The impact of corneal allograft rejection on the long-term outcome of corneal transplantation

© 2005. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/To examine the influence of corneal allograft rejection on the survival of penetrating corneal transplantation, to review the status of conventional therapies to improve graft survival, and to consider prospects for alternative approaches to reduce the impact of rejection. Perspective, including prospective, observational cohort study. An examination of the literature on human corneal graft rejection and data from the Australian Corneal Graft Registry, reviewed in the context of clinical experience. Corneal graft outcome is not improving with era. The sequelae of inflammation, whether occurring before corneal transplantation or subsequently, exert a profound influence by predisposing the graft to rejection. Of the developments that have been instrumental in reducing rejection in vascularized organ transplantation, living-related donation is not an option for corneal transplantation. However, HLA matching may be beneficial and requires reassessment. The evidence base to support the use of systemic immunosuppressive agents in corneal transplantation is thin, and topical glucocorticosteroids remain the drugs of choice to prevent or reverse rejection episodes. Experimental approaches to local allospecific immunosuppression, including the use of antibody-based reagents and gene therapy, are being developed but may be difficult to translate from the laboratory bench to the clinic. Corneal allograft rejection remains a major cause of graft failure. High-level evidence to vindicate the use of a particular approach or treatment to prevent or treat corneal graft rejection is lacking. In the absence of extensive data from randomized, controlled clinical trials, corneal graft registers and extrapolation from experimental models provide some clinically useful information

Rejection and acceptance of corneal allografts

Author version (post-print) made available in accordance with publisher policy.PURPOSE OF REVIEW: Corneal transplantation is successful in the short-term, but the long-term prognosis has not improved over the past 20 years. Here, we review recent findings that may contribute to improved corneal allograft survival. RECENT FINDINGS: A better understanding of the molecular pathways affecting corneal graft survival has led to more targeted approaches to immune modulation. Costimulatory molecule blockade, inhibition of chemokine-chemokine receptor interactions, modulation of apoptotic pathways, and reduction of corneal neovascularization and lymphangiogenesis have been shown to prolong corneal graft survival in animal models. Conventional immunosuppressive drugs have been tested in new combinations and formulations with some success. Two randomized prospective clinical trials in clinical penetrating corneal transplantation have been reported, but there remains little evidence on the long-term outcomes of the newer lamellar corneal graft procedures. SUMMARY: New approaches to reducing the impact of rejection on corneal graft survival have focussed on topical rather than systemic therapies, and on component corneal transplantation. The most successful experimental strategies have been those in which more than one pathway has been targeted; it now seems likely that to improve clinical allograft survival, simultaneous modulation of multiple axes of the rejection process will be necessary

Corneal transplantation for keratoconus: a registry study.

To determine factors influencing long-term graft survival and visual acuity in 4834 eyes of 4060 patients receiving their first penetrating corneal graft for keratoconus, a large cohort study was performed from a national register of corneal grafts in which data were recorded prospectively and analyzed retrospectively. Main outcome measures were graft survival and Snellen visual acuity. Follow-up extended up to 23 years. Results: Kaplan-Meier survival rates of first grafts for keratoconus were 89%, 49%, and 17% at 10, 20, and 23 years, respectively. After 15 years, the graft survival rate was no better than that of all other penetrating grafts (P = .36). Multivariate risk factors influencing failure of first grafts for keratoconus included time to suture removal, postgraft uveitis or microbial keratitis, corneal vascularization prior to or after graft, geographic location of surgery and follow-up (center effect), recipient age at graft, occurrence of rejection episodes, graft size, and surgeon workload. The timing of bilateral grafts made no difference to the risk of rejection. A Snellen visual acuity of 20/40 or better at the most recent follow-up was recorded in 74% of grafts. Conclusions: Penetrating grafts performed for keratoconus exhibited better visual outcome and graft survival than grafts performed for other indications. However, the Kaplan-Meier survival rate of first penetrating grafts for keratoconus was 17% at 23 years after graft and had not plateaued at this time, indicating that young patients are likely to need 1 or more repeated grafts during their lifetime

Repeat penetrating corneal transplantation in patients with keratoconus

To determine factors influencing penetrating corneal graft survival in patients receiving repeat grafts in the same eye after a failed first graft for keratoconus, a large cohort study was conducted from a national register of corneal grafts, in which data were recorded prospectively and analyzed retrospectively. Follow-up extended to 23 years. Participants Follow-up was available for 229 regrafts performed in 177 eyes of 173 patients. Regrafts were performed more than once in 16 eyes. Methods Corneal graft survival was analyzed using Kaplan–Meier survival plots and Cox proportional hazards regression, clustered by patient. Main Outcome Measures Graft survival. Results Graft survival was significantly worse (P<0.001) for second (n = 176) and third or greater grafts (n = 20), compared with first grafts for keratoconus (n = 4871). Kaplan–Meier survivals at 1, 5, and 15 years postgrafting were 88%, 69%, and 46% for second grafts, and 65%, 49%, and 33% for third and subsequent grafts, respectively (P<0.001). Risk factors associated with graft failure of repeat grafts in multivariate analysis were the geographic location of surgery (“center”; P = 0.04), failure of the previous graft within 10 years of surgery (P = 0.02), recipient age at graft ≥60 years (P = 0.04), occurrence of rejection episodes (P = 0.007), and corneal neovascularization postoperatively (P = 0.007). Repeat corneal grafts in eyes originally grafted for keratoconus showed better survival when the previous graft had survived ≥10 years, surgery was performed at a favorable location, the recipient was <60 years old at grafting, and graft rejection and neovascularization were circumvented.Funded by the Australian Organ and Tissue Donation Authority, Canberra, Australia. KAW was supported by a fellowship from the Australian National Health & Medical Research Council. The funding organizations had no role in the design or conduct of this research

Deep anterior lamellar keratoplasty versus penetrating keratoplasty for treating keratoconus

Published version made available following 12 month embargo from date of publication (22 July 2014) in accordance with publisher copyright policy.BACKGROUND: Keratoconus is an ectatic (weakening) disease of the cornea, which is the clear surface at the front of the eye. Approximately 10% to 15% of patients diagnosed with keratoconus require corneal transplantation. This may be full-thickness (penetrating) or partial-thickness (lamellar). OBJECTIVES: To compare visual outcomes after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty for keratoconus, and to compare additional outcomes relating to factors which may contribute to poor visual outcomes (e.g. astigmatism, graft rejection and failure). SEARCH METHODS: We searched a number of electronic databases including CENTRAL, PubMed and EMBASE without using any date or language restrictions. We last searched the electronic databases on 31 October 2013. We also handsearched the proceedings of several international ophthalmic conferences. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing the outcomes of DALK and penetrating keratoplasty in the treatment of keratoconus. DATA COLLECTION AND ANALYSIS: Two authors assessed trial quality and extracted data independently. For dichotomous data (graft failure, rejection, achievement of functional vision) results were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). For continuous data (postoperative best corrected visual acuity (BCVA), uncorrected visual acuity (UCVA), keratometric astigmatism and spherical equivalent) results were expressed as mean differences (MDs) and 95% CIs. MAIN RESULTS: We identified two completed studies, with a total of 111 participants (n = 30 and n = 81), both conducted in Iran, that met our inclusion criteria. Participants had moderate to severe keratoconus pre-operatively and were randomly allocated to receive either DALK or penetrating keratoplasty. Only one eye of each participant was treated as part of the trials. The smaller study had 12 month follow-up data for all participants. For the larger study, four DALK surgeries had to be abandoned due to technical failure and visual and refractive outcomes were not measured in these participants. Follow-up length for the remaining 77 participants ranged from 6.8 to 36.4 months, with all 77 followed for at least three months post-suture removal. Details of the randomisation procedure were unavailable for the smaller study and so sensitivity analyses were conducted to determine if the results from this study had affected the overall results of the review.Neither of the included studies reported a difference between groups on any of the measures of post-graft visual achievement, keratometric astigmatism or spherical equivalent. A single case of graft failure in a penetrating keratoplasty was reported. No postoperative graft failures were reported in the DALK group of either study.Instances of graft rejection were reported in both groups, in both studies. The majority of these cases were successfully treated with steroids. The data, which related to all cases in each study - given that the four cases that did not go ahead as planned had already technically failed without presence of rejection - showed that rejection was less likely to occur in DALK (odds ratio (OR): 0.33, 95% confidence interval (CI) 0.14 to 0.81, GRADE rating: moderate).Results of the sensitivity analysis indicated that inclusion of the Razmju 2011 study did not bias the results with regards to rejection episodes. While sensitivity analysis showed altered results with regards to failure rates, the data available from the Javadi 2010 study alone had a very wide 95% CI, suggesting an imprecise estimate. Therefore, even after removal of the Razmju 2011 data, it is still difficult to draw conclusions regarding superiority of one technique over another with regards to graft failure.DALK was unable to be completed as planned in four cases and in a further three cases, complications during dissection required further intervention. Other adverse events, of varying severity, were reported in both intervention groups with similar frequency. For both types of surgery, these included postoperative astigmatism, steroid induced ocular hypertension and persistent epithelial defects. In recipients of DALK, one participant had interface neovascularisation (a proliferation of blood vessels where the host and donor cornea come together) and one had wrinkling of Descemet's membrane, the basement membrane separating the corneal stroma from the corneal endothelium. In the penetrating keratoplasty groups, one participant required graft resuturing and one had an atonic pupil, a condition in which the pupil dilates and is non-reactive.Overall, the quality of the evidence was rated as very low to moderate, with methodological limitations, incomplete data analysis and imprecision of findings, as well as high risk of bias in several areas for both studies. AUTHORS' CONCLUSIONS: We found no evidence to support a difference in outcomes with regards to BCVA at three months post-graft or at any of the other time points analysed (GRADE rating: very low). We also found no evidence of a difference in outcomes with regards to graft survival, final UCVA or keratometric outcomes. We found some evidence that rejection is more likely to occur following penetrating keratoplasty than DALK (GRADE rating: moderate). The small number of studies included in the review and methodological issues relating to the two, mean that the overall quality of the evidence in this review is low. There is currently insufficient evidence to determine which technique may offer better overall outcomes - final visual acuity and time to attain this, keratometric stabilisation, risk of rejection or failure, or both, and risk of other adverse events - for patients with keratoconus. Large randomised trials comparing the outcomes of penetrating keratoplasty and DALK in the treatment of keratoconus are needed

Comparative outcomes of penetrating and component endothelial cell corneal allografts in outbred sheep

Lamellar (component-cell) corneal transplantation is replacing penetrating keratoplasty for some corneal disorders in humans; but the relative risks of immunological graft rejection for the two procedures are uncertain. A model of component endothelial cell keratoplasty (endokeratoplasty) was developed in the outbred sheep. Clinical and histological graft outcomes after endokeratoplasty were then compared with contemporaneous penetrating corneal allografts. No topical or systemic immunosuppression was administered to any recipient sheep. Endothelial cell allografts (n = 10) took significantly longer to achieve perfect transparency following surgery than did penetrating corneal grafts (n = 7) (day 10 versus day 4; p = 0.003; two-tailed Mann- Whitney U-test). The median day to rejection of penetrating grafts was post-operative day 18; and of endothelial cell grafts was day 48 (p = 0.04; two-tailed Mann-Whitney U-test). The clinical courses of the two procedures were quite different. Penetrating grafts gained clarity quickly but exhibited rapid graft neovascularization. Clinical rejection was preceded by inflammation in the anterior segment. Endothelial cell grafts exhibited a fluctuating; more indolent course of opacification; although all did eventually fail. Histological analysis confirmed immunological rejection in all failed grafts; but with different patterns of leukocytic infiltration in endokeratoplasties compared with penetrating keratoplasties. Inflammatory cells in endothelial cell grafts were generally fewer in number and were more often found in the posterior stroma. We conclude that in the absence of immunosuppression; all endothelial cell allografts do undergo immunological rejection; albeit at a slower tempo than penetrating grafts.This work was funded by the Ophthalmic Research Institute of Australia. KAW is supported by the Australian National Health & Medical Research Council (NHMRC)

The outcome of corneal transplantation in infants, children, and adolescents

© 2011. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/OBJECTIVE: To examine factors affecting penetrating corneal graft survival and visual outcomes in patients aged less than 20 years. DESIGN: Large prospective, cohort study. PARTICIPANTS: Records of 14 865 followed penetrating corneal grafts in 11 929 patients were searched to identify 765 grafts in 640 patients aged younger than 20 years of age at the time of graft. METHODS: Records submitted to the Australian Corneal Graft Registry by 381 ophthalmic surgeons and 253 follow-up practitioners from May 1985 to June 2009 were analyzed using Kaplan-Meier survival plots and Cox proportional hazards regression analysis. MAIN OUTCOMES MEASURES: Probability of corneal graft survival and Snellen acuity at the time of most recent follow-up and at defined intervals post-graft. RESULTS: Infants (<5 years) exhibited poorer graft survival than children aged 5 to 12 years. Adolescents (13-19 years) exhibited better corneal graft survival than other age groups; 86% of grafts in adolescents were for keratoconus. Factors significantly affecting corneal graft survival in pediatric patients included indication for graft, graft inflammation, history of intraocular surgery, vascularization, rejection episodes, post-graft operative procedures, and refractive surgery. Fourteen percent of pediatric grafts failed, of which 65% failed within 2 years post-graft. Forty-four percent of failures were due to unknown causes (18) or irreversible rejection (30). CONCLUSIONS: Corneal grafts for keratoconus in adolescents show excellent survival. Infants exhibit poor graft survival and visual outcomes, especially those undergoing transplantation for Peters' anomaly. Corneal graft survival and visual outcomes vary more by indication for graft than recipient age. The major reason for graft failure is irreversible rejection. Corneal transplantation improves overall bilateral vision in pediatric patients

The Influence of Rejection Episodes in Recipients of Bilateral Corneal Grafts

Author version made available in accordance with Publisher copyright policy.We investigated whether a rejection episode in one graft was associated with rejection in the other graft, in recipients with bilateral corneal transplants. In a prospectively maintained, national register of 14 865 followed corneal grafts, 1476 patients with bilateral penetrating corneal grafts were identified. Occurrence of rejection was a risk factor for graft failure (p < 0.0001). Logistic regression was used to calculate the adjusted odds ratio for rejection in one eye following rejection in the other eye. In the subset of 1118 patients with bilateral grafts but no history of previous grafts or rejections in either eye, the adjusted odds ratio for a rejection episode in the first eye following rejection in the second was 3.27 (95% confidence interval, CI 1.85, 5.79; p < 0.001). The adjusted odds ratio was 2.04 (95% CI 1.07, 3.91; p = 0.03) for rejection in the second eye following rejection in the first. The median time between the first rejection episode in one eye and the first rejection episode in the other eye was 15 months. Patients with bilateral corneal grafts who suffer a graft rejection episode in one eye are at significantly greater odds of suffering a rejection episode in the other corneal transplant