Stem cells to modulate IR: a regenerative medicine-based approach to organ preservation

Purpose of Review: Solid organ transplantation is limited by lack of suitable donor organs. Older and comorbid organs are frequently discarded on the basis that they will not withstand the overall process—principally the degree of ischemia reperfusion injury associated with preservation and transplantation. Interventions to prevent injury and promote regeneration are badly needed. Recent stem cells of multiple types including mesenchymal stem cells (MSCs) and adipose-derived regenerative cells (ADRCs) have been demonstrated to protect against tissue injury in multiple models relevant to transplantation. Recent Findings: Recent studies have improved our understanding of the multiple mechanisms underlying these beneficial effects including immunomodulatory and anti-inflammatory actions. Evidence suggests extracellular vesicular transfer of therapeutic factors, such as Sox9, cytokines, IL-17A, CCR2, and S1P has a key role in these effects. Summary: Several novel approaches such as stress treatments, culture techniques, and exogenous chemical manipulation show significant promise in improving the efficacy of stem cell populations in preventing tissue injury. There is even the possibility to harness the body’s own sources of such cells through interventions such as point-of-care fat modulation or mobilization of endogenous bone marrow-derived cells. The many unanswered questions and barriers to translating this promising technology to clinical transplantation are discussed

Perfusate composition and duration of ex-vivo normothermic perfusion in kidney transplantation: a systematic review

Ex-vivo normothermic perfusion (EVNP) is an emerging strategy in kidney preservation that enables resuscitation and viability assessment under pseudo-physiological conditions prior to transplantation. The optimal perfusate composition and duration, however, remain undefined. A systematic literature search (Embase; Medline; Scopus; and BIOSIS Previews) was conducted. We identified 1,811 unique articles dating from January 1956 to July 2021, from which 24 studies were deemed eligible for qualitative analysis. The perfusate commonly used in clinical practice consisted of leukocyte-depleted, packed red blood cells suspended in Ringer’s lactate solution with Mannitol, dexamethasone, heparin, sodium bicarbonate and a specific nutrient solution supplemented with insulin, glucose, multivitamins and vasodilators. There is increasing support in preclinical studies for non-blood cell-based perfusates, including Steen solution, synthetic haem-based oxygen carriers and acellular perfusates with supraphysiological carbogen mixtures that support adequate oxygenation whilst also enabling gradual rewarming. Extended durations of perfusion (up to 24 h) were also feasible in animal models. Direct comparison between studies was not possible due to study heterogeneity. Current evidence demonstrates safety with the aforementioned widely used protocol, however, extracellular base solutions with adequate oxygenation, supplemented with nutrient and metabolic substrates, show promise by providing a suitable environment for prolonged preservation and resuscitation. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021231381, identifier PROSPERO 2021 CRD4202123138

Pre-transplant CDKN2A expression in kidney biopsies predicts renal function and is a future component of donor scoring criteria

CDKN2A is a proven and validated biomarker of ageing which acts as an off switch for cell proliferation. We have demonstrated previously that CDKN2A is the most robust and the strongest pre-transplant predictor of post- transplant serum creatinine when compared to “Gold Standard” clinical factors, such as cold ischaemic time and donor chronological age. This report shows that CDKN2A is better than telomere length, the most celebrated biomarker of ageing, as a predictor of post-transplant renal function. It also shows that CDKN2A is as strong a determinant of post-transplant organ function when compared to extended criteria (ECD) kidneys. A multivariate analysis model was able to predict up to 27.1% of eGFR at one year post-transplant (p = 0.008). Significantly, CDKN2A was also able to strongly predict delayed graft function. A pre-transplant donor risk classification system based on CDKN2A and ECD criteria is shown to be feasible and commendable for implementation in the near future

Disentangling water, ion and polymer dynamics in an anion exchange membrane

Semipermeable polymeric anion exchange membranes are essential for separation, filtration and energy conversion technologies including reverse electrodialysis systems that produce energy from salinity gradients, fuel cells to generate electrical power from the electrochemical reaction between hydrogen and oxygen, and water electrolyser systems that provide H2 fuel. Anion exchange membrane fuel cells and anion exchange membrane water electrolysers rely on the membrane to transport OH− ions between the cathode and anode in a process that involves cooperative interactions with H2O molecules and polymer dynamics. Understanding and controlling the interactions between the relaxation and diffusional processes pose a main scientific and critical membrane design challenge. Here quasi-elastic neutron scattering is applied over a wide range of timescales (100–103 ps) to disentangle the water, polymer relaxation and OH− diffusional dynamics in commercially available anion exchange membranes (Fumatech FAD-55) designed for selective anion transport across different technology platforms, using the concept of serial decoupling of relaxation and diffusional processes to analyse the data. Preliminary data are also reported for a laboratory-prepared anion exchange membrane especially designed for fuel cell applications

Impact of intrapatient variability (IPV) in tacrolimus trough levels on long-term renal transplant function: multicentre collaborative retrospective cohort study protocol

Introduction: High intrapatient variability (IPV) in tacrolimus trough levels has been shown to be associated with higher rates of renal transplant failure. There is no consensus on what level of IPV constitutes a risk of graft loss. The establishment of such a threshold could help to guide clinicians in identifying at-risk patients to receive targeted interventions to improve IPV and thus outcomes. Methods and analysis: A multicentre Transplant Audit Collaborative has been established to conduct a retrospective study examining tacrolimus IPV and renal transplant outcomes. Patients in receipt of a renal transplant at participating centres between 2009 and 2014 and fulfilling the inclusion criteria will be included in the study. The aim is to recruit a minimum of 1600 patients with follow-up spanning at least 2 years in order to determine a threshold IPV above which a renal transplant recipient would be considered at increased risk of graft loss. The study also aims to determine any national or regional trends in IPV and any demographic associations. Ethics and dissemination: Consent will not be sought from patients whose data are used in this study as no additional procedures or information will be required from participants beyond that which would normally take place as part of clinical care. The study will be registered locally in each participating centre in line with local research and development protocols. It is anticipated that the results of this audit will be disseminated locally, in participating NHS Trusts, through national and international meetings and publications in peer-reviewed journals

Deleterious effects of phosphate on vascular and endothelial function via disruption to the nitric oxide pathway

Background: Hyperphosphataemia is an independent risk factor for accelerated cardiovascular disease in chronic kidney disease (CKD), although the mechanism for this is poorly understood. We investigated the effects of sustained exposure to a high-phosphate environment on endothelial function in cellular and preclinical models, as well as in human subjects. Methods: Resistance vessels from rats and humans (± CKD) were incubated in a normal (1.18 mM) or high (2.5 mM) phosphate concentration solution and cells were cultured in normal- (0.5 mM) or high-phosphate (3 mM) concentration media. A single-blind crossover study was performed in healthy volunteers, receiving phosphate supplements or a phosphate binder (lanthanum), and endothelial function measured was by flow-mediated dilatation. Results: Endothelium-dependent vasodilatation was impaired when resistance vessels were exposed to high phosphate; this could be reversed in the presence of a phosphodiesterase-5-inhibitor. Vessels from patients with CKD relaxed normally when incubated in normal-phosphate conditions, suggesting that the detrimental effects of phosphate may be reversible. Exposure to high-phosphate disrupted the whole nitric oxide pathway with reduced nitric oxide and cyclic guanosine monophosphate production and total and phospho endothelial nitric oxide synthase expression. In humans, endothelial function was reduced by chronic phosphate loading independent of serum phosphate, but was associated with higher urinary phosphate excretion and serum fibroblast growth factor 23. Conclusions: These directly detrimental effects of phosphate, independent of other factors in the uraemic environment, may explain the increased cardiovascular risk associated with phosphate in CKD

Anaesthesia Choice for Creation of Arteriovenous Fistula (ACCess) study protocol : a randomised controlled trial comparing primary unassisted patency at 1 year of primary arteriovenous fistulae created under regional compared to local anaesthesia.

INTRODUCTION: Arteriovenous fistulae (AVF) are the 'gold standard' vascular access for haemodialysis. Universal usage is limited, however, by a high early failure rate. Several small, single-centre studies have demonstrated better early patency rates for AVF created under regional anaesthesia (RA) compared with local anaesthesia (LA). The mechanistic hypothesis is that the sympathetic blockade associated with RA causes vasodilatation and increased blood flow through the new AVF. Despite this, considerable variation in practice exists in the UK. A high-quality, adequately powered, multicentre randomised controlled trial (RCT) is required to definitively inform practice. METHODS AND ANALYSIS: The Anaesthesia Choice for Creation of Arteriovenous Fistula (ACCess) study is a multicentre, observer-blinded RCT comparing primary radiocephalic/brachiocephalic AVF created under regional versus LA. The primary outcome is primary unassisted AVF patency at 1 year. Access-specific (eg, stenosis/thrombosis), patient-specific (including health-related quality of life) and safety secondary outcomes will be evaluated. Health economic analysis will also be undertaken. ETHICS AND DISSEMINATION: The ACCess study has been approved by the West of Scotland Research and ethics committee number 3 (20/WS/0178). Results will be published in open-access peer-reviewed journals within 12 months of completion of the trial. We will also present our findings at key national and international renal and anaesthetic meetings, and support dissemination of trial outcomes via renal patient groups. TRIAL REGISTRATION NUMBER: ISRCTN14153938. SPONSOR: NHS Greater Glasgow and Clyde GN19RE456, Protocol V.1.3 (8 May 2021), REC/IRAS ID: 290482

Mapping Obscured Star Formation in the Host Galaxy of FRB 20201124A

We present high-resolution 1.5--6 GHz Karl G. Jansky Very Large Array (VLA) and $\textit{Hubble Space Telescope}$ ($\textit{HST}$) optical and infrared observations of the extremely active repeating fast radio burst (FRB) FRB$\,$20201124A and its barred spiral host galaxy. We constrain the location and morphology of star formation in the host and search for a persistent radio source (PRS) coincident with FRB$\,$20201124A. We resolve the morphology of the radio emission across all frequency bands and measure a star formation rate SFR $\approx 8.9\,M_{\odot}$ yr$^{-1}$, a factor of $\approx 4-6$ larger than optically-inferred SFRs, demonstrating dust-obscured star formation throughout the host. Compared to a sample of all known FRB hosts with radio emission, the host of FRB$\,$20201124A has the most significant obscured star formation. While ${\it HST}$ observations show the FRB to be offset from the bar or spiral arms, the radio emission extends to the FRB location. We propose that the FRB progenitor could have formed $\textit{in situ}$ (e.g., a magnetar central engine born from the explosion of a massive star). It is still plausible, although less likely, that the progenitor of FRB$\,$20201124A migrated from the central bar of the host, e.g., via a runaway massive star. We further place a limit on the luminosity of a putative PRS at the FRB position of $L_{\rm 6.0 \ GHz}$$\lesssim$2.6$\times$$10^{27}$erg s$^{-1}$Hz$^{-1}$, two orders of magnitude below any PRS known to date. However, this limit is still broadly consistent with both magnetar nebulae and hypernebulae models assuming a constant energy injection rate of the magnetar and an age of$\gtrsim 10^{5}$ yr in each model, respectively.Comment: 21 pages, 6 figures, 3 tables, Submitte

The SARS-CoV-2 viral load in COVID-19 patients is lower on face mask filters than on nasopharyngeal swabs.

Face masks and personal respirators are used to curb the transmission of SARS-CoV-2 in respiratory droplets; filters embedded in some personal protective equipment could be used as a non-invasive sample source for applications, including at-home testing, but information is needed about whether filters are suited to capture viral particles for SARS-CoV-2 detection. In this study, we generated inactivated virus-laden aerosols of 0.3-2 microns in diameter (0.9 µm mean diameter by mass) and dispersed the aerosolized viral particles onto electrostatic face mask filters. The limit of detection for inactivated coronaviruses SARS-CoV-2 and HCoV-NL63 extracted from filters was between 10 to 100 copies/filter for both viruses. Testing for SARS-CoV-2, using face mask filters and nasopharyngeal swabs collected from hospitalized COVID-19-patients, showed that filter samples offered reduced sensitivity (8.5% compared to nasopharyngeal swabs). The low concordance of SARS-CoV-2 detection between filters and nasopharyngeal swabs indicated that number of viral particles collected on the face mask filter was below the limit of detection for all patients but those with the highest viral loads. This indicated face masks are unsuitable to replace diagnostic nasopharyngeal swabs in COVID-19 diagnosis. The ability to detect nucleic acids on face mask filters may, however, find other uses worth future investigation