Postoperative Risk Factors Influencing Corneal Graft

Survival in the Singapore Corneal Transplant Study

ARUNDHATI ANSHU, LAURENCE S. LIM, HLA MYINT HTOON, AND DONALD T. H. TAN
PURPOSE:

To determine postoperative risk factors that

influence long-term corneal graft survival.
DESIGN: Prospective cohort study.
METHODS: Nine-hundred one consecutive penetrating
keratoplasty procedures for optical, therapeutic, or tectonic indications from the Singapore Corneal Transplant
Study. Univariate and multivariate analysis was performed for postoperative risk factors; Cox proportional
hazards regression with a time-dependent covariate was
used for preoperative, intraoperative, donor, and postoperative risk factors in a combined model.
RESULTS: Raised intraocular pressure (20.7%) was the
most common complication, followed by rejection
(18.2%), whereas glaucoma surgery (7.9%) and repeat
grafting (7.3%) were the most common procedures after
penetrating keratoplasty. The primary graft failure rate
was 1.4%, and late failure was seen in 9.4% of eyes. In
the combined regression model, rejection (hazard ratio
[HR], 3.4; P .00), microbial keratitis (HR, 3.6; P
.00), endophthalmitis (HR, 7.7; P .00), primary
disease recurrence (HR, 73.9; P .00), wound dehiscence (HR, 2.8; P .02), lid surgery (HR, 2.3; P .02),
glaucoma surgery (HR, 2.46; P .02), and repeat grafting
(HR, 3.2; P .00) were the significant postoperative
failure predictors; the significant preoperative and intraoperative factors identified were female gender, graft size of
less than 7 mm and more than 9 mm, primary diagnosis,
preoperative inflammation, and preexisting perforation.
CONCLUSIONS: Postoperative complications and operative procedures after grafting have an adverse effect
on graft survival. (Am J Ophthalmol 2011;151:
442 448. 2011 by Elsevier Inc. All rights reserved.)

REOPERATIVE, INTRAOPERATIVE, AND POSTOPERA-

tive risk factors affecting corneal graft survival have

been described in numerous studies, mostly in white
populations,15 but most studies evaluating postoperative
risk factors assess risk factors individually,6 8 and there is
See Accompanying Editorial on page 397.
Accepted for publication Sep 3, 2010.
From the Singapore National Eye Centre, Singapore, Republic of
Singapore (A.A., L.S.L., D.T.H.T.); the Singapore Eye Research Institute, Singapore, Republic of Singapore (A.A., H.M.H., D.T.H.T.); and
the Department of Ophthalmology, Yong Loo Lin School of Medicine,
National University of Singapore, Singapore, Republic of Singapore
(D.T.H.T.).
Inquiries to Donald T. H. Tan, Singapore National Eye Centre, 11,
Third Hospital Avenue, Singapore 168751, Republic of Singapore;
e-mail: snecdt@pacific.net.sg

442

2011 BY

a paucity of data from multivariate analyses on the interactions between the postoperative risk factors and preoperative or intraoperative factors that may predict graft
survival.3,9
The Singapore Corneal Transplant Study is an ongoing,
prospective cohort study of all corneal transplantations
performed at a tertiary care center in Singapore, and we
recently reported on the indications, long-term survival
rates, and preoperative and intraoperative risk factors for
penetrating keratoplasty (PK) graft survival in the Singapore Corneal Transplant Study.4 The aims of this study
were to determine possible postoperative complications
and operative procedures that also may affect long-term
graft survival and to assess their interactions with other
previously reported risk factors for graft survival, so as to
enable appropriate postoperative management or preventive strategies to be implemented in transplant patients to
reduce graft failure rates.

METHODS
THE SINGAPORE CORNEAL TRANSPLANT STUDY IS AN ON-

going prospective cohort study spanning 18 years (1991

onward) and tracking more than 2750 consecutive corneal
transplantations performed at the Singapore National Eye
Centre, an ophthalmic tertiary referral center in Singapore
that performs approximately 80% of all corneal transplantations in Singapore. Details of the study population and
database composition have been described in an earlier
publication evaluating only preoperative and intraoperative risk factors.4
PK procedures performed before January 1, 2004 (total,
1130 consecutive cases) were included in the study to
ensure sufficient follow-up with regard to graft survival
analysis. To allow for accurate statistical analysis, only one
graft per patient was selected randomly, leaving a total of
901 grafts. Randomization was performed using an Excel
(Microsoft, Redmond, Washington, USA) random number generator. PK was defined as all grafting procedures
involving full-thickness replacement of corneal tissue. All
other forms of transplantation procedures were excluded
from the analysis.
Generally, all patients with missing follow-up data were
recalled for examination when possible. Cloudy graft or
graft failure was defined as irreversible loss of optical
clarity, with the date of onset of clouding selected at the

ELSEVIER INC. ALL

RIGHTS RESERVED.

0002-9394/$36.00
doi:10.1016/j.ajo.2010.09.002

time point of graft failure, with the precise clinical cause of

failure as recorded by the surgeon in the case notes.

TABLE 1. Postoperative Complications and Surgical

Procedures Performed after Penetrating Keratoplasty

POSTOPERATIVE THERAPEUTIC REGIMEN:

The general postoperative therapeutic regimen for the grafts involved commencement of topical prednisolone acetate 1%
or dexamethasone phosphate 0.1% at 3-hour intervals
along with either topical tobramycin, levofloxacin, or
moxifloxacin. Topical cyclosporine generally was used as
additional immunosuppression in high-risk cases (multiple
grafts, therapeutic grafts where steroids were withheld for
the first few weeks, eyes with significant vascularization,
glaucoma, ocular surface disease), or as a steroid-sparing
agent in cases of ocular hypertension. Topical steroids were
tapered gradually to once daily by the end of 1 year, with
antibiotic use in tandem stopped when steroid dosage was
reduced to a twice-daily regimen (antibiotics were continued beyond 6 months in view of a greater risk of the
occurrence of infective keratitis in our graft patients when
they were concurrently receiving topical steroids). In
low-risk grafts (eg, grafts performed for keratoconus, corneal scars, anterior stromal dystrophies), topical steroids
were continued for at least 1 year, whereas in immunologically high-risk grafts, low-dose steroids were continued
indefinitely without antibiotics. In cases of tectonic and
therapeutic grafts, topical steroids generally were withheld
for at least 1 week after surgery with the aim of reducing
the risk of exacerbating a recurrence of infection.
Oral steroids were commenced in the perioperative
period in immunologically high-risk grafts (vascularized
corneas, repeat grafts) in those patients who consented and
were fit for oral steroids and were tapered over 2 to 3 weeks
in the postoperative period. In selected high-risk cases
(based on individual surgeon preference, patient acceptance of therapy, as well as patient systemic fitness) and
with appropriate risk-to-benefit ratio assessment and counseling, oral cyclosporine (2 to 4 mg/kg daily) was commenced after surgery and maintained empirically for 12
months unless systemic toxicities developed in the patient.
Systemic mycophenolate mofetil was used in patients with
contraindication to systemic cyclosporine or in patients in
whom side effects from cyclosporine developed. Patients
with clinical evidence of rejection were managed aggressively with a combination of oral prednisolone (1 mg/kg
body weight) and topical prednisolone acetate 1% given at
1- to 2-hour intervals, with rapid tapering after resolution
of rejection.

Complication
Glaucoma/raised intraocular
pressure
Allograft rejection
Epithelial problems
Late graft failure
Microbial keratitis
Cataract formation
Wound dehiscence
Vitreoretinal (retinal detachment,
macular pathologic features,
diabetic retinopathy)
Posterior capsular opacity
Primary graft failure
Suture abscess
Activation of herpes simplex
infection
Endophthalmitis
Recurrence of primary disease
Others
Surgical procedure
Glaucoma surgery
Repeat corneal graft
Graft resuturing
Refractive surgery
Cataract surgery
Lid procedures
YAG capsulotomy
Others: retinal laser (n 9),
vitreoretinal surgery (n 8),
ocular surface procedures
(n 10)

Frequency (n)

Percent
(%)

187

20.7

164
141
85
48
32
27
26

18.2
15.6
9.4
5.3
3.5
3.0
2.9

24
13
12
10

2.3
1.4
1.3
1.1

6
5
5

0.7
0.5
0.5

71
66
51
36
34
25
16
27

7.7
7.3
5.7
4.0
3.8
2.8
1.8
3.0

YAG yttriumaluminum garnet.

laser procedures, repeat corneal grafting, graft resuturing,

various forms of graft refractive surgery, cataract surgery,
eyelid procedures, yttriumaluminum garnet capsulotomy, and vitreoretinal surgery). In addition, multivariate
analysis involving inclusion of other preoperative and
intraoperative risk factors identified in an earlier study
were combined with these postoperative risk factors for a
final overall analysis.4
STATISTICAL ANALYSIS:

RISK FACTORS ANALYZED:

A total of 17 potential
postoperative risk factors were identified. These included 9
postoperative graft complications (epithelial problems,
wound dehiscence, suture abscess, endophthalmitis, microbial keratitis, reactivation of herpes simplex infection,
recurrence of primary disease, glaucoma or raised intraocular pressure [IOP], and allograft rejection) and 8 postoperative surgical or laser procedures (glaucoma surgery or

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Kaplan-Meier survival analysis was conducted to analyze graft survival times for
postoperative factors. Postoperative follow-up factors were
categorized, highlighting reference categories for comparisons. The Kaplan-Meier product limit method was applied
to generate individual survival curves with corresponding
survival rates. To avoid time-dependent bias, Cox proportional hazards regression with time-dependent covariates
was used to analyze follow-up risk factors (eg, complica-

CORNEAL GRAFT SURVIVAL

443

FIGURE 2. Kaplan-Meier curves for the various forms of

glaucoma surgery after penetrating keratoplasty showing that
eyes with trabeculectomy survived longer than those with
glaucoma drainage devices or transscleral photocoagulation
(P .00).

FIGURE 1. Kaplan-Meier survival curve depicting reduced

corneal graft survival in eyes with allograft rejection (P .00).

tions and second surgery) associated with risk of graft

failure.10 Proportional hazards assumption was tested to
identify variables over time. The identified variables that
violated the proportional hazards were controlled in the
model during the analyses. In the combined preoperative,
intraoperative, and postoperative follow-up model, age was
tested for the proportional hazard assumption. Because age
violated the assumption, in the final model, age was no
longer treated as a fixed variable and was controlled for.
Univariate analyses were conducted for each variable to
assess the significance. The effect of each individual risk
factor was quantified and reported as a hazard ratio (HR)
compared with a referent group. The final models were
adjusted for age, sex, and time-dependent factors that
violated proportional hazard assumptions. The final models
also were checked for colinearity among variables by
inspecting the standard errors associated with each variable. The first model was tested for postoperative factors
only, and the second model was tested for combined
preoperative and postoperative factors. In the preoperative
and postoperative factors, multivariate analysis age and
primary diagnosis interaction also were taken into account
as identified in the first article.4 A P value (2-tailed) of less
than .05 was considered to be statistically significant. All
analyses were conducted using Statistical Package for
Social Sciences version 15.0 (SPSS, Inc, Chicago, Illinois,
USA).

of postoperative complications and surgical procedures

performed after PK is summarized in Table 1. Glaucoma or
raised IOP was the most common complication in the
postoperative period (187 eyes; 20.7%), followed by allograft rejection (164 eyes; 18.2%) and epithelial problems
(141 eyes; 15.6%). Primary graft failure was seen in 13
(1.4%) cases.
The most common surgical procedure performed was
glaucoma surgery (71 eyes; 7.7%). Of these, trabeculectomy (augmented with 5-fluorouracil or mitomycin C) was
performed in 38 eyes (56.7%), glaucoma drainage device
implantation was performed in 16 eyes (23.9%), and
trans-scleral cyclophotocoagulation was performed in 12
eyes (17.9%). For 6 eyes, data on the type of glaucoma
surgery were not available. Sixty-six eyes (7.3%) underwent repeat grafting, and 51 eyes (5.7%) required graft
resuturing. Of the various laser procedures, neodymium:
yttriumaluminum garnet laser capsulotomy was the most
common, accounting for 1.8% of cases.
The presence of one or more postoperative risk factors
reduced graft survival significantly (P .001). The 1-, 3-,
5-, and 10-year survival rates for eyes without postoperative risk factors were 96.4%, 90.8%, 87.7%, and 85.3%,
respectively, whereas for eyes with one or more postoperative risk factors, these were 78.8%, 58.6%, 48%, and
34.2%, respectively. In univariate analyses of postoperative
risk factors, endophthalmitis, microbial keratitis, recurrence of primary disease, allograft rejection, regrafts, glaucoma surgery, and lid surgery were found to be significant
predictors of graft failure, as depicted in the Kaplan-Meier
survival curves (Figures 1 and 2).
Postoperative risk factors significant in the univariate
model were subjected to multivariate analyses using the

RESULTS
DATA ON BASELINE DEMOGRAPHIC CHARACTERISTICS,

follow-up duration, indications for surgery and preoperative diagnoses, and preoperative and intraoperative risk
factors have been described in an earlier publication from
the Singapore Corneal Transplant Study.4 The incidence
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TABLE 2. Potential Preoperative, Intraoperative, and

Postoperative Risk Factors for Corneal Graft Failure That
Were Combined in a Multivariate Model to Analyze
Significant Predictors of Graft Failure in the Singapore
Corneal Transplant Study
Potential preoperative and intraoperative risk factors
Recipient gender
Recipient graft size
Primary diagnosis
Donor endothelial cell count
Pre-existing inflammation
Pre-existing glaucoma
Corneal neovascularization
Pre-existing corneal perforation
Potential postoperative risk factors
Postoperative infection/microbial keratitis
Endophthalmitis
Activation of herpes simplex virus
Glaucoma/raised intraocular pressure after
penetrating keratoplasty
Recurrence of primary disease
Wound dehiscence
Allograft rejection
Cataract formation
Repeat corneal graft
Glaucoma surgery
Lid surgery
Refractive surgery
Nd:YAG laser capsulotomy
Nd:YAG neodymium:yttriumaluminum garnet.

Cox regression model. We further combined the previously

described preoperative and intraoperative factors with the
postoperative risk factors in a time covariate-dependent
Cox regression model to determine risk factors of significance.4 The potential preoperative, intraoperative, and
postoperative risk factors that were evaluated in this
combined model are enumerated in Table 2.
In the final combined analysis (Table 3), 13 risk factors
were identified to be significant: female gender, primary
diagnosis or indication for corneal graft, recipient graft size
less than 7 mm and more than 9 mm, preoperative
inflammation and perforation, postoperative microbial keratitis, endophthalmitis, recurrence of primary disease, allograft rejection, wound dehiscence, repeat corneal graft,
glaucoma surgery, and lid surgery.

DISCUSSION
CORNEAL GRAFT SURVIVAL IN THE LONG TERM HAS BEEN

reported to range from 50% to 80%, with significant variation

associated with geographical and socioeconomic factors.1
3,5,1113 Reports from a number of large cohort studies in
Western populations, including the Australian Corneal Graft
Registry,2 the Collaborative Corneal Transplant Study,5 the
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RISK FACTORS

FOR

Corneal Transplant Follow-up Study,1 and the Canadian

Corneal Graft Outcome Study3 generally have reported
higher survival rates than in Asian populations, although data
are limited in the latter.4,11 Two large studies, the Australian
Corneal Graft Registry and the Canadian Corneal Graft
Outcome Study, have evaluated risk factors for graft failure in
a multivariate model looking at preoperative, intraoperative,
and postoperative risk factors.
The significant preoperative and intraoperative factors
identified in our multivariate analysis were recipient gender,
preoperative diagnosis, graft size, preoperative inflammation,
and perforation. These findings are consistent with our
previous report from the Singapore Corneal Transplant
Study.4 A number of fairly well-established factors, however,
were no longer significant when analyzed along with the
postoperative factors in our current study. These factors
included patient age, glaucoma, donor endothelial cell count,
and vascularization, suggesting that postoperative risk factors
may play a greater role in graft survival.
In general, the influence of recipient age on graft survival
is most significant because of the poor outcomes in pediatric
grafts.14 16 The small percentage of young patients in our
study (3.6% of participants 0 to 20 years of age4) may account
for the lack of association with age. Donor endothelial cell
loss has been shown to be greatest in the first 5 years after
transplantation, but to diminish to normal rates subsequently.17,18 Recent evidence from the Corneal Donor Study
has found that donor characteristics, including donor ECC,
were not significant risk factors for long-term graft failure.19
In our combined regression model, too, donor ECC failed to
reach statistical significance (P .23).
Corneal vascularization also is widely held to be a risk
factor for failure. Price and associates, however, reported that
vascularization was not a significant factor in a study of
corneal graft failure in 1819 eyes and attributed this to the
increased use of topical steroids.17 Our relatively prolonged
postoperative immunosuppression regimen with topical steroids and systemic immunosuppression (derived anecdotally
from our impression of Asian eyes being at a generally higher
risk of rejection) may be responsible for our similar finding
that vascularization is a less significant factor for graft failure.
However, a consequence of our heavy use of topical steroids
may be the relatively high incidence of raised IOP after
surgery, although postoperative raised IOP or glaucoma was
not associated with an increased risk for graft failure.
The recipient preoperative diagnosis is a well-established factor for graft survival,1,3,5,9 and this was further
confirmed in our multivariate analysis. Recipient gender
was found to have a small, but statistically significant,
effect on graft survival, with female recipients in our
series having a higher risk of graft failure other studies
also have suggested conflicting findings regarding the
importance of recipient gender in graft survival, and this
remains an intriguing risk factor for graft failure that is
still not well understood.

CORNEAL GRAFT SURVIVAL

445

TABLE 3. Multivariate Cox Regression Analysis of Preoperative, Intraoperative, and Postoperative Risk Factors Predictive of
Corneal Graft Failure in the Singapore Corneal Transplant Study
95% Confidence Interval for
Hazard Ratio
Risk Factor

P Value

Recipient gender (female)

Recipient age
Recipient graft size (mm)
7.5 to 7.9
7
7 to 7.4
8 to 8.4
8.5 to 8.9
Primary diagnosis
Keratoconus
Fuchs dystrophy
PBK/ABK
Active keratitis
Postinfection scar
Mechanical trauma
Regraft
Glaucoma
Others
Microbial keratitis (yes/no)
Activation of herpes simplex virus (yes/no)
Endophthalmitis (yes/no)
Glaucoma/raised intraocular pressure (yes/no)
Cataract formation (yes/no)
Allograft rejection (yes/no)
Wound dehiscence (yes)
Repeat corneal graft (yes/no)
Repeat wound suture (yes/no)
Glaucoma surgery (yes/no)
Cataract surgery (yes/no)
Nd:YAG capsulotomy (yes/no)
Lid surgery (yes/no)

Hazard Ratio

.00
.94
.00
.00
.68
.42
.09
.11
.00
.01
.00
.00
.02
.01
.00
.01
.01
.00
.34
.00
.49
.00
.00
.02
.00
.64
.02
.02
0.02
.02

Lower

Upper

1.64
1.00

1.18
.83

2.29
1.22

5.15
1.10
1.22
.41
1.60

2.01
.69
.75
.15
.90

13.23
1.76
1.99
1.15
2.87

1
14.83
22.95
18.76
12.01
13.91
29.73
17.52
17.05
3.64
.47
6.74
.82
.15
3.45
2.83
3.22
1.19
2.46
.23
0.29
2.31

1.85
3.03
2.39
1.56
1.78
3.97
2.08
2.27
2.19
.10
2.43
.47
.035
2.42
1.19
1.87
.57
1.12
.07
0.00
1.162

118.61
174.14
146.81
92.79
109.09
222.79
147.76
127.87
6.06
2.23
18.70
1.44
.62
4.92
6.71
5.53
2.45
5.40
.77
0.83
4.61

ABK aphakic bullous keratopathy; Nd:YAG neodymium:yttriumaluminum garnet; PBK pseudophakic bullous keratopathy.

The significant postoperative risk factors for graft survival in our study were microbial keratitis and endophthalmitis, allograft rejection, recurrence of primary disease,
repeat corneal graft, glaucoma surgery, and lid surgery.
Allograft rejection was noted in 164 eyes (18.2%), and 1
episode or more of graft rejection was associated with a
significantly poorer outcome in terms of graft survival in
our series (P .001). This is in keeping with previous
reports in the literature in which 1 rejection episode or
more led to graft failure in 30% to 50% eyes.3,18,19 In an
analysis of the preoperative factors influencing graft survival after an episode of endothelial rejection, Wagoner
and associates found that a history of rejection as well as
increased donor and recipient age were associated with a
higher risk of subsequent failure.6
Microbial keratitis after PK is a serious complication
that leads to significant ocular morbidity. The reported
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AMERICAN JOURNAL

incidence of bacterial keratitis after PK has ranged from

1.5% to 10.3%, with a predominance of gram-positive
organisms,7,20,21 and endophthalmitis occurs with a frequency of 0.2% to 0.5%.22 The prognosis for graft survival
after microbial keratitis generally is poor. Wagoner and
associates reported that immediate graft failure occurred in
45%, with graft survival rates at 1, 2, 3, and 4 years of
47.2%, 40.6%, 37.7%, and 35.8% only.7 Graft survival
after endophthalmitis has not been reported previously,
probably because of the relative rarity of the condition, but
intuitively also is likely to be poor, as our results show.
Finally, incomplete wound healing after PK leads to a
structurally weaker globe, and wound dehiscence occurs
with a frequency of 0.6% to 5.8%.2326 Grafts with a larger
extent of dehiscence have a higher risk of failure, and this
was confirmed further in our series, in which wound
dehiscence was a significant risk factor for graft failure.27
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Historically, 1 or more repeat grafts have been shown to

be associated with reduced graft survival, and our study
also showed that regrafts reduced long-term graft survival
significantly. In a direct comparison of initial and repeat
keratoplasty performed on 696 patients, Weisbrod and
associates reported a significant difference in 5-year survival (64.6% vs 45.6%, respectively; P .001).28 In many
institutions that perform large numbers of grafts, repeat
grafts continue to be one of the most common indications
for surgery, and various factors, including immune potentiation, greater patient age, recurrence of disease, and
increased vascularization, have been proposed as mediators
of accelerated graft failure.29,30
Several postoperative factors that were included in the
initial analysis either were protective against or not significantly associated with graft failure in multivariate analyses. Cataract development did not seem to influence graft
survival, and similar outcomes have been demonstrated in
other studies, with a reported graft failure rate following
subsequent cataract extraction of 3%.31,32 Patients who
had undergone cataract surgery after PK survived longer in
our multivariate analysis, and again, similar to refractive
surgery, this is likely because of patient selection, in which
eyes with better preoperative endothelial cell counts underwent cataract surgery. Neodymium:yttriumaluminum garnet posterior capsulotomy has been associated with increased
risk for graft failure, but we found enhanced survival in eyes
that underwent a laser capsulotomy, which is difficult to
explain but may be related to the small sample size.33
Glaucoma after PK has been associated with reduced
graft survival in several studies.9,34 In our study, multivariate analysis showed that the occurrence of glaucoma after
PK did not reduce graft survival significantly; however,
glaucoma surgery did. The likely reason for this is that

many of our patients may have had only raised IOP

without an associated optic neuropathy or glaucomatous
visual field defect, and it was well controlled medically.
With newer drugs like prostaglandin analogs in our armamentarium, more and more eyes with raised IOP or
glaucoma are likely to be treated medically, resulting in
better survival rates. However, it has been well documented that glaucoma surgery affects graft survival adversely.8,9,34 Glaucoma surgery generally indicates more
severe glaucoma and a failure of medical therapy, and
issues such as anterior chamber shallowing, tube corneal
touch with glaucoma drainage devices, and increased
inflammation are all prejudicial to graft survival.
In conclusion, we have described the postoperative risk
factors limiting long-term graft clarity in a multivariate
analysis on a large cohort of Asian patients. Our study
suggests that postoperative risk factors may play a greater
role in long-term graft survival, as compared with preoperative risk factors, and the lack of attention to this in part
may be the result of a paucity of keratoplasty cohorts with
accurate long-term tracking of postoperative complications
and further surgical interventions. The burden of corneal
blindness in Asia and the developing world currently
exceeds the availability of donor tissue, which highlights
the need for particular attention to be paid to specific risk
factors for failure.35,36 Although it is difficult to intervene
in the case of preoperative or intraoperative risk factors for
graft failure, a better understanding of the role of specific
postoperative complications as risk factors for failure will
enable active surveillance and closer attention to the
particular postoperative risk factors, and early detection
and proactive interventions subsequently may lead to
improved outcomes in PK in our patients.

THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. INVOLVED IN DESIGN OF THE
study (D.T.H.T., A.A.); Conduct of the study (A.A., L.S.L., D.T.H.T.); Data collection (A.A., H.M.H.); Analysis and data interpretation (A.A., L.S.L.,
D.T.H.T., H.M.H.); Preparation and writing of the manuscript (A.A., L.S.L., D.T.H.T.); and Review and approval of the manuscript (A.A., D.T.H.T.).
The Institutional Review Board of the Singapore Eye Research Institute approved the study.

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Biosketch
Professor Donald T.H Tan is the Director of Singapore National Eye Centre (SNEC), Chairman of Singapore Eye
Research Centre (SERI) and Heads the SNEC Cornea and Refractive Services. His extensive clinical and research
interests include myopia control, lamellar keratoplasty, including deep anterior lamellar keratoplasty and endothelial
keratoplasty, femtosecond laser-assisted corneal surgery, osteo-odonto-keratoprostheisis, ocular surface transplantation
including bioengineered stem-cell equivalents and drug-delivery devices. He has published extensively and is one of the
leading figures in the field of pterygium surgery and limbal/ocular surface transplantation.

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