Purpose
To report early, specific changes in donor endothelial cell morphology as a predictor of an upcoming allograft rejection after Descemet membrane endothelial keratoplasty (DMEK).
Design
Retrospective, observational case series.
Methods
Out of a cohort of 500 eyes that underwent DMEK at a tertiary referral center, 7 eyes developed typical clinical signs of an allograft rejection. Specular microscopy images before, during, and after the rejection episode were analyzed and compared with a case-control group of 49 asymptomatic DMEK eyes that matched baseline characteristics of the rejection group. Endothelial cell morphology was evaluated by subjective scoring (range 1–5) in a masked fashion as well as by an objective comparison of endothelial cell density, cell size, coefficient of variation, and hexagonality in rejection vs control eyes.
Results
Subjective scores (median) were higher before and after rejection (2.5 and 5, respectively) than in the DMEK control group (2.0 and 2.5, respectively) at comparable time points ( P = .0230 and P = .0005, respectively). Endothelial cell density also differed before ( P = .0106) and after rejection ( P = .0240), while hexagonality differed before ( P = .0499) but not after rejection ( P = .1767).
Conclusion
Our study suggests that allograft rejection may not be an acute event, but rather a slow-onset immune response. Early, specific changes in endothelial cell morphology were found to “announce” an upcoming allograft rejection. If so, monitoring donor endothelium after DMEK or other forms of keratoplasty may be used to anticipate a rejection episode and/or to prevent an allograft rejection from clinically manifesting itself.
Allograft rejection has been reported to occur in up to 15%–30% of cases after traditional penetrating keratoplasty. Lower incidences have been described after endothelial keratoplasty, in which 5%–12% of cases showed a rejection in a larger series of eyes that underwent “Descemet stripping (automated) endothelial keratoplasty” (DSEK/DSAEK), and in about 1%–5% of eyes that underwent “Descemet membrane endothelial keratoplasty” (DMEK).
These percentages may suggest that thinner grafts, carrying a lower antigen load, decrease the risk of rejection. However, an allograft rejection can still occur after DMEK, which may present with a Khodadoust line and/or keratic precipitates. There may not be a known diagnostic predictor for a keratoplasty episode, so that allograft rejection is commonly diagnosed only after the eye shows clinical signs like redness and anterior uveitis and the patient notices subjective complaints, such as a drop in visual acuity or ocular discomfort.
However, while performing routine specular microscopy evaluations in our entire cohort of DMEK patients, we observed characteristic endothelial changes in eyes that later developed a clinically manifest allograft rejection. Therefore, the aim of the current study was to evaluate which early endothelial cell changes could be detected by retrospective analysis of sequential, in vivo specular microscopy images at standardized time intervals before a rejection became clinically apparent in 7 DMEK eyes with a manifest allograft rejection. In addition, cell morphology in the rejection group was compared to that in a randomly selected group of asymptomatic DMEK control eyes.
Methods
A total of 500 consecutive eyes that underwent DMEK for Fuchs endothelial dystrophy, pseudophakic bullous keratopathy, or endothelial graft failure were included in our study. Of these 500 eyes, operated on between October 2007 and September 2012, 7 eyes of 6 patients (4 male, 2 female; with a mean age of 62 ±18 years) developed an allograft rejection 4–42 months after DMEK ( Tables 1 and 2 ). From the remaining 493 eyes, 49 asymptomatic eyes of 49 patients (35 male, 14 female; with a mean age of 64 ± 11 years) were selected as a control group, representing eyes without detectable clinical signs of allograft rejection throughout their overall mean follow-up time of 22 ± 17 months (range, 6–52 months) ( Tables 1 and 3 ). Per eye from the rejection group (n = 7), 7 control eyes (thus, n = 49 control eyes in total) were selected such that the baseline characteristics “recipient age,” “surgery indication,” “donor age,” “preoperative endothelial cell density,” and available “follow-up times” for Time Point 1 (before rejection) and Time Point 3 (after rejection) matched ( Table 1 ). Control eyes were selected without knowing the clinical outcome (visual acuity, endothelial cell density) for the respective eye.
| Rejection Eyes (n = 7) | Control Eyes (n = 49) | P Value | |
|---|---|---|---|
| Recipient age (y) (±SD, range) | 61.7 (±18.2, 31–78) | 64.1 (±10.8, 38–83) | .6255 |
| Recipient sex (F/M) | 2/5 | 14/35 | – |
| Surgery indication | |||
| Fuchs endothelial dystrophy | 5 | 35 | – |
| Bullous keratopathy | 1 | 7 | |
| Failed DSEK | 1 | 7 | |
| Preoperative pachymetry (μm) (±SD, range) | 676 (±126, 568–929) | 685 (±125, 516–1235) | .8536 |
| Average FU time for Time Point 1 (mo) (±SD, range) | 10.4 (±7.7, 1–24) | 10.3 (±7.8, 1–26) | .8147 |
| Average FU time for Time Point 3 (mo) (±SD, range) | 22.7 (±17.2, 6–48) | 22.3 (±17.4, 6–52) | .9546 |
| Donor age (y) (±SD, range) | 61.1 (±9.4, 49–75) | 63.8 (±8.9, 43–84) | .4746 |
| Preoperative donor ECD (cells/mm 2 ) (±SD, range) | 2534 (±105, 2380–2700) | 2536 (±195, 1900–2910) | .9807 |
| Donor sex (F/M) | 1/6 | 16/33 | – |
| Donor death cause, n (%) | – | ||
| Cardio/stroke | 3 (43%) | 27 (55%) | |
| Respiratory | 1 (14%) | 5 (10%) | |
| Cancer | 3 (43%) | 12 (27%) | |
| Trauma | – | 2 (4%) | |
| Other | – | 2 (4%) | |
| Death-preservation time (h) (±SD, range) | 21 (±6, 15–32) | 22 (±7, 9–36) | .3524 |
| Death-to-DMEK preparation time (d) (±SD, range) | 7 (±3, 4–12) | 7 (±4, 2–13) | .4646 |
| Death-to-surgery time (d) (±SD, range) | 15 (±4, 9–18) | 14 (±4, 8–23) | .3996 |
| Eyes With Allograft Rejection After DMEK | Case # | 1 | 2 | 3 a | 4 a | 5 | 6 | 7 |
|---|---|---|---|---|---|---|---|---|
| Patient data | Age/sex | 45/M | 77/F | 61/M | 62/M | 31/F | 78/M | 78/M |
| OD/OS | OS | OS | OS | OD | OD | OD | OS | |
| Indication for surgery | FED | FED | FED | FED | BK (after phakic IOL removal) | “Failed” DSEK | FED | |
| Lens status | Phakic | Pseudophakic | Pseudophakic | Pseudophakic | Phakic | Pseudophakic | Pseudophakic | |
| Time Point 1: no clinical signs, changes in endothelial cell morphology | Time after DMEK | 18 mo | 3 mo | 24 mo | 9 mo | 12 mo | 1 mo | 6 mo |
| Time before rejection | 12 mo | 1 mo | 18 mo | 1 mo | 6 mo | 6 mo | 1 mo | |
| Pachymetry | 607 μm | 559 μm | 573 μm | 552 μm | 508 μm | 503 μm | 441 μm | |
| Slit-lamp | Clear cornea | Clear cornea | Clear cornea | Clear cornea | Clear cornea | Clear cornea | Clear cornea | |
| Remarks | – | – | History of high myopia and retinal detachment | History of high myopia and retinal detachment | – | – | – | |
| Time Point 2: clinically manifest allograft rejection | Time after DMEK | 30 mo | 4 mo | 42 mo | 10 mo | 18 mo | 7 mo | 7 mo |
| Pachymetry | 622 μm | 700 μm | 628 μm | n.a. | 505 μm | 598 μm | n.a. | |
| Steroid regime | Discontinued steroids 24 mo after DMEK | FML drops 3× daily | FML drops 1× daily | FML drops 1× daily | FML drops 1× daily | FML drops 3× daily | FML drops 3× daily | |
| Slit-lamp | Clear cornea with dispersed keratic precipitates | Diffuse corneal edema with Khodadoust line | Clear cornea with whitish keratic precipitates and mild cellular reaction in AC | Cornea edematous whitish spots in the interface, mild cellular reaction in AC | Clear cornea with keratic precipitates | Corneal edema with keratic precipitates | Keratic precipitates, cells, and flare in AC | |
| Remarks | No subjective complaints | Subjective drop in VA, ocular redness, photophobia | Subjective slow drop in VA, ocular discomfort | Subjective ocular discomfort | No subjective complaints | Subjective drop in VA, ocular redness | Subjective ocular redness and discomfort | |
| Time Point 3: no clinical signs, persistent changes in endothelial cell morphology | Time after DMEK | 48 mo | 6 mo | 48 mo | 12 mo | 27 mo | 9 mo | 9 mo |
| Time after rejection | 18 mo | 4 mo | 6 mo | 2 mo | 9 mo | 2 mo | 2 mo | |
| Pachymetry | 610 μm | 597 μm | 818 μm | 637 μm | – | 493 μm | 452 μm | |
| Steroid regime to treat rejection | DexM 4× daily, tapered over 3 mo, then FML 1× daily | DexM 6× daily for 10 d, then Predn 6× daily tapered to 3× daily over 1 mo; then DexM 3× daily tapered over 6 mo to 1× daily | Predn 6× daily tapered over 3 mo, then FML 1× daily | Predn 6–8× daily tapered to 3× daily over 4 mo, then FML 4× daily | FML 4× daily, tapered to 1× daily over 7 mo | Predn 8× daily and DexM ointment (overnight) tapered to Predn 1× daily over 2 mo, then DexM 1× daily on the long term | Predn 8× daily and DexM ointment (overnight) tapered over 1 mo, then DexM 3× daily tapered to 1× daily over 2 mo | |
| Slit-lamp | Clear cornea, quiet AC | Clear cornea, quiet AC | Diffuse corneal decompensation | Diffuse corneal decompensation | Clear cornea, quiet AC | Clear cornea, quiet AC | Clear cornea, quiet AC | |
| Remarks | – | – | Re-DMEK 56 mo after initial DMEK | Re-DMEK 16 mo after initial DMEK | – | – | – |
| Rejection Eyes Median [IQR] | Control Eyes Median [IQR] | P Value | |
|---|---|---|---|
| Time Point 1: no clinical signs, changes in endothelial cell morphology | |||
| n = | 7 (7 analyzed) | 49 | – |
| Average follow-up time (mo) | 10 [Range, 1–24] | 10 [1–26] | – |
| Subjective score (1–5) | 2.5 [2.0–3.25] | 2.0 [2.0–2.5] | .0230 |
| ECD (cells/mm 2 ) | 1102 [869–1420] | 1616 [1378–1931] | .0106 |
| Coefficient of variation (%) | 28.0 [26–32] | 27.1 [23.7–30.0] | .2855 |
| Hexagonality (%) | 64 [58.5–66.0] | 56.3 [52–61] | .0499 |
| Time Point 2: clinically manifest allograft rejection | |||
| n = | 7 (3 analyzed, 4 n.a.) | 49 | – |
| Average follow-up time (mo) | 17 [Range, 4–42] | n.r. | – |
| Subjective score (1–5) | n.a. | n.r. | – |
| ECD (cells/mm 2 ) | 880 [Range, 325–1391] | n.r. | – |
| Cell size (μm 2 ) | 1140 [Range, 720–3235] | n.r. | – |
| Coefficient of variation (%) | 26 [Range, 23–31] | n.r. | – |
| Hexagonality (%) | 60 [Range, 49–65] | n.r. | – |
| Time Point 3: no clinical signs, persistent changes in endothelial cell morphology | |||
| n = | 7 (4 analyzed, 3 n.p.) | 48 | – |
| Average follow-up time (mo) | 23 [Range, 6–48] | 22 [6–52] | |
| Subjective score (1–5) a | 5.0 [2.25–5.0] | 2.5 [1.5–2.5] | .0005 |
| ECD (cells/mm 2 ) | 880 [840–1000] | 1401 [1195–1747] | .0240 |
| Coefficient of variation (%) | 27.5 [24.2–29.8] | 27.0 [24.0–29.2] | .3653 |
| Hexagonality (%) | 62.5 [49.0–66.5] | 59.0 [52.0–62.0] | .1767 |
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