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 a day 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 (eg, dexamethasone 0.1%, prednisolone acetate 1%) should be used every hour while awake and as frequently as possible at night for 2-3 days, followed by every two hours while awake. Treatment with higher potency topical ophthalmic steroids (eg, difluprednate) also can be considered. 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 a 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). Another option is a collagen shield soaked in corticosteroids and applied to the cornea combined with frequent corticosteroid eye drops. The shield acts as a depot reservoir for the drug that slowly releases its contents during the period between topical applications.
In cases of severe endothelial rejection or high-risk cases, systemic steroids or immunosuppressants (eg, oral prednisone, IV methylprednisolone, IV cyclosporine) are used, based largely on surgeon judgment and with wide variability in treatment use. [33] Oral prednisone generally is started at dosages of 60-80 mg daily and continued for as long as 1-2 weeks before tapering. 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. [39] A nonsignificant trend toward improved survival in all episodes of rejection in favor of pulsed steroids exists. In addition, pulsed steroids reduce the risk for 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. However, no solid evidence suggests that removing the donor epithelium is beneficial in reducing the risk for subsequent graft rejection.
If an acute graft rejection episode progresses to graft failure, repeat corneal transplantation may be indicated, typically endothelial keratoplasty.
Diet
No dietary restrictions have been identified.
Activity
No activity restrictions have been noted.
Complications
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
Topical corticosteroids are the mainstay of treatment after corneal transplant surgery, including full-thickness and partial-thickness keratoplasties. Given significantly lower rejection rates among lamellar and endothelial keratoplasty, there have been reports of cessation of long-term steroids; however, most authors and clinicians recommend prolonged or indefinite use of low-potency topical steroids in the absence of contraindications. [11] In high-risk cases, topical immunosuppressive agents have been used adjunctively with goals of reducing the onset or exacerbation of graft rejection, as well as reducing dependence of long-term topical steroids. For example, these agents may be employed in the postoperative period in cases of steroid-induced glaucoma. [33] However, data regarding their efficacy in reducing graft rejection remains unclear. Topical cyclosporine A (CsA, at concentrations of 0.05-2%) and topical tacrolimus (commonly 0.03%) have shown promise, whereas topical sirolimus and systemic mycophenolate mofetil (MMF) remain other studied options. [11, 40, 41] In a recent randomized study involving patients receiving high-risk PK, graft rejection among patients receiving topical tacrolimus 0.1% exhibited a significantly decreased graft rejection rate compared with the group receiving CsA 1%. [42] Current data also supports the use of systemic MMF in high-risk keratoplasties, with statistically significant reductions in occurrences of rejection compared with controls and mostly reversible side effects. [43, 44] However, It always is important to consider adverse effect profiles before starting any of these immunosuppressant agents – a thorough medical evaluation and review of patient medical history are warranted prior to initiation. Cost, affordability, and insurance coverage are other important considerations.
Other immunosuppressive modalities that may be explored as monotherapy or adjunctive therapy to topical or systemic steroids include basiliximab (monoclonal antibody negatively inhibiting activated T cells via the CD25 receptor), [45] rapamycin, [46] azathioprine, [47] corneal shields to enhance CsA penetration, [48] intracameral steroids, and oral tacrolimus. [49] Further human studies are needed to elucidate their efficacy in reducing rejection alongside varying safety profiles.
Reducing corneal neovascularization has the potential to reduce graft rejection, but many of the treatments to reduce corneal neovascularization have limited efficacy including off-label use of subconjunctival bevacizumab or ranibizumab, topical bevacizumab, or fine-needle thermal cauterization of visible corneal neovascularization. [50, 51] Corneal crosslinking also has been explored to reduce corneal neovascularization, prior to or concurrent with high-risk PK. [52]
Future studies and innovations in the frontiers of regenerative stem cells, [53] gene transfer, [54] and xenotransplantation [55] may one day play a role in corneal health and graft survival.
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This severely vascularized cornea would be at high risk for graft rejection following a penetrating keratoplasty. This patient experienced Stevens-Johnson syndrome.
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This is an example of an acute graft rejection episode. Note the graft edema, Descemet folds, and keratic precipitates.
