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• W2892071854 abstract "The OPTN Pancreas Transplantation Committee performed a multicenter retrospective study to determine if undetectable serum C-peptide levels correspond to center-reported pancreas graft failures. C-peptide data from seven participating centers (n = 415 graft failures for transplants performed from 2002 to 2012) were analyzed pretransplant, at graft failure, and at return to insulin. One hundred forty-nine C-peptide values were submitted at pretransplant, 94 at return to insulin, and 233 at graft failure. There were 77 transplants with two available values (at pretransplant and at graft failure). For recipients in the study with pretransplant C-peptide <0.75 ng/mL who had a posttransplant C-peptide value available (n = 61), graft failure was declared at varying levels of C-peptide. High C-peptide values at graft failure were not explained by nonfasting testing or by individual center bias. Transplant centers declare pancreas graft failure at varying levels of C-peptide and do not consistently report C-peptide data. Until February 28, 2018, OPTN did not require reporting of posttransplant C-peptide levels and it appears that C-peptide levels are not consistently used for evaluating graft function. C-peptide levels should not be used as the sole criterion for the definition of pancreas graft failure. The OPTN Pancreas Transplantation Committee performed a multicenter retrospective study to determine if undetectable serum C-peptide levels correspond to center-reported pancreas graft failures. C-peptide data from seven participating centers (n = 415 graft failures for transplants performed from 2002 to 2012) were analyzed pretransplant, at graft failure, and at return to insulin. One hundred forty-nine C-peptide values were submitted at pretransplant, 94 at return to insulin, and 233 at graft failure. There were 77 transplants with two available values (at pretransplant and at graft failure). For recipients in the study with pretransplant C-peptide <0.75 ng/mL who had a posttransplant C-peptide value available (n = 61), graft failure was declared at varying levels of C-peptide. High C-peptide values at graft failure were not explained by nonfasting testing or by individual center bias. Transplant centers declare pancreas graft failure at varying levels of C-peptide and do not consistently report C-peptide data. Until February 28, 2018, OPTN did not require reporting of posttransplant C-peptide levels and it appears that C-peptide levels are not consistently used for evaluating graft function. C-peptide levels should not be used as the sole criterion for the definition of pancreas graft failure. There has been concern that transplant centers report pancreas graft failure at different clinical endpoints.1Kandaswamy R Stock PG Gustafson SK et al.OPTN/SRTR 2016 annual data report: pancreas.Am J Transplant. 2018; 18: 114-171Crossref PubMed Scopus (61) Google Scholar Some reports that use pancreas graft failure as an outcome have completely avoided attempting to define pancreas graft failure, or simply referenced Organ Procurement and Transplantation Network (OPTN) data without specifying how pancreas graft failure was determined.2Stratta RJ Graft failure after solitary pancreas transplantation.Transpl Proc. 1998; 30: 289Crossref PubMed Scopus (0) Google Scholar, 3Waki K Terasaki PI Kadowaki T Long-term pancreas allograft survival in simultaneous pancreas-kidney transplantation by era.Diabetes Care. 2010; 33: 1789-1791Crossref PubMed Scopus (21) Google Scholar, 4Reddy KS Davies D Ormond D et al.Impact of acute rejection episodes on long-term graft survival following simultaneous kidney-pancreas transplantation.Am J Transplant. 2003; 3: 439-444Crossref PubMed Scopus (0) Google Scholar Other programs have attempted a more scientific definition; such as reporting a pancreatic graft as failed if there is loss of insulin independence,5Mittal S Nagendran M Franklin RH Sharples EJ Friend PJ Gough SCL Postoperative impaired glucose tolearance is an early predictor of pancreas graft failure.Diabetologia. 2014; 57: 2076-2080Crossref PubMed Scopus (0) Google Scholar or when the pancreas graft has been removed or the patient has died.6Sampaio MS Kuo HT Bunnapradist S Outcomes of simultaneous pancreas-kidney transplantation in type 2 diabetic recipients.Clin J Am Soc Nephrol. 2011; 6: 1198-1206Crossref PubMed Scopus (63) Google Scholar Other factors, such as C-peptide levels, hemoglobin A1C (HbA1C) levels,7Fradejas ML Kandil D Papadimitriou JC Del Pino Florez Rial M Prieto Sanchez E Drachenberg CB Islet amyloid in whole pancreas transplants for type 1 diabetes mellitus (DM): possible role of type 2 DM for graft failure.Am J Transplant. 2015; 15: 2495-2500Crossref PubMed Scopus (9) Google Scholar or dose and duration of insulin therapy are used by some programs to determine when graft failure has occurred (personal communication with committee members). As the OPTN uses statistical models based on center-reported and center-determined pancreas graft failure to assess pancreas program performance, differences in reporting may influence whether a pancreas program will be identified for poor outcomes. The current system of center-based self-reported pancreas graft failure in which one center uses one definition and another uses a different definition is not useful for assessing center performance or for comparing pancreas allograft outcomes between centers. In addition, not having a consistently applied definition of pancreas graft failure makes it difficult to compare pancreas transplantation outcomes to other treatment modalities, such as islet transplantation. Until now, the Scientific Registry of Transplant Recipients (SRTR) has refrained from reporting pancreas outcomes in program-specific reports1Kandaswamy R Stock PG Gustafson SK et al.OPTN/SRTR 2016 annual data report: pancreas.Am J Transplant. 2018; 18: 114-171Crossref PubMed Scopus (61) Google Scholar and has only reported overall “program-reported” graft failure rates for pancreas transplant recipients8Israni AK Skeans MA Gustafson SK et al.OPTN/SRTR 2012 annual data report: pancreas.Am J Transplant. 2014; 14: 45-68Crossref PubMed Scopus (26) Google Scholar while cautioning readers about these limitations due to variable reporting of graft failure. Therefore, the OPTN/United Network for Organ Sharing (UNOS) Pancreas Transplantation Committee (Committee) was tasked with defining pancreas graft failure in such a way that it can easily be compared and consistently applied across different transplant centers. At the start of this project in 2013, there was no specific definition for pancreas graft failure in OPTN policy.9OPTN/UNOS Pancreas Transplantation Committee. Definition of Pancreas Graft Failure, July 1, 2015. https://optn.transplant.hrsa.gov/media/1572/policynotice_20150701_pancreas.pdf. Accessed October 10, 2018.Google Scholar The general definition for graft failure for all organs stated that: “[Graft failure] occurs when an organ is removed, a recipient dies, or a recipient is placed on a chronic allograft support system.” In addition, there was Transplant Information Electronic Data Interchange (TIEDI) help documentation, which included guidance on how to categorize a pancreas allograft into one of the three categories (Table 1).TABLE 1TIEDI help documentation guidance for pancreas graft failureState of pancreas functionDefinitionFunctioningThe graft has sufficient function so that the recipient is NOT receiving any insulin or oral medication for blood sugar controlPartial functionThe patient is taking some insulin, but <50% of the usual amount taken before transplant, or C-peptide is presentFailedThe graft has totally failed and the patient is completely dependent upon insulin or oral medication for blood sugar control Open table in a new tab The Committee was unsatisfied with this approach because, by including a partial function category in TIEDI, it was not clear whether partial function constituted a graft failure or success. Moreover, the partial function category was rarely used to document the status of individual patients by any centers. One of the main points of discussion was whether a defined C-peptide level could serve as a threshold to define pancreas graft failure. Because the literature on C-peptide levels as a marker of graft failure was sparse and inconclusive,7Fradejas ML Kandil D Papadimitriou JC Del Pino Florez Rial M Prieto Sanchez E Drachenberg CB Islet amyloid in whole pancreas transplants for type 1 diabetes mellitus (DM): possible role of type 2 DM for graft failure.Am J Transplant. 2015; 15: 2495-2500Crossref PubMed Scopus (9) Google Scholar,10Pendon-Ruiz de Mier V Caballo N Martinez Vaquera S et al.High index insulin resistance in pancreas-kidney transplantation contributes to poor long-term survival of the pancreas graft.Transpl Proc. 2015; 47: 117-119Crossref PubMed Google Scholar, 11LaMattina J Sollinger H Becker Y Mezrich J Pirsch J Odorico J Long-term pancreatic allograft survival after renal retransplantation in prior simultaneous pancreas-kidney recipients.Am J Transplant. 2012; 12: 937-946Crossref PubMed Scopus (0) Google Scholar, 12Smith JL Hunsicker LG Yuh WT Wright Jr, FH Van Voorhis L Corry RJ Appearance of type II diabetes mellitus in type I diabetic recipients of pancreas allografts.Transplantation. 1989; 47: 304-311Crossref PubMed Scopus (32) Google Scholar and because C-peptide data are not routinely reported to the OPTN, the Pancreas Outcomes Subcommittee decided to perform their own multicenter retrospective C-peptide data collection study. The goal of this data collection was to determine whether a defined C-peptide level could serve as a threshold level to define pancreas graft failure as reported to the OPTN. Additionally, we review a discussion by the OPTN Pancreas Committee that occurred over a 2-year period about what should constitute a reasonable definition of pancreas allograft failure and why the current definition was chosen. As the OPTN did not previously request C-peptide data on pancreas transplant candidate registration forms or on follow-up forms, the SRTR did not have any data of this nature to analyze. To overcome this limitation, the OPTN Pancreas Committee recruited seven pancreas transplant centers (MNUM, WIUW, ILPL, INIM, CAGH, MDUM, NCBG) who voluntarily participated in the C-peptide data collection study. Solid organ kidney-pancreas and pancreas alone recipients whose grafts had failed were included. After obtaining internal IRB approval, each of the seven centers was supplied a spreadsheet containing all of the center’s pancreas graft failures as reported to the OPTN for transplants performed between 2002 through 2012 (Supplemental Table S1). All causes of graft failure were included. The spreadsheet included identifiers to link the submitted data back to the OPTN database, and included patient status and date, date of pancreas allograft removal (when applicable), the center submitted the date that corresponded to graft failure, the date that either insulin or oral hypoglycemic medication was resumed, and the primary cause of graft failure to aid study participants’ in linking to their own databases. Data were collected at three time points: pretransplant, at return to insulin, and at designated graft failure. The data requested from the participating centers included the C-peptide value, C-peptide type (fasting or stimulated), creatinine value, and corresponding measurement dates and units. C-peptide values reported in pmol/L were converted to ng/mL by dividing values by 333. Since C-peptides were collected from different centers with different laboratories, and often imported to the centers from outside laboratories, the precise assays used to measure C-peptide are unknown. Many values were submitted to the study as “<0.1” and “<0.5,” which represented the limits of detection for that particular laboratory or assay. For this study, “undetectable” C-peptide was defined as the limit of detection reported by each laboratory (ie, 0.1 or 0.5). Similarly, the normal range for C- peptide was different due to different laboratories and assays used for different patients, institutions, and their associated laboratories. The “normal range” for each laboratory was considered that patient’s normal range. The participants submitted their data and the committee analyzed the results to determine if a defined C-peptide threshold level correlated with a reported indication of graft failure or if a C-peptide value at graft failure could be determined based on the pretransplant C-peptide level. Analyses were performed using both SAS Version 9.3 (SAS Institute, Cary, NC) and RStudio with R Version 3.2.3 (package: ggplot2 [v 2.2.1]; R Studio, Inc., Boston, MA). Descriptive statistics including mean, standard deviations and empirical quantiles were generated to study the distribution of values of C-peptide submitted in this study at the different time points of interest. Frequency distributions were studied by center and time period to assess the number of cases that recorded C-peptide results and how many reported the values of pretransplant, and graft failure, and at return to insulin. Histograms were built to study the distribution of the actual C-peptide values at those time points, and bivariate scatter plots were examined to assess whether or not values pretransplant were indicative of graft failure levels of C-peptide. Values in the scatter plots were also labeled by whether they were Fasting/Stimulated and by the transplant center to try to elucidate patterns described by those factors. This study also used data from the Organ Procurement and Transplantation Network (OPTN). The OPTN data system includes data on all donor, wait-listed candidates, and transplant recipients in the US, submitted by the members of the OPTN, and has been described elsewhere. The Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services provides oversight to the activities of the OPTN contractor. A total of 415 graft failures were queried from the OPTN database and sent to the centers, originating from 1755 transplants done during that time period at participating centers. Table 2 shows the volume of data queried and submitted by each center. Center volume of graft failures ranged from 6 to 139, with a median of 66 graft failures (Table 2). The data illustrate that the transplant centers were not consistent in their practices regarding collection of C-peptide values at these three time points.TABLE 2Number of C-peptide values available for study at each of the three time points, pretransplant, at insulin resumption, and at graft failure by encrypted transplant center ID numberEncrypted centerGraft failures queriedPretransplant C-peptideAt return to insulin C-peptideAt graft failure C-peptideIDNNNNCenter 114234Center 26640639Center 3941094Center 4139585657Center 52121719Center 66503Center 775222217Total41514994233 Open table in a new tab Table 3 shows the empirical distribution of all C-peptide values, expressed in ng/mL, submitted at each time point for this project. The median C-peptide values at return to insulin were within the normal range, indicating that many patients require insulin to control the diabetes despite continued graft insulin output. Additionally, the data indicate that the median levels of C-peptide at center-determined graft failure are significantly different and lower than those values submitted at the time of initial return to insulin. However, even at graft failure, often C-peptide levels remain detectable and are higher than pretransplant, suggesting that an undetectable C-peptide level should not be a requirement for graft failure.TABLE 3Empirical distribution of C-peptide values (ng/mL) pretransplant, at insulin resumption, and at graft failure for data submitted through the Outcomes Subcommittee data collection projectNMeanSDMin25th %Median75th %MaxPretransplant1492.036.100.10.20.533Return to insulin942.282.20.10.61.463.412.1Graft failure2332.113.300.40.92.733 Open table in a new tab We then analyzed the distribution of C-peptide values at each time point, which is displayed in Figure 1. Over 90% of recipients had a C-peptide less than 0.75 ng/mL pretransplant. The distribution shifts to higher values for C-peptide at return to insulin and at graft failure, indicating that loss of C-peptide has not been an absolute requirement for a graft to be considered failed. Table 4 shows the total number of graft failures per center. More specifically, this table highlights how inconsistently C-peptide levels are used. Even through center-based data collection, many C-peptide values at return to insulin and at graft failure were not available, likely because they were not drawn. Despite 415 total graft failures, only 77 had pretransplant and graft failure values available. Even fewer (36) had values collected at all three designated time points. Interestingly, of these 36 recipients, 30 recipients returned to insulin at graft failure (data not shown). Some patients had high pretransplant C-peptide values, likely indicating the subset of patients that exhibited a type 2 diabetic phenotype (Figure 1). In order to eliminate confusion about the origin (native or transplant pancreas) of the posttransplant C-peptide levels in patients who had restarted insulin or been determined a graft failure, we then eliminated those patients who had measurable pretransplant C-peptide levels (>0.75 ng/mL). This left 61 presumably type 1 diabetic patients with graft failure for analysis (Table 4). Figure 2 shows the bivariate distribution for these 61 graft failures represented in this study with both pretransplant and graft failure C-peptide measurements, where all pretransplant C-peptide values were undetectable (≤0.75 ng/mL), by whether or not the value was obtained fasting or stimulated. Of the 61 pairs, three graft failure values did not indicate whether they were fasting or stimulated, four were stimulated, and the other 54 were fasting. Even though sample sizes are small, the fact that the higher values of C-peptide at graft failure were not biased by stimulated testing indicates that graft failure is not uniformly reported at any specific level of C-peptide. Furthermore, even though all patients had undetectable C-peptide levels pretransplant, graft failure was often declared when C-peptide was still being produced by the transplanted pancreas.TABLE 4Center specific reporting of graft failures, cases with c-peptide values at pretransplant and graft failure time points, and cases with data at all three time pointsEncrypted center IDN total graft failuresN with both pretransplant and at graft failure C-peptideN with C-peptide at all three pointsN with pretransplant C-peptide 0.75 or less (presumed type 1 diabetics) and graft failure value availableCenter 114000Center 26629328Center 394101Center 4139242422Center 5211977Center 66202Center 775221Total415773661 Open table in a new tab To determine whether there were any center-specific tendencies for determining graft failure relative to C-peptide levels, we examined Figure 2 by center. Figure 3 shows the same bivariate distribution as shown in Figure 2, with the paired C-peptide values marked by different shapes indicating the corresponding center. The data do not indicate that certain centers reported graft failures at consistently higher C-peptide levels than other centers. Thus, the data do not exhibit a strong center specific bias in reporting graft failures. Defining pancreas allograft failure is a vexing and complex challenge. How many pancreata still secrete C-peptide even after they are reported as graft failures? What level of elevated HbA1C level is indicative of graft failure? Has the graft failed if a recipient is taking one or more chronic oral hypoglycemic agents? How much insulin use, and for how long, is indicative of graft failure? How does the degree of renal dysfunction influence our view of whether a pancreatic allograft has failed or is still functioning (because this can affect insulin requirements)? Is a graft failed when a patient is re-listed, or does the graft not actually fail until retransplantation or death? Does death imply graft failure, even when the graft was functioning at death? Clearly, these are difficult questions with no easy answers. The study was limited by the fact that the only available indicator of allograft functional status was self-reported by centers on OPTN pancreas and kidney-pancreas registration and follow-up forms. Furthermore, few recipients had sequential C-peptide data from all the three time points, pretransplant, at return to insulin, and at declaration of graft failure. Additionally, since data were voluntarily submitted, they represent a retrospective collection of a population sample that may or may not be representative of all pancreas graft failures. The discussions held over several years by the Committee are summarized below to illustrate the complexity of decision-making involved in developing a new definition of pancreas allograft failure. Initially, there was discussion about using a fixed cutoff for C-peptide (≤0.4 ng/mL) as part of the definition for graft failure. Since this was an arbitrarily chosen number, there was particular concern regarding the validity of a C-peptide value of ≤0.4 ng/mL as a metric of graft failure. On review, current medical literature does not address a specific C-peptide value that corresponds with pancreas allograft failure.7Fradejas ML Kandil D Papadimitriou JC Del Pino Florez Rial M Prieto Sanchez E Drachenberg CB Islet amyloid in whole pancreas transplants for type 1 diabetes mellitus (DM): possible role of type 2 DM for graft failure.Am J Transplant. 2015; 15: 2495-2500Crossref PubMed Scopus (9) Google Scholar,10Pendon-Ruiz de Mier V Caballo N Martinez Vaquera S et al.High index insulin resistance in pancreas-kidney transplantation contributes to poor long-term survival of the pancreas graft.Transpl Proc. 2015; 47: 117-119Crossref PubMed Google Scholar, 11LaMattina J Sollinger H Becker Y Mezrich J Pirsch J Odorico J Long-term pancreatic allograft survival after renal retransplantation in prior simultaneous pancreas-kidney recipients.Am J Transplant. 2012; 12: 937-946Crossref PubMed Scopus (0) Google Scholar, 12Smith JL Hunsicker LG Yuh WT Wright Jr, FH Van Voorhis L Corry RJ Appearance of type II diabetes mellitus in type I diabetic recipients of pancreas allografts.Transplantation. 1989; 47: 304-311Crossref PubMed Scopus (32) Google Scholar Based on a lack of consensus in the literature related to C-peptide levels, and in general, to help guide a definition of graft failure, the OPTN Pancreas Committee undertook the present study to gain insight into the relationship between C-peptide levels and graft failure. Our analysis does not support using C-peptide levels as the only criterion for determining graft failure, as graft failure has been reported to occur at a variety of C-peptide levels. As others have shown previously, posttransplant diabetes can and does occur after pancreas transplantation, whether the patient is initially characterized as having either type 1 or type 2 diabetes.10Pendon-Ruiz de Mier V Caballo N Martinez Vaquera S et al.High index insulin resistance in pancreas-kidney transplantation contributes to poor long-term survival of the pancreas graft.Transpl Proc. 2015; 47: 117-119Crossref PubMed Google Scholar,11LaMattina J Sollinger H Becker Y Mezrich J Pirsch J Odorico J Long-term pancreatic allograft survival after renal retransplantation in prior simultaneous pancreas-kidney recipients.Am J Transplant. 2012; 12: 937-946Crossref PubMed Scopus (0) Google Scholar,13Dean PG Kudva YC Larson TS Kremers VK Stegall MD Posttransplant diabetes mellitus after pancreas transplantation.Am J Transplant. 2008; 8: 175-182Crossref PubMed Scopus (44) Google Scholar,14Neidlinger N Singh N Klein C et al.Incidence of and risk factors for posttransplant diabetes mellitus after pancreas transplantation.Am J Transplant. 2010; 10: 398-406Crossref PubMed Scopus (26) Google Scholar Even as early as 1989, Smith et al. noted that the presentation of diabetes after pancreas transplantation would be an important factor to consider in defining pancreas allograft failure.12Smith JL Hunsicker LG Yuh WT Wright Jr, FH Van Voorhis L Corry RJ Appearance of type II diabetes mellitus in type I diabetic recipients of pancreas allografts.Transplantation. 1989; 47: 304-311Crossref PubMed Scopus (32) Google Scholar Since C-peptide levels do not necessarily drop to “undetectable” levels before blood sugars rise and supplemental oral hypoglycemic agents or insulin are initiated, it seems to be incorrect to mandate an undetectable C-peptide level to determine graft failure. In addition, C-peptide is often detectable pretransplant in patients with type 2 diabetes; thus, type 2 diabetic recipients of pancreatic allografts would be exempt from graft failure if undetectable C-peptide levels were used to define graft failure. Figure 1 shows that more recipients have a higher C-peptide at the point of insulin resumption or at graft failure than pretransplant. Hence, physicians are deciding to treat with exogenous insulin at varying levels of pancreatic function; there is not one consistent C-peptide threshold that is used for all patients to determine when a pancreas allograft has failed. Moreover, as seen in Figure 2, where pretransplant and posttransplant C-peptide levels for each patient are linked, pretransplant and graft-failure C-peptide levels are highly unrelated to one another. All of these concerns led the Committee to decide against using C-peptide levels as a measure of pancreas graft failure. Due to inadequate data, the Committee did support adding a mandatory C-peptide field for pancreas transplants on future OPTN pancreas forms. This went into effect in February 2018. C-peptide alone is not an adequate measure of pancreas graft failure, and a more comprehensive definition for pancreas allograft failure needs to be developed. For some time after the C-peptide collection data were available, the Committee debated about whether to include a combination of HbA1C (above a certain threshold), insulin, or oral hypoglycemic use, and possibly C-peptide detection (see above) in the pancreas allograft failure definition. The Committee considered a combination of these factors because they appear to be interrelated. For example, one could circumvent starting insulin in order to avoid declaring a graft failure, but then the HbA1C level would reflect the resulting poor glucose control. Unfortunately, since these data points were not historically collected by the OPTN, it was impossible to model any further. This highlighted the need to collect and monitor these data points in the future, so they could be revisited and possibly incorporated into a more scientific definition of pancreas allograft failure. The idea to use insulin or oral hypoglycemic use as a measure of graft failure was not new to this discussion. Indeed, insulin and oral hypoglycemic use were previously embedded in the TIEDI help documentation for defining pancreas graft failure (Table 1). The Committee wanted to improve the definition of pancreas graft failure, mostly to increase understanding of pancreas graft failure among healthcare professionals. In reviewing the TIEDI help documentation, the Committee was concerned that the TIEDI definitions did not define a specific amount or duration of insulin use, nor did it address the use of oral hypoglycemic agents to improve glucose control. It also became clear that while a partial function category was included in the TIEDI guidance, it was rarely if ever used or reported, even though it is clear that numerous patients would at some point in time fall into this category. In our discussions, there ultimately was no consensus as to how much insulin and/or oral hypoglycemic use would constitute partial graft function, and thus, for now, we abandoned the concept of having a partial function tier as part of a graft function/failure definition. In order to qualify as a graft failure, the Committee agreed that the recipient needed to resume “full dose” insulin, but exactly how much was difficult to determine. For example, if a diabetic needs only minimal insulin support to maintain a normal HbA1C level, there is obviously still residual pancreatic function (this could be proven by a detectable C-peptide). In this case, there may be a gradual deterioration in pancreas allograft function, in the setting of chronic rejection or recurrent Type 1 diabetes, for instance. It is unclear at which point the pancreas allograft should justifiably be considered failed. Attempts to compare a ‘resumed’ amount of insulin to pretransplant dosages were unsuccessful, as many pancreas recipients also received a kidney allograft, and renal function and posttransplant immunosuppressive medications would certainly affect the amount of insulin required.11LaMattina J Sollinger H Becker Y Mezrich J Pirsch J Odorico J Long-term pancreatic allograft survival after renal retransplantation in prior simultaneous pancreas-kidney recipients.Am J Transplant. 2012; 12: 937-946Crossref PubMed Scopus (0) Google Scholar,15Chakkera HA Bodner JK Heilman RL et al.Outcomes after simultaneous pancreas and kidney transplantation and the discriminative ability of the C-peptide measurement pretransplant among type 1 and type 2 diabetes mellitus.Transplant Proc. 2010; 42: 2650-2652Crossref PubMed Scopus (0) Google Scholar Posttransplant weight gain could further confound this issue. Thus, the Committee agreed to establish a conservative threshold of 0.5 units/kg/day of insulin that would need to be exceeded before a pancreas allograft is considered to have failed. There are certainly situations in which insulin may be given temporarily (for example in a patient requiring short-term high dose corticosteroid therapy or having an acute infection) as this is likely not due to graft failure. Therefore, the Committee decided to include not only a threshold amount of insulin, but also a minimum period of time in order to allow short-term insulin use without erroneously declaring an allograft irreversibly failed. Ultimately, it was decided that a 90-day period should be long enough for temporary issues to be resolved and for a patient to return to baseline glucose control. The Committee accepted that the requirement for another transplant was appropriate to include in the definition of primary pancreas allograft failure. The Committee felt strongly that, rather than waiting until retransplantation, registration for any form of islet replacement therapy (ie, another pancreas transplant or an islet after pancreas transplant) would be an adequate indication of allograft failure. Even if partial function can still be demonstrated, once a recipient is re-listed for another transplant this would indicate that organ function is so inadequate that it should be considered equivalent to graft failure. This provocative issue has implications for other solid organ transplants as well. While pancreatectomy was immediately accepted as a form of graft failure, there was extensive debate regarding patient death in this definition of pancreas allograft failure. Ultimately, the Committee believed that the pancreas graft failure definition should include recipient death of all causes. If death is reported for the recipient, the consensus was to report graft status up until the time of death. All of the above results and considerations were reviewed and discussed by the Pancreas Outcomes Subcommittee, and the Pancreas Committee as a whole. The proposal for the definition of pancreas graft failure was passed by the OPTN/UNOS Board in June 2015, was approved by the federal Office of Management and Budget (OMB) in 2016, and has become official OPTN policy on February 28, 2018. According to the new definition, pancreas allograft failure now occurs when:1A recipient’s transplanted pancreas is removed;2A recipient re-registers for another pancreas transplant;3A recipient registers for an islet transplant after receiving a pancreas transplant;4A recipient’s total insulin use is greater than or equal to 0.5 units/kg/day for 90 consecutive days; or5A recipient dies. As more detailed data on relevant metrics (fasting C-peptide, HbA1C, insulin use) will be collected by the OPTN in the future on transplant candidate registration, transplant recipient registration, and transplant recipient follow-up forms, this new definition may be amended to reflect better science. Once sufficient data become available, a better model for graft failure could be developed by combining multiple different metrics measuring graft function, including, for example, C-peptide, HbA1C, insulin use, and renal function, among others. Defining pancreas allograft failure is not an easy task. While in some cases, graft failure is more obvious (for example, death, retransplantation, or graft removal), there are gray zones of residual function in which it is difficult to determine whether the organ is functioning or failing. We did agree that re-listing, rather than retransplantation, should be considered graft failure, since listing does not guarantee transplantation, because re-listing indicates inadequate graft function that is not serving the patient optimally. Many factors influence overall glucose control, which is the ultimate goal of pancreas transplantation. Posttransplant weight gain and requisite immunosuppression may confound the interpretation of how well the pancreatic graft is actually functioning. While we were able to show that C-peptide levels alone are not a good indicator of pancreas graft failure, we did not have enough data to determine whether a combination of a C-peptide threshold and other factors may be able to better detect or define pancreas graft failure. Furthermore, better standardization of C-peptide testing, along with additional data, such as HbA1C, renal function, knowledge of anti-diabetic medications, among others, will be necessary to reevaluate existing definitions for pancreas graft failure16Organ Procurement and Transplantation Network. Policies, September 1, 2018. https://optn.transplant.hrsa.gov/media/1200/optn_policies.pdf. Accessed October 10, 2018.Google Scholar and assess the clinical application of recently proposed or future definitions.17Rickels MR Stock PG de Koning EJP et al.Defining outcomes for β-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop.Transplanatation. 2018; 102: 1479-1486Crossref PubMed Scopus (0) Google Scholar, 18Piemonti L de Koning EJP Berney T et al.Defining outcomes for betal cell replacement therapy: a work in progress.Diabetologia. 2018; 61: 1273-1276Crossref PubMed Scopus (10) Google Scholar, 19Rickels MR Stock PG de Koning EJP et al.Defining outcomes for β-cell replacement therapy in the treatment of diabetes: a consensus report on the Igls criteria from the IPITA/EPITA opinion leaders workshop.Transpl Int. 2018; 31: 343-352Crossref PubMed Scopus (0) Google Scholar In the end, we present our consensus definition above that has now become policy. With additional data now required by OPTN policy, future analyses including more standardized and complete data may possibly yield more refined insights as to the true definition of pancreas graft function or failure." @default.
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• W2892071854 title "C-peptide levels do not correlate with pancreas allograft failure: Multicenter retrospective analysis and discussion of the new OPT definition of pancreas allograft failure" @default.
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