To report early, specific changes in donor endothelial cell morphology as a predictor of an upcoming allograft rejection after Descemet membrane endothelial keratoplasty (DMEK).

Retrospective, observational case series.

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.

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).

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.