Protein bound-uremic toxins (PBUTs) are not efficiently removed by hemodialysis in chronic kidney disease (CKD) patients and their accumulation leads to various co-morbidities via cellular dysfunction, inflammation and oxidative stress. Moreover, it has been shown that increased intrarenal expression of the NLRP3 receptor and IL-1β are associated with reduced kidney function, suggesting a critical role for the NLRP3 inflammasome in CKD progression. Here, we evaluated the effect of PBUTs on inflammasome-mediated IL-1β production in vitro and in vivo. Exposure of human conditionally immortalized proximal tubule epithelial cells to indoxyl sulfate (IS) and a mixture of anionic PBUTs (UT mix) increased expression levels of NLRP3, caspase-1 and IL-1β, accompanied by a significant increase in IL-1β secretion and caspase-1 activity. Furthermore, IS and UT mix induced the production of intracellular reactive oxygen species, and caspase-1 activity and IL-1β secretion were reduced in the presence of antioxidant N-acetylcysteine. IS and UT mix also induced NF-κB activation as evidenced by p65 nuclear translocation and IL-1β production, which was counteracted by an IKK inhibitor. In vivo, using subtotal nephrectomy CKD rats, a significant increase in total plasma levels of IS and the PBUTs, kynurenic acid and hippuric acid, was found, as well as enhanced urinary malondialdehyde levels. CKD kidney tissue showed an increasing trend in expression of NLRP3 inflammasome components, and a decreasing trend in superoxide dismutase-1 levels. In conclusion, we showed that PBUTs induce inflammasome-mediated IL-1β production in proximal tubule cells via oxidative stress and NF-κB signaling, suggesting their involvement in disease-associated inflammatory processes.

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Objective: To determine SARS-CoV-2 seroprevalence in a UK pregnancy cohort and assess associations with demographic factors and vaccination timing. Design: Observational cohort study. Setting: UK inner-city maternity centre. Sample: 960 pregnant women attending nuchal scans from July 2020-January 2022. Methods: Blood samples were tested for IgG antibodies against SARS-CoV-2 nucleocapsid (N) and spike (S) proteins. Self-reported demographics, vaccination status and previous Covid-19 infection were extracted from health records. Multivariable regression models determined factors associated with seroprevalence and antibody titers. Main outcome measures: IgG N- and S-protein antibody titers. Results: 196/960 (20.4%) women were SARS-CoV-2 seropositive from previous infection. Of these, 70 (35.7%) self-reported previous infection. Amongst unvaccinated women, black women were most likely to be SARS-CoV-2 seropositive (aRR 1.88 [95% CI, 1.35-2.61], P < 0.001). Women from black and mixed ethnic backgrounds were least likely to have a history of vaccination with seropositivity to S-protein (aRR 0.58 [95% CI, 0.40-0.84], P = 0.004 and aRR 0.56 [95% CI, 0.34-0.92], P = 0.021 respectively). Double vaccinated, previously infected women had higher IgG S-protein antibody titers than unvaccinated, previously infected women (mean difference: 4.76, 95% CI = [2.65, 6.86], P < 0.001). Vaccination timing before vs during pregnancy did not significantly affect IgG S antibody titers (F(1, 77) = [0.07], P = 0.785). Conclusions: This inner-city pregnancy cohort demonstrates high rates of asymptomatic SARS-CoV-2 infection with women of black ethnicity having higher infection risk and lower vaccine uptake. SARS-CoV-2 antibody titers were highest among double vaccinated, previously infected women.

Objective To determine severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) seroprevalence in pregnancy in an inner‐city setting and assess associations with demographic factors and vaccination timing. Design Repeated cross‐sectional surveillance study. Setting London maternity centre. Sample A total of 906 pregnant women attending nuchal scans, July 2020–January 2022. Methods Blood samples were tested for IgG antibodies against SARS‐CoV‐2 nucleocapsid (N) and spike (S) proteins. Self‐reported vaccination status and coronavirus disease 2019 (COVID‐19) infection were recorded. Multivariable regression models determined demographic factors associated with seroprevalence and antibody titres. Main outcome measures Immunoglobulin G N‐ and S‐protein antibody titres. Results Of the 960 women, 196 (20.4%) were SARS‐CoV‐2 seropositive from previous infection. Of these, 70 (35.7%) self‐reported previous infection. Among unvaccinated women, women of black ethnic backgrounds were most likely to be SARS‐CoV‐2 seropositive (versus white adjusted risk ratio [aRR] 1.88, 95% CI 1.35–2.61, p < 0.001). Women from black and mixed ethnic backgrounds were least likely to have a history of vaccination with seropositivity to S‐protein (versus white aRR 0.58, 95% CI 0.40–0.84, p = 0.004; aRR 0.56, 95% CI 0.34–0.92, p = 0.021, respectively). Double vaccinated, previously infected women had higher IgG S‐protein antibody titres than unvaccinated, previously infected women (mean difference 4.76 fold‐change, 95% CI 2.65–6.86, p < 0.001). Vaccination timing before versus during pregnancy did not affect IgG S‐antibody titres (mean difference −0.28 fold‐change, 95% CI −2.61 to 2.04, p = 0.785). Conclusions This cross‐sectional study demonstrates high rates of asymptomatic SARS‐CoV‐2 infection with women of black ethnic backgrounds having higher infection risk and lower vaccine uptake. SARS‐CoV‐2 antibody titres were highest among double‐vaccinated, infected women.

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