IgA vasculitis nephritis-outcomes in adult-onset disease.

OBJECTIVES: IgA vasculitis (IgAV) in adults has been relatively under-investigated. Since outcomes are worse in other forms of vasculitis with increasing age, we investigated the outcomes of IgAV comparing younger adults (18-34), middle aged adults (35-64) and elderly patients (≥64 years) focusing on kidney outcomes. METHODS: We identified patients with renal biopsy confirmed IgAV nephritis and collected data regarding clinical features and progression to end stage kidney disease (ESKD). The relationship between patient factors and ESKD was analysed by regression. RESULTS: We identified 202 cases, 34% aged 18-34, 43% aged 35-64 and 23% were elderly (>64 years). Median follow up was 44 months. Elderly patients were more likely to present with ESKD (23.9%) compared with middle aged (13.7%) and younger adults (2.9%)(χ2 11.6, p= 0.002). In patients with independent kidney function at biopsy, there was no difference in outcomes between age groups. Male gender, Black ethnicity, diabetes, histological evidence of chronic renal damage and eGFR < 30mls/min were risk factors for development of ESKD. In this observational study 68.3% of patients received glucocorticoids and 56.9% additional immunosuppression. CONCLUSIONS: Elderly patients with IgAV are more likely to have ESKD at presentation, but there is no difference in renal survival between age groups, among those presenting with independent renal function. Renal impairment at biopsy is an independent risk factor for subsequent development of ESKD. There is significant variability in the timing of kidney biopsy and management of these patients among specialist centres. Young adults have outcomes more in keeping with childhood IgAV.

Thromboembolism in nephrotic syndrome: controversies and uncertainties.

Thromboembolism is one of the most serious complications of nephrotic syndrome, including both arterial and venous thromboembolic events. Rates of thromboembolism depend on a multitude of factors, including the severity and cause of nephrotic syndrome, with primary membranous nephropathy having the highest reported rates. In relation to arterial thromboembolism, the risk can be as high as 8 times that of an age- and sex-matched population. However, extrapolating risks is challenging, with published studies not being homogeneous, several being single center and retrospective, and including different causes of primary nephrotic syndrome. Determining thromboembolic risk in nephrotic syndrome is essential to enable decision making on preventive strategies. However, lack of proven strategies to help estimate risk-benefit aspects underpins variations in clinical practice. Although the use of anticoagulation following a thrombotic event is clear, this still leaves us with a clinical dilemma as to if, and who, should receive prophylactic anticoagulation, with what agent, and for how long. In the absence of clear evidence to answer these questions, prophylactic anticoagulation strategies for nephrotic syndrome currently rely on expert consensus opinion, such as in the recently published 2021 Kidney Disease Improving Global Outcomes glomerular disease guidelines. In the mainstay, these recommendations relate to patients with membranous nephropathy. Here, we detail the current controversies still faced by clinicians around the risk of thromboembolism in nephrotic syndrome, use of prophylactic anticoagulation in nephrotic syndrome and propose ways of advancing existing knowledge and practice in this field to unravel the conundrum.

Postendoscopy Care for Patients Presenting With Esophageal Food Bolus Impaction: A Population-Based Multicenter Cohort Study.

INTRODUCTION: Esophageal food bolus impactions (FBI) are a common gastrointestinal emergency. Appropriate management includes not only index endoscopy for disimpaction but also medical follow-up and treatment for the underlying esophageal pathology. We evaluated the appropriateness of postendoscopy care for patients with FBI and assessed patient-related, physician-related, and system-related factors that may contribute to loss to follow-up. METHODS: We conducted a retrospective, population-based, multicenter cohort study of all adult patients undergoing endoscopy for FBI in the Calgary Health Zone, Canada, from 2016 to 2018. Appropriate postendoscopy care was defined by a composite of a clinical or endoscopic follow-up visit, appropriate investigations (e.g., manometry), or therapy (e.g., proton-pump inhibitors or endoscopic dilation). Predictors of inappropriate care were assessed using multivariable logistic regression. RESULTS: A total of 519 patients underwent endoscopy for FBI: 25.2% (131/519) did not receive appropriate postendoscopy care. Half of the patients (55.3%, 287/519) underwent follow-up endoscopy or attended clinic, and among this group, 22.3% (64/287) had a change in their initial diagnosis after follow-up, including 3 new cases of esophageal cancer. Patients in whom a suspected underlying esophageal pathology was not identified at the index endoscopy were 7-fold (adjusted odds ratio 7.28, 95% confidence interval 4.49-11.78, P < 0.001) more likely to receive inappropriate postendoscopy follow-up and treatment, even after adjusting for age, sex, rural residence, timing of endoscopy, weekend presentation, and endoscopic interventions. DISCUSSION: One-quarter of patients presenting with an FBI do not receive appropriate postendoscopy care. This is strongly associated with failure to identify a potential underlying pathology at index presentation.

Long-Term Safety, Clinical and Immunological Outcomes in Primary Membranous Nephropathy with Severe Renal Impairment Treated with Cyclophosphamide and Steroid-Based Regimen.

Introduction and Aims: Therapy of primary membranous nephropathy (PMN) with progressive advanced kidney dysfunction is challenging with limited literature and no clear therapeutic strategies. This is due to the scant evidence of effectiveness and uncertainty around the risk-benefit profile of immunosuppression (ImS) when eGFR is less than 30 mL/min. We aimed to determine long-term clinical outcomes in patients with PMN and severe renal impairment treated with combined cyclophosphamide and steroids. Methods: The study is a single-center retrospective longitudinal cohort study. All patients (between 2004 and 2019) with biopsy confirmed PMN who initiated combination therapy with steroids and cyclophosphamide and had an eGFR of ≤30 mL/min/1.73 m2 at the time of initiation of therapy were included for analysis. Clinical and laboratory parameters including anti-PLA2R-Ab were monitored as per standard clinical guidance. Primary outcome was achievement of partial remission. Secondary outcomes included immunological remission, need for renal replacement therapy, and adverse effects. Results: Eighteen patients with median age of 68 (IQR 58-73) years and 5:1 M:F ratio received the combination therapy when eGFR was ≤30 mL/min/1.73 m2 (CKD-EPI). At time of ImS, median eGFR and uPCR were 23 (IQR 18-27) mL/min/1.73 m2 and 8.4 (IQR 6.9-10.7) g/g, respectively. Median follow-up was for 67 (IQR 27-80) months. 16 patients (89%) achieved partial remission and 7 (39%) achieved complete remission. eGFR increased by 7 mL/min/1.73 m2 (27%) after 1 year of starting ImS treatment and 12 mL/min/1.73 m2 at end of follow-up. Two patients (11%) developed end-stage renal disease needing renal replacement therapy. 67% achieved both immunological and clinical remission. At the end of the follow-up period, 2 (11%) patients required hospitalization secondary to infections, 4 (22%) patients developed cancer and 4 patients died (22%). Conclusion: Combination therapy with cyclophosphamide and steroids is effective in achieving partial remission and improving renal function in PMN with advanced renal dysfunction. Prospective controlled studies are required to provide further evidence to rationalize treatment and improve outcomes in such patients.

Membranous nephropathy in the UK Biobank.

BACKGROUND: Despite MN being one of the most common causes of nephrotic syndrome worldwide, its biological and environmental determinants are poorly understood in large-part due to it being a rare disease. Making use of the UK Biobank, a unique resource holding a clinical dataset and stored DNA, serum and urine for ~500,000 participants, this study aims to address this gap in understanding. METHODS: The primary outcome was putative MN as defined by ICD-10 codes occurring in the UK Biobank. Univariate relative risk regression modelling was used to assess the associations between the incidence of MN and related phenotypes with sociodemographic, environmental exposures, and previously described increased-risk SNPs. RESULTS: 502,507 patients were included in the study of whom 100 were found to have a putative diagnosis of MN; 36 at baseline and 64 during the follow-up. Prevalence at baseline and last follow-up were 72 and 199 cases/million respectively. At baseline, as expected, the majority of those previously diagnosed with MN had proteinuria, and there was already evidence of proteinuria in patients diagnosed within the first 5 years of follow-up. The highest incidence rate for MN in patients was seen in those homozygous for the high-risk alleles (9.9/100,000 person-years). CONCLUSION: It is feasible to putatively identify patients with MN in the UK Biobank and cases are still accumulating. This study shows the chronicity of disease with proteinuria present years before diagnosis. Genetics plays an important role in disease pathogenesis, with the at-risk group providing a potential population for recall.

Low tidal volume ventilation for patients undergoing laparoscopic surgery: a secondary analysis of a randomised clinical trial.

BACKGROUND: We recently reported the results for a large randomized controlled trial of low tidal volume ventilation (LTVV) versus conventional tidal volume (CTVV) during major surgery when positive end expiratory pressure (PEEP) was equal between groups. We found no difference in postoperative pulmonary complications (PPCs) in patients who received LTVV. However, in the subgroup of patients undergoing laparoscopic surgery, LTVV was associated with a numerically lower rate of PPCs after surgery. We aimed to further assess the relationship between LTVV versus CTVV during laparoscopic surgery. METHODS: We conducted a post-hoc analysis of this pre-specified subgroup. All patients received volume-controlled ventilation with an applied PEEP of 5 cmH2O and either LTVV (6 mL/kg predicted body weight [PBW]) or CTVV (10 mL/kg PBW). The primary outcome was the incidence of a composite of PPCs within seven days. RESULTS: Three hundred twenty-eight patients (27.2%) underwent laparoscopic surgeries, with 158 (48.2%) randomised to LTVV. Fifty two of 157 patients (33.1%) assigned to LTVV and 72 of 169 (42.6%) assigned to conventional tidal volume developed PPCs within 7 days (unadjusted absolute difference, - 9.48 [95% CI, - 19.86 to 1.05]; p = 0.076). After adjusting for pre-specified confounders, the LTVV group had a lower incidence of the primary outcome than patients receiving CTVV (adjusted absolute difference, - 10.36 [95% CI, - 20.52 to - 0.20]; p = 0.046). CONCLUSION: In this post-hoc analysis of a large, randomised trial of LTVV we found that during laparoscopic surgeries, LTVV was associated with a significantly reduced PPCs compared to CTVV when PEEP was applied equally between both groups. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry no: 12614000790640.

"Catch-Store-Release" Strategy for the Stabilization of 4,4'-Methylene Diphenyl Diisocyanate (4,4'-MDI).

4,4'-Methylene diphenyl diisocyanate (MDI) is an industrially crucial compound, being one of the most utilized linkers in the polyurethane industry. However, its long-term stability is limited due to dimerization to form insoluble uretdione. Herein we demonstrate an organometallic "catch-store-release" concept aiming at improving the long-term chemical stability of MDI. Treatment of MDI with two equivalents of selected N-heterocyclic carbenes (NHC) forms stable MDI-NHC adducts. Treatment of the adducts with CuCl forms metastable di-CuI complexes that undergo decomposition to re-form MDI (up to 85 %), along with Cu-NHC complexes. The yield of re-formed MDI can be improved (up to 95 %) by the release of the NHC ligands in the form of thiourea; this prevents subsequent MDI dimerization/polymerization by the carbenes. Furthermore, the need to separate MDI from the reaction mixture can be eliminated by the direct reaction of MDI-NHC complexes with alcohols (as models for diols), that form dicarbamate (as a model for polyurethane) quantitatively.

Meta-analysis: Placebo rates in microscopic colitis randomised trials and applications for future drug development using a historical control arm.

BACKGROUND: Effective medical therapies for patients with microscopic colitis (MC) who fail budesonide are lacking. However, conducting randomised controlled trials (RCTs) in MC has been challenging due to small sample sizes. Understanding placebo responses can help inform more efficient future trials. AIMS: The aim of this study is to estimate clinical and histologic placebo response rates and to determine factors associated with placebo response in MC. METHODS: EMBASE, MEDLINE, and CENTRAL were searched until 7 January 2022, to identify placebo-controlled RCTs in adult patients with MC. Clinical and histologic response in the placebo arms were pooled using random-effects models. Stratified analyses based on disease- and trial-level characteristics, leave-one-out meta-analysis, and cumulative meta-analysis were performed. RESULTS: Twelve RCTs enrolling a total of 391 patients (placebo n = 163) with MC were included. Pooled clinical and histologic placebo response rates were 24.4% (95% CI: 12.4%-38.4%), I2  = 60.8%, p < 0.01, and 19.9% (95% CI: 5.3%-39.0%), I2  = 66.4%, p = 0.01 (tests for heterogeneity), respectively. Clinical response to placebo was numerically higher in patients with lymphocytic compared to collagenous colitis (39.9% vs. 19.8%, p = 0.08). Heterogeneity in clinical response to placebo was significantly reduced when the Miehlke 2014 RCT was excluded in the leave-one-out meta-analysis or when a more stringent secondary definition of response based on the Hjortswang criteria was applied. CONCLUSIONS: Approximately one-quarter of patients in MC trials respond to placebo, although with substantial heterogeneity, reflecting the need for standardised outcome definitions and study designs for MC. This analysis also serves to inform future MC trials that may consider incorporating an external, historical placebo control arm, rather than directly randomising patients to placebo.

Can use of the serum anti-PLA2R antibody negate the need for a renal biopsy in primary membranous nephropathy?

BACKGROUND: Since the emergence of the anti-PLA2R antibody (PLA2R-Ab) test, nephrology practice has not changed dramatically, with most nephrologists still relying on a kidney biopsy to diagnose membranous nephropathy. In this study, we examined the clinical accuracy of the anti-PLA2R antibody test using ELISA in routine clinical care. METHODS: We conducted a retrospective analysis of PLA2R-Ab testing in 187 consecutive patients seen at a single UK centre between 2003 and 2020. We compared the kidney biopsy findings with the PLA2R-ab antibody test. Patients' demography, urine protein creatinine ratios, serum albumin, and treatment characteristics including supportive and immunosuppressive treatment were recorded. The clinical accuracy of the test (e.g. sensitivity and specificity, positive [PPV] and negative [NPV] predictive values) was calculated using the kidney biopsy findings as the diagnostic reference. RESULTS: Mean levels of PLA2R-Ab titre in primary membranous nephropathy were 217RU/ml in comparison to 3RU/ml for both secondary membranous nephropathy and other diagnoses. Most patients with a positive PLA2R-Ab test had a confirmed renal biopsy diagnosis of primary membranous nephropathy with: PPV of 97.3%, sensitivity 75.5%, NPV was 79.8% and specificity was 97.8% at a cut-off threshold of >20 RU/ml. CONCLUSION: The anti-PLA2R antibody test is a highly specific test for diagnosing membranous nephropathy, and the test has the potential to allow for the diagnosis and treatment in up to 75% of PMN cases without the need for a renal biopsy. Nevertheless, patients with negative PLA2R-Ab tests will still require a biopsy to confirm their diagnosis.

Feminizing effects of ethinylestradiol in roach (Rutilus rutilus) populations with different estrogenic pollution exposure histories.

Experimental exposures aimed at assessing the risks posed by estrogens in waste-water treatment work (WwTW) effluents to fish populations have rarely considered whether populations differ in their sensitivity to estrogenic compounds. This is despite evidence that selection at genes involved in the estrogen response has occurred in wild populations, and evidence that genotype can influence estrogen-response. In this study we compare the effects of a two-year exposure to a low measured concentration (1.3 ng/L) of ethinylestradiol (EE2) on the sexual development of roach (Rutilus rutilus) whose parental generation was sampled from two river stretches heavily contaminated with WwTW effluent and from two without any known WwTW effluent contamination. Exposure to EE2 significantly reduced the proportion of genetic males and induced a range of feminized phenotypes in males. Significantly, exposure also increased the proportion of genetic females with vitellogenic oocytes from 51 to 96%, raising the possibility that estrogen pollution could impact populations of annually spawning fish species through advancing female reproduction by at least a year. However, there was no evidence that river origin affected sensitivity to estrogens in either sex. Thus, we conclude that chronic exposure to low level EE2 has reproductive health outcomes for both male and female roach, but we find no evidence that the nature or magnitude of the response is affected by the population origin.

Intraoperative low tidal volume ventilation and the risk of ICD-10 coded delirium and the use for antipsychotic medications.

BACKGROUND: Low tidal volume (VT) ventilation and its associated increase in arterial carbon dioxide (PaCO2) may affect postoperative neurologic function. We aimed to test the hypothesis that intraoperative low VT ventilation affect the incidence of postoperative ICD-10 coded delirium and/or the need for antipsychotic medications. METHODS: This is a post-hoc analysis of a large randomized controlled trial evaluating low vs. conventional VT ventilation during major non-cardiothoracic, non-intracranial surgery. The primary outcome was the incidence of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay, and the absolute difference with its 95% confidence interval (CI) was calculated. RESULTS: We studied 1206 patients (median age of 64 [55-72] years, 59.0% males, median ARISCAT of 26 [19-37], and 47.6% of ASA 3). ICD-10 coded delirium and /or antipsychotic medication use was diagnosed in 11.2% with similar incidence between low and conventional VT ventilation (11.1% vs. 11.3%; absolute difference, -0.24 [95%CI, -3.82 to 3.32]; p = 0.894). There was no interaction between allocation group and type of surgery. CONCLUSION: In adult patients undergoing major surgery, low VT ventilation was not associated with increased risk of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12614000790640 .

Synthesis, electronic structures, and reactivity of mononuclear and dinuclear low-valent molybdenum complexes in iminopyridine and bis(imino)pyridine ligand environments.

Molybdenum in redox non-innocent ligand environments features prominently in biological inorganic systems. While Holm and coworkers, along with many other researchers, have thoroughly investigated formally high-oxidation-state molybdenum (Mo(IV)-Mo(VI)) ligated by dithiolenes, less is known about molybdenum in other formal oxidation states and/or different redox-active ligand environments. This work focuses on the investigation of low-valent molybdenum in four different redox non-innocent nitrogen ligand type environments (mononucleating and dinucleating iminopyridine, mononucleating and dinucleating bis(imino)pyridine). The reaction of iminopyridine N-(2,6-diisopropylphenyl)-1-(pyridin-2-yl)methanimine (L1) with Mo(CO)3(NCMe)3 produced Mo(L1)(CO)3(NCMe). Mo(L1)(CO)3(NCMe) undergoes transformation to Mo(L1)(CO)4 upon treatment with CS2 or prolonged stirring in dichloromethane. The reaction of the open-chain dinucleating bis(iminopyridine) ligand N,N'-(2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis(1-(pyridin-2-yl)methanimine) (L2) similarly produced an hexacarbonyl complex Mo2(L2)(CO)6(NCMe)2 which also underwent transformation to the octacarbonyl Mo2(L2)(CO)8. Both complexes featured anti-parallel geometry of the chelating units. The oxidation of Mo(L1)(CO)3(NCMe) with I2 resulted in Mo(L1)(CO)3I2. The reaction of mononucleating potentially tridentate bis(imino)pyridine ligand (L3) (N-mesityl-1-(6-((E)-(mesitylimino)methyl)pyridin-2-yl)methanimine) with both Mo(CO)3(NCMe)3 and Mo(CO)4(NCMe)2 produced complexes Mo(L3)(CO)3(NCMe) and Mo(L3)(CO)4 in which L3 was coordinated in a bidentate fashion, with one imino sidearm unbound. The reaction of dinucleating macrocyclic di(bis(imino)pyridine) analogue (L4) led to the similar chemistry of Mo2(L4)(CO)6(NCMe)2 and Mo2(L4)(CO)8 complexes. Treatment of Mo(L3)(CO)3(NCMe) with I2 formed a mono(carbonyl) complex Mo(L3)(CO)I2 in which molybdenum was formally oxidized and L3 underwent coordination mode change to tridentate. The electronic structures of formally Mo(0) complexes in iminopyridine and bis(imino)pyridine ligand environments were investigated by density functional theory calculations.

Social dominance and rainfall predict telomere dynamics in a cooperative arid-zone bird.

In many vertebrate societies dominant individuals breed at substantially higher rates than subordinates, but whether this hastens ageing remains poorly understood. While frequent reproduction may trade off against somatic maintenance, the extraordinary fecundity and longevity of some social insect queens highlight that breeders need not always suffer more rapid somatic deterioration than their nonbreeding subordinates. Here, we used extensive longitudinal assessments of telomere dynamics to investigate the impact of dominance status on within-individual age-related changes in somatic integrity in a wild social bird, the white-browed sparrow-weaver (Plocepasser mahali). Dominant birds, who monopolise reproduction, had neither shorter telomeres nor faster telomere attrition rates over the long-term (1-5 years) than their subordinates. However, over shorter (half-year) time intervals dominants with shorter telomeres showed lower rates of telomere attrition (and evidence suggestive of telomere lengthening), while the same was not true among subordinates. Dominants may therefore invest more heavily in telomere length regulation (and/or somatic maintenance more broadly); a strategy that could mitigate the long-term costs of reproductive effort, leaving their long-term telomere dynamics comparable to those of subordinates. Consistent with the expectation that reproduction entails short-term costs to somatic integrity, telomere attrition rates were most severe for all birds during the breeding seasons of wetter years (rainfall is the key driver of reproductive activity in this arid-zone species). Our findings suggest that, even in vertebrate societies in which dominants monopolise reproduction, dominants may experience long-term somatic integrity trajectories indistinguishable from those of their nonreproductive subordinates.

Intra-operative ventilator mechanical power as a predictor of postoperative pulmonary complications in surgical patients: A secondary analysis of a randomised clinical trial.

BACKGROUND: Studies in critically ill patients suggest a relationship between mechanical power (an index of the energy delivered by the ventilator, which includes driving pressure, respiratory rate, tidal volume and inspiratory pressure) and complications. OBJECTIVE: We aimed to assess the association between intra-operative mechanical power and postoperative pulmonary complications (PPCs). DESIGN: Post hoc analysis of a large randomised clinical trial. SETTING: University-affiliated academic tertiary hospital in Melbourne, Australia, from February 2015 to February 2019. PATIENTS: Adult patients undergoing major noncardiothoracic, nonintracranial surgery. INTERVENTION: Dynamic mechanical power was calculated using the power equation adjusted by the respiratory system compliance (CRS). Multivariable models were used to assess the independent association between mechanical power and outcomes. MAIN OUTCOME MEASURES: The primary outcome was the incidence of PPCs within the first seven postoperative days. The secondary outcome was the incidence of acute respiratory failure. RESULTS: We studied 1156 patients (median age [IQR]: 64 [55 to 72] years, 59.5% men). Median mechanical power adjusted by CRS was 0.32 [0.22 to 0.51] (J min-1)/(ml cmH2O-1). A higher mechanical power was also independently associated with increased risk of PPCs [odds ratio (OR 1.34, 95% CI, 1.17 to 1.52); P < 0.001) and acute respiratory failure (OR 1.40, 95% CI, 1.21 to 1.61; P < 0.001). CONCLUSION: In patients receiving ventilation during major noncardiothoracic, nonintracranial surgery, exposure to a higher mechanical power was independently associated with an increased risk of PPCs and acute respiratory failure. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry no: 12614000790640.

Peptide GAM immunoadsorption in anti-PLA2 R positive autoimmune membranous nephropathy. The PRISM trial.

Membranous nephropathy associated with anti-PLA2 R autoantibody is a significant cause of nephrotic syndrome worldwide. Treatment remains empiric with a significant side-effect burden despite an increase in our understanding of the disease. We studied the effect of selectively removing this pathogenic autoantibody using immunoadsorption in adult patients with biopsy proven anti-PLA2 R membranous nephropathy. This was a multicenter, single-arm prospective clinical trial carried out in the United Kingdom. Twelve patients underwent five consecutive sessions of peptide GAM immunoadsorption with 12 months follow-up. Primary outcome was anti-PLA2 R titer at week 2. Secondary outcomes were safety and tolerability of therapy, antibody profile, and change in proteinuria, renal excretory function, serum albumin, total immunoglobulin, and quality of life at weeks 12, 24, and 52. Patients were also stratified by the presence or absence of the high-risk allele (heterozygous or homozygous for HLA-DQA1*05). Median pretreatment anti-PLA2 R was 702.50 U/mL, 1045.00 U/mL at week 2 (P-value .023) and 165.00 U/mL at week 52 (P-value .017). The treatment was well tolerated and safe. Two patients required rescue immunosuppression during the follow-up period. There was a significant improvement in serum albumin with a median at baseline of 20.50 g/L rising to 25.00 g/L at week 52 (P-value <.001). There was no statistical difference over the follow-up period in proteinuria or renal function. Patients in possession of a high-risk allele saw improvement in anti-PLA2 R titers, possibly representing a cohort more likely to benefit from immunoadsorption. Immunoadsorption therapy is a safe treatment and well-tolerated treatment in anti-PLA2 R positive autoimmune membranous nephropathy.

Chronic anticoagulation is not associated with a reduced risk of acute kidney injury in hospitalised Covid-19 patients.

BACKGROUND: Coronavirus-19 (COVID-19) has been declared a global pandemic by the World Health Organisation. Severe disease typically presents with respiratory failure but Acute Kidney Injury (AKI) and a hypercoagulable state can also occur. Early reports suggest that thrombosis may be linked with AKI. We studied the development of AKI and outcomes of patients with COVID-19 taking chronic anticoagulation therapy. METHODS: Electronic records were reviewed for all adult patients admitted to Manchester University Foundation Trust Hospitals between March 10 and April 302,020 with a diagnosis of COVID-19. Patients with end-stage kidney disease were excluded. AKI was classified as per KDIGO criteria. RESULTS: Of the 1032 patients with COVID-19 studied,164 (15.9%) were taking anticoagulant therapy prior to admission. There were similar rates of AKI between those on anticoagulants and those not anticoagulated (23.8% versus 19.7%) with no difference in the severity of AKI or requirement of renal replacement therapy between groups (1.2% versus 3.5%). Risk factors for AKI included hypertension, pre-existing renal disease and male sex. There was a higher mortality in those taking anticoagulant therapy (40.2% versus 30%). Patients taking anticoagulants were less likely to be admitted to the Intensive Care Unit (8.5% versus 17.4%) and to receive mechanical ventilation (42.9% versus 78.1%). CONCLUSION: Patients on chronic anticoagulant therapy did not have a reduced incidence or severity of AKI suggesting that AKI is unlikely to be thrombotic in nature. Therapeutic anticoagulation is currently still under investigation in randomised controlled studies to determine whether it has a potential role in COVID-19 treatment.

Associations between human leukocyte antigens and renal function.

Human leukocyte antigens (HLA) have been associated with renal function, but previous studies report contradictory findings with little consensus on the exact nature or impact of this observation. This study included 401,307 white British subjects aged 39-73 when they were recruited by UK Biobank. Subjects' HLA types were imputed using HLA*IMP:02 software. Regression analysis was used to compare 362 imputed HLA types with estimated glomerular filtration rate (eGFR) as a primary outcome and clinical indications as secondary outcome measures. 22 imputed HLA types were associated with increased eGFR (and therefore increased renal function). Decreased eGFR (decreased renal function) was associated with 11 imputed HLA types, seven of which were also associated with increased risk of end-stage renal disease and/or chronic kidney disease. Many of these HLA types are commonly inherited together in established haplotypes, for example: HLA-A*01:01, B*08:01, C*07:01, DRB1*03:01, DQB1*02:01. This haplotype has a population frequency of 9.5% in England and each allele was associated with decreased renal function. 33 imputed HLA types were associated with kidney function in white British subjects. Linkage disequilibrium in HLA heritance suggests that this is not random and particularly affects carriers of established haplotypes. This could have important applications for the diagnosis and treatment of renal disease and global population health.

HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients.

Recurrence of primary membranous nephropathy after transplantation occurs in up to 44% of patients and is driven by PLA2R antibody. Here, we asked whether genetic determinants could improve risk prediction. First, we sequenced PLA2R1 and HLA-D loci in 248 patients with primary membranous nephropathy and identified two independent single nucleotide polymorphisms (SNPs) at risk for primary membranous nephropathy at each locus. These were rs9271188 (intergenic between HLA-DRB1 and HLA-DQA1,) and rs9275086 (intergenic between HLA-DQB1 and HLA-DQA2) at the HLA-D locus along with rs6726925 and rs13018963 at the PLA2R1 locus. Then we investigated whether primary membranous nephropathy at-risk variants were associated with recurrence in a retrospective cohort of 105 donor-recipient pairs and a replication cohort of 40 pairs. Seven SNPs located between HLA-DRB1 and HLA-DQA1 in linkage disequilibrium with rs9271188, and three SNPs in the PLA2R1 region predicted recurrence when presented by the donor, but not when presented by the recipient. The two SNPs in the HLA-D region most strongly associated with recurrence (rs9271705 and rs9271550) were confirmed in the replication cohort. A genetic risk score based on the two best predictors at each locus (rs9271705, rs9271550, rs17830558, and rs3828323) identified a group of patients with high risk of recurrence. Thus, our results suggest that the graft contributes to recurrence of primary membranous nephropathy through the disease susceptibility HLA-D and PLA2R1 SNPs in an autoimmune milieu. Further studies are needed before implementation of genetic testing for these in donor selection.

Investigation into Adaptation in Genes Associated with Response to Estrogenic Pollution in Populations of Roach (Rutilus rutilus) Living in English Rivers.

Exposure of male fish to estrogenic substances from wastewater treatment works (WwTWs) results in feminization and reduced reproductive fitness. Nevertheless, self-sustaining populations of roach (Rutilus rutilus) inhabit river stretches polluted with estrogenic WwTW effluents. In this study, we examine whether such roach populations have evolved adaptations to tolerate estrogenic pollution by comparing frequency differences in single-nucleotide polymorphisms (SNPs) between populations sampled from rivers receiving either high- or low-level WwTW discharges. SNPs within 36 "candidate" genes, selected for their involvement in estrogenic responses, and 120 SNPs in reference genes were genotyped in 465 roaches. There was no evidence for selection in highly estrogen-dependent candidate genes, including those for the estrogen receptors, aromatases, and vitellogenins. The androgen receptor (ar) and cytochrome P450 1A genes were associated with large shifts in allele frequencies between catchments and in individual populations, but there is no clear link to estrogen pollution. Selection at ar in the effluent-dominated River Lee may have resulted from historical contamination with endocrine-disrupting pesticides. Critically, although our results suggest population-specific selection including at genes related to endocrine disruption, there was no strong evidence that the selection resulted from exposure to estrogen pollution.