Organ and Tissue Authority

Although antiviral prophylaxis with lamivudine monotherapy appears to reduce post-liver transplantation recurrence of hepatitis B virus (HBV) infection, breakthrough infections occur in at least 20% of the patients because of the development of drug resistance. Combined lamivudine and intravenous hepatitis B immune globulin (HBIG) therapy (10,000-IU doses) may reduce this risk, but its use is limited by cost ( approximately US $45,000/yr) and availability. We report the experience at liver transplant centers in Australia and New Zealand in which lamivudine has been used in combination with much lower doses of HBIG than used in conventional HBIG prophylaxis. Lamivudine, 100 mg/d, was administered to hepatitis B surface antigen (HBsAg)-positive candidates on listing for transplantation and was continued posttransplantation. HBIG, 400 or 800 IU, was administered intramuscularly (IM) daily for 1 week from transplantation and monthly thereafter. Thirty-seven HBsAg-positive patients underwent transplantation using this protocol. Thirty-six of these patients were HBV DNA positive by polymerase chain reaction (PCR) or hybridization assay. Thirty-four patients had chronic HBV, 2 patients had hepatitis B and C, and 1 patient had hepatitis B, C, and D. Five patients died within 1 month of transplantation and are not included in the analysis. Mean follow-up in the remaining 32 patients was 18.4 months (range, 5 to 45 months). Treatment was well tolerated, with no significant adverse events. Thirty-one of 32 patients were HBsAg negative, and all 32 patients were HBV DNA negative by PCR at latest follow-up. The cost of treatment was US $967 for lamivudine and between $2,290 and $4,480/yr for IM HBIG. Lamivudine and low-dose HBIG treatment prevents posttransplantation recurrence of hepatitis B and is likely to be more cost-effective than high-dose HBIG regimens.

Complete hematopoietic chimerism and tolerance of a liver allograft from a deceased male donor developed in a 9-year-old girl, with no evidence of graft-versus-host disease 17 months after transplantation. The tolerance was preceded by a period of severe hemolysis, reflecting partial chimerism that was refractory to standard therapies. The hemolysis resolved after the gradual withdrawal of all immunosuppressive therapy.

Due to the ongoing shortage of deceased-donor organs, novel strategies to augment kidney transplantation rates through expanded living donation strategies have become essential. These include desensitization in antibody-incompatible transplants and kidney paired donation (KPD) programs. KPD enables kidney transplant candidates with willing but incompatible living donors to join a registry of other incompatible pairs in order to find potentially compatible transplant solutions. Given the significant immunologic barriers with fewer donor options, single-center or small KPD programs may be less successful in transplanting the more sensitized patients; the optimal solution for the difficult-to-match patient is access to more potential donors and large multicenter or national registries are essential. Multicenter KPD programs have become common in the last decade, and now represent one of the most promising opportunities to improve transplant rates. To maximize donor-recipient matching, and minimize immunologic risk, these multicenter KPD programs use sophisticated algorithms to identify optimal match potential, with simultaneous two-, three- or more complex multiway exchanges. The article focuses on the recent progresses in KPD and it also reviews some of the differences and commonalities across four different national KPD programs.

Recent studies have established that memory B cells, largely thought to be circulatory in the blood, can take up long-term residency in inflamed tissues, analogous to widely described tissue-resident T cells. The dynamics of recruitment and retention of memory B cells to tissues and their immunological purpose remains unclear. Here, we characterized tissue-resident memory B cells (B RM ) that are stably maintained in the lungs of mice after pulmonary influenza infection. Influenza - specific B RM were localized within inducible bronchus-associated lymphoid tissues (iBALTs) and displayed transcriptional signatures distinct from classical memory B cells in the blood or spleen while showing partial overlap with memory B cells in lung-draining lymph nodes. We identified lung-resident markers, including elevated expression of CXCR3, CCR6, and CD69, on hemagglutinin (HA)– and nucleoprotein (NP)–specific lung B RM . We found that CCR6 facilitates increased recruitment and/or retention of B RM in lungs and differentiation into antibody-secreting cells upon recall. Although expression of CXCR3 and CCR6 was comparable in total and influenza-specific memory B cells isolated across tissues of human donors, CD69 expression was higher in memory B cells from lung and draining lymph nodes of human organ donors relative to splenic and PBMC-derived populations, indicating that mechanisms underpinning B RM localization may be evolutionarily conserved. Last, we demonstrate that human memory B cells in lungs are transcriptionally distinct to populations in lung-draining lymph nodes or PBMCs. These data suggest that B RM may constitute a discrete component of B cell immunity, positioned at the lung mucosa for rapid humoral response against respiratory viral infections.

PURPOSE OF REVIEW: To summarize the recent literature regarding descemetorhexis stripping without endothelial keratoplasty (DWEK), increasingly referred to as Descemet's stripping only (DSO). To report the characteristic clinical, confocal and histologic findings associated with this procedure. RECENT FINDINGS: Reported clearance rates following DSO range from 63 to 100% in recent series, with variation between surgical techniques. Topical Rho-kinase inhibitor has been reported as successfully salvaging failing cases. Its use as an adjuvant to the surgery is gaining widespread adoption with the results of early series now arriving. Apart from a phenotype of central guttata with clear periphery, patient characteristics which determine success remain elusive. Surgical factors affecting success are increasingly well understood, with stromal injury felt to be a retardant to healing. Characteristic clinical signs have been observed and are described herein. Clinical, confocal and light microscopic images are obtained from patients in clinical trials of DSO with ripasudil. SUMMARY: DSO is gaining acceptance as a surgical option for a subset of patients with Fuchs' Dystrophy. The addition of Rho-associated kinase inhibitor appears to improve predictability but further results to this effect must be published and scrutinized.

In 2016, the Transplantation Society of Australia and New Zealand, with the support of the Australian Government Organ and Tissue authority, commissioned a literature review on the topic of infectious disease transmission from deceased donors to recipients of solid organ transplants. The purpose of this review was to synthesize evidence on transmission risks, diagnostic test characteristics, and recipient management to inform best-practice clinical guidelines. The final review, presented as a special supplement in Transplantation Direct, collates case reports of transmission events and other peer-reviewed literature, and summarizes current (as of June 2017) international guidelines on donor screening and recipient management. Of particular interest at the time of writing was how to maximize utilization of donors at increased risk for transmission of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus, given the recent developments, including the availability of direct-acting antivirals for hepatitis C virus and improvements in donor screening technologies. The review also covers emerging risks associated with recent epidemics (eg, Zika virus) and the risk of transmission of nonendemic pathogens related to donor travel history or country of origin. Lastly, the implications for recipient consent of expanded utilization of donors at increased risk of blood-borne viral disease transmission are considered.

BACKGROUND: Reports on the relevance of immunogenetic factors in liver transplantation are often conflicting or inconclusive. We have, therefore, investigated a range of factors that may underlie liver graft survival. METHODS: The influences of HLA, flow cytometric, and enhanced cytotoxic crossmatching and immunoglobulin (Ig)A levels on graft survival, and acute and chronic rejection were investigated for a single center involving 446 patients over 13 years. RESULTS: The effect of HLA mismatching on graft survival was significant (P<10(-2)) and was reversed in recipients with autoimmune diseases (P<0.5x10(-2)), whereas the effect of HLA mismatches on the level of acute rejection was detrimental in all recipients. There was a significant effect of a positive cytotoxic crossmatch on 3-month (P<10(-5)) and 1-year (P<10(-4)) graft survival, and an additional effect of the flow cytometric crossmatch was seen for chronic rejection (P<10(-2)) and acute rejection (P<10(-2)). Recipients with HLA-A1,B8,DRB1*0301 had higher levels of acute rejection (P<0.5x10(-2)), and recipients who received an ABO compatible-nonidentical transplant have a significantly higher risk (P<10(-2)) of developing chronic rejection. Finally, the beneficial effect of high serum IgA and, specifically, IgA anti Fab, seen in renal transplants was not evident in liver transplants, and in fact the opposite may be true, at least for acute rejection (P<0.5x10(-2)). CONCLUSIONS: By separating the recipients with autoimmune disease from other patients and by including acute and chronic rejection as outcome parameters, we have used the power of a large single-centre study to delineate the significance of some of the important immunogenetic factors involved in liver transplantation.

1. Hepatitis C virus (HCV) infection in the allograft occurs in the setting of greater viral burden than in nontransplantation patients. 2. Infection of the allograft occurs early (within days and possibly during the intraoperative reperfusion phase). 3. Viral burden plateaus at 1 month posttransplantation and (in the absence of cholestatic HCV) peaks at the time of acute hepatitis (1 to 4 months). 4. Acute hepatitis is associated with immune cell infiltration and hepatocyte apoptosis. 5. Cholestatic HCV seems to be a disease of direct HCV cytopathic injury in the setting of extreme virus levels, an intrahepatic T helper subtype 2 cell (T(H)2)-like response, and lack of a specific HCV-directed response. 6. Chronic hepatitic HCV seems to behave at the molecular and/or cellular level in a similar fashion to the nontransplantation setting, with activation of T(H)1 inflammatory, profibrotic, and proapoptotic pathways. This process operates at a greater viral burden than pretransplantation and leads to more progressive disease. 7. More studies are required to examine and distinguish allograft rejection in the setting of HCV infection from HCV infection alone.

The brain-based determination of death (“brain death”) is now widely accepted throughout the world. It states that the irreversible cessation of brain functions is the fundamental criterion for human death. The recent World Brain Death Project provided a comprehensive cataloguing of all aspects of brain death including its medical and legal acceptance throughout the world.1 Organ donation after the brain-based determination of death (DBDD) currently accounts for the majority of multiorgan donations internationally. Organ donation after the circulatory determination of death (DCDD) has grown worldwide since the Institute of Medicine of the United States endorsed the practice of controlled DCDD in 20002 and a US national conference on DCDD in 2005 standardized its practice.3 DCDD donations are expanding but remain fewer than the number of DBDD donations. DCDD donor death determination requires the permanent absence of systemic circulation. When systemic circulation is absent, brain circulation ceases. The essential feature of the unified brain-based concept of death is that permanent cessation of systemic circulation produces permanent cessation of brain circulation and neuronal perfusion resulting in permanent cessation of brain functions. Thus, the determination of death by circulatory criteria is consistent with the determination of death by neurologic criteria. In situ normothermic regional perfusion (NRP) is emerging as a component of organ recovery procedures in controlled DCDD. Controlled DCDD is practiced in hospitalized patients after the planned withdrawal of life-sustaining therapy (WLST). NRP uses extracorporeal membrane oxygenation to reestablish circulation to specific regions of the body following death determination. The circulation reestablished may be restricted to the abdominal cavity (A-NRP) or may also include the thoracic cavity (TA-NRP). NRP reportedly improves organ utilization and recipient outcomes comparable with those of organs from DBDD donors,4,5 but it also raises complex medical, ethical, and legal questions that must be resolved.6-8 DCDD donor death determination requires the permanent absence of systemic circulation but NRP protocols reestablish systemic circulation. This situation raises the principal question in NRP: if resumption of circulation by NRP contradicts the conditions of the death declaration, how can a donor be declared dead by permanent cessation of circulation? The use of the unified brain-based concept of death resolves the dilemma by clarifying that the relevant circulation that must cease is circulation to the brain.9,10 If NRP is effectively restricted to ensure no circulation to the brain, thereby preventing brain perfusion and function, NRP fulfills the requirements of donor death determination and respects the dead donor rule. Ensuring that circulation to the brain has ceased permanently and will not be restarted allows donors to be declared dead based on the permanent cessation of brain functions despite the restoration of regional circulation to the abdomen or thorax. DEATH DETERMINATION IN DONATION AFTER CIRCULATORY DETERMINATION OF DEATH Under current DCDD protocols, a declaration of death requires determining that the potential organ donor’s circulation has ceased permanently. Three conditions establish permanent cessation of systemic circulation: (1) circulation has ceased completely, as evidenced by intra-arterial pressure monitoring, electrocardiography, or echocardiography; (2) no circulation persists beyond the time interval during which autoresuscitation has been reported to occur; and (3) no intervention is made to restore circulation after death has been declared.11 If these conditions are met, the permanence criterion is fulfilled, the donor is validly declared dead, and the subsequent recovery of donated organs does not violate the dead donor rule.11 Although legal standards differ among jurisdictions, physicians who follow DCDD protocols can be confident that they are acting in accordance with standards accepted around the world that have long equated death with permanent cessation of systemic circulation.8 In controlled DCDD protocols, a minimum of 5 min of absent circulation establishes that the heart will not restart spontaneously and that circulatory cessation is permanent. This controlled DCDD death standard was recommended by the Institute of Medicine2 and is in common use in the United States and in most European countries.12 The 5-min standard has been confirmed by a large prospective observational study of autoresuscitation, in which death was determined by circulatory criteria following WLST, in which the longest interval reported between asystole and autoresuscitation was 4 min and 24 s.13 THE UNIFIED BRAIN-BASED DEATH DETERMINATION IN DCDD There is a widespread medical acceptance that human death can be declared on the basis of the permanent cessation of brain functions, defined as the permanent loss of the capacity for consciousness, of the capacity to breathe, and of all brain stem reflexes.1,14 The permanent cessation of brain functions can be caused by primary brain pathology, such as traumatic head injury, stroke, or meningitis, or by hypoxic–ischemic brain damage secondary to the loss of brain perfusion during circulatory arrest. The unified brain-based concept of death provides that when the cessation of brain function results from circulatory arrest, the relevant circulation which has ceased is that of the brain.9,10 In applying the unified brain-based concept of death to the determination of death in DCDD, permanent cessation of systemic circulation initially causes brain circulation to cease. Permanent cessation of brain circulation results in the permanent absence of neuronal perfusion, which results in the permanent cessation of brain functions. Thus, the unified brain-based concept of death provides that, in DCDD, the permanent cessation of systemic circulation leads to the permanent cessation of brain functions.9,10 Physiologic studies of patients dying following WLST show that cessation of brain activity closely correlates with cessation of systemic circulation. The electroencephalogram becomes isoelectric within 30 s of cardiac arrest resulting in absent circulation to the brain15 and can occur even sooner when WLST is followed by severe hypotension and hypoxemia before cardiac arrest.16,17 Cessation of brain circulation triggers a physiologic cascade: cessation of brain perfusion leading to cessation of brain neuronal activity leading to cessation of brain function. After 5 min of complete cessation of brain circulation, death can be declared on the grounds that brain circulatory cessation is permanent and, therefore, the cessation of brain functions is permanent. Permanence is established when the interval during which autoresuscitation can occur has elapsed and no resuscitative intervention will be attempted. A physiologic function that ceases irreversibly means that the function cannot be restored. A physiologic function that ceases permanently means that the function will not be restored.18 From its inception, the determination of brain death has confirmed the irreversible cessation of brain functions. The testing that enables a formal brain death determination is a retrospective assessment of brain functions that had ceased previously (they cannot be restored). The determination of death by circulatory criteria is a prospective (real time) assessment that requires only the permanent absence of circulation to the brain to ensure the permanent absence of brain functions. According to the unifying brain-based concept of death, the permanent cessation of circulation to the brain enables a valid determination of death because it results in the permanent cessation of brain functions (see Figure 1). Cessation of brain functions is the true endpoint of the brain-based concept of death, which is the consequence of the permanent cessation of circulation to the brain.FIGURE 1.: Brain functions are time dependent on circulation to the brain.After circulation has ceased permanently, direct testing of brain functions would be the ideal method to prove its absence. But for technical reasons, electrophysiological assessment of brain function is not feasible in the DCDD donor, particularly the assessment of brain stem functions. Therefore, in DCDD protocols, the cessation of circulation to the brain is used as a surrogate for the cessation of brain functions. This practice is justified by the strict causal relationship between brain function and circulation that exists when brain circulation ceases: brain function cannot continue in the absence of brain circulation. However, the mere presence of measurable brain circulation does not necessarily imply the presence of brain functions because detected blood flow may not achieve the necessary perfusion threshold to allow brain functions. Yet, the presence of brain blood flow indicates that brain functions remain possible. These precise thresholds are currently unknown. THE GOAL OF TA-NRP IS TO RESTORE CIRCULATION TO THORACIC AND ABDOMINAL ORGANS NRP has been added to DCDD protocols after the declaration of death as an in situ preservation strategy to reperfuse organs, reduce warm ischemic damage, and allow organs to be better assessed before being recovered for transplantation. In A-NRP, the aorta is clamped or blocked to restrict circulation to the abdominal organs, whereas TA-NRP requires stapling of the aortic arch vessels. The purpose of the arch vessel or abdominal aortic clamping is to exclude blood flow to the brain and restrict blood flow to only those organs being recovered for transplantation. When TA-NRP is initiated, mechanical ventilation is also restarted. The donor’s heart is assessed for transplantation suitability after the resumption of sinus rhythm and cardiac contractions. The restarted donor heart provides circulation to perfuse thoracic and abdominal organs and also provides an opportunity to assess the heart’s functional suitability for transplantation. But do these techniques succeed in totally excluding brain circulation? POTENTIAL INADEQUACIES OF CLAMPING THE AORTIC ARCH VESSELS TA-NRP Brain circulation may not be completely excluded by arch vessel clamping because of potential collateral arterial circulation to the brain and the dynamics of brain circulatory autoregulation. Brain circulation is a robust system of direct and collateral arteries distributed by the aorta. Blood flow proceeds from the arch to the brain through the carotid and vertebral arteries that ultimately form the Circle of Willis. At the level of the medulla, the vertebral arteries give off branches that merge to form the anterior spinal artery. The anterior spinal artery distributes blood flow to the spinal cord and brain from collateral supply derived from branches from the aorta in cervical (C1–T3), thoracic (T4–T8), and lumbar regions (T9 to the conus medullaris) via the spinal artery of Adamkiewicz. That artery can direct blood flow cephalad toward the collateral branches along the spinal cord if the circulation to the brain is impaired through the major arch routes of blood flow. Clamping of the brain’s main arteries may stimulate collateral circulation to the brain by cerebral autoregulation in the presence of the cephalad arterial blood flow generated by NRP.19 Current human data are insufficient to assure zero brain blood flow during in situ NRP, although animal models are reassuring.20 A recent TA-NRP experiment in a small sample of pigs found that clamping of the arch vessels prevented brain activity as assessed by electroencephalogram, evoked potentials, cerebral blood flow, and oxygen uptake.21 But because of the uncertainty that complete cessation of blood flow to the brain results by only clamping the arch vessels, current protocols in the United Kingdom and Spain have added the step of severing the arch vessels distal to the clamps and draining or aspirating blood from the cephalad ends of the severed vessels while exposed to atmospheric pressure.22 This technical maneuver is intended to divert any possible collateral blood flow away from the brain. For a unified brain-based circulatory determination of death to be valid in NRP, it is essential that all brain circulation has ceased completely and is not restored by NRP or any other means. Animal and human studies must be performed to reassure that brain circulation is eliminated completely when TA-NRP is incorporated into controlled DCDD protocols. These studies could also inform the best methods of clinical direct brain monitoring during TA-NRP. To resolve the clinical uncertainty over restoring circulation to the brain, studies, such as those planned in the United Kingdom and Spain, should be conducted to assess brain blood flow during TA-NRP, for example, by contrast angiography. Given that brain monitoring is not sufficiently sensitive to detect functioning, particularly in areas difficult to examine, like the brain stem, one must assume that the presence of brain perfusion indicates the potential for brain functioning. RECOMMENDATIONS TO DEVELOP AN INTERNATIONAL CONSENSUS ON A UNIFIED BRAIN-BASED CONCEPT OF DEATH WHEN NRP IS IMPLEMENTED International Professional Societies That Develop Medical Standards Should Work to Achieve a Consensus on the Unified Brain-based Concept of Death The unified brain-based concept of death is applicable to both DBDD and DCDD although the clinical criteria for death determination are distinct. The brain-based concept of death provides that the permanent absence of brain functions is achieved by the permanent absence of circulation to the brain.23 Determining death by the permanent cessation of brain functions is consistent with the medical standards for determining death outside the context of organ donation.1 If circulation to the brain ceases completely and permanently, no brain function can continue. Establishing international professional consensus on the unified brain-based concept of death will provide a framework for TA-NRP DCDD policy and practice, thereby promoting public trust and addressing potential barriers to opportunities for donation and transplantation. Such a consensus has been accomplished previously by international expert collaboratives on death determination based on solid scientific evidence.1,14,24 Future clinical and laboratory research should determine if any residual brain circulation exceeds the threshold for neuronal perfusion necessary for brain functions, even when the most restrictive vascular blocking techniques of NRP protocols are implemented. Protocols of DCDD Organ Recovery, Especially With In Situ Organ Preservation Using TA-NRP, Must Ensure the Permanent Absence of Circulation to the Brain Current protocols in TA-NRP must be validated to provide assurance that the techniques to stop or divert collateral blood flow to the brain are experimentally proven and clinically effective. Programs using TA-NRP before such validation is available should consider implementing a system of brain monitoring using sensitive techniques to provide reassurance in the complete and continued absence of brain functions during TA-NRP–assisted organ recovery.25 The Surgical Recovery Maneuvers Used to Prevent Circulation to the Brain During NRP Must Be Legally, Ethically, and Socially Acceptable Discussions between qualified organ donation professionals and potential donor families should include information about the aims, methods, and technical maneuvers of NRP protocols that are sufficient to allow family members and surrogates to make informed decisions about authorizing organ donation. Transparency in these conversations ensures public trust in the system of organ donation. Some commentators have emphasized the desirability of pursuing ex situ normothermic perfusion because it avoids the ethical and legal issues of in situ NRP while providing many of its benefits.26 However, this alternative is associated with substantially higher costs and has its own limits in countries where legislation requires an observation period longer than the 5-min standard for the declaration of death. To support the development of best practices for communicating with potential donors and families, studies of donor families and hospital personnel should be conducted to explore their attitudes and understanding of TA-NRP. Transparency in these conversations ensures public trust in the system of organ donation. We are encouraged by the efforts of the Canadian panel that has adopted the unified brain-based concept of death into a national clinical practice guideline for death determination after the arrest of circulation and brain functions.27 Their rationale and recommendations can serve as a model worldwide, particularly where TA-NRP is implemented. Alignment between NRP protocols and prevailing clinical, ethical, and legal standards remains necessary.7,8

Liver transplantation (LT) in Australia and New Zealand began in 1985. Over this time until December 2014, LT took place in 3700 adults and 800 children. LT is regulated with 1 unit, supported by the government, per state or region. Currently approximately 270 transplants take place per year. Organ donation rates are moderate in Australia (17 per 1 million of population) but very low in New Zealand (11 per 1 million of population). All the units share organ donors for fulminant hepatic failure cases (status 1). Recipient listing criteria and organ allocation criteria are commonly agreed to via National and Trans-Tasman agreements, which are published online. Current survival rates indicate approximately 94% 1-year survival with median survival in adults of approximately 20 years, whereas 75% of children are alive at 20 years. All units collaborate in research projects via the Australia and New Zealand Liver Transplant Registry and have published highly cited articles particularly on the prevention of hepatitis B virus recurrence. Outcomes for indigenous populations have also been analyzed. In conclusion, LT in Australia and New Zealand is well developed with transparent processes related to criteria for listing and organ allocation together with publication of outcomes. Liver Transplantation 22 830-838 2016 AASLD.

Numbers of deceased organ donors in Australia have increased, but rates of consent to donation remain at around 60%. Increasing family consent is a key target for the Australian Organ and Tissue Authority. Reasons for donation decisions have been reported in the international literature, but little is known of reasons for Australian families' decisions. Potential organ donors in four Melbourne hospitals were identified and 49 participants from 40 families (23 consenting and 17 non-consenting) were interviewed to understand reasons for consent decisions. Themes for consent to organ donation included that: donation was consistent with the deceased's explicit wishes or known values, the desire to help others or self-including themes of altruism, pragmatism, preventing others from being in the same position, consolation received from donation and aspects of the donation conversation and care that led families to believe donation was right for them. Themes for non-consent included: lack of knowledge of wishes; social, cultural and religious beliefs; factors related to the donation process and family exhaustion; and conversation factors where negative events influenced decisions. While reasons for consent were similar to those described in international literature, reasons for non-consent differed in that there was little emphasis on lack of trust of the medical profession, concerns regarding level of care provided to the potential donor, preserving the deceased's body, fears of body invasion or organ allocation fairness.

New approaches to increase kidney transplantation rates through expansion of live donor kidney transplantation have become necessary due to ongoing shortage of deceased donor organs. These strategies include desensitization in antibody-incompatible transplants to overcome the barrier of blood group incompatibility or human leucocyte antigen antibodies between recipient and donor and kidney paired donation (KPD) programmes. In KPD, a kidney transplant candidate with an incompatible live donor joins a registry of other incompatible pairs in order to find potentially compatible transplant solutions. To match the largest possible number of donor-recipient pairs while minimizing immunologic risk, KPD programmes use sophisticated algorithms to identify suitable matches with simultaneous two-way or more complex multi-way exchanges as well as including non-directed anonymous donors to start a chain of compatible transplantations. Because of the significant immunologic barriers when fewer donor options are available, the optimal solution for difficult-to-match, highly sensitized patients is access to more potential donors using large multi-centre or national KPD registries. This review focuses on the first 4 years of experience with the Australian multi-centre KPD programme that was established in October 2010.

BACKGROUND: Obtaining family consent to organ donation is a significant obstacle to improving further Australian deceased organ donation rates. Currently, neither the consent rates for donors eligible to donate after circulatory death, nor factors that influence decision to decline or consent to donation in general are known in Australia. METHODS: This study at four university teaching hospitals in Melbourne, Victoria, examined consecutive patients where organ donation was discussed with the family RESULTS: A total of 123 cases were identified; the family consent rate was 52.8%, and 34.1% proceeded to donation. Consent to donation was related to potential donor factors such as country of birth, cultural background in Australia, a non-religious or Christian background and registration on the Australian Organ Donor Register. Family-related factors included being English speaking and having knowledge of the deceased's wishes about organ donation. Family of donation after circulatory death-eligible donors were less likely to consent to donation than the family of donation after brain death-eligible donors, although not reaching statistical significance. Among consented potential donors, those eligible for donation after brain death and with a shorter length of stay were more likely to proceed to donating organs for transplantation. CONCLUSION: Despite a small sample size, these findings describe current consent and donation rates and associated factors and may assist in improving conversations about organ donation.

Free arachidonic acid (AA) is an important precursor of lipid mediators such as leukotrienes and prostaglandins that induces inflammation and is associated with atherosclerosis progression. Recent studies have shown that lysophosphatidylcholine acyltransferase-3 (LPCAT3) converts lysophosphatidylcholine (LPC) and free AA into phosphatidylcholine (PC)-containing AA (arachidonyl-PC) and thereby can regulate intracellular free-AA levels. However, the association between LPCAT3 and atherosclerosis remains to be established. In this study, we analyzed human and mouse atherosclerotic tissues to gain insight into the arachidonyl-PC metabolism involving LPCAT3 using imaging mass spectrometry. The data revealed a complementary distribution of arachidonyl-PC and LPC in human atherosclerotic tissues with arachidonyl-PC decreasing and LPC increasing as atherosclerosis progressed. Furthermore, we found a homologous distribution of LPCAT3 expression and arachidonyl-PC based on atherosclerotic progression. In contrast, in ApoE-deficient mice, atherosclerosis increased both arachidonyl-PC accumulation and LPCAT3 expression. Taken together, these findings suggest that the regulation of LPCAT3 expression might be associated with atherosclerotic progression in humans.

OBJECTIVE: To determine the potential for organ donation after circulatory death (DCD) in Australia by applying ideal and expanded organ suitability criteria, and to compare this potential with actual DCD rates. DESIGN: Retrospective cohort study. Setting, methods: We analysed DonateLife audit data for patients aged 28 days to 80 years who died between July 2012 and December 2014 in an intensive care unit or emergency department, or who died within 24 hours of discharge from either, in the 75 Australian hospitals contributing data to DonateLife. Ideal and expanded organ donation criteria were derived from international and national guidelines, and from expert opinion. Potential DCD organ donors were identified by applying these criteria to patients who had been intubated and were neither confirmed as being brain-dead nor likely to have met brain death criteria at the official time of death. RESULTS: 8780 eligible patients were identified, of whom 202 were actual DCD donors. For 193 potential ideal (61%) and 313 potential expanded criteria DCD donors (72%), organ donation had not been discussed with their families; most were potential donors of kidneys (416 potential donors) or lungs (117 potential donors). Potential donors were typically older, dying of non-neurological causes, and more frequently had chronic organ disease than actual donors. Identifying all these potential donors, assuming a consent rate of 60%, would have increased Australia's donation rate from 16.1 to 21.3 per million population in 2014. CONCLUSIONS: The untapped potential for DCD in Australia, particularly of kidneys and lungs, is significant. Systematic review of all patients undergoing end-of-life care in critical care environments for donor suitability could result in significant increases in organ donation rates.

The aim of this study was to investigate possible differences in the frequencies of alleles at the HLA loci and at microsatellite loci within the HLA region among patients suffering from psoriatic arthritis (PsA) and healthy controls. Fifty-eight Croatian PsA patients (28 male and 30 female) and 157 healthy unrelated controls were typed for HLA alleles (A, B, Cw and DRB1) by the polymerase chain reaction-sequence-specific primers (PCR-SSP) method, while microsatellite alleles (D6S265, D6S273, MHC class I chain-related gene (MICA) and MIB) were analysed by electrophoresis in an ALFexpress sequencer (Pharmacia Biotech, Uppsala, Sweden). The findings from this study were: (1) the frequencies of B*39 and B*57 were significantly increased in PsA patients; (2) differences in the frequencies of B*13 and B*27 were not statistically significant after correction; (3) the B*0702, B*18, and B*38 alleles were decreased in patients only before correction; (4) none of the alleles at other HLA loci tested were associated with PsA in Croatia; (5) polymorphism at D6S265, D6S273, and MIB microsatellites in patients did not show any statistically significant differences when compared to controls; (6) the increase in the MICA-A4 allele frequency in PsA patients was independent of the B*39 and B*57 alleles.

We aimed to describe the experiences of families of potential organ and tissue donors eligible for donation after circulatory death or brain death. Forty-nine family members of potential donors from four Melbourne hospitals were interviewed to assess their experiences of communication, processes and the outcomes of donation. Interviews were recorded, transcribed verbatim and analysed thematically. Families expressed a range of perspectives on themes of communication, hospital processes and care, the processes of consent and donation and reflected on decisions and outcomes. They expressed satisfaction overall with communication when receiving bad news, discussing death and donation. Honest and frank communication and being kept up-to-date and prepared for potential outcomes were important aspects for families, especially those of post circulatory death donors. Participants reported high levels of trust in healthcare professionals and satisfaction with the level of care received. Many donor families indicated the process was lengthy and stressful, but not significantly enough to adversely affect their satisfaction with the outcome. Both the decision itself and knowing others' lives had been saved provided them with consolation. No consenting families, and only some non-consenting families, regretted their decisions. Many expressed they would benefit from a follow-up opportunity to ask questions and clarify possible misunderstandings. Overall, while experiences varied, Australian families valued frank communication, trusted health professionals, were satisfied with the care their family member received and with donation processes, despite some apparent difficulties. Family satisfaction, infrequently assessed, is an important outcome and these findings may assist education for Australian organ donation professionals.

OBJECTIVE: To evaluate whether the admission of a palliative patient to the intensive care unit for end-of-life care and consideration of organ donation provides an equivalent net benefit in quality-adjusted life-years (QALYs) compared with the admission of a non-palliative patient for active management. DESIGN: Relevant publications from the period 1995-2015 were reviewed to estimate the mean QALYs gained from ICU admission of a critically ill patient and mean QALYs gained from transplantation of solid organs from an organ donor. Australian audit data were used to estimate the likelihood of a palliative patient admitted to the ICU progressing to organ donation. We calculated probabilities of each outcome and developed an algorithm to illustrate possible pathways for a patient who may progress to organ donation. RESULTS: A non-palliative ICU admission provides to the patient about 1.0 QALY per ICU bed-day. An ICU bed provided to a patient admitted to the ICU for palliation and consideration of organ donation results in 7.3 QALYs gained for the community per ICU bed-day. CONCLUSION: The admission of a dying patient to the ICU when organ donation may be possible is of considerable community benefit, yielding an average of over seven times the QALYs per ICU bed-day compared with the average benefit for ICU patients expected to survive. When it is possible to offer end-of-life care in the ICU, it should not be denied on the basis of concerns about lack of benefit or inappropriate use of resources.

THE DONOR The 9-year-old donor had been febrile and probably had a seizure on the day of a submersion injury. He was declared brain dead after 60 hr of sedation, ventilation, and cooling. He did not have evidence of significant respiratory illness, was not immunized against influenza, and had not received antiviral agents. After allocation of kidneys, liver, and lungs, the organ procurement center was notified by the donor hospital that a donor nasopharyngeal aspirate demonstrated influenza B virus by immunofluorescence. Positive status was later confirmed by nested reverse- transcription polymerase chain reaction (RT-PCR) and cultures. At the time of notification, the lung recipient had native lung removal in progress. Organ recipient centers for liver and kidneys were notified of this risk and accepted the organs. Recipient clinical management details and investigative workup are summarized in Table 1.TABLE 1: Summary of the progress and management of all organ recipientsRENAL TRANSPLANT—KIDNEY 1 The recipient of kidney 1 was a 14-year-old boy with end-stage kidney disease secondary to hypoplastic kidneys. He had not received the 2008 seasonal influenza vaccine. This retrieved kidney was biopsied and was positive for influenza B RNA by RT-PCR. Initially, standard immunosuppression of basiliximab, mycophenolate, tacrolimus, and methylprednisone was used. A pretransplant dose of oseltamivir was given. After transplant, there was delayed graft function requiring peritoneal dialysis at 18 hr. Oseltamivir was administered daily. At 30-hr posttransplant, the patient developed severe respiratory distress and fever. By day 4, ventilation was required. A chest x-ray demonstrated widespread interstitial infiltrates (see Figure 1A, Supplemental Digital Content 1,https://links.lww.com/TP/A203). Because of delayed graft function, and this severe possibly infective illness, immunosuppression other than methylprednisone was withdrawn. Multiple RT-PCRs for influenza B RNA were performed on blood and tracheal aspirate samples. By day 6, oseltamivir was ceased as all investigations were negative. All other cultures and immunofluoresence studies were also negative. By day 6, the patient was extubated. A nonidentified infectious agent or an acute drug hypersensitivity reaction was proposed as a cause of the respiratory illnesses. On day 14, a renal biopsy, performed because of continued oliguria, demonstrated acute cellular rejection. Influenza B RNA was not detected in this biopsy. Following muro monah-CD3 (OKT3) and methylprednisone, renal function improved. Six months posttransplant, the patient's creatinine level was 67 μmol/L. Follow- up influenza serology did not demonstrate an increase in titers. LUNG TRANSPLANT The lung transplant recipient was a 17-year-old girl with end-stage lung disease because of neonatal onset pulmonary fibrosis. She had received yearly seasonal influenza vaccine. Induction therapy comprised steroids alone. After transplant, she received standard immunosuppression with cyclosporine, azathioprine, and methylprednisolone. Given the donor's influenza B status, oseltamivir was prescribed daily for 10 days in addition to routine broad spectrum antibiotic and inhaled antifungal therapy. The patient was noted to have widespread crackles on chest auscultation on postoperative day 0. Chest x-ray demonstrated diffuse bilateral interstitial infiltrates (see Figure 1B, Supplemental Digital Content 1,https://links.lww.com/TP/A203). During bronchoscopy, the airway anastomoses and distal bronchial tree were macroscopically normal, but bronchoalveolar lavage was tested positive for influenza B virus on direct immunofluorescence and culture on postoperative days 0 and 1 but negative by day 10. She was extubated successfully on day 6 and discharged on day 20. Spirometry improved from a forced expiratory volume in 1 sec/forced vital capacity (FVC) of 0.84/0.88 preoperatively to 1.89/2.04 by 6 months at which stage she was well and attending school. OTHER ORGAN RECIPIENTS The other kidney recipient showed no symptoms to suggest a donor-derived influenza infection. The liver recipient's posttransplant course was also unaltered by this donor-derived influenza risk. RESULTS OF INFLUENZA B VIRUS IDENTIFICATION Typing of influenza B virus in the explant kidney of recipient 1 and the lung recipient showed that the donor was B/Florida/4/2006 type (Table 1). Phylogenetic analysis based on partial nonstructural gene showed that the kidney and lung recipient strains were closely related with 98.9% amino acid identity across the partial nonstructural gene (see Figure 2, Supplemental Digital Content 2,https://links.lww.com/TP/A204). The strains shared more than 97.8% amino acid identity with B/Florida/4/2006, the influenza B-like strain in the Australian 2008 to 2009 influenza virus vaccine. DISCUSSION This case unfolded before the novel influenza A/H1N1 pandemic and the publication of recommendations for preventing donor-derived influenza infection (both seasonal and pandemic) (1, 2). Donor-derived influenza infection, however, has been documented rarely, with one reported case of influenza A transmission (3). To our knowledge, our case is the first report of influenza B transmission through lung transplantation. Although the recipient survived and is currently well, it is acknowledged that the outcome could have been different. Apart from acute risks, transplant- associated respiratory virus infection leading to bronchiolitis obliterans syndrome and graft dysfunction has been proposed as a potential longer term issue. However, there is no clear data to support influenza specifically as a causative agent in bronchiolitis obliterans syndrome (4). Given theoretical high likelihood of influenza transmission through lung transplantation, and potentially more significant recipient risk, a general recommendation by the transplantation society has been to defer a lung transplant in such a risk setting (1). Another approach, as recommended by The Australian Organ and Tissue Donation and Transplantation Authority, especially to be considered where recipient organ need is dire, is an individual case risk benefit analysis with informed consent (2). In our report, a donor kidney was shown to harbor influenza B virus during implantation, and although the recipient developed a respiratory illness, this was not related to influenza B. The presence of influenza in solid organs has been reported by authors in nontransplant settings (5). As far as we are aware, however, there are no reports of solid organ transplant transmission of influenza. This transmission risk remains to be clarified. Current guidelines recommend a cautious consideration to transplant in this risk setting (1, 2). Recognition of potentially influenza- infected donors, early donor screening, and antiviral use are the key initial steps in managing donor transmission risk of influenza viruses. If donation is to be considered, informed recipient consent is vital, with use of donor and recipient neuraminidase inhibitors (oseltamivir or zanamivir). This approach should be used in any donor influenza risk setting, regardless of subtype. Amelia K. Le Page1 Gad Kainer1 Allan R. Glanville2 Elise Tu3 Deepak Bhonagiri4 William D. Rawlinson3 1Department of Nephrology Sydney Children's Hospital Randwick, Australia 2The Lung Transplant Unit St. Vincent's Hospital Darlinghurst, Australia 3Virology Department of Microbiology SEALS, Prince of Wales Hospital Randwick, Australia 4NSW Organ and Tissue Donation Service St George Hospital Kogarah, Australia

Objective Apolipoproteins are amphipathic molecules and the major components of plasma lipoproteins. This study aims to investigate the effects of dysregulated apolipoprotein (apo) profiles and their ratios on type 2 diabetes mellitus (T2DM) and diabetic retinopathy (DR) further to test the hypothesis that altered serum level of apolipoproteins is strong biomarkers for DR. Research Design and Methods This case-control study consists of 157 patients with T2DM including DM without DR, non-proliferative DR (NPDR), and proliferative DR (PDR). Fifty-eight age- and sex-matched healthy subjects were enrolled as normal controls. Blood biochemistry profile including serum levels of glucose, glycated hemoglobin (HbA1c), lipid profile [total cholesterol (TC), Triglycerides (TG), high and low-density lipoprotein (HDL-C and LDL-C)] was estimated. Apolipoproteins (apos, A-I, A-II, B, C-II, C-III, and E) was evaluated by protein chips (Luminex technology). Apolipoprotein ratios and arteriosclerosis-associated plasma indices were calculated. The Kruskal–Wallis test, independent sample t-test or Mann–Whitney U test, and multivariate regression analysis were performed to investigate the association of serum lipid biomarkers and the DR severity. Results Serum level of apoA-I was negatively correlated with TC-(HDL-C)/HDL-C ( p &amp;lt; 0.001), fasting glucose ( p &amp;lt; 0.001), HbA1c ( p &amp;lt; 0.001), and ( p &amp;lt;0.001), while apoE, apoC-II/apoC-III, apoA-II/apoA-I were positively correlated with above traditional biomarkers ( p &amp;lt; 0.001). Single variable logistic analysis results showed that body mass index (BMI) ( p = 0.023), DM duration ( p &amp;lt; 0.001), apoE ( p &amp;lt; 0.001), apoC-II/apo C-III ( p &amp;lt; 0.001), apoE/apoC-II ( p &amp;lt; 0.001), atherogenic index ( p = 0.013), fasting glucose ( p &amp;lt; 0.001), HbA1c ( p &amp;lt; 0.001), LPA ( p = 0.001), and LDL-C/HDL-C ( p = 0.031) were risk factors for the occurrence and severity of DR. Multivariate logistic regression mode showed that apoC-II/apoC-III and apoB/non–HDL-C ( p &amp;lt; 0.001) as well as apoE/apoC-II ( p = 0.001) were the independent risk factors for the occurrence and severity of DR—apopA-I and apoA-II are protective factors for DR—after controlling for the duration of DM, HbA1c, fasting glucose, and LPA. Conclusions apoE, apoC-II/apoC-III, apoE/apoC-II, and apoB/non–HDL-C could be used as novel biomarkers for occurrence and severity of DR, whereas apoA-I and apoA-II resulted as protective factors for DR.