Nephrotic Syndrome: Oedema Formation and Its Treatment With Diuretics

Oedema is a defining element of the nephrotic syndrome. Its’ management varies considerably between clinicians, with no national or international clinical guidelines, and hence variable outcomes. Oedema may have serious sequelae such as immobility, skin breakdown and local or systemic infection. Treatment of nephrotic oedema is often of limited efficacy, with frequent side-effects and interactions with other pharmacotherapy. Here, we describe the current paradigms of oedema in nephrosis, including insights into emerging mechanisms such as the role of the abnormal activation of the epithelial sodium channel in the collecting duct. We then discuss the physiological basis for traditional and novel therapies for the treatment of nephrotic oedema. Despite being the cardinal symptom of nephrosis, few clinical studies guide clinicians to the rational use of therapy. This is reflected in the scarcity of publications in this field; it is time to undertake new clinical trials to direct clinical practice

Nephrotic Syndrome: Oedema Formation and Its Treatment With Diuretics

Oedema is a defining element of the nephrotic syndrome. Its’ management varies considerably between clinicians, with no national or international clinical guidelines, and hence variable outcomes. Oedema may have serious sequelae such as immobility, skin breakdown and local or systemic infection. Treatment of nephrotic oedema is often of limited efficacy, with frequent side-effects and interactions with other pharmacotherapy. Here, we describe the current paradigms of oedema in nephrosis, including insights into emerging mechanisms such as the role of the abnormal activation of the epithelial sodium channel in the collecting duct. We then discuss the physiological basis for traditional and novel therapies for the treatment of nephrotic oedema. Despite being the cardinal symptom of nephrosis, few clinical studies guide clinicians to the rational use of therapy. This is reflected in the scarcity of publications in this field; it is time to undertake new clinical trials to direct clinical practice

Cocaine-induced granulomatosis with polyangiitis—an under-recognized condition

Objectives: Cocaine and cocaine mixed with levamisole are increasingly used in the UK and result in significant direct nasal damage in addition to promoting vasculitis. Our aims were as follows: (1) to identify the main symptoms and presentation of cocaine-induced vasculitis; (2) to provide evidence regarding the best practice for the investigation and diagnosis of cocaine-induced vasculitis; and (3) to analyse the clinical outcomes of patients in order to understand the optimal management for the condition./ Methods: We performed a retrospective case series analysis of patients presenting with cocaine-induced midline destructive lesions or vasculitis compatible with granulomatosis with polyangiitis (GPA) from two large tertiary vasculitis clinics between 2016 and 2021./ Results: Forty-two patients (29 Birmingham, 13 London) with cocaine-induced midline lesions or systemic disease were identified. The median age was 41 years (range 23–66 years). Current cocaine use was common, and 20 of 23 samples provided were positive when routine urine toxicology was performed; 9 patients who denied ever using cocaine were identified as using cocaine based on urine toxicology analysis, and 11 who stated they were ex-users still tested positive. There was a high incidence of septal perforation (75%) and oronasal fistula (15%). Systemic manifestations were less common (27%), and only one patient had acute kidney injury. Fifty-six per cent of our patients were PR3-ANCA positive, with none testing positive for MPO-ANCA. Symptom remission required cocaine discontinuation even when immunosuppression was administered./ Conclusion: Patients with destructive nasal lesions, especially young patients, should have urine toxicology performed for cocaine before diagnosing GPA and considering immunosuppressive therapy. The ANCA pattern is not specific for cocaine-induced midline destructive lesions. Treatment should be focused on cocaine cessation and conservative management in the first instance in the absence of organ-threatening disease

Secondary and tertiary transfer of latent fingermarks using a sticky note – A feasibility study

Latent fingermarks are enhanced in order to be visible and available for comparison to determine source. Once a fingermark has been identified to a source, the activity that led to it being left on a particular surface may need to be determined. It has been previously shown that under certain conditions fingermarks initially deposited onto a surface (the primary transfer) can be transferred on to another substrate through direct contact – secondary transfer. This study investigates the possibility of secondary and subsequent tertiary transfer using sticky notes. To explore secondary transfer, fingermarks were deposited directly onto two different brands of sticky notes, spanning the adhesive and non-adhesive areas, and then placed in direct contact with paper for up to 72 h under a 5 kg weight. For some donors, there was transfer of fingermarks from the sticky note to the paper, with better results for the adhesive areas. The quality of the transferred fingermarks was dependent on initial fingermark quality and the transferred fingermark was a mirror image of the original. The type of paper used as the secondary substrate was also shown to have an effect. Given the adhesive nature of sticky notes tertiary transfer was also investigated and the potential to lift fingermarks from a glass slide and transfer them onto paper or a second glass slide. In the case of transfer to paper, there were only tertiary transferred fingermarks considered to be of useful quality (score 3 or 4) in 6% of samples and a further 33% of samples were detected but provided evidence of contact only (score 1 or 2) (n = 120). For transfer to glass, tertiary transferred samples were of poorer quality with no useful fingermarks and only 3% of samples scoring 1 or 2 (n = 120). The latter was in part due to the deposition of sticky note adhesive traces obscuring the fingermarks. In the case of tertiary transfer, fingermarks on the final tertiary surface were in the correct orientation. This work demonstrates that whilst tertiary transfer of fingermarks is possible under the laboratory conditions used, the likelihood of the effective transfer of a useful and potentially identifiable fingermark is in reality low

Leukocyte and serum S100A8/S100A9 expression reflects disease activity in ANCA-associated vasculitis and glomerulonephritis.

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) commonly results in glomerulonephritis, in which neutrophils and monocytes have important roles. The heterodimer calprotectin (S100A8/S100A9, mrp8/14) is a Toll-like receptor-4 ligand found in neutrophils and monocytes and is elevated in inflammatory conditions. By immunohistochemistry of renal biopsies, patients with focal or crescentic glomerular lesions were found to have the highest expression of calprotectin and those with sclerotic the least. Serum levels of calprotectin as measured by ELISA were elevated in patients with active AAV and the levels decreased but did not normalize during remission, suggesting subclinical inflammation. Calprotectin levels in patients with limited systemic disease increased following treatment withdrawal and were significantly elevated in patients who relapsed compared with those who did not. As assessed by flow cytometry, patients with AAV had higher monocyte and neutrophil cell surface calprotectin expression than healthy controls, but this was not associated with augmented mRNA expression in CD14(+) monocytes or CD16(+) neutrophils. Thus, serum calprotectin is a potential disease biomarker in patients with AAV, and may have a role in disease pathogenesis

Beta cell death by cell-free DNA and outcome after clinical islet transplantation

Background: Optimizing engraftment and early survival after clinical islet transplantation is critical to long-term function, but there are no reliable, quantifiable measures to assess beta cell death. Circulating cell free DNA (cfDNA) derived from beta cells has been identified as a novel biomarker to detect cell loss, and was recently validated in new-onset type 1 diabetes and in islet transplant patients. Methods: Herein we report beta cell cfDNA measurements after allotransplantation in 37 subjects and the correlation with clinical outcomes. Results: A distinctive peak of cfDNA was observed 1hr after transplantation in 31/37 (83.8%) of subjects. The presence and magnitude of this signal did not correlate with transplant outcome. The 1hr signal represents dead beta cells carried over into the recipient after islet isolation and culture, combined with acute cell death post infusion. Beta cell cfDNA was also detected 24hrs post-transplant (8/37 subjects, 21.6%). This signal was associated with higher 1-month insulin requirements (p=0.04), lower 1-month stimulated C-peptide levels (p=0.01) and overall worse 3-month engraftment, by insulin independence (ROC:AUC=0.70, p=0.03) and Beta 2 score (ROC:AUC=0.77, p=0.006). Conclusions: cfDNA-based estimation of beta cell death 24hrs after islet allotransplantation correlates with clinical outcome and could predict early engraftment.B.G.-L. is supported through the Alberta Innovates :Health Solutions (AIHS) Clinician Fellowship and through the CNTRP. A.P. is supported through AIHS Postgraduate Fellowship and CNTRP. A.M.J.S. is supported through AIHS, and holds a Canada Research Chair in Transplantation Surgery and Regenerative Medicine funded through the Government of Canada. A.M.J.S. is also funded by AIHS Collaborative Research and Innovation Opportunity Team Award and the Diabetes Research Institute Foundation of Canada (DRIFCan). Supported by grants from the Juvenile Diabetes Research Foundation (JDRF) (3-SRA-2014-38-Q-R, to Y.D. and A.M.J.S.), National Institute of Health (NIH) (HIRN grant UC4 DK104216, to Y.D.), DON foundation (Stichting Diabetes Onderzoek Nederland) (to Y.D), the European Union (ELASTISLET project, to Y.D.) and the Kahn foundation (to Y.D., R.S., and B.G.). Supported in part by a grant from The United States Agency for International Development (USAID) American Schools and Hospitals Abroad Program for the upgrading of the Hebrew University sequencing core facilit

The first national subject benchmark statement for UK higher education in policing: the importance of effective partnership and collaboration

Purpose (limit 100 words) The Quality Assurance Agency (QAA) for Higher Education in the UK focuses on maintaining, enhancing and standardising the quality of higher education. Of significant impact are the development of subject benchmark statements (SBS) by the QAA, which describe the type and content of study along with the academic standards expected of graduates in specific disciplines. Prior to 2022, the QAA did not have a SBS to which higher education policing programmes could be directly aligned. Design/methodology/approach (limit 100 words) Over 12-months, a SBS advisory group with representatives from higher education across England, Scotland, Wales and Northern Ireland, The College of Policing, QAA, Police Federation of England and Wales, and policing, worked in partnership to harness their collective professional experience and knowledge to create the first UK SBS for policing. Post publication of the SBS, permission was sought and granted from both the College of Policing and QAA for members of the advisory group to reflect in an article on their experiences of collaborating and working in partnership to achieve the SBS. Findings (limit 100 words) There is great importance of creating a shared vision and mutual trust, developed through open facilitated discussions, with representatives championing their cause and developing a collaborative and partnership approach to completing the SBS. Practical implications (limit 100 words) A collaborative and partnership approach is essential in developing and recognising the academic discipline of policing. This necessarily requires the joint development of initiatives, one of which is the coming together of higher education institutions, PSRBs and practitioner groups to collaborate and design QAA benchmark statements. Originality/value (limit 100 words) The SBS for policing is the first across the UK. The authors experiences can be used to assist others in their developments of similar subject specific benchmarking or academic quality standards. Social implications (limit 100 words) The SBS advisory group has further driven forward the emergence of policing as a recognised academic discipline to benefit multiple stakeholders

Effects of PACK guide training on the management of asthma and chronic obstructive pulmonary disease by primary care clinicians: a pragmatic cluster randomised controlled trial in Florianópolis, Brazil

Introduction The Practical Approach to Care Kit (PACK) guide was localised for Brazil, where primary care doctors and nurses were trained to use it. Methods Twenty-four municipal clinics in Florianópolis were randomly allocated to receive outreach training and the guide, and 24 were allocated to receive only the guide. 6666 adult patients with asthma or chronic obstructive pulmonary disease (COPD) were enrolled, and trial outcomes were measured over 12 months, using electronic medical records. The primary outcomes were composite scores of treatment changes and spirometry, and new asthma and COPD diagnosis rates. Results Asthma scores in 2437 intervention group participants were higher (74.8%, 20.4% and 4.8% with scores of 0, 1 and 2, respectively) than in 2633 control group participants (80.0%, 16.8% and 3.2%) (OR for higher score 1.32, 95% CI 1.08 to 1.61, p=0.006). Adjusted for asthma scores recorded in each clinic before training started, the OR was 1.24 (95% CI 1.03 to 1.50, p=0.022). COPD scores in 1371 intervention group participants (77.7%, 17.9% and 4.3% with scores of 0, 1 and 2) did not differ from those in 1181 control group participants (80.5%, 15.8% and 3.7%) (OR 1.21, 95% CI 0.94 to 1.55, p=0.142). Rates of new asthma and COPD diagnoses, and hospital admission, and indicators of investigation, diagnosis and treatment of comorbid cardiovascular disease, diabetes and depression, and tobacco cessation did not differ between trial arms. Conclusion PACK training increased guideline-based treatment and spirometry for asthma but did not affect COPD or comorbid conditions, or diagnosis rates

A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy

INTRODUCTION: Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults and is characterized by detectable autoantibodies against glomerular antigens, most commonly phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain containing 7A (THSD7A). In Europeans, genetic variation in at least five loci, PLA2R1, HLA-DRB1, HLA-DQA1, IRF4, and NFKB1, affects the risk of disease. Here, we investigated the genetic risk differences between different autoantibody states. METHODS: 1,409 MN individuals were genotyped genome-wide with a dense SNV array. The genetic risk score (GRS) was calculated utilizing the previously identified European MN loci, and results were compared with 4,929 healthy controls and 422 individuals with steroid-sensitive nephrotic syndrome. RESULTS: GRS was calculated in the 759 MN individuals in whom antibody status was known. The GRS for MN was elevated in the anti-PLA2R1 antibody-positive (N = 372) compared with both the unaffected control (N = 4,929) and anti-THSD7A-positive (N = 31) groups (p < 0.0001 for both comparisons), suggesting that this GRS reflects anti-PLA2R1 MN. Among PLA2R1-positive patients, GRS was inversely correlated with age of disease onset (p = 0.009). Further, the GRS in the dual antibody-negative group (N = 355) was intermediate between controls and the PLA2R1-positive group (p < 0.0001). CONCLUSION: We demonstrate that the genetic risk factors for PLA2R1- and THSD7A-antibody-associated MN are different. A higher GRS is associated with younger age of onset of disease. Further, a proportion of antibody-negative MN cases have an elevated GRS similar to PLA2R1-positive disease. This suggests that in some individuals with negative serology the disease is driven by autoimmunity against PLA2R1