What is Corneal Graft Rejection?
The cornea and the front part of your eye can protect themselves from immune system responses to some degree. But even with this protection, corneal grafts, or cornea transplants, often fail due to the recipient’s immune system rejecting the donor tissue. For first-time recipients without any pre-existing conditions in their cornea, the success rate for a two-year graft survival is usually above 90%. But, if the recipient has factors that increase the risk of rejection, this success rate can drop to between 35% and 70%.
In one-third of all corneal graft failures, the immune system is observed actively damaging the new tissue. The graft’s failure leads to a decrease in specific cells called ‘endothelial cells’, which are needed for the cornea to stay transparent. Because human endothelial cells don’t naturally replace themselves, a decrease in these cells could result in a loss of clarity in the recipient’s vision. This issue occurs when the number of cells dips below the minimum amount required to prevent swelling in the cornea.
The loss of these cells can happen either due to an irreversible rejection of the graft or after one or more rejections that have been temporarily reversed with treatment. Even though it’s generally easier to reverse acute graft rejections in the cornea compared to other organ transplants, finding effective prevention strategies for high-risk corneal graft recipients remains a challenge.
Historically, the first successful corneal graft was performed in 1906. But it wasn’t until 50 years later when the first case of a previously clear graft becoming cloudy was described. It was suggested that the cause of the graft deterioration was due to the donor being sensitized by the recipient. This theory was later confirmed in a study using rabbits as a model for corneal transplants. It was shown that donor corneas could indeed trigger an immune reaction. Studies conducted on rats and mice have further helped us understand why graft rejection happens.

congestion, well opposed graft host junction, stromal edema, suture marks,
stromal scar with ghost vessels at 2 o’clock adjacent to the graft host
junction. Close observation reveals deep vascularization of 2 quadrants from 12
to 6 o’clock infiltrating the graft host junction suggestive of a case of
chronic stromal rejection
What Causes Corneal Graft Rejection?
Specific conditions in the eye that is going to receive a donor graft might indicate a high risk of graft failure. High-risk examples include eyes with a lot of blood vessels in it or eyes that have previously rejected a graft and remain inflamed at the time of transplantation.
Other factors that may increase the risk, though the evidence isn’t as strong, include grafts in children, using large-sized donor corneas, or if the donor cornea is very close to the edge of the recipient’s cornea.
It’s also possible for a patient to have more than one of these high-risk factors. Moreover, the patient may also have other issues, like glaucoma or problems with the eye surface, that could lead to a higher chance of graft rejection. Doctors have to check these risk factors before deciding to proceed with an eye graft.
Once the graft is successfully completed, careful measures must be taken to avoid problems after surgery, such as vascular growth on the recipient’s cornea or graft wound, loosened sutures, or graft infections, that can lead to rejection.
Risk Factors and Frequency for Corneal Graft Rejection
Large studies show that 18% to 21% of people receiving a corneal graft (a way of replacing a damaged cornea, the front part of the eye) experience some form of rejection after the transplant. In those who do experience this, successful reversal of the rejection occurs in 50% to 90% of cases.
Most often, rejection happens in the six months following the graft but in some cases, more than 10% of reactions can happen as late as four years after the surgery. This means that all corneal grafts require long-term monitoring as they can be at risk indefinitely. Different types of graft rejections are noted:
- Epithelial rejections, which make up about 2% of cases.
- Subepithelial rejections, which are less common, showing up in around 1% of cases.
- Endothelial rejections, the most common type, with an occurrence rate of 50%.
- Mixed rejections, which occur in about 30% of cases.
- Stromal immune rejections following a specific form of transplantation called deep anterior lamellar keratoplasty, with incidence between 1-24%.
According to the American Academy of Ophthalmology (AAO), in a procedure called Descemet stripping endothelial keratoplasty (DSEK), the average rate of primary graft failure is 5%, and mean endothelial rejection rate is 10%.
In another procedure, Descemet membrane endothelial keratoplasty, the graft rejection rate ranges from 0-5.9% with an average of 1.9%. The rate of both primary and secondary graft failure was 1.7% and 2.2%, respectively. Another study found about 14% of grafts were rejected due to issues with sutures and blood vessel growth before and after the surgery.
Signs and Symptoms of Corneal Graft Rejection
Corneal graft rejection can present in different ways. Some patients with epithelial or stromal rejection may have no symptoms or mild eye discomfort. Still, those with endothelial rejection often experience visual disturbances and symptoms of iritis. Early signs of rejection include anterior chamber cell infiltration without other abnormal signs, but as symptoms progress, signs such as aggregated cells on the graft endothelium and localized edema can develop. Visibility of graft precipitates implies irreversible endothelial cell loss, leading to stroma edema in severe cases.
Detailed examinations can reveal characteristic signs of graft rejection. These may include rejection lines in the epithelium, subepithelial focal infiltrates, corneal edema, appearance of keratic precipitates, neovascularization, and more. A graft is considered failed if the rejection does not clear after two months of intensive treatment.
There are several preoperative, intraoperative, and postoperative risk factors that can increase the chance of graft rejection. Factors can include, but are not limited to, the antigen load of the donor, previous graft failure or rejection, ocular surface diseases, and age. Other factors can include the thickness of the graft, the presence of corneal vascularization, and prior history of ocular inflammatory disease.
- Various types of graft rejection can present with different clinical features:
- Epithelial rejection often presents with an epithelial rejection line beginning from the graft host junction and extending to the donor graft.
- Hyperacute stromal rejection may present with congestion, patchy stromal infiltrates and edema, and haze in the stroma.
- Chronic stromal rejection typically shows a predominance of subepithelial infiltrates on the graft.
- Stromal and endothelial rejection in a regraft starts from the host cornea with diffuse cells, but does not include an endothelial rejection line.
- Chronic focal rejection can present with pain, redness, blurred vision, epithelial and stromal edema, Khodadoust line, and mild anterior chamber activity.
It is important to note that stromal graft rejection has unique characteristics. For example, the rejection band migrates away from the vascularized cornea. Also, endothelial rejection can be classified into possible, probable, and definite categories based on the presentation of inflammation, KPs on the endothelium, graft edema, and the presence of an endothelial rejection line
Finally, graft rejection in a regraft has its own distinct features and usually has a higher risk and higher incidence of graft failure.
Testing for Corneal Graft Rejection
Visual acuity testing is essential for tracking the condition of eye grafts. The Snellen test, which measures both corrected and uncorrected visual acuity, needs to be taken at every visit. It can tell doctors how clear the graft is and whether the body is rejecting it.
Another important factor to monitor after corneal transplantation is intraocular pressure, as it can indicate the development of secondary glaucoma, a serious complication. A method called non-contact tonometry is preferred for this measurement to avoid touching the transplanted tissue and risking rejection or damage.
Refraction testing and retinoscopy are also crucial to determine the best vision correction. They show the required lens power (spherical and cylindrical), any vision distortion caused by sutures (astigmatism), and the overall lens power needed to correct vision (spherical equivalent).
For cases with high astigmatism, Scheimpflug imaging is recommended. It provides information about the varying curvature of the lens, which can help plan suture removal to reduce vision distortion.
Another essential tool is specular microscopy. It is used before surgery to verify the health of the donor tissue, and after surgery to check the transplanted tissue’s condition in endothelial keratoplasty patients.
Anterior Segment Optical Coherence Tomography is used to check for any thinning or opacity in the eye tissue and to ensure the graft is attached properly after DSEK and DMEK procedures.
Fluorescein staining is used to detect issues like dry eyes, surface staining, or any damages to the outer layer of the eye.
A B-scan ultrasound can help assess the status of the retina in cases when it’s hard to see directly, like during graft rejection or when the pupil is small. It can also explain vision loss when the graft appears clear.
Macular optical coherence tomography can be used to identify any swelling or formation of a membrane on the macula, which is the central part of the retina responsible for detailed vision.
Treatment Options for Corneal Graft Rejection
The goal of treating cornea transplant rejection is to quickly stop the rejection, save the cells in the donated cornea, and maintain its normal function. With corneal transplants, a highly effective treatment is frequently administering a topical corticosteroid such as dexamethasone 0.1%. Cornea transplants are on the surface of the eye, so the medication can be applied directly to the area. In many cases where the steroid does not stop the rejection, it’s usually because it was noticed too late or the treatment didn’t start quickly enough, causing major losses in donor cornea cells.
Sometimes, using other steroids can be beneficial. For some patients, a single dose of a steroid called methylprednisolone administered intravenously (injected into a vein) can be more effective than consuming it orally, but only if the patient had the rejection symptoms for less than eight days. Having a second dose does not provide more benefits as compared to the first dose. However, there’s no proven significant benefit of administering this unintentional steroid with a topical steroid related to corneal transplant function or the time taken for another rejection episode to occur within the two years following the treatment.
The best approach to corneal transplant rejection is prevention, and there are multiple ways to do so before, during, and after the operation.
Before the operation, the goal is to minimize the differences between the host and donor cornea and reduce the potential for the body to reject the donor cells. During the operation, surgeons try to prevent factors like a poorly positioned or loose stitches graft or an uneven junction between the graft and the host, which can increase the risk of rejection. After the operation, frequent check-ups and reducing the host’s immune reaction to the donor graft can prevent rejection episodes. The administration of steroids on time and stitches management can help prevent rejections by reducing blood vessel development related to the stitches.
Once cornea transplant rejection has occurred, it is crucial to detect and treat it with aggressive steroid therapy as soon as possible. Patients should be informed about the symptoms of graft rejection, such as pain, redness, and diminished vision, and advised to immediately report if any of these symptoms occur. When this condition occurs, corticosteroid medication is the treatment of choice.
Topical steroids are often preferred since they penetrate the anterior chamber of the eye well and have potent properties to suppress the immune response. The regimen, which varies from center to center, includes hourly application for 2-3 days, then 6 times for 15 days, and then 4/3/2/1 times for 3 months each. In case of acute graft rejection, the hourly regimen should be maintained until the signs of reversal are noted or until the rejection is halted. Topical steroid therapy should be followed up with intravenous steroids.
Alternatively, systemic corticosteroids can be given either orally or via injection. Oral prednisolone should be administered in a higher-than-usual dosage of around 60-80 mg daily and then reduced based on the response to treatment for about 6-8 weeks.
There are other non-steroid medications available as well, including Cyclosporin A and Azathioprine, but these are generally used in the early stages of graft rejection. Treatment plans should be adapted individually based on the risk evaluation for corneal transplant rejection.
Yet, the most effective approach is a combination of corticosteroids and immunomodulators like Cyclosporin A for both treating acute graft rejection and preventing future episodes. Researchers continue to explore new medications for better outcomes in treating and preventing corneal graft rejection.
What else can Corneal Graft Rejection be?
When dealing with eye conditions, your doctor may be investigating several issues like:
- Disciform keratitis, an inflammation of the cornea
- Sterile or infectious endophthalmitis, which is an inflammation of the interior of the eye
- Recurrent herpetic keratitis, a recurring eye infection caused by the herpes virus
- Endothelial decompensation, a problem with the layer of cells at the back of the cornea
- Endothelitis, an inflammation of the endothelium, the inner layer of the cornea
- Epithelial down growth, a condition where one layer of eye tissue grows into another layer
- Fuchs heterochromic iridocyclitis, a rare condition that causes changes in the color and function of the iris
- Late graft failure, which means a transplant has failed some considerable time after the operation
- Infectious keratitis, an infectious condition that causes inflammation of the cornea
- Posner-Schlossman Syndrome (PSS), a condition that causes sudden, often painless vision loss
Your doctor will look at all these possibilities and use appropriate tests to find the precise issue.
What to expect with Corneal Graft Rejection
The success of a corneal transplant can depend on various factors such as careful pre-surgery examination, accurate timing, how the donor tissue was stored and transported, the surgical method used, detailed post-surgery checks, early discovery and management of rejection, and quick use of corticosteroids.
The clarity of vision after the surgery depends on how well the graft and the host’s eye align, how central and clear the graft is, and how well it survives after the operation. It’s estimated that about 75% of cases where the body initially rejects the transplant can be managed in a way that still leads to excellent vision. According to some analysis, approximately half of the grafts that are attached to blood vessels, and two-thirds of those that aren’t, can be reversed if rejection occurs.
However, the chances of success decline when multiple transplants are needed. Younger patients face a higher risk of having their bodies reject the graft because their immune systems are stronger. In cases where a graft is done again, the level of blood vessels in the failed graft can impact the success of the next one. One study graded the blood vessels in the graft and scored the rejection, which influenced the chances of success.
Additionally, the chances of a successful outcome are also affected by the patient’s understanding of the procedure, adherence to medication regimens, how soon they seek treatment after rejection, their financial status, and regular follow-up sessions. Even though factors like matching donor and recipient human leukocyte antigen (HLA) and blood type (ABO) can play a role, there are no definitive guidelines for this.
Possible Complications When Diagnosed with Corneal Graft Rejection
After having certain eye procedures, there’s a chance you could experience a number of side effects. These include:
- Failed graft: This happens when the transplanted tissue doesn’t work as expected.
- Persistent epithelial defect: This is a non-healing wound on the surface of the eye.
- Infective keratitis: This is an infection of the cornea, the clear tissue at the front of the eye.
- Corneal melt: This is a serious condition where the cornea begins to break down.
- Pseudocornea: This is when scar tissue forms a new surface on the front of the eye.
- Descemetoceles: This occurs when a layer of the cornea starts to bulge outward.
- Corneal scarring: Scars form on the cornea following injury or inflammation.
- Band shaped keratopathy: This is a type of clouding of the cornea.
- Urrets Zavalia syndrome: A rare condition characterized by a fixed, dilated pupil and other eye symptoms.
- Secondary glaucoma: This is a type of glaucoma that occurs as a result of another eye condition.
- Angle-closure glaucoma: A type of glaucoma where the normal fluid channels in the eye are blocked.
- Recurrent uveitis: This is a recurring inflammation of the middle layer of the eye.
- Occlusio pupillae: This is when the pupil of the eye becomes obscured or closed off.
- Seclusio pupillae: Similar to occlusio pupillae, but implies a more total closure of the pupil.
- Festooned pupil: The pupil becomes irregular and scalloped in shape.
- Cystoid macular edema: This is a condition that causes fluid-filled cysts to form on the retina, impacting vision.
- Endophthalmitis: This is a serious inflammation of the inside of the eye, often caused by infection.
- Panophthalmitis: This is a severe inflammation that affects all parts of the eye.
- Ciliary shutdown: This is when the ciliary body inside the eye stops working, leading to vision problems.
- Phthisis: A condition where the eye shrinks and hardens, resulting in vision loss.
- Permanent blindness: Losing vision entirely.
Recovery from Corneal Graft Rejection
If a patient shows signs of their body rejecting a graft, they should be taken to the hospital immediately. Treatment will likely include an intravenous (directly into the vein) dose of strong steroids (100 mg dexamethasone or 500 mg prednisolone) in a mixture of a type of sugar solution (5% dextrose) twice a day for three days. This is paired with topical steroids applied directly to the affected area (1% prednisolone or 0.1% dexamethasone), initially every two hours for three days then less frequently over the following 15 days. The dosage schedule decreases (from 6 times a day to just once) over three months, depending on how the individual responds to the treatment.
Additional medications can include drugs like 5% homatropine twice a day (relieves muscle spasms in the eye and prevents irregular connections from forming), and 0.5% timolol also twice a day (to avoid a condition called secondary glaucoma related to elevated eye pressure).
If a patient needs regrafting, the treatment plan remains the same. It’s essential to teach patients about the importance of steroids in keeping the graft healthy. They should be warned about the negative consequences of not following the suggested treatment and potential side effects of excessive steroid use.
Each patient should be given a schedule of their medication and dates for future doctor visits as they leave the hospital. Then, at each visit, the patient should be checked for signs of graft success (clarity), the sharpness of vision, eye pressure, and any side effects from surgery or their medication.
Preventing Corneal Graft Rejection
Before undergoing a corneal transplant, it is crucial for patients to understand the potential risks and benefits. Patients should be made aware of the possibility of the body’s immune system rejecting the transplant, and the importance of taking steroid medication regularly and on time to help prevent this.
Understanding the signs and symptoms of graft rejection is also important; should this happen, seeking immediate treatment from a cornea specialist is essential. Additionally, information on the expected quality of vision, the likelihood of the transplant remaining clear, and how the surgery might affect the patient’s overall quality of life should also be provided. In this way, patients can be prepared and proactive throughout the entire process.