Inflammatory Mediators of Glaucoma After Corneal Transplantation (AH-Tears)

Study Overview
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Brief Summary
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Glaucoma is the most common threat to vision rehabilitation in patients with Boston keratoprosthesis type 1 (KPro) implantation. High intraocular pressure (IOP) is the most important risk factor for glaucoma and may lead to irreversible retinal and optic nerve damage. Glaucoma drainage device (GDD) surgery is used to divert aqueous humor (AH) from the anterior chamber to an external reservoir to regulate flow and decrease the IOP. The AH is in direct communication with any corneal damage or surgery undertaken in the anterior chamber and can serve as a source of potential biomarkers to detect early inflammatory or glaucomatous changes. Tears are also one of the most accessible and non-invasive source of biomarkers, especially in Kpro eyes where the central optic allows communication between aqueous humor and the tears at the surface of the eye. The investigators propose to test the hypothesis that distinct inflammatory mediators in the AH and tears can serve as biomarkers for glaucoma development and progression after CT, making them specifically amenable to targeted treatment strategies to minimize vision loss.

Detailed Description
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The only curative treatment for corneal diseases that progress to vision loss is corneal transplantation (CT). Penetrating keratoplasty (PK) involves the surgical replacement of the host cornea with a donor cornea. In cases of graft failure with standard PK, the Boston keratoprosthesis (KPro), the most common artificial cornea, can alternatively restore vision rapidly. A current limitation in the use of KPro is that the vast majority of patients are at high risk of developing glaucoma. Glaucoma contributes to significant ocular morbidity after CT surgery and is the leading cause of irreversible vision loss after CT. High intraocular pressure (IOP) is the most important risk factor for glaucoma and may lead to irreversible retinal and optic nerve damage. Glaucoma is treated using drops or surgery to reduce IOP. When IOP-lowering drugs and laser surgery fail, glaucoma drainage device (GDD) surgery is used to divert aqueous humor (AH) from the anterior chamber to an external reservoir to regulate flow and decrease the IOP. The cause and mechanisms of glaucoma development and progression following CT are still unknown. Neuroinflammation has been suggested to play a key role in glaucomatous damage following CT. The role of inflammatory biomarkers in glaucoma pathogenesis after CT remains poorly understood and must be further studied. The AH is in direct communication with any corneal damage or surgery undertaken in the anterior chamber and can serve as a source of potential biomarkers to detect inflammatory changes in glaucoma. Tears are also one of the most accessible and non-invasive source of biomarkers, especially in Kpro eyes where the central optic allows communication between AH and the tears at the surface of the eye. Full thickness corneal transplantation (penetrating keratoplasty and Boston KPro) and intraocular surgeries for glaucoma, cataract and retina that are required by the participants of the study offer the opportunity to have access to the AH and tears in an accessible and safe way, without additional risks. These samples of AH and tears will be analyzed for multiple inflammatory mediators simultaneously. HYPOTHESIS: The investigators propose to test the hypothesis that distinct inflammatory mediators in the AH and tears can serve as biomarkers for glaucoma development and progression after CT, making them specifically amenable to targeted treatment strategies to minimize vision loss. OBJECTIVES: To examine the (a) presence and (b) concentration of inflammatory mediators in glaucoma after corneal transplantation. To examine the correlation between the presence and concentration of inflammatory mediators and clinical ophthalmological data. To examine the correlation between the inflammatory mediators found in aqueous humor and tears.

Official Title
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Uncovering Inflammatory Mediators of Glaucoma Pathogenesis After Corneal Transplantation in Aqueous Humor and Tears

Conditions
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Glaucoma, Corneal Transplantation, Inflammation

Intervention / Treatment
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* Other: Sampling of tears
* Other: Sampling of aqueous humor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years old or older Informed consent Ability to be followed for the duration of the study Presence of ocular disease specified for each group Specific criteria for each group: Group 1 : have no glaucoma and no systemic diseases Group 2 : need to have glaucoma filtration surgery without prior corneal transplantation Group 3 : need to have corneal transplantation (penetrating keratoplasty or Boston keratoprosthesis), with or without glaucoma Group 4 : need to have intraocular surgery after prior corneal transplantation (penetrating keratoplasty or Boston keratoprosthesis) Group 5 : need to have glaucoma filtration surgery with prior corneal transplantation (penetrating keratoplasty or Boston keratoprosthesis) Exclusion Criteria: Aged less than 18 Inability to give informed consent Presence of ocular diseases other than those studied herein

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 5 groups will be compared: participant needing cataract surgery without glaucoma participant needing glaucoma filtration surgery without prior corneal transplantation (penetrating keratoplasty or Boston keratoprosthesis) participant needing corneal transplantation (penetrating keratoplasty or Boston keratoprosthesis), with or without glaucoma participant needing intraocular surgery (cataract, retina or glaucoma) with prior corneal transplantation (penetrating keratoplasty or Boston keratoprosthesis) participant needing glaucoma filtration surgery with prior corneal transplantation (penetrating keratoplasty or Boston keratoprosthesis)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Cataract surgery only<br>Participants needing cataract surgery, without glaucoma or any other corneal diseases. | Other: Sampling of tears<br>* Tears will be collected at the start of any of surgery for which the participant presents. It will be collected using a tear-wash method to allow for protein collection. 0.06 ml of saline solution 0.9% will be instilled on the ocular surface. The participants will turn their eyes with eyes closed. The tear-wash fluid will be collected from the inferior fornix of the eye using a micropipette. Tear-was fluid will be placed in codified tubes stored at -150 degrees.<br>Other: Sampling of aqueous humor<br>* Aqueous humor will be collected at the start of any of surgery for which the participant presents. A paracentesis of the anterior chamber is a common first step in intraocular surgeries. Aqueous humor is then commonly diluted with viscoelastic material injected inside the anterior chamber to avoid collapse of the anterior chamber. This way, the aqueous humor is commonly diluted or replaced entirely by the viscoelastic material injected during intraocular surgeries. A volume of 0.1 ml of aqueous humor will be taken by paracentesis using a 30-gauge needle connected to a 1-ml syringe. It consists of less than half of the total volume of aqueous humor in the eye. Aqueous humor will be placed in codified tubes stored at -80 degrees.<br>|
| Sham Comparator: Glaucoma surgery only<br>Participants needing glaucoma filtration surgery, without any prior corneal transplantation. | Other: Sampling of tears<br>* Tears will be collected at the start of any of surgery for which the participant presents. It will be collected using a tear-wash method to allow for protein collection. 0.06 ml of saline solution 0.9% will be instilled on the ocular surface. The participants will turn their eyes with eyes closed. The tear-wash fluid will be collected from the inferior fornix of the eye using a micropipette. Tear-was fluid will be placed in codified tubes stored at -150 degrees.<br>Other: Sampling of aqueous humor<br>* Aqueous humor will be collected at the start of any of surgery for which the participant presents. A paracentesis of the anterior chamber is a common first step in intraocular surgeries. Aqueous humor is then commonly diluted with viscoelastic material injected inside the anterior chamber to avoid collapse of the anterior chamber. This way, the aqueous humor is commonly diluted or replaced entirely by the viscoelastic material injected during intraocular surgeries. A volume of 0.1 ml of aqueous humor will be taken by paracentesis using a 30-gauge needle connected to a 1-ml syringe. It consists of less than half of the total volume of aqueous humor in the eye. Aqueous humor will be placed in codified tubes stored at -80 degrees.<br>|
| Experimental: Corneal transplantation<br>Participants needing corneal transplantation (penetrating keratoplasty or Boston keratoprosthesis), with or without glaucoma. This allows analyzing samples at baseline (time 0), at the time of the corneal transplantation procedure. | Other: Sampling of tears<br>* Tears will be collected at the start of any of surgery for which the participant presents. It will be collected using a tear-wash method to allow for protein collection. 0.06 ml of saline solution 0.9% will be instilled on the ocular surface. The participants will turn their eyes with eyes closed. The tear-wash fluid will be collected from the inferior fornix of the eye using a micropipette. Tear-was fluid will be placed in codified tubes stored at -150 degrees.<br>Other: Sampling of aqueous humor<br>* Aqueous humor will be collected at the start of any of surgery for which the participant presents. A paracentesis of the anterior chamber is a common first step in intraocular surgeries. Aqueous humor is then commonly diluted with viscoelastic material injected inside the anterior chamber to avoid collapse of the anterior chamber. This way, the aqueous humor is commonly diluted or replaced entirely by the viscoelastic material injected during intraocular surgeries. A volume of 0.1 ml of aqueous humor will be taken by paracentesis using a 30-gauge needle connected to a 1-ml syringe. It consists of less than half of the total volume of aqueous humor in the eye. Aqueous humor will be placed in codified tubes stored at -80 degrees.<br>|
| Experimental: Intraocular surgery following corneal transplantation<br>Participants needing intraocular surgery (cataract, retina or glaucoma), with prior corneal transplantation (penetrating keratoplasty or Boston keratoprosthesis). This allows analyzing samples during the potential development or progression of glaucoma in participants who have previously undergone corneal transplantation. | Other: Sampling of tears<br>* Tears will be collected at the start of any of surgery for which the participant presents. It will be collected using a tear-wash method to allow for protein collection. 0.06 ml of saline solution 0.9% will be instilled on the ocular surface. The participants will turn their eyes with eyes closed. The tear-wash fluid will be collected from the inferior fornix of the eye using a micropipette. Tear-was fluid will be placed in codified tubes stored at -150 degrees.<br>Other: Sampling of aqueous humor<br>* Aqueous humor will be collected at the start of any of surgery for which the participant presents. A paracentesis of the anterior chamber is a common first step in intraocular surgeries. Aqueous humor is then commonly diluted with viscoelastic material injected inside the anterior chamber to avoid collapse of the anterior chamber. This way, the aqueous humor is commonly diluted or replaced entirely by the viscoelastic material injected during intraocular surgeries. A volume of 0.1 ml of aqueous humor will be taken by paracentesis using a 30-gauge needle connected to a 1-ml syringe. It consists of less than half of the total volume of aqueous humor in the eye. Aqueous humor will be placed in codified tubes stored at -80 degrees.<br>|
| Experimental: Glaucoma surgery following corneal transplantation<br>Participants needing glaucoma filtration surgery, with prior corneal transplantation (penetrating keratoplasty or Boston keratoprosthesis). This allows analyzing samples once glaucoma is confirmed in participants who have previously undergone corneal transplantation. | Other: Sampling of tears<br>* Tears will be collected at the start of any of surgery for which the participant presents. It will be collected using a tear-wash method to allow for protein collection. 0.06 ml of saline solution 0.9% will be instilled on the ocular surface. The participants will turn their eyes with eyes closed. The tear-wash fluid will be collected from the inferior fornix of the eye using a micropipette. Tear-was fluid will be placed in codified tubes stored at -150 degrees.<br>Other: Sampling of aqueous humor<br>* Aqueous humor will be collected at the start of any of surgery for which the participant presents. A paracentesis of the anterior chamber is a common first step in intraocular surgeries. Aqueous humor is then commonly diluted with viscoelastic material injected inside the anterior chamber to avoid collapse of the anterior chamber. This way, the aqueous humor is commonly diluted or replaced entirely by the viscoelastic material injected during intraocular surgeries. A volume of 0.1 ml of aqueous humor will be taken by paracentesis using a 30-gauge needle connected to a 1-ml syringe. It consists of less than half of the total volume of aqueous humor in the eye. Aqueous humor will be placed in codified tubes stored at -80 degrees.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of inflammatory mediators in aqueous humor | Concentration (pg/mL) of inflammatory mediators in aqueous humor measured by ELISA multiplex. | Baseline | 
| Concentration of inflammatory mediators in tears | Concentration (pg/mL) of inflammatory mediators in tears measured by ELISA multiplex. | Baseline | 
| Correlation between tears and aqueous humor | Correlation between the concentration of inflammatory mediators in tears and aqueous humor, determined by Spearman correlation test. | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of anterior structural changes | Incidence of anterior structural changes in the eye (iris, iridocorneal angle, trabecular meshwork, cornea), evaluated by anterior segment optical coherence tomography (AS-OCT) imaging. | Baseline, 3 months, 6 months, 12 months | 
| Change of visual acuity through time | Change of visual acuity at each time point compared to baseline visual acuity. The visual acuity is measured using the Snellen chart. | Baseline, 3 months, 6 months, 12 months | 
| Proportion of participants with visual field loss of 30% or more | Proportion of participants with visual field loss of 30% or more at each time point, measured using the automated Humphrey 24-2 visual field. The loss of 30% or more of visual field is calculated using the baseline test as reference. | Baseline, 3 months, 6 months, 12 months | 
| Intraocular pressure | Evaluation of intraocular pressure (units of mmHg) at each time point using Goldman tonometry. | Baseline, 3 months, 6 months, 12 months | 
| Incidence of posterior structural changes | Incidence of posterior structural changes in the eye (optic nerve and retina), evaluated by spectral domain optical coherence tomography (SD-OCT) imaging. | Baseline, 3 months, 6 months, 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Boston keratoprosthesis type 1, Glaucoma, Aqueous Humor, Tears, Inflammation, Penetrating keratoplasty