Search for indicators of an upcoming allograft rejection after DMEK

The cornea is the most anterior transparent part of the eye and consists of
five layers which include: epithelium, Bowman*s layer, stroma, Descemet
membrane, and endothelium. The cornea transmits light to the lens and retina
and therefore, abnormalities in the cornea such as observed e.g. with Fuchs
endothelial dystrophy (FED) or bullous keratopathy (BK) can significantly
reduce vision. In these diseases, mainly the endothelial cells, which main
function is to keep the cornea thin and transparent, are affected. This results
in corneal swelling and loss of transparency, which greatly impairs the
transmission of light. The abnormal corneal layers may be replaced by healthy
tissue from a deceased donor, i.e. a corneal transplant.
There are several types of corneal transplantation, such as penetrating
keratoplasty (PK), in which all corneal layers (including the healthy lamellae)
are replaced by that of a donor, and lamellar keratoplasty, in which ideally
only the affected parts of the cornea are replaced. For FED, a lamellar
technique called DMEK in which only the diseased DM and endothelium are
replaced was developed by NIIOS about 10 years ago. Compared to PK,
suture-related complications are eliminated, ocular infections and recovery
time are considerably reduced whereas visual outcome is improved. In addition,
the risk of graft rejection is reduced: from 5-15% after PK, to about 2.5%
after DMEK. Although the chance of a clinically manifested graft rejection
after DMEK is low, it is still a serious complication because when not
recognized in time, it may lead to graft failure requiring repeat surgery. The
second surgery in turn might further increase the risk of graft rejection of
the second transplant.
However, some DMEK patients do not experience any clinical signs and symptoms
and report no subjective complaints during the rejection episode, which
increases the risk of irreversible damage to the DMEK-graft when the rejection
episode is not diagnosed and treated in time. Therefore, the prediction, early
detection, and timely treatment of graft rejection are of the utmost importance
to maintain graft survival and functionality. If not detected and treated on
time, an upcoming allograft rejection may irreversibly damage the graft which
eventually requires repeat transplantation.
For some DMEK patients with an allograft rejection, we could retrospectively
identify signs of an upcoming rejection by either routine Scheimpflug imaging
of the cornea or by routine specular microscopy imaging of the endothelial cell
layer. However, not all DMEK patients with a clinically manifested rejection
episode showed clear signs of these alterations. Either the alterations were
too subtle to be detected with the aforementioned imaging techniques or they
might have been present in other corneal layers or in the aqueous humour. In
either case, addition of two other routine ophthalmic examination techniques
for the detection of an upcoming allograft rejection might provide valuable
information: confocal microscopy and laser flare photometry. Confocal
microscopy is a non-invasive, in vivo imaging technique. This is a reliable
clinical diagnostic tool which we standardly use in our clinic to assess
patients that show signs of endothelial cell alterations as detected by
specular microscopy. It provides detailed images of endothelial cell morphology
and also shows if other corneal layers such as the stroma, are affected. It may
also detect changes in the endothelium which may not be visible by specular
microscopy. Laser flare photometry, on the other hand, is used to
non-invasively measure intraocular inflammation levels.
In this prospective study, we would like to extend the use of confocal
microscopy and laser flare photometry to identify parameters associated with an
upcoming or sub-clinical graft rejection episode. Early detection of these
parameters would allow prompt intervention with medications to possibly avoid
irreversible graft damage or (ideally) prevent clinical manifestation of the
allograft rejection.
These two diagnostic tools may allow the detection of intraocular inflammatory
signs that can not be visualized on slit-lamp or specular microscopy
examination. Thus, an upcoming allograft rejection or eyes that may be at risk
to develop an allograft rejection may be earlier recognized. This may then
allow us in the future to monitor the inflammation status, as well as the
response to treatment more precisely.
Therefore, in this observational study we intend to employ both tools next to
our standard ophthalmic examinations after DMEK. The investigators intend to
perform a prospective observational study with a cohort of patients that
undergo DMEK in order to identify early signs of an upcoming allograft
rejection that may not be detected with conventional devices used for
evaluating post DMEK eyes.
Importantly, not only DMEK patients may benefit from the results of this study,
but also patients that received other keratoplasty techniques such as PK and
Descemet (automated) stripping endothelial keratoplasty where the chance of
graft rejection is considerably higher than after DMEK. Preventing graft
failure and thus not requiring a new transplant would indirectly also alleviate
the problem of corneal donor tissue shortage and it would lower cost burden on
our healthcare system (corneal transplantation is the most common type of
human-transplant surgery with over 1400 corneas transplants done annually in
The Netherlands only).

To identify parameters that may *announce* or even predict an upcoming
allograft rejection after DMEK using routine ophthalmic diagnostic devices.

Observational study.

250 patients with Fuchs endothelial dystrophy, bullous keratopathy or failed
previous corneal transplants scheduled for DMEK transplantation will be
included.
In this observational study, we will prospectively perform study related
measurements at regular follow-up visits. Patients that received DMEK at our
institute are normally followed seven times during the first year (before
surgery, 1 day, 1 week and at 1, 3, 6, 9, 12 months), and optionally four times
in the second and third year (e.g. at 18, 24, 30 and 36 months postoperative).
Confocal microscopy will be used to scan the parts of the cornea to analyze its
cellular structures including (activated) keratocytes, immune cells and nerves,
and laser flare photometry will be use to evaluate intraocular inflammation
levels.
These examinations will be added to our routine standard specular microscopy
that is used to determine the central endothelial cell density and other
standard ocular examinations using Scheimpflug imaging (Pentacam HR, Oculus,
Wetzlar, Germany), anterior segment optical coherence tomography (Slit-Lamp
OCT, Heidelberg Engineering GmbH, Heidelberg, Germany), slit-lamp photography
(Topcon Medical Europe BV) and ophthalmic examinations (slit-lamp examination,
visual acuity evaluation, eye pressure measurement, etc.).
*

During every follow-up visit, patent will have to undergo two additional
examinations (using confocal microscopy and laser flare photometry). The total
duration of the additional examinations is about 30-45 minutes.

The risk for participating in this study is the same as for patients that are
not included in the study since the DMEK procedure itself is not altered.
Burden is limited to the additional time and costs needed for these additional
measurements. Assessments will be scheduled at the time of regular visits.
Study related measurements include confocal microscopy and laser flare
photometry next to the standard ophthalmic measurements. Extra measurements
will take about 30-45 minutes.
The only recognized potential health burden is that during the confocal
microscopy examination the surface layer of cornea (epithelium) may be rubbed
off, which usually heals within several days without any remaining damage. This
risk is the same as with other ophthalmic contact procedures, like the standard
intraocular pressure measurements performed by applanation.


We believe that health benefits from study participation outweigh risks and
burdens to a research subject.