Ethical analysis examining the prioritisation of living donor transplantation in times of healthcare rationing.

The transplant community has faced unprecedented challenges balancing risks of performing living donor transplants during the COVID-19 pandemic with harms of temporarily suspending these procedures. Decisions regarding postponement of living donation stem from its designation as an elective procedure, this despite that the Centers for Medicare and Medicaid Services categorise transplant procedures as tier 3b (high medical urgency-do not postpone). In times of severe resource constraints, health systems may be operating under crisis or contingency standards of care. In this manuscript, the United Network for Organ Sharing Ethics Workgroup explores prioritisation of living donation where health systems operate under contingency standards of care and provide a framework with recommendations to the transplant community on how to approach living donation in these circumstances.To guide the transplant community in future decisions, this analysis suggests that: (1) living donor transplants represent an important option for individuals with end-stage liver and kidney disease and should not be suspended uniformly under contingency standards, (2) exposure risk to SARS-CoV-2 should be balanced with other risks, such as exposure risks at dialysis centres. Because many of these risks are not quantifiable, donors and recipients should be included in discussions on what constitutes acceptable risk, (3) transplant hospitals should strive to maintain a critical transplant workforce and avoid diverting expertise, which could negatively impact patient preparedness for transplant, (4) transplant hospitals should consider implementing protocols to ensure early detection of SARS-CoV-2 infections and discuss these measures with donors and recipients in a process of shared decision-making.

Liver Paired Exchange: Programmatic Hopes and Fears.

The dearth of deceased liver donors has created a supply demand gap, necessitating creation of living donor liver transplantation. However, living donor liver transplantation has relied on directed donation, whereby many potential directed donors are rejected based on ABO blood group incompatibility, hepatic size incompatibility, or the need for biliary or arterial reconstruction during transplant surgery. Much like kidney paired exchange, liver paired exchange (LPE) circumvents these incompatibility issues by relying on anonymous, nondirected, or bridge donors that are better anatomical or histological matches for recipients. Although Asia has taken the lead in LPE, the process has only recently been adopted in North America, with the first successful surgery done in the United States in 2019. Our review article sheds light on the process of LPE and the success of LPE in the United States thus far and, additionally, highlights the several logistical and ethical challenges that must be considered as transplant centers adopt and scale up LPE across the United States to address the increased demand for liver allografts.

Utilizing Social Media to Identify Potential Living Donors: Learning from US Living Donor Programs.

Purpose of Review: Living donor transplantation provides the best possible recipient outcomes in solid organ transplantation. Yet, identifying potential living donors can be a laborious and resource intensive task that heavily relies on the recipient's means and social network. Social media has evolved to become a key tool in helping to bring recipients and potential living donors together given its ease of utilization, widespread access, and improved recipient's comfort with public solicitation. However, in the USA, formal guidelines to direct the use of social media in this context are lacking. Recent Findings: To better inform the landscape and opportunities utilizing social media in living donation, the OPTN Living Donor Committee surveyed US transplant programs to explore programs' experiences and challenges when helping patients use social media to identify potential living donors (September 2019). A large majority of survey participants (N = 125/174, 72%) indicated that their program provided education to use social media to identify potential living donors and most programs tracking referral source confirmed an increase utilization over time. The use of social media was compounded with program and recipient's challenges including concerns about privacy, inadequate technology access, and knowledge gaps. In this review, we discuss the results of this national survey and recent literature, and provide suggestions to inform program practices and guidance provided to patients wishing to use social media to identify potential living donors. Summary: Transplant programs should become competent in the use of social media for potential living donor identification to empower patients interested in using this tool. Social media education should be provided to all patients regardless of voiced interest and, when appropriate, revisited at multiple time points. Programs should consider developing a "team of experts" that can provide focused education and support to patients embarking in social media living donor campaigns. Care should be taken to avoid exacerbating disparities in access to living donor transplantation. Effective and timely guidance to patients in the use of social media could enhance the identification of potential living donors. Supplementary Information: The online version contains supplementary material available at 10.1007/s40472-022-00382-1.

The structural conundrum of parolees and kidney transplantation.

In the United States, there are a large number of incarcerated individuals, resulting in high numbers of previously incarcerated individuals out on parole undergoing reentry into society. An aging prison population translates to an older parolee population and increased incidence of kidney disease requiring either long-term dialysis or transplantation. This paper argues that due to challenges specific to the parolee population as well as societal biases and priorities, Transplant Centers and healthcare professionals face an ethical imperative to attend to the needs of parolees as a class and take steps to address challenges related to access to Centers for renal transplantation evaluation for this disadvantaged group. It will first review the regulatory context of kidney transplantation and highlight the specific ways it effects parolees. The paper will then discuss the broader social context of parolee reentry into society and barriers faced by parolees in this process. This ethical analysis examines the complexity of these issues, and deliberates on ways to balance the competing priorities of justice, respect for this patient population as individuals and as a disadvantaged class, and the societal interests regarding organ allocation and considerable economic burdens of end-stage renal disease on parolees, the justice system, and the public.

Ethical considerations during the COVID-19 pandemic.

The care of patients during the COVID-19 pandemic has added many layers of complexity to ethical issues. Our response emphasizes the importance of having an ethically sound framework to inform our decisions, requiring caregivers to consider what is ethically optimal and feasible for the patient. It is increasingly important to understand the ethical principles and to appropriately apply them to both patient management decisions and guide scarce resource allocation. If we are to be prepared to face the many challenges of this pandemic, we must prioritize the ethical demands to our treatment and management concerns.

Access to transplantation for persons with intellectual disability: Strategies for nondiscrimination.

Disqualifying patients with intellectual disabilities (ID) from transplantation has received growing attention from the media, state legislatures, the Office of Civil Rights, and recently the National Council on Disability, as well as internationally. Compared with evidence-based criteria used to determine transplant eligibility, the ID criterion remains controversial because of its potential to be discriminatory, subjective, and because its relationship to outcomes is uncertain. Use of ID in determining transplant candidacy may stem partly from perceived worse adherence and outcomes for patients with ID, fear of penalties to transplant centers for poor outcomes, and stigma surrounding the quality of life for people with ID. However, using ID as a contraindication to solid organ transplantation is not evidence-based and reduces equitable access to transplantation, disadvantaging an already vulnerable population. Variability and lack of transparency in referral and evaluation allows for gatekeeping, threatens patient autonomy, limits access to lifesaving treatment, and may be seen as unfair. We examine the benefits and harms of using ID as a transplant eligibility criterion, review current clinical evidence and ethical considerations, and make recommendations for transplant teams and regulatory agencies to ensure fair access to transplant for individuals with ID.

When a Child Needs a Transplant but Lacks Familial Social Support.

We present the case of a 19-month-old boy with complex congenital heart disease. His single father is skeptical of traditional medicine and does not offer the social support needed to make heart transplantation successful for his son. After the father demonstrates commitment to transplant success and provides enhanced social support, doctors place the child on a Berlin Heart (a biventricular assist device) as a bridge to transplantation and list him for transplant. When the child is matched to a donor heart, the father refuses transplantation, despite that it is the child's only chance for survival. His doctors report the case to child protective services, but they decline to take protective custody. The father then changes his mind and asks that the child be put back on the waiting list for transplant. By this time, the social supports the father implemented are no longer in place. This case raises a number of issues. First, should courts order heart transplantation when doctors believe that it is in the child's best interest and parents do not consent? Second, once parents refuse a transplant, can they change their minds? Third, if there are uncertainties regarding whether the child has the social support to make transplantation successful, should the child be relisted? Finally, should a child who is not currently a transplant candidate but who may become one in the future be supported with ventricular assist devices?

IP3 receptor type 2 deficiency is associated with a secretory defect in the pancreatic acinar cell and an accumulation of zymogen granules.

Acute pancreatitis is a painful, life-threatening disorder of the pancreas whose etiology is often multi-factorial. It is of great importance to understand the interplay between factors that predispose patients to develop the disease. One such factor is an excessive elevation in pancreatic acinar cell Ca(2+). These aberrant Ca(2+) elevations are triggered by release of Ca(2+) from apical Ca(2+) pools that are gated by the inositol 1,4,5-trisphosphate receptor (IP3R) types 2 and 3. In this study, we examined the role of IP3R type 2 (IP3R2) using mice deficient in this Ca(2+) release channel (IP3R2(-/-)). Using live acinar cell Ca(2+) imaging we found that loss of IP3R2 reduced the amplitude of the apical Ca(2+) signal and caused a delay in its initiation. This was associated with a reduction in carbachol-stimulated amylase release and an accumulation of zymogen granules (ZGs). Specifically, there was a 2-fold increase in the number of ZGs (P<0.05) and an expansion of the ZG pool area within the cell. There was also a 1.6- and 2.6-fold increase in cellular amylase and trypsinogen, respectively. However, the mice did not have evidence of pancreatic injury at baseline, other than an elevated serum amylase level. Further, pancreatitis outcomes using a mild caerulein hyperstimulation model were similar between IP3R2(-/-) and wild type mice. In summary, IP3R2 modulates apical acinar cell Ca(2+) signals and pancreatic enzyme secretion. IP3R-deficient acinar cells accumulate ZGs, but the mice do not succumb to pancreatic damage or worse pancreatitis outcomes.

Pharmacological and genetic inhibition of calcineurin protects against carbachol-induced pathological zymogen activation and acinar cell injury.

Acute pancreatitis is a major health burden for which there are currently no targeted therapies. Premature activation of digestive proenzymes, or zymogens, within the pancreatic acinar cell is an early and critical event in this disease. A high-amplitude, sustained rise in acinar cell Ca(2+) is required for zymogen activation. We previously showed in a cholecystokinin-induced pancreatitis model that a potential target of this aberrant Ca(2+) signaling is the Ca(2+)-activated phosphatase calcineurin (Cn). However, in this study, we examined the role of Cn on both zymogen activation and injury, in the clinically relevant condition of neurogenic stimulation (by giving the acetylcholine analog carbachol) using three different Cn inhibitors or Cn-deficient acinar cells. In freshly isolated mouse acinar cells, pretreatment with FK506, calcineurin inhibitory peptide (CiP), or cyclosporine (CsA) blocked intra-acinar zymogen activation (n = 3; P < 0.05). The Cn inhibitors also reduced leakage of lactate dehydrogenase (LDH) by 79%, 62%, and 63%, respectively (n = 3; P < 0.05). Of the various Cn isoforms, the ß-isoform of the catalytic A subunit (CnAß) was strongly expressed in mouse acinar cells. For this reason, we obtained acinar cells from CnAß-deficient mice (CnAß-/-) and observed an 84% and 50% reduction in trypsin and chymotrypsin activation, respectively, compared with wild-type controls (n = 3; P < 0.05). LDH release in the CnAß-deficient cells was reduced by 50% (n = 2; P < 0.05). The CnAß-deficient cells were also protected against zymogen activation and cell injury induced by the cholecystokinin analog caerulein. Importantly, amylase secretion was generally not affected by either the Cn inhibitors or Cn deficiency. These data provide both pharmacological and genetic evidence that implicates Cn in intra-acinar zymogen activation and cell injury during pancreatitis.

A comparison of presentation and management trends in acute pancreatitis between infants/toddlers and older children.

OBJECTIVES: Acute pancreatitis is a necroinflammatory disease that leads to 210,000 hospitalizations in the United States annually. Recent reports suggest that there may be important differences in clinical features between infants/toddlers and older children. Thus, in this study we make a direct comparison between the pediatric age groups in presentation and management trends of acute pancreatitis. PATIENTS AND METHODS: We examined all children (ages 0 to 20 years) admitted to Yale-New Haven Children's Hospital with pancreatitis between 1994 and 2007. RESULTS: Two hundred seventy-one cases met inclusion criteria for acute pancreatitis. Infants and toddlers manifested fewer signs and symptoms of abdominal pain, epigastric tenderness, and nausea compared with older children (43% vs 93%; 57% vs 90%; and 29% vs 76%, respectively; P < 0.05 for all comparisons). They were more likely to be diagnosed by serum lipase than by amylase and to undergo radiographic evaluation (P < 0.05). They had a longer hospital stay (19.5 vs 4 days; P < 0.05) and were less likely to be directly transitioned to oral nutrition (14% vs 71%; P < 0.05). CONCLUSIONS: Infants and toddlers with acute pancreatitis present with fewer classical symptoms and are managed differently from older children. We believe these data will be helpful in evaluating and understanding treatment practices in this age group.

Dantrolene mitigates caerulein-induced pancreatitis in vivo in mice.

Acute pancreatitis is a painful, inflammatory disorder for which adequate treatments are lacking. An early, critical step in its development is the aberrant signaling of Ca(2+) within the pancreatic acinar cell. This Ca(2+) release is modulated by the intracellular Ca(2+) channel the ryanodine receptor (RYR). We have previously shown that RYR inhibition reduces pathological intra-acinar protease activation, an early marker of pancreatitis. In this study, we examined whether pretreatment with the RYR inhibitor dantrolene attenuates the severity of caerulein-induced pancreatitis in mice. Immunofluorescent labeling for RYR from mouse pancreatic sections showed localization to the basolateral region of the acinar cell. After 1 h of caerulein hyperstimulation in vivo, dantrolene 1) reduced pancreatic trypsin activity by 59% (P < 0.05) and 2) mitigated early ultrastructural derangements within the acinar cell. Eight hours after pancreatitis induction, dantrolene reduced pancreatic trypsin activity and serum amylase by 61 and 32%, respectively (P < 0.05). At this later time point, overall histological severity of pancreatitis was reduced by 63% with dantrolene pretreatment (P < 0.05). TUNEL-positive cells were reduced by 58% (P < 0.05). These data suggest that the RYR plays an important role in mediating early acinar cell events during in vivo pancreatitis and contributes to disease severity. Blockade of Ca(2+) signals and particularly RYR-Ca(2+) may be useful as prophylactic treatment for this disease in high-risk settings for pancreatitis.