A consolidated biovigilance system for blood, tissue and organs: one size does not fit all.

Biovigilance systems to assess and analyze risks for disease transmission through the transfer of organs, tissue, cells and blood between people is part of administrative oversight and has impact upon clinical practice and policy. In 2009, a formal recommendation by the Public Health Service requested that Health and Human Services fund and support efforts to consolidate national biovigilance efforts. There are differences in the biovigilance issues involved in organ and tissue donation/transplantation. If disease avoidance is made the dominant principle guiding organ donor testing, an unintended consequence may be an increase in deaths on the waiting list. We propose that overall benefit for the organ transplant recipient, tempered by patient informed awareness of limited organ availability and assessment processes, should be the guiding principle of such a system.

The impact of variation in donation after cardiac death policies among donor hospitals: a regional analysis.

The Joint Commission requires all hospitals have a policy regarding donation after cardiac death. To this date however, a quantitative analysis of adult hospital donation after cardiac death (DCD) policies and its impact on transplantation outcomes has not been reported. Specific characteristics for DCD polices were identified from 90 of the 164 (54.9%) hospitals within the New England Organ Bank's donor service area. Forty-five policies (50.0%) allow family members to be present during withdrawal of life-sustaining therapy (WLST) whereas eight (8.9%) prohibit this. Seventeen policies (18.9%) require WLST to occur in the operating room (OR); 20 (22.2%) specify a location outside of the OR. Fifty-six (62.2%) policies fail to state the method of determining death; however, some require arterial line (15 policies, 16.6%) and/or EKG (10 policies, 11.1%). These variables were not associated with organ recovery, utilization or donor ischemia time. Our regional analysis highlights the high degree of variability of hospital DCD policies, which may contribute to misunderstanding and confusion among providers and patients that may influence acceptance of this mode of donation.

Characterization of the withdrawal phase in a porcine donation after the cardiac death model.

Transplantation of donation after cardiac death (DCD) livers has higher rates of organ failure and complications, specifically ischemic biliary injuries. Reported large animal DCD models all employ active means to halt circulation, contrary to human DCD protocol. We report a DCD porcine model in which the animal passively progresses to cardiac death, thereby more closely mimicking human DCD scenario. Sixteen Yorkshire pigs (10 females, 6 males, 30-45 kg) had a mean time of 26:19 min ± 14:14 from withdrawal of ventilatory support (WVS) to circulatory arrest and 44:38 min ± 16:37 from WVS to electrical standstill. Cessation of hepatic flow (HF) occurred well before electrical standstill (22:15 min ± 10:09), previously not described in human or animal DCD. Histologically comparing livers from our DCD model demonstrated a dramatic increase in hepatocyte vacuolization, disorganization of endoplasmic reticulum, formation of mitochondrial inclusions and apoptosis compared with control specimens. Subtle changes were also evident in biliary epithelial cells (BEC). This results in severe cellular changes before reperfusion. Early histologic evidence suggests that there is severe hepatocyte and biliary cell disruption in our DCD model. Further research using this model may provide a deeper understanding of the pathophysiology of the DCD liver.

The 'indirect' effects of cytomegalovirus infection.

Cytomegalovirus (CMV) remains the most important infection in the immunocompromized host even in the era of effective therapy. CMV is usually acquired early in life and can be transmitted by contact with infected body fluids. In the immunocompetent population, primary infection is almost always of little clinical consequence. However, CMV infection in immunocompromized patients, especially those naive to CMV exposure, can cause tissue invasive disease, severe symptoms and/or death. However, beyond these direct effects, increasing in vitro evidence is accumulating that suggests CMV has many other effects on the host's immune response which may explain some of the detrimental consequences for the immunosuppressed patient, and may also be partially responsible for a variety of conditions in immunocompetent individuals. In its latent state, CMV employs several mechanisms to evade detection by the host's immune system. The virus also employs other methods to take advantage of activation of the immune system and replicate in sites of inflammation. This review focuses on the immunosuppressive and inflammatory mechanisms that have been attributed to CMV and will relate them to some of the clinical sequellae that have been associated with the indirect effects of CMV infection.

Stimulus for organ donation: a survey of the American Society of Transplant Surgeons membership.

Federal legislation has been proposed to modify the National Organ Transplant Act in a way that would permit government-regulated strategies, including financial incentives, to be implemented and evaluated. The Council and Ethics Committee of the American Society of Transplant Surgeons conducted a brief web-based survey of its members' (n = 449, 41.6% response rate) views on acceptable or unacceptable strategies to increase organ donation. The majority of the membership supports reimbursement for funeral expenses, an income tax credit on the final return of a deceased donor and an income tax credit for registering as an organ donor as strategies for increasing deceased donation. Payment for lost wages, guaranteed health insurance and an income tax credit are strategies most strongly supported by the membership to increase living donation. For both deceased and living donation, the membership is mostly opposed to cash payments to donors, their estates or to next-of-kin. There is strong support for a government-regulated trial to evaluate the potential benefits and harms of financial incentives for both deceased and living donation. Overall, there is strong support within the ASTS membership for changes to NOTA that would permit the implementation and careful evaluation of indirect, government-regulated strategies to increase organ donation.

ASTS recommended practice guidelines for controlled donation after cardiac death organ procurement and transplantation.

The American Society of Transplant Surgeons (ASTS) champions efforts to increase organ donation. Controlled donation after cardiac death (DCD) offers the family and the patient with a hopeless prognosis the option to donate when brain death criteria will not be met. Although DCD is increasing, this endeavor is still in the midst of development. DCD protocols, recovery techniques and organ acceptance criteria vary among organ procurement organizations and transplant centers. Growing enthusiasm for DCD has been tempered by the decreased yield of transplantable organs and less favorable posttransplant outcomes compared with donation after brain death. Logistics and ethics relevant to DCD engender discussion and debate among lay and medical communities. Regulatory oversight of the mandate to increase DCD and a recent lawsuit involving professional behavior during an attempted DCD have fueled scrutiny of this activity. Within this setting, the ASTS Council sought best-practice guidelines for controlled DCD organ donation and transplantation. The proposed guidelines are evidence based when possible. They cover many aspects of DCD kidney, liver and pancreas transplantation, including donor characteristics, consent, withdrawal of ventilatory support, operative technique, ischemia times, machine perfusion, recipient considerations and biliary issues. DCD organ transplantation involves unique challenges that these recommendations seek to address.

Moving kidney allocation forward: the ASTS perspective.

In 2008, the United Network for Organ Sharing issued a request for information regarding a proposed revision to kidney allocation policy. This plan described combining dialysis time, donor characteristics and the estimated life years from transplant (LYFT) each candidate would gain in an allocation score that would rank waiting candidates. Though there were some advantages of this plan, the inclusion of LYFT raised many questions. Foremost, there was no clear agreement that LYFT should be the main criterion by which patients should be ranked. Moreover, to rank waiting candidates with this metric, long-term survival models were required in which there was no incorporation of patient preference or discounting for long survival times and for which the predictive accuracy did not achieve accepted standards. The American Society of Transplant Surgeons was pleased to participate in the evaluation of the proposal. Ultimately, the membership did not favor this proposal, because we felt that it was too complicated and that the projected slight increase in overall utility was not justified by the compromise in individual justice that was required. We offer alternative policy options to address some of the unmet needs and issues that were brought to light during this interesting process.

Transplantation risks and the real world: what does 'high risk' really mean?

Candidates for, and recipients of, transplants face numerous risks that receive varying degrees of attention from the media and transplant professionals. Characterizations such as 'high risk donor' are not necessarily accurate or informative unless they are discussed in context with the other risks patients face before and after transplantation. Moreover, such labels do not provide accurate information for informed consent discussions or decision making. Recent cases of donor-transmitted diseases from donors labeled as being at 'high risk' have engendered concern, new policy proposals and attempts to employ additional testing of donors. The publicity and policy reactions to these cases do not necessarily better inform transplant candidates and recipients about these risks. Using comparative risk analysis, we compare the various risks associated with waiting on the list, accepting donors with various risk characteristics, posttransplant survival and everyday risks we all face in modern life to provide some quantitative perspective on what 'high risk' really means for transplant patients. In our analysis, donor-transmitted disease risks are orders of magnitude less than other transplantation risks and similar to many everyday occupational and recreational risks people readily and willingly accept. These comparisons can be helpful for informing patients and guiding future policy development.

Liver and intestine transplantation in the United States, 1997-2006.

Liver transplantation in 2006 generally resembled previous years, with fewer candidates waiting for deceased donor liver transplants (DDLT), continuing a trend initiated with the implementation of the model for end-stage liver disease (MELD). Candidate age distribution continued to skew toward older ages with fewer children listed in 2006 than in any prior year. Total transplants increased due to more DDLT with slightly fewer living donor liver transplants (LDLT). Waiting list deaths and time to transplant continued to improve. In 2006, there also were fewer DDLT for patients with MELD <15, fewer pediatric Status 1A/B transplants and more transplants from donation after cardiac death (DCD) donors. Adjusted patient and graft survival rates were similar for LDLT and DDLT. This article also contains in-depth analyses of transplantation for hepatocellular carcinoma (HCC). Recipients with HCC had lower adjusted 3-year posttransplant survival than recipients without HCC. HCC recipients who received pretransplant ablative treatments had superior adjusted 3-year posttransplant survival compared to HCC recipients who did not. Intestinal transplantation continued to slowly increase with the largest number of candidates on the waiting list since 1997. Survival rates have increased over time. Small children waiting for intestine grafts continue to have the highest waiting list mortality.

Fetal cells participate over time in the response to specific types of murine maternal hepatic injury.

BACKGROUND: In humans, fetal microchimeric cells transferred to maternal tissues during pregnancy can adopt a hepatocyte phenotype. Our objective was to determine whether fetal cells participate in the response to specific murine post-partum hepatic injuries. METHODS: Wild-type female mice were bred to males transgenic for the enhanced green fluorescent protein (GFP) (n = 42). Following delivery, we created models of chemical or surgical injury with carbon tetrachloride (CCl(4)) injection or by performing partial hepatectomy. Liver injury was assessed histologically. Fetal cells in maternal liver were detected and measured by real-time PCR amplification of the gfp transgene and by immunofluorescence using anti-GFP antibodies. RESULTS: PCR results showed that in chemical but not surgical injury, fetal GFP+ cells were detectable in maternal liver and spleen and that fetal cell presence was significantly increased over time following injury (4 versus 8 weeks, P = 0.006 for liver and P = 0.0006 for spleen). In some animals, following chemical injury, GFP+ cells were detected by immunofluorescence. CONCLUSIONS: The results of this preliminary study suggest that specific types of injury may elicit different fetal cell responses in maternal organs. There is a significant effect of time on fetal cell presence in liver and spleen. Furthermore, real-time PCR amplification is more sensitive than immunofluorescence for the detection of microchimeric fetal cells.

Waiting list removal rates among patients with chronic and malignant liver diseases.

Equitable liver allocation should ensure that nonelective removal rates are fairly distributed among waiting candidates. We compared removal rates for adults entered with nonmalignant (NM) (N = 9379) and hepatocellular cancer (HCC) (N = 2052) diagnoses on the Organ Procurement and Transplantation Network (OPTN) list between April 30, 2003, and December 31, 2004. Unadjusted removal rates for NM vs. HCC diagnoses were 9.4% vs. 8.7%, 13.5% vs. 16.9% and 19.1% vs. 31.8% at 90, 180 and 365 days, respectively after listing. For NM candidates, model for end-stage liver disease (MELD) score (RR = 1.16), age (RR = 1.03) and metabolic disease diagnoses (RR = 1.66) had higher risks of removal; and PSC (RR = 0.62) and alcoholic cirrhosis (RR = 0.82) had lower risks of removal. For HCC candidates, MELD score at listing (RR = 1.09), AFP (RR = 1.02), maximum tumor size (RR = 1.16) and age at listing (RR = 1.02) had increased risks of removal. The equation 1 - 0.920 exp[0.09369 (MELD at listing - 12.48) + 0.00193 (AFP - 97.4) + 0.1505 (maximum tumor size - 2.59) defined the probability of dropout for HCC candidates within 90 days of listing. We conclude that factors associated with the risk of removal for HCC are different from NM candidates, although MELD score at listing remains the most predictive for both groups. Liver transplant candidates with HCC may be prioritized using a risk score analogous to the MELD score.

Excellent liver transplant survival rates under the MELD/PELD system.

The MELD/PELD (M/P) system for liver allocation was implemented on February 27, 2002, in the United States. Since then sufficient time has elapsed to allow for assessment of posttransplant survival rates under this system. We analyzed 4163 deceased donor liver transplants performed between February 27, 2002, and December 31, 2003, for whom follow-up reporting was 95% and 67% complete at 6 and 12 months, respectively. Kaplan-Meier survival analysis revealed 1-year patient and graft survival rates for status 1 of 76.9% and 70.4%, respectively, and 87.3% and 82.9% for patients prioritized by M/P (P < .0001 for status 1 vs M/P). When adult candidates were stratified by MELD score quartile at transplant, 1-year survival rates were 89.5%, 88.3%, 86.6%, and 78.1% for lowest to highest quartile (P = .0002) and graft survival rates were similarly distributed (85.0%, 84.5%, 82.7%, 73.0%, P < .0001). Candidates with hepatocellular cancer (89.6%) and other MELD score exceptions (88.8%) had slightly higher 1-year survival rates compared with standard MELD recipients (86.0%), which did not reach statistical significance (P = .089). Pediatric recipients had slightly better patient (88.7%) and graft (86.5%) survival rates at 1 year than adults but there were no significant differences among the PELD strata due to small numbers of patients in each PELD quartile. We conclude that patient and graft survival have remained excellent since implementation of the MELD/PELD system. Although recipients with MELD scores in the highest quartile have reduced survival compared with other quartiles, their 1-year survival rate is acceptable when their extreme risk of dying without a transplant is taken into consideration.

MELD/PELD: one year later.

The liver allocation policy in the United States was changed on February 27, 2002, to a continuous scale with almost no weight given to time waiting on the list. This was based on the dissatisfaction with the old categorical system and an understanding that waiting time as not a good discriminator of medical urgency. To assess the effects of this change, liver allocation results for the first 6 months of this new system (February 27, 2002, to August 30, 2002, era 2) with the corresponding 6 month period 1 year earlier (February 27, 2001, to August 30, 2001, era 1) were compared. Fewer registrations on the waiting list, fewer removals from the waiting list because of death or "too sick," and an increase in the number of cadaveric transplants under the new system were observed. Patients with hepatocellular cancer received additional priority with the new policy and there was a significant increase in the number of candidates transplanted with this diagnosis in era 2. Early posttransplant patient survival has not changed under the new system. Although there are many areas for improvement, which will be addressed in future refinements, the new US liver allocation plan has provided a more objective, patient-specific system to better rank waiting liver transplant candidates.