Allograft Rejection Risk in Penetrating Keratoplasty Examined

Investigators reviewed the potential to reduce allograft rejection risk in cases of high-risk penetrating keratoplasty.

Human leukocyte antigen (HLA) class II matching did not reduce allograft rejection risk in high-risk penetrating keratoplasty (PK), according to research results published in the British Journal of Ophthalmology. 

In a randomized clinical trial, researchers sought to evaluate the role of HLA class II matching in high-risk PK. In particular, the research team evaluated whether this class matching reduces the risk of allograft rejection in this patient population. Primary study outcome was time to first rejection episode, regardless of treatment success. 

The total study population included 1133 transplants in 980 patients, 1078 of whom met the full study inclusion criteria and were randomly assigned to 1 of 3 study groups: group 0 (n=182), group 1 (n=483) or group 2 (n=413), based on HLA class II mismatches. Overall 5-year rejection-free survival rate for these groups was 63% (95% CI, 60%-66%); overall rejection-free survival estimate in the same timeframe was 67% (95% CI, 64%-71%). Of the 298 reported first rejection episodes, 79% occurred within the first 2 years following transplant; subsequent years saw 12%, 6%, and 3% of rejections in years 3, 4, and 5, respectively. 

A univariate analysis of donor factors found that the only factor influencing rejection risk was the storage time of the corneas in organ culture. Kaplan-Meier rejection-free survival estimate was higher for corneas stored in organ culture for more than 21 days compared with corneas stored for 15 days or less (69% vs 55%, respectively; P =.04). Donor age, gender, cause of death, time from death to enucleation, and endothelial cell density did not influence risk rejection. 

On the recipient side, age played a marked role in rejection risk. Younger patients had a considerably increased rejection risk compared with older patients (P <.0001); indication for transplantation, chronic glaucoma, ocular surface disease, deep vascularization, and whether the penetrating keratoplasty was a regraft were all preoperative risk factors that increased rejection risk. A higher number of risk factors was correlated with a lower rate of rejection-free survival at 5 years. 

A Cox proportional hazards regression demonstrated that in recipients 40 years old or younger, the rejection risk was roughly double that for patients between 61 and 80 years of age (hazard ratio [HR], 0.51; 95% CI, 0.36-0.73; P =.0003) as well as for patients older than 80 years (HR, 0.49; 95% CI, 0.30-0.81; P =.005). If the patient had 2 or more present preoperative risk factors, that more than doubled the risk of rejection (HR, 2.11; 95% CI, 1.28-3.47; P =.003). 

These results support the findings of earlier retrospective studies performed in the United Kingdom, with age-related immune system changes possibly explaining the findings of risk rejection in recipients 60 years and older. 

“Unlike in renal transplants, HLA class II matching did not reduce the risk of rejection in high-risk, full-thickness corneal transplantation,” the researchers concluded. “Other factors are…likely to play an important role in corneal transplant immunology. The reduced risk of rejection with increasing recipient age certainly warrants further investigation.” 

Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures. 


Armitage WJ, Winton HL, Jones MNA, et al. Corneal transplant follow-up study II: A randomized trial to determine whether HLA class II matching reduces the risk of allograft rejection in penetrating keratoplasty. Published online December 2, 2020. Br J Ophthalmol. doi:10.1136/bjophthalmol-2020-317543