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The Nuffield Department of Surgical Sciences is the academic department of surgery at the University of Oxford, and hosts a multidisciplinary team of senior clinical academic surgeons, senior scientists, junior clinicians and scientists in training.
A nationwide evaluation of deceased donor kidney transplantation indicates detrimental consequences of early graft loss.
Early graft loss (EGL) is a feared outcome of kidney transplantation. Consequently, kidneys with an anticipated risk of EGL are declined for transplantation. In the most favorable scenario, with optimal use of available donor kidneys, the donor pool size is balanced by the risk of EGL, with a tradeoff dictated by the consequences of EGL. To gauge the consequence of EGL we systematically evaluated its impact in an observational study that included all 10,307 deceased-donor kidney transplantations performed in The Netherlands between 1990 and 2018. Incidence of EGL, defined as graft loss within 90 days, in primary transplantation was 8.2% (699/8,511). The main causes were graft rejection (30%), primary nonfunction (25%), and thrombosis or infarction (20%). EGL profoundly impacted short- and long-term patient survival (adjusted hazard ratio; 95% confidence interval: 8.2; 5.1-13.2 and 1.7; 1.3-2.1, respectively). Of the EGL recipients who survived 90 days after transplantation (617/699) only 440 of the 617 were relisted for re-transplantation. Of those relisted, only 298 were ultimately re-transplanted leading to an actual re-transplantation rate of 43%. Noticeably, re-transplantation was associated with a doubled incidence of EGL, but similar long-term graft survival (adjusted hazard ratio 1.1; 0.6-1.8). Thus, EGL after kidney transplantation is a medical catastrophe with high mortality rates, low relisting rates, and increased risk of recurrent EGL following re-transplantation. This implies that detrimental outcomes also involve convergence of risk factors in recipients with EGL. The 8.2% incidence of EGL minimally impacted population mortality, indicating this incidence is acceptable.
SARS-CoV-2 RNA detected in blood products from patients with COVID-19 is not associated with infectious virus.
Background: Laboratory diagnosis of SARS-CoV-2 infection (the cause of COVID-19) uses PCR to detect viral RNA (vRNA) in respiratory samples. SARS-CoV-2 RNA has also been detected in other sample types, but there is limited understanding of the clinical or laboratory significance of its detection in blood. Methods: We undertook a systematic literature review to assimilate the evidence for the frequency of vRNA in blood, and to identify associated clinical characteristics. We performed RT-PCR in serum samples from a UK clinical cohort of acute and convalescent COVID-19 cases (n=212), together with convalescent plasma samples collected by NHS Blood and Transplant (NHSBT) (n=462 additional samples). To determine whether PCR-positive blood samples could pose an infection risk, we attempted virus isolation from a subset of RNA-positive samples. Results: We identified 28 relevant studies, reporting SARS-CoV-2 RNA in 0-76% of blood samples; pooled estimate 10% (95%CI 5-18%). Among serum samples from our clinical cohort, 27/212 (12.7%) had SARS-CoV-2 RNA detected by RT-PCR. RNA detection occurred in samples up to day 20 post symptom onset, and was associated with more severe disease (multivariable odds ratio 7.5). Across all samples collected ≥28 days post symptom onset, 0/494 (0%, 95%CI 0-0.7%) had vRNA detected. Among our PCR-positive samples, cycle threshold (ct) values were high (range 33.5-44.8), suggesting low vRNA copy numbers. PCR-positive sera inoculated into cell culture did not produce any cytopathic effect or yield an increase in detectable SARS-CoV-2 RNA. There was a relationship between RT-PCR negativity and the presence of total SARS-CoV-2 antibody (p=0.02). Conclusions: vRNA was detectable at low viral loads in a minority of serum samples collected in acute infection, but was not associated with infectious SARS-CoV-2 (within the limitations of the assays used). This work helps to inform biosafety precautions for handling blood products from patients with current or previous COVID-19.
OUTCOMES OF PATIENTS SUSPENDED FROM THE NATIONAL KIDNEY TRANSPLANT WAITING LIST IN THE UNITED KINGDOM BETWEEN 2000 AND 2010.
BACKGROUND: In the UK, 1 in 3 patients on the National Kidney Transplant Waiting List (NKTWL) are suspended from the list at least once during their wait. The mortality of this large cohort of patients remains underreported and poorly described. METHODS: We linked patient records from the UK Transplant Registry to mortality data from the Office of National Statistics and evaluated the impact of a clinically induced suspension event by estimating hazard ratios (HR) that compared mortality and graft survival between those who had experienced a suspension event and those who had not. RESULTS: Between Jan 1, 2000, and Dec 31, 2010, 16.7% (2221/13 322) of all patients registered on the NKTWL were suspended. 48.0% (588/1225) of those who were suspended and who were never transplanted died, most often from cardiothoracic causes. A suspension event was associated with increased mortality from the time of listing (aHR: 1·79, 1·64-1·95) and from the time of transplantation (aHR: 1·20, 1.06-1.37, p=0005). Graft survival was also poorer in those who had been suspended (aHR: 1·13, 1·01-1·28, p=0·04). CONCLUSIONS: Patients suspended on the NKTWL have a significantly higher rate of mortality both on the waiting list and following transplantation. Earlier prioritisation of patients at risk of experiencing a suspension event may improve their outcomes.
Ischemia and Reperfusion Injury in Kidney Transplantation: Relevant Mechanisms in Injury and Repair.
Ischemia and reperfusion injury (IRI) is a complex pathophysiological phenomenon, inevitable in kidney transplantation and one of the most important mechanisms for non- or delayed function immediately after transplantation. Long term, it is associated with acute rejection and chronic graft dysfunction due to interstitial fibrosis and tubular atrophy. Recently, more insight has been gained in the underlying molecular pathways and signalling cascades involved, which opens the door to new therapeutic opportunities aiming to reduce IRI and improve graft survival. This review systemically discusses the specific molecular pathways involved in the pathophysiology of IRI and highlights new therapeutic strategies targeting these pathways.
Physical diagnostics - Measuring muscle strength
Measuring muscle strength and establishing paretic symptoms are done first of all by having the patient perform actions or movements that require normal muscle strength. Measuring or grading the strength of separate muscle groups is usually done by means of the socalled Medical Research Council (MRC) scale that runs from 0 to 5, with the movement against gravity as an important criterion. This scale is not very valid in tract 4 (more strength than needed to overcome gravity, but still subnormal). Using a manual dynamometer or a fixed dynamometer it is possible to measure the strength of most clinically important muscle groups of the extremities and to compare them with values found in a normal population. For following the individual patient with a neuromuscular disorder, strength measurement with the dynamometer is more reliable than grading using the MRC scale.
Subclinical effects of remote ischaemic conditioning in human kidney transplants revealed by quantitative proteomics.
BACKGROUND: Remote ischaemic conditioning (RIC) is currently being explored as a non-invasive method to attenuate ischaemia/reperfusion injuries in organs. A randomised clinical study (CONTEXT) evaluated the effects of RIC compared to non-RIC controls in human kidney transplants. METHODS: RIC was induced prior to kidney reperfusion by episodes of obstruction to arterial flow in the leg opposite the transplant using a tourniquet (4 × 5 min). Although RIC did not lead to clinical improvement of transplant outcomes, we explored whether RIC induced molecular changes through precision analysis of CONTEXT recipient plasma and kidney tissue samples by high-resolution tandem mass spectrometry (MS/MS). RESULTS: We observed an accumulation of muscle derived proteins and altered amino acid metabolism in kidney tissue proteomes, likely provoked by RIC, which was not reflected in plasma. In addition, MS/MS analysis demonstrated transient upregulation of several acute phase response proteins (SAA1, SAA2, CRP) in plasma, 1 and 5 days post-transplant in RIC and non-RIC conditions with a variable effect on the magnitude of acute inflammation. CONCLUSIONS: Together, our results indicate sub-clinical systemic and organ-localised effects of RIC.
Urine recirculation prolongs normothermic kidney perfusion via more optimal metabolic homeostasis-a proteomics study.
We describe a proteomics analysis to determine the molecular differences between normothermically perfused (normothermic machine perfusion, NMP) human kidneys with urine recirculation (URC) and urine replacement (UR). Proteins were extracted from 16 kidney biopsies with URC (n = 8 donors after brain death [DBD], n = 8 donors after circulatory death [DCD]) and three with UR (n = 2 DBD, n = 1 DCD), followed by quantitative analysis by mass spectrometry. Damage-associated molecular patterns (DAMPs) were decreased in kidney tissue after 6 hours NMP with URC, suggesting reduced inflammation. Vasoconstriction was also attenuated in kidneys with URC as angiotensinogen levels were reduced. Strikingly, kidneys became metabolically active during NMP, which could be enhanced and prolonged by URC. For instance, mitochondrial succinate dehydrogenase enzyme levels as well as carbonic anhydrase were enhanced with URC, contributing to pH stabilization. Levels of cytosolic and the mitochondrial phosphoenolpyruvate carboxykinase were elevated after 24 hours of NMP, more prevalent in DCD than DBD tissue. Key enzymes involved in glucose metabolism were also increased after 12 and 24 hours of NMP with URC, including mitochondrial malate dehydrogenase and glutamic-oxaloacetic transaminase, predominantly in DCD tissue. We conclude that NMP with URC permits prolonged preservation and revitalizes metabolism to possibly better cope with ischemia reperfusion injury in discarded kidneys.
Treating Ischemically Damaged Porcine Kidneys with Human Bone Marrow- and Adipose Tissue-Derived Mesenchymal Stromal Cells During Ex Vivo Normothermic Machine Perfusion.
Pretransplant normothermic machine perfusion (NMP) of donor kidneys offers the unique opportunity to perform active interventions to an isolated renal graft before transplantation. There is increasing evidence that mesenchymal stromal cells (MSCs) could have a paracrine/endocrine regenerative effect on ischemia-reperfusion injury. The purpose of this study was to determine which cytokines are secreted by MSCs during NMP of a porcine kidney. Viable porcine kidneys and autologous whole blood were obtained from a slaughterhouse. Warm ischemia time was standardized at 20 min and subsequent hypothermic machine perfusion was performed during 2-3 h. Thereafter, kidneys were machine perfused at 37°C during 7 h. After 1 h of NMP, 0, 107 cultured human adipose tissue-derived MSCs, or 107 cultured bone marrow-derived MSCs were added (n = 5 per group). In a fourth experimental group, 7-h NMP was performed with 107 adipose tissue-derived MSCs, without a kidney in the circuit. Kidneys perfused with MSCs showed lower lactate dehydrogenase and neutrophil gelatinase-associated lipocalin levels in comparison with the control group. Also, elevated levels of human hepatocyte growth factor, interleukin (IL)-6, and IL-8 were found in the perfusate of the groups perfused with MSCs compared to the control groups. This study suggests that MSCs, in contact with an injured kidney during NMP, could lead to lower levels of injury markers and induce the release of immunomodulatory cytokines.
The C-seal trial: colorectal anastomosis protected by a biodegradable drain fixed to the anastomosis by a circular stapler, a multi-center randomized controlled trial.
BACKGROUND: Anastomotic leakage is a major complication in colorectal surgery and with an incidence of 11% the most common cause of morbidity and mortality. In order to reduce the incidence of anastomotic leakage the C-seal is developed. This intraluminal biodegradable drain is stapled to the anastomosis with a circular stapler and prevents extravasation of intracolonic content in case of an anastomotic dehiscence.The aim of this study is to evaluate the efficacy of the C-seal in reducing anastomotic leakage in stapled colorectal anastomoses, as assessed by anastomotic leakage leading to invasive treatment within 30 days postoperative. METHODS: The C-seal trial is a prospective multi-center randomized controlled trial with primary endpoint, anastomotic leakage leading to re-intervention within 30 days after operation. In this trial 616 patients will be randomized to the C-seal or control group (1:1), stratified by center, anastomotic height (proximal or distal of peritoneal reflection) and the intention to create a temporary deviating ostomy. Interim analyses are planned after 50% and 75% of patient inclusion. Eligible patients are at least 18 years of age, have any colorectal disease requiring a colorectal anastomosis to be made with a circular stapler in an elective setting, with an ASA-classification < 4. Oral mechanical bowel preparation is mandatory and patients with signs of peritonitis are excluded. The C-seal student team will perform the randomization procedure, supports the operating surgeon during the C-seal application and achieves the monitoring of the trial. Patients are followed for one year after randomization en will be analyzed on an intention to treat basis. DISCUSSION: This Randomized Clinical trial is designed to evaluate the effectiveness of the C-seal in preventing clinical anastomotic leakage.
Machine perfusion versus cold storage for the preservation of kidneys from donors ≥ 65 years allocated in the Eurotransplant Senior Programme.
BACKGROUND: In the Eurotransplant Senior Programme (ESP), kidneys from donors aged ≥ 65 years are preferentially allocated locally and transplanted into patients aged ≥ 65 years on dialysis. The purpose of this study was to analyse whether the results of transplantation in the ESP can be improved by preservation of organs by hypothermic machine perfusion (MP) compared with simple cold storage (CS). METHODS: Overall, 85 deceased heart-beating donors ≥ 65 years of age were included in this analysis with follow-up until 1 year post-transplant. For each donor, one kidney was randomly assigned to preservation by CS and the contralateral kidney to MP from organ procurement until transplantation. Delayed graft function (DGF), primary non-function (PNF) and 1-year patient and graft survival rates were evaluated as primary and secondary endpoints. RESULTS: The median recipient age was 66 years in both groups and the median cold ischaemia time was 11 h for MP and 10.5 h for CS (P = 0.69). The DGF rate was 29.4% for MP and 34.1% for CS (P = 0.58). Only extended duration of cold ischaemia time was an independent risk factor for the development of DGF (odds ratio 1.2, P < 0.0001). PNF was significantly reduced (3.5% MP versus 12.9% CS, P = 0.02). The 1-year patient and graft survival rates were similar for MP and CS (94% versus 95% and 89 versus 81%, P > 0.05). The 1-year graft survival rate was significantly improved after MP in recipients who developed DGF (84% MP versus 48% CS, P = 0.01). CONCLUSIONS: Continuous pulsatile hypothermic MP for kidneys from donors aged ≥ 65 years can reduce the rate of never-functioning kidneys and improve the 1-year graft survival rate of kidneys with DGF. In this small cohort, the known advantage of MP for the reduction of DGF could not be confirmed, possibly due to relatively short cold ischaemia times.
The role of personal characteristics in the relationship between health and psychological distress among kidney transplant recipients
Although kidney transplantation improves overall quality of life and physical functioning, improvements of psychological distress are often modest. However, apparent stressors such as comorbidity are only weakly associated with psychological distress and their impact differs considerably between patients. Wilson and Cleary proposed a theoretical model to explain these relationships. This model has been supported by research, but has never been applied in a population of kidney transplant recipients. Findings of the current study are based on a cross-sectional study carried out in 2008 in the northern Netherlands. An elaborated version of Wilson and Cleary's model specifying hypothesized relationships of objective health, functional status, subjective health, personal characteristics and psychological distress was evaluated with structural equation modelling. After elimination of non-significant paths the final model provided a good fit for the data, X2 (2)=4.23, p=0.12; RMSEA=0.047, CIRMSEA (0; 0.11); ECVI=0.060, ECVIsat=0.059. Results suggest that objective health has an indirect effect on psychological distress, in size comparable to the effects exerted by functional status and subjective health. Personal characteristics are the strongest determinant of psychological distress, but are directly and indirectly affected by objective health. Results indicate that poor health might cause psychological distress by increasing coping demands while simultaneously decreasing coping resources. © 2012 Elsevier Ltd.
Cost-effectiveness of hypothermic machine preservation versus static cold storage in renal transplantation
Static cold storage (CS) is the most widely used organ preservation method for deceased donor kidney grafts but there is increasing evidence that hypothermic machine perfusion (MP) may result in better outcome after transplantation. We performed an economic evaluation of MP versus CS alongside a multicenter RCT investigating short- and long-term cost-effectiveness. Three hundred thirty-six consecutive kidney pairswere included, one of which was assigned to MP and one to CS. The economic evaluation combined the short-term results based on the empirical data from the study with a Markov model with a 10-year time horizon. Direct medical costs of hospital stay, dialysis treatment, and complications were included. Data regarding long-term survival, quality of life, and long-term costswere derived from literature. The short-termevaluation showed that MP reduced the risk of delayed graft function and graft failure at lower costs than CS. The Markov model revealed cost savings of $86 750 per life-year gained in favor of MP. The corresponding incremental cost-utility ratio was minus $496 223 per quality-adjusted life-year (QALY) gained. We conclude that life-years and QALYs can be gained while reducing costs at the same time, when kidneys are preserved by MP instead of CS. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.
Prevention of postoperative recurrence of Crohn's disease
Background: Up to 75% of patients with Crohn's disease (CD) will have intestinal resection during their life. Most patients will, however, develop postoperative recurrence (endoscopic, clinical or surgical). Several medical and surgical strategies have been attempted to prevent postoperative recurrence. This review evaluates the efficacy of different drug regimens and surgical techniques in the prevention of clinical, endoscopic and surgical postoperative recurrence of CD. Methods: A literature search for randomized controlled trials on medical or surgical interventions was performed. The endpoints for efficacy were clinical, endoscopic and surgical recurrence. Meta-analyses were performed in case two or more RCTs evaluated the same drug or surgical technique. Results: Mesalamine is more effective in preventing clinical recurrence than placebo (P. =. 0,012), as well as nitroimidazolic antibiotics at one year follow-up (P.
Lipid peroxidation products in machine perfusion of older donor kidneys.
BACKGROUND: Owing to the shortage of donors, organs with an increased risk potential such as grafts recovered from expanded criteria donors are increasingly being used in transplants. Machine perfusion (MP) technology offers the possibility of determining the biomarkers in the perfusion solution so that conclusions might be drawn regarding the effectiveness of organ preservation and organ viability. METHODS: All kidneys from the MP arm of our multicenter, randomized, controlled trial of MP whose donors were aged 55 years or older were included in the present study. The biomarkers, total glutathione-S-transferase (GST), α-GST, and π-GST and markers for lipid peroxidation and cell decay were determined in the MP perfusate and correlated with the outcomes after kidney transplantation. RESULTS: A total of 111 machine perfused kidneys were included in the present study. The mean donor age was 64.1 ± 6.6 y. The average cold ischemic time was 13.8 ± 5.3 h. Total GST, α-GST, and lipid peroxidation markers were significantly elevated at the end of MP. However, according to the multivariate analysis, only the lipid peroxidation markers were independent predictors of delayed graft function after transplantation. CONCLUSIONS: Our data suggest that routine determination of lipid peroxidation markers in the perfusate of expanded criteria donor kidneys can provide the opportunity to identify the kidneys that have sustained severe oxidative damage and should be excluded from transplantation. Additional analysis of a larger cohort with more primary nonfunction cases is needed to confirm these findings.
Effects of preexistent hypertension on blood pressure and residual renal function after donor nephrectomy
Background.: Living kidney donor selection has become more liberal with acceptation of hypertensive donors. Here, we evaluate short-term and 1-and 5-year renal outcome of living kidney donors with preexistent hypertension. Methods.: We compared outcome of hypertensive donors by gender, age, and body mass index with matched control donors. Hypertension was defined as predonation antihypertensive drug use. All donors had glomerular filtration rate ( 125I-iothalamate) and effective renal plasma flow ( 131I-hippuran) measured 4 months before and 2 months after donation. A subset of donors had serum creatinine measured 1 year after donation or a renal function measurement 5 years after donation. Results.: Included were 47 hypertensive donors and 94 control donors (both 53% male; mean age, 57±7 years; and body mass index, 28±4 kg/m 2). Pre-and early postdonation, systolic blood pressure, and mean arterial pressure were significantly higher in hypertensive donors. Control donors showed a rise in diastolic blood pressure after donation, and thus the predonation difference was lost postdonation. Both at 1 year (29 hypertensive donors, 58 controls) and 5 years after donation (13 hypertensive donors and 26 controls) blood pressure was similar. Renal function was similar at all time points. Discussion.: In summary, hypertensive living kidney donors have similar outcome in terms of blood pressure and renal function as control donors, early and 1 and 5 years after donation. © 2012 by Lippincott Williams & Wilkins.
[C-seal for prevention of anastomotic leakage following colorectal anastomosis].
The C-seal is a new product for prevention of anastomotic leakage following colorectal anastomosis. Anastomotic leakage is a much-feared complication of colorectal surgery, with an incidence of around 11%. The C-seal is a biodegradable sheath that is attached to the inner surface of the bowel, just above the colorectal anastomosis, with a circular stapler. Intestinal contents drain from the body via the C-seal. The C-seal can be used in stapled anastomoses at up to 15 cm from the anus and is compatible with all circular staplers. To date, 50 patients have been treated with a C-seal. Results are encouraging and therefore the C-seal is soon to be investigated under randomized study conditions.