NELL-1 positive membranous nephropathy in association with antisynthetase syndrome

Membranous nephropathy (MN) is an important cause of nephrotic syndrome and is associated with significant adverse health outcomes including progression to end-stage kidney disease, complications relating to volume overload and increased risk of venous thromboembolism. Primary MN is frequently linked to antibodies against the phospholipase A2 receptor, although a broader range of target autoantigens are emerging. We report a case of a man in his mid-60s who had been recently diagnosed with antisynthetase syndrome presenting with nephrotic syndrome. A kidney biopsy revealed findings in keeping with MN, including positive immunohistochemical staining for the neural epidermal growth factor-like 1 protein (NELL-1) autoantigen. This report highlights a possible novel association between antisynthetase syndrome and NELL-1 positive MN

Prevalence and outcomes of chronic liver disease in patients receiving dialysis: systematic review and meta-analysis

© 2021 The Author(s) . Published by Oxford University Press on behalf of the ERA. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License, https://creativecommons.org/licenses/by-nc/4.0/Background Patients receiving dialysis for end-stage kidney disease (ESKD) commonly co-exhibit risk factors for hepatic impairment. This systematic review and meta-analysis aimed to quantify the co-existence of chronic liver disease (CLD) and characterise risk factors and outcomes. Methods We searched the following databases from inception to May 2021: CINAHL, Cochrane Library, EMBASE, Kings Fund Library, MEDLINE and PubMed. The protocol was pre-registered on PROSPERO (study ID: CRD42020206486). Studies were assessed against three inclusion criteria: (1) adults (>18 years) with ESKD receiving dialysis (2) primary outcome involving CLD prevalence (3) publications in English. Moderator analysis was performed for age, gender, study size, and publication year. Sensitivity analysis was performed where applicable by removing outlier results and studies at high risk of bias. Results Searches yielded 7,195 articles, 15 met the inclusion criteria. 320,777 patients were included. Prevalence of cirrhosis and non-alcoholic fatty liver disease (NAFLD) was 5% and 55%, respectively. Individuals with CLD had two-fold higher mortality than those without (OR 2.19; 95% confidence interval 1.39-3.45). Hepatitis B (OR 13.47;1.37-132.55) and hepatitis C (OR 7.05; 4.00-12.45), but not diabetes, conferred increased cirrhosis risk. All studies examining NAFLD were judged to be at high risk of bias. We found no data on non-alcoholic steatohepatitis (NASH). Deaths from CLD, cancer and infection were greater amongst cirrhotic patients. Conclusions CLD is prevalent in dialysis patients. Hepatitis B and C confer increased risk of CLD. The impact of NAFLD and NASH cirrhosis requires further study. CLD associates with increased mortality risk in this setting.Peer reviewe

Beta-glucans in advanced CKD : role in endotoxaemia and inflammation

BACKGROUND/AIMS: (1-3)-β-D glucans (BG) are cellular components of yeasts and fungi. Elevated blood levels may be an adjunct in diagnosing invasive fungal infection, though can be high in dialysis patients without fungaemia. BG can also induce false positive signals in endotoxin detection assays (Limulus Amoebocyte Lysate [LAL] assay). We explored the relationship between BG levels, renal impairment, endotoxaemia and inflammation. METHODS: We measured serum BG levels, markers of inflammation and blood endotoxin levels in 20 controls, 20 with stages 1-3 chronic kidney disease (CKD), 20 with stages 4-5 CKD, 15 on peritoneal dialysis (PD) and 60 on haemodialysis (HD). Another 30 patients were studied before and after HD initiation. RESULTS: BG levels increased with advancing CKD, being highest in HD patients, 22% of whom had elevated levels (> 80 pg/ml). Levels increased significantly following HD initiation. Levels also correlated positively with CRP, TNFα, IL-6 levels, independently of CKD stage. Blood endotoxin was detectable by LAL assays in 10-53% of the CKD cohort, being most prevalent in the HD group, and correlating positively with BG levels. Adding BG blocking agent to the assay reduced endotoxin detection confining it to only 5% of HD patients. Levels of inflammatory markers were higher in those with detectable endotoxin - whether false- or true positives. CONCLUSION: BG levels increased with decreasing renal function, being highest in dialysis patients. High BG levels were associated with false positive blood endotoxin signals, and with markers of inflammation, independently of CKD stage. The cause for high BG levels is unknown but could reflect increased gut permeability and altered mononuclear phagocytic system function.Peer reviewe

Outcomes following surgery for fractured neck of femur in dialysis patients: a 5-year review from a district general hospital in the United Kingdom

BACKGROUND: Neck of femur fractures are associated with high mortality and have increased prevalence in dialysis patients. Delays in operating on dialysis patients can occur as a result of logistical or medical issues; it has previously been shown that delays on operating on neck of femur fractures in the general population results in increased mortality. METHODS: Medical records of 27 dialysis patients admitted to a large district general hospital in the UK with a fractured neck of femur between January 2009 and January 2014 were analysed alongside records of 27 age and sex-matched non-dialysis patients. Fisher’s exact test and the unpaired t test were applied to data to explore outcomes. Odds ratio was also used to compare mortality between the dialysis and non-dialysis groups. RESULTS: Thirty-day mortality amongst dialysis patients was 22 %, compared to 7 % in the non-dialysis cohort. One-year mortality amongst dialysis patients was 70 %, compared to 15 % in the non-dialysis cohort (odds ratio 13.7 (3.56–52.4, 95 % confidence interval; p = 0.0001)). Average length of survival in dialysis patients overall was 311 days; average length of survival if the patient was operated on within 48 h of admission was 450 days (192–708 days, 95 % confidence interval) and was 224 days (45–402, 95 % confidence interval) if operated on after more than 48 h of admission (p = 0.16). CONCLUSIONS: Dialysis patients had higher post-operative mortality than the non-dialysis cohort. Odds ratio for death was significantly greater at one-year in the cohort of dialysis patients compared to the non-dialysis patients. Delay to operation amongst the dialysis patient cohort did not contribute significantly to mortality in this study. The higher rates of coronary artery disease, diabetes mellitus and malignancy may confound mortality amongst patients on dialysis who sustain a fractured neck of femur. Limitations of this study included small patient numbers, data from only one centre being used, and some missing data for certain patients

Attitudes in Patients with Autosomal Dominant Polycystic Kidney Disease Toward Prenatal Diagnosis and Preimplantation Genetic Diagnosis

Final publication is available from Mary Ann Liebert, Inc., publishers http://dx.doi.org/10.1089/gtmb.2016.0050AIMS: No recommendations currently exist regarding implementation of both prenatal diagnosis and preimplantation genetic diagnosis (PGD) for autosomal dominant polycystic kidney disease (ADPKD). This study evaluated attitudes in ADPKD patients with either chronic kidney disease (CKD) stages I-IV or end-stage renal failure (ESRF) toward prenatal diagnosis and PGD. METHODS: Ninety-six ADPKD patients were recruited from an outpatient clinic, wards, and dialysis units. Thirty-eight patients had ESRF and 58 had CKD stages I-IV. Participants were given an information sheet on prenatal diagnosis and PGD and subsequently completed a questionnaire. RESULTS: The median age of participants was 51.5 years. Seventeen percent of ADPKD patients with CKD and 18% of ADPKD patients with ESRF would consider prenatal diagnosis and termination of pregnancy for ADPKD. Fifty percent with CKD would have opted for PGD (or might consider it in the future) were it available and funded by the UK National Health Service, compared to 63% in the ESRF group (p = 0.33). Sixty-nine percent in the CKD group and 68% in the ESRF group believed that PGD should be offered to other patients. DISCUSSION: There was a spectrum of attitudes among this cohort. A proportion of patients believe that PGD should be made available to prospective parents with this disease. The discrepancy between the low proportion (17% CKD, 18% ESRF) who would consider prenatal diagnosis and termination of pregnancy and the higher number who hypothetically express an intention or wish to access PGD (50% CKD and 63% ESRF) indicates far greater acceptability for diagnostic methods that occur before embryo implantation. It is not known how the development of methods to identify patients whose renal function is likely to decline rapidly and treatments altering the natural history of ADPKD will affect these attitudes.Peer reviewe

Writing about health inequality:recommendations for accurate and impactful presentation of evidence

Health and development agendas and programmes often prioritize the reduction of unfair and remediable health inequalities. There is a growing amount of data pertaining to health inequalities. Written outputs, including academic research papers, are key tools for describing health inequalities. Epidemiologists, data analysts, policy advisors and health equity scholars can have greater impact through accurate, concise and compelling presentation of this evidence and so assist those advocating for action to close health gaps. We make recommendations to improve the accuracy and impact of written evidence on health inequality. Focusing on the micro, macro and meta aspects of developing written reports, we drew from our varied experiences promoting health inequality monitoring to identify key strategies specific to this field, which were further expanded and explored through literature searches and consultation with experts. We recommend four general strategies: (i) using terminology deliberately and consistently; (ii) presenting statistical content accurately and with sufficient detail; (iii) adhering to guidelines and best practices for reporting; and (iv) respecting and upholding the interests of affected communities. Specifically, we address the use of terminology related to health inequality and health inequity, dimensions of inequality and determinants of health, economic inequality and economic-related inequality, sex and gender, and race and ethnicity. We present common pitfalls related to reporting statistical content, underscoring the importance of clarity when reporting association and causation. We advocate for engaged and inclusive writing processes that use affirming language and adopt strength-based messaging. This guidance is intended to increase the impact of written evidence on efforts to tackle avoidable health inequalities.</p

Post‐Hemodialysis Flow‐Dependent Hepatic Function Impairment in Individuals With End Stage Kidney Disease and Chronic Inflammation

Introduction: The liver plays an important role to prevent translocation of gut‐derived toxins from the portal to the systemic circulation. Chronic inflammation is common in patients receiving hemodialysis, and increased gut permeability to microbial material has been implicated in its pathogenesis. This study sought to establish if flow‐dependent hepatic function was impaired in chronically inflamed individuals treated with hemodialysis. Methods: Fifty adults receiving outpatient hemodialysis were recruited. Subjects with known liver or gastrointestinal disease, acute inflammation, and hemodynamic instability during hemodialysis were excluded. Participants were divided into two groups (n = 25): individuals with chronic inflammation (defined as a median high‐sensitivity C‐reactive protein (hs‐CRP) ≥ 5 mg/dL over the preceding 3 months) with no apparent cause and a noninflamed group. Flow‐dependent hepatic function (defined as a composite of hepatic perfusion, hepatocyte clearance and biliary excretion) was assessed following hemodialysis by indocyanine green clearance to derive: (1) indocyanine green‐plasma disappearance rate and (2) indocyanine green‐retention after 15 min. Serum beta‐D‐glucan levels pre‐ and post‐hemodialysis were measured as surrogate markers of gastrointestinal permeability. Findings: Indocyanine green‐plasma disappearance rate was reduced in the inflamed group versus the noninflamed group (19.4 (8.7)%/min vs. 23.8 (14.4)%/min; p = 0.02). Indocyanine green‐retention after 15 min was higher in the inflamed group (5.4 (6.8)% vs. 2.9 (5.0)%; p = 0.02). Noninvasive hepatic fibrosis and steatosis assessments were similar in both groups. Pre‐hemodialysis beta‐D‐glucan levels were similar (63 (42) pg/ml vs. 49 (11) pg/ml; p = 0.13), whereas post‐hemodialysis beta‐D‐glucan levels were higher in the inflamed group (82 (48) pg/ml vs. 58 (27) pg/ml; p < 0.001), and in those with flow‐dependent hepatic impairment (72 (45) vs. 55 (32) pg/ml; p = 0.004). In linear regression analysis, indocyanine green‐retention after 15 min and post‐hemodialysis beta‐D‐glucan levels were independent predictors of median hs‐CRP, explaining 21% of the variation. Discussion: Individuals with otherwise unexplained inflammation had impaired hepatic function post‐hemodialysis and higher post‐hemodialysis beta‐D‐glucan levels. These findings are compatible with the notion that impaired hepatic gut‐derived toxin removal propagates chronic inflammation in hemodialysis

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements