Aetiology

Corneal transplant rejection is the most common cause of transplant failure in the post-operative period. Immune rejection remains the leading cause of graft failure following penetrating keratoplasty (PKP). 30% of transplanted corneas experience at least one episode of immune rejection, and a proportion of these eventually lead to transplant failure. 

The incidence of graft rejection depends on the presence of risk characteristics, e.g. corneal neovascularization. In ‘high-risk’ corneal transplant recipients up to 70% fail within 10 years despite local or systemic immunosuppressive therapy.

ABO blood type and sex match between donor and host may reduce graft rejection in high-risk cases. Human leukocyte antigen (HLA) typing to match recipient and donor has been shown in a large, randomised study not to reduce rejection or promote survival of high-risk PKP.

Corneal transplant rejection may be reversible or irreversible and can affect both full thickness- and lamellar transplants, although immunological rejection is less common following lamellar procedures (including Deep Anterior Lamellar Keratoplasty (DALK) and endothelial keratoplasty (EK)). Detachment of the graft and primary graft failure are the most common reasons for failure in EK.

Predisposing factors

• host corneal stromal vascularisation
  – for example, risk doubled if all four quadrants involved
• young recipient (particularly aged less than 10 years)
• donor/recipient gender mismatch
  – male donor to female recipient
• large diameter (≥9.5mm) or eccentric transplant
• loose or exposed sutures
• recent decrease in steroid therapy
• previous rejection
• previous transplant in the same eye
• iris adhesion to transplant/host interface
• time since operation: most rejections occur with one year of surgery, but can occur at any time
• Herpes simplex, bacterial or other infection
• inflammatory disease (e.g. anterior uveitis)
• glaucoma
• subsequent intra-ocular surgery (e.g. cataract surgery, vitrectomy)
• tear deficiency
• trauma (chemical, mechanical)

Symptoms of corneal transplant rejection

• photophobia
• redness (may be perilimbal)
• epiphora
• blurred vision
• discomfort or pain

Signs of corneal transplant rejection

Following full-thickness corneal transplantation (Penatrating Keratoplasty, PK), rejection may involve any cellular layer of the cornea (epithelium, stroma or endothelium). Of these, endothelial rejection is potentially the most serious as it threatens the viability of the transplant. Endothelial rejection is also of concern following posterior lamellar transplantation (Descemet’s Stripping Automated Endothelial Keratoplasty, DSAEK, and Descemet’s Membrane Endothelial Keratoplasty, DMEK), although it does not occur following DALK where rejection may occur in the epithelium or stroma layers.

Some or all of the following signs may be present:

• sub-epithelial opacities similar in appearance to adenovirus keratitis (Krachmer spots)
• anterior ciliary injection (perilimbal hyperaemia)
• transplant oedema (may be regional)
• rejection line
  • endothelial (Khodadoust line) or epithelial
• keratic Precipitates (KP) on transplant endothelium
• anterior chamber flare and cells
• raised IOP (occurs in up to a third of eyes post transplantation. Increased risk with corticosteroid therapy)

Differential diagnosis

• transplant decompensation, also known as ‘graft failure’ (no inflammation)
• suture-related infection
• infective keratitis
• anterior uveitis

Management by optometrist

Practitioners should recognise their limitations and where necessary seek further advice or refer the patient elsewhere

GRADE* Level of evidence and strength of recommendation always relates to the statement(s) immediately above

None

None

Management category

A1: emergency (same day) referral; no intervention. 
Emphasise to the patient the urgency of the condition and instruct them to attend the local hospital eye department or hospital A&E the same day, explaining that you will leave a message so that they are expected. Telephone the department to explain what you have done, preferably leaving your message with a doctor or other health care professional

Possible management by ophthalmologist

• intensive topical steroid therapy
• in more severe cases steroids may be administered by sub-Tenon’s injection
• possible addition of systemic steroid
• possible immunosuppressant therapy e.g. ciclosporin, tacrolimus
• topical antivirals where there is a history of Herpes simplex infection
• possible admission to hospital

Evidence base

Abudou M, Wu T, Evans JR, Chen X. Immunosuppressants for the prophylaxis of corneal graft rejection after penetrating keratoplasty. Cochrane Database Syst Rev. 2015;8:CD007603

Akanda ZZ, Naeem A, Russell E, Belrose J, Si FF, Hodge WG. Graft rejection rate and graft failure rate of penetrating keratoplasty (PKP) vs lamellar procedures: a systematic review. PLoS One. 2015;10(3):e0119934.

Armitage WJ, Goodchild C, Griffin MD, Gunn DJ, Hjortdal J, Lohan P, Murphy CC, Pleyer U, Ritter T, Tole DM, Vabres B. High-risk Corneal Transplantation: Recent Developments and Future Possibilities. Transplantation. 2019;103(12):2468-2478

Armitage WJ, Winton HL, Jones MNA, Downward L, Crewe JM, Rogers CA, Tole DM, Dick AD. Corneal Transplant Follow-up Study II: a randomised trial to determine whether HLA class II matching reduces the risk of allograft rejection in penetrating keratoplasty. Br J Ophthalmol. 2022;106(1):42-46.

Bachmann B, Taylor R, Cursiefen C: Corneal Neovascularization as a Risk Factor for Graft Failure and Rejection after Keratoplasty. Ophthalmology 2010;117(7):1300-5

Borderie V et al: Graft rejection and graft failure after Anterior Lamellar versus Penetrating Keratoplasty. Am J Ophthalmol 2011;151(6):1024-9

Di Zazzo A, Kheirkhah A, Abud TB, Goyal S, Dana R. Management of high-risk corneal transplantation. Surv Ophthalmol. 2017;62(6):816-827

Guilbert E, Bullet J, Sandali O, Basli E, Laroche L, Borderie VM. Long- term rejection incidence and reversibility after penetrating and lamellar keratoplasty. Am J Ophthalmol. 2013;155(3):560-9

Hopkinson CL, Romano V, Kaye RA et al (OTAG Study 20). The Influence of Donor and Recipient Gender Incompatibility on Corneal Transplant Rejection and Failure. Am J Transplant. 2017;17(1):210-7

Stulting RD, Lass JH, Terry MA, Benetz BA, Cohen NJ, Ayala AR, et al; Cornea Preservation Time Study Group. Factors Associated With Graft Rejection in the Cornea Preservation Time Study. Am J Ophthalmol. 2018;196:197-207

Yin J. Advances in corneal graft rejection. Curr Opin Ophthalmol. 2021;32(4):331-337.

Corneal transplant rejection
Version 13
Date of search 30.09.22
Date of revision 20.12.22
Date of publication 09.01.23
Date for review 29.09.24
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