High-risk Penetrating Keratoplasty Research Articles

Predictors And Associated Outcomes Of Adherence To Treatment In Russian Patients Undergoing Corneal Transplantation

Corneal blindness affects approximately 8 million people worldwide. The effectiveness of keratoplasty depends on several factors, including surgical technique, clinical characteristics of the patients, and social factors such as their adherence to treatment. Objective — To analyze nonattendance of doctor’s appointments and associated clinical outcomes in Russian patients who underwent high-risk and low-risk penetrating keratoplasty (PKP). Material and Methods — We conducted a retrospective cohort study to analyze the pre- and postoperative records of patients who underwent PKP. The low-risk group included 28 people with keratoconus (their mean age was 33±3 years), while high-risk group included 54 people with corneal opacity of various etiologies (their mean age was 67±13 years). The study assessed adherence to treatment by examining attendance at postoperative physician visits. Successful corneal transplant engraftment was considered favorable outcome, whereas graft failure or opacification was considered adverse outcome. The duration of observation was 12 months. Results — Patients in the low-risk group were twice as likely to attend postoperative appointments compared with patients in the high-risk group (p=0.0001). Patients over 70 years of age showed lower adherence to treatment (p=0.016), while those with higher education had significantly improved appointment attendance (p=0.017). Moreover, poor adherence increased the odds of adverse PKP outcome at 12 months in high-risk patients (OR=4.31; p=0.045). Conclusion — Failure to attend postoperative appointments in the high-risk group was associated with older patient age and lower education level, and correlated with adverse clinical outcome in Russian patients.

Topical tacrolimus for high-risk corneal transplantation: a randomized, clinical trial

BackgroundThe prevalence of rejection is 10–30% in penetrating keratoplasty (PKP) case, and the rate is higher in cases of high-risk patients. Although using topical corticosteroids is a standard method for management the rejection of post-PKP patients, it may not be sufficiently potent in high-risk patients. Topical administration of tacrolimus (TAC) may be effective in suppression rejection after corneal transplantation. This study aimed to investigate the efficacy and safety of topical TAC in high-risk PKP patients in Japan.MethodsThis study was a single centre, single-blinded, randomized controlled trial. Patients with a history of PKP, graft rejection, atopic dermatitis, or deep corneal neovascularisation who underwent PKP were enrolled. They were randomly assigned to receive 0.1% TAC ophthalmic suspension or artificial tear (AT) up to week 52 after surgery. All participants received 0.1% betamethasone up to week 13 after surgery then they received 0.1% fluorometholone up to week 52. The incidence of immunological rejection during the observation period was the main outcome measure in this study.ResultsThirty patients were enrolled in this study, and 12 eyes in the TAC group and 13 eyes in the AT group completed the study, respectively. Five out of 30 patients discontinued participation after providing informed consent. No serious adverse effects were developed in patients who received 0.1% TAC ophthalmic suspension. No rejection episodes occurred in the TAC group, while one eye in the AT group had rejection. Graft clarity, best spectacle-corrected visual acuity, intraocular pressure, and corneal endothelial cell density were not significantly different between the TAC and AT groups.ConclusionOur results demonstrated that good tolerability of 0.1% TAC ophthalmic suspension. However, we failed to demonstrate its efficacy in preventing immunological rejection in high-risk patients undergoing PKP.Trial registrationThis study was first registered in the University Hospital Medical Information Network (UMIN000029669, Date of registration: November 1, 2017). With the enforcement of the Clinical Trial Act in Japan, the study re-registered in the Japan Registry of Clinical Trials (jRCTs031180342, Date of registration: March 18, 2019).

Suppression of Neovascularization by Topical and Subconjunctival Bevacizumab After High-Risk Corneal Transplantation

To assess the effectiveness of topical and subconjunctival bevacizumab in suppressing vascularization in graft and host bed after high-risk corneal transplantation. Secondary analysis of prospective, randomized, double-blind, placebo-controlled multicentric clinical trial. The study includes patients aged > 18 years who underwent high-risk penetrating keratoplasty, which was defined as corneal vascularization in ≥ 1 quadrants of the corneal graft and host bed, excluding the limbus. Patients were randomized to treatment and control groups. The patients in the treatment group received subconjunctival injection of bevacizumab (2.5 mg/0.1 ml) on the day of the procedure, followed by topical bevacizumab (10 mg/ml) 4 times per day for 4 weeks. The patients in control group received injection of vehicle (0.9% sodium chloride) on the day of procedure, followed by topical vehicle (carboxymethylcellulose sodium 1%) 4 times a day for 4 weeks. Vessel and invasion area of vessels in the corneal graft and host beds. This study included 56 eyes of 56 patients who underwent high-risk corneal transplantation, with equal numbers in the bevacizumab and vehicle (control) treatment groups. The mean age of patients who received bevacizumab was 61.2 ± 15.9 years, and the mean age of those treated with vehicle was 60.0 ± 16.1 years. The vessel area at baseline was comparable in the bevacizumab (16.72% ± 3.19%) and control groups (15.48% ± 3.12%; P= 0.72). Similarly, the invasion areas were also similar in the treatment (35.60% ± 2.47%) and control (34.23% ± 2.64%; P= 0.9) groups at baseline. The reduction in vessel area was significantly higher in the bevacizumab-treated group (83.7%) over a period of 52 weeks compared with the control group (61.5%; P < 0.0001). In the bevacizumab-treated group, invasion area was reduced by 75.8% as compared with 46.5% in the control group. The vessel area was similar at 52 weeks postprocedure in cases of first (3.54% ± 1.21%) and repeat (3.80% ± 0.40%) corneal transplantation in patients who received bevacizumab treatment. In the vehicle-treated patients, the vessel area was significantly higher in repeat (9.76% ± 0.32%) compared with first (8.06% ± 1.02%; P < 0.0001) penetrating keratoplasty. In the bevacizumab treatment group, invasion areas at week 52 were comparable in first (11.70% ± 3.38%) and repeat (11.64% ± 1.74%) procedures, whereas invasion area was significantly higher in repeat (27.87% ± 2.57%) as compared with first (24.11% ± 2.17%) penetrating keratoplasty in vehicle-treated patients. In patients undergoing vascularized high-risk corneal transplantation, bevacizumab is efficacious in reducing vascularization of corneal graft and host bed, thereby reducing the risk of corneal graft rejection in vascularized host beds. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A new method to treat persistent corneal erosions after high-risk keratoplasty

Purpose: to compare the effectiveness of conventional preserved amnion and amnion saturated with platelet-rich (PRP) plasma lysate for the treatment of persistent corneal erosions (PCE) after high-risk keratoplasty.Materials and methods. 40 patients with persistent corneal erosions after high-risk penetrating keratoplasty, followed up for 12 months, were divided into two clinical groups of 20 people each. The main group of patients, aged 34 to 84, received Flexamer amniotic membrane + PRP lysate, while the comparison group, aged 41 to 80, received Flexamer amniotic membrane only. Amniotic membrane coating was used in persistent corneal erosions of penetrating keratoplasty after unsuccessful conservative treatment. The amnion was sewn 2 mm from the limb with a continuous suture and covered with a soft contact lens. As a source of platelets, we used the blood of healthy volunteers, from which platelet-rich plasma with platelet concentration of over 1000 thousand/µl was taken, which was then frozen at -40 °C and defrosted at 0…4 °C to obtain PRP lysate. The criteria for evaluating the effectiveness of both groups were the times of epithelialization, the number of amniotic membrane coatings, and the number of preserved transplants at the end of the follow-up.Results. Lyophilized amniotic membrane saturated with autologous PRP lysate growth factors was shown to be biocompatible. It was found to be safe for the patients, to reduce the epithelialization time, to reduce the number of operations required to cover the PÑE with the amnion, and to increase the likelihood of successful transparent and translucent engraftment of a penetrating keratograft.Conclusion. The use of a lyophilized amniotic membrane enriched with growth factors of autologous PRP lysate is a promising method for the treatment of PCE of the penetrating corneal graft after high-risk keratoplasty.

Bevacizumab in High-Risk Corneal Transplantation: A Pilot Multicenter Prospective Randomized Control Trial

To determine the efficacy of local (subconjunctival and topical) bevacizumab (Avastin) treatment in patients undergoing vascularized high-risk corneal transplantation. Pilot, prospective, randomized, double-blind, placebo-controlled clinical trial conducted at 5 clinical centers in the United States, India, and Brazil. Patients aged > 18 years undergoing high-risk penetrating keratoplasty, defined as corneal neovascularization (NV) in 1 or more quadrants ≥2 mm from the limbus or extension of corneal NV to the graft-host junction in a previously failed graft. Patients were randomized to receive subconjunctival bevacizumab (2.5 mg/0.1 ml) or placebo at the time of surgery, followed by topical bevacizumab (10 mg/ml) or topical placebo, administered 4 times per day for 4 weeks. The 52-week endothelial immune rejection rate. Ninety-two patients were randomized to receive bevacizumab (n= 48) or control (n= 44). The 52-week endothelial rejection rate was 10% in the bevacizumab group and 19% in the control group (P= 0.20). Post hoc, extended follow-up at the lead study site showed an endothelial rejection rate of 3% in the bevacizumab group and 38% in the control group (P= 0.003). Treatment with bevacizumab was found to have a hazard ratio of 0.15 (95% confidence interval, 0.03-0.65, P= 0.01) in a post hoc Cox regression analysis. In patients undergoing vascularized high-risk corneal transplantation, there was no statistically significant difference in the rate of endothelial rejection at 1 year in the bevacizumab treatment group compared with the control group. This study may have been underpowered to detect a difference between treatment groups, and taken together, our data suggest that, in the current trial design, bevacizumab has a positive but not (yet) significant effect on endothelial rejection.

Cutting Edge: Novel Treatment Options Targeting Corneal Neovascularization to Improve High-Risk Corneal Graft Survival.

Corneal neovascularization is an important risk factor for graft rejection after keratoplasty, although its role in posterior lamellar keratoplasty is not yet well defined. The aim of this work was to describe clinically available approaches that target corneal neovascularization preoperatively to improve graft survival after subsequent penetrating keratoplasty (PK) and to present findings on Descemet membrane endothelial keratoplasty (DMEK) in eyes with neovascularization. Recent work on the use of anti-vascular endothelial growth factor agents, fine needle diathermy (FND), and corneal collagen crosslinking (CXL) to regress corneal neovascularization before PK is summarized. Furthermore, studies that have investigated the outcome of DMEK in vascularized eyes are presented. Pretreatment of recipient corneas with FND combined with anti-vascular endothelial growth factor agents is an effective method to reduce long-standing corneal neovascularization and results in relatively low rejection rates after subsequent high-risk PK. Peripheral CXL also seems to be a potent method to regress corneal neovascularization, although data on the impact of pretransplant CXL on long-term graft survival are not yet available. There are only limited data on graft rejection rates after DMEK in vascularized eyes, but initial studies indicate that DMEK seems to be a viable therapeutic option when no stromal scars are present. Furthermore, preexisting stromal neovascularization seems to regress after high-risk DMEK. Several angioregressive strategies to treat corneal neovascularization before PK have entered the clinic with promising initial results, which warrants larger trials with longer follow-up. Studies will also have to define the precise role of preexisting corneal neovascularization in high-risk DMEK.

Advances in corneal graft rejection.

Immune rejection after corneal transplantation is a major risk for graft failure. We aim to summarize recent advances in the understanding and management of graft rejection. Immune rejection remains the leading cause of graft failure in penetrating keratoplasty (PKP). While ABO blood type and sex match between donor and recipient may reduce rejection, human leucocyte antigens class II matching in a randomized study did not reduce the risk of rejection in high-risk PKP. Compared with PKP, deep anterior lamellar keratoplasty, descemet stripping automated endothelial keratoplasty, and descemet membrane endothelial keratoplasty have lower immune rejection rates of 1.7-13%, 5-11.4%, and 1.7-2.8%, respectively, based on long-term (5 years and more) studies. Whether immune rejection is a major risk factor for graft failure in these lamellar keratoplasties is unclear. While there have not been major advances in the systemic management of graft rejection, topical nonsteroid agents such as tacrolimus and anti-vascular endothelial growth factor have shown promise in high-risk cases. Immune rejection remains the leading cause of graft failure in PKP. Lamellar keratoplasties have significantly lower rejection rates compared with PKP. The significance of rejection in the failure of lamellar grafts warrants further investigation.

Corneal Transplant Follow-up Study II: a randomised trial to determine whether HLA class II matching reduces the risk of allograft rejection in penetrating keratoplasty

PurposeA randomised trial to test the hypothesis that human leucocyte antigen (HLA) class II matching reduces the risk of allograft rejection in high-risk penetrating keratoplasty (PK).MethodsAll transplants were matched for...

Observation of topical tacrolimus on high-risk penetrating keratoplasty patients: a randomized clinical trial study

Background/ObjectivesTo evaluate the clinical efficacy of topical tacrolimus 0.1% and cyclosporine 1% on high-risk penetrating keratoplasty (PKP) patients.Subjects/MethodsA series of 49 high-risk PKP patients (49 eyes), 20 males, 29 females from the age of 4 months to 74 years of age with the mean of 32.5 from 2012 to 2017 were recruited in this study. The patients were randomly divided into two groups by receiving either topical tacrolimus 0.1% or cyclosporine 1% respectively. Twenty five patients were treated with topical tacrolimus 0.1% and 24 patients with topical cyclosporine 1%. The traditional baseline management on these two groups were Tobramycin and Dexamethasone eye drops in the first 3 weeks and then tapered off. Clinical procedures and postoperative follow-up were documented.ResultsAfter 6–54 months follow-up, with the average of 24 months, 11 of 24 high-risk patients (11 eyes) had graft rejection, the rejection rate was 45.8% in topical cyclosporine 1% group. The rejections occurred from 35 days to 20 months after PKP. Three patients had irreversible rejection. On topical tacrolimus 0.1% group, the rejection occurred in four patients (four eyes) with rejection rate of 16%, and no irreversible rejection was observed. The graft rejection episodes were documented between 23 days and 24 months. As compared with the topical cyclosporine 1%, topical tacrolimus 0.1%, a key immunosuppressant, significantly decreased corneal graft rejection rate (p = 0.02).ConclusionsTopical tacrolimus 01% on high-risk PKP patients significantly prevented corneal graft rejection, and it had less adverse effects and was very safe to high-risk patients as to topical cyclosporine 1%. Further case controlled randomized clinical trial studies are needed to establish the best management option for these high-risk patients.

The effectiveness and safety of topical 0.1% tacrolimus after high-risk penetrating keratoplasty

Objective: To observe the effectiveness and safety of topical 0.1% tacrolimus(FK506) as immunosuppressant in high-risk penetrating corneal transplantation to prevent the immune rejection and to compare the outcomes with topical 1% Cyclosporin A (CsA). Methods: The study consists of 49 patients (50 eyes), who were fitted with the high-risk corneal transplantation standard and undergone the penetrating keratoplasty(PKP) or combined operation in Beijing Tongren hospital between March 2015 to September. With the time sequence, the patients were divided into observation group (FK506 group) and the control group (CsA group). The observation group included 9 females and 16 males with an average age of 57.8±14.8. Twenty-four patients were in the control group (25 eyes), including 10 females and 14 males, with an average age of (45.1±16.2). Observation group was treated with topical 0.1% tacrolimus, and the control group treated with topical 1%CsA. Both groups' treatment combined glucocorticoid as well. Two groups had 1 year follow-up observation. The incidence of rejection was compared by statistical methods of Cox regression. The adverse reactions were graded and compared using Mann-Whitney U test. Results: After one year, 22 cases of the observation group and 23 cases of the control group were accomplished all observations. The rejection rate was 4.54% in observation group and 27.23% in control group. The difference between the groups was statistically significant (χ(2)=4.291, P=0.038). Control group had high rejection rate. Besides, there was no severe side effects happened in both groups. After 1 month after surgery, 36.4% of the observation group showed mild corneal edema. The ratio of mild to moderate corneal edema in the control group was 26.1% and 8.7%. Three months after surgery, 4.5% of the observation group showed mild corneal edema, while 13.0% and 13.0% of the control group was found mild to moderate corneal edema. Six months after surgery, 4.5% of the observation group showed moderate corneal edema. The ratio of mild, moderate to severe corneal edema in the control group was 17.4%, 17.4% and 8.7%. The degree of corneal edema in the control group was more serious in three monthes(Z=-2.770, -2.018, -2.941, P<0.05). The differences in both monthes were statistically significant. Mild neovascularization occurred in the 13.6% of observation group. Mild to severe neovascularization occurred in the 13.0%, 4.3%, and 4.3% control groups. The degree of neovascularization in the control group was higher than that in the observation group(Z=-3.221, P=0.001). The differences in both months were statistically significant. Mild to moderate neovascularization occurred in the 18.2% and 9.1% of observation group. Mild to extremely severe neovascularization occurred in the 17.4%, 26.1%, 4.3% and 4.3% control groups. The degree of neovascularization in the control group was higher than that in the observation group(Z=-1.988, P=0.047).The differences in both monthes were statistically significant. Conclusions: Both 0.1% tacrolimus and 1% cyclosporine A are safe and effective in reducing the rejection after high-risk corneal transplantation. (Chin J Ophthalmol, 2019, 55: 419-427).

Rapamycin Nano-Micelle Ophthalmic Solution Reduces Corneal Allograft Rejection by Potentiating Myeloid-Derived Suppressor Cells' Function.

Allograft rejection is the major cause of corneal allograft failure. Rapamycin (RAPA) has been reported as an effective and novel immunosuppressive agent for patients undergoing corneal transplantation. However, its high water insolubility and low bioavailability have strongly constrained its clinical application. In this study, we successfully developed a RAPA nano-micelle ophthalmic solution and found that corneal allograft survival in recipients treated with RAPA nano-micelle ophthalmic solution was significantly prolonged for more than 2 months, with less inflammatory infiltration, decreased production of pro-inflammatory factors, and elevated recruitment of myeloid-derived suppressor cells (MDSCs). MDSCs from mice treated with RAPA nano-micelle ophthalmic solution could significantly inhibit the proliferation of CD4+T cells through increased expressions of inducible nitric oxidase (iNOS) and arginase-1 (Arg-1). The activity blockade of Arg-1 and iNOS pharmacologically reversed their immunosuppressive ability. Moreover, the effects of RAPA were antagonized by the administration of anti-Gr-1 antibody or by inhibiting the activity of iNOS pharmacologically. In addition, RAPA nano-micelle also effectively alleviated allograft rejection in high-risk rabbit penetrating keratoplasty (PKP) models with corneal vascularization. Collectively, our results demonstrate that RAPA nano-micelle ophthalmic solution could improve the immunosuppressive activity of MDSCs through elevated expression of Arg-1 and iNOS, which highlights the possible therapeutic applications of RAPA against corneal allograft rejection.

Cyclosporine a drug-delivery system for high-risk penetrating keratoplasty: Stabilizing the intraocular immune microenvironment.

Cyclosporine A (CsA) is an essential medication used to prevent corneal allograft rejection. Our preliminary studies revealed that CsA drug-delivery system (DDS) was more effective in preventing high-risk corneal allograft rejection than topical CsA application. However, the impacts of CsA DDS on the intraocular immune microenvironment were not fully elucidated. In the present study, we investigated the effect of CsA DDS on the cornea allograft, aqueous humor, and iris-ciliary body using a rabbit model of high-risk penetrating keratoplasty. New Zealand white rabbits were divided into four groups: a normal control group, an untreated group, a CsA eye drop group and a CsA DDS group. Graft survival was monitored for 12 weeks, and the therapeutic effects of CsA DDS were evaluated at 3 and 12 weeks after high-risk keratoplasty. In the CsA DDS group, the mean graft survival time was significantly prolonged when compared with the untreated and CsA eye drop groups. At all time-points, Langerhans cell density, inflammatory cell density, and central corneal thickness in the CsA DDS group were much lower(all p < 0.01) than the untreated and CsA eye drop groups, in which their parameters were significantly higher than the normal control group (all p < 0.01). Compared with the untreated and CsA eye drop groups, an implanted CsA DDS markedly decreased the CD11b+ and CD8+ T cell infiltration in the corneal grafts. CsA DDS treatment also greatly reduced the CD4+ T cell density and the expression of interferon-gamma, interleukin-2 (IL-2), IL-6, CD80, and CD86 mRNA both in the corneal graft and iris-ciliary body (all p < 0.01). Moreover, CsA DDS significantly reduced the IL-2 level in aqueous humor (p < 0.01). Taken together, our results suggest that CsA DDS implanted into the anterior chamber create a relative immunosuppressive microenvironment in the corneal graft, iris-ciliary body, and aqueous humor. Stabilizing the intraocular immune microenvironment could partially elucidate the mechanism of CsA DDS in suppressing corneal graft rejection.

Observation on the efficacy of Tacrolimus eye drops for preventing rejection after high-risk corneal transplantation

Objective To observe the efficacy of Tacrolimus eye drops for preventing rejection after treatment of high-risk penetrating keratoplasty in patients with poor response to Cyclosporin A eye drops. Methods The data of 10 eyes of 9 patients with high-risk penetrating keratoplasty from Apr. 2008 to Jun. 2015 were analyzed retrospectively. Cyclosporine A eye drops were applied after the first penetrating keratoplasty. Five eyes were treated with Tacrolimus eye drops after secondary penetrating keratoplasty, and the other 5 eyes were treated with Cyclosporine A eye drops. Results Ten eyes were followed up for (41.70±8.53) months after corneal transplantating, rejection happened in 9 eyes(90.00%) . All eyes underwent penetrating keratoplasty due to grafts opacification. Five eyes were treated with Tacrolimus eye drops and followed up for (16.00±2.68) months. The rejection occurred in 2 eyes(40.00%). The other 5 eyes were treated with Cyclosporin A and followed up for (36.20±7.95) months. The rejection rate was 100.00%. After treatment of Tacrolimus eye drops, the grafts of 5 eyes were transparent and followed up for (13.40±3.17) months. In the follow-up period, rejection occurred in 1 eye(20.00%). Conclusion Tacrolimus eye drops is applied for preventing rejection in high-risk keratoplasty patients with poor response to Cyclosporin A eye drops, most patients can get better anti-immune rejection effects. Key words: Keratoplasty, penetrating; Eye drops, Tacrolimus; Rejection, immune; Efficacy

Outcomes of Penetrating Keratoplasty Following Autologous Cultivated Limbal Epithelial Stem Cell Transplantation.

The purpose of this study is to investigate the outcomes of penetrating keratoplasty (PKP) following autologous cultivated limbal epithelial stem cell transplantation (CLET). A prospective, single center, interventional cohort study investigating patients with unilateral total limbal stem cell deficiency (LSCD) treated with CLET who underwent PKP. Patients with confirmed corneal re-epithelialization > 6 months post-CLET, and with best-corrected visual acuity (BCVA) <0.3 logMAR were offered PKP. CLET survival assessed by slit lamp, corneal impression cytology (CIC), and in vivo confocal microscopy. Confirmation of corneal re-epithelialization by histological and immunocytochemical (ICC) examination of trephined corneal buttons. Mean change in best-corrected visual acuity (logMAR) following PKP and PKP survival at 12 months were calculated. Twenty patients underwent PKP. Mean time of PKP was 19 months (range 11-41 months, SD 7.26) post-CLET. Median follow-up time post-PKP was 15 months (range 1-32, SD 10.2). CIC and ICC of all corneas confirmed corneal re-epithelialization before PKP. Mean pre-PKP BCVA was 1.46 (range 0.3-2.7, SD 0.94) improving to a mean post-PKP BCVA of 0.74 (range 0-2.7, SD 0.87); mean improvement in BCVA post-PKP of 36 letters (95% CI 15.0-57.1, p = .002). Kaplan-Meier mean graft survival was 90.9% (95% CI 50.8-98.7) at 12 months. We recommend a two-stage approach with CLET followed by PKP >12 months later. Patients experienced a significant improvement in BCVA following PKP. PKP did not have a detrimental effect on CLET survival. PKP survival post-CLET is better than that reported for high risk PKP. Stem Cells 2018;36:925-931.

Effect of sorafenib in a murine high risk penetrating keratoplasty model.

To evaluate the effect of sorafenib in murine high risk keratoplasty model. Graft survival, corneal neovascularization, and corneal lymphangiogenesis were compared among the sorafenib, dexamethasone, dimethyl sulfoxide (DMSO), and phosphate buffered saline (PBS) groups following subconjunctival injection in mice that underwent high risk penetrating keratoplasty (HRPK). Real-time polymerase chain reaction was performed to quantify the expression of inflammatory cytokines and vascular endothelial growth factor (VEGF)-A, VEGF-C, vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3. The two-month graft survival rate for HRPK was 42.86% in sorafenib group, 37.50% in dexamethasone group, 0 in DMSO group, and 0 in PBS group. Sorafenib significantly increased graft survival compared to the DMSO and PBS group (P<0.05). The sorafenib didn't show significant effect in decreasing neovascularization compared with dexamethsone, DMSO, and PBS group. The sorafenib showed less total lymphangiogenesis than the dexamethasone, DMSO, and PBS group (P=0.011, P<0.001, P<0.001, respectively). The sorafenib group showed reduced expression of VEGF-C, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, VEGFR-2 and VEGFR-3 compared with DMSO group and PBS group (all P<0.05). The sorafenib group didn't show difference in the expression of VEGF-A compared with DMSO, neither with PBS. The sorafenib group showed reduced expression of VEGFR-3 compared with dexamethasone (P=0.051). The subconjunctivally administered sorafenib shows significant anti-lymphangiogenic effect, resulting in increased transplant survival in a murine high risk keratoplasty model. We suggest that a close linkage between decreased VEGF-C/VEGFR-2 and -3 signaling and increased corneal graft survival by sorafenib seems to exist.

Update on the Management of High-Risk Penetrating Keratoplasty.

In this article, we review the indications and latest management of high-risk penetrating keratoplasty. Despite the immune-privilege status of the cornea, immune-mediated graft rejection still remains the leading cause of corneal graft failure. This is particularly a problem in the high-risk graft recipients, namely patients with previous graft failure due to rejection and those with inflamed and vascularized corneal beds. A number of strategies including both local and systemic immunosuppression are currently used to increase the success rate of high-risk corneal grafts. Moreover, in cases of limbal stem cell deficiency, limbal stem cells transplantation is employed. Corticosteroids are still the top medication for prevention and treatment in cases of corneal graft rejection. Single and combined administration of immunosuppressive agents e.g. tacrolimus, cyclosporine and mycophenolate are promising adjunctive therapies for prolonging graft survival. In the future, cellular and molecular therapies should allow us to achieve immunologic tolerance even in high-risk grafts.

High-risk penetrating keratoplasty

Background: Loss of immune privilege has important connotations for graft survival, often in clinical scenarios where the other eye is irreversibly blind. This article looks at the state of the evidence-based treatment available for high-risk penetrating keratoplasty (P.K.). Materials and Methods: Review of pathophysiological and immunological mechanisms present was done. Conclusion: Pre-, intra-, and post-operative considerations in P.K. in high-risk situation along with the role of immune-suppression are discussed. Success in high-risk keratoplasty depends on an ongoing effort during as well as life-long after P.K. The role of nonimmunological factors such as glaucoma, reactivation of infection, and unstable ocular surface are important determinants in graft failure.

Systemic immunosuppression with mycophenolate mofetil to prevent corneal graft rejection after high-risk penetrating keratoplasty: a 2-year follow-up study.

PurposeIn this study, we aimed to evaluate the efficacy and safety of systemic immunosuppression with mycophenolate mofetil (MMF) to prevent corneal graft rejection after high-risk penetrating keratoplasty.MethodsOne hundred and ninety-six consecutive patients who underwent high-risk penetrating keratoplasty defined as the presence of deep vascularization in more than two quadrants, keratouveitis, emergency keratoplasties, and retransplantations were enrolled in the study. Ninety-eight prospectively followed up patients were treated with MMF [with dose adjustment based on mycophenolic acid (MPA) serum concentration], and 98 patients were in the non–MMF-treated retrospectively assessed control group.ResultsDuring a mean of 24 months of observation, immune reactions occurred in eight cases (8 %) and graft rejection with subsequent graft failure occurred in three cases (3 %) in the MMF group. In the control group, graft rejection occurred in 76 cases (78 %) and failure due to graft rejection occurred in 30 cases (31 %). Kaplan–Meier analysis demonstrated that 93 % of the grafts in the MMF-treated group and 47 % in the control group showed no immune rejection (p < 0.01, log-rank test) after a year. Cox regression analysis proved that MMF treatment decreased the risk of graft rejection 11 times (RR = 11, 95.0 % CI 4.8–25, p < 0.0001). Among 98 MMF-treated patients, 13 had gastric discomfort, three developed leucopenia, and two had anemia that resolved after MMF dose reduction.ConclusionsMMF treatment after high risk penetrating keratoplasty is safe and reduces the incidence of immune graft rejection and graft failure. Side effects were rare and reversible in all but one case.

Trans-scleral diode laser cyclophotocoagulation for refractory glaucoma after high-risk penetrating keratoplasty.

To analyze the intraocular pressure reduction, number of anti-glaucoma medications needed, and post-operative complications of trans-scleral diode laser cyclophotocoagulation (DCPC) in patients with high-risk penetrating keratoplasty (PKP) and secondary refractory glaucoma. Prospective interventional, longitudinal, non-comparative series of cases, including 16 eyes of 15 patient's post-PKP on maximal anti-glaucoma medical therapy with intraocular pressures above 22mmHg. All patients received 18 shots, 360° peri-limbal (avoiding the long posterior ciliary nerves and arteries at 3 and 9 o'clock positions) of trans-scleral DCPC (2000mW, time: 2.0s/shot). There was a 55.5% reduction (total of 14.0mmHg) of the mean pre-operative IOP (31.5mmHg) after the first diode laser application (p=0.0020). Re-treatment was required in 31.2% of eyes over a mean period of 10.7months. In these five eyes, the mean pre-operative IOP was 40.4mmHg, which decreased to 15.0mmHg post-therapy, and a mean IOP reduction of 25.4mmHg (p=0.0218). There was a 51.0% reduction in the mean number of medications used after the first, and a 57.1% reduction after a second laser application. The incidence of failure (IOP≥22mmHg or need of additional medical therapy) from initial intervention to loss of follow-up was 1.3% per person-month. DCPC effectively reduces the intraocular pressure and the number of anti-glaucoma medications with few complications in patients after high-risk PKP and secondary glaucoma. Only, one-third of the eyes needed a second intervention to control the intraocular pressure. Post-DCPC complications were limited to phthisis bulbi and endothelial dysfunction, one eye each. Please check and confirm the author names and initials are correct. Also, kindly confirm the details in the metadata are correct.

Systemic immunosuppression with mycophenolate mofetil to prevent corneal graft rejection after high risk penetrating keratoplasty: a 2‐year follow‐up study

PurposeThe study aimed to evaluate the efficacy and safety of systemic immunosuppression with mycophenolate mofetil (MMF) to prevent corneal graft rejection after high risk penetrating keratoplasty.MethodsOne hundred ninety‐six consecutive patients who underwent high risk penetrating keratoplasty defined as the presence of deep vascularization in more than two quadrants, keratouveitis, emergency keratoplasties, and retransplantations were enrolled in the study. Ninety‐eight prospectively followed‐up patients were treated with MMF (with dose adjustment based on mycophenolic acid [MPA] serum concentration), and 98 patients were in the non‐MMF‐treated retrospectively assessed control group.ResultsDuring a mean of 24 months’ observation, immune reactions occurred in 8 cases (8%) and graft rejection with subsequent graft failure occurred in 3 cases (3%) in the MMF group. In the control group, graft rejection occurred in 76 cases (78%) and failure due to graft rejection occurred in 30 cases (31%). Kaplan–Meier analysis showed that after a year 93% of the grafts in the MMF‐treated group and 47% in the control group showed no immune rejection (p &lt; 0.01, log‐rank test). Cox regression analysis showed that MMF treatment decreased the risk of graft rejection 11 times (RR = 11, 95.0% CI 4.8–25, p &lt; 0.0001). Among 98 MMF‐treated patients, 13 had gastric discomfort, 3 developed leucopenia, and 2 had anemia that resolved after MMF dose reduction.ConclusionsMMF treatment after high risk penetrating keratoplasty is safe and reduces the incidence of immune graft rejection and graft failure. Side effects were rare and reversible in all but one case.