The impact of time to death in donors after circulatory death on recipient outcome in simultaneous pancreas-kidney transplantation.

The time to arrest donors after circulatory death is unpredictable and can vary. This leads to variable periods of warm ischemic damage prior to pancreas transplantation. There is little evidence supporting procurement team stand-down times based on donor time to death (TTD). We examined what impact TTD had on pancreas graft outcomes following donors after circulatory death (DCD) simultaneous pancreas-kidney transplantation. Data were extracted from the UK transplant registry from 2014 to 2022. Predictors of graft loss were evaluated using a Cox proportional hazards model. Adjusted restricted cubic spline models were generated to further delineate the relationship between TTD and outcome. Three-hundred-and-seventy-five DCD simultaneous kidney-pancreas transplant recipients were included. Increasing TTD was not associated with graft survival (adjusted hazard ratio HR 0.98, 95% confidence interval 0.68-1.41, P = .901). Increasing asystolic time worsened graft survival (adjusted hazard ratio 2.51, 95% confidence interval 1.16-5.43, P = .020). Restricted cubic spline modeling revealed a nonlinear relationship between asystolic time and graft survival and no relationship between TTD and graft survival. We found no evidence that TTD impacts pancreas graft survival after DCD simultaneous pancreas-kidney transplantation; however, increasing asystolic time was a significant predictor of graft loss. Procurement teams should attempt to minimize asystolic time to optimize pancreas graft survival rather than focus on the duration of TTD.

A Bayesian approach for two-stage multivariate Mendelian randomization with mixed outcomes.

Many research studies have investigated the relationship between baseline factors or exposures, such as patient demographic and disease characteristics, and study outcomes such as toxicities or quality of life, but results from most of these studies may be problematic because of potential confounding effects (eg, the imbalance in baseline factors or exposures). It is important to study whether the baseline factors or exposures have causal effects on the clinical outcomes, so that clinicians can have better understanding of the diseases and develop personalized medicine. Mendelian randomization (MR) provides an efficient way to estimate the causal effects using genetic instrumental variables to handle confounders, but most of the existing studies focus on a single outcome at a time and ignores the correlation structure of multiple outcomes. Given that clinical outcomes like toxicities and quality of life are usually a mixture of different types of variables, and multiple datasets may be available for such outcomes, it may be much more beneficial to analyze them jointly instead of separately. Some well-established methods are available for building multivariate models on mixed outcomes, but they do not incorporate MR mechanism to deal with the confounders. To overcome these challenges, we propose a Bayesian-based two-stage multivariate MR method for mixed outcomes on multiple datasets, called BMRMO. Using simulation studies and clinical applications on the CO.17 and CO.20 studies, we demonstrate better performance of our approach compared to the commonly used univariate two-stage method.

Beyond donation to organ utilization in the UK.

PURPOSE OF REVIEW: Optimizing deceased donor organ utilization is gaining recognition as a topical and important issue, both in the United Kingdom (UK) and globally. This review discusses pertinent issues in the field of organ utilization, with specific reference to UK data and recent developments within the UK. RECENT FINDINGS: A multifaceted approach is likely required in order to improve organ utilization. Having a solid evidence-base upon which transplant clinicians and patients on national waiting lists can base decisions regarding organ utilization is imperative in order to bridge gaps in knowledge regarding the optimal use of each donated organ. A better understanding of the risks and benefits of the uses of higher risk organs, along with innovations such as novel machine perfusion technologies, can help clinician decision-making and may ultimately reduce the unnecessary discard of precious deceased donor organs. SUMMARY: The issues facing the UK with regards to organ utilization are likely to be similar to those in many other developed countries. Discussions around these issues within organ donation and transplantation communities may help facilitate shared learning, lead to improvements in the usage of scarce deceased donor organs, and enable better outcomes for patients waiting for transplants.

Utilization and clinical outcomes of kidney transplants from deceased donors with albuminuria in the UK: a national cohort study.

BACKGROUND: Urinalysis is a standard component of potential deceased kidney donor assessment in the UK. The value of albuminuria as a biomarker for organ quality is uncertain. We examined the relationship between deceased donor albuminuria and kidney utilization, survival and function. METHODS: We performed a national cohort study on adult deceased donors and kidney transplant recipients between 2016 and 2020, using data from the UK Transplant Registry. We examined the influence of donor albuminuria, defined as ≥2+ on dipstick testing, on kidney utilization, early graft function, graft failure and estimated glomerular filtration rate (eGFR). RESULTS: Eighteen percent (1681/9309) of consented donors had albuminuria. After adjustment for confounders, kidneys from donors with albuminuria were less likely to be accepted for transplantation (74% versus 82%; odds ratio 0.70, 95% confidence interval 0.61 to 0.81). Of 9834 kidney transplants included in our study, 1550 (16%) came from donors with albuminuria. After a median follow-up of 2 years, 8% (118/1550) and 9% (706/8284) of transplants from donors with and without albuminuria failed, respectively. There was no association between donor albuminuria and graft failure (hazard ratio 0.91, 95% confidence interval 0.74 to 1.11). There was also no association with delayed graft function, patient survival or eGFR at 1 or 3 years. CONCLUSIONS: Our study suggests reluctance in the UK to utilize kidneys from deceased donors with dipstick albuminuria but no evidence of an association with graft survival or function. This may represent a potential to expand organ utilization without negatively impacting transplant outcomes.

Effect of delayed graft function on longer-term outcomes after kidney transplantation from donation after circulatory death donors in the United Kingdom: A national cohort study.

Kidneys from donation after circulatory death (DCD) donors are utilized variably worldwide, in part due to high rates of delayed graft function (DGF) and putative associations with adverse longer-term outcomes. We aimed to determine whether the presence of DGF and its duration were associated with poor longer-term outcomes after kidney transplantation from DCD donors. Using the UK transplant registry, we identified 4714 kidney-only transplants from controlled DCD donors to adult recipients between 2006 and 2016; 2832 recipients (60·1%) had immediate graft function and 1882 (39·9%) had DGF. Of the 1847 recipients with DGF duration recorded, 926 (50·1%) had DGF < 7 days, 576 (31·2%) had DGF 7-14 days, and 345 (18·7%) had DGF >14 days. After risk adjustment, the presence of DGF was not associated with inferior long-term graft or patient survivals. However, DGF duration of >14 days was associated with an increased risk of death-censored graft failure (hazard ratio 1·7, p = ·001) and recipient death (hazard ratio 1·8, p < ·001) compared to grafts with immediate function. This study suggests that shorter periods of DGF have no adverse influence on graft or patient survival after DCD donor kidney transplantation and that DGF >14 days is a novel early biomarker for significantly worse longer-term outcomes.

The use of third-party packed red blood cells during ex situ normothermic machine perfusion of organs for transplantation: Underappreciated complexities?

Ex situ normothermic machine perfusion (NMP) is being used increasingly in the assessment of higher risk deceased donor organs and to facilitate prolonged organ storage. Third-party packed red blood cells (pRBCs) are often used as an oxygen carrier in the perfusate of ex situ NMP. Despite the increasing interest in NMP, comparatively little attention has been paid to the appropriate selection of pRBCs. This includes the choice of ABO blood group and Rhesus D status, the need for special requirements for selected recipients, and the necessity for traceability of blood components. Flushing organs with cold preservation solution after NMP removes the overwhelming majority of third-party allogeneic pRBCs, but residual pRBCs within the organ may have biologically relevant effects following implantation as they enter the recipient's circulation. This review considers these issues, and suggests that national transplant and blood transfusion agencies work together to develop a co-ordinated approach within each country. This is especially important given the possibility of organ re-allocation between centers after ex situ NMP, and the ongoing development of organ perfusion hubs.

Outcomes after simultaneous pancreas-kidney transplantation from donation after circulatory death donors: A UK registry analysis.

There are concerns that simultaneous pancreas-kidney (SPK) transplants from donation after circulatory death (DCD) donors have a higher risk of graft failure than those from donation after brain death (DBD) donors. A UK registry analysis of SPK transplants between 2005 and 2018 was performed. Pancreas survivals of those receiving organs from DCD or DBD donors were compared. Multivariable analyses were used to adjust for baseline differences between the two groups and to identify factors associated with pancreas graft loss. A total of 2228 SPK transplants were implanted; 403 (18.1%) were from DCD donors. DCD donors were generally younger, slimmer, less likely to have stroke as a cause of death, with lower terminal creatinines and shorter pancreas cold ischemic times than DBD donors. Median (IQR) follow-up was 4.2 (1.6-8.1) years. On univariable analysis, there were no statistically significant differences in 5-year death-censored pancreas graft survival between the two donor types (79.5% versus 80.4%; p = .86). Multivariable analysis showed no statistically significant differences in 5-year pancreas graft loss between transplants from DCD (n = 343) and DBD (n = 1492) donors (hazard ratio 1.26, 95% CI 0.76-1.23; p = .12). The findings from this study support the increased use of SPK transplants from DCD donors.

Outcomes of pregnancy in simultaneous pancreas and kidney transplant recipients: A single-center retrospective study.

Simultaneous pancreas and kidney (SPK) transplantation, in uremic women with insulin-dependent diabetes, increases the chance of a successful pregnancy and minimizes the risk to infants. The aim of this study was to document pregnancy and explore the challenges in this cohort of women. Retrospective analysis of women who underwent pancreas transplantation between January 1, 1998 and 8 January, 2019 was conducted. Seventeen pregnancies were identified in 13 women. Mean transplant-to-pregnancy interval was 4.6 years (range, 1.1-10.2 years). Eleven pregnancies resulted in live birth (65%), and six (35%) ended in miscarriage/fetal loss at a median gestational age of 8.5 weeks. Mean gestational age at delivery was 34.9 weeks (SD ±3 weeks). Preeclampsia and C-section rates were 77% and 67%, respectively. Adverse fetal and graft outcomes were observed in 100% of unplanned pregnancies, compared to 10% of planned pregnancies (P < .001). One kidney allograft was lost during pregnancy; one pancreas and two kidney allografts were lost within 3 years of pregnancy. This is a high-risk group for grafts and offspring. Pre-pregnancy planning is vital. A multidisciplinary approach by obstetric and transplant teams is important pre-pregnancy, antenatally, and peripartum. This is the largest published series of pregnancies in SPK recipients from a single center.

Donor-Transmitted Cancer in Orthotopic Solid Organ Transplant Recipients: A Systematic Review.

Donor-transmitted cancer (DTC) has major implications for the affected patient as well as other recipients of organs from the same donor. Unlike heterotopic transplant recipients, there may be limited treatment options for orthotopic transplant recipients with DTC. We systematically reviewed the evidence on DTC in orthotopic solid organ transplant recipients (SOTRs). We searched MEDLINE, EMBASE, PubMed, Scopus, and Web of Science in January 2020. We included cases where the outcome was reported and excluded donor-derived cancers. We assessed study quality using published checklists. Our domains of interest were presentation, time to diagnosis, cancer extent, management, and survival. There were 73 DTC cases in liver (n = 51), heart (n = 10), lung (n = 10) and multi-organ (n = 2) recipients from 58 publications. Study quality was variable. Median time to diagnosis was 8 months; 42% were widespread at diagnosis. Of 13 cases that underwent re-transplantation, three tumours recurred. Mortality was 75%; median survival 7 months. Survival was worst in transmitted melanoma and central nervous system tumours. The prognosis of DTC in orthotopic SOTRs is poor. Although re-transplantation offers the best chance of cure, some tumours still recur. Publication bias and clinical heterogeneity limit the available evidence. From our findings, we suggest refinements to clinical practice. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020165001, Prospero Registration Number: CRD42020165001.

SARS-CoV-2 infection and early mortality of waitlisted and solid organ transplant recipients in England: A national cohort study.

Patients waitlisted for and recipients of solid organ transplants (SOT) are perceived to have a higher risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and death; however, definitive epidemiological evidence is lacking. In a comprehensive national cohort study enabled by linkage of the UK transplant registry and Public Health England and NHS Digital Tracing services, we examined the incidence of laboratory-confirmed SARS-CoV-2 infection and subsequent mortality in patients on the active waiting list for a deceased donor SOT and recipients with a functioning SOT as of February 1, 2020 with follow-up to May 20, 2020. Univariate and multivariable techniques were used to compare differences between groups and to control for case-mix. One hundred ninety-seven (3.8%) of the 5184 waitlisted patients and 597 (1.3%) of the 46 789 SOT recipients tested positive for SARS-CoV-2. Mortality after testing positive for SARS-CoV-2 was 10.2% (20/197) for waitlisted patients and 25.8% (154/597) for SOT recipients. Increasing recipient age was the only variable independently associated with death after positive SARS-CoV-2 test. Of the 1004 transplants performed in 2020, 41 (4.1%) recipients have tested positive for SARS-CoV-2 with 8 (0.8%) deaths reported by May 20. These data provide evidence to support decisions on the risks and benefits of SOT during the coronavirus disease 2019 pandemic.

Early allograft pancreatectomy-Technical failure or acute pancreatic rejection?

INTRODUCTION: "Technical failure" is still perceived to be a frequent cause of graft loss after pancreas transplantation. However, some early graft losses currently attributed to technical failure could be due to unrecognized acute pancreas rejection (APR). METHODS: We investigated the apparent incidence of APR in cases of early allograft pancreatectomy (EAP) that had previously been attributed to technical failure. We performed an analysis of 198 patients who underwent pancreas transplantation between January 2009 and January 2016 and identified all those with EAP within 90 days of transplantation. Explanted grafts of EAP recipients were re-examined histologically to evaluate for evidence of APR using current Banff criteria. RESULTS: Twenty-three EAPs were identified (11.6%; 23/198). APR was identified histologically in 9 out of the 15 recipients who lost their grafts due to duodenal leaks or recurrent peripancreatic collections, but was not identified in any of the patients whose grafts were lost due to thrombosis or ischemia. INTERPRETATION: Unsuspected APR appears common in the explanted grafts of recipients who have undergone EAP for apparently "technical" reasons. We suggest that EAP should be defined as a technical failure only when APR of the pancreas (or duodenum) has been excluded by histological analysis.

Chronic histological changes in deceased donor kidneys at implantation do not predict graft survival: a single-centre retrospective analysis.

The use of preimplantation kidney biopsies (PIKBs) to aid deceased donor kidney utilization decisions is controversial. Outcomes of transplants that had been biopsied after the decision had been made to implant were analysed, in order to determine the association between chronic histological changes at implantation and graft outcomes. A retrospective analysis of transplants between the year range 2006-2015 was performed. Karpinski scores on biopsies were collected, and graft outcomes were analysed using univariate and multivariable techniques. Also, Karpinski scores from single and dual kidney transplants from older donors were examined to determine if knowledge of the score preoperatively would have altered utilization. Four hundred and eight single kidneys were transplanted. Although kidneys with scores >4 had lower 1- and 3-year median (IQR) estimated glomerular filtration rates (eGFRs) than those scoring 0-4 (51 (37-66) vs. 35 (26-52) ml/min/1.73 m2 , P < 0.001, and 52 (34-64) vs. 35 (24-52) ml/min/1.73 m2 , P < 0.001, respectively), there was no significant association between Karpinski score and death-censored graft survival on univariate or multivariable analyses. The utilization analysis (75 single and 25 dual kidney transplant recipients) suggested that systematic use of PIKBs would have resulted in 29% fewer patients being transplanted. This analysis does not support the systematic use of PIKBs to determine deceased donor kidney utilization.

Utilisation of small paediatric donor kidneys for transplantation.

With the increasing need for kidney transplantation in the paediatric population and changing donor demographics, children without a living donor option will potentially be offered an adult deceased donor transplant of marginal quality. Given the importance of long-term graft survival for paediatric recipients, consideration is now being given to kidneys from small paediatric donors (SPDs). There exist a lack of consensus and a reluctance amongst some centres in transplanting SPDs due to high surgical complication rates, graft loss and concerns regarding low nephron mass and long-term function. The aim of this review is to examine and present the evidence base regarding the transplantation of these organs. The literature in both the paediatric and adult renal transplant fields, as well as recent relevant conference proceedings, is reviewed. We discuss the surgical techniques, long-term graft function and rates of complications following transplantation of SPDs. We compare graft survival of SPDs to adult deceased donors and consider the use of small paediatric donors after circulatory death (DCD) organs. In conclusion, evidence is presented that may refute historically held paradigms regarding the transplantation of SPDs in paediatric recipients, thereby potentially allowing significant expansion of the donor pool.

Dissemination of a novel organ perfusion technique: ex vivo normothermic perfusion of deceased donor kidneys.

Ex vivo normothermic perfusion (EVNP) technology is a promising means of organ preservation, assessment, and preconditioning prior to kidney transplantation, which has been pioneered by a single group. We describe the challenges of setting up clinical EVNP programs in 2 new centers, as well as early patient outcomes. Governance, training, and logistical pathways are described. In order to demonstrate safety and proficiency in this new technique, early patient outcomes are also described. Patient outcomes included the incidence of primary nonfunction, delayed graft function, graft and patient survival at 1 year. Contralateral kidneys undergoing static cold storage alone were used as a comparator group. Between March 2016 and July 2017, EVNP was performed on 14 kidneys from 12 donors (11 kidneys in center 1, 3 kidneys in center 2). Of the 14 kidneys that underwent EVNP, 12 organs were implanted into 10 recipients. Two pairs of kidneys were implanted as dual grafts and 1 kidney was implanted simultaneously with a pancreas. The remaining 7 kidneys were transplanted as single allografts. Seven pairs of kidneys were available for paired analysis comparing EVNP versus static cold storage. Graft and patient outcomes were comparable between the 2 preservation techniques. The introduction of a clinical EVNP service requires a careful multimodal approach, drawing on the expertise of specialists in transplantation, hematology, and microbiology. Both new clinical EVNP programs demonstrated proficiency and safety when a structured dissemination process was followed.

Graft nephrectomy in children.

Kidney transplantation is recognised as the gold standard treatment of end-stage renal disease in most children, with excellent graft survival rates. When graft failure occurs, renal transplant recipients (RTRs) have the option of removal of the transplant (graft nephrectomy [GN]), or leaving the failed transplant in situ. The aims of this review are to discuss the indications for GN, surgical techniques, outcomes after GN (including risks of allosensitisation and the impact on subsequent transplants), and the possible role of routine GN in the asymptomatic RTR with a failed renal allograft. Literature in both the pediatric and adult renal transplant fields is reviewed. We also discuss how future research in this area could advance our knowledge of which patients to select for GN, and the most appropriate surgical approach.

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-2(d) 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-2(d) 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.

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.