Vascularized composite allotransplantation in the United States: A retrospective analysis of the Organ Procurement and Transplantation Network data after 5 years of the Final Rule

Abstract

On July 3, 2014, the Organ Procurement and Transplantation Network (OPTN) began overseeing vascularized composite allotransplantation/allografts (VCA) in the United States. For the past 6 years, centers performing VCAs have been requested to submit data into a biometric repository, in parallel with systems used by solid organ transplant centers. Currently, 62 VCAs are reported in the entire OPTN database, with 36 of these transplants reported as performed after VCA was added to the OPTN Final Rule. Of these 36 recipients, 16 received uterus transplants, most of which (11) occurred from living donors. Ten patients received hand transplants and 6 received face transplants. Two patients received abdominal wall transplants, 1 patient received a scalp transplant, and 1 patient received a penile transplant. The present manuscript represents the query of a nationalized database for VCA type, immunosuppression treatment, and clinical outcomes for VCAs. This manuscript provides a report of the current VCA data reported to the OPTN after the Final Rule. On July 3, 2014, the Organ Procurement and Transplantation Network (OPTN) began overseeing vascularized composite allotransplantation/allografts (VCA) in the United States. For the past 6 years, centers performing VCAs have been requested to submit data into a biometric repository, in parallel with systems used by solid organ transplant centers. Currently, 62 VCAs are reported in the entire OPTN database, with 36 of these transplants reported as performed after VCA was added to the OPTN Final Rule. Of these 36 recipients, 16 received uterus transplants, most of which (11) occurred from living donors. Ten patients received hand transplants and 6 received face transplants. Two patients received abdominal wall transplants, 1 patient received a scalp transplant, and 1 patient received a penile transplant. The present manuscript represents the query of a nationalized database for VCA type, immunosuppression treatment, and clinical outcomes for VCAs. This manuscript provides a report of the current VCA data reported to the OPTN after the Final Rule. Vascularized composite allotransplantation (VCA) refers to the transplantation of components such as nerve, tendon, skin, and/or bone as a functional unit to reconstruct tissues that cannot be reconstructed with autologous tissue. VCA is an evolving field of transplantation that is built upon foundational science in vascular biology, microsurgery, and immunology. The first successful solid organ transplantation (SOT) by Joseph Murray in 1954 depended upon precepts developed decades earlier by immunologists like Karl Landsteiner and Peter Medawar.1Tuffaha S Broyles J Shores JT. Experimental Models and Clinical Tools to Assess Nerve Regeneration and Functional Outcomes.in: Brandacher G The Science of Reconstructive Transplantation. Springer, New York2015: 315-327Crossref Google Scholar Landsteiner, best remembered for his discovery of ABO blood groups, spent parts of his early career transplanting lymph nodes between guinea pigs,2Landsteiner K Chase MW. Experiments on transfer of cutaneous sensitivity to simple compounds.Proc Soc Exp Biol Med. 1942; 49: 688-690Crossref Scopus (203) Google Scholar and Medawar began his immunology research by transplanting soft tissues in wounded British soldiers.3Medawar P. A second study of the behaviour and fate of skin homografts in rabbits; a report to the War Wounds Committee of the Medical Research Council.J Anat. 1945; 79: 157-176Google Scholar Coupled with improved immunomodulatory drugs and refinement of vascular and microsurgical techniques,4Levin SM. Alexis Carrel’s historic leap of faith.J Vasc Surg. 2015; 61: 832-833Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar,5Carrel A. The transplantation of organs: a preliminary communication.JAMA. 1905; XLV: 1645-1646Crossref Scopus (32) Google Scholar VCAs have become technically feasible, with the first successful hand transplantation in 1998.6Diaz-Siso JR Bueno EM Sisk GC et al.Vascularized composite tissue allotransplantation–state of the art.Clin Transplant. 2013; 27: 330-337Crossref PubMed Scopus (56) Google Scholar Today, an increasing number of organs have been transplanted, including upper extremities, face, abdominal wall, and uterus. The United Network for Organ Sharing (UNOS) has managed the Organ Procurement and Transplantation Network (OPTN) contract from the US Department of Health and Human Services (HHS) since 1986. Under this contract, UNOS operates the nation’s solid organ donation and transplantation system. Effective July 3, 2014, these guidelines were amended such that VCA would be included within the OPTN Final Rule’s definition of “covered human organs.”7Cendales L Granger D Henry M et al.Implementation of vascularized composite allografts in the United States: recommendations from the ASTS VCA Ad Hoc Committee and the Executive Committee.Am J Transplant. 2011; 11: 13-17Crossref PubMed Scopus (31) Google Scholar, 8Glazier A. Regulatory oversight in the United States of vascularized composite allografts.Transplant Int. 2016; 29: 682-685Crossref PubMed Scopus (22) Google Scholar, 9OPTN. OPTN policy notice on membership requirements for VCA transplant programs. 2019. https://optn.transplant.hrsa.gov/governance/public-comment/membership-requirements-for-vca-transplant-programs/. Accessed November 22, 2019.Google Scholar Under the OPTN Final Rule, all centers that perform SOT (and now VCAs) are required to submit a variety of data including patient demographics, wait times, blood types, donor authorization requirements, and clinical outcomes.10Cherikh WS Cendales LC Wholley CL et al.Vascularized composite allotransplantation in the United States: A descriptive analysis of the Organ Procurement and Transplantation Network Data.Am J Transplant. 2019; 19: 865-875Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar The primary goal of such requirements is to promote safety and improvement pf patient outcomes. A previous publication from our group explored the state of VCAs in a 3-year period and another reviewed OPTN data on hand transplantations.10Cherikh WS Cendales LC Wholley CL et al.Vascularized composite allotransplantation in the United States: A descriptive analysis of the Organ Procurement and Transplantation Network Data.Am J Transplant. 2019; 19: 865-875Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,11Hein RE Ruch DS Klifto CS et al.Hand Transplantation in the United States: A review of the Organ Procurement and Transplantation Network/United Network for Organ Sharing Database.Am J Transplant. 2019; 00 (https://doi.org/10.1111/ajt.15704): 1-7Google Scholar The present manuscript is an effort to analyze all available OPTN data on VCAs, with a focus on all VCA types reported 5 years after the Final Rule. An advantage of OPTN data is access to a large aggregated database that enables investigators to approach questions that any one center could not do alone. Just as these tools are important for large-volume organs like kidneys, so too do smaller volume VCA centers have an obligation to openly communicate and share their data. Given the small number of VCAs occurring nationwide, it is essential that data-sharing be encouraged to move the field forward. What follows is an analysis of the OPTN data for all VCAs reported after the Final Rule from July 3, 2014 through March 31, 2019. We have used bioinformatic methods to define the drug therapies, donor and recipient immunophenotypes, perioperative variables, and clinical outcomes for living- vs deceased-donor organs and outcome data per VCA type. The OPTN database was received directly from the OPTN with all VCA types and follow-up data reported to the OPTN from 1999 to 2019; there are 62 total recipients reported. Our current analysis focused only on those recipients with transplant surgery dates reported from July 3, 2014 through March 31, 2019. Only patients with a documented date of transplant are included; patients who are entered in the data set but without a transplant date (ie, waitlist patients) are excluded from analysis. The database includes a discrete variable for “graft failure date,” which our analysis defines as a failed or graft loss. When a recipient is reported to have an “acute rejection episode,” this is noted as an event but is not a graft failure. For those recipients with reported visits, but with subsequent lack of reported entries, the last-reported clinical status of the graft is carried forward. Grafts that have not been reported as lost are thereby considered free from graft failure for a set time period. This is computed as the number of days between the transplantation surgery and the latest clinical encounter wherein the graft is reported as not failed. SAS 9.2 (SAS Institute, Cary, NC) was used to parse and analyze organ-specific OPTN data. Additional data analysis was performed with Excel 16.29 (Microsoft, Redmond, WA) and Prism 8.2 (GraphPad, San Diego, CA). Figures were produced with Adobe InDesign 14.0.3 (Adobe, Mountain View, CA), with some image rendering by PowerPoint 16.29 (Microsoft). The OPTN database reports clinical data for patients who have undergone VCA beginning in 1999; the present analysis is focused on transplant surgeries and their follow-up encounters reported after the Final Rule. Baseline or preoperative (preop) characteristics are defined by 219 variables, and the follow-up (postop) clinical data are defined by 463 variables. One challenge in VCA is the aggregation of different organ types (ie, hand, face, abdominal wall) within a single analytic framework; for example, variables for “decannulation of tracheostomy” are not applicable for patients undergoing hand transplant. In the present database, many clinical variables (eg, the perioperative use of inotropes in VCA donors or the Banff score of recipients’ rejection episodes) have null values reported, imparting no clinical utility to the analysis. Given the small number of VCAs per organ type, no attempt was made to mathematically impute missing values. Toward generating a clinically legible manuscript, these underreported variables have been excluded from analysis. Examples of these variables include donor crossmatch results, VCA recipients’ preop and postop calculated panel-reactive antibodies (CPRA), social functioning scores, and body mass index. Table S10 presents an excerpted list of such variables. Also excluded from this analysis is the location the transplant procedures occurred. The OPTN database uses encrypted numbers for regional transplant centers, but the data include state-of-origin information for VCA recipients. Because of the small number of VCAs performed nationwide, and in keeping with OPTN principles of patient confidentiality, no effort was made to analyze the data by geography. Variables of clinical significance that are electively included in the analysis despite underreporting include the Epstein-Barr virus (EBV) and cytomegalovirus (CMV)-seropositivity of donor–recipient pairs12Jaskula E Bochenska J Kocwin E et al.CMV Serostatus of Donor-Recipient Pairs Influences the Risk of CMV Infection/Reactivation in HSCT Patients.Bone Marrow Res. 2012; : 375075PubMed Google Scholar and all functional outcome data available (especially for hand and face transplants). All VCAs reported donor/recipient ABO status and matched congruently; it is not detailed herein for simplicity. As the degree of acute rejection episodes is not consistently reported, any reported rejection episode is presumed to be at least Banff classification I.13Schneider M Cardones ARG Selim MA et al.Vascularized composite allotransplantation: a closer look at the banff working classification.Transplant Int. 2016; 29: 663-671Crossref PubMed Scopus (31) Google Scholar The data reported here have been supplied by UNOS as the contractor for the OPTN. The interpretation and reporting of these data are the responsibility of the author(s) and not an official policy of or interpretation by the OPTN or the US Government. Prior to initiation of this work, all authors signed an OPTN/UNOS Data Use Agreement, affirming their commitment to these principles of data integrity and patient confidentiality. In the period from July 3, 2014 to March 31, 2019, a total of 36 patients are reported to have undergone VCA transplantation (Figure 1, Figure 2, Table S1). A commonly transplanted organ is the uterus, with a total of 16 procedures, 11 of which occurred with living donors and 5 through a deceased donor. There are 10 total recipients of hand transplants in the OPTN data from 2014 to 2019 (when combining those patients who received a bilateral or unilateral procedure). Of the 10 hand transplant recipients, one patient (10%) is reported to have had a graft loss. A total of 6 recipients of face transplant are reported in the data; none (0%) have reported graft failure or a date of graft loss. Two abdominal wall transplants are reported; neither of these have a reported date of graft loss or failure. There is 1 recipient of a penile transplant and 1 recipient of a scalp transplant; although the penile transplant recipient had an episode of acute rejection, neither of these patients have reported graft loss or failure.FIGURE 2Number of transplants reported after the Final Rule by year. VCAs reported to occur between July 3, 2014 and March 31, 2019 by year of transplantation [Color figure can be viewed at wileyonlinelibrary.com]View Large Image Figure ViewerDownload Hi-res image Download (PPT) Overall, among the 16 uterus transplants, 44% (7 recipients) are reported as failures with reported dates of graft loss. Among the 9 recipients whose grafts are not lost, the mean number of days free from graft failure is 159 days. One living-donor uterine recipient is reported to have had her graft in place for 436 days. Of the 7 patients who are reported to have undergone graft failure, 3 of these report a specific etiology: 2 are described as due to “thrombosis, outflow congestion,” and one reports “arterial thrombosis.” The other 3 failed grafts do not report a specific etiology. Uterus transplants are the only VCA in the data reported to occur with a living donor. The degree of HLA mismatch is not reported for the living-donor transplant procedures. Among deceased-donor uterus recipients who lost their grafts, an average HLA mismatch of 6 loci is reported. Among deceased-donor uterus recipients without reported graft failure, the average HLA mismatch is 5 loci (Tables S2 and S3). The majority of uterus transplants occurred among donor/recipient who were for and All uterus transplant recipients of and and are reported in the data and data include the of The average time is 1 for all reported uterus transplants (Tables S2 and S3). immunosuppression included for of uterus recipients. and are reported as drug for acute rejection episodes in living-donor uterus recipients. graft is the only outcome event reported; the in Figure presents the data as from graft for all uterus recipients. 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Of the 6 recipients, are reported to have or 1 acute rejection One patient is reported to have had 7 acute rejection rejection include or and Among the 6 bilateral hand transplant recipients, have reported preoperative and the average score improvement was per of the 6 bilateral hand transplant recipients have documented preoperative and in the these an average of per patient are reported for 5 of the recipients with an average postop score of A total of 6 face are reported, none of which are reported to have graft failure Among the 6 face transplant recipients, 5 report the degree of HLA at an average of 5 The most commonly reported for face transplant recipients are and The mean time among face transplants is time is reported for 3 for a mean time of 3 and were by of the recipients. rejection episodes are reported to occur for of the face transplant recipients, for a total of per is reported for face transplants, with and A variety of functional outcomes are reported for face transplants, with postop functional reported for of recipients. 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