The Contribution of Serum Complement Component 3 Levels to 90-Day Mortality in Living Donor Liver Transplantation

The contributions of the complement system have been elucidated in the process of solid organ transplantation, including kidney transplantation. However, the role of complement in liver transplantation is unknown. We sought to elucidate the time-dependent changes of peritransplantational serum complement levels and the relationships with posttransplant outcomes and other immunological biomarkers. We enrolled 82 patients who underwent living-related donor liver transplantation (LDLT). Nine patients (11%) died within 90 days after LDLT (non-survivors). The following immunomarkers were collected preoperatively and at 1, 2, and 4 week(s) after LDLT: serum C3, C4, immunoglobulin G (IgG), and peripheral blood leukocyte populations characterized by CD3, CD4, CD8, CD16, CD19, CD20, CD22, and CD56. Consequently, C3 and C4 increased time-dependently after LDLT. Preoperatively, C3 was negatively correlated with the MELD score, Child–Pugh score, CD16-positive leukocyte percentage, and the CD56-positive leukocyte percentage. Non-survivors had lower levels of C3 at 2 weeks in comparison to survivors (median [interquartile range]: 56 [49-70] mg/dL vs. 88 [71-116] md/dL, p=0.0059). When the cutoff value of C3 at 2 weeks to distinguish non-survivors was set to 71 mg/dL, the sensitivity, specificity, and area under the ROC curve were 87.5%, 75.0%, and 0.80, respectively. A principal component analysis showed an inverse relationship between the C3 and C4 levels and the percentage of CD8-, CD16-, and CD56-positive leukocytes at 1 and 2 week(s). All non-survivors were included in the cluster that showed higher percentages of CD8-, CD16-, and CD56-positive leukocytes at 2 weeks. In conclusion, we demonstrated the relationship between complement, outcomes, and other immunomarkers in LDLT and suggested the usefulness of C3 at 2 weeks after LDLT in distinguishing the mortality.

Serum Complement C3 and C4 and COVID-19 Severity and Mortality: A Systematic Review and Meta-Analysis With Meta-Regression

Activation of the complement system has been observed in coronavirus disease 19 (COVID-19). We conducted a systematic review and meta-analysis with meta-regression to investigate possible differences in the serum concentrations of two routinely measured complement components, C3 and C4, in COVID-19 patients with different severity and survival status. We searched PubMed, Web of Science and Scopus, between January 2020 and February 2021, for studies reporting serum complement C3 and C4, measures of COVID-19 severity, and survival. Eligibility criteria were a) reporting continuous data on serum C3 and C4 concentrations in COVID-19 patients, -b) investigating COVID-19 patients with different disease severity and/or survival status, c) adult patients, d) English language, e) ≥10 patients, and f) full-text available. Using a random-effects model, standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated to evaluate differences in serum C3 and C4 concentrations between COVID-19 patients with low vs. high severity or survivor vs. non-survivor status. Risk of bias was assessed using the Newcastle-Ottawa scale whereas publication bias was assessed with the Begg’s and Egger’s tests. Certainty of evidence was assessed using GRADE. Nineteen studies in 3,764 COVID-19 patients were included in the meta-analysis. Both C3 and C4 concentrations were significantly lower in patients with high disease severity or non-survivor status than patients with low severity or survivor status (C3 SMD=-0.40, 95% CI -0.60 to -0.21, p<0.001; C4 SMD=-0.29, 95% CI -0.49 to -0.09, p=0.005; moderate certainty of evidence). Extreme between-study heterogeneity was observed (C3, I2 = 82.1%; C4, I2 = 84.4%). Sensitivity analysis, performed by sequentially removing each study and re-assessing the pooled estimates, showed that the magnitude and direction of the effect size was not modified. There was no publication bias. In meta-regression, the SMD of C3 was significantly associated with white blood cell count, C-reactive protein (CRP), and pro-thrombin time, whereas the SMD of C4 was significantly associated with CRP, pro-thrombin time, D-dimer, and albumin. In conclusion, lower concentrations of C3 and C4, indicating complement activation, were significantly associated with higher COVID-19 severity and mortality. C3 and C4 might be useful to predict adverse clinical consequences in these patients.Systematic Review Registration: PROSPERO, Registration number: CRD42021239634.

AB0839 A STUDY OF SERUM COMPLEMENT AND SERUM CALPROTECTIN LEVEL IN SYSTEMIC LUPUS ERYTHEMATOSUS

Background:Serum calprotectin, also known as MRP8/14 or S100A8/A9, has gained attention in recent years as a candidate biomarker in inflammatory diseases like SLE.1 Proteins of the complement pathway (serum C3 and C4) are linked to the pathogenesis of SLE and their levels have been measured as a means to assess the disease activity.2Objectives:[1]To study the relation of serum complement and serum calprotectin levels to disease activity in SLE[2]To study the relation between serum complement and serum calprotectin level in SLEMethods:Our study was a hospital based observational study conducted in a tertiary care centre in North-East India during the period of June 2019 to May 2020. A total of 102 patients of SLE were taken up for the study. Disease activity was assessed using SLEDAI-2K scores and serum calprotectin level was measured by ELISA. Serum C3 level was assessed by Nephelometric and C4 level by Turbidimetric immunoassay. The statistical significance was fixed at 5% level of significance (p<0.05) for all analysis.Results:Our study found a predominantly female population (Female: Male ratio 24.5: 1) with majority of the patients (49.02%) in the 30-39 years age group. Higher calprotectin levels were seen in patients with higher disease activity (SLEDAI) and this relation was statistically significant (r=0.84, p<0.001). There was significant negative correlation between disease activity (SLEDAI) and serum C3 (r=-0.35, p<0.001) and serum C4 (r=-0.4, p<0.001) level. There was a significant negative correlation between complement levels and serum calprotectin levels (r=-0.53, p<0.001).Conclusion:We found a significant positive correlation between serum calprotectin level and disease activity with a significant negative correlation between complement level and disease activity in SLE patients. There was a significant negative correlation between serum complement and serum calprotectin levels. These findings suggest serum calprotectin levels could be a substantial addition in the existing diagnostic array of tools in assessing lupus disease activity.References:[1]García-Arias M, Pascual-Salcedo D, Ramiro S, Ueberschlag ME, Jermann TM, Cara C, et al. Calprotectin in rheumatoid arthritis: Association with disease activity in a cross-sectional and a longitudinal cohort. Mol Diagnosis Ther. 2013;17(1):49–56.[2]Walport MJ. Complement and systemic lupus erythematosus. Arthritis Res. 2002;4(Suppl 3):S279-293.Disclosure of Interests:None declared

AB0391 LOW SERUM COMPLEMENT C3 LEVEL AS A RISK FACTOR FOR RELAPSE OF ANTINEUTROPHIL CYTOPLASMIC ANTIBODY-ASSOCIATED VASCULITIS: A RETROSPECTIVE COHORT STUDY

Background:The alternative pathway of complement activation has recently been recognized as a key pathogenic event in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Some previous studies have reported that low serum complement C3 level in AAV patients is associated with more severe renal disease, worse renal prognosis, or higher mortality. However, the correlation between low serum C3 level and AAV relapse remains unclear.Objectives:To analyze the clinical characteristics and outcomes of AAV patients with low serum C3 levels at the time of diagnosis.Methods:We conducted a retrospective observational cohort study including 83 consecutive patients diagnosed with AAV in our hospital from January 1999 to December 2020. Serum C3 levels were measured at diagnosis. AAV included microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA); patients with ANCA-negative AAV were excluded. Patients were divided into low- and high-C3 groups (C3 < 100 and ≥ 100 mg/dL, respectively). We compared the clinical characteristics, and relapse-free and overall survival rates, of the two groups, and identified predictors of AAV relapse.Results:Of the 83 patients (MPA, n = 61; GPA, n = 18; EGPA, n = 4), 20 (24%) were in the low-C3 group. We found no significant group difference in sex, body mass index, disease type, ANCA subtype, Birmingham Vasculitis Activity Score (BVAS), or treatment. The low-C3 group patients were older (p=0.01), and had a higher Five Factor Score (FFS) (p=0.01) and a lower remission rate (p=0.02), than the high-C3 group. The generalized Wilcoxon test revealed that the relapse-free survival time was significantly shorter in the low-C3 group (29 months; 95% confidence interval [CI]: 15–49) than in the high-C3 group (82 months; 95% CI: 61–NA; p=0.01) (Figure 1A). The overall survival was also shorter in the low-C3 group (83 months; 95% CI: 8-121) than in the high-C3 group (112 months; 95% CI: 77-NA; p=0.03) (Figure 1B). In the Cox proportional hazards model, a low C3 level (< 100 mg/dL) (hazard ratio [HR], 3.01; 95% CI: 1.29–7.04], p=0.01) and GPA (HR, 3.04; 95% CI: 1.32–7.01; p=0.01) were independent predictors of AAV relapse.Figure 1.Kaplan-Meier estimates of the relapse-free (A) and overall (B) survival rates of AAV patients by baseline serum C3 levels. Eight patients who did not show remission were excluded in the relapse-free survival analysis. Black line: high-C3 group (≥ 100 mg/dL); red line: low-C3 group (< 100 mg/dL).Conclusion:AAV patients with low C3 levels at diagnosis were at higher risk of relapse. Larger prospective studies are required to confirm these findings.Disclosure of Interests:None declared

Pre-pregnancy serum complement C3 level is a predictor of preterm birth for pregnancies with systemic lupus erythematosus

Background This study aimed to clarify predictors of preterm birth in pregnancy of women with systemic lupus erythematosus (SLE). We investigated the predictors of preterm birth before pregnancy from the perspective of the importance of preconception care. Methods We analysed fetal outcomes of 108 pregnancies in 74 SLE patients in a retrospective study. We compared pre-pregnancy clinical characteristics and disease activity in these women between the preterm birth and full-term birth groups to select predictive factors for preterm birth before pregnancy. Results Eighty-three of 108 pregnancies resulted in live births, of which 27 (25.0%) were preterm births. Pre-pregnancy serum complement 3 (C3) level was significantly lower in the preterm birth group (77.0 mg/dl) than the full-term birth group (87.5 mg/dl) (P = 0.029). Multivariate analysis identified history of lupus nephritis (odds ratio: 5.734, 95% CI 1.568–21.010, P = 0.008) and low C3 level (< 85 mg/dl) at pre-pregnancy (odds ratio 4.498, 95% CI 1.296–15.616, P = 0.018) as risk factors for preterm birth. The greater the number of these risk factors, the higher was the preterm birth rate (P = 0.0007). In the case of SLEDAI score ≤ 4, the preterm birth rate was higher in the pre-pregnancy low C3 group (< 85 mg/dl) (42.1%) than in the high C3 group (C3 ≥ 85 mg/dl) (14.7%) (P = 0.018). Conclusion For patients with a history of LN, treatment management focusing on pre-pregnancy serum complement levels is very important.