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.

The UK kidney donor risk index poorly predicts long-term transplant survival in paediatric kidney transplant recipients.

Background: The UK kidney offering scheme introduced a kidney donor risk index (UK-KDRI) to improve the utility of deceased-donor kidney allocations. The UK-KDRI was derived using adult donor and recipient data. We assessed this in a paediatric cohort from the UK transplant registry. Methods: We performed Cox survival analysis on first kidney-only deceased brain-dead transplants in paediatric (<18 years) recipients from 2000-2014. The primary outcome was death-censored allograft survival >30 days post-transplant. The main study variable was UK-KDRI derived from seven donor risk-factors, categorised into four groups (D1-low risk, D2, D3 and D4-highest risk). Follow-up ended on 31-December-2021. Results: 319/908 patients experienced transplant loss with rejection as the main cause (55%). The majority of paediatric patients received donors from D1 donors (64%). There was an increase in D2-4 donors during the study period, whilst the level of HLA mismatching improved. The KDRI was not associated with allograft failure. In multi-variate analysis, increasing recipient age [adjusted HR and 95%CI: 1.05(1.03-1.08) per-year, p<0.001], recipient minority ethnic group [1.28(1.01-1.63), p<0.05), dialysis before transplant [1.38(1.04-1.81), p<0.005], donor height [0.99 (0.98-1.00) per centimetre, p<0.05] and level of HLA mismatch [Level 3: 1.92(1.19-3.11); Level 4: 2.40(1.26-4.58) versus Level 1, p<0.01] were associated with worse outcomes. Patients with Level 1 and 2 HLA mismatches (0 DR +0/1 B mismatch) had median graft survival >17 years regardless of UK-KDRI groups. Increasing donor age was marginally associated with worse allograft survival [1.01 (1.00-1.01) per year, p=0.05]. Summary: Adult donor risk scores were not associated with long-term allograft survival in paediatric patients. The level of HLA mismatch had the most profound effect on survival. Risk models based on adult data alone may not have the same validity for paediatric patients and therefore all age-groups should be included in future risk prediction models.

Youngest pancreas transplantation alone in the UK for type 1 diabetes and severe subcutaneous insulin resistance.

A child diagnosed with type 1 diabetes mellitus during her middle childhood developed severe subcutaneous insulin resistance as her illness progressed. This resulted in recurrent episodes of diabetic ketoacidosis and hypoglycaemia, eventually leading to intravenous insulin dependence. Despite intensive investigations, an organic cause was not found.The patient was in her late adolescence when she eventually received her pancreas transplant alone, the youngest patient in the UK. This case highlights severe peripheral insulin resistance as an important indication for whole organ pancreas transplantation in the paediatric population, as well as early recognition in the failure of conventional medical therapy.

Evidence for Roux-en-Y Pancreatic Duct Drainage Versus Standard Anastomosis in Pancreatic Transplantation.

OBJECTIVES: Pancreatic transplantation is usually performed simultaneously with renal transplantation in the setting of end-stage nephropathy and type 1 diabetes. Surgical methods for dealing with exocrine secretions include bladder drainage, direct duodenojejunostomy and Roux-en-Y (ReY) enteric drainage. Roux-en-Y may confer an advantage over duodenojejunostomy because it distances enteric content from the transplant duodenal anastomosis. We examined the effect of enteric drainage method on transplant outcomes. METHODS: Data were obtained from the UK transplant registry on 2172 consecutive pancreatic transplants. Early graft loss was the primary endpoint. Secondary endpoints included return to theater, length of inpatient stay, readmission with pancreatitis, graft survival, and patient survival. RESULTS: There was no protective effect of ReY drainage (early graft loss, 4.6% vs 3.1%, P = 0.30; hazard ratio, 0.98; 95% confidence interval, 0.63-1.52; P = 0.91). There was a significant association between ReY and return to theater, reflecting either the technique or indication for ReY (multivariate odds ratio, 2.05; 95% confidence interval, 1.38-3.06; P < 0.01). The effect of transplant center on graft survival was assessed and adjusted for. CONCLUSIONS: There was no evidence of a protective benefit of ReY drainage over duodenojejunostomy, but there was an increased risk of return to theater.

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.

Ex vivo delivery of Mirococept: A dose-finding study in pig kidney after showing a low dose is insufficient to reduce delayed graft function in human kidney.

The complement system plays a pivotal role in the pathogenesis of ischemia-reperfusion injury in solid organ transplantation. Mirococept is a potent membrane-localizing complement inhibitor that can be administered ex vivo to the donor kidney prior to transplantation. To evaluate the efficacy of Mirococept in reducing delayed graft function (DGF) in deceased donor renal transplantation, we undertook the efficacy of mirococept (APT070) for preventing ischaemia-reperfusion injury in the kidney allograft (EMPIRIKAL) trial (ISRCTN49958194). A dose range of 5-25 mg would be tested, starting with 10 mg in cohort 1. No significant difference between Mirococept at 10 mg and control was detected; hence the study was stopped to enable a further dose saturation study in a porcine kidney model. The optimal dose of Mirococept in pig kidney was 80 mg. This dose did not induce any additional histological damage compared to controls or after a subsequent 3 hours of normothermic machine perfusion. The amount of unbound Mirococept postperfusion was found to be within the systemic dose range considered safe in the Phase I trial. The ex vivo administration of Mirococept is a safe and feasible approach to treat DGF in deceased donor kidney transplantation. The porcine kidney study identified an optimal dose of 80 mg (equivalent to 120 mg in human kidney) that provides a basis for further clinical development.

Biological Mesh Repair of a Large Incisional Hernia Containing a Kidney Transplant in the Presence of Inflammation.

The incidence of incisional hernia after kidney transplantation varies between 1.1% and 3.8%. These are usually repaired electively using polypropylene mesh. We present here a case where a patient presented as an emergency, with a large painful incisional hernia over his kidney transplant, and evidence of local erythema and systemic inflammation. As this could have represented either infection or rejection, the patient was started on antibiotics and subsequently underwent graft nephrectomy and hernia repair using a biological (porcine-derived) acellular dermal matrix, Strattice™, with a satisfactory outcome. In addition, histology showed evidence of allograft rejection. This is the first reported case of an incisional hernia containing a rejecting kidney allograft, managed with nephrectomy and biological mesh repair.

Spinal Cord Ischemia in Pancreas Transplantation: The UK Experience.

BACKGROUND: Spinal cord ischemia (SCI) is a rare but devastating condition that can occur in the perioperative period resulting in paraplegia. Although diabetes mellitus is a risk factor for SCI in other types of major surgery, SCI is not widely recognized in transplantation. The aim of this study was to quantify the risk of SCI in pancreatic transplantation. METHODS: All UK pancreas transplant units were surveyed between 2017 and 2018. The risk of SCI in pancreas transplantation was estimated using the number of radiologically confirmed cases relative to the number of pancreatic transplants from UK registry data during the same time period. RESULTS: There have been 6 cases of SCI during pancreas transplantation since 2002. No aortic clamping occurred in any recipient. During or after surgery, all patients experienced episodes of hypotension (systolic blood pressure ≤ 90 mm Hg) before the onset of neurological symptoms. Epoprostenol, epidural anesthesia, and postoperative hemodialysis may have contributed to systemic hypotension. The mainstay of early treatment for SCI for all cases was blood pressure control. CONCLUSIONS: Based on these findings, there is approximately a 1:440 risk of SCI in pancreas transplantation. Hypotension appears to be a prominent risk factor. Strategies for mitigating the risk of SCI are discussed, drawing on evidence from thoraco-abdominal aortic aneurysm surgery. The risk of long-term neurological deficit should be discussed with prospective pancreas recipients given the potential impact on posttransplant quality of life.

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.

First UK case report of kidney transplantation from an HIV-infected deceased donor to two HIV-infected recipients.

Kidney transplantation is now considered the treatment of choice for many human immunodeficiency virus (HIV)-infected patients with end-stage renal disease (ESRD). Graft survival rates using HIV-negative donors and carefully selected HIV-positive ESRD patients are similar to those observed in HIV-uninfected kidney transplant recipients. To address the relative shortfall in donated organs it has been proposed that organs from HIV-infected deceased donors might be allocated to HIV-infected patients on the transplant waiting list. Preliminary experience in South Africa reports promising short-term outcomes in a small number of HIV-infected recipients of kidney transplants from HIV-infected donors. We sought to replicate this experience in the UK by accepting kidney offers from HIV infected deceased donors for patients with HIV-infection on the kidney transplant waiting list. Here we report the UK's first cases of kidney transplantation between HIV-positive donors and recipients.

A double-blind randomised controlled investigation into the efficacy of Mirococept (APT070) for preventing ischaemia reperfusion injury in the kidney allograft (EMPIRIKAL): study protocol for a randomised controlled trial.

BACKGROUND: Delayed graft function (DGF) is traditionally defined as the requirement for dialysis during the first week after transplantation. DGF is a common complication of renal transplantation, and it negatively affects short- and long-term graft outcomes. Ischaemia reperfusion injury (IRI) is a prime contributor to the development of DGF. It is well established that complement system activation plays a pivotal role in the pathogenesis of IRI. Mirococept is a highly effective complement inhibitor that can be administered ex vivo to the donor kidney just before transplantation. Preclinical and clinical evidence suggests that Mirococept inhibits inflammatory responses that follow IRI. The EMPIRIKAL trial (REC 12/LO/1334) aims to evaluate the efficacy of Mirococept in reducing the incidence of DGF in cadaveric renal transplantation. METHODS/DESIGN: EMPIRIKAL is a multicentre double-blind randomised case-control trial designed to test the superiority of Mirococept in the prevention of DGF in cadaveric renal allografts, as compared to standard cold perfusion fluid (Soltran®). Patients will be randomised to Mirococept or placebo (Pbo) and will be enrolled in cohorts of N = 80 with a maximum number of 7 cohorts. The first cohort will be randomised to 10 mg of Mirococept or Pbo. After the completion of each cohort, an interim analysis will be carried out in order to evaluate the dose allocation for the next cohort (possible doses: 5-25 mg). Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. The enrolment will take approximately 24 months, and patients will be followed for 12 months. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Secondary endpoints include duration of DGF, functional DGF, renal function at 12 months, acute rejection episodes at 6 and 12 months, primary non-function and time of hospital stay on first admission and in the first year following transplant. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events. DISCUSSION: The EMPIRIKAL trial is the first study to evaluate the efficacy of an ex vivo administered complement inhibitor (Mirococept) in preventing DGF in cadaveric human renal transplantation. Mirococept has a unique 'cytotopic' property that permits its retention in the organ microvasculature. TRIAL REGISTRATION: ISRCTN registry, ISRCTN49958194 . Registered on 3 August 2012.

Insights in Transplanting Complex Pediatric Renal Recipients With Vascular Anomalies.

BACKGROUND: Children with end-stage kidney disease may have coexisting iatrogenic or congenital vascular anomalies making transplantation difficult. We describe our approach in 5 recipients with vascular anomalies and significant comorbidities, including one case of blood group incompatibility. METHODS: Five children aged 3 to 17 years (median, 7 years), weighing 14 to 34 kg (median, 18 kg) kg of whom 4 had occluded inferior vena cava or iliac veins and 2 had previous complex vascular reconstructions before transplantation for midaortic syndrome and multiple aortic aneurysms, respectively underwent renal transplantation. To establish implant feasibility surgery was commenced in 2 recipients before the donor surgery. RESULTS: There was 4 (80%) of 5 patient survival after 1 death from sepsis (with a functioning graft) and 2 cases of delayed graft function. At the latest median follow-up of 19 months, there was 100% (death-censored) renal allograft survival with estimated glomerular filtration rates (mL/min per 1.73 m) of 43 to 72 (median, 55). CONCLUSIONS: We conclude that major vascular anomalies do not necessarily preclude transplantation in complex pediatric patients and that surgical exploration of the recipient before commencing the donor surgery is valuable where feasibility and safety are uncertain. In addition, we have developed a novel classification system of congenital vascular abnormalities and propose its use in complex pediatric transplantation.

Desensitization protocol enabling pediatric crossmatch-positive renal transplantation: successful HLA-antibody-incompatible renal transplantation of two highly sensitized children.

BACKGROUND: Renal transplantation improves quality of life (QoL) and survival in children requiring renal replacement therapy (RRT). Sensitization with development of a broad-spectrum of anti-HLA antibodies as a result of previous transplantation or after receiving blood products is an increasing problem. There are no published reports of desensitization protocols in children allowing renal transplantation from HLA-antibody-incompatible living donors. METHODS: We adopted our well-established adult desensitization protocol for this purpose and undertook HLA antibody-incompatible living donor renal transplants in two children: a 14-year-old girl and a 13-year-old boy. RESULTS: After 2 and 1.5 years of follow-up, respectively, both patients have stable renal allograft function despite a rise in donor-specific antibodies in one case. CONCLUSIONS: HLA-incompatible transplantation should be considered in selected cases for sensitized children.

A Re-evaluation of Discarded Deceased Donor Kidneys in the UK: Are Usable Organs Still Being Discarded?

BACKGROUND: A significant proportion of procured deceased donor kidneys are subsequently discarded. The UK Kidney Fast-Track Scheme (KFTS) was introduced in 2012, enabling kidneys at risk of discard to be simultaneously offered to participating centers. We undertook an analysis of discarded kidneys to determine if unnecessary organ discard was still occurring since the KFTS was introduced. METHODS: Between April and June 2015, senior surgeons independently inspected 31 consecutive discarded kidneys from throughout the United Kingdom. All kidneys were biopsied. Organs were categorized as usable, possibly usable pending histology, or not usable for implantation. After histology reports were available, final assessments of usability were made. RESULTS: There were 19 donors (6 donations after brain death, 13 donations after circulatory death), with a median (range) donor age of 67 (29-83) years and Kidney Donor Profile Index of 93 (19-100). Reasons for discard were variable. Only 3 discarded kidneys had not entered the KFTS. After initial assessment postdiscard, 11 kidneys were assessed as usable, with 9 kidneys thought to be possibly usable. Consideration of histological data reduced the number of kidneys thought usable to 10 (10/31; 32%). CONCLUSIONS: The KFTS scheme is successfully identifying organs at high risk of discard, though potentially transplantable organs are still being discarded. Analyses of discarded organs are essential to identify barriers to organ utilization and develop strategies to reduce unnecessary discard.

High alcohol intake in deceased donors has no effect on pancreas graft survival: a registry analysis.

Outcomes of pancreas transplantation from donors with high alcohol consumption are poorly described. The UK Transplant Registry was used to determine whether donor alcohol intake influenced pancreas survival in simultaneous pancreas-kidney (SPK) transplants performed between 2006 and 2012 (n = 770). Recipients were stratified by donor alcohol intake: group I (n = 122)-high recent alcohol intake (>21 or >14 units of alcohol/week in males or females, respectively) or previous alcohol abuse and group II (n = 648)-low/unknown current intake and no previous alcohol abuse. Median current alcohol intake was higher in group I than group II: 36.3 vs. 10 units/week; P < 0.001. One- and five-year pancreas graft survivals were 88.5% and 73.6% in group I, and 87% and 74.9% in group II. There was no difference in unadjusted graft survival between groups I and II (P = 0.76), and no difference between group II and a subgroup of group I with a donor history of alcohol abuse and high current intake (P = 0.26), or from donors with current alcohol consumption of >50 units/week (P = 0.41). Pancreas donors with past alcohol abuse or current high intake are common, and graft outcomes appear to be acceptable. This analysis suggests that high donor alcohol intake, by itself, should not exclude consideration of pancreas transplantation.

Management of Abdomino-scrotal hydrocele (ASH)/Scrotal-inguino-retroperitoneal (SIR) hydrocele in a renal transplant patient.

Abdomino-scrotal hydrocele (ASH) is a very rare clinical entity. It is an unusual condition, in which there is an hourglass communication between a large hydrocele and the retroperitoneal space, through the inguinal canal. First described by Dupuytren in 1834 and defined by Bickle in 1919, the condition is rarely seen. Surgical management usually involves excision of the sac as the definitive treatment option. The pathogenesis of ASH remains unclear and numerous theories have been postulated. We favour the term scrotal-inguino-retroperitoneal (SIR) hydrocele as a more accurate description. The paper presents a unique case of a 24-year-old gentleman, with a functioning kidney transplant, who developed a large ASH/SIR hydrocele that required a midline laparotomy to fenestrate the sac.

First case of pancreas transplant alone in a patient with diabetes and HIV infection.

Chronic conditions have largely replaced opportunistic infections as the leading causes of mortality in human immunodeficiency virus (HIV) infection. Pancreas transplantation alone can be performed for people with difficult to manage diabetes associated with severe hypoglycaemic unawareness. For carefully selected patients, pancreas transplantation alone has the potential to dramatically improve quality and quantity of life. Historically, HIV was considered a contraindication to transplantation; however, today renal transplantation for people with end-stage kidney disease and HIV infection is increasingly common. We describe the use of a standard immunosuppression regimen in combination with effective antiretroviral control using a stable highly active antiretroviral therapy regimen with minimal interaction with immunosuppressants. We describe what is, to our knowledge, the first case of pancreas transplantation alone performed for this particularly challenging group, resulting in complete resolution of hypoglycaemic symptoms. We suggest that this group of patients should receive optimal diabetes management, including access to transplantation where appropriate, and demonstrate that pancreas transplantation alone is feasible for people with HIV infection.

A longitudinal interpretative phenomenological analysis of the process of kidney recipients' resolution of complex ambiguities within relationships with their living donors.

Much previous research into living kidney donation has focused on the decision-making of the donor, despite evidence suggesting this may be a more psychologically challenging time for the recipient. This longitudinal study explores the experiences of four recipients of kidneys from living donors throughout the transplant process. Transcripts were analysed using interpretative phenomenological analysis. Three themes arose from the data, which were as follows: changing perceptions of relationships with kidney donors; upbeat, temporal strategies for remaining positive and journey of the self. Findings from the first theme are presented in detail here. It was found that each participants' relationship with their donor grew and developed in different ways, presenting their own complex challenges in terms of developing relationships and ambiguity around the decision to use the chosen donor.

Do we need a different organ allocation system for kidney transplants using donors after circulatory death?

BACKGROUND: There is no national policy for allocation of kidneys from Donation after circulatory death (DCD) donors in the UK. Allocation is geographical and based on individual/regional centre policies. We have evaluated the short term outcomes of paired kidneys from DCD donors subject to this allocation policy. METHODS: Retrospective analysis of paired renal transplants from DCD's from 2002 to 2010 in London. Cold ischemia time (CIT), recipient risk factors, delayed graft function (DGF), 3 and 12 month creatinine) were compared. RESULTS: Complete data was available on 129 paired kidneys.115 pairs were transplanted in the same centre and 14 pairs transplanted in different centres. There was a significant increase in CIT in kidneys transplanted second when both kidneys were accepted by the same centre (15.5 ± 4.1 vs 20.5 ± 5.8 hrs p<0.0001 and at different centres (15.8 ± 5.3 vs. 25.2 ± 5.5 hrs p=0.0008). DGF rates were increased in the second implant following sequential transplantation (p=0.05). CONCLUSIONS: Paired study sequential transplantation of kidneys from DCD donors results in a significant increase in CIT for the second kidney, with an increased risk of DGF. Sequential transplantation from a DCD donor should be avoided either by the availability of resources to undertake simultaneous procedures or the allocation of kidneys to 2 separate centres.