Donor, Recipient, and Operative Factors Associated With Increased Endothelial Cell Loss in the Cornea Preservation Time Study.

1. Cornea Image Analysis Reading Center, Department of Ophthalmology and Visual Sciences, University Hospitals Eye Institute, Case Western Reserve University, Cleveland, Ohio.
Authors
Lass JH¹
Benetz BA¹
Szczotka-Flynn LB¹
Menegay HJ¹
(4 authors)
2. Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota.
Authors
Patel SV²
(1 author)
3. Jaeb Center for Health Research, Tampa, Florida.
Authors
O'Brien R³
Ayala AR³
(2 authors)
4. Center for Preventive Ophthalmology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Authors
Maguire MG⁴
(1 author)
5. The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland.
Authors
Daoud YJ⁵
(1 author)

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ORCIDs linked to this article

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JAMA Ophthalmology, 01 Feb 2019, 137(2):185-193
https://doi.org/10.1001/jamaophthalmol.2018.5669 PMID: 30422157 PMCID: PMC6439830

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This article has been corrected. See JAMA Ophthalmol. 2019 Feb 1;137(2):233.

Abstract

Importance

Determining factors associated with endothelial cell loss after Descemet stripping automated endothelial keratoplasty (DSAEK) could improve long-term graft survival.

Objective

To evaluate the associations of donor, recipient, and operative factors with endothelial cell density (ECD) 3 years after DSAEK in the Cornea Preservation Time Study.

Design, setting, and participants

This cohort study was a secondary analysis of data collected in a multicenter, double-masked, randomized clinical trial. Forty US clinical sites with 70 surgeons participated, with donor corneas provided by 23 US eye banks. Individuals undergoing DSAEK for Fuchs dystrophy or pseudophakic/aphakic corneal edema were included.

Interventions

The DSAEK procedure, with random assignment of a donor cornea with a preservation time of 0 to 7 days or 8 to 14 days.

Main outcomes and measures

Endothelial cell density at 3 years as determined by a reading center from eye bank and clinical specular or confocal central endothelial images.

Results

The study included 1090 participants (median age, 70 years) with 1330 affected eyes (240 bilateral cases [22.0%]), who underwent DSAEK for Fuchs dystrophy (1255 eyes [94.4%]) or pseudophakic/aphakic corneal edema (PACE) (75 eyes [5.6%]). Of these, 801 eyes (60.2%) belonged to women and 1207 (90.8%) to white individuals. A total of 749 participants (913 eyes; 164 [21.9%] bilateral cases) had functioning grafts with acceptable endothelial images preoperatively and at 3 years postoperatively and were included in this analysis. Factors associated with a lower ECD at 3 years (estimated effect with 99% CI) in the final multivariable model included donors with diabetes (-103 [-196 to -9] cells/mm2), lower screening ECD (-234 [-331 to -137] per 500 cells/mm2), recipient diagnosis of PACE (-257 [-483 to -31] in cells/mm2), and operative complications (-324 [-516 to -133] in cells/mm2). Endothelial cell loss (ECL) from a preoperative measurement to a 3-year postoperative measurement was 47% (99% CI, 42%-52%) for participants receiving tissue from donors with diabetes vs 43% (99% CI, 39%-48%) without diabetes; it was 53% (99% CI, 44%-62%) for participants diagnosed with PACE vs 44% (99% CI, 39%-49%) for those diagnosed with Fuchs dystrophy, and 55% (99% CI, 48%-63%) in participants who experienced operative complications vs 44% (99% CI, 39%-48%) in those who did not. No other donor, recipient, or operative factors were significantly associated with 3-year ECD.

Conclusions and relevance

Donor diabetes, lower screening ECD, a PACE diagnosis in the recipient, and operative complications were associated with lower ECD at 3 years after DSAEK surgery and may be associated with long-term graft success. While causation cannot be inferred, further studies on the association of donor diabetes and PACE in recipients with lower 3-year ECD warrant further study.

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JAMA Ophthalmol. 2019 Feb; 137(2): 185–193.

Published online 2018 Oct 26. https://doi.org/10.1001/jamaophthalmol.2018.5669

PMCID: PMC6439830

PMID: 30422157

Donor, Recipient, and Operative Factors Associated With Increased Endothelial Cell Loss in the Cornea Preservation Time Study

Jonathan H. Lass, MD,¹ Beth Ann Benetz, MA,¹ Sanjay V. Patel, MD, FRC Ophth,² Loretta B. Szczotka-Flynn, OD, PhD,¹ Robert O’Brien, PhD,³ Allison R. Ayala, MS,³ Maureen G. Maguire, PhD,⁴ Yassine J. Daoud, MD,⁵ Mark A. Greiner, MD,⁶ Sadeer B. Hannush, MD,⁷ W. Barry Lee, MD,⁸ Thomas F. Mauger, MD,⁹ Harry J. Menegay, PhD,¹ Mark D. Mifflin, MD,¹⁰ Michael B. Raizman, MD,¹¹ Jennifer Rose-Nussbaumer, MD,¹² Robert L. Schultze, MD,¹³ Gregory A. Schmidt, CEBT,¹⁴ Alan Sugar, MD,¹⁵ Mark A. Terry, MD,¹⁶ and David D. Verdier, MD¹⁷, for the Cornea Preservation Time Study Group

Jonathan H. Lass

¹Cornea Image Analysis Reading Center, Department of Ophthalmology and Visual Sciences, University Hospitals Eye Institute, Case Western Reserve University, Cleveland, Ohio

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Beth Ann Benetz

¹Cornea Image Analysis Reading Center, Department of Ophthalmology and Visual Sciences, University Hospitals Eye Institute, Case Western Reserve University, Cleveland, Ohio

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Sanjay V. Patel

²Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota

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Loretta B. Szczotka-Flynn

¹Cornea Image Analysis Reading Center, Department of Ophthalmology and Visual Sciences, University Hospitals Eye Institute, Case Western Reserve University, Cleveland, Ohio

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Robert O’Brien

³Jaeb Center for Health Research, Tampa, Florida

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Allison R. Ayala

³Jaeb Center for Health Research, Tampa, Florida

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Maureen G. Maguire

⁴Center for Preventive Ophthalmology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia

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Yassine J. Daoud

⁵The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland

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Mark A. Greiner

⁶University of Iowa Hospitals and Clinics, Iowa City

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Sadeer B. Hannush

⁷Sadeer Hannush, P. C., Langhorne, Pennsylvania

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W. Barry Lee

⁸Eye Consultants of Atlanta, Atlanta, Georgia

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Thomas F. Mauger

⁹The Ohio State University Wexner Medical Center-Havener Eye Institute, Columbus

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Harry J. Menegay

¹Cornea Image Analysis Reading Center, Department of Ophthalmology and Visual Sciences, University Hospitals Eye Institute, Case Western Reserve University, Cleveland, Ohio

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Mark D. Mifflin

¹⁰Moran Eye Center, University of Utah, Salt Lake City

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Michael B. Raizman

¹¹Ophthalmic Consultants of Boston, Boston, Massachusetts

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Jennifer Rose-Nussbaumer

¹²University of California, San Francisco

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Robert L. Schultze

¹³Cornea Consultants of Albany, Slingerlands, New York

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Gregory A. Schmidt

¹⁴Iowa Lions Eye Bank, Iowa City

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Alan Sugar

¹⁵Kellogg Eye Center, University of Michigan, Ann Arbor

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Mark A. Terry

¹⁶Devers Eye Institute, Portland, Oregon

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David D. Verdier

¹⁷Verdier Eye Center, Grand Rapids, Michigan

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Author information Article notes Copyright and License information Disclaimer

¹Cornea Image Analysis Reading Center, Department of Ophthalmology and Visual Sciences, University Hospitals Eye Institute, Case Western Reserve University, Cleveland, Ohio

²Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota

³Jaeb Center for Health Research, Tampa, Florida

⁴Center for Preventive Ophthalmology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia

⁵The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland

⁶University of Iowa Hospitals and Clinics, Iowa City

⁷Sadeer Hannush, P. C., Langhorne, Pennsylvania

⁸Eye Consultants of Atlanta, Atlanta, Georgia

⁹The Ohio State University Wexner Medical Center-Havener Eye Institute, Columbus

¹⁰Moran Eye Center, University of Utah, Salt Lake City

¹¹Ophthalmic Consultants of Boston, Boston, Massachusetts

¹²University of California, San Francisco

¹³Cornea Consultants of Albany, Slingerlands, New York

¹⁴Iowa Lions Eye Bank, Iowa City

¹⁵Kellogg Eye Center, University of Michigan, Ann Arbor

¹⁶Devers Eye Institute, Portland, Oregon

¹⁷Verdier Eye Center, Grand Rapids, Michigan

Corresponding author.

Article Information

Group Information: The Cornea Preservation Time Study Group members are listed at the end of this article.

Corresponding Author: Jonathan H. Lass, MD, University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Cleveland, OH 44106 ([email protected]).

Accepted for Publication: September 26, 2018.

Correction: This article was corrected on December 13, 2018, to correct a P value in the Table. The P value for the Multivariable Model in the Diabetic donor row was presented as .01 but should be .005. The error has been corrected.

Published Online: October 26, 2018. 10.1001/jamaophthalmol.2018.5669

Author Contributions: Dr Lass and Ms Ayala had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lass, Benetz, Patel, Szczotka- Flynn, O'Brien, Maguire, Ayala.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Lass, Benetz, Patel, Szczotka-Flynn, O'Brien.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: O'Brien, Maguire.

Obtained funding: Lass, Ayala.

Administrative, technical, or material support: All authors.

Study supervision: Lass, Benetz, Patel, Szczotka-Flynn, Ayala.

Conflict of Interest Disclosures: Drs Terry and Lee report financial relationships with Bausch & Lomb, which manufactures corneal storage solutions (considered relevant to this work). Dr Terry reports receiving royalties for endothelial keratoplasty surgical instruments and educational grants. Dr Lee reports receiving speaker’s bureau fees. No other disclosures were reported.

Funding/Support: This study was supported by cooperative agreements with the National Eye Institute/National Institutes of Health(grants EY20797 and EY20798). Additional support was provided by Eye Bank Association of America, The Cornea Society, Vision Share, Inc, Alabama Eye Bank, Cleveland Eye Bank Foundation, Eversight, Eye Bank for Sight Restoration, Iowa Lions Eye Bank, Lions Eye Bank of Albany, San Diego Eye Bank, and SightLife.

Role of the Funder/Sponsor: The National Eye Institute had roles in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication. The other sponsors had no role in the design and conduct of the study; management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication, but provided additional support for ancillary work pertaining to this study.

Group Members: The Cornea Preservation Time Study Group members are as follows: Operations Committee: Jonathan Lass, MD; Allison Ayala, MS; Beth Ann Benetz, MA; Loretta Szczotka-Flynn, OD, PhD; Roy Beck, MD, PhD; Robin Gal, MSPH; and Maryann Redford, DDS, MPH. Executive Committee: Operations Committee as well as Anthony J. Aldave, MD; Steven P. Dunn, MD; Ty L. McCall, MD; Lisa Navarro; Sudeep Pramanik, MD; Kevin W. Ross, MS, MPH; George O. Rosenwasser, MD; Mark A. Terry, MD; and David T. Verdier, MD; Eye Bank Advisory Committee: Kevin W. Ross, MS MPH (chair); Patricia Dahl, BS; Donna C. Drury, BS, MBA; Sameera M. Farazdaghi, BS, MPH; Caroline K. Hoover, CEBT; Jeffery G. Penta, AS, BS, MBA; Mark C. Soper BS, CEBT; Chris G. Stoeger, CEBT, MBA; Doyce V. Williams, CEBT, CTBS, BS, MA; Data and Safety Monitoring Committee: David C. Musch, PhD, MPH (DSMC chair), William Bourne, MD, Kathryn A. Colby, MD, PhD, Marian Fisher, PhD, Rabbi Samuel Fishman, Maryann Redford, DDS, MPH; Clinical Site Principal Investigators: Anthony Aldave, MD; Gregg Berdy, MD; John Bokosky, MD; Christopher Croasdale, MD; Yassine Daoud, MD; Steven Dunn, MD; Thomas Gillette, MD; Kenneth Goins, MD; Pankaj Gupta, MD; Kristen Hammersmith, MD; Sadeer Hannush, MD; David Hardten, MD; Bennie Jeng, MD; Marc Jones, MD; William Lahners, MD; W. Barry Lee, MD; Marian Macsai, MD; Thomas Mauger, MD; Kenneth Maverick, MD; Tyrone McCall, MD; Woodford Van Meter, MD; Shahzad Mian, MD; Mark Mifflin, MD; Verinder Nirankari, MD; Michael Nordlund, MD, PhD; Matthew Oliva, MD; Sanjay Patel, MD; Sudeep Pramanik, MD; Irving Raber, MD; Michael Raizman, MD; Jennifer Rose-Nussbaumer, MD; George Rosenwasser, MD; Robert Schultze, MD; John Seedor, MD; Neda Shamie, MD; Jonathan Song, MD; Walter Stark, MD; R. Doyle Stulting, MD, PhD; Alan Sugar, MD; Shachar Tauber, MD; Mark Terry, MD; Kristina Thomas, MD; Elmer Tu, MD; David Verdier, MD; and Sonia Yoo, MD. Eye Bank Principal Investigators: Victoria Adler, RN, BSN, CPTC, CEBT; Wilfred Caraballo; Patricia Dahl, BS; Gregory Dorn, CEBT; Donna Drury, BS, MBA; Sameera Farazdaghi, BS, MPH; Elizabeth Fout-Caraza, MHSA; Patrick Gore, RN, CEBT; Veronique Grimes, COMT, CEBT; Caroline Hoover, CEBT; Debora Van Klinken, CEBT; Nai Liang, CEBT; Tina Mays, CEBT; Kristen McCoy, BS; Wade McEntire, MPH; Eric Meinecke, BA; Jeffrey Penta, AS, BS, MBA; Kevin Ross, MS, MPH; Mikelanne Schipper; Gregory Schmidt, BS, CEBT; Chris Stoeger, CEBT, MBA; Michael Tramber, MBA, BS, CEBT, CTBS.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Eye Institute or the National Institutes of Health.

Meeting Presentation: This paper was presented at the Cornea and Eye Banking Forum; October 26, 2018; Chicago, Illinois.

This article has been corrected. See JAMA Ophthalmol. 2018 December 13; 137(2): 233.

This article has been cited by other articles in PMC.

Associated Data

Supplementary Materials: Supplement: eTable 1. Factors Not Associated with 3-year Endothelial Cell Density in the Cornea Preservation Time Study
eTable 2. Mean Endothelial Cell Density Over Time by Select Recipient, Donor, and Operative Factors in the Cornea Preservation Time Study
jamaophthalmol-e185669-s001.pdf (278K)

Key Points

Question

What donor, recipient, and operative factors are associated with endothelial cell density 3 years after Descemet stripping automated endothelial keratoplasty (DSAEK) in the Cornea Preservation Time Study cohort?

Findings

In this study, donors with diabetes, diagnosis of pseudophakic/aphakic corneal edema in the recipient, and operative complications were associated with lower endothelial cell density at 3 years.

Meaning

Optimizing donor selection and minimizing surgical trauma could help minimize endothelial cell loss and improve graft survival after DSAEK. Mechanisms whereby corneal tissue from diabetes in donors and pseudophakic/aphakic corneal edema in recipients affect endothelial cell density warrant further study.

Abstract

Importance

Determining factors associated with endothelial cell loss after Descemet stripping automated endothelial keratoplasty (DSAEK) could improve long-term graft survival.

Objective

To evaluate the associations of donor, recipient, and operative factors with endothelial cell density (ECD) 3 years after DSAEK in the Cornea Preservation Time Study.

Design, Setting, and Participants

Interventions

The DSAEK procedure, with random assignment of a donor cornea with a preservation time of 0 to 7 days or 8 to 14 days.

Main Outcomes and Measures

Endothelial cell density at 3 years as determined by a reading center from eye bank and clinical specular or confocal central endothelial images.

Results

The study included 1090 participants (median age, 70 years) with 1330 affected eyes (240 bilateral cases [22.0%]), who underwent DSAEK for Fuchs dystrophy (1255 eyes [94.4%]) or pseudophakic/aphakic corneal edema (PACE) (75 eyes [5.6%]). Of these, 801 eyes (60.2%) belonged to women and 1207 (90.8%) to white individuals. A total of 749 participants (913 eyes; 164 [21.9%] bilateral cases) had functioning grafts with acceptable endothelial images preoperatively and at 3 years postoperatively and were included in this analysis. Factors associated with a lower ECD at 3 years (estimated effect with 99% CI) in the final multivariable model included donors with diabetes (−103 [−196 to −9] cells/mm²), lower screening ECD (−234 [−331 to −137] per 500 cells/mm²), recipient diagnosis of PACE (−257 [−483 to −31] in cells/mm²), and operative complications (−324 [−516 to −133] in cells/mm²). Endothelial cell loss (ECL) from a preoperative measurement to a 3-year postoperative measurement was 47% (99% CI, 42%-52%) for participants receiving tissue from donors with diabetes vs 43% (99% CI, 39%-48%) without diabetes; it was 53% (99% CI, 44%-62%) for participants diagnosed with PACE vs 44% (99% CI, 39%-49%) for those diagnosed with Fuchs dystrophy, and 55% (99% CI, 48%-63%) in participants who experienced operative complications vs 44% (99% CI, 39%-48%) in those who did not. No other donor, recipient, or operative factors were significantly associated with 3-year ECD.

Conclusions and Relevance

Introduction

Risk factors for endothelial cell loss (ECL) have been described after penetrating keratoplasty (PK) in the Specular Microscopy Ancillary Study^1,2,3 and other large studies,^4,5 as well as after Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) in single-center studies.^6,7 Given key differences in eye bank and surgical methods for DSAEK compared with PK, understanding the main factors that influence ECL after DSAEK is important for prolonging the health of the participants with these grafts through appropriate donor selection, understanding the effects of recipient preoperative diagnosis, and optimizing surgical techniques.

The Cornea Preservation Time Study (CPTS) was a prospective, randomized clinical trial designed to determine the effect of donor preservation time (PT) on graft survival and endothelial cell loss after DSAEK.⁸ At 3 years after DSAEK, a donor PT of 12 to 14 days was associated with a lower graft survival rate, but differences were small when PT was shorter than 12 days.⁹ There was a small but significant difference in ECL at 3 years between corneas preserved for 0 to 7 days (37%) and those preserved for 8 to 14 days (40%).¹⁰ In this study, we evaluate other donor factors, as well as recipient and operative factors, associated with endothelial cell density (ECD) during the first 3 years after DSAEK, complementing a recent study examining the association of these factors with graft success.¹¹

Methods

Details of the CPTS protocol and primary results have been published previously.^8,9,10 Briefly, participants undergoing DSAEK were randomized to receive tissue preserved for 0 to 7 days or 8 to 14 days with a primary outcome of graft survival at 3 years. The protocol was approved by institutional review boards governing each investigational site, and individual participants gave written informed consent to participate in the study. The study adhered to the tenets of the Declaration of Helsinki and was registered as a clinical trial (NCT01537393).

Participants were enrolled between April 2012 and February 2014; eligible participants had corneal endothelial dysfunction, including Fuchs endothelial corneal dystrophy (FECD) and pseudophakic/aphakic corneal edema (PACE). Donors had a minimum eye bank–measured central ECD of 2300 cells/mm², and donor corneas were stored at 2° C to 8° C in either Optisol GS (Bausch & Lomb) or Life 4° C (Numedis, Inc).⁸

We have recently defined and assessed multiple donor, recipient, and operative factors influencing graft success in the CPTS.¹¹ These same parameters were assessed in this analysis. In brief, donor information was gathered and reported by the 23 Eye Bank Association of America–accredited eye banks in the CPTS. Using methods consistent with standard eye bank practice, the eye banks recorded donor data, including donor age, sex, race/ethnicity, cause of death, and history of diabetes (yes/no) determined from medical records and/or next of kin, as was done in the Cornea Donor Study.^12,13 Additional parameters involving procurement information, tissue preparation, recipient data (including sex, race/ethnicity, diabetes [historically determined as in the Cornea Donor Study^12,13], ocular history and medications, and preoperative recipient diagnosis), operative details, and surgical complications were collected prospectively and analyzed in this study.

Endothelial Imaging and Image Analysis

The Corneal Image Analysis Reading Center (CIARC) at Case Western Reserve University and University Hospitals Eye Institute (Cleveland, Ohio), was the reading center determining ECD and was responsible for quality control measures at the eye banks and clinical sites, including image quality, certification, and calibration procedures.^8,10,14,15 Eye banks obtained 1 to 3 initial specular image(s) of the central endothelium and then determined ECD by their usual analysis method (referred to as screening ECD). This assessment was performed prior to randomization and was not standardized. If a donor cornea was CPTS assigned, eye banks also obtained 3 study images, termed preoperative, either after lamellar dissection, or, if the donor cornea was to be surgeon prepared, prior to shipment. Postoperatively, 3 specular or confocal microscopic images of the central corneal endothelium of the graft were obtained at 6, 12, 24, and 36 months, depending on how long a participant remained in the follow-up cohort without graft failure or regraft. All preoperative donor and postoperative clinical images were transferred to CIARC by the Data Management and Analysis Center (Jaeb Center for Health Research, Tampa, Florida) in a deidentified manner with the study number and date of acquisition.

Endothelial Cell Density Determination

Details of CIARC procedures have been previously described with variable frame analysis for ECD determination by 2 masked independent readers, and adjudication, if indicated.^8,10,14 In brief, the ECD of all analyzable images was independently determined by 2 readers using the variable frame analysis method.¹⁵ If the ECDs determined by the 2 readers differed by 5.0% or more, a third independent determination of ECD was made by an adjudicator. Final ECD was the average of all ECDs that were within 5% of each other.

Statistical Analysis

The analysis was restricted to eyes with a functioning graft at 3 years after DSAEK and analyzable preoperative and 3-year endothelial images. The preoperative ECD was considered the baseline for these analyses. Associations between donor, recipient, and operative factors, including complications⁹ and 3-year ECD (in cells/mm²), were evaluated in multivariable linear mixed models. All candidate factors that were considered are listed in the Table and eTable 1 in the Supplement. Continuous covariates were included in all models in continuous form but were categorized for display and ease of interpretation in the Table and eTable 1 in the Supplement. Missing data were treated as a separate category for discrete factors, and a missing indicator was created for continuous factors.

Table.

Factors Associated With 3-Year Endothelial Cell Density and Endothelial Cell Loss in the Cornea Preservation Time Study

Characteristic	No. (N=913)	Base Model^a		Multivariable Model^b		Mean Loss, % (99%CI) ^b^,^c
Characteristic	No. (N=913)	Mean ECD at 3 y (99% CI), Cells/mm²	P Value	Mean ECD at 3 y (99% CI), Cells/mm²	P Value	Mean Loss, % (99%CI) ^b^,^c
Significant donor factors
Screening ECD (eye bank–determined), cells/mm²
<2500	196	1356 (1200-1512)	<.001	1374 (1218-1530)	<.001	50 (44-55)
2500-2749	336	1443 (1307-1580)		1461 (1322-1599)		46 (41-51)
2750-2999	212	1555 (1408-1701)		1572 (1424-1719)		42 (37-48)
≥3000	169	1765 (1602-1928)		1754 (1592-1916)		37 (31-43)
Preoperative ECD (Cornea Image Analysis Reading Center determined), cells/mm²
<2500	216	1206 (1058-1353)	<.001	1318 (1168-1469)	<.001	43 (37-48)
2500-2749	252	1502 (1360-1644)		1542 (1401-1683)		41 (35-46)
2750-2999	236	1577 (1433-1720)		1553 (1410-1696)		45 (40-51)
≥3000	209	1764 (1616-1911)		1664 (1511-1817)		49 (43-54)
Diabetic donor
No	674	1543 (1417-1668)	.003	1550 (1423-1677)	.005	43 (30-48)
Yes	239	1431 (1288-1573)	.003	1447 (1305-1589)	.005	47 (42-52)
Significant recipient factors
Recipient diagnosis
Pseudophakic/aphakic corneal edema only	36	1281 (1028-1533)	.006	1276 (1032-1520)	.003	53 (43-62)
Fuchs endothelial corneal dystrophy	877	1532 (1410-1653)	.006	1533 (1407-1659)	.003	44 (39-49)
Baseline intraocular pressure, mm Hg^d
8-19	839	1503 (1381-1625)	.005	1511 (1386-1636)	.004	45 (40-49)
20-27	74	1666 (1472-1861)	.005	1667 (1477-1856)	.004	39 (32-46)
Significant operative factors
Operative complications^e
No	867	1537 (1413-1662)	<.001	1539 (1414-1665)	<.001	44 (39-48)
Yes	46	1188 (964-1411)	<.001	1215 (999-1431)	<.001	55 (48-63)
Nonsignificant donor factors
Donor age, y
≤30	52	1731 (1513-1948)	.002	1643 (1430-1856)	.08	41 (34-49)
31-50	144	1552 (1395-1710)		1553 (1397-1709)		43 (37-49)
51-60	232	1524 (1382-1667)		1521 (1378-1663)		44 (39-50)
61-70	352	1456 (1322-1589)		1481 (1347-1616)		46 (41-51)
71-75	133	1533 (1372-1695)		1560 (1401-1720)		43 (37-49)
Storage solution
Life 4°C (Numedic)	35	1189 (836-1541)	.01	1206 (863-1550)	.01	55 (43-68)
Optisol GS (Bausch & Lomb)	878	1531 (1412-1651)	.01	1539 (1416-1662)	.01	44 (39-48)
Change in solution^f
Original	256	1617 (1408-1827)	.02	1617 (1403-1831)	.03	41 (33-49)
Fresh	388	1449 (1313-1584)		1463 (1324-1601)		46 (41-52)
Surgeon dissected tissue	269	1639 (1446-1832)		1636 (1444-1827)		40 (33-47)
Descemet stripping automated endothelial keratoplasty lenticule thickness, μm^g
<100	138	1463 (1288-1638)	.05	1459 (1289-1630)	.06	46 (40-53)
100-<125	266	1546 (1402-1691)		1560 (1416-1703)		43 (38-48)
125-<150	244	1523 (1376-1670)		1546 (1400-1692)		44 (38-49)
≥150	231	1474 (1321-1627)		1482 (1330-1633)		46 (41-52)
Any eye bank observations^h
No	522	1505 (1381-1629)	.06	1511 (1384-1638)	.10	45 (40-49)
Yes	122	1451 (1282-1620)		1477 (1310-1644)		46 (40-52)
Surgeon dissected tissue	269	1646 (1451-1840)		1643 (1450-1835)		40 (33-47)
Nonsignificant recipient factors
Recipient age, y
42-65	254	1553 (1410-1696)	.03	1556 (1414-1699)	.12	43 (38-48)
66-75	405	1528 (1395-1661)		1520 (1386-1654)		44 (39-49)
76-91	254	1460 (1319-1601)		1494 (1352-1635)		46 (40-51)
Nonsignificant operative factors
Complete air fill duration, minⁱ
<10	23	1655 (1316-1993)	.08	1629 (1302-1956)	.03	40 (28-52)
10-19	667	1523 (1384-1661)		1531 (1391-1671)		44 (39-49)
≥20	218	1488 (1318-1659)		1500 (1330-1671)		46 (39-52)
Injection of viscoelastic
No	143	1371 (1185-1558)	.01	1418 (1231-1605)	.06	48 (41-55)
Yes	770	1562 (1435-1689)	.01	1557 (1426-1687)	.06	43 (30-48)
Concomitant cataract surgery
No	416	1467 (1337-1598)	.01	1491 (1358-1624)	.09	46 (41-51)
Yes	497	1565 (1434-1697)	.01	1555 (1422-1688)	.09	43 (38-48)

Abbreviation: ECD, endothelial cell density.

^aAdjusted for recipient and surgeon (random effects) and preoperative ECD (as determined by the Cornea Image Analysis Reading Center) and preservation time group (fixed effects).

^bAdjusted for preoperative ECD and preservation time group with random effects for recipient and surgeon. The model includes recipient diagnosis, baseline intraocular pressure, eye bank screening ECD, donor diabetes history, and operative complications.

^cThe percentage of 3-year ECD loss is calculated as [(3-Year ECD

−

Baseline ECD)/Baseline ECD]

100.

^dThis was no longer significant after excluding eyes that were treated for glaucoma medically or surgically before Descemet stripping automated endothelial keratoplasty.

^eIncludes vitreous loss (unplanned), posterior capsule rupture, suprachoroidal hemorrhage, significant hyphema, inverted donor tissue, difficult unfolding and positioning without use of positioning hook, difficult unfolding and positioning with use of positioning hook, difficult air fill and retention in positioning, and reinsertion of donor after extrusion.

^fCorneas dissected by the eye bank were either kept in the original solution the entire time until surgery or they were placed in fresh solution before surgery.

^gThere are 34 eyes for which Descemet stripping automated endothelial keratoplasty lenticule thickness values were missing. These values were eye bank–determined by optical coherence tomography (441 eyes), ultrasonic pachymetry (140 eyes), specular microscopy (53 eyes), optical (10 eyes), or surgeon determined by ultrasonic pachymetry (235 eyes).

^hEye bank observations include significant increase in the degree of stromal folds, significant increase of stress lines, decrease in posterior stroma clarity, posterior stromal edema, Descemet membrane tear or perforation, stromal cap unclear or noncentered (within 1 mm of the center), stromal cap not adhered to stromal bed, gross variation in graft thickness, chatter or irregularities noticed within the cut, observed touches of endothelium during mounting or removal from the artificial chamber, air bubbles noted at the interface, other observations during or after cutting that could affect surgical technique, and other write-in observations.

ⁱThere are 5 eyes for which complete air fill duration values were missing.

The base model for evaluating candidate factors included PT, because of its influence on ECD in the CPTS,¹⁰ and preoperative ECD measured by the CIARC to account for differing initial ECDs among donor tissues. All models included surgeon and recipient as random effects to account for possible correlation between grafts performed by the same surgeon (which is called a surgeon effect) and fellow eyes of the same recipient. Each factor was evaluated first by adding the factor to the base model. Candidate factors were selected for inclusion in a final multivariable model in 2 stages. In stage 1, baseline donor and recipient factors with P values less than .10 were included in a backward multivariable model selection procedure.¹⁶ In stage 2, all factors selected in stage 1 were retained and operative factors with P values less than .10 were included in another backward multivariable model selection procedure to yield a final model. To provide additional information, effects adjusted for the factors in the final model were provided for each factor discarded during variable selection. Owing to the multiple comparisons, only donor and recipient factors with P values less than .01 at the first stage and operative factors with P values less than .01 at the second stage were considered statistically significant and remained in the final model.

The effect of categorical factors on ECD at 3 years was reported as the estimate of the mean difference in ECD from the reference category with 99% CI. For ease of interpretation, the effect of continuous factors on ECD at 3 years was expressed as the estimate of the mean difference in ECD associated with a clinically relevant difference in the continuous factor and corresponding 99% CI. All reported P values are 2-sided. The data were analyzed using SAS version 9.4 (SAS Institute) and R version 3.4 (R Foundation for Statistical Computing)¹⁷ from September 2017 to September 2018.

Results

A total of 1090 individuals with 1330 eyes (including 240 individuals [22.0%] with bilateral cases) were enrolled. Participants were 42 to 90 years old (median age, 70 years) at the time of enrollment between April 2012 and February 2014. Of the 1330 eyes, 801 (60.2%) belonged to women, and 1207 [90.8%) belonged to white individuals. A total of 1255 eyes (94.4%) had FECD, and 75 eyes (5.6%) had PACE. This analysis includes 913 clear grafts of the 1330 eyes included in the CPTS (68.5%) in 749 participants with available screening, preoperative, and 3-year images.

Donors contributing corneas were 12 to 75 years old (median age, 61 years). Those in the 0-day to 7-day PT group had a median PT of 6 days; those in the 8-day to 14-day PT group had a median of 11 days. The recipient and donor baseline characteristics of this subset were similar to the characteristics of the full CPTS cohort.^8,10 Of those excluded from this analysis, 32 eyes lacked CIARC-determined preoperative ECD values. The CIARC did not obtain 16 of these 32 images from the eye banks, while the other 16 were attained but not analyzable.

The 3-year ECD adjusted mean estimates are shown in the Table and eTable 1 in the Supplement for each candidate factor. Factors with a corresponding P value of less than .10 when included in the base model are included in the Table. After accounting for PT and preoperative ECD, the final multivariable model showed the donor factors independently associated with a lower ECD at 3 years included lower screening ECD (−234 [99% CI, −331 to −137] cells/mm² at 3 years for every 500 cells/mm² difference in the screening ECD) and donors with diabetes (−103 [99% CI, −196 to −9] cells/mm²) compared with those without diabetes. The recipient factors associated with lower ECD at 3 years were a recipient diagnosis of PACE (−257 [99% CI, −483 to −31] cells/mm²) vs FECD and lower baseline intraocular pressure (IOP) (−80 [99% CI, −151 to −9] cells/mm² for every 5–mm Hg difference in baseline IOP level). Notably, baseline IOP level was not significant after excluding eyes that were treated for glaucoma medically or surgically before DSAEK. Finally, the sole operative factor associated with lower ECD at 3 years was operative complications (−324 [99% CI, −516 to −133]) (Table). The small numbers of eyes with intraoperative complications in subgroups, as listed in the Table, precluded analysis of the influence of each of these complications on ECD at 3 years.

The associations between screening and preoperative ECD and 3-year ECD are also shown as scatterplots in Figure 1 and Figure 2. Although eye bank screening ECD and CIARC preoperative ECD were correlated (ρ=0.53), each provided independent predictive information on 3-year ECD.

An external file that holds a picture, illustration, etc.
Object name is jamaophthalmol-e185669-g001.jpg

Figure 1.

Scatterplot of Endothelial Cell Density (ECD) 3 Years After Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) by Cornea Image Analysis Reading Center–Determined Preoperative Endothelial Cell Density in the Cornea Preservation Time Study

The line represents a LOESS curve fitted to the data points (0.628; ρ=0.30).

An external file that holds a picture, illustration, etc.
Object name is jamaophthalmol-e185669-g002.jpg

Figure 2.

Scatterplot of Endothelial Cell Density (ECD) 3 Years After Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) by Eye Bank–Determined Screening Endothelial Cell Density in the Cornea Preservation Time Study

The line represents a LOESS curve fitted to the data points (0.605; ρ=0.36).

Donor factors (age, storage solution, replacement of storage solution [if performed], lenticule thickness, eye bank observations), recipient age, and operative factors (complete air fill duration, viscoelastic injection, and concomitant cataract surgery) were included in the model selection, but were not independent risk factors (ie, P≥.01) after adjusting for the factors included in the final model (Table). Mean percentage of ECL was 47% (99% CI, 42%-52%) for participants receiving tissue from donors with diabetes vs 43% (99% CI, 39%-48%) for those receiving tissue from donors without diabetes, 53% (99% CI, 44%-62%) for participants with PACE vs 44% (99% CI, 39%-49%) for participants with FECD, and 55% (99% CI, 48%-63%) when operative complications occurred vs 44% (99% CI, 39%-48%) when operative complications did not occur (Table). No other preoperative donor, recipient, or operative factors were included in the model selection procedure (base model P value >.10; eTable 1 in the Supplement). Neither the method of insertion, whether protected or not protected (eTable 1 in the Supplement), nor wound incision size were statistically significant. eTable 2 in the Supplement shows mean ECD over time for select candidate factors.

Discussion

The CPTS was primarily designed to determine the effect of donor PT on graft success and ECL. Longer PT was associated with greater ECL at 3 years after DSAEK surgery, although much of the effect was attributed to the very longest PTs, which were from 12 to 14 days.¹⁰ In this prespecified secondary analysis, lower ECD at 3 years was also associated with the additional factors of diabetes in the donor, recipient diagnosis, and operative complications.

Donor Factors

Diabetes

Donors with diabetes were associated with lower ECD at 3 years after DSAEK, including adjustment for the preoperative ECD difference between donors without and with diabetes (66 cells/mm²; eTable 2 in the Supplement). These findings support the known deleterious effects of diabetes on the corneal endothelium biochemically,^18,19 morphologically,^20,21,22,23 and functionally,^20,21,24,25 in mitochondrial damage²⁶ and Descemet membrane strength.²⁷ Although previous studies did not find an effect of donor diabetes on ECL after PK^2,12 and Descemet membrane endothelial keratoplasty (DMEK),²⁸ these studies were limited by historical diabetes characterization. Notably, we have also reported a significant association between diabetes in the donor and graft failure after DSAEK, particularly primary or early failures,¹¹ unlike previous studies of PK,^12,13 DSAEK,²⁹ and DMEK,²⁸ which did not find a deleterious effect. These studies were also limited by less rigorous historical diabetes characterization.

ECD

Lower screening and preoperative ECD were both associated with lower postoperative ECD at 3 years; however, ECD preoperatively may not be as important as the rate of ECL postoperatively, especially in the short term, and graft survival.^30,31 The association of screening with preoperative ECD, postoperative ECD, and graft failure in the CPTS will be examined in future analyses performed similarly in the Specular Microscopy Ancillary Study.³¹

Other Donor Factors

Donor factors that were not associated with greater ECL included cause of death, time from death to preservation, lenticule thickness, eye bank-dissected vs surgeon-dissected donor lenticule tissue, and donor sex. Female donors were associated with lower ECL at 5 years in the Cornea Donor Study,² but not in the CPTS, adding to the controversy regarding sex mismatch and graft success.^32,33 A trend toward higher ECL with older donor age was observed, although the association became nonsignificant in the final statistical model. Older donor age (66 to 75 years, compared with 12 to 65 years) is known to be associated with a higher rate of ECL after PK.³ Death to refrigeration time, refrigeration to preservation time, and death to preservation time were not significant risk factors for ECL, although the range of each of these times was limited (≤10, 18, and 22 hours, respectively). Notably, eye bank slitlamp observations did not have an association with 3-year ECD, in contrast with surgeon-reported operative complications. This can be explained by the eye bank criteria that were in place for selecting appropriate donor tissue according to the CPTS protocol.

Recipient Factors

Diagnosis

Recipient diagnosis was the main recipient factor that affected ECL at 3 years. Endothelial cell loss was greater for participants with PACE compared with participants with FECD, paralleling our graft survival findings¹¹ and others.⁶ The differing percentage of ECL at 3 years by recipient diagnosis in the CPTS (53% for participants with PACE vs 44% for participants with FECD) could be explained by peripheral host corneal endothelial health, with higher ECL associated with diminished peripheral ECD in individuals with PACE. In individuals with FECD, peripheral-to-central endothelial cell migration may occur after removing the central endothelium without³⁴ or with the topical ρ-kinase inhibitor ripasudil,³⁵ resulting in clear corneas, whereas similar success has not been reported in participants with PACE who have poor peripheral ECD. Similarly, after successful DSAEK procedures, healthier peripheral endothelial cells could help sustain central ECD in participants with FECD compared with participants with PACE.

Preoperative IOP

Lower preoperative IOP was also associated with greater ECL 3 years after DSAEK procedures; however, this was no longer significant after excluding participants whose eyes were treated for glaucoma medically or surgically before DSAEK. Greater complication and failure rates of DSAEK owing to endothelial failure after trabeculectomy and shunt tube placement have been reported.^36,37 In the participants in the CPTS whose eyes maintained normal anterior chamber anatomy and were medically well controlled, glaucoma history did not seem to influence long-term ECD.

Diabetes

The CPTS did not find an association of recipient diabetes with greater ECL nor failure.¹¹ Previously, recipient diabetes had been associated with worse PK survival³⁸ and greater ECL after DMEK.²⁸

Operative Factors

Operative Complications

The only operative factor associated with greater ECL was a surgeon-reported operative complication. The measured ECL at 3 years was 55% when a surgeon-reported operative complication occurred, compared with 44% when the surgeon did not report such complication. This parallels the findings on graft success¹¹ and is therefore potentially one of the most important modifiable risk factors that affects graft outcome and long-term ECL. High early ECL after PK was associated with late graft failure from nonimmunologic endothelial attrition in 1 long-term study,³⁰ and early ECL is much higher with DSAEK than PK.³⁹

Insertion Methods and Incision Size

Insertion method was not associated with 3-year ECD in this study. Although the model-based mean 3-year ECD for the glide-pull method was markedly lower (1355 cells/mm²) than in other methods (ranging from a mean of 1415 cells/mm² for the Sheets glide/shovel method to 1676 cells/mm² for the Busin glide method), there were only 21 cases with this method, far fewer than the next least frequent method (ie, the 92 cases via the pull-through method). The lack of significance for insertion methods may be associated with the number of cases in each group compared with other studies,^{40,41,42,43,44} or it may indicate that when the technique is successfully performed, it does not affect ECL. Incision size was also not a statistically significant factor for lower 3-year ECD, as long as insertion was protected for smaller length incisions (4.0 mm and shorter), unlike a previous report with a smaller incision (ie, 3.2 mm) and unprotected insertion.⁴⁵ Finally, after PK, the Cornea Donor Study found that larger diameter grafts were associated with higher ECD postoperatively,² while the CPTS² and Terry et al⁴⁶ did not observe an effect for DSAEK, even though larger mean diameter grafts were used compared with the Cornea Donor Study.³

Limitations

The CPTS prospective study design, large sample size, inclusion of many surgeons and eye banks, centralized endothelial cell analysis, and very low percentage of nonanalyzable images preoperatively (2%) and at 3 years (2%)¹⁰ enable the data from this study to be generally applied to DSAEK procedures that use cold storage of donor corneas. However, the endothelial cell data reported are only from surviving recipients and grafts at 3 years postoperatively. The issue of drop out of participants with graft failure has been approached by mathematical modeling,^6,47,48,49 but the relatively short follow-up time of 3 years is not suitable for this statistical approach. Excluding failed grafts could introduce bias,¹⁰ but the magnitude of any bias is likely small in our analysis, since only 34 of the 79 failures were not primary or early failures.⁹ Of the original 1330 eyes in this study, 913 (68.5%) were available for analysis, resulting in meaningful conclusions similar to our studies in the Specular Microscopy Ancillary Study.² In addition, the risk factors reported in this study do not include postoperative events, such as graft dislocation or rejection, that could also be important for ECL and graft survival after DSAEK compared with PK; these risk factors will be reported separately (R. Doyle Stulting, MD, written communication, October 1, 2018).

Having shown the effect of diabetes in the donor on both ECL and lower graft success¹¹ compared with the previous literature,^12,28,29 a randomized clinical trial seems warranted based on rigorous assessment of diabetes status of the donor. To provide greater precision in such a trial, diabetes should be better characterized in the donor as well as the recipient, by not only historical means, but also via diabetes severity grading,⁵⁰ as well as hemoglobin A_1c testing⁵¹ to enable the detection of undiagnosed diabetes.⁵²

Conclusions

The CPTS has shown that, in addition to PT, donor diabetes, PACE, and operative complications are associated with lower 3-year ECD; however, with the putative exception of PT, causation cannot be inferred from these associations. Optimizing donor selection and minimizing surgical trauma and operative complications could help minimize ECL and improve graft survival after DSAEK with findings that may be applicable to DMEK with a similar ECL pattern.^53,54,55

Notes

Supplement.

eTable 1. Factors Not Associated with 3-year Endothelial Cell Density in the Cornea Preservation Time Study

eTable 2. Mean Endothelial Cell Density Over Time by Select Recipient, Donor, and Operative Factors in the Cornea Preservation Time Study

Click here to view.^{(278K, pdf)}

References

1. Lass JH, Gal RL, Dontchev M, et al. ; Cornea Donor Study Investigator Group . Donor age and corneal endothelial cell loss 5 years after successful corneal transplantation: specular microscopy ancillary study results. Ophthalmology. 2008;115(4):627-632.e8. 10.1016/j.ophtha.2008.01.004 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

2. Lass JH, Beck RW, Benetz BA, et al. ; Cornea Donor Study Investigator Group . Baseline factors related to endothelial cell loss following penetrating keratoplasty. Arch Ophthalmol. 2011;129(9):1149-1154. 10.1001/archophthalmol.2011.102 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

3. Lass JH, Benetz BA, Gal RL, et al. ; Writing Committee for the Cornea Donor Study Research Group . Donor age and factors related to endothelial cell loss 10 years after penetrating keratoplasty: Specular Microscopy Ancillary Study. Ophthalmology. 2013;120(12):2428-2435. 10.1016/j.ophtha.2013.08.044 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

4. Ing JJ, Ing HH, Nelson LR, Hodge DO, Bourne WM. Ten-year postoperative results of penetrating keratoplasty. Ophthalmology. 1998;105(10):1855-1865. 10.1016/S0161-6420(98)91030-2 [Abstract] [CrossRef] [Google Scholar]

5. Patel SV, Diehl NN, Hodge DO, Bourne WM. Donor risk factors for graft failure in a 20-year study of penetrating keratoplasty. Arch Ophthalmol. 2010;128(4):418-425. 10.1001/archophthalmol.2010.27 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

6. Price MO, Calhoun P, Kollman C, Price FW Jr, Lass JH. Descemet stripping endothelial keratoplasty: ten-year endothelial cell loss compared with penetrating keratoplasty. Ophthalmology. 2016;123(7):1421-1427. 10.1016/j.ophtha.2016.03.011 [Abstract] [CrossRef] [Google Scholar]

7. Li JY, Terry MA, Goshe J, Shamie N, Davis-Boozer D. Graft rejection after Descemet’s stripping automated endothelial keratoplasty: graft survival and endothelial cell loss. Ophthalmology. 2012;119(1):90-94. 10.1016/j.ophtha.2011.07.007 [Abstract] [CrossRef] [Google Scholar]

8. Lass JH, Szczotka-Flynn LB, Ayala AR, et al. ; Writing Committee for the Cornea Preservation Time Study Group . Cornea preservation time study: methods and potential impact on the cornea donor pool in the United States. Cornea. 2015;34(6):601-608. 10.1097/ICO.0000000000000417 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

9. Rosenwasser GO, Szczotka-Flynn LB, Ayala AR, et al. ; Cornea Preservation Time Study Group . Effect of cornea preservation time on success of Descemet stripping automated endothelial keratoplasty: a randomized clinical trial. JAMA Ophthalmol. 2017;135(12):1401-1409. 10.1001/jamaophthalmol.2017.4989 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

10. Lass JH, Benetz BA, Verdier DD, et al. ; Cornea Preservation Time Study Group . Corneal endothelial cell loss 3 years after successful Descemet stripping automated endothelial keratoplasty in the Cornea Preservation Time Study: a randomized clinical trial. JAMA Ophthalmol. 2017;135(12):1394-1400. 10.1001/jamaophthalmol.2017.4970 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

11. Terry MA, Aldave AJ, Szczotka LB, et al. . Donor, recipient, and operative factors associated with graft success in the Cornea Preservation Time Study. Ophthalmology. 2018;125:1700-09. 10.1016/j.ophtha.2018.08.002 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

12. Lass JH, Riddlesworth TD, Gal RL, et al. ; Cornea Donor Study Research Group . The effect of donor diabetes history on graft failure and endothelial cell density 10 years after penetrating keratoplasty. Ophthalmology. 2015;122(3):448-456. 10.1016/j.ophtha.2014.09.012 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

13. Mannis MJ, Holland EJ, Gal RL, et al. ; Writing Committee for the Cornea Donor Study Research Group . The effect of donor age on penetrating keratoplasty for endothelial disease: graft survival after 10 years in the Cornea Donor Study. Ophthalmology. 2013;120(12):2419-2427. 10.1016/j.ophtha.2013.08.026 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

14. Benetz BA, Gal RL, Ruedy KJ, et al. ; Cornea Donor Study Group . Specular microscopy ancillary study methods for donor endothelial cell density determination of Cornea Donor Study images. Curr Eye Res. 2006;31(4):319-327. 10.1080/02713680500536738 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

15. Sayegh RR, Benetz BA, Lass JH. Specular microscopy. In: Mannis MJ, Holland EJ, eds. Cornea: Fundamentals, Diagnosis, Management. Vol 1. New York, NY: Elsevier; 2016:160-179. [Google Scholar]

16. Derksen S, Keselman HJ. Backward, forward, and stepwise automated subset selection algorithms: frequency of obtaining authentic and noise variable. Br J Math Stat Psychol. 1992;45:265-282. 10.1111/j.2044-8317.1992.tb00992.x [CrossRef] [Google Scholar]

17. R Development Core Team . A Language and Environment for Statistical Computing. Vienna, Austria: The R Foundation for Statistical Computing. 2018. [Google Scholar]

18. Kim J, Kim CS, Sohn E, Jeong IH, Kim H, Kim JS. Involvement of advanced glycation end products, oxidative stress and nuclear factor-kappa B in the development of diabetic keratopathy. Graefes Arch Clin Exp Ophthalmol. 2011;249(4):529-536. 10.1007/s00417-010-1573-9 [Abstract] [CrossRef] [Google Scholar]

19. Skeie JM, Aldrich BT, Goldstein AS, Schmidt GA, Reed CR, Greiner MA. Proteomic analysis of corneal endothelial cell-Descemet membrane tissues reveals influence of insulin dependence and disease severity in type 2 diabetes mellitus. PLoS One. 2018;13(3):e0192287. 10.1371/journal.pone.0192287 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

20. Lass JH, Spurney RV, Dutt RM, et al. . A morphologic and fluorophotometric analysis of the corneal endothelium in type I diabetes mellitus and cystic fibrosis. Am J Ophthalmol. 1985;100(6):783-788. 10.1016/S0002-9394(14)73367-7 [Abstract] [CrossRef] [Google Scholar]

21. Larsson LI, Bourne WM, Pach JM, Brubaker RF. Structure and function of the corneal endothelium in diabetes mellitus type I and type II. Arch Ophthalmol. 1996;114(1):9-14. 10.1001/archopht.1996.01100130007001 [Abstract] [CrossRef] [Google Scholar]

22. Shenoy R, Khandekar R, Bialasiewicz A, Al Muniri A. Corneal endothelium in patients with diabetes mellitus: a historical cohort study. Eur J Ophthalmol. 2009;19(3):369-375. 10.1177/112067210901900307 [Abstract] [CrossRef] [Google Scholar]

23. Liaboe CA, Aldrich BT, Carter PC, et al. . Assessing the impact of diabetes mellitus on donor corneal endothelial cell density. Cornea. 2017;36(5):561-566. 10.1097/ICO.0000000000001174 [Abstract] [CrossRef] [Google Scholar]

24. McNamara NA, Brand RJ, Polse KA, Bourne WM. Corneal function during normal and high serum glucose levels in diabetes. Invest Ophthalmol Vis Sci. 1998;39(1):3-17. [Abstract] [Google Scholar]

25. Ziadi M, Moiroux P, d’Athis P, Bron A, Brun JM, Creuzot-Garcher C. Assessment of induced corneal hypoxia in diabetic patients. Cornea. 2002;21(5):453-457. 10.1097/00003226-200207000-00004 [Abstract] [CrossRef] [Google Scholar]

26. Aldrich BT, Schlötzer-Schrehardt U, Skeie JM, et al. . Mitochondrial and morphologic alterations in native human corneal endothelial cells associated with diabetes mellitus. Invest Ophthalmol Vis Sci. 2017;58(4):2130-2138. 10.1167/iovs.16-21094 [Abstract] [CrossRef] [Google Scholar]

27. Schwarz C, Aldrich BT, Burckart KA, et al. . Descemet membrane adhesion strength is greater in diabetics with advanced disease compared to healthy donor corneas. Exp Eye Res. 2016;153:152-158. 10.1016/j.exer.2016.10.015 [Abstract] [CrossRef] [Google Scholar]

28. Price MO, Lisek M, Feng MT, Price FW Jr. Effect of donor and recipient diabetes status on Descemet membrane endothelial keratoplasty adherence and survival. Cornea. 2017;36(10):1184-1188. [Abstract] [Google Scholar]

29. Vislisel JM, Liaboe CA, Wagoner MD, et al. . Graft survival of diabetic versus nondiabetic donor tissue after initial keratoplasty. Cornea. 2015;34(4):370-374. 10.1097/ICO.0000000000000378 [Abstract] [CrossRef] [Google Scholar]

30. Nishimura JK, Hodge DO, Bourne WM. Initial endothelial cell density and chronic endothelial cell loss rate in corneal transplants with late endothelial failure. Ophthalmology. 1999;106(10):1962-1965. 10.1016/S0161-6420(99)90409-8 [Abstract] [CrossRef] [Google Scholar]

31. Lass JH, Sugar A, Benetz BA, et al. ; Cornea Donor Study Investigator Group . Endothelial cell density to predict endothelial graft failure after penetrating keratoplasty. Arch Ophthalmol. 2010;128(1):63-69. 10.1001/archophthalmol.2010.128.63 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

32. Potapenko IO, Samolov B, Armitage MC, Byström B, Hjortdal J. Donor endothelial cell count does not correlate with Descemet stripping automated endothelial keratoplasty transplant survival after 2 years of follow-up. Cornea. 2017;36(6):649-654. 10.1097/ICO.0000000000001189 [Abstract] [CrossRef] [Google Scholar]

33. Hopkinson CL, Romano V, Kaye RA, et al. ; National Health Service Blood Transplant Ocular Tissue Advisory Group and Contributing Ophthalmologists (OTAG study 20) . The influence of donor and recipient gender incompatibility on corneal transplant rejection and failure. Am J Transplant. 2017;17(1):210-217. 10.1111/ajt.13926 [Abstract] [CrossRef] [Google Scholar]

34. Borkar DS, Veldman P, Colby KA. Treatment of Fuchs endothelial dystrophy by Descemet stripping without endothelial keratoplasty. Cornea. 2016;35(10):1267-1273. 10.1097/ICO.0000000000000915 [Abstract] [CrossRef] [Google Scholar]

35. Moloney G, Petsoglou C, Ball M, et al. . Descemetorhexis without grafting for Fuchs endothelial dystrophy-supplementation with topical ripasudil. Cornea. 2017;36(6):642-648. 10.1097/ICO.0000000000001209 [Abstract] [CrossRef] [Google Scholar]

36. Aldave AJ, Chen JL, Zaman AS, Deng SX, Yu F. Outcomes after DSEK in 101 eyes with previous trabeculectomy and tube shunt implantation. Cornea. 2014;33(3):223-229. 10.1097/ICO.0000000000000028 [Abstract] [CrossRef] [Google Scholar]

37. Anshu A, Price MO, Price FW. Descemet’s stripping endothelial keratoplasty: long-term graft survival and risk factors for failure in eyes with preexisting glaucoma. Ophthalmology. 2012;119(10):1982-1987. 10.1016/j.ophtha.2012.04.031 [Abstract] [CrossRef] [Google Scholar]

38. Price MO, Thompson RW Jr, Price FW Jr. Risk factors for various causes of failure in initial corneal grafts. Arch Ophthalmol. 2003;121(8):1087-1092. 10.1001/archopht.121.8.1087 [Abstract] [CrossRef] [Google Scholar]

39. Wacker K, Baratz KH, Maguire LJ, McLaren JW, Patel SV. Descemet stripping endothelial keratoplasty for Fuchs’ endothelial corneal dystrophy: five-year results of a prospective study. Ophthalmology. 2016;123(1):154-160. 10.1016/j.ophtha.2015.09.023 [Abstract] [CrossRef] [Google Scholar]

40. Terry MA, Straiko MD, Goshe JM, et al. . Endothelial keratoplasty: prospective, randomized, masked clinical trial comparing an injector with forceps for tissue insertion. Am J Ophthalmol. 2013;156(1):61-68.e3. 10.1016/j.ajo.2013.01.025 [Abstract] [CrossRef] [Google Scholar]

41. Foster JB, Swan KR, Vasan RA, Greven MA, Walter KA. Small-incision Descemet stripping automated endothelial keratoplasty: a comparison of small-incision tissue injector and forceps techniques. Cornea. 2012;31(1):42-47. 10.1097/ICO.0b013e3182120f9d [Abstract] [CrossRef] [Google Scholar]

42. Ang M, Saroj L, Htoon HM, Kiew S, Mehta JS, Tan D. Comparison of a donor insertion device to sheets glide in Descemet stripping endothelial keratoplasty: 3-year outcomes. Am J Ophthalmol. 2014;157(6):1163-1169.e3. 10.1016/j.ajo.2014.02.049 [Abstract] [CrossRef] [Google Scholar]

43. Khor WB, Han SB, Mehta JS, Tan DT. Descemet stripping automated endothelial keratoplasty with a donor insertion device: clinical results and complications in 100 eyes. Am J Ophthalmol. 2013;156(4):773-779. 10.1016/j.ajo.2013.05.012 [Abstract] [CrossRef] [Google Scholar]

44. Gangwani V, Obi A, Hollick EJ. A prospective study comparing EndoGlide and Busin glide insertion techniques in Descemet stripping endothelial keratoplasty. Am J Ophthalmol. 2012;153(1):38-43.e1. 10.1016/j.ajo.2011.06.013 [Abstract] [CrossRef] [Google Scholar]

45. Price MO, Bidros M, Gorovoy M, et al. . Effect of incision width on graft survival and endothelial cell loss after Descemet stripping automated endothelial keratoplasty. Cornea. 2010;29:523-527. 10.1097/ICO.0b013e3181c11e5d [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

46. Terry MA, Li J, Goshe J, Davis-Boozer D. Endothelial keratoplasty: the relationship between donor tissue size and donor endothelial survival. Ophthalmology. 2011;118(10):1944-1949. 10.1016/j.ophtha.2011.02.023 [Abstract] [CrossRef] [Google Scholar]

47. Riddlesworth TD, Kollman C, Lass JH, et al. . A mathematical model to predict endothelial cell density following penetrating keratoplasty with selective dropout from graft failure. Invest Ophthalmol Vis Sci. 2014;55(12):8409-8415. 10.1167/iovs.14-15683 [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]

48. Armitage WJ, Dick AD, Bourne WM. Predicting endothelial cell loss and long-term corneal graft survival. Invest Ophthalmol Vis Sci. 2003;44(8):3326-3331. 10.1167/iovs.02-1255 [Abstract] [CrossRef] [Google Scholar]

49. Böhringer D, Böhringer S, Poxleitner K, et al. . Long-term graft survival in penetrating keratoplasty: the biexponential model of chronic endothelial cell loss revisited. Cornea. 2010;29(10):1113-1117. 10.1097/ICO.0b013e3181d21d07 [Abstract] [CrossRef] [Google Scholar]

50. Williams RS, Mayko ZM, Friend DJ, Straiko MD, Clay RD, Stoeger CG. Descemet membrane endothelial keratoplasty (DMEK) tissue preparation: a donor diabetes mellitus categorical risk stratification scale for assessing tissue suitability and reducing tissue loss. Cornea. 2016;35(7):927-931. 10.1097/ICO.0000000000000892 [Abstract] [CrossRef] [Google Scholar]

51. Soper MC, Marcovina SM, Hoover CK, et al. . Validity of postmortem glycated hemoglobin to determine status of diabetes mellitus in corneal donors. Cornea. 2017;36(8):942-947. 10.1097/ICO.0000000000001211 [Abstract] [CrossRef] [Google Scholar]

52. Centers for Disease Control and Prevention . Diabetes home: data and statistics. https://www.cdc.gov/diabetes/data/index.html. Published 2018. Accessed October 11, 2018.

53. Rodríguez-Calvo-de-Mora M, Quilendrino R, Ham L, et al. . Clinical outcome of 500 consecutive cases undergoing Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2015;122(3):464-470. 10.1016/j.ophtha.2014.09.004 [Abstract] [CrossRef] [Google Scholar]

54. Baydoun L, Ham L, Borderie V, et al. . Endothelial survival after Descemet membrane endothelial keratoplasty: effect of surgical indication and graft adherence status. JAMA Ophthalmol. 2015;133(11):1277-1285. 10.1001/jamaophthalmol.2015.3064 [Abstract] [CrossRef] [Google Scholar]

55. Peraza-Nieves J, Baydoun L, Dapena I, et al. . Two-year clinical outcome of 500 consecutive cases undergoing Descemet membrane endothelial keratoplasty. Cornea. 2017;36(6):655-660. 10.1097/ICO.0000000000001176 [Abstract] [CrossRef] [Google Scholar]

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Donor, Recipient, and Operative Factors Associated With Increased Endothelial Cell Loss in the Cornea Preservation Time Study.

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Donor, Recipient, and Operative Factors Associated With Increased Endothelial Cell Loss in the Cornea Preservation Time Study

Jonathan H. Lass

Beth Ann Benetz

Sanjay V. Patel

Loretta B. Szczotka-Flynn

Robert O’Brien

Allison R. Ayala

Maureen G. Maguire

Yassine J. Daoud

Mark A. Greiner

Sadeer B. Hannush

W. Barry Lee

Thomas F. Mauger

Harry J. Menegay

Mark D. Mifflin

Michael B. Raizman

Jennifer Rose-Nussbaumer

Robert L. Schultze

Gregory A. Schmidt

Alan Sugar

Mark A. Terry

David D. Verdier

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Endothelial Imaging and Image Analysis

Endothelial Cell Density Determination

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Diabetes

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Diagnosis

Preoperative IOP

Diabetes

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Insertion Methods and Incision Size

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