Curcumin Benefits in Children with Active Lupus Nephritis via NLRP3 Inflammasome Inhibition‐ A Randomized Controlled Trial

The Use of Serological Tests in the Care of Patients with Lupus Nephritis.

Background: Lupus nephritis (LN) is a significant manifestation of systemic lupus erythematosus (SLE) that affects the kidneys. Differentiating between active and inactive LN is essential for determining disease activity, tailoring treatment strategies, and monitoring patient outcomes. The clinical and laboratory status of LN patients provides valuable insights into the severity of renal involvement, response to treatment, and the potential for disease progression. Objective: To asses clinical and laboratory status of active and inactive LN patients. Method: This cross sectional study was conducted in the Department of Nephrology, Dhaka Medical College Hospital, Dhaka from January, 2017 to June, 2018. This cross sectional study was performed on 60 biopsy proven lupus nephritis patients and 30 age and sex matched apparently healthy control subjects. All the patients were recruited as per inclusion and exclusion criteria. Diagnosed SLE patients who had renal involvement and undergone renal biopsy for standard clinical indications were recruited by purposive sampling and divided into two groups of active and inactive LN as per operational definition. Results: During the study, Mean age of the lupus nephritis patients in active and inactive LN was 26.60 ± 8.36 years and 28.80 ± 9.18 years respectively. Most of the patients in both groups were female. Anaemia and edema was observed significantly higher in active than that of inactive lupus nephritis. Systolic and diastolic blood pressure was significantly higher in active lupus nephritis than that of inactive lupus nephritis patients. Hb, serum C3 and eGFR were significantly lower in active LN than that of inactive LN. RBC, WBC, platelet count were also lower in active LN than that of inactive LN but no significant difference was observed between two groups. ESR, serum creatinine, proteinuria, Anti ds DNA Ab titre and uMCP-1 were significantly higher in active LN than that of inactive LN. There was no difference between active and inactive LN patients with regards the use of medications. There was no difference in renal biopsy classes in between two groups. Conclusion: According to our study findings, active lupus nephritis (LN) patients exhibited elevated systolic and diastolic blood pressure compared to those with inactive LN. Additionally, active LN patients displayed lower levels of hemoglobin, serum C3, and estimated glomerular filtration rate (eGFR) compared to inactive LN patients. While red blood cell (RBC), white blood cell (WBC), and platelet counts were also lower in active LN patients, the difference between the two groups did not reach statistical significance. Furthermore, there were no notable differences in medication usage between active and inactive LN patients, and the distribution of renal biopsy classes was similar in both groups.

Background:Lupus nephritis (LN) is one of the most serious organic manifestations of systemic lupus erythematosus (SLE). Ethnicity can contribute to disparities in the prevalence and disease activity of LN.Objectives:To assess the prevalence of LN in Brazilian patients with SLE and to determine factors associated with LN activity across the country.Methods:This cross-sectional study (GSK Study 207353) was carried out through face-to-face interviews and review of medical records (12-month study period). Adult patients with SLE (American College of Rheumatology [ACR] criteria, 1997) were included. Five SLE reference teaching centres were selected: North (NO), Northeast (NE), Midwest (CO), Southeast (SE), and South (SU). Patients with another disease whose morbidity surpassed SLE were excluded. LN was defined as reported in the medical record or history of confirmed renal biopsy; disease activity by pre-defined changes in SLE Disease Activity Index (SLEDAI) or the patient’s kidney disease during the study. Activity was assessed during (T0), 6 months before (T6), and 12 months before (T12) the interview. Systemic Lupus International Collaborating Clinics/ACR Damage Index score mapped damage accrual. Two pairings were performed, aiming to discriminate factors associated with LN and its activity, respectively. Matching technique was used to select similar individuals based on propensity scores, obtained from a logistic regression model. A bootstrapping method explored characteristic variables associated with the risk of progressing to LN.Results:Overall, 300 Brazilian patients with SLE were included in the study. Two groups were paired: LN group (N=150) and non-LN group (N = 141). The prevalence of LN in the paired sample (N=291) was 51.5%, with a disparity between centres (p<0.001; Figure 1A). Most patients were female (LN: 92.7%; non-LN: 94.3%) and the mean (standard deviation [SD]) age for the LN and non-LN groups was 39.46 (11.86) and 43.96 (12.18), respectively. History of serositis was associated with the presence of LN (42 [28.0%] vs 21 [14.9%] non-LN; p=0.010). Type IV histological class predominated in both groups, with no disparity between centres. Social disparities were noted between groups. Non-active workers prevailed among the LN group (115 [76.7%] vs 98 [69.5%] for non-LN, p=0.024).When pairing for disease activity at T12, 73 (50.3%) patients with LN (N=145) had active disease. There was regional disparity in terms of disease activity (Figure 1B), with a predominance of active LN in the NO (28 [68.3%]) and SU (16 [55.2%], p=0.026). Type IV histological class was the component most associated with active LN (active: 32 [43.8%]; non-active: 11 [15.3%], p<0.001). Variation in SLEDAI during the study period discriminated between active and non-active LN. The mean (SD) SLEDAI score at T12 was substantially higher in those with active LN compared with non-active LN (7.18 [4.83] vs 2.47 [4.63], p<0.001). As for the pattern of care, corticosteroids users prevailed in those with active LN (62 [84.9%] vs 45 [62.5%] for non-active LN, p=0.004). There was no disparity in the use of immunosuppressants, with the exception of cyclophosphamide use, noted among 16 (21.9%) patients with active LN and 6 (8.3%) patients with non-active LN (p=0.041). Psychotropic or anticonvulsant use was higher in patients with non-active LN (32 [44.4%] vs 17 [23.3%] patients with active LN, p=0.012). Consultation with a neurologist was verified in 15 (20.8%) patients with non-active LN and 6 (8.2%) with active LN (p=0.055). Hospitalisation occurred in 17 patients with non-active (23.6%) and active (23.3%) LN.Conclusion:Disparities in the prevalence of LN and its activity were evident between the regions across Brazil, highlighting differences in clinical factors, regional factors, and patterns of care.Funding:GSKFigure 1.Prevalence of A) LN among regional centres, comparing them to disease activity profile and prescriptive practice, and B) Active and non-active LN according to prescriptive practiceCQ, chloroquine; HCQ, hydroxychloroquine*At T12Acknowledgements:Medical writing assistance was provided by Helen Taylor, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK.Disclosure of Interests:Mirhelen Abreu Grant/research support from: GSK, Amgen, Biogen, Libbs, Odirlei Monticielo Speakers bureau: GSK, AbbVie, UCB, Roche, Novartis, Consultant of: GSK, AbbVie, Janssen, Vander Fernandes Speakers bureau: Janssen, Novartis, Roche, AbbVie, Pfizer, Grant/research support from: Novartis, GSK, Pfizer, Alexandre Cristovão Maiorano: None declared, Fernando dos Santos Beserra: None declared, Flavia Lamarao Employee of: GSK, Nathalie David Shareholder of: GSK, Employee of: GSK, Bruna de Veras Employee of: GSK, Blanca Bica: None declared, Domingos Sávio Nunes de Lima Grant/research support from: GSK, Marta Maria das Chagas Medeiros: None declared

To study the correlation of anti-C1q antibodies with active systemic lupus erythematosus (SLE) and lupus nephritis (LN) in children, as well as their diagnostic value for active SLE and LN. A retrospective selection of 90 hospitalized children with SLE at the Children's Medical Center of Second Xiangya Hospital, Central South University from January 2016 to March 2019 as the SLE group, all of whom were tested for anti-C1q antibodies. A control group was formed by collecting 70 hospitalized children with other autoimmune diseases (OAD) during the same period. The differences in anti-C1q antibody levels were compared between two groups.The correlation of anti-C1q antibodies with various indicators of SLE and LN was analyzed, and the diagnostic value of anti-C1q in SLE and LN was evaluated. The serum levels of anti-C1q antibodies in the SLE group were higher than those in the OAD group (P<0.05). The SLE disease activity index score was positively correlated with anti-C1q antibodies (rs=0.371, P<0.001) and positively correlated with anti-double-stranded DNA antibodies (rs=0.370, P<0.001). The sensitivity and specificity of anti-C1q antibodies for diagnosing active SLE were 89.90% and 53.90%, respectively, with an area under the curve of 0.720 (P<0.05) and a critical value of 5.45 U/mL. The sensitivity and specificity of anti-C1q antibody levels for diagnosing active LN were 58.50% and 85.00%, respectively, with an area under the curve of 0.675 (P<0.05) and a critical value of 22.05 U/mL. Anti-C1q antibodies can serve as non-invasive biomarkers for evaluating the activity of SLE or predicting the activity of LN in children.

The NLRP3 inflammasome is a critical component of the innate immune system. NLRP3 activation is induced by diverse stimuli associated with bacterial infection or tissue damage, but its inappropriate activation is involved in the pathogenesis of inherited and acquired inflammatory diseases. However, the mechanism by which NLRP3 is activated remains poorly understood. In this study, we explored the role of kinases in NLRP3 inflammasome activation by screening a kinase inhibitor library and identified 3,4-methylenedioxy-β-nitrostyrene (MNS) as an inhibitor for NLRP3 inflammasome activation. Notably, MNS did not affect the activation of the NLRC4 or AIM2 (absent in melanoma 2) inflammasome. Mechanistically, MNS specifically prevented NLRP3-mediated ASC speck formation and oligomerization without blocking potassium efflux induced by NLRP3 agonists. Surprisingly, Syk kinase, the reported target of MNS, did not mediate the inhibitory activity of MNS on NLRP3 inflammasome activation. We also found that the nitrovinyl group of MNS is essential for the inhibitory activity of MNS. Immunoprecipitation, mass spectrometry, and mutation studies suggest that both the nucleotide binding oligomerization domain and the leucine-rich repeat domain of NLRP3 were the intracellular targets of MNS. Administration of MNS also inhibited NLRP3 ATPase activity in vitro, suggesting that MNS blocks the NLRP3 inflammasome by directly targeting NLRP3 or NLRP3-associated complexes. These studies identified a novel chemical probe for studying the molecular mechanism of NLRP3 inflammasome activation which may advance the development of novel strategies to treat diseases associated with abnormal activation of NLRP3 inflammasome.

Background: Lupus nephritis (LN) is a common and serious complication in systemic lupus erythematosus (SLE) andis associated with significant mortality and morbidity of SLE patients. The conventional laboratory markers used in clinicalpractice such as serum complement levels and double-stranded DNA antibodies are unreliable indicators of LN as they lackboth sensitivity and specificity for prediction of active or relapsing LN. Studies have shown that podocyte injury occurs in the early stages of glomerular damage in LN, and that quantification of podocyturia could be used as a marker for active disease. Podocalyxin (PCX) is probably the most frequently used marker protein for podocyturia. Aim of the work: To investigate urinary podocalyxin (u-PCX) as a marker of lupus nephritis (LN) disease activity. Methods: 63 patients with clinical and biopsy proven LN were recruited and divided into two groups; 35(55.56%) patients with active LN & 28(44.44%) patients with inactive LN. Estimation of u-PCX/creatinine ratio, urine protein /creatinine ratio (PCR), erythrocyte sedimentation rate, C reactive protein, serum albumin, serum complement C3 and C4, anti-double stranded DNA antibody titers, serum creatinine, estimated glomerular filtration rate and renal biopsy were done. Results: Patients with active LN had significant higher levels of PCR (1159.38±724.37 Vs 332.29±145.10), u-PCX (109.18±28.21 Vs 67.93±8.24), and SLEDAI-2K renal score (6.83±2.16 Vs 2.0±1.17) (P<0.001). However, active LN group had significant lower serum albumin (2.87±0.51 Vs 3.61±0.22, P<0.001). In active LN; u-PCX correlated positively with PCR (r=0.516, p=0.002), SLEDAI-2k (renal) (r=0.568, p<0.001), ads DNA ab (r=0.362, p<0.032) and negatively with serum albumin (r= - 0.421, p=0.014).Moreover, SLEDAI-2k renal score was negatively correlated with serum albumin(r=-0.710, P<0.001). Conclusion: u-PCX could be served as a marker of LN disease activity. [Egypt J Rheumatology & Clinical Immunology, 2016; 4(1): 23-31]

BackgroundA urine ‘biomarker panel’ comprising alpha-1-acid-glycoprotein (AGP), ceruloplasmin (CP), transferrin (TF) and lipocalin-like-prostaglandin-D synthase (LPGDS) has been shown to cross-sectionally perform to an ‘excellent’ level for Lupus Nephritis (LN) identification...

The NLRP3 Inflammasome Promotes Age-Related Thymic Demise and Immunosenescence

AimTo measure the level of serum renalase and to clarify its relation to lupus nephritis (LN) activity and histopathological classification.Patients and methodsThis study was carried out on 40 patients with systemic lupus erythematosus (SLE), diagnosed according to systemic lupus international collaborating clinics classification criteria (SLICC) criteria, and 20 healthy controls. They were 20 patients without nephritis and 20 patients with LN (17 active and three inactive LN). Venous blood samples were taken from all participants for complete blood count, erythrocyte sedimentation rate, kidney function, anti-double-stranded DNA, C3, C4, and renalase level. The serum renalase levels were determined by enzyme-linked immunosorbent assay. Assessments of protein in 24-h urine collection and protein/creatinine (P/C) ratio were done. Renal biopsies were obtained from patients with LN, with staging and activity and chronicity indices assessment. SLE disease activity was measured by Systemic Lupus Erythematosus Disease Activity Index, and LN activity was estimated by renal Systemic Lupus Erythematosus Disease Activity Index.ResultsRenalase levels were higher in patients with LN than both patients with SLE without LN and control group. The serum renalase levels of patients with LN were positively correlated with P/C ratio, 24-h proteinuria and C3, but negatively correlated with Systemic Lupus Erythematosus Disease Activity Index. For patients with active LN, there was no significant correlation between their serum renalase levels and the indicators of renal activity, including erythrocyte sedimentation rate, proteinuria, P/C ratio, anti-double-stranded DNA, C3, C4, and activity index of renal biopsy. The median of renalase as a marker for diagnosis of LN was 134.65, with a cutoff value of 100 μg/ml.ConclusionSerum renalase may be involved in LN pathogenesis but was not a good predictor for either LN activity or various stages of LN histopathology.

<h3>Background</h3> Neutrophil Extracellular Traps (NETs) have been implicated in Lupus Nephritis (LN) pathogenesis. SLE neutrophils release High Mobility Group Box-1 (HMGB1) protein, in turn, HMGB1 in NETs correlates with histologic...

Objective To investigate the relationship between serum renalase and disease activity in lupus nephritis (LN). Methods Total of 70 patients with LN and 35 healthy volunteers admitted in Renji Hospital of Shanghai Jiao Tong University from March 2012 to March 2013 were enrolled in the study. LN patients were classified into two groups according to their systemic lupus erythematosus disease activity index (SLEDAI) scores: patients with SELDAI score lower than 8 were defined as inactive LN while others were defined as active LN. Serum samples were collected after an overnight fast and serum renalase level was determined by ELISA. Twenty active LN patients were followed up for six-months, and serum renalase was also determined before and after treatment. The differences in serum renalase level between LN patients and healthy controls were assessed, as well as the association of serum renalase with disease activity in LN. Results In 70 LN patients, 35 were classified active LN while others were inactive LN. Serum renalase level was significantly higher in LN patients than than in healthy controls (P<0.01). Moreover, active LN patients had higher serum renalase level compared to patients with inactive LN (P<0.01). Active LN patients had higher 24-hour urine protein excretion, erythrocyte sedimentation rate and anti-dsDNA antibody titers than inactive LN patients. Serum albumin was lower in inactive LN patients compared to active LN patients. There were no differences in gender, age, blood pressure and C-reactive protein between the two groups. Serum renalase levels were positively correlated with SLEDAI, 24-hour urine protein excretion, ds-DNA and ESR but inversely correlated with serum albumin and C3. Renalase amounts decreased significantly after six-months of standard therapy. The performance of renalase as a marker for diagnosis of active LN was 0.894 with a cutoff value of 66.67 mg/L. Logistic regression showed that serum renalase (OR=1.078, 95%CI 1.031-1.120, P=0.001) and complement C3 (OR=0.022, 95%CI 0.002-0.326, P=0.005) is independent indicators for disease activity in LN. Conclusions Serum renalase level was correlated with disease activity in LN. Serum renalase may serve as a potential indicator for disease activity in LN. Key words: Lupus nephritis; Disease activity; Renalase

Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE). It remains unclear whether antiphospholipid antibodies (aPL) alter the course of LN. We thus investigated the impact of aPL on short-term and long-term renal outcomes in patients with LN. We assessed levels of aPL cross-sectionally in SLE patients diagnosed with (n = 204) or without (n = 294) LN, and prospectively in 64 patients with active biopsy-proven LN (52 proliferative, 12 membranous), before and after induction treatment (short-term outcomes). Long-term renal outcome in the prospective LN cohort was determined by the estimated glomerular filtration rate (eGFR) and the Chronic Kidney Disease (CKD) stage, after a median follow-up of 11.3 years (range: 3.3–18.8). Cross-sectional analysis revealed no association between LN and IgG/IgM anticardiolipin or anti-β2-glycoprotein I antibodies, or lupus anticoagulant. Both aPL positivity and levels were similar in patients with active LN and non-renal SLE. Following induction treatment for LN, serum IgG/IgM aPL levels decreased in responders (p<0.005 for all), but not in non-responders. Both at active LN and post-treatment, patients with IgG, but not IgM, aPL had higher creatinine levels compared with patients without IgG aPL. Neither aPL positivity nor levels were associated with changes in eGFR from either baseline or post-treatment through long-term follow-up. Moreover, aPL positivity and levels both at baseline and post-treatment were similar in patients with a CKD stage ≥3 versus 1–2 at the last follow-up. In conclusion, neither aPL positivity nor levels were found to be associated with the occurrence of LN in SLE patients. However, IgG aPL positivity in LN patients was associated with a short-term impairment of the renal function while no effect on long-term renal outcome was observed. Furthermore, IgG and IgM aPL levels decreased following induction treatment only in responders, indicating that aPL levels are affected by immunosuppressive drugs in a response-dependent manner.

ObjectiveTo investigate second kidney biopsy as predictor of end-stage kidney disease (ESKD) in active lupus nephritis (LN).MethodsPatients with biopsy-proven LN (International Society of Nephrology/Renal Pathology Society 2003) who had undergone...

Evaluation of visfatin in patients with systemic lupus erythematosus: Correlation with disease activity and lupus nephritis

BackgroundAccurate identification of prevalent cases of lupus nephritis (LN) is essential for timely patient monitoring and treatment, advancing research, and informing public health initiatives for the management of LN. However,...