Normothermic machine perfusion for the assessment and transplantation of declined human kidneys from donation after circulatory death donors.

BACKGROUND: A significant proportion of donation after circulatory death (DCD) kidneys are declined for transplantation because of concerns over their quality. Ex vivo normothermic machine perfusion (NMP) provides a unique opportunity to assess the quality of a kidney and determine its suitability for transplantation. METHODS: In phase 1 of this study, declined human DCD kidneys underwent NMP assessment for 60 min. Kidneys were graded 1-5 using a quality assessment score (QAS) based on macroscopic perfusion, renal blood flow and urine output during NMP. In phase 2 of the study, declined DCD kidneys were assessed by NMP with an intention to transplant them. RESULTS: In phase 1, 18 of 42 DCD kidneys were declined owing to poor in situ perfusion. After NMP, 28 kidneys had a QAS of 1-3, and were considered suitable for transplantation. In phase 2, ten of 55 declined DCD kidneys underwent assessment by NMP. Eight kidneys had been declined because of poor in situ flushing in the donor and five of these were transplanted successfully. Four of the five kidneys had initial graft function. CONCLUSION: NMP technology can be used to increase the number of DCD kidney transplants by assessing their quality before transplantation.

Incidental lymphadenopathy in renal transplantation.

INTRODUCTION: Iliac lymphadenectomy is performed to provide anastomotic access during the vascular implantation procedure in renal transplantation. Iliac lymph nodes (LNs) are often enlarged, but there are no standardised guidelines for the management of incidentally enlarged LNs during transplantation. We aimed to evaluate histological findings of LNs sent for examination at our unit. METHODS: Patients were evaluated in two distinct date cycles. In the first cycle, lymphadenectomy and histological assessment were performed at the discretion of the transplanting surgeon. In the second cycle, all incidentally enlarged LNs were sent for histological assessment, regardless of size. RESULTS: In the first cycle (n = 76), 11 patients (14.47%) had incidentally enlarged iliac LNs on lymphadenectomy and histology showed only reactive changes. In the second cycle (n = 165), eight patients (4.85%) had incidentally enlarged LNs on lymphadenectomy. One patient was found to have mature B cell chronic lymphocytic leukaemia. The patient was referred to haematology and a "watch and wait" approach was taken, with the patient still alive at last follow-up (511 days post-transplantation). DISCUSSION: There are currently no published guidelines on the management of incidentally enlarged iliac LNs during transplantation. Current literature suggests that clinically significant lymphadenopathy needs to be investigated in all patients. Based on our centre's experience of a 5.26% (1 in 19) positive pathological LN sampling, we recommend that all incidental LNs with suspicious features and/or that are greater than 10mm in diameter should be considered for histological, microbiological and molecular assessment as appropriate.

A national survey on enhanced recovery for renal transplant recipients: current practices and trends in the UK.

INTRODUCTION: Enhanced recovery after surgery (ERAS) is well established in many specialties but has not been widely adopted in renal transplantation. The aim of this survey was to understand current national practices and sentiment concerning ERAS for renal transplant recipients in the UK. METHODOLOGY: A national web-based survey was sent to consultant surgeons at all 23 UK adult renal transplant units. Completed questionnaires were collected between May and July 2020. Data were analysed according to individual responses and grouped according to the existence of formal ERAS pathways within units. RESULTS: All transplant units were represented in this survey. Three units had a formal ERAS pathway for all recipients. Of the remaining units, 65.9% considered implementing an ERAS pathway in the near future. The most commonly perceived barrier to ERAS implementation was 'embedded culture within transplant units' (54.8% of respondents). A fifth of respondents insert surgical drains selectively and 11.7% routinely discontinue patient-controlled analgesia on postoperative day 1. Most respondents routinely remove urinary catheters on day 5 (70%) and ureteric stents 4-6 weeks post-transplantation (81.7%). Median length of stay for deceased donor kidney transplant recipients was lower in units with ERAS programmes (5-7 days versus 8-10 days, respectively). The main cited barriers for discharge were 'suboptimal fluid balance' and 'requirement of treatment for rejection'. CONCLUSIONS: Despite slow uptake of ERAS in kidney transplantation, appetite appears to be increasing, particularly in the post-COVID-19 era. The current practice and opinions of transplant specialists highlighted in this survey may help to establish nationally agreed ERAS guidelines in this field.

Risk factors and impact of early anastomotic biliary complications after liver transplantation: UK registry analysis.

BACKGROUND: Biliary leaks and anastomotic strictures are common early anastomotic biliary complications (EABCs) following liver transplantation. However, there are no large multicentre studies investigating their clinical impact or risk factors. This study aimed to define the incidence, risk factors and impact of EABC. METHODS: The NHS registry on adult liver transplantation between 2006 and 2017 was reviewed retrospectively. Adjusted regression models were used to assess predictors of EABC, and their impact on outcomes. RESULTS: Analyses included 8304 liver transplant recipients. Patients with EABC (9·6 per cent) had prolonged hospitalization (23 versus 15 days; P < 0·001) and increased chance for readmission within the first year (56 versus 32 per cent; P < 0·001). Patients with EABC had decreased estimated 5-year graft survival of 75·1 versus 84·5 per cent in those without EABC, and decreased 5-year patient survival of 76·9 versus 83·3 per cent; both P < 0.001. Adjusted Cox regression revealed that EABCs have a significant and independent impact on graft survival (leak hazard ratio (HR) 1·344, P = 0·015; stricture HR 1·513, P = 0·002; leak plus stricture HR 1·526, P = 0·036) and patient survival (leak HR 1·215, P = 0·136, stricture HR 1·526, P = 0·001; leak plus stricture HR 1·509; P = 0·043). On adjusted logistic regression, risk factors for EABC included donation after circulatory death grafts, graft aberrant arterial anatomy, biliary anastomosis type, vascular anastomosis time and recipient model of end-stage liver disease. CONCLUSION: EABCs prolong hospital stay, increase readmission rates and are independent risk factors for graft loss and increased mortality. This study has identified factors that increase the likelihood of EABC occurrence; research into interventions to prevent EABCs in these at-risk groups is vital to improve liver transplantation outcomes.

Liver transplantation for unresectable malignancies: Beyond hepatocellular carcinoma.

Indications for liver transplantation have expanded over the past few decades owing to improved outcomes and better understanding of underlying pathologies. In particular, there has been a growing interest in the field of transplant oncology in recent years that has led to considerable developments which have pushed the boundaries of malignant indications for liver transplantation beyond hepatocellular carcinoma (HCC). In this article, we review and summarise the published evidence for liver transplantation in non-HCC primary and metastatic liver malignancies and highlight ongoing clinical trials that address unresolved questions therein. We also examine the current technical, immunological and oncological challenges that face liver transplantation in this growing field and explore potential approaches to overcome these barriers.

Donor risk factors for renal graft thrombosis.

Graft thrombosis is one of the most devastating complications of transplantation. In obtaining consent prior to transplant, it is useful to share potential risk factors with the recipient. In order to do this, we explored the impact of different risk factors that could contribute to this complication. Using multivariate analysis we found that neither multiple vessels nor vascular injury had a bearing on the risk of graft thrombosis but atheroma did (P < .02).

Comparison of HTK and hypertonic citrate to intraarterial cooling in human non-heart-beating kidney donors.

Intraarterial cooling (IAC) of non-heart-beating donors (NHBD) for renal donation requires a cheap, low-viscosity solution. HTK contains a high hydrogen ion buffer level that theoretically should reduce the observable acidosis associated with ongoing anaerobic metabolism. A retrospective comparison of all retrieved NHBD kidneys as well as of viability on the Organ Recovery Systems Lifeporter machine perfusion circuit was performed with respect to the preservation solution HTK or Marshall's HOC. Forty-two NHBD kidneys (19 HTK and 23 HOC) were machine perfused between February 2004 and May 2005. Most of the HTK kidneys were obtained from uncontrolled donors (12 vs 5; Fisher exact test, P = .01). As a consequence, the glutathione-s-transferase viability assay (411 vs 292 IU/L, P = .12) and the lactate concentrations (2.33 vs 1.94 mmol/L, P = .13) were higher among the HTK cohort. There was evidence of greater buffering capacity in HTK, since the lactate:hydrogen ion ratios were consistently lower during the first 2 perfusion hours (1 hour P = .03, 2 hour P = .02). A linear regression analysis confirmed that this was related to the IAC solution (ANCOVA, P < .001). All controlled donor kidneys passed viability testing and were transplanted. In contrast, 83% (10/12) of the uncontrolled donor kidneys preserved with HTK passed the viability test and were transplanted, compared with only 20% (1/5) of the HOC-treated comparators (Fisher exact test, P = .03). It may be concluded that the postulated advantages of improved pH buffering with HTK appear to have clinical relevance.

Preservation solutions for solid organ transplantation.

Solid organ transplantation was one of the greatest medical advances of the 20th century. Current preservation technology falls short of maintaining organs ex vivo in perpetuity. This review examines the biochemical basis of organ degradation in response to ischaemia, preservation solution composition and potential future organ preservation technology.

Non-heart-beating kidney transplantation: 6-year outcomes.

Non-heart-beating donor kidneys (NHBD) are being used to increase the donor pool due to the scarcity of cadaveric heart beating donors (HBD). We evaluated the long-term outcomes of renal transplantation using NHBD kidneys, comparing the first 100 NHBD kidneys transplanted at our facility to the next consecutive cadaveric HBD kidneys for graft survival, recipient survival, and quality of graft function. Recipient survival (P = .22) and graft survival (P = .19) at 6 years did not differ between recipients of NHBD (83%, 80%) and HBD (89%, 87%) kidneys. Quality of graft function using the mean glomular filtration rates were significantly lower in the NHBD group up to 3 months following discharge (41 +/- 2 vs 47 +/- 2, P = .007) but were then comparable up to 6 years following transplantation (43 +/- 5 vs 46 +/- 4, P = .55).

Caspase-2 deficiency accelerates chemically induced liver cancer in mice.

Aberrant cell death/survival has a critical role in the development of hepatocellular carcinoma (HCC). Caspase-2, a cell death protease, limits oxidative stress and chromosomal instability. To study its role in reactive oxygen species (ROS) and DNA damage-induced liver cancer, we assessed diethylnitrosamine (DEN)-mediated tumour development in caspase-2-deficient (Casp2(-/-)) mice. Following DEN injection in young animals, tumour development was monitored for 10 months. We found that DEN-treated Casp2(-/-) mice have dramatically elevated tumour burden and accelerated tumour progression with increased incidence of HCC, accompanied by higher oxidative damage and inflammation. Furthermore, following acute DEN injection, liver injury, DNA damage, inflammatory cytokine release and hepatocyte proliferation were enhanced in mice lacking caspase-2. Our study demonstrates for the first time that caspase-2 limits the progression of tumourigenesis induced by an ROS producing and DNA damaging reagent. Our findings suggest that after initial DEN-induced DNA damage, caspase-2 may remove aberrant cells to limit liver damage and disease progression. We propose that Casp2(-/-) mice, which are more susceptible to genomic instability, are limited in their ability to respond to DNA damage and thus carry more damaged cells resulting in accelerated tumourigenesis.

Sex-specific alterations in glucose homeostasis and metabolic parameters during ageing of caspase-2-deficient mice.

Gender-specific differences are commonly found in metabolic pathways and in response to nutritional manipulation. Previously, we identified a role for caspase-2 in age-related glucose homeostasis and lipid metabolism using male caspase-2-deficient (Casp2 (-/-) ) mice. Here we show that the resistance to age-induced glucose tolerance does not occur in female Casp2 (-/-) mice and it appears to be independent of insulin sensitivity in males. Using fasting (18 h) as a means to further investigate the role of caspase-2 in energy and lipid metabolism, we identified sex-specific differences in the fasting response and lipid mobilization. In aged (18-22 months) male Casp2 (-/-) mice, a significant decrease in fasting liver mass, but not total body weight, was observed while in females, total body weight, but not liver mass, was reduced when compared with wild-type (WT) animals. Fasting-induced lipolysis of adipose tissue was enhanced in male Casp2 (-/-) mice as indicated by a significant reduction in white adipocyte cell size, and increased serum-free fatty acids. In females, white adipocyte cell size was significantly smaller in both fed and fasted Casp2 (-/-) mice. No difference in fasting-induced hepatosteatosis was observed in the absence of caspase-2. Further analysis of white adipose tissue (WAT) indicated that female Casp2 (-/-) mice may have enhanced fatty acid recycling and metabolism with expression of genes involved in glyceroneogenesis and fatty acid oxidation increased. Loss of Casp2 also increased fasting-induced autophagy in both male and female liver and in female skeletal muscle. Our observations suggest that caspase-2 can regulate glucose homeostasis and lipid metabolism in a tissue and sex-specific manner.

Routine intraoperative ureteric stenting for kidney transplant recipients.

BACKGROUND: Major urological complications (MUCs) after kidney transplantation contribute to patient morbidity and compromise graft function. The majority arise from the vesico-ureteric anastomosis and present early after transplantation. Ureteric stents have been successfully used to treat such complications. A number of centres have adopted a policy of universal prophylactic stenting, at the time of graft implantation, to reduce the incidence of urine leaks and ureteric stenosis. Stents are associated with specific complications and some centres advocate a policy of only stenting selected anastomoses. OBJECTIVES: To examine the benefits and harms of routine ureteric stenting to prevent urological complications in kidney transplant recipients. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL in The Cochrane Library), MEDLINE, EMBASE, reference lists of articles, books and abstracts and contacted companies, authors and experts to identify relevant randomised controlled trials (RCTs). SELECTION CRITERIA: All RCTs and quasi-RCTs were included in our meta-analysis. DATA COLLECTION AND ANALYSIS: Four reviewers assessed the trials for quality against four criteria (allocation concealment, blinding, intention-to-treat and completeness of follow-up). The primary outcome was the incidence of MUCs. Further outcomes of interest were graft and patient survival and the incidence of adverse events (urinary tract infection (UTI), haematuria, irritative symptoms, pain and stent migration). Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) with 95% confidence intervals (CI). MAIN RESULTS: Seven RCTs (1154 patients) of low or moderate quality were identified. The incidence of MUCs was significantly reduced (RR 0.24, 95% CI 0.07 to 0.77, P = 0.02, NNT 13) by universal prophylactic stenting. This was dependent on whether the same surgeon performed, or was in attendance, during the operations. Two patients lost their grafts to infective urinary tract complications in the stented group. UTIs, in general, were more common in stented patients (RR 1.49, 95% CI 1.04 to 2.15) unless the patients were prescribed cotrimoxazole 480 mg/d: in which case the incidence was equivalent (RR 0.97, 95% CI 0.71 to 1.33). Stents appeared generally well tolerated, although trials using longer stents (>/= 20 cm) for longer periods (> 6 weeks) had more problems with encrustation and migration. AUTHORS' CONCLUSIONS: Routine prophylactic stenting reduces the incidence of MUCs. Trials comparing selective stenting and universal prophylactic stenting, whilst difficult to design and analyse, would address the unresolved quality of life and economic issues.

Caspase-2 protects against oxidative stress in vivo.

Caspase-2 belongs to the caspase family of cysteine proteases with established roles in apoptosis. Recently, caspase-2 has been implicated in nonapoptotic functions including maintenance of genomic stability and tumor suppression. Our previous studies demonstrated that caspase-2 also regulates cellular redox status and delays the onset of several ageing-related traits. In the current study, we tested stress tolerance ability in caspase-2-deficient (Casp2(-/-)) mice by challenging both young and old mice with a low dose of the potent reactive oxygen species (ROS) generator, PQ that primarily affects lungs. In both groups of mice, PQ induced pulmonary damage. However, the lesions in caspase-2 knockout mice were consistently and reproducibly more severe than those in wild-type (WT) mice. Furthermore, serum interleukin (IL)-1ß and IL-6 levels were higher in PQ-exposed aged Casp2(-/-) mice indicating increased inflammation. Interestingly, livers from Casp2(-/-) mice displayed karyomegaly, a feature commonly associated with ageing and aneuploidy. Given that Casp2(-/-) mice show impaired antioxidant defense, we tested oxidative damage in these mice. Protein oxidation significantly increased in PQ-injected old Casp2(-/-) mice. Moreover, FoxO1, SOD2 and Nrf2 expression levels were reduced and induction of superoxide dismutase (SOD) and glutathione peroxidase activity was not observed in PQ-treated Casp2(-/-) mice. Strong c-Jun amino-terminal kinase (JNK) activation was observed in Casp2(-/-) mice, indicative of increased stress. Together, our data strongly suggest that caspase-2 deficiency leads to increased cellular stress largely because these mice fail to respond to oxidative stress by upregulating their antioxidant defense mechanism. This makes the mice more vulnerable to exogenous challenges and may partly explain the shorter lifespan of Casp2(-/-) mice.

Age-related proteostasis and metabolic alterations in Caspase-2-deficient mice.

Ageing is a complex biological process for which underlying biochemical changes are still largely unknown. We performed comparative profiling of the cellular proteome and metabolome to understand the molecular basis of ageing in Caspase-2-deficient (Casp2(-/-)) mice that are a model of premature ageing in the absence of overt disease. Age-related changes were determined in the liver and serum of young (6-9 week) and aged (18-24 month) wild-type and Casp2(-/-) mice. We identified perturbed metabolic pathways, decreased levels of ribosomal and respiratory complex proteins and altered mitochondrial function that contribute to premature ageing in the Casp2(-/-) mice. We show that the metabolic profile changes in the young Casp2(-/-) mice resemble those found in aged wild-type mice. Intriguingly, aged Casp2(-/-) mice were found to have reduced blood glucose and improved glucose tolerance. These results demonstrate an important role for caspase-2 in regulating proteome and metabolome remodelling during ageing.

Meningitis associated with tuberculous arthritis of the knee.

This case report describes two uncommon manifestations of tuberculosis, meningitis and arthritis, occurring in a patient without pulmonary disease. Difficulties in diagnosis and results of treatment are discussed.

The subxiphoid approach to pericardial disease.

During the 36-month period from July, 1978, through July, 1981, 25 patients underwent a subxiphoid pericardial window procedure for diagnosis and therapy. Twelve patients were operated on for uremic pericarditis, 6 for malignancy, and 7 for etiological diagnosis of the pericarditis. All 12 patients with renal failure had enlarging effusions, despite aggressive dialysis. Eleven of the 12 are alive, free from recurrence, 3 to 36 months postoperatively. Six patients were operated on for suspected pericardial malignancy with hemodynamic compromise. Histological diagnosis was made from the pericardial tissue in all patients; only 1 patient lived more than 43 days following the procedure. In the group of 7 patients operated on for diagnosis, 4 were thought preoperatively to have tuberculous pericarditis. All 4 were treated with anti-tuberculosis chemotherapy and are asymptomatic, without evidence of calcification, 12 to 31 months postoperatively. This diverse group of patients demonstrates that the subxiphoid pericardial window is an effective approach for relief of uremic effusions and may adequately treat effusive tuberculous pericarditis when combined with multidrug chemotherapy. Patients with suspected malignant pericardial disease and hemodynamic compromise need to be carefully studied before an operative procedure is considered as a means of diagnosis and therapy.

Establishing the right of the terminally ill to adequate palliative care: the litigation alternative.

The Bazelon Center For Mental Health Law in Washington, D.C., has undertaken a palliative care project to examine how litigation might be used to secure the rights of terminally ill patients to receive adequate palliative care, including the medications necessary to relieve the pain that often accompanies a final illness. One area of inquiry is the Medicare Hospice Benefit and the requirement that, to qualify for the benefit, a patient must have a prognosis of 6 months or less to live. A second major area of inquiry is regulatory restrictions on the prescription of opioids for pain relief of terminally ill patients and whether those restrictions improperly impede the physicians in their ability to engage in effective and appropriate pain management.

Extra-anatomical approach to the congenital subclavian steal syndrome.

A young female with cerebral and left arm symptoms from the congenital subclavian steal syndrome is presented. Surgical correction was performed using an axillary-axillary bypass. Pre-operative noninvasive vascular evaluation demonstrated reversal of flow in the left carotid artery which was corrected postoperatively. There was complete relief of symptoms and equal upper extremity blood pressure. This report represents the first instance in which this extremely rare congenital disorder was fully evaluated with noninvasive vascular techniques, and the first to be treated with an extra-anatomical surgical approach.

Prospective randomised trial of the use of Daclizumab in renal transplantation using kidneys from non heart beating donors.

OBJECTIVES: Transplantation using non-heart beating donors (NHBD) is one way of reducing the global kidney shortage. Unfortunately the large warm ischaemic insult sustained by the graft leads to a high rate of delayed graft function (DGF). We have investigated the use of a regimen utilising an II-2r blocker (DZB) in place of Tacrolimus for the initial post-operative immunosupression with the aim of reducing the incidence of DGF. METHODS: Prospective randomised controlled trial based in two NHBD UK centres (Leicester and Newcastle). 51 patients were enrolled over two years and randomised into two treatment arms: 1. DZB/MMF/Steroids (Tacrolimus started when creatinine dropped below 350 micromol/l) 2. Tacro/MMF/Steroids. RESULTS: There was one death, during the study period, in a patient who had had a non-functioning graft removed. The overall incidence of immediate function (IF) was higher than expected (28%), no significant difference was found in the incidence of immediate graft function between the two groups (35% group 1 and 22% group 2). Sub-group analysis however has shown a significant advantage for the delayed introduction of Tacrolimus for machine perfused grafts (IF: 53% vs 13%, chi2 p=0.015). There was no difference in the rate of rejection. CONCLUSIONS: The delayed introduction of Tacrolimus reduces the incidence of DGF in machine-perfused NHBD kidney transplantation.