included if they met the following criteria: (1) Population: Patients undergoing high-risk corneal transplantation due to glaucoma or keratoconus (especially in cases with severe corneal scarring, previous failed transplants, concurrent eye diseases, and advanced stages), regardless of age or geographic location. (2) Outcome measures: Studies reporting on graft survival, postoperative visual acuity, and complications related to high-risk corneal transplantation. (3) Study design: Observational studies (e.g., cohort, case-control, or cross-sectional studies) that reported on the clinical outcomes and risk factors for high-risk corneal transplantation. (4) Language: Articles published in English. (5) Accessibility: Studies with full-text availability. This criterion was applied to ensure complete data extraction and quality assessment. Because definitions of high-risk corneal transplantation varied slightly across studies, eligibility was determined based on whether the study population included patients with recognized high-risk features such as glaucoma, keratoconus, or prior graft failure. This approach allowed inclusion of studies with comparable clinical contexts while acknowledging potential variability in study-level definitions.

Studies were excluded if they met any of the following criteria: (1) Language: Articles published in languages other than English (e.g., Chinese, French, or German). (2) Animal Studies: Studies conducted exclusively on animal models. (3) Comorbidities: Studies that included patients with significant comorbidities such as cancer treated with chemotherapy or radiotherapy, or patients with renal failure or spinal cord injuries. (4) Interventions: Studies involving patients who underwent combined interventions with other surgical procedures that might confound the results (e.g., combined glaucoma surgeries or corneal transplantations for other pathologies). (5) Population data: Studies that did not report data separately for glaucoma or keratoconus patients or included patients with other corneal conditions without stratification. (6) Study quality: Abstract-only publications, conference proceedings, case reports, reviews, and editorials were excluded to ensure high-quality evidence.

Titles and abstracts of all retrieved records were screened independently by two reviewers according to the predefined inclusion and exclusion criteria. Among the 432 records initially identified, 23 studies were considered potentially eligible after title and abstract screening and were subsequently evaluated through full-text review. Following full-text assessment, 11 studies met the inclusion criteria and were included in the final meta-analysis. Disagreements during the screening process were resolved through discussion or consultation with a third reviewer.

Data extraction
Data extraction was performed independently by two reviewers using a standardized data collection form. The following information was extracted from each study: (1) Study characteristics (first author, publication year, country); (2) Study design; (3) Participant characteristics (age, gender distribution); (4) Clinical variables (presence of glaucoma, keratoconus, diabetes, and intraocular pressure); (5) Outcome measures (graft survival, postoperative visual acuity, complications). In cases of discrepancies or conflicting results, a third investigator conducted a blinded review to resolve these issues. A final consensus on all extracted data was reached through detailed discussion and agreement among the three investigators, ensuring the accuracy and consistency of the dataset. The extracted information included key study characteristics such as the first author and year of publication, study design, and country or ethnicity of participants. Participant demographics, including age, smoking status, drinking habits, gender distribution, and the presence of comorbidities such as diabetes and dry eye syndrome, were also extracted. Data on sample size, the number of successful transplants, and preoperative IOP (mmHg) for both the case and control groups were recorded. Additionally, the Newcastle-Ottawa Scale (NOS) score for quality assessment was extracted for each study¹⁷. These variables formed a comprehensive dataset to evaluate the efficacy and factors influencing the success of high-risk corneal transplantation for glaucoma and keratoconus.

Statistical analysis
Statistical analyses were conducted using STATA version 18.0. Both categorical and continuous variables were included in the analysis. For categorical data, the effect size was represented by odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Meta-analysis was performed using the STATA command metan to calculate pooled effect estimates and generate forest plots. To assess heterogeneity across studies, Cochran's Q test and the I² statistic were used. A value of I² > 50% indicated substantial heterogeneity¹⁷. In cases of low heterogeneity (I² ≤ 50%, p > 0.10), a fixed-effects model was applied for the meta-analysis. In contrast, when significant heterogeneity was observed (I² > 50%, p ≤ 0.10), a random-effects model was employed to accommodate variations across studies. Subgroup analyses were performed to evaluate the influence of predefined clinical variables, including age, gender, diabetes status, and preoperative intraocular pressure, on transplantation outcomes. Studies were stratified according to these variables, and pooled effect sizes were calculated within each subgroup. The subgroup thresholds (e.g., age <60 years, age <30 years, and intraocular pressure ≤25 mmHg) were derived from the categorization reported in the included studies rather than prespecified analytical cutoffs. Publication bias was assessed using funnel plots, and statistical tests such as Egger’s test or Begg’s test were used to quantify the bias. Funnel plots were generated using the STATA command metafunnel, and Egger’s and Begg’s tests were performed using the metabias command, with p < 0.05 indicating significant publication bias. Sensitivity analyses were performed to evaluate the stability of the results by systematically excluding each study and reassessing the pooled estimates. Sensitivity analysis was conducted using the STATA command metainf, which sequentially omits each study and recalculates the pooled effect estimate. Because the primary objective of this meta-analysis was to evaluate the impact of clinical risk factors (e.g., glaucoma, keratoconus, diabetes, and intraocular pressure) rather than compare surgical techniques, studies employing different corneal transplantation procedures (including penetrating keratoplasty, DSAEK, and DMEK) were pooled. These procedures share common biological mechanisms of graft survival and rejection, allowing meaningful synthesis of risk-related outcomes across techniques. All statistical tests were two-sided, with a p-value of less than 0.05 considered statistically significant.

Results

Baseline characteristics of patients
In this meta-analysis, the initial search identified 432 articles. After screening titles and abstracts, 23 articles were found to meet the inclusion criteria. Upon a detailed review of the full texts, 12 articles were excluded, including 4 due to unavailable data and 8 due to unrelated intervention methods. Ultimately, 11 eligible articles, encompassing a total of 10,558 cases of corneal transplantation, were included in the meta-analysis. These comprised 4,012 c...

Discussion

Corneal transplantation is a critical procedure for restoring vision in patients suffering from various corneal diseases²⁹. Corneal transplantation provides an important opportunity to improve the quality of life of patients with advanced corneal diseases. In recent decades, advances in surgical techniques, including Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK), have substantially improved graft outcomes²⁰

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Cochrane Library	Cochrane Collaboration	N/A	Systematic review database
Embase	Elsevier	N/A	Biomedical literature retrieval
EndNote	Clarivate Analytics	v20	Reference management
Microsoft Excel 2021	Microsoft Corporation, Redmond, WA, USA	v2021	Data tabulation and visualization
Newcastle–Ottawa Scale (NOS)	Ottawa Hospital Research Institute	N/A	Study quality evaluation
PRISMA 2020	EQUATOR Network	DOI:10.1136/bmj.n71	Reporting guideline compliance
PubMed	National Library of Medicine (NLM)	N/A	Literature retrieval
STATA (v18.0)	StataCorp LLC, College Station, TX, USA	v18.0	Statistical analysis (meta-analysis, heterogeneity, funnel plots)
Web of Science	Clarivate Analytics	N/A	Citation and reference tracking