Background Acute kidney injury (AKI) is a global health issue known to cause avoidable harm and death. Improvement in its prevention and management is therefore considered an important goal for the health-care sector. The work here aimed to develop a tool which could be used to robustly and reliably measure, monitor, and compare the effectiveness of health-care interventions related to AKI across the Welsh NHS, a mechanism which did not exist previously. Methods Using serum creatinine (SCr) as a biomarker for AKI and a validated national data-set collected from the all Wales Laboratory Information Management System, work involved applying Donabedian’s framework to develop indicators with which to measure outcomes related to AKI, and exploring the potential of statistical process control (SPC) techniques for analysing data on these indicators. Results Rate of AKI incidence and 30-day AKI-associated mortality are proposed as valid, feasible indicators with which to measure the effectiveness of health-care interventions related to AKI. The control chart, funnel plot, and Pareto chart are proposed as appropriate, robust SPC techniques to analyse and visualise variation in AKI-related outcomes. Conclusions This work demonstrates that routinely collected large SCr data offer a significant opportunity to monitor and therefore inform improvement in patient outcomes related to AKI. Moreover, while this work concerns utilisation of SCr data for improvement in AKI strategies, it is a proof of concept which could be replicated for other routinely collected clinical laboratory data, to improve the prevention and/or management of the conditions to which they relate.

Administration of Gum Arabic (GA) was associated with an increase in estimated Glomerular filtration rate (eGFR) at three months (pre 24.64 ± 8.89 vs 26.20 ± 10.1p = 0.02). Subsequently there was no significant fall in eGFR. This translated to positive change in Δ eGFR within quarter at three months, (Δ eGFR 4.89 ml/min/year p=<0.001 vs pre) and six months (Δ eGFR 0.79 ml/min/year, p < 0.001 vs pre) compared to pre-intervention values. At 9 and 12 months although the mean Δ eGFR in quarter was negative, this rate of decline in renal function remained significantly less than prior to intervention (9 months Δ eGFR −1.27 ml/min/year, p= <0.001 vs pre, 12 months delta Δ eGFR −1.54 ml/min/year, p < 0.001 vs pre). Similarly, mean reciprocal creatinine, declined by 11% in the pre-intervention period but was no different to the pre-intervention values for the duration of intervention. In conclusion oral administration of Gum Arabic attenuates the rate of decline in renal function.

Progressive fibrosis leads to loss of organ function and affects many organs as a result of excessive extracellular matrix production. The ubiquitous matrix polysaccharide hyaluronan (HA) is central to this through association with its primary receptor, CD44, which exists as standard CD44 (CD44s) or multiple splice variants. Mediators such as profibrotic transforming growth factor (TGF)-β1 and proinflammatory interleukin (IL)-1β are widely associated with fibrotic progression. TGF-β1 induces myofibroblast differentiation, while IL-1β induces a proinflammatory fibroblast phenotype that promotes fibroblast binding to monocyte/macrophages. CD44 expression is essential for both responses. Potential CD44 splice variants involved, however, are unidentified. The TGF-β1-activated CD44/epidermal growth factor receptor complex induces differentiation of metastatic cells through interactions with the matrix metalloproteinase inducer, CD147. This study aimed to determine the CD44 variants involved in TGF-β1- and IL-1β-mediated responses and to investigate the potential profibrotic role of CD147. Using immunocytochemistry and quantitative PCR, standard CD44s were shown to be essential for both TGF-β1-induced fibroblast/myofibroblast differentiation and IL-1β-induced monocyte binding. Co-immunoprecipitation identified that CD147 associated with CD44s. Using CD147-siRNA and confocal microscopy, we also determined that incorporation of the myofibroblast marker, αSMA, into F-actin stress fibers was prevented in the absence of CD147 and myofibroblast-dependent collagen gel contraction was inhibited. CD147 did not associate with HA, but removal of HA prevented the association of CD44s with CD147 at points of cell-cell contact. Taken together, our data suggest that CD44s/CD147 colocalization is essential in regulating the mechanical tension required for the αSMA incorporation into F-actin stress fibers that regulates myofibroblast phenotype.

Background Little is known regarding the impact of acute kidney injury (AKI) on renal transplant outcome. Our aim was to define the incidence and outcome of AKI in renal transplant patients using data collected from a national AKI electronic alert system Methods The study represents a prospective national cohort study collecting data on 1224 renal transplants recipients with a functioning renal transplant, between April 2015 and March 2019. Results Four hundred forty patients experienced at least one episode of AKI giving an incidence rate of 35.4%. Sixty-four point seven% of episodes were AKI stage 1, 7.3% AKI stage 2 and 28% AKI stage 3. Only 6.2% of episodes occurred in the context of rejection. Forty-three point five% of AKI episodes were associated with sepsis. AKI was associated with pre-existing renal dysfunction, and a primary renal diagnosis of diabetic nephropathy. AKI was more prevalent in recipients from a donor after cardiac death (26.4% vs. 21.4%, p < 0.05) compared to the non-AKI cohort. Following AKI, 30-day mortality was 19.8% and overall mortality was 34.8%, compared to 8.4% in the non AKI cohort (RR 4.06, 95% CI 3.1–5.3, p < 0.001). Graft survival (GS), and death censored graft survival (DCGS) censored at 4 years, in the AKI cohort were significantly lower than in the non AKI group (p < 0.0001 for GS and DCGS). Conclusion The study provides a detailed characterisation of AKI in renal transplant recipients highlighting its significant negative impact on patient and graft survival.

Objective To define the incidence and outcome of acute kidney injury (AKI) in pediatrics using data collected from a national electronic alert system. Study design A prospective national cohort study was undertaken to collect data on all cases of pediatric AKI, excluding neonates, identified by an e-alert, from April 2015 to March 2019. Results There were 2472 alerts in a total of 1719 patients, giving an incidence of 77.3 per 100 000 person-years. Of the patients, 84.2% of all AKI were stage 1 and 58.3% occurred with a triggering creatinine within the reference range. The incidence of AKI was associated with measures of social deprivation. Thirty-day mortality was 1.7% but was significantly higher in hospital-acquired AKI (2.1%), compared with community-acquired AKI (0.8%, P<.001) and was associated with the severity of AKI at presentation. A significant proportion of patients had no repeat measure of creatinine (39.8%). This was higher in community-acquired AKI (69.7%) compared with hospital-acquired AKI (43.0%, P<.001), and higher in patients alerting with patients triggering with a creatinine within the reference range (48.4% vs 24.5%, P<.001). The majority of patients (84.7%) experienced only 1 AKI episode. Repeated episodes of AKI were associated with increased 30-mortaltiy (11.6% vs 4.6%, P<.001) and higher residual renal impairment (13.3% vs 5.4%, P<.001). Conclusions The results suggest that the significance of the alert is missed in many cases reflecting that a large proportion of cases represent modest elevations in serum creatinine (SCr), triggered by a SCr level that may be interpreted as being normal despite a significant increase from the baseline for the patient.

Background and objective: Quality management of Acute Kidney Injury (AKI) is dependent on early detection, which is currently deemed to be suboptimal. The aim of this study was to identify combinations of variables associated with AKI and to derive a prediction tool for detecting patients attending the emergency department (ED) or hospital with AKI (ED-AKI). Design, setting, participants and measurements: This retrospective observational study was conducted in the ED of a tertiary university hospital in Wales. Between April and August 2016 20,421 adult patients attended the ED of a University Hospital in Wales and had a serum creatinine measurement. Using an electronic AKI reporting system, 548 incident adult ED-AKI patients were identified and compared to a randomly selected cohort of adult non-AKI ED patients (n = 571). A prediction model for AKI was derived and subsequently internally validated using bootstrapping. The primary outcome measure was the number of patients with ED-AKI. Results: In 1119 subjects, 27 variables were evaluated. Four ED-AKI models were generated with C-statistics ranging from 0.800 to 0.765. The simplest and most practical multivariate model (model 3) included eight variables that could all be assessed at ED arrival. A 31-point score was derived where 0 is minimal risk of ED-AKI. The model discrimination was adequate (C-statistic 0.793) and calibration was good (Hosmer & Lomeshow test 27.4). ED-AKI could be ruled out with a score of <2.5 (sensitivity 95%). Internal validation using bootstrapping yielded an optimal Youden index of 0.49 with sensitivity of 80% and specificity of 68%. Conclusion: A risk-stratification model for ED-AKI has been derived and internally validated. The discrimination of this model is objective and adequate. It requires refinement and external validation in more generalisable settings. (c) 2020 Elsevier Inc. All rights reserved.

Background . Oxidative processes might increase in patients with end-stage renal disease (ESRD) according to the current literature. Oxidative stress (OS) is a risk factor of atherosclerosis and cardiovascular complications, which are major causes of mortality among ESRD patients. Haemodialysis (HD) is life-saving procedure, nevertheless it is an active chronic inflammatory status that could augment cardiovascular disease and increase mortality. Gum Arabic (GA) has been claimed to act as an antioxidant and anti-inflammatory agent in experimental studies and clinical trials. Therefore, we assumed GA supplementation among haemodialysis patients would reduce oxidative stress and consequently reduce the state of chronic inflammatory activation associated with haemodialysis. Methods . Forty end-stage renal failure (ESRF) patients aged 18–80 years who were on regular haemodialysis in Arif Renal Center, Omdurman, Sudan, were recruited. All recruited patients met the inclusion criteria and signed informed consent prior to enrolment. The patients received 30 g/day of GA for 12 weeks. C-reactive protein (CRP) and complete blood count (CBC) were measured as baseline and monthly. Total antioxidant capacity (TAC) and oxidative stress marker malondialdehyde (MDA) levels were measured before and after GA intake. Ethical approval from the National Medicines and Poisons Board was obtained. Results . Gum Arabic significantly augmented total antioxidant capacity level ( P < 0.001) (95% CI, 0.408–0.625) and also attenuated oxidative marker MDA and C-reactive protein ( P < 0.001). Conclusions . GA has revealed potent antioxidative and anti-inflammatory properties in haemodialysis patients. Oral digestion of GA (30 g/day) decreased oxidative stress and inflammatory markers among haemodialysis patients. Trial registration. ClinicalTrials.gov Identifier: NCT03214692 , registered 11 July 2017 (prospective registration).

Fibroblasts are central to wound healing and fibrosis through Transforming Growth Factor- β 1 (TGF- β 1)-triggered differentiation into contractile, α -smooth muscle actin ( α -sma)-positive myofibroblasts. This is mediated by accumulation of a pericellular matrix of hyaluronan (HA) and the HA-dependent co-localisation of CD44 with the Epidermal Growth Factor Receptor (EGFR). Interactions of HA with hyaladherins, such as Inter-alpha-Inhibitor (IaI) and Tumour Necrosis Factor-stimulated gene-6 (TSG-6) are also essential for differentiation. This study investigated the mechanisms involved. TSG-6 and α -sma had different kinetics of induction by TGF-β 1, with TSG-6 peaking before α -sma. siCD44 or EGFR

BACKGROUNDElectronic alerts for acute kidney injury (AKI) have been widely advocated. Our aim was to describe the changes in AKI demographics and outcomes following implementation of a national electronic AKI alert programme.METHODSA prospective national cohort study was undertaken to collect data on all cases of AKI in adult patients (≥18 years of age) between 1 April 2015 and 31 March 2019.RESULTSOver the period of data collection, there were 193 838 AKI episodes in a total of 132 599 patients. The lowest incidence of AKI was seen in the first year after implementation of electronic alerts. A 30-day mortality was highest in Year 1 and significantly lower in all subsequent years. A direct comparison of mortality in Years 1 and 4 demonstrated a significantly increased relative risk (RR) of death in Year 1: RR = 1.08 [95% confidence interval (CI) 1.054-1.114 P < 0.001]. This translates into a number needed to treat in Year 4 for one additional patient to survive of 69.5 (95% CI 51.7-106.2) when directly comparing the outcomes across the 2 years. The increase in the number of cases and improved outcomes was more pronounced in community-acquired AKI, and was associated with a significant increase in patient hospitalization.CONCLUSIONSThis study represents the first large-scale dataset to clearly demonstrate that a national AKI alerting system which highlights AKI is associated with a change in both AKI demographics and patient outcomes.

e21634 Background: Hyperprogressive disease(HPD) is a recently recognized type of accelerated tumor progression with immune checkpoint inhibitor(ICI) therapy. A recent meta-analysis identified serum lactate dehydrogenase(LDH) above upper limit of normal(ULN), liver metastases and > 2 metastatic sites to be associated with increased likelihood of HPD. Methods: We performed a single-center retrospective analysis of NSCLC patients treated with ICI from 2/2017-1/2020. We defined HPD using combined criteria of failure to complete > 4 cycles of ICI and radiological progression with development of new lesions or marked clinical progression where restaging was not achievable because of rapid decline in performance status. Treatment discontinuation/interruption because of toxicity alone, was not designated as HPD. Results: HPD was seen in 9/41(22%) patients treated with at least 1 cycle of ICI. In 6/9 there was marked radiological progression (new lesions/significant progression of existing lesions); in the remaining 3 restaging was not possible because of rapid decline which mandated treatment cessation. Patients with HPD were more likely to have a raised LDH, liver metastases or > 2 metastatic sites but these differences were not statistically significant. 9/9 versus 5/32 patients in the HPD/non-HPD cohorts respectively progressed within 10 weeks of treatment (p < 0.001) and 7/9 versus 12/32 respectively did not survive beyond 6months (p = 0.057). Conclusions: This small study has shown a non-statistically significant trend for association between HPD, raised LDH, liver metastases and presence of > 2 metastatic sites. A better understanding of risk/predictive factors for HPD is essential for improved patient selection for treatment with ICI. [Table: see text]

David Malcolm Thomas (“Dave”) was born to be a great doctor. He trained at Cambridge and St Thomas’ Hospital and did house jobs in London. After two years as a registrar in Exeter, …

Hyaluronidase (HYAL)-2 is a weak, acid-active, hyaluronan-degrading enzyme broadly expressed in somatic tissues. Aberrant HYAL2 expression is implicated in diverse pathology. However, a significant proportion of HYAL2 is enzymatically inactive; thus the mechanisms through which HYAL2 dysregulation influences pathobiology are unclear. Recently, nonenzymatic HYAL2 functions have been described, and nuclear HYAL2 has been shown to influence mRNA splicing to prevent myofibroblast differentiation. Myofibroblasts drive fibrosis, thereby promoting progressive tissue damage and leading to multimorbidity. This study identifies a novel HYAL2 cytoplasmic function in myofibroblasts that is unrelated to its enzymatic activity. In fibroblasts and myofibroblasts, HYAL2 interacts with the GTPase-signaling small molecule ras homolog family member A (RhoA). Transforming growth factor beta 1-driven fibroblast-to-myofibroblast differentiation promotes HYAL2 cytoplasmic relocalization to bind to the actin cytoskeleton. Cytoskeletal-bound HYAL2 functions as a key regulator of downstream RhoA signaling and influences profibrotic myofibroblast functions, including myosin light-chain kinase-mediated myofibroblast contractility, myofibroblast migration, myofibroblast collagen/fibronectin deposition, as well as connective tissue growth factor and matrix metalloproteinase-2 expression. These data demonstrate that, in certain biological contexts, the nonenzymatic effects of HYAL2 are crucial in orchestrating RhoA signaling and downstream pathways that are important for full profibrotic myofibroblast functionality. In conjunction with previous data demonstrating the influence of HYAL2 on RNA splicing, these findings begin to explain the broad biological effects of HYAL2.

BACKGROUNDAcute Kidney Injury (AKI) is associated with adverse outcomes; therefore identifying patients who are at risk of developing AKI in hospital may lead to targeted prevention.AIMWe undertook a UK-wide study in acute medical units (AMUs) to define those who develop hospital-acquired AKI (hAKI); to determine risk factors associated with hAKI and to assess the feasibility of developing a risk prediction score.DESIGNProspective multi-centre cohort study across 72 AMUs in the UK.METHODSData collected from all patients who presented over a 24-h period. Chronic dialysis, community-acquired AKI (cAKI) and those with fewer than two creatinine measurements were excluded. Primary outcome was the development of h-AKI.RESULTSTwo thousand four hundred and fourty-six individuals were admitted to the seventy-two participating centres. Three hundred and eighty-four patients (16%) sustained AKI of whom two hundred and eighty-seven (75%) were cAKI and ninety-seven (25%) were hAKI. After exclusions, chronic kidney disease [Odds Ratio (OR) 3.08, 95% Confidence Interval (CI) 1.96-4.83], diuretic prescription (OR 2.33, 95% CI 1.5-3.65), a lower haemoglobin concentration and elevated serum bilirubin were independently associated with development of hAKI. Multi-variable model discrimination was only moderate (c-statistic 0.75).CONCLUSIONSAKI in AMUs is common and associated with worse outcomes, with the majority of cases community acquired. Only a small proportion of patients develop hAKI. Prognostic risk factor modelling demonstrated only moderate discrimination implying that widespread adoption of such an AKI clinical risk score across all AMU admissions is not currently justified. More targeted risk assessment or automated methods of calculating individual risk may be more appropriate alternatives.

BACKGROUND:Patients with renal disease are less likely to undergo percutaneous coronary intervention (PCI) due to concerns about poor outcomes.AIM:We describe outcomes following PCI in individuals with chronic kidney disease (CKD), as compared with matched controls with comparable CKD who did not undergo PCI. We also identified factors predictive of poor outcomes following PCI amongst patients with CKD.DESIGN:Retrospective observational case-control study.METHODS:Cases were individuals with CKD (stages 1-5) undergoing PCI between 2008 and 2014. Controls were age, gender and creatinine-matched individuals not requiring PCI. We compared mortality between groups using Kaplan-Meier curves and Cox regression modelling. We assessed changes in serum creatinine using Wilcoxon Rank testing. We explored the relationship between biochemical and haematological measures (baseline creatinine, calcium, phosphate, calcium-phosphate product, parathyroid hormone, white cell count, haemoglobin, platelet count, c-reactive protein and total cholesterol) and post-PCI mortality, using logistic regression.RESULTS:We identified 144 cases and 144 controls. Mortality was significantly lower amongst cases compared with controls [hazard ratio 0.46 (95% confidence intervals 0.31, 0.69)]. PCI did not result in a significant change in renal function (P=0.52). Amongst cases, serum creatinine and calcium-phosphate product were predictors of mortality following PCI.CONCLUSION:Cases undergoing PCI had lower mortality, and PCI was not associated with accelerated CKD progression. On this data, PCI should not be deferred as a treatment option in patients with CKD. Serum creatinine and calcium-phosphate product predict mortality following PCI in this cohort, and may be useful in risk-stratifying patients with CKD being considered for PCI.

Introduction: This study examined the relationship among age, measures of social deprivation, and incidence and outcome of acute kidney injury (AKI). Methods: The Welsh National electronic AKI reporting system was used to identify all cases of AKI in patients 18 years or older between March 2015 and January 2017. Socioeconomic classification of patients was derived from the Welsh Index of Multiple Deprivation (WIMD). Patients were grouped according to their WIMD score, and Multivariate Cox proportional hazard modeling was used to adjust the data for age. The ranked data were categorized into percentiles and correlated with incidence, and measures of AKI severity and outcome. Results: Analysis included 57,654 patients. For the whole cohort, the highest 90-day survival was associated with the most socially deprived cohorts. There was a significant negative relationship between age-adjusted incidence of AKI and the WIMD score. In patients 60 years or older, there was an inverse correlation between WIMD score and survival that was not evident in those younger than 60. AKI severity at presentation was worse in patients from areas of social deprivation. Social deprivation was associated with a significantly higher proportion of preexisting chronic kidney disease (CKD) in patients with AKI older than 60, but not in those younger than 60. Conclusion: Overall mortality following AKI was higher in least-deprived areas, reflecting an older patient cohort. In contrast, social deprivation was associated with higher age-adjusted AKI incidence and age-adjusted mortality following AKI. The excess mortality observed in more deprived areas was associated with more severe AKI and a higher proportion of preexisting CKD.

Water-soluble beta-D-glucan was obtained from wild Cordyceps sinensis by alkali solution and ethanol precipitation. The structure characteristics were determined using high-performance anion-exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD), methylation combined with gas chromatography-mass spectrometry, and one-/two-dimensional nuclear magnetic resonance spectroscopy. Results showed that beta-D-glucan had a structure of every seven (1 -> 3)-beta-D-Glcp backbone residues with two (1 -> 6)-beta-D-Glcp branches. Additionally, conformation properties in different solvents were investigated by static light scattering, dynamic light scattering, and HPSEC with multiple detectors. It was found that beta-D-glucan in 0.5 M NaOH had a narrow unimodal distribution of hydrodynamic radius displaying a spherical coil conformation, whereas it formed severe aggregation in dimethyl sulfoxide. In 0.1 M NaNO3, beta-D-glucan mainly existed as a rod-like conformation corresponding to a helical structure together with small aggregates (10%). This work added more information to the understanding of C. sinensis polysaccharides.

Background. This study examined the impact of recurrent episodes of acute kidney injury (AKI) on patient outcomes. Methods. The Welsh National electronic AKI reporting system was used to identify all cases of AKI in patients >= 18 years of age between April 2015 and September 2018. Patients were grouped according to the number of AKI episodes they experienced with each patient's first episode described as their index episode. We compared the demography and patient outcomes of those patients with a single AKI episode with those patients with multiple AKI episodes. Analysis included 153 776 AKI episodes in 111 528 patients. Results. Of those who experienced AKI and survived their index episode, 29.3% experienced a second episode, 9.9% a third episode and 4.0% experiencedu fourth or more episodes. Thirty-day mortality for those patients with multiple episodes of AKI was significantly higher than for those patients with a single episode (31.3% versus 24.9%, P < 0.001). Following a single episode, recovery to baseline renal function at 30 days was achieved in 83.6% of patients and was significantly higher than for patients who had repeated episodes (77.8%, P < 0.001). For surviving patients, non-recovery of renal function following any AKI episode was significantly associated with a higher probability of a further AKI episode (33.4% versus 41.0%, P < 0.001). Furthermore, with each episode of AKI the likelihood of a subsequent episode also increased (31.0% versus 43.2% versus 51.2% versus 51.7% following a first, second, third and fourth episode, P < 0.001 for all comparisons). Conclusions. The results of this study provide an important contribution to the debate regarding the need for risk stratification for recurrent AKI. The data suggest that such a tool would be useful given the poor patient and renal outcomes associated with recurrent AKI episodes as highlighted by this study.

Cystic fibrosis (CF) is an autosomal recessive condition, mostly diagnosed in infancy. It is uncommon for adults to be diagnosed with CF, especially after the age of 65. Individuals, who are diagnosed later in life, usually have milder disease and single organ involvement which can be challenging for clinicians to diagnose. Adult CF patients are more likely to be pancreatic sufficient. They have predominantly upper lobe bronchiectasis, lower incidence of Pseudomonas aeruginosa compared with Staphylococcus aureus and are more likely to have mutations other than ΔF508.