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Clinical science
The impact of donor age and endothelial cell density on graft survival following penetrating keratoplasty
  1. M J Wakefield1,
  2. W J Armitage2,3,
  3. M N A Jones4,
  4. S B Kaye5,
  5. D F P Larkin6,
  6. D Tole4,7,
  7. J Prydal1
  8. on behalf of the National Health Service Blood and Transplant Ocular Tissue Advisory Group (OTAG Audit Study 19)
  1. 1Department of Ophthalmology, Leicester Royal Infirmary, Leicester, UK
  2. 2National Health Service Blood and Transplant, Bristol Eye Bank, Bristol, UK
  3. 3School of Clinical Sciences, University of Bristol, Bristol, UK
  4. 4National Health Service Blood and Transplant, Bristol, UK
  5. 5St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, UK
  6. 6Moorfields Eye Hospital, London, UK
  7. 7Bristol Eye Hospital, Bristol, UK
  1. Correspondence to Dr Matthew J Wakefield, Leicester Royal Infirmary, Infirmary Square, Leicester LE1 5WW, UK; Matthew.wakefield{at}uhl-tr.nhs.uk

Abstract

Purpose To determine if donor age and preoperative endothelial cell density (ECD) affect corneal endothelial failure following penetrating keratoplasty (PK).

Methods Preoperative and postoperative data for PKs performed in the UK between April 1999 and March 2012 were analysed. Donor age was split into three groups (0–60, 61–75 and >75 years) and donor ECD was split into three groups (≤2400, 2401–2600 and >2600 cells/mm2). Cox proportional hazards regression was used to determine whether the selected subgroups of donor age and donor ECD have an impact on endothelial failure and a systematic analysis of the interaction between donor ECD and donor age was conducted. The analysis was stratified for primary corneal diagnosis (Fuchs endothelial dystrophy (FED), pseudophakic bullous keratopathy (PBK) and other) and corrected for potentially confounding factors (human leukocyte antigen matching, donor trephine diameter, deep vascularisation, the occurrence of reversible rejection episodes and receipt of systemic antiviral medication, long-term steroids or other immunosuppressive agents).

Results A total of 9415 patients, from the National Health Service Blood and Transplant UK Transplant Registry, who received their first PK for visual reasons were included in this study. The overall 5-year graft survival rate due to endothelial failure was 89%. Survival rates in recipients with FED, PBK and ‘all other indications’ were 95%, 83% and 89%, respectively. Our analysis shows that donor ECD did not affect outcome following corneal graft within the preselected categories, irrespective of diagnosis and after allowing for any potential confounding factors. Furthermore, HRs for each level of donor ECD, relative to >2600 cells/mm2, for each combination of age group and indication, were not statistically significant.

Conclusions We were unable to detect a significant effect of donor age, up to 90 years, and preoperative donor ECD, above the lower limit of 2200 cells/mm2, on endothelial failure at 5 years following PK.

  • Cornea
  • Eye (Tissue) Banking
  • Treatment Surgery
  • Epidemiology

https://doi.org/10.1136/bjophthalmol-2015-306871

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    Introduction

    The duration of graft survival is a key outcome indicator after penetrating keratoplasty (PK). The loss of corneal clarity due to endothelial cell loss, and subsequent endothelial dysfunction, is an important cause of non-rejection-associated graft failure. In the Australian Corneal Graft Registry (ACGR) 2012 Report, endothelial failure accounted for 15% of all causes of graft failure, second only to rejection (31%).1 The aetiology of endothelial failure is not fully understood and is likely a complex interaction of several variables, including donor factors, tissue storage and preparation techniques, as well as surgical and host postoperative factors.

    Endothelial failure in corneal grafts is associated with endothelial cell density (ECD) in the range 250–500 cells/mm2,2–4 and, as ECD is known to decline with age,2 ,5 ,6 it would seem intuitive that donor factors of age and ECD should be important determinants of graft survival. Data from the UK have previously demonstrated that the ECD in donor corneas decreases with donor age.7 Endothelial cell loss is also greatly exacerbated following transplantation8 and this increased rate of cell loss continues for several years after surgery.9 Thus, it was suggested that a low donor ECD is a risk factor for long-term endothelial failure.9 However, publications from the ACGR1 ,10 and the Cornea Donor Study (CDS),11 ,12 plus its ancillary Specular Microscopy Ancillary Study (SMAS),13 have not demonstrated an association between donor age or preoperative ECD and graft survival.

    In the UK, there is no upper limit to donor age and a lower limit of 2200 cells/mm2 for PK is applied as a cut-off point below which a donor cornea will not be issued by eye banks for PK. The purpose of this study was to use collected data to analyse the impact of donor age and preoperative ECD, as independent variables, on graft survival due to endothelial failure.

    Materials and methods

    The National Health Service Blood and Transplant (NHSBT) service collects follow-up data on all corneal transplants performed in the UK at the time of surgery and postoperatively at 1, 2 and 5 years. The return of complete data is mandatory for surgeons using NHSBT ocular tissue. At the time of surgery, a transplant record form is completed, which includes information on the indication for grafting, type of graft, surgical details (including other procedures performed at the same time) and any risk factors for graft failure. Graft outcome data are collected on follow-up forms and include visual acuity, refractive outcomes, postoperative complications and any other subsequent surgical procedures. These data are stored on the UK Transplant Registry (UKTR) maintained by NHSBT. A total of 13 262 patients with graft outcome data who received their first PK for visual reasons between April 1999 and March 2012 were reported to NHSBT. Of these, 3847 patients had either keratoconus, complications at surgery, were grafted for other non-visual reasons (cosmetic, therapeutic or other), experienced postoperative endophthalmitis or received corneas from donors aged greater than 90 years and were therefore excluded from this analysis. Keratoconus was excluded from this analysis as only a very small number of these patients experience endothelial failure (1% within 5 years). In total, 9415 patients were included in this study. All of these corneas were stored in organ culture for up to 4 weeks in one of the Corneal Transplant Service Eye Banks in Bristol and Manchester.

    Donor age was initially split into four groups for analysis (0–45, 45–60, 61–75 and 76–90 years) and donor ECD was split into four groups (≤2400, 2401–2600, 2601–2800 and >2800 cells/mm2). These groupings were predetermined by the UK Ocular Tissue Advisory Group (OTAG) prior to data collection and analysis. Univariate results were then presented to OTAG in July 2011 and, because of issues with sample size, it was decided to perform a further analysis grouping data into larger groups. The first two age groups and the final two ECD groups were combined, leaving three age groups (0–60, 61–75 and 76–90 years) and three ECD groups (≤2400, 2401–2600 and >2600 cells/mm2). Indication for corneal grafting was grouped according to diagnosis; Fuchs endothelial dystrophy (FED) and pseudophakic bullous keratopathy (PBK), with all other indications were grouped together. Other dystrophies, aphakic bullous keratopathy, infection, injury and opacification are the main indications for grafting that comprise ‘all other indications’ and, apart from keratoconus, there were no other exclusions from the study based on indication.

    Cox proportional hazards regression was used to determine whether the selected subgroups of donor age and donor ECD have an impact on endothelial failure at 5 years. A systematic analysis of the interaction between donor ECD and donor age was conducted. The data were split into two data sets; one for modelling, in particular to assess the significance of the donor age group by donor ECD interaction for each indication and a second validation data set for estimating the effect of different cell densities on survival for each age group and indication. The model was stratified by indication rather than undertaking a separate analysis of each and adjusted for potentially confounding factors; human leukocyte antigen matching, donor trephine diameter, deep vascularisation, the occurrence of reversible rejection episodes and receipt of systemic antiviral medication, long-term steroids or other immunosuppressive agents. Bonferroni correction was used to allow for multiple comparisons between the combinations of donor age and donor ECD. All statistical analyses were performed with SAS V.9.1 software (SAS Institute Inc, Cary, North Carolina, USA).

    Results

    The 5-year graft survival rate due to endothelial failure for FED was 95% (95% CI 93% to 96%), for PBK was 83% (95% CI 80% to 85%) and for all other indications was 89% (95% CI 87% to 91%). The overall 5-year graft survival rate due to endothelial failure was 89% (95% CI 88% to 90%).

    Cox regression analysis showed that the three-way interaction between donor ECD, donor age and indication was not significant (p=0.91) after adjustment for the potentially confounding factors (outlined above). This means that the interaction between donor ECD and donor age did not have a significantly different pattern for each indication. We also found that a two-way interaction between donor ECD and donor age was not significant (p=0.88) and therefore concluded that the effect of donor ECD on graft survival due to endothelial failure did not depend on donor age. In further analyses, neither the interaction between indication and donor age, nor the interaction between indication and donor ECD was significant (p=0.4 and 0.6, respectively). This means that there was no evidence to suggest that the effect of donor age and donor ECD on graft survival due to endothelial failure differs between the indications for transplantation. Finally, the main effects of donor ECD and donor age were not significant (p=0.2 and 0.6, respectively), again after adjustment for the chosen confounding factors.

    HRs for each level of donor ECD, relative to >2600 cells/mm2, for each combination of age group and indication, are presented in table 1. The p values for individual HRs in the validation data set are broadly similar to those in the modelling data set. As the patterns in the two data sets are so similar, we have chosen to present the HRs for the nine combinations of donor ECD and donor age, for each indication, based on the full data set.

    View this table:
    Table 1

    HRs for each level of donor endothelial cell density, relative to >2600 cells/mm², for each combination of donor age group and indication

    This gave 18 individual HRs for comparison. We took account of these multiple comparisons using Bonferroni correction and a significance level of 0.05/18=0.003 was used to determine whether an individual HR was significantly different from unity. Using this criterion, none of these HRs were significantly different from unity, but it does appear that there are increasing hazards for FED, PBK and other indications in the 76-year to 90-year donor age group with donor ECD≤2600. Of these, the only p value to be significant at the 5% level was that of other indications and this might be expected by chance alone. A further analysis adjusting for recipient age showed that the results were similar to the original analysis and therefore it was not felt appropriate to adjust for recipient age.

    Discussion

    A record number for the UK of 3615 corneal transplants for visual rehabilitation were performed in 2012/2013. Despite adequate availability of corneal tissue for donation in the UK,14 ,15 NHSBT policy decisions on the minimum quality of tissue provided to transplant surgeons should be informed by good evidence, thus balancing the need to maximise utilisation of donated tissue while maintaining high standards for graft survival and visual outcome. However, the influence of donor age and preoperative ECD on graft survival remains controversial.

    The overall graft survival rates in this study are comparable with those of other corneal graft registries, including the ACGR,1 ,10 the US CDS,11 ,12 the Swedish Corneal Transplant Registry (SCTR),16 the Public Health Ophthalmology Service India17 and the Price Vision Group, Indiana (USA).18 The conclusion from our data analysis is that donor age and ECD do not affect outcome following corneal grafting within the given preselected categories after allowing for potentially confounding factors. Furthermore, the 18 calculated HRs for different levels of donor ECD, for each combination of age group and indication, were not different from unity (pc>0.003). It does appear that there are increasing HRs for FED, PBK and other indications in the 76-year to 90-year donor age group with donor ECD ≤2600, but further studies would be required to confirm this apparent trend.

    These findings are in agreement with the majority of early studies that considered the effect of increasing corneal donor age on outcome and reported no association with adverse outcome.19–24 The first prospective comparative study examining two cornea donor age groups, over or under 85 years, found no evidence of a difference in either graft survival or visual outcome, but follow-up was limited to a mean duration of 2 years.25 This result was encouraging as age matching for donors and recipients would otherwise underestimate the functional value of donor corneas from the older age group. The lack of association between donor age and corneal graft survival was further supported by the 1997 ACGR Report.10 Subsequently in 2012, using data for over 16 000 PKs with up to 21 years follow-up, the ACGR published the median graft survival for donor age groups 1–20, 21–40,41–60, 61–80 and >80 years of 15.35, 15.71, 13.54, 11.80 and 12.94 years, respectively.1 These rates were not significantly different; however, in a subgroup analysis, when excluding keratoconus as the indication for transplantation, a significant association for reduced graft survival with increasing age of donor was found. It should be highlighted that donor age was not a significant variable in their multivariate analysis1 and, as for previous studies, the better graft survival for younger donors is potentially confounded by the fact that these corneas may tend to be used for lower risk PK indications such as keratoconus.

    The CDS prospective cohort study of corneal grafts with two donor age groups of 12–65 and 66–75 years reported 10-year follow-up data of almost 1200 PKs. The minimum ECD for this study, which used cold-stored corneas, was 2300 cells/mm². It was concluded that donor age should not be an important factor in most transplants for endothelial disease.11 ,12 The 10-year success rate was constant for donors aged 34–71 years. However, after 6 years of follow-up, the donor age group 72–75 years began to show a modest decrease in graft survival.11 This study led to changes in US guidance to increase the maximum donor age from 65 to 75 years. Our results would support this change.

    With respect to preoperative donor ECD, the SMAS showed a greater rate of endothelial cell loss with older donor age at 10 years,13 an association supported by Böhringer et al,26 but opposed by other studies.27 ,28 Ing et al29 demonstrated a greater cell loss with younger age donors. Also, higher rates of cell loss at a younger age would mimic the physiological changes described by Møller-Pedersen4 with annual loss of only 0.3% in those older than 14 years compared with 2.9% in under 14-year-olds.

    In 1998, Ing et al29 demonstrated that 5–10 years after PK, endothelial cell loss occurs at a rate seven times higher than normal attrition. The pleomorphism, polymegethism and corneal thickness also increased significantly leading to an increasing rate of late endothelial failure due to endothelial instability and dysfunction.29 An accelerated rate for ECD loss has also been demonstrated for up to 20 years following transplantation in a study of 500 consecutive grafts.9 After the first 5 postoperative years, endothelial failure was the primary cause of graft failure. Interestingly, the late endothelial failure grafts had fewer cells immediately after transplantation, rather than losing endothelial cells at a greater rate than the surviving grafts.9 Neither the ACGR1 results at 3 years, nor SMAS30 ,31 at 5 years showed an association between preoperative ECD and graft failure; although in the SMAS the ECD at 6 months postoperatively was found to be associated with graft failure. These findings, along with lack of dependence of graft failure on donor ECD in this study, would support the suggestion that the more important determinant for graft survival is the immediate postoperative ECD rather than preoperative donor ECD.

    This study has the advantage of a large cohort, second only to the ACGR, and standardised eye banking and ECD measurement techniques across only two sites in the UK. Also, the mandatory audit of corneal graft outcomes by NHSBT ensures the completeness and quality of data reported here.

    Modelling techniques predict that a donor ECD of over 2000 cells/mm2 should provide sufficient endothelial capacity for at least 20 years,8 based on a critical ECD level of 500 cells/mm2,10 Furthermore, the median graft survival in the ACGR is 14 years1 and other studies have only begun to detect an appreciable drop in graft survival after 5 years of follow-up.17 ,32 It is therefore acknowledged that the transplant follow-up in this study may not extend long enough to comment fully on the effects of donor age and preoperative ECD on transplants in the longer term.

    In summary, we were unable to detect a significant effect of donor age, up to 90 years, and preoperative donor ECD, above the lower limit of 2200 cells/mm2, on endothelial failure at 5 years following PK. These data support the current UK NHSBT policy of no upper age limit for corneal donation if a lower limit of donor ECD is applied. Based on the current evidence, such corneas have sufficient endothelial capacity to allow acceptable rates of graft survival.

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    Footnotes

    • Contributors All listed authors have been involved in the development of the published article and have either contributed to the study design, data analysis or manuscript preparation. All listed authors have contributed to editing and approving the final version.

    • Funding This research was supported in part by the National Institute for Health Research (NIHR) Moorfields Biomedical Research Centre, London, UK.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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