Familial vasculitides: granulomatosis with polyangitis and microscopic polyangitis in two brothers with differing anti-neutrophil cytoplasm antibody specificity

Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of rare autoimmune diseases. Although the aetiology of AAV is uncertain, it is likely that genetic and environmental factors contribute. We report the unusual case of two brothers presenting with AAV with differing clinical pictures and differing ANCA specificity. There is a recently identified difference in genetic risk factors associated with ANCA specificity, making it surprising that first-degree relatives develop AAV with differing clinical and serological features. Our report illustrates the complex aetiology of AAV and suggests that further research on the interaction of genetic and environmental factors is needed

P2X7 receptor antagonism ameliorates renal dysfunction in a rat model of sepsis

Sepsis is a major clinical problem associated with significant organ dysfunction and high mortality. The ATP‐sensitive P2X7 receptor activates the NLRP3 inflammasome and is a key component of the innate immune system. We used a fluid‐resuscitated rat model of fecal peritonitis and acute kidney injury (AKI) to investigate the contribution of this purinergic receptor to renal dysfunction in sepsis. Six and 24 h time‐points were chosen to represent early and established sepsis, respectively. A selective P2X7 receptor antagonist (A‐438079) dissolved in dimethyl sulfoxide (DMSO) was infused 2 h following induction of sepsis. Compared with sham‐operated animals, septic animals had significant increases in heart rate (−1(−4 to 8)% vs. 21(12–26)%; P = 0.003), fever (37.4(37.2–37.6)°C vs. 38.6(38.2–39.0)°C; P = 0.0009), and falls in serum albumin (29(27–30)g/L vs. 26(24–28); P = 0.0242). Serum IL‐1β (0(0–10)(pg/mL) vs. 1671(1445–33778)(pg/mL); P < 0.001) and renal IL‐1β (86(50–102)pg/mg protein vs. 200 (147–248)pg/mg protein; P = 0.0031) were significantly elevated in septic compared with sham‐operated animals at 6 h. Serum creatinine was elevated in septic animals compared with sham‐operated animals at 24 h (23(22–25) μmol/L vs. 28 (25–30)μmol/L; P = 0.0321). Renal IL‐1β levels were significantly lower in A‐438079‐treated animals compared with untreated animals at 6 h (70(55–128)pg/mg protein vs. 200(147–248)pg/mg protein; P = 0.021). At 24 h, compared with untreated animals, A‐438079‐treated animals had more rapid resolution of tachycardia (22(13–36)% vs. −1(−6 to 7)%; P = 0.019) and fever (39.0(38.6–39.1)°C vs. 38.2(37.6–38.7)°C; P < 0.024), higher serum albumin (23(21–25)g/L vs. (27(25–28)g/L); P = 0.006), lower arterial lactate (3.2(2.5–4.3)mmol/L vs. 1.4(0.9–1.8)mmol/L; P = 0.037), and lower serum creatinine concentrations (28(25–30)μmol/L vs. 22(17–27)μmol/L; P = 0.019). P2X7A treatment ameliorates the systemic inflammatory response and renal dysfunction in this clinically relevant model of sepsis‐related AKI

Severe COVID-19 is associated with endothelial activation and abnormal glycosylation of von Willebrand factor in patients undergoing hemodialysis

Background: A major clinical feature of severe coronavirus diease 2019 (COVID-19) is microvascular thrombosis linked to endothelial cell activation. Consistent with this, a number of studies have shown that patients with severe COVID-19 have highly elevated plasma levels of von Willebrand Factor (VWF) that may contribute to the prothrombotic phenotype. In the current study, we investigated the extent of endothelial activation in patients receiving hemodialysis who had either mild or severe COVID-19. Methods: Plasma VWF, ADAMTS-13, angiopoietin-2 (Ang2), and syndecan-1 levels were determined by ELISA. The sialic acid content of VWF was investigated using a modified ELISA to measure elderberry bark lectin, specific for sialic acid residues, binding to VWF. Results: Patients receiving hemodialysis with severe COVID-19 had significantly higher plasma levels of VWF and lower ADAMTS-13. VWF levels peaked and were sustained during the first 10 days after positive confirmation of infection. While Ang2 trended toward being higher in severely ill patients, this did not reach significance; however, severely ill patients had significantly higher soluble syndecan-1 levels, with high levels related to risk of death. Finally, higher VWF levels in severely ill patients were correlated with lower VWF sialic acid content. Conclusions: Severe COVID-19 in patients undergoing hemodialysis is associated with both acute and sustained activation of the endothelium, leading to alteration of the VWF/ADAMTS-13 axis. Lower VWF sialic acid content represents altered VWF processing and further confirms the disturbance caused to the endothelium in COVID-19

Characterisation of an enhanced preclinical model of experimental MPO-ANCA autoimmune vasculitis

Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a four-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. This article is protected by copyright. All rights reserved

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow assay for antibody prevalence studies following vaccination: a diagnostic accuracy study

Background: Lateral flow immunoassays (LFIAs) are able to achieve affordable, large scale antibody testing and provide rapid results without the support of central laboratories. As part of the development of the REACT programme extensive evaluation of LFIA performance was undertaken with individuals following natural infection. Here we assess the performance of the selected LFIA to detect antibody responses in individuals who have received at least one dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Methods: This was a prospective diagnostic accuracy study. Sampling was carried out at renal outpatient clinic and healthcare worker testing sites at Imperial College London NHS Trust. Two cohorts of patients were recruited; the first was a cohort of 108 renal transplant patients attending clinic following two doses of SARS-CoV-2 vaccine, the second cohort comprised 40 healthcare workers attending for first SARS-CoV-2 vaccination and subsequent follow up. During the participants visit, finger-prick blood samples were analysed on LFIA device, while paired venous sampling was sent for serological assessment of antibodies to the spike protein (anti-S) antibodies. Anti-S IgG was detected using the Abbott Architect SARS-CoV-2 IgG Quant II CMIA. A total of 186 paired samples were collected. The accuracy of Fortress LFIA in detecting IgG antibodies to SARS-CoV-2 compared to anti-spike protein detection on Abbott Assay Results: The LFIA had an estimated sensitivity of 92.0% (114/124; 95% confidence interval [CI] 85.7% to 96.1%) and specificity of 93.6% (58/62; 95% CI 84.3% to 98.2%) using the Abbott assay as reference standard (using the threshold for positivity of 7.10 BAU/ml) Conclusions: Fortress LFIA performs well in the detection of antibody responses for intended purpose of population level surveillance but does not meet criteria for individual testing

Long-term outcome in biopsy-proven acute interstitial nephritis treated with steroids

BACKGROUND: There are no prospective randomized controlled trials describing the outcome of acute interstitial nephritis (AIN) treated with steroids, and retrospective studies are limited. METHODS: We identified adult patients with a diagnosis of AIN without glomerular pathology over a 14-year period. Treated patients all received oral prednisolone and three also recieved IV methylprednisolone. Data were collected retrospectively on estimated glomerular filtration rate (eGFR), change in eGFR from time of biopsy, dependence on renal replacement therapy (RRT) and mortality, and outcomes were analysed according to the treatment prescribed. RESULTS: A total of 187 eligible patients with AIN were identified and 158 were treated with steroids. There was no difference in median eGFR or dependence on RRT at the time of biopsy. Steroid-treated patients had significantly higher eGFR at all time points post-biopsy up to 24 months, when median eGFR was 43 mL/min in the steroid-treated group and 24 mL/min in the untreated group (P  =  0.01). Fewer patients in the steroid-treated group were dialysis dependent by 6 months (3.2% versus 20.6%, P  =  0.0022) and 24 months (5.1% versus 24.1%, P  =  0.0019). CONCLUSIONS: This large retrospective study suggests a benefit of steroids in treatment of AIN with greater improvement in eGFR and fewer patients progressing to end-stage renal disease

Growing small solid nodules in lung cancer screening: safety and efficacy of a 200 mm3 minimum size threshold for multidisciplinary team referral

The optimal management of small but growing nodules remains unclear. The SUMMIT study nodule management algorithm uses a specific threshold volume of 200 mm3 before referral of growing solid nodules to the multidisciplinary team for further investigation is advised, with growing nodules below this threshold kept under observation within the screening programme. Malignancy risk of growing solid nodules of size >200 mm3 at initial 3-month interval scan was 58.3% at a per-nodule level, compared with 13.3% in growing nodules of size ≤200 mm3 (relative risk 4.4, 95% CI 2.17 to 8.83). The positive predictive value of a combination of nodule growth (defined as percentage volume change of ≥25%), and size >200 mm3 was 65.9% (29/44) at a cancer-per-nodule basis, or 60.5% (23/38) on a cancer-per-participant basis. False negative rate of the protocol was 1.9% (95% CI 0.33% to 9.94%). These findings support the use of a 200 mm3 minimum volume threshold for referral as effective at reducing unnecessary multidisciplinary team referrals for small growing nodules, while maintaining early-stage lung cancer diagnosis

Temporal multi-omics analysis of COVID-19 in end-stage kidney disease

\ua9 2025 The Author(s). Patients with end-stage kidney disease (ESKD) are at high risk of severe COVID-19. We performed longitudinal single-cell immune profiling of ESKD patients with COVID-19. Transcriptome, surface proteome, and immunoreceptor sequencing data were generated on 580,040 high-quality cells, derived from 187 samples from 61 patients. For a subset of individuals, we obtained samples before and during infection, allowing intra-individual comparison. Longitudinal profiling demonstrated distinct temporal gene expression trajectories in severe/critical versus mild/moderate COVID-19. We identified a population of transcriptionally distinct monocytes that emerged in peripheral blood following glucocorticoid treatment. Evaluation of clonal T cell dynamics showed that the fastest expanding clones were enriched in known SARS-CoV-2-specific sequences and shared across multiple patients. Comparison with external datasets revealed upregulation of immune cell TGF-β pathway expression in ESKD, irrespective of COVID-19 status. Our data delineate the temporal dynamics of the immune response in COVID-19 in a high-risk population

ANCA vasculitis induction management during the COVID-19 pandemic

As the severe acute respiratory syndrome coronavirus 2 pandemic evolved and became a global health threat, the safety of immunosuppression in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) became of utmost important for clinicians and patients. Although timely initiation of immunosuppressive therapy is critical to quell the acute inflammation and prevent AAV-associated mortality and morbidity, concerns for increased susceptibility to Coronavirus Disease 2019 (COVID-19), delayed viral clearance, and decreased humoral response to infection led to speculation about modification in induction therapy practices may be deployed by physicians caring for patients with AAV. This international retrospective cohort study investigated the influence of the COVID-19 pandemic on AAV induction therapy and patient outcomes in different parts of the world by studying differences in treatment regimens in the United States, United Kingdom, and Europe