BLOG: Corneal transplant procedures carry different risks
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Following up on our previous entries introducing various corneal transplant surgeries and preoperative considerations, we now move on to the topic of corneal transplant rejection.
Compared to other transplants, the cornea is a relatively great tissue for transplantation and is, in most cases, easily managed with a simple topical steroid. (Fun fact: The first corneal transplant, a penetrating keratoplasty performed in 1905, is also considered the first successful organ transplant ever.)
Currently there is no genetic matching for corneal transplants. Several factors are in our favor concerning the innate immune privilege of the cornea: the cornea is avascular, alymphatic (and largely lacking indigenous antigen-presenting cells necessary to mount a cell-mediated immune response) and even has reduced human leukocyte antigen (HLA) expression on corneal cell surfaces.
Immune response
In order to more fully discuss corneal transplant rejection, we should briefly review some immunology. If we haven’t already lost you, we have HLA markers on corneal cells including epithelium, stromal keratocytes and endothelium. These HLA markers are the major histocompatibility complex proteins in humans – how our bodies determine self-cells from invading non-self. After a corneal transplant, donor epithelium will be replaced by host tissue in about 2 weeks. Keratocytes in the stroma are a reservoir of graft antigen that takes about 1 year to replace with host cells; however, they are few and far between, mounting a less reactive immune response. Collagen, making up the majority of the stroma, is inert. Collagen is not a target for immune response, but any of these HLA-tagged cells are.
Despite the immune privilege the cornea enjoys, we all know there are cases where things go wrong. Why is there a risk of graft rejection, and why do the rates vary dramatically between the different transplant surgeries?
Corneal transplants
We’ve discussed the epithelium and keratocytes but are left to consider the endothelium. As we know, this layer of vital corneal cells cannot be replaced. Therefore, if donor endothelium is being rejected by the host, there is a greater risk of permanent graft failure. With this in mind, we can start to understand why rejection rates vary among the different corneal transplants: penetrating keratoplasty (PK), Descemet’s stripping automated endothelial keratoplasty (DSAEK), Descemet’s membrane endothelial keratoplasty (DMEK) and deep anterior lamellar keratoplasty (DALK).
PK replaces all layers (and, therefore, we end up with donor epithelium, keratocytes and endothelium) and has the highest rate of rejection up to 20% (Rahman et al.). Additionally, PK involves sutures that can invite angiogenesis and, with that, neovascularization, lymphatics, immune response and rejection are all the more likely to follow. Some providers recommend lifelong prednisolone use for PK patients; however, we rarely get the chance to trial taking these patients off a steroid as they tend to self-discontinue after a time.
DSAEK replaces endothelium, Descemet’s and a thin layer of stroma and has a 12% rejection rate (Anshu et al.). DMEK, replacing endothelium and Descemet’s only, has a risk of about 1% rejection (Gorovoy), less than DSAEK. Patients undergoing both DSAEK and DMEK are usually tapered off a steroid over 12 to 18 months. DALK effectively just replaces stroma with its sparse keratocytes and has less than a 1% rate of rejection (Sari et al.). This transplant leaves the host endothelium intact, significantly decreasing the risk of rejection, and results in shorter healing time/steroid use compared to other transplants. In DALK, the steroid is often tapered over 9 months or more.
Interestingly, antigen-presenting cells that are sparse in the cornea are found in the aqueous humor of the anterior chamber where they can interact with donor endothelium, depending on the type of corneal transplant. If we’re not donor matching our PKs, forget the 20% rejection rate – Why do they ever work? Well, thankfully, the body is even smarter than we knew: The cornea actually mounts a decreased immunological response against foreign invaders compared to other parts of the body, promoting immune tolerance rather than mounting immune response to an antigen. This is a delayed response known as anterior chamber-associated immune deviation (ACAID). This is novel; instead of the usual priming of antigen-presenting cells with the eventual production of antibodies against a foreign invader, our corneas actively decrease immune response or, thinking about it another way, increase tolerance. In this way, ACAID works to protect the eye from the collateral damage of an immune response, such as scarring and opacification of the cornea. This is not an accident or immunological ignorance but an active process that suppresses what would otherwise be destructive immunological responses in what should be clear tissue.
Recognizing rejection
However, despite all of the immune privilege enjoyed by the human cornea, it can be overcome by trauma, infection and chronic inflammation, all very real possibilities in a postsurgical eye. Keeping transplant rejection from becoming failure starts by educating the patient to monitor for symptoms such as discomfort, light sensitivity, redness and decreased vision. Behind the slit lamp, it is vital to recognize signs, including corneal edema, keratic precipitates or KPs (specifically KPs of the corneal graft but not on the peripheral recipient cornea), corneal vascularization, stromal infiltrates, subepithelial infiltrates, iritis and, in extreme cases, a Khodadoust line.
Some define graft failure as immunological rejection that does not clear in 2 months, therefore appropriate treatment is paramount. Anti-VEGF injections can be used to treat corneal neovascularization. For epithelial and subepithelial rejections, which have a higher rate of reversibility, topical corticosteroids can be started at six times per day or every hour (dosage will depend on severity of rejection and strength of steroid prescribed), with a slow, tapered dosing over several months. In contrast, severe endothelial rejection can require topical corticosteroids prescribed as frequently as multiple times an hour with very close monitoring. Significant cases may call for systemic therapy such as oral prednisone. Unsurprisingly, endothelial rejection alone accounts for more than half of corneal transplant failures.
Corneal grafts
Even without rejection, the longevity of corneal grafts can vary greatly. All donor grafts lose endothelium with transplantation alone, and one should consider that the majority of graft donors are older with subsequent reduced endothelial density even prior to manipulation and transplantation. More than half of U.S. donors are 60 or older, despite the fact that most eye banks have an age limit of 65 for cornea donors. While studies show that donor age is not an important factor in transplant success, eligible donor tissue can have endothelial cell density as low as 2,300 cells/mm2 (Lass et al.). With this in mind, it should be no surprise that PK often decompensate in 30+ years and there is the possible need for repeat corneal transplant surgery in a patient’s lifetime, especially younger patients. (For example, PK transplants a few decades old can present with Fuch’s-like changes. These patients may benefit from a DMEK on their PK!) DMEK and DSAEK can endure for 20 years or longer. DMEK may possibly have less durability than DSAEK, while a DALK leaves the host’s endothelium intact and is likely to last a patient’s lifetime.
Different risks
To wrap up, there are different risks for different transplant surgeries, and one must consider the level(s) of cornea affected by disease. A PK transplant is full thickness, DSAEK/DMEK replace endothelium, and DALK effectively replaces the stroma. For these patients, surgical planning is always a balance between the most appropriate transplant, graft longevity, recovery time, potential visual outcome and risk of complication, including the different rates of rejection for different corneal transplants.
When it comes down to it, the cornea remains a great tissue for transplantation with immune privilege as an avascular and alymphatic tissue with ACAID, all of which increases immune tolerance to an ocular antigen such as transplanted tissue. When taking all of these factors into account and selecting and treating our patients appropriately, these can be life-changing surgeries.
Join us next month when we’ll discuss corneal transplant suture manipulation, transplant-specific risks, recovery and expected time to visual stability.
References:
Anshu A, et al. Ophthalmology. 2012;doi:org/10.1016/j.ophtha.2011.09.019.
Gorovoy MS. Cornea. 2014;doi:10.1097/ICO.0000000000000023.
Lass J, et al. Arch Ophthalmol. 2010;doi:org/10.1001/archophthalmol.2010.128.63.
Rahman I, et al. Eye. 2009;doi:10.1038/eye.2008.305.
Sari E, et al. Am J Ophthalmol. 2013;doi:org/10.1016/j.ajo.2013.03.007.