Corneal Graft Rejection Treatment & Management

Updated: Oct 16, 2018
  • Author: Michael Taravella, MD; Chief Editor: Hampton Roy, Sr, MD  more...
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Medical Care

Treatment of graft rejection depends on the type of rejection; however, in all cases, topical corticosteroids are the mainstay of treatment. Epithelial or stromal rejection without endothelial involvement usually does not progress to graft failure. As previously noted, epithelial rejection may be a self-limited process. Nonetheless, epithelial and stromal rejection should be aggressively treated, because they indicate host immunologic recognition of the graft and may precede a more severe endothelial rejection. Topical corticosteroids (eg, dexamethasone 0.1%, prednisolone acetate 1%) are prescribed 4-6 times/d until the signs of rejection resolve, followed by a slow tapering of the topical medication. These patients should be followed closely to be certain that the signs of rejection are improving and that endothelial rejection has not developed.

In cases of endothelial rejection, treatment must be more aggressive if the episode is to be reversed. Topical corticosteroids should be used every hour while awake and as frequently as possible at night for 2-3 days, followed by every 2 hours while awake. Steroid ointment may be used at bedtime. Therapy should be continued until signs of rejection resolve. Topical medications should be tapered slowly over several weeks to a few months depending upon the patient's response to treatment. Therapy should be continued for at least 4 weeks in the absence of response before judging that the graft has failed.

Other routes of administration of corticosteroids can be used in more severe endothelial rejections, in recurrent rejections, or if the patient is at high risk (eg, alkali burns, patients with vascularized corneas). Corticosteroids may be given by subconjunctival injection (eg, dexamethasone phosphate 2 mg, betamethasone 3 mg in 0.5 mL). A less painful alternative is a collagen shield soaked in corticosteroids and applied to the cornea combined with frequent corticosteroid eye drops. The collagen shield results in a higher local concentration of steroid than can be obtained by the use of corticosteroid drops alone. The shield acts as a depot reservoir for the drug that slowly releases its contents during the period between topical applications. Higher steroid concentrations have been noted in the cornea, aqueous humor, iris, and vitreous, compared with hourly drops alone.

Systemic corticosteroids can also be used in cases of severe endothelial rejection. Oral prednisone is generally started at dosages of 60-80 mg daily and continued for as long as 1-2 weeks before tapering. In line with findings in other fields of medicine, data suggest that pulsed intravenous (IV) steroids may be more effective than oral prednisone in reversing corneal graft rejection. Pulsed steroids (a single IV administration of 500 mg methylprednisolone) have been shown to improve the percentage of graft survival compared with oral steroids in patients who present early (within the first 8 days) in a rejection episode. A nonsignificant trend toward improved survival in all episodes of rejection in favor of pulsed steroids exists. In addition, pulsed steroids reduce the risk of subsequent rejection episodes, which may be a significant benefit in higher risk corneal grafts. Pulsed steroids also avoid prolonged administration of oral steroids.

In all cases of rejection, intraocular pressure should be monitored closely, especially when frequent corticosteroids are used. If necessary, elevated intraocular pressure should be controlled by topical medications to prevent glaucoma and to improve the chance of graft survival.


Surgical Care

No surgical care has proven beneficial during an episode of acute graft rejection.

Some transplant surgeons scrape the donor corneal epithelium to reduce the antigen load.

No solid evidence suggests that removing the donor epithelium is beneficial in reducing the risk of subsequent graft rejection.

If an acute graft rejection episode progresses to graft failure, repeat corneal transplantation may be indicated, including penetrating keratoplasty or endothelial keratoplasty.



No dietary restrictions have been identified.



No activity restrictions have been noted.



Depending on the degree of injury sustained by the graft, graft rejection episodes can progress to graft failure due to rejection.


Long-Term Monitoring

Patients should receive close follow-up care with an ophthalmologist for corneal graft rejection.


Frontiers in Corneal Graft Rejection Therapy

Systemic immunosuppression with cyclosporine in high-risk corneal transplantation has yielded varying results. [13] Cyclosporin A is a potent immunosuppressive agent that has revolutionized transplant therapy by reducing rejection in heart, kidney, liver, and other organ transplants. Cyclosporine is a fungal protein that has a high degree of specificity for T-cell lymphocytes and inhibits T-cell–mediated immune responses. In some studies, systemic cyclosporin A (blood levels 130-170 mcg/L) has been shown to greatly increase the rate of graft survival in high-risk corneal transplantation when used prophylactically for 12 months following transplantation. Cyclosporin A therapy carries known significant risks, including hypertension, renal toxicity, hepatotoxicity, and neurotoxicity; it should be used only after a thorough medical evaluation. Careful postoperative monitoring is essential and is generally best completed in conjunction with other physicians.

Topical administration of cyclosporin A also has been examined [15] and has yielded conflicting results for both prophylaxis and treatment of graft rejection episodes. Substitution of topical cyclosporine for topical corticosteroids may decrease intraocular pressure in cases of postkeratoplasty ocular hypertension or glaucoma but result in an increased risk of graft rejection. [16, 17] Cyclosporin A is not readily able to penetrate the corneal epithelium. Differences in drug vehicle and corneal penetration may account for the different outcomes seen in the use of topical cyclosporin A. Interestingly, collagen shields impregnated with cyclosporin A increase the corneal penetration of cyclosporine and can successfully reverse graft rejection in rabbits. Although methods that improve corneal penetration of cyclosporin A may improve its efficacy, they also may increase its potential systemic adverse effects. Note that blood levels of cyclosporin A have been recorded after topical administration of cyclosporin A in olive oil.

Other potential agents in the treatment of corneal graft rejection include antimetabolites (eg, azathioprine, 6-mercaptopurine) and immunosuppressives (eg, tacrolimus [FK-506], rapamycin). Relatively few studies have been performed using these agents in corneal transplantation, and their role in corneal transplantation therapy has yet to be determined. Each of these medications is associated with significant systemic adverse effects.

Tacrolimus has received more study than the other agents. One group in England reported significant success in preventing and reversing corneal and limbal allograft rejection in high-risk eyes. [18, 19] They found that no patient with therapeutic levels of tacrolimus suffered irreversible graft rejection. Several patients suffered from systemic adverse effects, including irreversible renal failure. In the United States, tacrolimus has only rarely been used in the setting of corneal transplantation. In another study of patients with high-risk corneal transplants treated with systemic tacrolimus, 65% had clear grafts at 2 years. [20] Topical tacrolimus has also been used successfully for the treatment of graft rejection. [21]

One significant issue is that the cost of tacrolimus for this indication is not always covered.