Ghrelin, a stomach-derived orexigenic hormone, has stimulated great interest as a potential target for obesity control. Pharmacological evidence indicates that ghrelin’s effects on food intake are ...mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the central nervous system. These include intracerebroventricular application of antibodies to neutralize NPY and AgRP, and the application of an NPY Y1 receptor antagonist, which blocks some of the orexigenic effects of ghrelin. Here we describe treatment of Agrp−/−;Npy−/− and Mc3r−/−;Mc4r−/− double knockout mice as well as Npy−/− and Agrp−/− single knockout mice with either ghrelin or an orally active nonpeptide ghrelin agonist. The data demonstrate that NPY and AgRP are required for the orexigenic effects of ghrelin, as well as the involvement of the melanocortin pathway in ghrelin signaling. Our results outline a functional interaction between the NPY and AgRP pathways. Although deletion of either NPY or AgRP caused only a modest or nondetectable effect, ablation of both ligands completely abolished the orexigenic action of ghrelin. Our results establish an in vivo orexigenic function for NPY and AgRP, mediating the effect of ghrelin.
Vascular renal resistance (RR) during hypothermic machine perfusion (HMP) is frequently used in kidney graft quality assessment. However, the association between RR and outcome has never been ...prospectively validated. Prospectively collected RR values of 302 machine‐perfused deceased donor kidneys of all types (standard and extended criteria donor kidneys and kidneys donated after cardiac death), transplanted without prior knowledge of these RR values, were studied. In this cohort, we determined the association between RR and delayed graft function (DGF) and 1‐year graft survival. The RR (mmHg/mL/min) at the end of HMP was an independent risk factor for DGF (odds ratio 21.12 1.03–435.0; p = 0.048) but the predictive value of RR was low, reflected by a c‐statistic of the receiver operator characteristic curve of 0.58. The RR was also found to be an independent risk factor for 1‐year graft failure (hazard ratio 12.33 1.11–136.85; p = 0.004). Determinants of transplant outcome are multifactorial in nature and this study identifies RR as an additional parameter to take into account when evaluating graft quality and estimating the likelihood of successful outcome. However, RR as a stand‐alone quality assessment tool cannot be used to predict outcome with sufficient precision.
Increased renal resistance during hypothermic machine perfusion of deceased donor kidneys associates with the development of delayed graft function and 1‐year graft survival, but cannot be used exclusively in the process of accepting a kidney graft.
The gap between supply and demand in kidney transplantation has led to increased use of marginal kidneys; however, kidneys with acute kidney injury are often declined/discarded. To determine whether ...this policy is justified, we analyzed outcomes of donor kidneys with acute kidney injury (AKI) in a large UK cohort. A retrospective analysis of the UK Transplant Registry evaluated deceased donors between 2003 and 2013. Donors were classified as no AKI, or AKI stage 1–3 according to Acute Kidney Injury Network (AKIN) criteria. Relationship of AKI with delayed graft function/primary nonfunction (DGF/PNF), estimated glomerular filtration rate (eGFR), and graft‐survival at 90 days and 1 year was analyzed. There were 11 219 kidneys (1869 17% with AKI) included. Graft failure at 1 year is greater for donors with AKI than for those without (graft survival 89% vs. 91%, p = 0.02; odds ratio (OR) 1.20 95% confidence interval (CI): 1.03–1.41). DGF rates increase with donor AKI stage (p < 0.005), and PNF rates are significantly higher for AKIN stage 3 kidneys (9% vs. 4%, p = 0.04) Analysis of association between AKI and recipient eGFR suggests a risk of inferior eGFR with AKI versus no AKI (p < 0.005; OR 1.25 95% CI: 1.08–1.31). We report a small reduction in 1‐year graft‐survival of kidneys from donors with AKI. We conclude that AKI stage 1 or 2 kidneys should be used; however, caution is advised for AKI stage 3 donors.
This analysis of the UK transplant registry investigates the use of kidneys from deceased donors with acute kidney injury and analyzes the outcomes of transplanted kidneys with injury.
The increased demand for organs has led to the increased usage of “higher risk” kidney and liver grafts. These grafts from donation after circulatory death or expanded criteria donors are more ...susceptible to preservation injury and have a higher risk of unfavorable outcomes. Dynamic, instead of static, preservation could allow for organ optimization, offering a platform for viability assessment, active organ repair and resuscitation. Ex situ machine perfusion and in situ regional perfusion in the donor are emerging as potential tools to preserve and resuscitate vulnerable grafts. Preclinical findings have ignited clinical organ preservation research that investigates dynamic preservation, its various modes (continuous, preimplantation) and temperatures (hypo‐, sub, or normothermic). This review outlines the current status of dynamic preservation of kidney and liver grafts and describes ongoing research and emerging clinical trials.
The authors summarize recent advances in the field of dynamic preservation of kidneys and livers, and detail ongoing and upcoming research that will advance the field.
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 pairs were 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 costs were derived from literature. The short‐term evaluation 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.
This economic evaluation alongside a randomized clinical trial of hypothermic machine preservation versus static cold storage in kidney transplantation shows that machine preservation is cost‐effective in terms of one‐year graft survival and long‐term patient survival.
A juvenile grey‐headed flying fox (GHFF) (Pteropus poliocephalus) presented to the Australia Zoo Wildlife Hospital after a wildlife carer found the animal hanging on the outside of an aviary. On ...presentation, the animal was emaciated and moribund with disseminated, multifocal, depigmented and proliferative lesions on the wing membranes and skin of the neck. Histopathology revealed multiple, well‐circumscribed proliferative epidermal lesions with intracytoplasmic inclusion bodies. A poxvirus was identified via transmission electron microscopy and next‐generation sequencing (NGS). Analysis of sequences obtained demonstrated 99% nucleotide identity to Pteropox virus strain Australia (GenBank KU980965). To the authors' knowledge, this paper describes the first case of Pteropox virus infection in a GHFF.
Renal functional reserve could be relevant for the maintenance of renal function after kidney donation. Low‐dose dopamine induces renal vasodilation with a rise in glomerular filtration rate (GFR) in ...healthy subjects and is thought to be a reflection of reserve capacity (RC). Older age and higher body mass index (BMI) may be associated with reduced RC. We therefore investigated RC in 178 consecutive living kidney donors (39% males, age 48 ± 11 years, BMI 25.5 ± 4.1). RC was determined as the rise in GFR (125I‐iothalamate), 4 months before and 2 months after donor nephrectomy. Before donor nephrectomy, GFR was 114 ± 20 mL/min, with a reduction to 72 ± 12 mL/min after donor nephrectomy. The dopamine‐induced rise in GFR of 11 ± 10% was reduced to 5 ± 7% after donor nephrectomy (p < 0.001). Before donor nephrectomy, older age and higher BMI did not affect reserve capacity. After donor nephrectomy, the response of GFR to dopamine independently and negatively correlated with older age and higher BMI. Moreover, postdonation reserve capacity was absent in obese donors. The presence of overweight had more impact on loss of RC in younger donors. In conclusion, donor nephrectomy unmasked an age‐ and overweight‐induced loss of reserve capacity. Younger donors with obesity should be carefully monitored.
This study shows that after living kidney donation, renal reserve capacity ‐ obtained as the rise in GFR on dopamine infusion ‐ was lower in older or overweight donors and even absent in obese donors.
Purpose
Tension-free mesh repair of inguinal hernia has led to uniformly low recurrence rates. Morbidity associated with this operation is mainly related to chronic pain. No consensus guidelines ...exist for the management of this condition. The goal of this study is to design an expert-based algorithm for diagnostic and therapeutic management of chronic inguinal postoperative pain (CPIP).
Methods
A group of surgeons considered experts on inguinal hernia surgery was solicited to develop the algorithm. Consensus regarding each step of an algorithm proposed by the authors was sought by means of the Delphi method leading to a revised expert-based algorithm.
Results
With the input of 28 international experts, an algorithm for a stepwise approach for management of CPIP was created. 26 participants accepted the final algorithm as a consensus model. One participant could not agree with the final concept. One expert did not respond during the final phase.
Conclusion
There is a need for guidelines with regard to management of CPIP. This algorithm can serve as a guide with regard to the diagnosis, management, and treatment of these patients and improve clinical outcomes. If an expectative phase of a few months has passed without any amelioration of CPIP, a multidisciplinary approach is indicated and a pain management team should be consulted. Pharmacologic, behavioral, and interventional modalities including nerve blocks are essential. If conservative measures fail and surgery is considered, triple neurectomy, correction for recurrence with or without neurectomy, and meshoma removal if indicated should be performed. Surgeons less experienced with remedial operations for CPIP should not hesitate to refer their patients to dedicated hernia surgeons.
Hypoxia‐inducible factors are the universal cellular oxygen‐sensitive transcription factors that activate a number of hypoxia responsive genes, some of which are responsible for protective cellular ...functions. During organ donation, allografts are exposed to significant periods of hypoxia and ischemia. Exploiting this pathway during donor management and organ preservation could prevent and reduce allograft injury and improve the outcomes of organ transplantation. We review the evidence on this pathway in organ preservation, drawing on experimental studies on donor management and ischemia reperfusion injury focusing on kidney, liver, cardiac and lung transplantation. We review the major technical and experimental challenges in exploring this pathway and suggest potential future avenues for research.
The authors provide a descriptive review of the current experimental evidence relevant to the role of the Hypoxia Inducible Factor system in organ donation and transplantation.
Kidney transplantation is associated with harmful processes affecting the viability of the graft. One of these processes is associated with the phenomenon of ischaemia–reperfusion injury. Anaesthetic ...conditioning is a widely described strategy to attenuate ischaemia–reperfusion injury. We therefore conducted the Volatile Anaesthetic Protection of Renal Transplants-1 trial, a pilot project evaluating the influence of two anaesthetic regimens, propofol- vs sevoflurane-based anaesthesia, on biochemical and clinical outcomes in living donor kidney transplantation.
Sixty couples were randomly assigned to the following three groups: PROP (donor and recipient propofol), SEVO (donor and recipient sevoflurane), and PROSE (donor propofol and recipient sevoflurane). The primary outcome was renal injury reflected by urinary biomarkers. The follow-up period was 2 yr.
Three couples were excluded, leaving 57 couples for analysis. Concentrations of kidney injury molecule-1 (KIM-1), N-acetyl-β-d-glucosaminidase (NAG), and heart-type fatty acid binding protein (H-FABP) in the first urine upon reperfusion showed no differences. On day 2, KIM-1 concentrations were higher in SEVO 952.8 (interquartile range 311.8–1893.0) pg mmol−1 compared with PROP 301.2 (202.0–504.7) pg mmol−1. This was the same for NAG: SEVO, 1.835 (1.162–2.457) IU mmol−1vs PROP, 1.078 (0.819–1.713) IU mmol−1. Concentrations of H-FABP showed no differences. Measured glomerular filtration rate at 3, 6, and 12 months showed no difference. After 2 yr, there was a difference in the acute rejection rate (P=0.039). Post hoc testing revealed a difference between PROP (35%) and PROSE (5%; P=0.020). The difference between PROP and SEVO (11%) was not significant (P=0.110).
The SEVO group showed higher urinary KIM-1 and NAG concentrations in living donor kidney transplantation on the second day after transplantation. This was not reflected in inferior graft outcome.
NCT01248871.
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