eMedicine Specialties > Ophthalmology > Cornea

Corneal Graft Rejection

Author: Jason Jacobs, MD, Clinical Faculty, Department of Ophthalmology, University of Colorado Health Sciences Center
Coauthor(s): Michael Taravella, MD, Director of Cornea and Refractive Surgery, Rocky Mountain Lions Eye Institute; Associate Professor, Department of Ophthalmology, University of Colorado School of Medicine
Contributor Information and Disclosures

Updated: Sep 25, 2007

Introduction

Background

Although described for more than 100 years, corneal transplantation has become increasingly common since the 1960s. Over 40,000 transplants were performed in 1990 in the United States and Canada. The 5-year failure rate for corneal grafts is approximately 35%; corneal graft rejection is the most common cause of graft failure in the late postoperative period.

Pathophysiology

The term graft rejection refers to the specific immunologic response of the host to the donor corneal tissue. As it is a specific process, it should be distinguished from other causes of graft failure that are not immune mediated. A corneal graft that has suffered this immunologic response may or may not ultimately fail. Some physicians distinguish between graft reaction, which is reversible with medical therapy, and graft rejection, in which the immunologic end stage has been reached and the process is irreversible. Other physicians simply use graft rejection to refer to this immunologic process at any stage of its development, noting that some cases will progress to graft failure because of rejection. This second terminology is used in this article since it is in line with terminology used in other types of organ transplantation. Furthermore, at the time of presentation, it is not possible to know with certainty whether an immune process is reversible.

Frequency

United States

Over 40,000 transplants were performed in 1990 in the United States and Canada. The 5-year failure rate for corneal grafts is approximately 35%.

Mortality/Morbidity

Corneal graft rejection is the most common cause of graft failure in the late postoperative period.

Race

No known difference in corneal graft rejection between different races exists.

Sex

No known sex predilection for corneal graft rejection exists.

Age

Host age may influence the risk of corneal graft rejection. Although it is not certain, some investigators have concluded that a lower risk of corneal graft rejection exists for hosts who are older than 60 years. It is generally believed that infants have higher rates of graft rejection than adults.

Clinical

History

Diagnosis of corneal graft rejection should be made only in grafts that have remained clear for at least 2 weeks following keratoplasty. By observing this guideline, graft rejection can be distinguished easily from other causes of graft failure that are more common in the early postoperative period (eg, primary donor failure). It is possible, but quite rare, for a sensitized host to exhibit immunologic graft rejection before this 2-week period. Graft rejection has been observed to occur as late as 20 years after transplantation. Incidence of graft rejection is greatest in the first year following transplantation.

• No symptoms are related universally to corneal graft rejection. Although, astute patients may complain of the following:
  • Decrease in visual acuity
  • Redness
  • Pain
  • Irritation
  • Photophobia
• Depending on the severity of the graft rejection, patients may be asymptomatic. Any patient with a corneal graft should be instructed to seek ophthalmologic care if these symptoms occur for more than a few hours.

Physical

• Animal models of graft rejection reveal that the 3 corneal layers, epithelium, stroma, and endothelium, can be rejected separately. Although these separate rejection processes have been observed in humans, it is important to realize that many patients will manifest combinations of epithelial, stromal, and endothelial rejection.
• Epithelial rejection presents in 1 of 2 manners, as follows:
  • The first type is characterized by an irregular, elevated epithelial rejection line that stains with fluorescein or rose bengal. The rejection line progresses rapidly across the cornea over several days to 2 weeks. A variant of this presentation may occur in which the epithelial rejection line takes the form of a ring, concentric with the limbus, which begins peripherally at the graft-host junction and progresses by shrinking centrally to a point. The rejection line represents a region of destruction of donor epithelium; the resulting epithelial defect is covered by host epithelium that grows inward from the remaining host cornea and limbus to cover the graft.
  • The second type of epithelial rejection is characterized by the presence of subepithelial infiltrates. These infiltrates consist of leukocytes and frequently have an appearance similar to the subepithelial infiltrates seen in adenoviral keratoconjunctivitis. These lesions may change location and shape over time, and they generally disappear on their own after several weeks.
  • Both types of epithelial rejection are steroid responsive, but, in many cases, the patient is either asymptomatic or has symptoms only of minimal irritation. As a result, the patient may not present to the ophthalmologist during these episodes. Although epithelial rejection generally is self-limited and tends not to cause visual disturbance on its own, it should be treated when found on examination as it may herald a more severe endothelial rejection.
• Stromal rejection: Generally, stromal rejection in humans accompanies endothelial rejection and is difficult to demonstrate alone. It is characterized by peripheral full-thickness haze with limbal injection in a previously clear graft. An arc-shaped infiltrate may be noted peripherally at the graft-host junction that progresses centrally.
• Endothelial rejections
  • Classic endothelial rejection presents with an endothelial rejection line (Khodadoust line) that usually begins at a vascularized portion of the peripheral graft-host junction and progresses, if untreated, across the endothelial surface over several days. The rejection line consists of mononuclear white cells that damage endothelial cells as the line sweeps across the endothelium.
  • Generally, a mild-to-moderate anterior chamber reaction is present. The damaged endothelium is unable to properly dehydrate the corneal graft; as a result, the donor cornea is clear ahead of the rejection line and is cloudy and edematous behind it.
  • A second variant of endothelial rejection is more diffuse in character, with scattered keratic precipitates and an anterior chamber reaction indicative of endothelial rejection and damage. In this type of endothelial rejection, stromal edema typically is not localized, but rather generalized throughout the graft, consistent with the generalized endothelial damage. The combination of keratic precipitates, an anterior chamber reaction, circumcorneal injection, and regions of corneal edema should be diagnosed as corneal graft rejection. In some cases, it may be difficult to distinguish graft edema from rejection and graft edema from endothelial insufficiency. Since rejection may be reversible, it is best in these situations to treat patients as if they have graft rejection.

Causes

• Risk factors for rejection
  • A great deal of energy has been expended in trying to determine clinical risk factors for corneal graft rejection. Since corneal graft rejection is the leading cause of graft failure in the late postoperative period, it would be useful to be able to identify and treat those patients at highest risk for graft rejection. Unfortunately, patients undergoing corneal transplantation represent a heterogeneous population, and it is difficult to prove that certain factors uniformly increase the risk of graft rejection. Differences in study designs exacerbate these difficulties.
  • Potential risk factors for corneal graft rejection are outlined below.
    • Host corneal vascularization
    • Larger and eccentric grafts
    • Human leukocyte antigen A (HLA-A) and human leukocyte antigen (HLA-B) and ABO blood type incompatibility
    • Presence of donor epithelium upon transplantation
    • History of previous graft failure of any cause
    • Bilateral penetrating keratoplasty
    • Pretransplantation corneal tissue media and preservation
    • Host age (lower risk with age >60 y, much higher risk in infants)
  • Of these risk factors, the only factor that has been decidedly proven to increase the risk of rejection is host corneal vascularization. Multiple studies have confirmed an increased risk of corneal graft rejection with increasing host vascularization, ranging from rates of 0-10% of graft rejection in avascular host corneas to rates of up to 25-50% in severely vascularized host corneas. The precise cause for this increased risk is unclear, although it is believed to be due to the relative loss of immune privilege that accompanies the usually avascular central cornea.
  • The other risk factors listed above remain in some dispute. In some cases, multiple studies have yielded contradictory results, whereas, in other cases, an insufficient number of clinical studies exist. In all cases, these risk factors will be modified by the particular clinical situation. In particular, studies regarding the role of the major histocompatibility complex and HLAs have yielded contradictory data, although several studies indicate a trend toward a decreased incidence of graft rejection occurring in matched corneal grafts. At the present time, corneal grafts are not HLA typed and matched, unlike other organ transplants. Further evidence is needed to justify the added cost and complexity of performing HLA typing prior to corneal transplantation.

• Search for CME/CE on This Topic »

• Case-Control Study of Subconjunctival Triamcinolone Acetonide Injection Vs Intravenous Methylprednisolone Pulse in the Treatment of Endothelial Corneal Allograft Rejection