C. J. Callaghan

Outcomes of transplantation of livers from donation after circulatory death donors in the UK: a cohort study

Objectives Outcomes of liver transplantations from donation after circulatory death (DCD) donors may be inferior to those achieved with donation after brain death (DBD) donors. The impact of using DCD donors is likely to depend on specific national practices. We compared risk-adjusted graft loss and recipient mortality after transplantation of DCD and DBD livers in the UK. Design Prospective cohort study. Multivariable Cox regression and propensity score matching were used to estimate risk-adjusted HR. Setting 7 liver transplant centres in the National Health Service (NHS) hospitals in England and Scotland. Participants Adults who received a first elective liver transplant between January 2005 and December 2010 who were identified in the UK Liver Transplant Audit. Interventions Transplantation of DCD and DBD livers. Outcomes Graft loss and recipient mortality. Results In total, 2572 liver transplants were identified with 352 (14%) from DCD donors. 3-year graft loss (95% CI) was higher with DCD livers (27.3%, 21.8% to 33.9%) than with DBD livers (18.2%, 16.4% to 20.2%). After adjustment with regression, HR for graft loss was 2.3 (1.7 to 3.0). Similarly, 3-year mortality was higher with DCD livers (19.4%, 14.5% to 25.6%) than with DBD livers (14.1%, 12.5% to 16.0%) with an adjusted HR of 2.0 (1.4 to 2.8). Propensity score matching gave similar results. Centre-specific adjusted HRs for graft loss and recipient mortality seemed to differ among transplant centres, although statistical evidence is weak (p value for interaction 0.08 and 0.24, respectively). Conclusions Graft loss and recipient mortality were about twice as high with DCD livers as with DBD livers in the UK. Outcomes after DCD liver transplantation may vary between centres. These results should inform policies for the use of DCD livers.

Anthracycline-based chemotherapy as first-line treatment in adults with malignant posttransplant lymphoproliferative disorder after solid organ transplantation.

Background. Recommended first-line treatment for posttransplant lymphoproliferative disorder (PTLD) is reduction in immunosuppressive therapy, irrespective of histopathological type. Second-line treatment with chemotherapy is generally reserved for tumors that fail to respond to reduced immunosuppression. In view of the similarities between monomorphic PTLD and non-Hodgkins lymphoma in the general population, our policy is to treat monomorphic PTLD with anthracycline-based chemotherapy as first-line treatment. Methods. A retrospective single-center analysis of 18 adults who developed PTLD following liver or kidney transplantation was undertaken, with particular emphasis on tumor histology, treatment received, and clinical outcome. Results. Of the 18 patients with PTLD, 13 had high-grade malignant lymphoma on diagnostic biopsy and received anthracycline-based chemotherapy and reduction in immunosuppression as first-line therapy. Nine (69%) of the 13 patients achieved complete remission and eight (62%) remained in complete remission five years after diagnosis. There was no graft loss from rejection or drug toxicity. Four (22%) patients had polymorphic PTLD on diagnostic biopsy (of which two were re-classified as monomorphic) and one had a low-grade malignant lymphoma. All five patients were treated by reduction in immunosuppression without chemotherapy and were in complete remission at a median of two years after diagnosis. Overall, complete remission was seen in 14 out of 18 patients (78%) at one year following diagnosis. Conclusion. The use of anthracycline-based chemotherapy and reduction of immunosuppression as first-line treatment in adults with monomorphic PTLD is well tolerated and achieves sustained complete remission in around 70% of patients with a low risk of graft loss.

Outcomes of simultaneous pancreas–kidney transplantation from brain‐dead and controlled circulatory death donors

Organ scarcity has prompted increased use of organs from donation after circulatory death (DCD) donors. An early single‐centre experience of simultaneous pancreas–kidney (SPK) transplantation from controlled DCD donors is described here.

Copresentation of Intact and Processed MHC Alloantigen by Recipient Dendritic Cells Enables Delivery of Linked Help to Alloreactive CD8 T Cells by Indirect-Pathway CD4 T Cells

In transplantation, direct-pathway CD8 T cells that recognize alloantigen on donor cells require CD4 help for activation and cytolytic function. The ability of indirect-pathway CD4 T cells to provide this help remains unexplained, because a fundamental requirement for epitope linkage is seemingly broken. The simultaneous presentation, by host dendritic cells (DCs), of both intact MHC class I alloantigen and processed alloantigen would deliver linked help, but has not been demonstrated definitively. In this study, we report that following in vitro coculture with BALB/c DCs, small numbers (∼1.5%) of C57BL/6 (B6) DCs presented acquired H-2d alloantigen both as processed allopeptide and as unprocessed Ag. This represented class I alloantigen provides a conformational epitope for direct-pathway allorecognition, because B6 DCs isolated from cocultures and transferred to naive B6 mice provoked cytotoxic CD8 T cell alloimmunity. Crucially, this response was dependent upon simultaneous presentation of class II–restricted allopeptide, because despite acquiring similar amounts of H-2d alloantigen upon coculture, MHC class II–deficient B6 DCs failed to elicit cytotoxic alloimmunity. The relevance of this pathway to solid-organ transplantation was then confirmed by the demonstration that CD8 T cell cytotoxicity was provoked in secondary recipients by transfer of DCs purified from wild-type, but not from MHC class II–deficient, C57BL/6 recipients of BALB/c heart transplants. These experiments demonstrate that representation of conformationally intact MHC alloantigen by recipient APC can induce cytotoxic alloimmunity, but simultaneous copresentation of processed allopeptide is essential, presumably because this facilitates linked recognition by indirect-pathway CD4 Th cells.

Current Status of Renal Transplantation

Renal transplantation is the best treatment for most patients with end-stage renal failure. It markedly improves quality of life and in some cases increases life expectancy. Advances in immunosuppression and other areas of practice have led to an incremental improvement in outcome; 1- and 5-yr graft survival after cadaveric renal transplantation is now around 90 and 70%, respectively. This success has led to increased demand for transplantation that cannot be met by cadaveric heart-beating donors, numbers of which have remained relatively static. Increasing use is now being made of kidneys from so-called marginal or extended criteria cadaveric donors and from non-heart-beating donors. More reliance is also being placed on living kidney donation, which accounts for around 25% of kidney transplants in the United Kingdom and 50% of transplants in the United States. Much effort in renal transplantation is now being directed toward improving long-term outcomes. This chapter provides an overview of these and other issues in renal transplantation, focusing on some of the topics of current interest.

Should surgeons take a break after an intraoperative death? Attitude survey and outcome evaluation

Abstract Objectives To investigate attitudes of cardiac surgeons and anaesthetists towards working immediately after an intraoperative death and to establish whether an intraoperative death affects the outcome of subsequent surgery. Design Questionnaire on attitudes to working after an intraoperative death and matched cohort study. Setting UK adult cardiac surgery centres and regional cardiothoracic surgical centre. Participants 371 consultant cardiac surgeons and anaesthetists in the United Kingdom were asked to complete a questionnaire, and seven surgeons from one centre who continued to operate after intraoperative death. Main outcome measures Outcome for 233 patients operated on by a surgeon who had experienced an intraoperative death within the preceding 48 hours compared with outcome of 932 matched controls. Hospital mortality and length of stay as a surrogate for hospital morbidity. Results The questionnaire response rate was 76%. Around a quarter of surgeons and anaesthetists thought they should stop work after an intraoperative death and most wanted guidelines on this subject. Overall, there was no increased mortality in patients operated on in the 48 hours after an intraoperative death. However, mortality was higher if the preceding intraoperative death was in an emergency or high risk case. Survivors operated on within 48 hours after an intraoperative death had longer stay in intensive care (odds ratio 1.64, 95% confidence interval 1.08 to 2.52, P = 0.02) and longer stay in hospital (relative change 1.15, 1.03 to 1.24, P = 0.02). Conclusion Mortality is not increased in operations performed in the immediate aftermath of an intraoperative death, but survivors have longer stays in intensive care and on the hospital ward.

Comparison of liver transplantation outcomes from adult split liver and circulatory death donors

Adult whole‐organ donation after circulatory death (DCD) and ‘split’ extended right lobe donation after brain death (ERL‐DBD) liver transplants are considered marginal, but direct comparison of outcomes has rarely been performed. Such a comparison may rationalize the use of DCD livers, which varies widely between UK centres.

The discard of deceased donor kidneys in the UK

It is essential to minimize the unnecessary discard of procured deceased donor kidneys, but information on discard rates and the extent to which discard can be avoided are limited. Analysis of the UK Transplant Registry revealed that the discard rate of procured deceased donor kidneys has increased from 5% in 2002‐3 to 12% in 2011‐12. A national offering system for hard‐to‐place kidneys was introduced in the UK in 2006 (the Declined Kidney Scheme), but just 13% of kidneys that were subsequently discarded until 2012 were offered through the scheme. In order to examine the appropriateness of discard, 20 consecutive discarded kidneys from 13 deceased donors were assessed to determine if surgeons agreed with the decision that they were not implantable. Donors had a median (range) age of 67 (31–80) yr. Kidneys had been offered to a median of 3 (1–12) centers before discard. Four (20%) of the discarded kidneys were thought to be usable, and nine (45%) were possibly usable. As a result of these findings, major changes to the UK deceased donor kidney offering system have been implemented, including simultaneous offering and broader entry criteria for hard‐to‐place kidneys. Organizational changes are necessary to improve utilization of deceased donor kidneys.

Successful Transplantation of Kidneys From Elderly Circulatory Death Donors by Using Microscopic and Macroscopic Characteristics to Guide Single or Dual Implantation

Most kidneys from potential elderly circulatory death (DCD) donors are declined. We report single center outcomes for kidneys transplanted from DCD donors over 70 years old, using preimplantation biopsy Remuzzi grading to inform implantation as single or dual transplants. Between 2009 and 2012, 43 single transplants and 12 dual transplants were performed from elderly DCD donors. Remuzzi scores were higher for dual than single implants (4.4 vs. 3.4, pu2009<u20090.001), indicating more severe baseline injury. Donor and recipient characteristics for both groups were otherwise similar. Early graft loss from renal vein thrombosis occurred in two singly implanted kidneys, and in one dual‐implanted kidney; its pair continued to function satisfactorily. Death‐censored graft survival at 3 years was comparable for the two groups (single 94%; dual 100%), as was 1 year eGFR. Delayed graft function occurred less frequently in the dual‐implant group (25% vs. 65%, pu2009=u20090.010). Using this approach, we performed proportionally more kidney transplants from elderly DCD donors (23.4%) than the rest of the United Kingdom (7.3%, pu2009<u20090.001), with graft outcomes comparable to those achieved nationally for all deceased‐donor kidney transplants. Preimplantation biopsy analysis is associated with acceptable transplant outcomes for elderly DCD kidneys and may increase transplant numbers from an underutilized donor pool.

Clinically Significant Peripancreatic Fluid Collections After Simultaneous Pancreas-Kidney Transplantation

Background Peripancreatic fluid collections (PPFC) are a serious complication after simultaneous pancreas-kidney transplantation (SPKTx). Methods Retrospective study for all 223 SPKTx performed from December 8, 1996, to October 10, 2011, to evaluate the risk factors (RF) and impact of PPFCs on outcomes was conducted. Results Clinically significant PPFCs were seen in 36 (16%) cases, all within 3 months after transplantation. Radiologic drainage resolved 2 (6%) cases, and 34 required laparotomy (mean [SD], 4 [7]). Compared with the non-PPFC group (n=186), the PPFC group had similar patient and total kidney graft survivals but significantly lower total pancreas survival (68% vs. 85%) and greater incidence of infections (75% vs. 46%, all P<0.05) at 5 years. PPFCs were associated with early graft pancreatitis in 18 (50%), pancreatic fistula in 20 (56%, 9 with obvious duodenal stump leak) and infection in the collection in 20 (56%) cases. Comparison of PPFCs with pancreas graft loss to the PPFCs with surviving grafts showed that the incidence of pancreatic fistula was greater in the former (90% pancreas graft loss vs. 42% pancreas graft survival, P<0.01). Binary logistic regression analysis of RF for developing PPFC showed a donor age >30 years to be significant (P=0.03; odds ratio, 3.4; confidence interval, 1.1–10.5) and a trend of association with donor body mass index >30 and pancreas cold ischemia time greater than 12 hr. Conclusions PPFCs are associated with significant reduction in pancreas allograft survival and impact resource use. Donor age >30 years is a significant RF for their development. PPFCs associated with pancreatic fistula carry a greater risk for pancreas graft loss.