Lupus Nephritis

Lupus nephritis (LN) is a prevalent and severe manifestation of systemic lupus erythematosus (SLE), leading to significant morbidity and mortality. OTUB1, a deubiquitinating enzyme, has emerged as a potential therapeutic target due to its role in cellular protection and regulation of ferroptosis, a form of cell death linked to LN. Our study revealed significantly reduced OTUB1 expression in the glomeruli of LN patients and podocytes, correlated with disease severity. CRISPR/Cas9-mediated OTUB1 knockout in podocytes resulted in pronounced injury, indicated by decreased levels of nephrin and podocin. Ferrostatin-1 treatment effectively mitigated this injury, restoring SLC7A11 expression and significantly reducing MDA levels, Fe2+ levels, BODIPY C11 expression, and normalized cysteine and glutathione expression. In the MRL/lpr mouse model, Ferrostatin-1 significantly improved renal function decreased proteinuria, and ameliorated renal histopathological changes, including reduced glomerular endothelial swelling, mesangial cell proliferation, and leukocyte infiltration. These results underscore the protective role of Ferrostatin-1 in modulating the pathogenesis of LN. OTUB1 plays a crucial protective role against podocyte injury in LN by regulating ferroptosis. Ferrostatin-1 effectively mitigates podocyte damage induced by OTUB1 deficiency, suggesting that targeting ferroptosis could be a promising therapeutic strategy for LN.

ObjectiveTo investigate the role of curcumin in the treatment of lupus nephritis (LN) by inhibiting the migration of neutrophils and the underlying mechanism involved.MethodsTwo lupus mouse models, MRL/lpr mice and R848-treated mice, were treated with 50 mg/kg curcumin by intraperitoneal injection. H&E and Masson staining were used to estimate histopathological changes in the kidney. Immunofluorescence was used to assess the deposition of immune complexes. The expression of inflammatory factors was detected by enzyme-linked immunosorbent assay (ELISA) and real-time reverse transcription polymerase reaction (RT-PCR), and the protein expression was detected by western blotting.ResultsWe revealed the remarkable potential of curcumin in improving inflammatory conditions in both MRL/lpr mice and R848-induced lupus mice. Curcumin effectively decelerates the progression of inflammation and diminishes the infiltration of neutrophils and their release of pivotal inflammatory factors, thereby reducing inflammation in renal tissues. Mechanistically, curcumin significantly inhibits the expression of p-PI3K, p-AKT and p-NF-κB, which are upregulated by interleukin-8 to induce neutrophil migration and renal inflammation, thereby reducing neutrophil migration and the release of inflammatory factors.ConclusionCurcumin significantly inhibits the recruitment of neutrophils and the release of proinflammatory factors in the kidney by inhibiting the PI3K/AKT/NF-κB signalling pathway, providing new therapeutic targets and medication strategies for the treatment of LN.

ObjectiveTo evaluate the value of NLR (neutrophil to lymphocyte ratio), PLR (platelet to lymphocyte ratio), and SII (systemic immune-inflammation index) in reflecting disease activity and induction therapy remission in patients with lupus nephritis (LN).MethodsActive LN patients from STAR cohort were enrolled. We analyzed the trends of complete blood count parameters with Generalized Estimated Equation. Bivariate correlation analyses, Chi-square tests, t-tests and logistic regression were employed to assess variable associations and identify prognostic factors for LN remission.Results310 active LN patients were enrolled in the study. All patients had active lupus with SLEDAI-2K 17.1 ± 6.1, median 24h-Urine Protein (UTP) level of 3.1 (1.5, 5.4) g. During the 12-month follow-up of induction therapy, NLR and PLR showed a decreasing trend. Both baseline NLR and SII were positively correlated with baseline UTP and serum creatinine (SCr) levels (r = 0.112-0.148, pvs. 4.0 (2.6, 6.5), p = 0.024] and pyuria [5.4 (3.4, 8.8) vs. 3.8 (2.6, 6.6), p r = 0.244, p=0.013; SII: r = 0.199, p=0.043). Furthermore, the changes of NLR and SII were also positively correlated with changes in UTP and SCr during 6 and 12 months (r = 0.143-0.175, pConclusionOur findings suggested that NLR and SII were valuable indicators of disease activity in LN, correlating with UTP, SCr and AI score of renal pathology. NLR, PLR and SII provided us a quick, simple and cost-effective supervision way in monitoring and managing LN patients.

ObjectiveThe objective of this study was to evaluate the efficacy and safety of s.c. secukinumab 300 mg combined with standard of care (SoC) in adult patients with active LN.MethodsThe core study was a phase III randomized, placebo-controlled, double-blind study (planned duration: 104 weeks) of patients with active LN. Eligible patients were randomized to receive secukinumab 300 mg or placebo for the first 4 weeks, followed by a monthly maintenance dose, with all patients receiving a SoC background regimen. Patients completing the 104-week treatment of the core study were eligible for an open-label extension study (planned duration: up to 260 weeks) to receive secukinumab 300 mg every 4 weeks. The primary end point of the core study was the proportion of patients achieving complete renal response (CRR) at week 52.ResultsBoth studies were terminated early, following a planned futility analysis in the core study that showed no clinically meaningful benefit of secukinumab over placebo. In the core study, the proportion of patients achieving CRR at week 52 was lower after receiving secukinumab (24.2%) than after receiving the placebo (36.3%). No differences were observed between the secukinumab and placebo groups in any of the secondary end points of the core study. The incidence of treatment-emergent adverse events was comparable between the secukinumab and placebo groups. In the extension study, the results were not interpretable, owing to the low patient number included in the data analysis (n = 31).ConclusionSecukinumab did not demonstrate superior efficacy over placebo in patients with active LN. Secukinumab was well-tolerated with no new or unexpected safety signals detected.Trial registrationhttps://clinicaltrials.gov/study/NCT04181762, NCT04181762 (Novartis study code: CAIN457Q12301). https://www.clinicaltrials.gov/study/NCT05232864, NCT05232864 (Novartis study code: CAIN457Q12301E1).