Douglas John Coster

Factors Predictive of Corneal Graft Survival: Report from the Australian Corneal Graft Registry

Risk factors for graft failure after penetrating keratoplasty were investigated in 961 patients from records collected prospectively by the Australian Corneal Graft Registry. The most common cause of graft failure was irreversible rejection. A multivariate proportional hazards regression analysis indicated that the key predictors of graft failure were: an indication for graft other than keratoconus or corneal dystrophy; a failed previous graft (ipsilateral eye); aphakia; inflammation at the time of graft; presence of an anterior chamber or iris-clip intraocular lens; graft size outside the range of 7.0 to 7.9 mm diameter; and corneal vascularization occurring in the postoperative period.

How successful is corneal transplantation? A report from the Australian Corneal Graft Register.

Corneal graft outcome was assessed within a large, prospectively collected database of 4499 records. Penetrating corneal graft survival was 91% at 1 year, 72% at 5 years and 69% at 7 years. The three most common indications for graft were keratoconus (30%), bullous keratopathy (25%) and failed previous graft (18%); the three most common causes of graft failure were rejection (34%), infection (18%) and glaucoma (9%). The vast majority of grafts were performed for improved visual acuity. About four-fifths of recipients achieved at least one line of better acuity on the Snellen chart post-operatively; of the remainder with unchanged or worse acuity, only 21% had failed grafts. Overall, 43% of recipients achieved a best corrected Snellen acuity of 6/12 or better, 52% achieved 6/18 or better, and 20% had acuitities of less than 6/60. Reasons for poor post-operative acuity (recorded as less than 6/60) included graft failure (41%) and co-morbidities in the grafted eye (43%). A number of risk factors for graft failure were examined: in most instances, there was little room for decision-making or expert intervention.

Penetrating keratoplasty for keratoconus: visual outcome and success.

OBJECTIVE To determine the long-term effect on vision of penetrating keratoplasty performed for keratoconus. DESIGN Retrospective noncomparative case series. PARTICIPANTS All patients with keratoconus who received a corneal graft and who remained in our center for follow-up and visual rehabilitation during the study period. INTERVENTION Penetrating keratoplasty was performed in 93 eyes of 78 patients. MAIN OUTCOME MEASURES Graft survival, visual acuity, and astigmatism. RESULTS One (1.08%) graft failure was encountered over a mean follow-up of 46 months. Mean preoperative (best corrected) and postoperative visual acuity is (best-tolerated correction) were 0.9 (20/160) and 0.24 (20/80) logMAR, respectively. Visual acuity in 86% of eyes was 0.3 logMAR (20/40) or better at the latest follow-up, with 67% of eyes being corrected with spectacles. Mean preoperative corneal power by keratometry was more than 52 diopters (D) in 83% of eyes; mean postoperative corneal power was 45 +/- 2 D. No significant predictors of postgraft astigmatism were found. Mean preoperative and postoperative best-eye acuities of the better eye were 0.32 (20/40-1) and 0.18 (20/32+1) logMAR, respectively (P < 0.001). CONCLUSIONS Graft survival was excellent. A corrected visual acuity of 20/40 or better was obtained in 86% of eyes. Astigmatism could not be predicted from preoperative factors. Visual acuity measured in the better eye improved by 0.14 logMAR (1.4 lines), implying an overall functional gain for the patient.

How effective is penetrating corneal transplantation? Factors influencing long-term outcome in multivariate analysis

Background. In a large patient cohort, we investigated long-term corneal graft outcome, risk factors for graft failure, and whether corneal graft survival had improved over time. Methods. Records of 10,952 full-thickness corneal grafts with associated archival follow-up were examined within a prospectively-maintained, national database of 13,831 records, with follow-up extending for up to 18 years. Kaplan-Meier survival analysis was used to indicate variables of interest for Cox proportional hazards regression analysis. A model clustered by individual patient to control for inter-eye or inter-graft dependence was constructed to identify variables best predicting penetrating corneal graft failure. Results. Probability of corneal graft survival was 0.86 at 1 year, 0.73 at 5 years, 0.62 at 10 years, and 0.55 at 15 years. Graft survival did not improve over a 15-year timeframe. Variables predicting graft failure in multivariate analysis included transplant centre, donor age, preoperative diagnosis, number of previous ipsilateral grafts, lens status, history of corneal neovascularisation, ocular inflammation or raised intraocular pressure in the grafted eye, requirement for anterior vitrectomy, graft size, early suture removal, postoperative events including graft neovascularisation, rise in intraocular pressure, and rejection episodes, type of treatment for raised intraocular pressure, and arrangements for recipient follow-up. A further 11 variables showing a significant influence on graft survival in univariate analysis were not included in the final Cox model. Conclusion. The long-term results of corneal transplantation are no better than for other forms of transplantation and have shown no measurable improvement over the past 15 years.

Prolongation of sheep corneal allograft survival by ex vivo transfer of the gene encoding interleukin-10.

Background. Modification of a donor cornea by gene therapy ex vivo has potential to modulate irreversible rejection, the major cause of corneal graft failure. Our aim was to transfer the gene encoding mammalian IL-10 to ovine donor corneas and to determine subsequent orthotopic corneal allograft survival in an outbred sheep model. Methods. The replicative capacity of ovine corneal endothelium was determined by autoradiography after deliberate injury. A replication-defective adenovirus was used to deliver the lacZ reporter gene to ovine corneas and transfected corneas were organ-cultured in vitro to allow transfection efficiency, duration of reporter gene expression, and toxicity attributable to the vector to be determined. A cDNA encoding full-length ovine IL-10 was cloned into an adenoviral vector that was used to transfect donor corneas ex vivo before transplantation. Orthotopic penetrating corneal transplantation was performed in outbred sheep. Results. Sheep corneal endothelium was found to be essentially amitotic. Transfection of >70% corneal endothelial cells was achieved with the viral vector and expression was maintained for 28 days in vitro. IL-10 mRNA was detectable in transfected, organ-cultured corneas for 21 days in vitro. Donor corneas transfected with cDNA encoding IL-10 showed significantly prolonged survival after penetrating keratoplasty (median 55 days, range 19 ⩾300 days) compared with control corneas (median 20.5 days, range 18–32 days, P =0.011). Conclusion. Local gene therapy-mediated expression of the immunomodulatory cytokine IL-10 has the potential to reduce the incidence of corneal graft rejection and to prolong corneal allograft survival.

Risk factors for human corneal graft failure within the Australian corneal graft registry.

Background. Our aims were to examine graft survival and visual outcome after full-thickness corneal transplantation. Methods. Records of 18,686 penetrating corneal grafts, 14,622 with archival follow-up from 1 to 22 years, were examined within a national database. Kaplan-Meier survival analysis indicated variables of interest for Cox proportional hazards regression analysis. A model clustered by patient to control intereye or intergraft dependence was constructed to identify variables best predicting penetrating corneal graft failure. Visual acuity in the grafted eye was measured by Snellen acuity. Results. Probability of corneal graft survival was 0.87, 0.73, 0.60, and 0.46 at 1, 5, 10, and 15 years, respectively. Reasons for graft failure included irreversible rejection (34%), corneal endothelial cell failure including cases of glaucoma (24%), and infection (14%). Variables predicting graft failure in multivariate analysis included transplant center, location and volume of surgeon’s case-load, graft era, indication for graft, number of previous ipsilateral grafts, lens status, corneal neovascularization at transplantation, a history of ocular inflammation or raised intraocular pressure, graft diameter, and postoperative events including graft neovascularization and rejection. Best-corrected Snellen acuity of 6/12 or better was achieved by 45%, and of less than 6/60 by 26%, of grafted eyes at last follow-up. Conclusions. The short-term survival of penetrating corneal transplants is excellent, but the eventual attrition rate appears inexorable and many factors that influence graft survival significantly are not amenable to change. Most penetrating grafts are performed for visual improvement, and excellent acuity will be achieved by approximately half of all grafts.

Long-term Outcome after Corneal Transplantation: Visual Result and Patient Perception of Success

Snellen acuity, reading line, and keratometry were measured in a cohort of 60 patients at 2 or more years after penetrating keratoplasty was performed. Patients were asked to complete a questionnaire to elicit information on their perceptions of visual function and the success of the procedure. Using preferred correction, a Snellen acuity of 6/18 or better was achieved by 65%, and a reading line of N8 or better was achieved by 57% of index grafts. Thirty-eight percent had more than 5 diopters (D) of astigmatism in the graft. Approximately 75% of patients reported satisfaction with their graft (satisfaction being associated with better acuity in the grafted eye than the other eye), graft clarity, and a perceived improvement in lifestyle. Dissatisfaction appeared to be associated with graft failure and problems with contact lens wear. The findings have implications for patient selection for corneal transplantation and for the measurement of outcome.

Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus

PURPOSE Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease. METHODS Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype. RESULTS The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10(-7)) and rs17501108 (P = 9.9 × 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036). CONCLUSIONS Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.

The immunobiology of corneal transplantation.

Corneal allotransplantation is highly successful in the short term, but much less successful in the longer term. Many corneal grafts in recipients with corneal neovascularization or the sequelae of ocular inflammation undergo irreversible rejection, despite topical immunosuppression with glucocorticosteroids. Sensitization to cornea-derived alloantigen proceeds by both direct and indirect routes, but the anatomic location of sensitization remains unclear. Multiple and redundant mechanisms operate in the effector phase of corneal graft rejection, which is largely cell-mediated rather than antibody-mediated. Human leukocyte antigen matching may improve outcomes in high-risk patients but systemic immunosuppression is frequently ineffective and is seldom used.

The long term outcome of limbal allografts: the search for surviving cells

BACKGROUND/AIMS Limbal allotransplantation is increasingly being used for ocular surface repair in patients with limbal stem cell dysfunction. However, it is uncertain whether donor cells survive long term on the ocular surface and whether patients maintain the early benefits of the procedure. The aims of this study were to investigate the long term outcome of clinical limbal allografts and to correlate outcome with donor cell survival. METHODS Five patients who had undergone allotransplantation—four keratolimbal allografts and one tarsoconjunctival allograft—from 3–5 years previously, and for whom residual frozen donor ocular tissue was available, were reviewed. Survival of donor cells lifted from the recipient ocular surface by impression cytology was investigated by DNA fingerprinting using primers detecting variable nucleotide tandem repeat sequences. Recipient buccal cells and scleral samples from the remnant donor eye were used to genotype recipients and donors, respectively. Polymerase chain reaction products were sized by Genescan analysis. RESULTS An objective long term benefit from the procedure (improved Snellen acuity, reduced frequency of epithelial defects, reduced vascularisation, and scarring) was recorded for four patients. Some subjective benefit was also reported. However, in no instances were donor cells recovered from the ocular surface at 3–5 years post-graft. Initial experiments to examine sensitivity indicated that any surviving donor cells must have constituted less than 2.5% of cells sampled. CONCLUSION Limbal stem cell allotransplantation can provide long term benefits, as measured by objective criteria. However, such benefits do not necessarily correlate with survival of measurable numbers of donor cells on the ocular surface.