Study Design

We retrospectively studied 1641 consecutive penetrating keratoplasties (PK), anterior lamellar keratoplasties (ALK), and Descemet stripping with endothelial keratoplasties (DSEK) carried out in 1438 patients at the Centre Hospitalier National d’Ophtalmologie des XV-XX, Paris, France, between December 1, 1992 and December 31, 2010. In the 203 patients (14.1%) who received 2 grafts in the same or contralateral eye during the study period, only the first graft was included in the study, yielding a total of 1438 procedures performed in 1438 patients. Between 1992 and 2001 all patients underwent penetrating keratoplasty. From 2002 to 2010, patients with isolated stromal corneal diseases underwent ALK when technically possible, whereas patients with corneal diseases involving both the corneal endothelium and stroma underwent penetrating keratoplasty. From 2006 to 2010, patients with isolated endothelial dysfunction were operated using DSEK technique. Surgical techniques have been reported elsewhere. Donor corneas were stored at 31 C in organ culture medium before surgery. They were not specifically selected to be ABO-, Rhesus D-, HLA-, or HY-compatible with the recipients except for high-risk recipients who received ABO-compatible grafts. A graft is HY-compatible if it corresponds to one of the following combinations: male donor with male recipient, female donor with female recipient, and female donor with male recipient. Conversely, male donor with female recipient results in HY mismatch. All transplants were performed at a single institution.

The study was submitted to the Ethical Committee of the French Society of Ophthalmology (Paris, France), which waived approval since no modifications to French standards of treatment or follow-up were made. The study and data accumulation were in conformity with all French laws, informed consent for the treatment or surgery was obtained, and the study was in adherence to the tenets of the Declaration of Helsinki.

Recipients and Transplant Outcome

High-risk recipients were defined as having a vascularized cornea (2 or more quadrants of corneal vascularization) or a history of irreversible corneal allograft rejection in the operated eye. Only grafts done for optical indication were included in the study. Based on the type of surgery and the recipient corneal endothelium condition, patients were divided into 4 surgical groups as follows: penetrating keratoplasty performed in a recipient eye with impaired corneal endothelium (n = 828), penetrating keratoplasty performed in a recipient eye with normal corneal endothelium (n = 381), anterior lamellar keratoplasty performed in a recipient eye with normal corneal endothelium (n = 165), Descemet stripping with endothelial keratoplasty performed in a recipient eye with impaired corneal endothelium (n = 64). Patients’ characteristics are shown in Table 1 .

Patients were examined at 1 and 2 weeks; at 1, 3, 6, 9, 12, 18, 24, and 36 months; and at 4, 5, 6, 8, 10, and 15 years after surgery. Slit-lamp findings and intraocular pressure were recorded at each examination. Pathologic events involving the graft but not the recipient cornea and progressing toward the center of the graft were considered as features of rejection. Epithelial rejection was defined as an epithelial rejection line appearing as a raised ridge of epithelium. Subepithelial rejection was defined as subepithelial infiltrates resembling those seen in epidemic keratoconjunctivitis. Stromal rejection was defined as stromal infiltrates and/or vascularization crossing the wound, involving the graft (or its interface with the recipient remaining posterior stroma), and progressing towards the center of the graft. Neither vascularization of the recipient peripheral cornea with no graft involvement nor an infectious suture abscess or superficial vascularization progressing along sutures was considered as rejection. Endothelial rejection was diagnosed when at least 2 of the following features were present: Khodadoust line, keratic precipitates, stromal edema, ciliary injection, and aqueous cells.

The diagnosis of rejection was made only if the transplant had remained clear for an interval of at least 2 weeks after surgery. The criteria for graft failure were persistent graft stromal edema or corneal opacification at least 6 months after a rejection episode. Irreversible rejection was defined as a rejection episode leading to graft failure. A rejection episode was classified as reversible if the graft cleared after the rejection episode. Grafts that experienced a rejection episode, cleared, and then developed endothelial decompensation at some later time point were therefore classified as reversible rejection episode.

After transplantation, all patients were treated with topical dexamethasone (1 mg/mL) and neomycin (3400 IU/mL). The initial corticosteroid regimen was 1 drop hourly in high-risk recipients and 1 drop every 6 hours in low-risk recipients. The average steroid regimen for low-risk recipients was 1 drop every 6 hours during the first postoperative month, 1 drop every 8 hours for the next 3 months, 1 drop every 12 hours for the next 3 months, and then 1 drop every day. For high-risk recipients the average steroid regimen was as follows: 16 drops / 24 hours (ie, 1 drop every hour from 7:00 AM to 10:00 PM) for 1 week, 8 drops / 24 hours for 1 week, 6 drops / 24 hours for 2 weeks, 5 drops / 24 hours for 2 weeks, 4 drops / 24 hours for 1 month, 3 drops / 24 hours for 3 months, 2 drops / 24 hours for 3 months, then 1 drop / 24 hours. When the intraocular pressure increased over 21 mm Hg, dexamethasone was replaced by fluorometholone, rimexolone, or hydrocortisone. Corticosteroid use was never stopped in high-risk recipients and it was discontinued when all the sutures were removed in low-risk recipients. In high-risk eyes the objective was to find the lowest steroid regimen permitting absence of rejection episodes. Treatment of rejection episodes has been described elsewhere. Management of rejection episodes included topical dexamethasone every hour in all cases, subconjunctival dexamethasone injections every day in moderately severe cases, and intravenous methylprednisolone 500 mg / 24 hours for 3 days in severe cases.

Statistical Analysis

The Kaplan-Meier method was used to analyze survival data. The univariate effects of variables on survival were assessed with the log-rank test for qualitative variables and Cox model for quantitative variables. Then multivariate analysis was performed with Cox models including variables significant at univariate level ( P < .05).

To describe postoperative endothelial cell loss, the biphasic linear model was fitted to grafts with at least 3 endothelial cell density (ECD) measurements in time. In this model, the endothelial density is described as a mixed piecewise linear model in time with a change in slope 1 year after surgery: ECD = ECD0 − (t × E), for t < 1 year; ECD = A − (t × L), for t > 1 year; where E is the slope of the early-phase endothelial cell loss and L is the slope of the late-phase endothelial cell loss. The least square estimates were used to calculate the coefficients of the various equations for each patient.

For quantitative variables, the unpaired t test and analysis of variance were used to compare groups of eyes. Qualitative variables were analyzed using the χ ² test. Multivariate logistic regression was then used to analyze the effect of variables significant in univariate analysis on rejection reversibility.

As multiple comparisons were made, the significance levels were corrected for the total number of comparisons using the Bonferroni method. A corrected P value <5% was considered statistically significant.

Statistical analysis was performed using a software program (Statistica version 6.1; StatSoft France, Maisons-Alfort, France).

Characteristics of the Study Population and Graft Survival

The characteristics of the study population are shown in Table 1 . The average follow-up time (from surgery to failure for unsuccessful grafts or from surgery to the date of last visit for successful grafts) was 45.6 ± 39.0 months (range 0.5-198 months). It was 40 months (0.5-197 months) for PK performed in eyes with impaired recipient endothelium, 62 months (0.5-198) for PK performed in eyes with normal recipient endothelium, 47 months (1-110) for ALK, and 20 months (0.5-64) for DSEK. The number of eyes with a follow-up time of at least 36/60 months was, respectively, 392/205 for PK performed in eyes with impaired recipient endothelium, 248/160 for PK performed in eyes with normal recipient endothelium, 104/50 for ALK, and 20/6 for DSEK.

Overall 299 rejection episodes were observed during the study period in 277 out of 1438 eyes (19.3%). Rejection episodes led to graft failure in 149 out of 277 eyes (53.8%). Among the 277 eyes with at least 1 rejection episode, 260 had 1 episode, 12 had 2 episodes, and 5 had 3 episodes. The cumulative incidence of rejection episodes was 8.0% (95% confidence interval: 6.5%-9.4%) at 12 months, 24.3% (21.5%-27.0%) at 60 months, and 30.1% (25.8%-34.4%) at 120 months. The average keratoplasty-to-rejection time was 19.8 ± 20.4 months (range 0.5-158 months).

The observed 1-, 5-, and 10-year overall graft survival estimates were 94.0% (92.7%-95.2%), 75.9% (73.2%-78.5%), and 64.7% (60.0%-69.5%), respectively. The mean early-phase and late-phase annual rates of endothelial cell loss were respectively −29.5% ± 19.6% and −9.2% ± 6.6% in eyes with at least 1 rejection episode and −23.8% ± 18.6% and −7.2% ± 5.6% in eyes with no rejection episodes ( P < .05).

Factors Influencing the Occurrence of Rejection Episodes

In multivariate analysis recipient age, rejection risk, lens status, and surgical group significantly influenced the cumulative incidence of rejection episodes ( Table 2 ). The maximum cumulative incidence of rejection episodes was found for recipients younger than 20 years and for recipients aged 41-50 years. The cumulative incidence of rejection episodes was higher for high-risk compared with low-risk recipients. It was higher for aphakic eyes and eyes with anterior chamber intraocular lens (IOL) than for eyes with posterior chamber IOL and phakic eyes ( P < .01). Conversely, there were no significant differences between aphakic eyes and eyes with anterior chamber IOL ( P = .50) and between eyes with posterior chamber IOL and phakic eyes ( P = .93). The cumulative incidence of rejection episodes was higher for eyes with PK (whatever the recipient endothelium condition was) than for eyes with ALK ( P < .05).

Table 2

Risk Factors for Rejection and Rejection Irreversibility After Penetrating and Lamellar Keratoplasty ^a

	Rejection Episodes		Irreversible Rejection
	5-Year Cumulative Incidence of Rejection Episodes	P (Univariate Log-rank Test) / P (Multivariate Cox Model) b	Percentage of Irreversible Rejection Episodes (Odds Ratio vs Reference Subgroup)	P (Univariate Analysis) / P (Multivariate Logistic Regression)
Recipient age
– 0-10 y (n = 9)	37.5%	.25 / .00002	100% (1.76) c	<.00001 / .14
– 11-20 y (n = 50)	30.6%		7% (0.11) c
– 21-30 y (n = 160)	23.4%		16% (0.27) c
– 31-40 y (n = 126)	20.6%		15% (0.26) c
– 41-50 y (n = 129)	42.3%		48% (0.81)
– 51-60 y (n = 129)	22.1%		56% (0.95)
– 61-70 y (n = 218)	25.1%		65% (1.10)
– 71-80 y (n = 378)	24.1%		59% (1.00)
– 81-90 y (n = 223)	20.1%		73% (1.23)
– ≥91 y (n = 16)	23.6%		50% (0.85)
Recipient rejection risk
– High risk (n = 312)	37.1%	.00001 / .0003	58% (1.34)	.39 / .02
– Low risk (n = 1126)	22.1%		43% (1.00)
Preoperative IOP
– Glaucoma or IOP >20 mm Hg (n = 313)	33.5%	.30	71% (1.76) c	.00003 / .009
– No glaucoma and IOP ≤20 mm Hg (n = 1125)	23.2%		41% (1.00)
Postoperative lens status
– Aphakic (n = 113)	37.2%	.0026 / .00003	57% (3.70) c	.00003 / .24
– Anterior chamber IOL (n = 338)	34.7%		74% (4.86) c
– Posterior chamber IOL (n = 470)	21.0%		57% (3.71) c
– Phakic (n = 517)	21.5%		15% (1.00)
Preoperative diagnosis
– Regraft (n = 127)	42.3%	.0026 / .16	60% (33.86) c	.00003 / – b
– Bullous keratopathy (n = 508)	34.4%		66% (37.05) c
– Trauma (n = 53)	21.5%		62% (34.46) c
– Stromal dystrophies (n = 26)	19.1%		50% (28.00) c
– Corneal scar after infectious keratitis (n = 184)	22.9%		40% (22.40) c
– Endothelial dystrophies (n = 208)	6.3%		46% (25.85) c
– Keratoconus (n = 332)	21.0%		2% (1.00)
Surgical group
– PK and impaired recipient endothelium (n = 828)	28.7%	.25 / .035	64% (1.00)	.00003 / .03
– PK and normal recipient endothelium (n = 381)	23.8%		24% (0.38) c
– ALK and normal recipient endothelium (n = 165)	15.1%		0% (<0.01) c
– DSEK and impaired recipient endothelium (n = 64)	– d		43% (0.67)
Combined surgery
– Vitrectomy (n = 276)	28.9%	>.5	72% (1.68) c	.002/.47
– No vitrectomy (n = 1162)	24.5%		43% (1.00)
Rejection classification
– Diffuse endothelial rejection (n = 150)			55% (1.00)	.00003 / .02
– Progressive endothelial rejection (Khodadoust line, n = 27)			48% (0.87)
– Stromal rejection (n = 22)			0% (<0.01) c
– Epithelial rejection (n = 7)			0% (<0.01) c
– Subepithelial rejection (n = 4)			0% (<0.01) c
– Mixed cases of rejection (n = 89)			55% (0.99)
logMAR visual acuity at presentation
– >1.30 (visual acuity <20/400, n = 143)			60% (2.24) c	<.00001 / .002
– ≤1.30 (visual acuity ≥20/400, n = 156)			27% (1.00)
Change in central corneal thickness between the time of presentation and the previous examination
– ≤150 μm (n = 155)			30% (1.00)	.00004 / – b
– >150 μm (n = 144)			52% (1.77) c

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