Membranous nephropathy is a common cause of nephrotic syndrome in adults. Traditional glucocorticoid and cyclophosphamide treatment regimens have significant associated toxicity. Over the last two decades, immunological understanding of this disease has significantly advanced and selective B-cell depletion with rituximab is now recommended as a first line treatment. Our centre has now used rituximab for primary membranous nephropathy for over a decade, with several patients receiving maintenance treatment. Here, we examine the outcomes of rituximab therapy for primary membranous nephropathy in our centre. We performed a single centre, retrospective cohort study of patients who received treatment with rituximab for primary membranous nephropathy between January 2011–August 2024. Patients were identified from both a local database and a search of VitalData, the South-East Scotland electronic patient record. Immunosuppressive treatment regimens were recorded. Laboratory data were collected from the time of diagnosis, prior to each rituximab treatment and at 3-monthly intervals thereafter including phospholipase A2 receptor antibody levels and CD19 count where available. Episodes of thrombosis and severe infection (defined as infection requiring hospitalisation) were identified. Complete remission was defined as a protein:creatinine ratio (PCR) <30 mg/mmol and a normal serum albumin; partial remission was defined as a PCR of 30–350 mg/mmol (or <350 mg/mmol and a 50% decrease from baseline) with improved serum albumin and stable serum creatinine. Data were censored at the point of further immunosuppressive treatment. Forty-seven patients (72% male; mean age 51 ± 2 years) received at least one treatment with rituximab (2 × 1 g 14 days apart) for primary membranous nephropathy, of whom three had post-transplant disease recurrence. Baseline serum albumin was 21 ± 1 g/L, urine PCR was 750 (410–1,323) mg/mmol) and estimated glomerular filtration rate (eGFR) was 50 (36–83) mL/min/1.73 m2. Baseline serum phospholipase A2-receptor antibody levels were available for 23 patients and were elevated in 13 (57%). Most patients (67%) were managed conservatively prior to rituximab, with a median time to immunosuppression 7 (4–18) months. Eleven patients received simultaneous treatment for membranous nephropathy with at least one additional immunosuppressive agent (6 received prednisolone, 4 tacrolimus, 1 cyclophosphamide, 1 mycophenolate mofetil). In the 45 patients with at least 6 months follow-up, overall remission rate was 77% (18 complete remissions; 18 partial remission). Of the 9 patients who did not achieve remission, 3 had a ≥50% reduction in proteinuria and a ≥50% rise in serum albumin. The median time to remission was 15 (9–21) months. At last follow-up, median serum albumin was 36 (30–38) g/L and urine PCR 50 (60–209) mg/mmol (P < 0.0001 for both in comparison to baseline), and eGFR was stable (48 (27–79) mL/min/1.73 m2, P = 0.067 compared to baseline). Twenty-two patients received additional maintenance rituximab treatment (median cumulative dose 4 g (range 3–9 g). Three patients developed severe infections within 12 months of rituximab. Of these, two were kidney transplant recipients on additional immunosuppression and the third died due to covid-19. We have successfully treated 47 patients with rituximab for primary membranous nephropathy. In a real-world setting, we find rituximab to be a safe and effective treatment. We are moving towards maintenance treatment for many patients.

Abstract Background Automated Item Generation (AIG) uses computer software to create multiple items from a single question model. There is currently a lack of data looking at whether item variants to a single question result in differences in student performance or human-derived standard setting. The purpose of this study was to use 50 Multiple Choice Questions (MCQs) as models to create four distinct tests which would be standard set and given to final year UK medical students, and then to compare the performance and standard setting data for each. Methods Pre-existing questions from the UK Medical Schools Council (MSC) Assessment Alliance item bank, created using traditional item writing techniques, were used to generate four ‘isomorphic’ 50-item MCQ tests using AIG software. Isomorphic questions use the same question template with minor alterations to test the same learning outcome. All UK medical schools were invited to deliver one of the four papers as an online formative assessment for their final year students. Each test was standard set using a modified Angoff method. Thematic analysis was conducted for item variants with high and low levels of variance in facility (for student performance) and average scores (for standard setting). Results Two thousand two hundred eighteen students from 12 UK medical schools participated, with each school using one of the four papers. The average facility of the four papers ranged from 0.55–0.61, and the cut score ranged from 0.58–0.61. Twenty item models had a facility difference > 0.15 and 10 item models had a difference in standard setting of > 0.1. Variation in parameters that could alter clinical reasoning strategies had the greatest impact on item facility. Conclusions Item facility varied to a greater extent than the standard set. This difference may relate to variants causing greater disruption of clinical reasoning strategies in novice learners compared to experts, but is confounded by the possibility that the performance differences may be explained at school level and therefore warrants further study.

Editor – Allocation to UK Foundation Programme training posts has long been an issue of contention. Following recent analysis of the allocation process, the UK Foundation Programme Office has now moved away from the use of a Situational Judgement Test (SJT) and the Educational Performance Measure

Objectives ANCA-associated vasculitis (AAV) is a rare autoimmune disorder that commonly involves the kidney. Early identification of kidney involvement, assessing treatment-response and predicting outcome are important clinical challenges. Here, we assessed the potential utility of interval kidney biopsy in AAV. Methods In a tertiary referral centre with a dedicated vasculitis service, we identified patients with AAV who had undergone interval kidney biopsy, defined as a repeat kidney biopsy (following an initial biopsy showing active AAV) undertaken to determine the histological response in the kidney following induction immunosuppression. We analysed biochemical, histological and outcome data, including times to kidney failure and death for all patients. Results We identified 57 patients with AAV who underwent at least one interval kidney biopsy (59 interval biopsies in total; median time to interval biopsy similar to 130 days). Of the 59 interval biopsies performed, 24 (41%) patients had clinically suspected active disease at time of biopsy which was confirmed histologically in only 42% of cases; 35 (59%) patients were in clinical disease-remission, and this was correct in 97% of cases. The clinician's impression was incorrect in one in four patients. Hematuria at interval biopsy did not correlate with histological activity. Interval biopsy showed fewer acute lesions and more chronic damage compared with initial biopsy and led to immunosuppressive treatment-change in 75% (44/59) of patients. Clinical risk prediction tools tended to operate better using interval biopsy data. Conclusion Interval kidney biopsy is useful for determining treatment-response and subsequent disease management in AAV. It may provide better prognostic information than initial kidney biopsy and should be considered for inclusion into future clinical trials and treatment protocols for patients with AAV.

Acute kidney injury (AKI) is common and associated with increased risks of cardiovascular and chronic kidney disease. Causative molecular/physiological pathways are poorly defined. There are no therapies to improve long-term outcomes. An activated endothelin system promotes cardiovascular and kidney disease progression. We hypothesized a causal role for this in the transition of AKI to chronic disease. Plasma endothelin-1 was threefold higher; urine endothelin-1 was twofold higher; and kidney preproendothelin-1, endothelin-A, and endothelin-B receptor message up-regulated in patients with AKI. To show causality, AKI was induced in mice by prolonged ischemia with a 4-week follow-up. Ischemic injury resulted in hypertension, endothelium-dependent and endothelium-independent macrovascular and microvascular dysfunction, and an increase in circulating inflammatory Ly6C high monocytes. In the kidney, we observed fibrosis, microvascular rarefaction, and inflammation. Administration of endothelin-A antagonist, but not dual endothelin-A/B antagonist, normalized blood pressure, improved macrovascular and microvascular function, and prevented the transition of AKI to CKD. Endothelin-A blockade reduced circulating and renal proinflammatory Ly6C high monocytes and B cells, and promoted recruitment of anti-inflammatory Ly6C low monocytes to the kidney. Blood pressure reduction alone provided no benefits; blood pressure reduction alongside blockade of the endothelin system was as effective as endothelin-A antagonism in mitigating the long-term sequelae of AKI in mice. Our studies suggest up-regulation of the endothelin system in patients with AKI and show in mice that existing drugs that block the endothelin system, particularly those coupling vascular support and anti-inflammatory action, can prevent the transition of AKI to chronic kidney and cardiovascular disease.

Background The use of remote online delivery of summative assessments has been underexplored in medical education. Due to the COVID-19 pandemic, all end of year applied knowledge multiple choice question (MCQ) tests at one UK medical school were switched from on campus to remote assessments. Methods We conducted an online survey of student experience with remote exam delivery and compared test performance in remote versus invigilated campus-based forms of similar assessments for Year 4 and 5 students across two academic years. Results Very few students experienced technical or practical problems in completing their exam remotely. Test anxiety was reduced for some students but increased for others. The majority of students preferred the traditional setting of invigilated exams in a computer lab, feeling this ensured an even playing field for all candidates. Mean score was higher for Year 4 students in the remotely-delivered versus campus-based form of the same exam (76.53% [SD 6.57] vs. 72.81% [6.64]; t 438.38 = 5.94, p = 0.001; d = 0.56), whereas candidate performance was equivalent across both forms for Year 5 students. Conclusions Remote online MCQ exam delivery is an effective and generally acceptable approach to summative assessment, and could be used again in future without detriment to students if onsite delivery is not possible.

Background Due to differing assessment systems across UK medical schools, making meaningful cross-school comparisons on undergraduate students’ performance in knowledge tests is difficult. Ahead of the introduction of a national licensing assessment in the UK, we evaluate schools’ performances on a shared pool of “common content” knowledge test items to compare candidates at different schools and evaluate whether they would pass under different standard setting regimes. Such information can then help develop a cross-school consensus on standard setting shared content. Methods We undertook a cross-sectional study in the academic sessions 2016-17 and 2017-18. Sixty “best of five” multiple choice ‘common content’ items were delivered each year, with five used in both years. In 2016-17 30 (of 31 eligible) medical schools undertook a mean of 52.6 items with 7,177 participants. In 2017-18 the same 30 medical schools undertook a mean of 52.8 items with 7,165 participants, creating a full sample of 14,342 medical students sitting common content prior to graduation. Using mean scores, we compared performance across items and carried out a “like-for-like” comparison of schools who used the same set of items then modelled the impact of different passing standards on these schools. Results Schools varied substantially on candidate total score. Schools differed in their performance with large (Cohen’s d around 1) effects. A passing standard that would see 5 % of candidates at high scoring schools fail left low-scoring schools with fail rates of up to 40 %, whereas a passing standard that would see 5 % of candidates at low scoring schools fail would see virtually no candidates from high scoring schools fail. Conclusions Candidates at different schools exhibited significant differences in scores in two separate sittings. Performance varied by enough that standards that produce realistic fail rates in one medical school may produce substantially different pass rates in other medical schools – despite identical content and the candidates being governed by the same regulator. Regardless of which hypothetical standards are “correct” as judged by experts, large institutional differences in pass rates must be explored and understood by medical educators before shared standards are applied. The study results can assist cross-school groups in developing a consensus on standard setting future licensing assessment.

Abstract Objective ANCA-associated vasculitis (AAV) is a small vessel vasculitis that commonly presents in the elderly. However, there are few long-term outcome data for these patients. Here, we assessed long-term outcomes in a single-centre cohort of elderly patients with AAV. Additionally, we tested whether a pre-morbid frailty score could aid prognosis. Methods Using a prospectively-compiled dataset, we investigated patients over the age of 65 who presented with AAV between 2005 and 2017 to a regional vasculitis centre. We used a Cox model to determine the factors associated with mortality. We also compared outcomes in pre-specified subgroups stratified by baseline frailty score, ANCA serotype and induction immunosuppression (with cyclophosphamide, rituximab or mycophenolate mofetil used as the main glucocorticoid-sparing agent). Results 83 patients were included in the study and were followed for a median of 1203 days. Median age was 74 years (range 65–92). Two- and five-year survival in the overall cohort were 83% (95% CI 75, 92%) and 75% (95% CI 65, 86%), respectively. The median cumulative dose of oral prednisolone was 2030 mg during the first three months. Only one patient received intravenous glucocorticoids. Age, frailty score and CRP at presentation were independently associated with mortality; all deaths occurred in patients aged over 75 at presentation. Patients treated with a cyclophosphamide-based induction regimen tended to be younger than those treated with rituximab or mycophenolate mofetil. Survival was better in the cyclophosphamide-treated group. Conclusion In the contemporary era, the overall prognosis of AAV in elderly patients is good. Baseline frailty associates with disease outcomes including mortality. A low-dose glucocorticoid regimen (avoiding intravenous methylprednisolone) can be used to treat AAV effectively in elderly patients.

The endothelin system may be an important player in hypertensive end-organ injury as endothelin-1 increases blood pressure and is pro-inflammatory. The immune system is emerging as an important regulator of blood pressure and we have shown that the early hypertensive response to angiotensin-II infusion was amplified in mice deficient of myeloid endothelin-B (ETB) receptors (LysM-CreEdnrblox/lox). Hypothesizing that these mice would display enhanced organ injury, we gave angiotensin-II to LysM-CreEdnrblox/lox and littermate controls (Ednrblox/lox) for six weeks. Unexpectedly, LysM-CreEdnrblox/lox mice were significantly protected from organ injury, with less proteinuria, glomerulosclerosis and inflammation of the kidney compared to controls. In the eye, LysM-CreEdnrblox/lox mice had fewer retinal hemorrhages, less microglial activation and less vessel rarefaction. Cardiac remodeling and dysfunction were similar in both groups at week six but LysM-CreEdnrblox/lox mice had better endothelial function. Although blood pressure was initially higher in LysM-CreEdnrblox/lox mice, this was not sustained. A natriuretic switch at about two weeks, due to enhanced ETB signaling in the kidney, induced a hypertensive reversal. By week six, blood pressure was lower in LysM-CreEdnrblox/lox mice than in controls. At six weeks, macrophages from LysM-CreEdnrblox/lox mice were more anti-inflammatory and had greater phagocytic ability compared to the macrophages of Ednrblox/lox mice. Thus, myeloid cell ETB receptor signaling drives this injury both through amplifying hypertension and by inflammatory polarization of macrophages.

Antineutrophil cytoplasmic antibody (ANCA)−associated vasculitis is a multisystem autoimmune disease that often involves the lungs. It can be serious and sometimes fatal, and requires prompt recognition and treatment. Cyclophosphamide is a well-established alkylating agent that is widely used in the treatment of ANCA vasculitis. The most common side effects of cyclophosphamide are infection and the risk of malignancy.

Aims Hypertension is common. Recent data suggest that macrophages (M) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying M number and phenotype. Methods and results In vitro, M phi ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Using the CD11b-DTR mouse and novel mice with myeloid cell-specific endothelin-B (ETB) receptor deficiency (LysMET(B)(-/-)), we explored the effects of modifying M phi number and phenotype on the hypertensive effects of ET-1, angiotensin II (ANG II), a model that is ET-1 dependent, and salt. In patients with small vessel vasculitis, the impacts of M phi depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human M phi expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of M phi with exogenous ET-1 did not polarize M phi phenotype. Interestingly, both mouse and human M phi cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. M phi depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMET(B)(-/-) mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received M phi depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies. Conclusion M phi and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.

Objective To assess the utility and ability of the novel prescribing very short answer (VSA) question format to identify the sources of undergraduate prescribing errors when compared with the conventional single best answer (SBA) question format and assess the acceptability of machine marking prescribing VSAs. Design A prospective study involving analysis of data generated from a pilot two-part prescribing assessment. Setting Two UK medical schools. Participants 364 final year medical students took part. Participation was voluntary. There were no other inclusion or exclusion criteria. Outcomes (1) Time taken to mark and verify VSA questions (acceptability), (2) differences between VSA and SBA scores, (3) performance in VSA and (4) SBA format across different subject areas and types of prescribing error made in the VSA format. Results 18 200 prescribing VSA questions were marked and verified in 91 min. The median percentage score for the VSA test was significantly lower than the SBA test (28% vs 64%, p<0.0001). Significantly more prescribing errors were detected in the VSA format than the SBA format across all domains, notably in prescribing insulin (96.4% vs 50.3%, p<0.0001), fluids (95.6% vs 55%, p<0.0001) and analgesia (85.7% vs 51%, p<0.0001). Of the incorrect VSA responses, 33.1% were due to the medication prescribed, 6.0% due to the dose, 1.4% due to the route and 4.8% due to the frequency. Conclusions Prescribing VSA questions represent an efficient tool for providing detailed insight into the sources of significant prescribing errors, which are not identified by SBA questions. This makes the prescribing VSA a valuable formative assessment tool to enhance students’ skills in safe prescribing and to potentially reduce prescribing errors.

Macrophage-colony stimulating factor (M-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF) play key roles in the differentiation of macrophages and dendritic cells (DCs). We examined the effect of treatment with M-CSF-containing macrophage medium or GM-CSF-containing DC medium upon the phenotype of murine bone marrow-derived macrophages and DCs. Culture of macrophages for 5 days in DC medium reduced F4/80 expression and increased CD11c expression with cells effectively stimulating T cell proliferation in a mixed lymphocyte reaction. DC medium treatment of macrophages significantly reduced phagocytosis of both apoptotic cells and latex beads and strongly induced the expression of the chemokine receptor CCR7 known to be involved in DC trafficking to lymph nodes. Lysates of obstructed murine kidneys expressed both M-CSF and GM-CSF though M-CSF expression was dominant (M-CSF:GM-CSF ratio ∼30:1). However, combination treatment with both M-CSF and GM-CSF (ratio 30:1) indicated that small amounts of GM-CSF skewed macrophages towards a DC–like phenotype. To determine whether macrophage phenotype might be modulated in vivo we tracked CD45.1+ bone marrow-derived macrophages intravenously administered to CD45.2+ mice with unilateral ureteric obstruction. Flow cytometry of enzyme dissociated kidneys harvested 3 days later indicated CD11c and MHC Class II upregulation by adoptively transferred CD45.1+ cells with CD45.1+ cells evident in draining renal lymph nodes. Our data suggests that GM-CSF modulates mononuclear phagocyte plasticity, which likely promotes resolution of injury and healing in the injured kidney.

Objectives Given the absence of a common passing standard for students at UK medical schools, this paper compares independently set standards for common one from five' single-best-answer (multiple-choice) items used in graduation-level applied knowledge examinations and explores potential reasons for any differences.Methods A repeated cross-sectional study was conducted. Participating schools were sent a common set of graduation-level items (55 in 2013-2014; 60 in 2014-2015). Items were selected against a blueprint and subjected to a quality review process. Each school employed its own standard-setting process for the common items. The primary outcome was the passing standard for the common items by each medical school set using the Angoff or Ebel methods.Results Of 31 invited medical schools, 22 participated in 2013-2014 (71%) and 30 (97%) in 2014-2015. Schools used a mean of 49 and 53 common items in 2013-2014 and 2014-2015, respectively, representing around one-third of the items in the examinations in which they were embedded. Data from 19 (61%) and 26 (84%) schools, respectively, met the inclusion criteria for comparison of standards. There were statistically significant differences in the passing standards set by schools in both years (effect sizes (f(2)): 0.041 in 2013-2014 and 0.218 in 2014-2015; both p < 0.001). The interquartile range of standards was 5.7 percentage points in 2013-2014 and 6.5 percentage points in 2014-2015. There was a positive correlation between the relative standards set by schools in the 2 years (Pearson's r = 0.57, n = 18, p = 0.014). Time allowed per item, method of standard setting and timing of examination in the curriculum did not have a statistically significant impact on standards.Conclusions Independently set standards for common single-best-answer items used in graduation-level examinations vary across UK medical schools. Further work to examine standard-setting processes in more detail is needed to help explain this variability and develop methods to reduce it.

Renal involvement is common in systemic lupus erythematosus. Early diagnosis of lupus nephritis (LN), allowing the instigation of appropriate therapy, remains an important clinical challenge. Current biomarkers in clinical practice are less than ideal, lacking both sensitivity and specificity. In the previous issue of Arthritis Research & Therapy , Schwartz and colleagues demonstrated the potential value of urinary TNF-like weak inducer of apoptosis (uTWEAK) as a biomarker for LN. They showed that uTWEAK is elevated in subjects with LN at diagnosis compared with those with systemic lupus erythematosus but no renal disease, and correlates with the degree of clinical disease activity. These data are thought-provoking and provide the platform for future longer- term studies.

A 56-year-old woman presented with nephrotic syndrome, lethargy, and a rash. Recently, after a long-haul flight, she was diagnosed with bilateral pulmonary emboli and was being treated with warfarin. She had no history of other thromboses, emboli, or miscarriages. Although the patient had signs and symptoms of autoimmune disease, the definitive autoantibodies were not found during serologic testing.

Quantum dots are semiconductor fluorescent nanocrystals that exhibit excellent characteristics compared with more commonly used organic fluorescent dyes. For many years quantum dot conjugated products have been available in multiple forms for fluorescence imaging of tissue sections under the trademark name Qdot®. They have much increased brightness, narrow emission spectrum, large Stokes shift and photostability compared with conventional organic fluorescent dyes, which together make them the fluorophores of choice for demanding requirements. Vivid Qdots are recent replacements for original Qdots, modified to improve brightness, however this has affected the fluorescence stability in commonly used conditions for immunohistochemistry. We present here our investigation of the stability of original and Vivid Qdots in solution and in immunohistochemistry, highlight the potential pitfalls and propose a protocol for stable and reliable multiplex staining with current commercially available original and Vivid Qdots.