Induction treatment of ANCA-associated vasculitis with a single dose of rituximab.

OBJECTIVES: Rituximab is effective in inducing remission in ANCA-associated vasculitis (AAV), with randomized evidence to support its use as four infusions of 375 mg/m(2) (the conventional lymphoma dosing schedule). As B cell depletion (BCD) appears to occur very rapidly after the first dose, we questioned the need for repeat dosing and adopted a standard single-dose protocol of 375 mg/m(2) to treat active AAV. METHODS: All consecutive cases with newly diagnosed or relapsing AAV for whom conventional immunosuppression was contraindicated or ineffective were enrolled. All were rituximab naive. Circulating CD19(+) B cells and clinical and serological markers of disease activity were recorded at regular intervals. Complete remission (CR) was defined as the absence of clinical features of AAV with a prednisolone dose <10 mg/day. RESULTS: Nineteen patients were included, 17 (89%) with generalized disease and 2 (11%) with severe disease (creatinine level >500 µM). Eight (42%) were on additional immunosuppression at the time of rituximab treatment. Satisfactory BCD (<0.005 cells/µl) was achieved in 89% of patients after a median of 13 days. Three-month BCD probability was 89%. Median time to CR following a single dose of rituximab was 38 days and the 3-month probability of CR was 80%. Median time to B cell repopulation was 9.2 months and to disease relapse/redose was 27 months. Use of this single-dose protocol saved an estimated £4533/patient (US$7103; €5276) compared with a 4 × 375 mg/m(2) dosing schedule. CONCLUSION: Our single-centre experience suggests that a single dose of rituximab of 375 mg/m(2) is a reasonable and more cost-effective therapy for inducing remission in patients with AAV.

Multi-omics identify falling LRRC15 as a COVID-19 severity marker and persistent pro-thrombotic signals in convalescence.

Patients with end-stage kidney disease (ESKD) are at high risk of severe COVID-19. Here, we perform longitudinal blood sampling of ESKD haemodialysis patients with COVID-19, collecting samples pre-infection, serially during infection, and after clinical recovery. Using plasma proteomics, and RNA-sequencing and flow cytometry of immune cells, we identify transcriptomic and proteomic signatures of COVID-19 severity, and find distinct temporal molecular profiles in patients with severe disease. Supervised learning reveals that the plasma proteome is a superior indicator of clinical severity than the PBMC transcriptome. We show that a decreasing trajectory of plasma LRRC15, a proposed co-receptor for SARS-CoV-2, is associated with a more severe clinical course. We observe that two months after the acute infection, patients still display dysregulated gene expression related to vascular, platelet and coagulation pathways, including PF4 (platelet factor 4), which may explain the prolonged thrombotic risk following COVID-19.

Plasma Lectin Pathway Complement Proteins in Patients With COVID-19 and Renal Disease.

We do not understand why non-white ethnicity and chronic kidney disease increase susceptibility to COVID-19. The lectin pathway of complement activation is a key contributor to innate immunity and inflammation. Concentrations of plasma lectin pathway proteins influence pathway activity and vary with ethnicity. We measured circulating lectin proteins in a multi-ethnic cohort of chronic kidney disease patients with and without COVID19 infection to determine if lectin pathway activation was contributing to COVID19 severity. We measured 11 lectin proteins in serial samples from a cohort of 33 patients with chronic kidney impairment and COVID19. Controls were single plasma samples from 32 patients on dialysis and 32 healthy individuals. We demonstrated multiple associations between recognition molecules and associated proteases of the lectin pathway and COVID-19, including COVID-19 severity. Some of these associations were unique to patients of Asian and White ethnicity. Our novel findings demonstrate that COVID19 infection alters the concentration of plasma lectin proteins and some of these changes were linked to ethnicity. This suggests a role for the lectin pathway in the host response to COVID-19 and suggest that variability within this pathway may contribute to ethnicity-associated differences in susceptibility to severe COVID-19.

Longitudinal proteomic profiling of dialysis patients with COVID-19 reveals markers of severity and predictors of death.

End-stage kidney disease (ESKD) patients are at high risk of severe COVID-19. We measured 436 circulating proteins in serial blood samples from hospitalised and non-hospitalised ESKD patients with COVID-19 (n = 256 samples from 55 patients). Comparison to 51 non-infected patients revealed 221 differentially expressed proteins, with consistent results in a separate subcohort of 46 COVID-19 patients. Two hundred and three proteins were associated with clinical severity, including IL6, markers of monocyte recruitment (e.g. CCL2, CCL7), neutrophil activation (e.g. proteinase-3), and epithelial injury (e.g. KRT19). Machine-learning identified predictors of severity including IL18BP, CTSD, GDF15, and KRT19. Survival analysis with joint models revealed 69 predictors of death. Longitudinal modelling with linear mixed models uncovered 32 proteins displaying different temporal profiles in severe versus non-severe disease, including integrins and adhesion molecules. These data implicate epithelial damage, innate immune activation, and leucocyte-endothelial interactions in the pathology of severe COVID-19 and provide a resource for identifying drug targets.

COVID-19 varies from a mild illness in some people to fatal disease in others. Patients with severe disease tend to be older and have underlying medical problems. People with kidney failure have a particularly high risk of developing severe or fatal COVID-19. Patients with severe COVID-19 have high levels of inflammation, causing damage to tissues around the body. Many drugs that target inflammation have already been developed for other diseases. Therefore, to repurpose existing drugs or design new treatments, it is important to determine which proteins drive inflammation in COVID-19. Here, Gisby, Clarke, Medjeral-Thomas et al. measured 436 proteins in the blood of patients with kidney failure and compared the levels between patients who had COVID-19 to those who did not. This revealed that patients with COVID-19 had increased levels of hundreds of proteins involved in inflammation and tissue injury. Using a combination of statistical and machine learning analyses, Gisby et al. probed the data for proteins that might predict a more severe disease progression. In total, over 200 proteins were linked to disease severity, and 69 with increased risk of death. Tracking how levels of blood proteins changed over time revealed further differences between mild and severe disease. Comparing this data with a similar study of COVID-19 in people without kidney failure showed many similarities. This suggests that the findings may apply to COVID-19 patients more generally. Identifying the proteins that are a cause of severe COVID-19 ­ rather than just correlated with it ­ is an important next step that could help to select new drugs for severe COVID-19.

Temporal changes in complement activation in haemodialysis patients with COVID-19 as a predictor of disease progression.

BACKGROUND: Complement activation may play a pathogenic role in patients with severe coronavirus disease 2019 (COVID-19) by contributing to tissue inflammation and microvascular thrombosis. METHODS: Serial samples were collected from patients receiving maintenance haemodialysis (HD). Thirty-nine patients had confirmed COVID-19 and 10 patients had no evidence of COVID-19. Plasma C5a and C3a levels were measured using enzyme-linked immunosorbent assay. RESULTS: We identified elevated levels of plasma C3a and C5a in HD patients with severe COVID-19 compared with controls. Serial sampling identified that C5a levels were elevated prior to clinical deterioration in patients who developed severe disease. C3a more closely mirrored both clinical and biochemical disease severity. CONCLUSIONS: Our findings suggest that activation of complement plays a role in the pathogenesis of COVID-19, leading to endothelial injury and lung damage. C5a may be an earlier biomarker of disease severity than conventional parameters such as C-reactive protein and this warrants further investigation in dedicated biomarker studies. Our data support the testing of complement inhibition as a therapeutic strategy for patients with severe COVID-19.

Phasic Stimulation of Midbrain Dopamine Neuron Activity Reduces Salt Consumption.

Salt intake is an essential dietary requirement, but excessive consumption is implicated in hypertension and associated conditions. Little is known about the neural circuit mechanisms that control motivation to consume salt, although the midbrain dopamine system, which plays a key role in other reward-related behaviors, has been implicated. We, therefore, examined the effects on salt consumption of either optogenetic excitation or chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons in male mice. Strikingly, optogenetic excitation of dopamine neurons decreased salt intake in a rapid and reversible manner, despite a strong salt appetite. Importantly, optogenetic excitation was not aversive, did not induce hyperactivity, and did not alter salt concentration preferences in a need-free state. In addition, we found that chemogenetic inhibition of dopamine neurons had no effect on salt intake. Lastly, optogenetic excitation of dopamine neurons reduced consumption of sucrose following an overnight fast, suggesting a more general role of VTA dopamine neuron excitation in organizing motivated behaviors.

Weight gains and increased blood pressure in outpatient hemodialysis patients due to change in acid dialysate concentrate supplier.

INTRODUCTION: Sodium balance during hemodialysis is predominantly achieved by ultrafiltration. The additional effect of diffusional sodium losses and gains remains unclear. We recently changed our dialysate acid concentrate supplier, and although both concentrates were instructed to be diluted 1:44, we audited the practical effects of this change. METHODS: Review of electronic dialysis and laboratory records of patients attending a satellite dialysis center. RESULTS: 91 adult hemodialysis patients, mean age 61.4 ± 1.7 years, 65% male, 52% diabetic, median dialysate sodium machine setting at 137 mmol/l (137-138), following change in acid dialysate patients dialyzed against a mean measured dialysate sodium of 4.8 (95%cCL 3.6-6.1) mmol/l higher than setting. After six weeks, pre-dialysis weight increased from 75.5 ± 1.9 kg to 76.6 ± 1.9 kg, p<0.001, with increased mean weight loss on dialysis from 2.38 ± 0.1% to 3.28 ± 0.13%, p<0.001, and increase in pre-dialysis mean arterial blood pressure from 91.2 ± 1.5 mmHg to 95.4 ± 1.5 mmHg, p<0.001. Post-dialysis serum sodium increased from 0 (-3 to +3) mmol/l to +3 (1 to 5.5) mmol/l compared to pre-dialysis value, p<0.001. Monthly symptomatic episodes of intradialytic hypotension fell from 69 to 46. After correcting the dialysate sodium setting, blood pressure and weight gains resolved over 4 weeks. CONCLUSIONS: Changing dialysate acid concentrates, both labeled 1:44 dilution, led to the delivery of a higher dialysate sodium, resulting in weight gains, increased pre-dialysis blood pressure, but less symptomatic intradialytic hypotension. Following readjustment of volumetric dialysate mixing, excess weight gains and increased blood pressure resolved over 4 weeks, highlighting the importance of checking the delivered dialysate sodium following a change in dialysate acid concentrate.