Red Flags in the Living Kidney Donor Process.

BACKGROUND: Ideally, no live kidney donor should regret their decision or feel they were not fully prepared for the process. Unfortunately, this is not a reality for all donors. The aim of our study is to identify areas for improvement, focusing on factors (red flags) that predict less favorable outcomes from a donor perspective. MATERIALS AND METHODS: A total of 171 living kidney donors responded to a questionnaire with 24 multiple-choice questions and space for comments. Less favorable outcomes were defined as lower satisfaction, extended physical recovery period, long-term fatigue, and longer sick leave. RESULTS: Ten red flags were identified. Of these factors, more fatigue (range, P = .000-0.040) or pain (range, P = .005-0.008) than expected while still in hospital, the actual experience being harder or different than expected (range, P = .001-0.010), and the donor wishing to have had but not having been offered a previous donor as mentor (range, P = .008-.040) correlated significantly with at least 3 of the 4 less favorable outcomes. Another significant red flag was keeping existential issues to oneself (P = .006). CONCLUSION: We identified several factors indicating that a donor could be at an increased risk for a less favorable outcome after donation. Four of these factors have, to our knowledge, not been described earlier: more early fatigue than expected, more postoperative pain than anticipated, not having been offered a mentor at an early stage, and keeping existential issues to oneself. Attention to these red flags already during the donation process could help health care professionals to act early to avoid unfavorable outcomes.

Potential living kidney donors' positive experiences of an information letter from healthcare: a descriptive qualitative study.

BACKGROUND: Patients who need a live donor kidney transplant (LDKT) must often ask potential donors (PLDs) themselves. This is a difficult task and healthcare could unburden them by making this first contact, ensuring also that PLDs receive correct information. We investigated how PLDs experience receiving a letter from healthcare about LDKT, live kidney donation, and inviting them to meet with professionals to get more information. METHODS: The letter (LD-letter) was sent to a cohort of 46 individuals, from which a purposeful sample of 15 were interviewed using a semi-structured guide covering their experience of the letter, views on being approached by healthcare, and opinions on style and content. Interviews were analyzed using conventional inductive analysis. RESULTS: We identified three categories of experiences: Category (1) Reflections on receiving the letter, contains three subcategories relating to how the letter did not induce pressure to donate, did not affect the PLD's relationship with the patient with kidney disease, and made the letter-receiver feel important in the transplant process; Category (2) The letter creates clarification and trust, also contains three subcategories, relating to how it clarified the voluntariness of donation and neutrality of healthcare providers with respect to the PLD's decision, elucidated the patient with kidney disease's current stage of disease (where transplantation was approaching), and unburdened patients from the responsibility of contacting PLDs on their own; Category (3) Opinions and suggestions about the letter and further communication, with four subcategories, relating to preference of a letter as the first step for communication about LDKT, suggestions on style and content, views on following up the letter, and how open meetings about LDKT were an important information source. Furthermore, 80% of the interviewees found the letter's information comprehensive, 67% found it easy to read and respectful, and 86% rated it as good or very good. CONCLUSION: Potential donors prefer and recommend a letter as the first step for communication regarding LD. The LD-letter unburdens patients from the task of asking PLDs and stresses the voluntariness of donation, does not leave PLDs feeling coerced or lead to negative effects in their relationship with the patient.

What do people agree to when stating willingness to donate? On the medical interventions enabling organ donation after death.

PURPOSE OF THE STUDY: The purpose of this study is to explore donor relatives' experiences of the medical interventions enabling organ donation, as well as to examine the donor relatives' attitudes towards donating their own organs, and whether or not their experiences have influenced their own inclination to donate. METHODS: The experiences of donor relatives were explored via in-depth interviews. The interviews covered every step from the deceased family member being struck by a severe bleeding in the brain till after the organ recovery, including the medical interventions enabling organ donation. The interviews were analysed through qualitative and quantitative content analysis. RESULTS: Brain death and organ donation proved to be hard to understand for many donor relatives. The prolonged interventions provided after death in order to enable organ donation misled some relatives to believe that their family member still was alive. In general, the understanding for what treatment aimed at saving the family member and what interventions aimed at maintaining organ viability was low. However, most donor relatives were either inspired to, or reinforced in their willingness to, donate their own organs after having experienced the loss of a family member who donated organs. CONCLUSIONS: There is a need for greater transparency regarding the whole chain of events during the donation process. Yet, having experienced the donation process closely did not discourage the donor relatives from donating their own organs-but rather inspired a willingness to donate. This indicates an acceptance of the medical procedures necessary in order to enable organ donation after death.

Prevention of Transnational Transplant-Related Crimes-What More Can be Done?

BACKGROUND: Many nations are able to prosecute transplant-related crimes committed in their territory, but transplant recipients, organ sellers and brokers, and transplant professionals may escape prosecution by engaging in these practices in foreign locations where they judge the risk of criminal investigation and prosecution to be remote. METHODS: The Declaration of Istanbul Custodian Group convened an international working group to evaluate the possible role of extraterritorial jurisdiction in strengthening the enforcement of existing laws governing transplant-related crimes across national boundaries. Potential practical and ethical concerns about the use of extraterritorial jurisdiction were examined, and possible responses were explored. RESULTS: Extraterritorial jurisdiction is a legitimate tool to combat transplant-related crimes. Further, development of a global registry of transnational transplant activities in conjunction with a standardized international referral system for legitimate travel for transplantation is proposed as a mechanism to support enforcement of national and international legal tools. CONCLUSIONS: States are encouraged to include provisions on extraterritorial jurisdiction in their laws on transplant-related crimes and to collaborate with professionals and international authorities in the development of a global registry of transnational transplant activities. These actions would assist in the identification and evaluation of illicit activities and provide information that would help in developing strategies to deter and prevent them.

From hesitation to appreciation: the transformation of a single, local donation-nurse project into an established organ-donation service.

This study evaluates the transition from a local project to promote organ donation to a permanent county-based donation service inspired by the Spanish model. To address the problem of declining donation rates, a project with one donation-specialized nurse (DOSS) was initiated at a single neuro-intensive care unit. This project was later expanded into a permanent on-call service consisting of seven DOSSes, covering a large urban county. During the different periods (before, during project and during permanent service), the DOSS function's effect on donation rates was significant, and the number of eligible donors that became actual donors increased from 37% to 73% and 74%, respectively. The effect on family vetoes was as prominent with a decrease from 34% to 8% and 14%. The staff appreciation of the DOSS function was also evident during the periods; all areas included in the questionnaire (family care, donor care and staff support) have improved greatly owing to the DOSS. The transition from a single, local donation-nurse project, to an on-call service with several DOSSes covering a large urban county was a success considering the donation rates as well as the staff's appreciation. Hence, organizational models from abroad can be adjusted and successfully adopted.

Multipotent mesenchymal stromal cells synergize with costimulation blockade in the inhibition of immune responses and the induction of Foxp3+ regulatory T cells.

Multipotent mesenchymal stromal cell (MSC) therapy and costimulation blockade are two immunomodulatory strategies being developed concomitantly for the treatment of immunological diseases. Both of these strategies have the capacity to inhibit immune responses and induce regulatory T cells; however, their ability to synergize remains largely unexplored. In order to study this, MSCs from C57BL/6 (H2b) mice were infused together with fully major histocompatibility complex-mismatched Balb/c (H2d) allogeneic islets into the portal vein of diabetic C57BL/6 (H2b) mice, which were subsequently treated with costimulation blockade for the first 10 days after transplantation. Mice receiving both recipient-type MSCs, CTLA4Ig, and anti-CD40L demonstrated indefinite graft acceptance, just as did most of the recipients receiving MSCs and CTLA4Ig. Recipients of MSCs only rejected their grafts, and fewer than one half of the recipients treated with costimulation blockade alone achieved permanent engraftment. The livers of the recipients treated with MSCs plus costimulation blockade contained large numbers of islets surrounded by Foxp3+ regulatory T cells. These recipients showed reduced antidonor IgG levels and a glucose tolerance similar to that of naïve nondiabetic mice. Intrahepatic lymphocytes and splenocytes from these recipients displayed reduced proliferation and interferon-γ production when re-exposed to donor antigen. MSCs in the presence of costimulation blockade prevented dendritic cell maturation, inhibited T cell proliferation, increased Foxp3+ regulatory T cell numbers, and increased indoleamine 2,3-dioxygenase activity. These results indicate that MSC infusion and costimulation blockade have complementary immune-modulating effects that can be used for a broad number of applications in transplantation, autoimmunity, and regenerative medicine.

Rat islets are not rejected by anti-islet antibodies in mice treated with costimulation blockade.

BACKGROUND: Costimulation blockade can prevent rejection of islet xenografts in naïve but not sensitized recipients. Donor-specific antibodies (DSA) may partly explain this observation. The effect of DSA on rat islet xenograft survival in mice receiving costimulation blockade was investigated. METHODS: Naïve C57BL/6 mice with alloxan-induced diabetes were transplanted under the left kidney capsule with 100 Lewis rat islets. Recipients were divided into three groups receiving: (i) isotype control antibodies (Abs); (ii) anti-CD154 and CTLA4Ig; or (iii) anti-CD154, CTLA4Ig, and anti-LFA-1 every second day, day 0-8. At the time of transplantation (Tx), half of the animals in each group received naïve mouse serum and half xenoimmune serum derived from mice previously transplanted with rat islets. Non-fasting blood glucose levels and body weight were followed daily. Cured mice were examined by intraperitoneal glucose tolerance (IPGT) tests at 1 and 4 months after transplantation. RESULTS: Donor-specific antibodies were detected in immune serum-injected recipients up to at least 96 h post-Tx. Short term (≤96 h), there was no significant difference with regard to graft mass, infiltrating and apoptotic cells between groups of mice receiving naïve and immune sera. A moderate infiltration of polymorphonuclear and mononuclear cells was seen 96 h post-Tx in mice given control Abs, whether or not they received immune or naïve mouse serum. Mice given costimulation blockade had well-maintained endocrine tissue and very little cell infiltration. There was no significant difference in islet xenograft function and survival long term between groups receiving naïve and immune sera in combination with costimulation blockade. About half of the mice receiving costimulation blockade lost graft function within 110 days. CONCLUSION: The presence at Tx of DSA does not appear to negatively influence early and late islet xenograft survival in mice receiving costimulation blockade.

Organ trafficking and transplant tourism: the role of global professional ethical standards-the 2008 Declaration of Istanbul.

By 2005, human organ trafficking, commercialization, and transplant tourism had become a prominent and pervasive influence on transplantation therapy. The most common source of organs was impoverished people in India, Pakistan, Egypt, and the Philippines, deceased organ donors in Colombia, and executed prisoners in China. In response, in May 2008, The Transplantation Society and the International Society of Nephrology developed the Declaration of Istanbul on Organ Trafficking and Transplant Tourism consisting of a preamble, a set of principles, and a series of proposals. Promulgation of the Declaration of Istanbul and the formation of the Declaration of Istanbul Custodian Group to promote and uphold its principles have demonstrated that concerted, strategic, collaborative, and persistent actions by professionals can deliver tangible changes. Over the past 5 years, the Declaration of Istanbul Custodian Group organized and encouraged cooperation among professional bodies and relevant international, regional, and national governmental organizations, which has produced significant progress in combating organ trafficking and transplant tourism around the world. At a fifth anniversary meeting in Qatar in April 2013, the DICG took note of this progress and set forth in a Communiqué a number of specific activities and resolved to further engage groups from many sectors in working toward the Declaration's objectives.

The TheraCyte™ device protects against islet allograft rejection in immunized hosts.

Clinically, many candidates for islet transplantation are already immunized, which increases their risk of graft rejection. Encapsulation of pancreatic islets using the TheraCyte™ device has been shown to protect against allograft rejection in nonimmunized recipients. However, the capacity of the TheraCyte™ device to prevent rejection in immunized recipients has not yet been studied. In this study, the protective capacity of the TheraCyte™ device was evaluated in an allogeneic rat model. Lewis rats were used as islet donors, and nonimmunized (control) and alloimmunized, diabetic Wistar-Furth (WF) rats were used as recipients. Graft survival was shorter in immunized recipients than in nonimmunized recipients (mean survival, 5.3 ± 2.7 and 9.3 ± 1.6 days, respectively, p < 0.01) when nonencapsulated islets were transplanted under the kidney capsule. When islets were transplanted into the TheraCyte™ device, graft function was maintained during the 6-month study period in both immunized and nonimmunized rats. In oral glucose tolerance tests performed at 1 month after transplantation, both groups had similar insulin and blood glucose levels indicating similar metabolic functions. Volume densities and absolute volumes of tissue inside the devices 6 months after transplantation were also comparable between the two groups, indicating that both groups maintained similar amounts of endocrine tissue. A higher number of IFN-γ-producing CD8+ T-cells were detected in immunized WF rats compared to control WF rats transplanted with encapsulated islets. This suggests that donor-specific alloreactivity in recipient rats was sustained throughout the study period. This study suggests that the TheraCyte™ device protects islet allografts also in immunized recipients. Our results further highlight the potential for using macroencapsulation to avoid immunosuppressive therapy in clinical islet transplantation.

Exendin-4 increases the expression of hypoxia-inducible factor-1α in rat islets and preserves the endocrine cell volume of both free and macroencapsulated islet grafts.

In this study, we evaluated the effects of exendin-4 on free and encapsulated islet grafts in a rodent model. We also investigated the role of a transcription factor, hypoxia-inducible factor-1 (HIF-1), in mediating the beneficial effects of exendin-4. Diabetic athymic mice were transplanted with free rat islets under the kidney capsule or with macroencapsulated rat islets SC with or without exendin-4, islet preculture (exendin-4 0.1 nM for 20 h), and/or recipient treatment (IP 100 ng/day, day 0-7). The mice were followed for 4 weeks and the graft function and ß-cell volume were evaluated. The effects of exendin-4 on islet HIF-1α mRNA and protein expression and on ATP content in a rat insulinoma cell line (INS-1E) were also examined. Preculture with exendin-4 followed by recipient treatment improved the outcome of both free (73% graft function vs. 26% in controls, p = 0.03) and macroencapsulated islet grafts (100% vs. 25% in controls, p = 0.02). In macroencapsulated grafts, the exendin-4-treated group had significantly larger endocrine volume, less graft necrosis, and more blood vessels around the capsule. In rat islets cultured with exendin-4, HIF-1α mRNA and protein expression were significantly enhanced. ATP content was increased in exendin-4-treated INS-1E cells under hypoxic conditions. The improved functional outcome after transplantation of a marginal islet mass with a brief initial treatment with exendin-4 is related to a larger surviving endocrine cell volume. Exendin-4 may improve islet graft resistance to hypoxia during the peritransplant period by increasing the expression of HIF-1α.

One-step purification of functional human and rat pancreatic alpha cells.

Pancreatic alpha cells contribute to glucose homeostasis by the regulated secretion of glucagon, which increases glycogenolysis and hepatic gluconeogenesis in response to hypoglycemia. Alterations of glucagon secretion are observed in diabetic patients and exacerbate the disease. The restricted availability of purified primary alpha cells has limited our understanding of their function in health and disease. This study was designed to establish convenient protocols for the purification of viable alpha cells from rat and human pancreatic islets by FACS, using intrinsic cellular properties. Islets were isolated from the pancreata of Wistar rats or deceased human organ donors. Dispersed islet cells were separated by FACS based on light scatter and autofluorescence. Purity of sorted cells was evaluated by immunocytochemistry using hormone specific antibodies. Relative hormone expression was further determined by quantitative RT-PCR. Viability was determined by Annexin V and propidium iodide staining and function was assessed by monitoring cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) using Fura-2/AM. We developed species-specific FACS gating strategies that resulted in populations consisting mainly of alpha cells (96.6 ± 1.4%, n = 3 for rat; 95.4 ± 1.7%, n = 4 for human, mean ± SEM). These cell fractions showed ~5-fold and ~4-fold enrichment (rat and human, respectively) of glucagon mRNA expression compared to total ungated islet cells. Most of the sorted cells were viable and functional, as they responded with an increase in [Ca(2+)](i) upon stimulation with L-arginine (10 mM). The majority of the sorted human alpha cells responded also to stimulation with kainate (100 µM), whereas this response was infrequent in rat alpha cells. Using the same sample preparation, but a different gating strategy, we were also able to sort rat and human populations enriched in beta cells. In conclusion, we have simplified and optimized a method for the purification of rat alpha cells, as well as established a novel approach to separate human alpha cells using neither antibodies nor dyes possibly interfering with cellular functions.

Transplanted functional islet mass: donor, islet preparation, and recipient factors influence early graft function in islet-after-kidney patients.

BACKGROUND: The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal. METHODS: Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio (ΔCP/GCr). RESULTS: Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to ΔCP/GCr. A negative association to ΔCP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after-kidney data set. CONCLUSION: The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation.

Using HTK for prolonged pancreas preservation prior to human islet isolation.

BACKGROUND: Histidine-tryptophan-ketoglutarate (HTK) has been established as an alternative to University-of-Wisconsin solution (UWS) for abdominal organ preservation, but data about HTK efficiency to preserve pancreata during prolonged cold ischemia time (CIT) are conflicting. In human islet transplantation, HTK provided similar isolation outcomes after short CIT. The present study aimed to investigate whether islets can be successfully isolated from HTK-preserved pancreata after prolonged CIT compared with UWS. MATERIALS AND METHODS: Sixty-four human pancreata retrieved from donors meeting criteria for kidney donation were perfused utilizing either HTK or UWS and preserved for more or less than 10 h prior to islet isolation. Along with parameters related to isolation and islet quality assessment, the dry-to-wet weight ratio was evaluated. RESULTS: Donor- and procurement-related factors did not vary between HTK- and UWS-perfused pancreata. The dry-to-wet weight ratio was lower in HTK-preserved pancreata indicated tissue edema (21.0% ± 3.5% versus 24.8% ± 2.0%, P = 0.007). Isolation-related variables differed between experimental groups after prolonged CIT with respect to purified packed tissue volume (9.1 ± 5.0 versus 17.2 ± 8.1 µL/g, P = 0.004) and islet yield (1910 ± 980 versus 3150 ± 1420 IE/g, P = 0.012). Islet purity and survival after culture were similar after HTK or UWS perfusion. The preservation solution did not affect in vitro function and transplantability of isolated islets. CONCLUSIONS: Compared with UWS, HTK has similar efficiency to preserve human pancreata for subsequent islet isolation during <10 h CIT but seems to be limited for prolonged cold storage.

The critical pathway for deceased donation: reportable uniformity in the approach to deceased donation.

The critical pathway of deceased donation provides a systematic approach to the organ donation process, considering both donation after cardiac death than donation after brain death. The pathway provides a tool for assessing the potential of deceased donation and for the prospective identification and referral of possible deceased donors.

The kidney recipient's path to transplantation: a comparison between living and deceased kidney donor recipients in Stockholm, Sweden.

BACKGROUND: Much remains to be done to facilitate the transplantation process for patients with end-stage renal disease. The aim here was to explore these patients' experiences of the donation process and factors related to whether the actual donors of the recipients were living or deceased and describe which issues needed attention in a quality development project. METHOD: A specially constructed questionnaire was sent to 246 recipients of living and deceased kidney transplants who had been transplanted at the Karolinska University Hospital in Stockholm, Sweden. The response rate was 87%. RESULTS: Six conditions were identified as problematic: --Most living-donor kidney recipients perceived the evaluation period for the donors as too long. --Although a living donor was available, most living-donor kidney recipients had to undergo dialysis for a relatively long period. --A majority of the patients perceived it difficult to ask for a donation. Deceased-donor kidney recipients were least satisfied with the offered support in finding a living donor. --Patients perceived fear as the main reason for potential living donors to refuse donation. --About one-fourth of living-donor kidney recipients thought that the donors were abandoned by healthcare after nephrectomy. --Older patients and singles were least likely to receive a living-donor kidney. CONCLUSIONS: The problem issues outlined above should be scrutinized and improved. Checking these issues can be used in quality control when analysing living kidney donation at local and national levels.