Corneal Graft Failure

Corneal graft failure is the most common reason why corneal transplants stop working, affecting thousands of patients worldwide each year. While the cornea has special properties that usually protect it from rejection, in about one-third of failed grafts, doctors find clear signs that the body’s immune system has attacked the donated tissue.

Table of contents

• What Is Corneal Graft Failure?
• Why the Cornea Usually Resists Rejection
• Main Causes of Graft Failure
• Success Rates and Risk Factors
• The Critical Role of Endothelial Cells
• Signs and Symptoms
• Types of Corneal Graft Rejection
• Treatment Approaches
• Complications Related to Glaucoma Surgery

What Is Corneal Graft Failure?

Corneal graft failure happens when a transplanted cornea stops working properly and can no longer provide clear vision. This is different from graft rejection, which is a specific process where the body’s immune system attacks the donor tissue. While rejection can lead to failure, not all graft failures are caused by rejection^[1].

A graft may fail for various reasons, including problems with the cells that pump fluid out of the cornea, infections, or other eye surface diseases. When doctors use the term “graft failure,” they mean the transplant has stopped functioning and become cloudy, preventing useful vision, regardless of the underlying cause^[2].

Why the Cornea Usually Resists Rejection

The cornea has unique characteristics that help protect it from immune rejection. Both the corneal bed (the tissue where the new cornea is placed) and the anterior chamber (the space inside the front of the eye) are considered “immune-privileged sites”^[1]. This means they have special features that reduce the risk of the immune system attacking foreign tissue.

The cornea lacks blood vessels, which limits how immune system cells can reach it. There are also no nearby lymph nodes or lymphatic vessels, which normally help the immune system detect and respond to foreign tissue. Additionally, the cornea produces fewer proteins that trigger immune responses compared to other body tissues^[2].

However, these protective features can be weakened by long-lasting inflammation, extensive growth of blood vessels into the cornea, and other factors. When this happens, the risk of rejection increases significantly^[2].

Main Causes of Graft Failure

Despite the cornea’s natural protection, immune rejection remains the most common cause of corneal graft failure in all reported studies. In approximately one-third of all failed corneal grafts, doctors observe clear signs of a destructive immune system attack^[1].

Corneal graft rejection is the most common reason for graft failure in the late period after surgery^[2]. The rate of rejection varies widely depending on the type of transplant performed and individual risk factors. In the United States, where approximately 80,000 corneal transplants were performed in 2021, rejection continues to be a major concern for both patients and doctors^[2].

Success Rates and Risk Factors

For patients receiving their first corneal transplant with no blood vessels growing into their corneal bed, the outlook is quite good. Two-year survival rates exceed 90% in these low-risk patients^[1].

However, the picture changes dramatically for patients with high-risk factors. In these cases, two-year survival rates drop to between 35% and 70%. High-risk factors include having blood vessels in the recipient’s corneal bed, previous corneal transplants, certain inflammatory conditions, and a history of chemical burns to the eye^[1].

The type of transplant procedure also affects success rates. Penetrating keratoplasty (full-thickness transplant) has long-term survival rates ranging from 52% to 98.8%, depending on the patient’s specific circumstances. At five years after surgery, 23% of patients had experienced at least one rejection episode, and 37% of those who had rejection went on to experience graft failure^[2].

Newer partial-thickness transplant techniques generally show lower rejection rates. Deep anterior lamellar keratoplasty (DALK), which replaces only the front layers of the cornea, has success rates between 77.0% and 99.3%, with rejection rates of 6% to 19.7%^[2].

The Critical Role of Endothelial Cells

The cells lining the back surface of the cornea, called endothelial cells, are absolutely critical for maintaining corneal clarity. These cells work like tiny pumps, constantly moving fluid out of the cornea to keep it clear^[1].

A rejection episode causes a loss of these donor endothelial cells. Because human endothelial cells cannot repair themselves by dividing to create new cells, any loss is permanent. If too many cells are lost and the density falls below a critical threshold, the cornea swells with fluid and becomes cloudy. This is why endothelial cells are considered the main target in immune rejection responses^[1].

Endothelial decompensation (failure of these cells to function) results either from an acute rejection episode that cannot be reversed, or it develops some time after one or more rejection episodes that were initially treated successfully^[1].

Signs and Symptoms

Patients experiencing graft rejection typically notice one or more of these symptoms: redness of the eye, pain, sensitivity to light (photophobia), and decreased vision^[12].

During an eye examination, doctors look for several clinical findings that suggest rejection. These include swelling of the cornea, deposits on the cornea’s surface, inflammation inside the front chamber of the eye, special deposits called keratic precipitates on the graft, and redness where the cornea meets the white of the eye^[12].

One finding that is particularly characteristic of graft rejection is a “rejection line,” which can appear on either the surface or the inside layer of the cornea^[12].

Types of Corneal Graft Rejection

Corneal graft rejection can affect different layers of the cornea, and recognizing the type helps determine the best treatment approach.

Epithelial rejection occurs at the outer surface of the graft, typically at the edge. Doctors see swollen blood vessels and a raised ridge of surface cells that picks up fluorescent dye during examination. This type may sometimes resolve on its own^[7][12].

Stromal rejection affects the middle layer of the cornea and shows as whitish deposits that can look similar to viral eye infections. This similarity can sometimes lead to misdiagnosis, so doctors must carefully distinguish between the two conditions^[12].

Endothelial rejection is the most common form, occurring in up to 50% of rejection cases. It affects the critical inner cell layer and causes redness where the cornea meets the white of the eye, graft swelling, inflammation inside the eye, deposits on the inner cornea, and a distinctive pattern called a Khodadoust line. This line consists of a sharp border between swollen and clear areas of the cornea, with white blood cells visible along the edge^[12].

Understanding how severe the rejection is matters greatly for graft survival. Research shows that after a rejection episode, graft failure occurs in up to one-third of cases within six months^[12].

Treatment Approaches

Treatment for graft rejection depends on which type of rejection is occurring, but in all cases, corticosteroids (steroid medications) applied directly to the eye are the main treatment^[7].

For epithelial or stromal rejection without involvement of the endothelial layer, topical steroid eye drops such as dexamethasone 0.1% or prednisolone acetate 1% are prescribed four to six times daily until signs of rejection disappear. The medication is then slowly reduced over time. Although these forms of rejection usually don’t lead to graft failure, they should still be treated aggressively because they show the immune system has recognized the graft and more serious rejection could follow^[7].

Endothelial rejection requires much more intensive treatment. Eye drops must be used every hour while awake and as often as possible at night for two to three days, then every two hours while awake. Steroid ointment may be applied at bedtime. Treatment continues until rejection signs resolve, and medications are tapered slowly over several weeks to months. Doctors should continue therapy for at least four weeks even if there’s no response before concluding the graft has failed^[7].

For severe or recurrent rejections, or in high-risk patients, steroids can be given in other ways. Options include injections under the surface tissue of the eye, special collagen shields soaked in steroids and placed on the cornea, or systemic medications. Oral prednisone typically starts at 60-80 mg daily for one to two weeks before being reduced. A single intravenous dose of 500 mg methylprednisolone (called pulsed steroids) has been shown to improve graft survival compared to oral steroids, especially when given early (within the first eight days) of a rejection episode^[7].

For patients with multiple previous graft failures, some doctors use combinations of systemic medications including prednisone, azathioprine, and cyclosporine to prevent rejection in repeat transplants. While these approaches show promise in keeping grafts clear, they require careful monitoring for side effects^[9].

Complications Related to Glaucoma Surgery

Corneal graft failure can also occur as a complication of other eye surgeries. Glaucoma tube implant surgeries (procedures that create new drainage pathways for eye fluid) have become increasingly popular for treating difficult-to-control glaucoma. However, these tubes can cause corneal problems^[3].

Late complications after tube shunt surgery include corneal swelling from persistently low eye pressure, and corneal decompensation (breakdown of corneal clarity) when the tube touches the cornea. If the cornea becomes severely damaged, a penetrating keratoplasty may be needed to restore vision^[3].