Low molecular weight dextran sulfate as complement inhibitor and cytoprotectant in solid organ and islet transplantation

Complement is an essential part of the innate immune system and plays a crucial role in organ and islet transplantation. Its activation, triggered for example by ischemia/reperfusion (I/R), significantly influences graft survival, and blocking of complement by inhibitors has been shown to attenuate I/R injury. Another player of innate immunity are the dendritic cells (DC), which form an important link between innate and adaptive immunity. DC are relevant in the induction of an immune response as well as in the maintenance of tolerance. Modulation or inhibition of both components, complement and DC, may be crucial to improve the clinical outcome of solid organ as well as islet transplantation. Low molecular weight dextran sulfate (DXS), a well-known complement inhibitor, has been shown to prevent complement-mediated damage of the donor graft endothelium and is thus acting as an endothelial protectant. In this review we will discuss the evidence for this cytoprotective effect of DXS and also highlight recent data which show that DXS inhibits the maturation of human DC. Taken together the available data suggest that DXS may be a useful reagent to prevent the activation of innate immunity, both in solid organ and islet transplantation.

Role of patient factors, preferences, and distrust in health care and access to liver transplantation and organ donation.

Despite major improvements in access to liver transplantation (LT), disparities remain. Little is known about how distrust in medical care, patient preferences, and the origins shaping those preferences contribute to differences surrounding access. We performed a single-center, cross-sectional survey of adults with end-stage liver disease and compared responses between LT listed and nonlisted patients as well as by race. Questionnaires were administered to 109 patients (72 nonlisted; 37 listed) to assess demographics, health care system distrust (HCSD), religiosity, and factors influencing LT and organ donation (OD). We found that neither HCSD nor religiosity explained differences in access to LT in our population. Listed patients attained higher education levels and were more likely to be insured privately. This was also the case for white versus black patients. All patients reported wanting LT if recommended. However, nonlisted patients were significantly less likely to have discussed LT with their physician or to be referred to a transplant center. They were also much less likely to understand the process of LT. Fewer blacks were referred (44.4% versus 69.7%; P = 0.03) or went to the transplant center if referred (44.4% versus 71.1%; P = 0.02). Fewer black patients felt that minorities had as equal access to LT as whites (29.6% versus 57.3%; P < 0.001). For OD, there were more significant differences in preferences by race than listing status. More whites indicated OD status on their driver's license, and more blacks were likely to become an organ donor if approached by someone of the same cultural or ethnic background (P < 0.01). In conclusion, our analysis demonstrates persistent barriers to LT and OD. With improved patient and provider education and communication, many of these disparities could be successfully overcome. Liver Transplantation 22 895-905 2016 AASLD.

A comparison of registered and unregistered organ donors’ perceptions about transplant recipients

Background: We examined whether registered and unregistered donors’ perceptions about transplant recipients’ previous behavior (e.g., substance use) and responsibility for illness differed based on their deceased organ donor registration decisions. ----- ----- ----- Methods: Students and community members from Queensland, Australia were surveyed about their perceptions of transplant recipients.----- ----- ----- Results: Respondents (N = 465) were grouped based on their organ donor registration status to determine if their perceptions about transplant recipients differed. Compared to registered respondents, a higher proportion of unregistered respondents held more negative and less favorable perceptions of recipients. Multivariate analysis of variance confirmed statistically that unregistered respondents evaluated recipients more negatively than registered respondents, F(6,449) = 5.33, p <.001. Unregistered respondents were more likely to view recipients as a smoker, substance user, or alcohol dependent and as undeserving of a transplant, blameworthy, and responsible for their illness. ----- ----- ----- Conclusion: Potential donors’ perceptions of transplant recipients’ behavior and responsibility for illness differ according to their registration status. Future interventions should challenge negative perceptions about recipients’ deservingness and responsibility and promote the perspective that people from all walks of life need transplants in the aim of ultimately encouraging an increase in donor registration.

Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).

BACKGROUND: Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. METHODS: The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. RESULTS: During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. CONCLUSIONS: We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.

Unrecognized pretransplant and donor‐derived cryptococcal disease in organ transplant recipients.

BACKGROUND: Cryptococcosis occurring ≤30 days after transplantation is an unusual event, and its characteristics are not known. METHODS: Patients included 175 solid-organ transplant (SOT) recipients with cryptococcosis in a multicenter cohort. Very early-onset and late-onset cryptococcosis were defined as disease occurring ≤30 days or >30 days after transplantation, respectively. RESULTS: Very early-onset disease developed in 9 (5%) of the 175 patients at a mean of 5.7 days after transplantation. Overall, 55.6% (5 of 9) of the patients with very early-onset disease versus 25.9% (43 of 166) of the patients with late-onset disease were liver transplant recipients (P = .05). Very early cases were more likely to present with disease at unusual locations, including transplanted allograft and surgical fossa/site infections (55.6% vs 7.2%; P < .001). Two very early cases with onset on day 1 after transplantation (in a liver transplant recipient with Cryptococcus isolated from the lung and a heart transplant recipient with fungemia) likely were the result of undetected pretransplant disease. An additional 5 cases involving the allograft or surgical sites were likely the result of donor‐acquired infection. CONCLUSIONS: A subset of SOT recipients with cryptococcosis present very early after transplantation with disease that appears to occur preferentially in liver transplant recipients and involves unusual sites, such as the transplanted organ or the surgical site. These patients may have unrecognized pretransplant or donor-derived cryptococcosis.

Donor identification and consent for deceased organ donation: summary of NICE guidance.

Organ donation plays a major role in the management of patients with single organ failure of the kidneys, liver, pancreas, heart, or lung, or with combined organ failure of heart and lung (such as in cystic fibrosis) or of kidney and pancreas (such as in diabetes). A shortage of transplant organs has resulted in long waits for transplantation. Currently about 500 people in the United Kingdom die each year because of a shortage of donated organs,1 and at 31 March 2011 almost 7000 patients were waiting for a kidney transplant1 and would be having costly dialysis with serious morbidity and impact on quality of life. This shortage of organs is partly the result of relatively low numbers of road traffic deaths (lower than in many countries) but is also the result of inefficiencies in the donor identification and consent processes. This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on improving donor identification and consent rates for deceased organ donation.2

Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation

The lack of suitable donors for all solid-organ transplant programs is exacerbated in lung transplantation by the low utilization of potential donor lungs, due primarily to donor lung injury and dysfunction, including pulmonary edema. The current studies were designed to determine if intravenous clinical-grade human mesenchymal stem (stromal) cells (hMSCs) would be effective in restoring alveolar fluid clearance (AFC) in the human ex vivo lung perfusion model, using lungs that had been deemed unsuitable for transplantation and had been subjected to prolonged ischemic time. The human lungs were perfused with 5% albumin in a balanced electrolyte solution and oxygenated with continuous positive airway pressure. Baseline AFC was measured in the control lobe and if AFC was impaired (defined as

How Critical Care Nurses' Role and Education Affect Organ Donation

Organ and tissue dysfunction and failure cause high mortality rates around the world. Tissue and organs transplantation is an established, cost-effective, life-saving treatment for patients with organ failure. However, there is a large gap between the need for and the supply of donor organs. Acute and critical care nurses have a central role in the organ donation process, from identifying and assessing potential donors and supporting their families to involvement in logistics. Nurses with an in-depth knowledge of donation understand its clinical and technical aspects as well as the moral and legal considerations. Nurses have a major role to play in tackling organ and tissue shortages. Such a role cannot be adequately performed if nurses are not fully educated about donation and transplant. Such education could be incorporated into mandatory training and completed by all nurses.

Donor-derived aspergillosis from use of a solid organ recipient as a multiorgan donor.

The growing need for organs and the scarcity of donors has resulted in an increased use of extended criteria donors. We report a case where a recipient of a cardiac graft was used as an organ donor. Death of the recipient occurred 9 days after transplantation and was attributed to presumed cerebral hemorrhage, which post mortem was diagnosed as invasive aspergillosis of the brain. One recipient of a kidney transplant lost the graft due to infection with Aspergillus fumigatus, whereas prompt initiation of therapy successfully prevented disseminated aspergillosis in the other recipients. Despite the pressure to extend the use of organs by lowering the acceptance criteria, organs should only be accepted if the cause of death of the donors is unequivocally explained.

Ten years of lung transplantation in Switzerland: results of the Swiss Lung Transplant Registry.

Lung transplantation has evolved from an experimental procedure to a viable therapeutic option in many countries. In Switzerland, the first lung transplant was performed in November 1992, more than ten years after the first successful procedure world-wide. Thenceforward, a prospective national lung transplant registry was established, principally to enable quality control. The data of all patients transplanted in the two Swiss Lung Transplant centres Zurich University Hospital and Centre de Romandie (Geneva-Lausanne) were analysed. In 10 years 242 lung transplants have been performed. Underlying lung diseases were cystic fibrosis including bronchiectasis (32%), emphysema (32%), parenchymal disorders (19%), pulmonary hypertension (11%) and lymphangioleiomyomatosis (3%). There were only 3% redo procedures. The 1, 5 and 9 year survival rates were 77% (95% CI 72-82), 64% (95% CI 57-71) and 56% (95% CI 45-67), respectively. The 5 year survival rate of patients transplanted since 1998 was 72% (95% CI 64-80). Multivariate Cox regression analysis revealed that survival was significantly better in this group compared to those transplanted before 1998 (HR 0.44, 0.26-0.75). Patients aged 60 years and older (HR 5.67, 95% CI 2.50-12.89) and those with pulmonary hypertension (HR 2.01, 95% CI 1.10-3.65) had a significantly worse prognosis The most frequent causes of death were infections (29%), bronchiolitis obliterans syndrome (25%) and multiple organ failure (14%). The 10-year Swiss experience of lung transplantation compares favourably with the international data. The best results are obtained in cystic fibrosis, pulmonary emphysema and parenchymal disorders.

Absence of residual Hodgkin's disease demonstrated by PET/CT in a deceased organ donor.

With the current limited availability of organs for transplantation, it is important to consider marginal donor candidates, including survivors of potentially curable malignancies such as lymphoma. The absence of refractory/recurrent residual disease at the time of brain death can be difficult to establish. Therefore, it is critical to have objective data to decide whether to proceed or not with organ procurement and transplantation. We report a unique situation in which (18)F-fluorodeoxyglucose positron emission tomography (PET) was used to rule out Hodgkin's lymphoma recurrence in a 33-year-old, heart-beating, brain-dead, potential donor with a past history of Hodgkin's disease and a persistent mediastinal mass. PET showed no significant uptake in the mass, allowing organ donation and transplantation to occur. We present a new means of evaluating potential brain-dead donors with a past history of some lymphoma, whereby PET may help transplant physicians by optimizing donation safety while rationalizing the inclusion of marginal donors.

Improved renal function after kidney transplantation is associated with heme oxygenase-1 polymorphism

Heme oxygenase-1 (HO-1) has a microsatellite polymorphism based on the number of guanosine-thymidine nucleotide repeats (GT) repeats that regulates expression levels and could have an impact on organ survival post-injury. We correlated HO-1 polymorphism with renal graft function. The HO-1 gene was sequenced (N = 181), and the allelic repeats were divided into subclasses: short repeats (S) (< 27 repeats) and long repeats (L) (>= 27 repeats). A total of 47.5% of the donors carried the S allele. The allograft function was statistically improved six months, two and three yr after transplantation in patients receiving kidneys from donors with an S allele. For the recipients carrying the S allele (50.3%), the allograft function was also better throughout the follow-up, but reached statistical significance only three yr after transplantation (p = 0.04). Considering only those patients who had chronic allograft nephropathy (CAN; 74 of 181), allograft function was also better in donors and in recipients carrying the S allele, two and three yr after transplantation (p = 0.03). Recipients of kidney transplantation from donors carrying the S allele presented better function even in the presence of CAN.

Autofluorescence spectroscopy in liver transplantation: Preliminary results from a pilot clinical study

The evaluation of graft function at various stages after transplantation is relevant, particularly at the moment of organ harvest, when a decision must be made whether to use the organ. Autofluorescence spectroscopy is noninvasive technique to monitor the metabolic condition of a liver graft throughout its course, from an initial evaluation in the donor, through cold ischemia transportation, to reperfusion and reoxygenation in the recipient. Preliminary results are presented in six liver transplantations spanning the periods from liver harvest to implant. The laser-induced fluorescence spectrum at 532-mn excitation was investigated before cold perfusion (autofluorescence), during cold ischemia, at the back table procedure, as well as 5 and 60 minutes after reperfusion. The results showed that the fluorescence analysis was sensitive to changes during the transplantation procedure. Fluorescence spectroscopy potentially provides a real-time, noninvasive technique to monitor liver graft function. The information could potentially be valuable for surgical decisions and transplant success.

Protection behaviour : a phenomenon affecting organ and tissue donation in the 21st century?

UK statistics show that whilst waiting lists for transplantation surgery continue to increase, donor numbers are static. This paper describes the hermeneutic phase of a mixed method study and puts forward the concept of protection behaviour as one explanation for nurses’ reticence to discuss post-mortem donation wishes with patients’ relatives. The desire to protect appears to influence attitudes, confidence levels and perceived ability to become involved in donor identification and donation discussion, consequently affecting the availability of transplantable organs and tissue. By understanding more fully why protective behaviours are employed, it increases the likelihood of a solution being found.