Medscape is available in 5 Language Editions – Choose your Edition here.


Corneal Graft Rejection Treatment & Management

  • Author: Michael Taravella, MD; Chief Editor: Hampton Roy, Sr, MD  more...
Updated: Feb 18, 2016

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.


Frontiers in Corneal Graft Rejection Therapy

Systemic immunosuppression with cyclosporine in high-risk corneal transplantation has yielded varying results.[12] 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[14] 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.[15, 16] 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.[17, 18] 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.[19]

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

Contributor Information and Disclosures

Michael Taravella, MD Director of Cornea and Refractive Surgery, Rocky Mountain Lions Eye Institute; Professor, Department of Ophthalmology, University of Colorado School of Medicine

Michael Taravella, MD is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, Eye Bank Association of America

Disclosure: Received none from AMO/VISX for consulting.


William G Gensheimer, MD Capt, USAF, Ophthalmologist, Warfighter Eye Center, Malcolm Grow Medical Clinics and Surgery Center, Joint Base Andrews

William G Gensheimer, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Society of Military Ophthalmologists

Disclosure: Nothing to disclose.

Specialty Editor Board

Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, Association for Research in Vision and Ophthalmology, American Glaucoma Society

Disclosure: Nothing to disclose.

Christopher J Rapuano, MD Professor, Department of Ophthalmology, Jefferson Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director of Refractive Surgery Department, Wills Eye Hospital

Christopher J Rapuano, MD is a member of the following medical societies: American Academy of Ophthalmology, American Ophthalmological Society, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, International Society of Refractive Surgery, Cornea Society, Eye Bank Association of America

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cornea Society, Allergan, Bausch & Lomb, Bio-Tissue, Shire, TearScience, TearLab<br/>Serve(d) as a speaker or a member of a speakers bureau for: Allergan, Bausch & Lomb, Bio-Tissue, TearScience.

Chief Editor

Hampton Roy, Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy, Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

Additional Contributors

Jack L Wilson, PhD Distinguished Professor, Department of Anatomy and Neurobiology, University of Tennessee Health Science Center College of Medicine

Jack L Wilson, PhD is a member of the following medical societies: American Association of Anatomists, American Heart Association, American Association of Clinical Anatomists

Disclosure: Nothing to disclose.

  1. Eye Bank Association of America 2014 Eye Banking Statistical Report. Available at Accessed: June 16, 2015.

  2. Tan DT, Dart JK, Holland EJ, Kinoshita S. Corneal transplantation. Lancet. 2012 May 5. 379(9827):1749-61. [Medline].

  3. Ritter T, Wilk M, Nosov M. Gene therapy approaches to prevent corneal graft rejection: where do we stand?. Ophthalmic Res. 2013. 50(3):135-40. [Medline].

  4. Panda A, Vanathi M, Kumar A, Dash Y, Priya S. Corneal graft rejection. Surv Ophthalmol. 2007 Jul-Aug. 52 (4):375-96. [Medline].

  5. Stulting RD, Sugar A, Beck R, Belin M, Dontchev M, Feder RS, et al. Effect of donor and recipient factors on corneal graft rejection. Cornea. 2012 Oct. 31 (10):1141-7. [Medline].

  6. Ang M, Wilkins MR, Mehta JS, Tan D. Descemet membrane endothelial keratoplasty. Br J Ophthalmol. 2016 Jan. 100 (1):15-21. [Medline].

  7. Guerra FP, Anshu A, Price MO, Giebel AW, Price FW. Descemet's membrane endothelial keratoplasty: prospective study of 1-year visual outcomes, graft survival, and endothelial cell loss. Ophthalmology. 2011 Dec. 118 (12):2368-73. [Medline].

  8. Cornea Donor Study Investigator Group, gal RL, Dontchev M, Beck RW, Mannis MJ, Holland EJ, et al. The effect of donor age on corneal transplantation outcome results of the cornea donor study. Ophthalmology. 2008 Apr. 115 (4):620-626.e6. [Medline].

  9. Keenan TD, Jones MN, Rushton S, Carley FM. Trends in the indications for corneal graft surgery in the United Kingdom: 1999 through 2009. Arch Ophthalmol. 2012 May 1. 130(5):621-8. [Medline].

  10. Lee HS, Kim MS. Influential factors on the survival of endothelial cells after penetrating keratoplasty. Eur J Ophthalmol. 2009 Nov-Dec. 19(6):930-5. [Medline].

  11. Monnereau C, Bruinsma M, Ham L, Baydoun L, Oellerich S, Melles GR. Endothelial cell changes as an indicator for upcoming allograft rejection following descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2014 Sep. 158 (3):485-95. [Medline].

  12. Coster DJ, Williams KA. The impact of corneal allograft rejection on the long-term outcome of corneal transplantation. Am J Ophthalmol. 2005 Dec. 140 (6):1112-22. [Medline].

  13. Sel S, Schlaf G, Schurat O, Altermann WW. A novel ELISA-based crossmatch procedure to detect donor-specific anti-HLA antibodies responsible for corneal allograft rejections. J Immunol Methods. 2012 Jul 31. 381(1-2):23-31. [Medline].

  14. Bertelmann E, Pleyer U. Immunomodulatory therapy in ophthalmology - is there a place for topical application?. Ophthalmologica. 2004 Nov-Dec. 218(6):359-67. [Medline].

  15. Perry HD, Donnenfeld ED, Kanellopoulos AJ, Grossman GA. Topical cyclosporin A in the management of postkeratoplasty glaucoma. Cornea. 1997 May. 16 (3):284-8. [Medline].

  16. Perry HD, Donnenfeld ED, Acheampong A, Kanellopoulos AJ, Sforza PD, D'Aversa G, et al. Topical Cyclosporine A in the management of postkeratoplasty glaucoma and corticosteroid-induced ocular hypertension (CIOH) and the penetration of topical 0.5% cyclosporine A into the cornea and anterior chamber. CLAO J. 1998 Jul. 24 (3):159-65. [Medline].

  17. Sloper CM, Powell RJ, Dua HS. Tacrolimus (FK506) in the management of high-risk corneal and limbal grafts. Ophthalmology. 2001 Oct. 108(10):1838-44. [Medline].

  18. Magalhaes OA, Marinho DR, Kwitko S. Topical 0.03% tacrolimus preventing rejection in high-risk corneal transplantation: a cohort study. Br J Ophthalmol. 2013 Nov. 97(11):1395-8. [Medline].

  19. Joseph A, Raj D, Shanmuganathan V, Powell RJ, Dua HS. Tacrolimus immunosuppression in high-risk corneal grafts. Br J Ophthalmol. 2007 Jan. 91 (1):51-5. [Medline].

  20. Boisjoly HM, Tourigny R, Bazin R, Laughrea PA, Dube I, Chamberland G, et al. Risk factors of corneal graft failure. Ophthalmology. 1993 Nov. 100(11):1728-35. [Medline].

  21. Chen YF, Gebhardt BM, Reidy JJ, Kaufman HE. Cyclosporine-containing collagen shields suppress corneal allograft rejection. Am J Ophthalmol. 1990 Feb 15. 109(2):132-7. [Medline].

  22. Hegde S, Beauregard C, Mayhew E. CD4(+) T-cell-mediated mechanisms of corneal allograft rejection: role of Fas-induced apoptosis. Transplantation. 2005 Jan 15. 79(1):23-31. [Medline].

  23. Hill JC. Systemic cyclosporine in high-risk keratoplasty. Short- versus long-term therapy. Ophthalmology. 1994 Jan. 101(1):128-33. [Medline].

  24. Hill JC. The use of cyclosporine in high-risk keratoplasty. Am J Ophthalmol. 1989 May 15. 107(5):506-10. [Medline].

  25. Hill JC, Maske R, Watson P. Corticosteroids in corneal graft rejection. Oral versus single pulse therapy. Ophthalmology. 1991 Mar. 98(3):329-33. [Medline].

  26. Hwang DG, Stern WH, Hwang PH, MacGowan-Smith LA. Collagen shield enhancement of topical dexamethasone penetration. Arch Ophthalmol. 1989 Sep. 107(9):1375-80. [Medline].

  27. Khodadoust AA, Silverstein AM. Transplantation and rejection of individual layers of the cornea. Investigative Ophthalmologic and Visual Sciences. Vol 8.: 180-195.

  28. Reidy JJ, Gebhardt BM, Kaufman HE. The collagen shield. A new vehicle for delivery of cyclosporin A to the eye. Cornea. 1990 Jul. 9(3):196-9. [Medline].

  29. Smolin G, Thoft RA. The cornea. Scientific Foundations and Clinical Practice. 3rd ed. Lippincott William & Wilkins; 1994.

  30. Wang M, Lin Y, Chen J, Liu Y, Xie H, Ye C. Studies on the effects of the immunosuppressant FK-506 on the high-risk corneal graft rejection. Yan Ke Xue Bao. 2002 Sep. 18(3):160-4. [Medline].

  31. Wilson SE, Kaufman HE. Graft failure after penetrating keratoplasty. Surv Ophthalmol. 1990 Mar-Apr. 34(5):325-56. [Medline].

This severely vascularized cornea would be at high risk for graft rejection following a penetrating keratoplasty. This patient experienced Stevens-Johnson syndrome.
This is an example of an acute graft rejection episode. Note the graft edema, Descemet folds, and keratic precipitates.
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.