Serum C3 Levels Research Articles

The effects of curcumin supplementation on inflammatory markers in systemic lupus erythematosus patients: a randomized placebo-controlled trial.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multisystem involvement. This study was designed to examine the effects of curcumin, a polyphenolic compound isolated from turmeric rhizomes, on inflammatory markers in SLE patients. Seventy 18-60 years old SLE patients were recruited in this randomized triple-blinded placebo-controlled trial, and 62 completed the study. Curcumin group received 1000mg curcumin daily and the placebo group received placebo capsules for 10 weeks. Dietary intakes and serum levels of complement C3 and C4, complement hemolytic 50%, rheumatoid factor, anti-double stranded DNA (anti-ds DNA), erythrocyte sedimentation rate, high-sensitivity C-reactive protein, interlukine-6 (IL-6) and tumor necrosis factor-α were assessed before and after intervention period. Curcumin supplementation caused a significant reduction in anti-ds DNA and IL-6 levels at the end of the trial in comparison with baseline (52.57 ± 40.21 vs. 43.27 ± 28.34, p = 0.014 and 127.11 ± 76.63 vs. 101.49 ± 59.08, p = 0.002, respectively). Analysis of covariance which was adjusted for confounding variables also revealed that anti-ds DNA and IL-6 levels decreased significantly in curcumin group compared to placebo group by the end of the intervention period (change:-9.30 ± 19.59 vs. -2.55 ± 17.55, p = 0.018 and - 25.62 ± 42.33 vs. -7.34 ± 34.32, p = 0.043, respectively). No significant changes were observed in levels of other variables during the study (p > 0.05). Curcumin as an effective and safe adjuvant therapy, ameliorated the autoimmune activity and inflammation in SLE patients via reducing anti-ds DNA and IL-6 levels. irct.behdasht.gov.ir, identifier: IRCT20210425051077N1.

Poststreptococcal acute glomerulonephritis with 22F pneumococcal bacteremia.

Pneumococcal vaccines have been available worldwide since the early 2000s; consequently, few reports exist of poststreptococcal acute glomerulonephritis (PSAGN) or complications of pneumococcal infection. We describe a patient with PSAGN and bacteremia with Streptococcus pneumoniae serotype 22F (not covered by the 13-valent pneumococcal vaccine (PCV 13)). A 5-year-old boy received the PCV13 vaccine and was admitted to our hospital with a fever and gross hematuria. A throat swab was positive for a streptococcal antigen, and his serum anti-streptolysin O and creatinine levels were increased. Low serum C3 levels suggested PSAGN, with an infiltrating shadow on chest X-ray. His blood culture isolated S. pneumoniae serotype 22F, and he was administered intravenous ceftriaxone for 10days. His kidney function, pneumonia, and bacteremia improved. Children with PSAGN should be evaluated for pneumococcal bacteremia due to strains not covered by the vaccine.

Long-term outcome of tacrolimus-based immunosuppressive treatment for patients with paediatric-onset lupus nephritis.

We have previously reported the mid-term efficacy and safety of tacrolimus (Tac)-based immunosuppressive therapy in such patients, and herein, we aimed to determine their long-term outcomes (over 10 years). We retrospectively evaluate the data of 13 consecutive patients with biopsy-proven long-standing LN who underwent a long-term Tac-based treatment regimen. Tac was administered once daily at a dose of 3 mg as reinduction or maintenance treatment. Treatment outcomes were defined using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), urinary protein/creatinine ratio (Up/cr), serum creatinine, estimated glomerular filtration rate (eGFR) and serological lupus markers (complement C3, complement hemolytic activity [CH 50], and anti-dsDNA antibody titre), and the concomitantly administered prednisolone (PDN) dose. Data on clinical parameters and serological lupus activity were collected annually from each patient throughout the study period. The patients' baseline characteristics at the treatment initiation were as follows: mean age, 18 years; Up/cr, 0.63 ± 0.69; serum C3 level, 57.2 ± 22.4 mg/dL (normal range, 79-152 mg/dL); CH50, 27.9 ± 15.7 U/mL (normal range, 23.0-46.0 U/mL); serum anti-dsDNA antibody titre, 111.7 ± 123.4 IU/mL (normal range, <12.0 IU/mL); serum creatinine, 0.60 ± 0.19 mg/dL; eGFR, 115.6 ± 21.3 mL/min and SLEDAI, 13 ± 8.1. Despite the gradual tapering of the concomitantly administered PDN dose from 18.7 ± 13.5 mg/day at baseline to 3.5 ± 2.8 mg/day at 10 years (p = .002), a marked improvement in the outcomes, compared with the baseline values, was observed within a year. Additionally, these favourable changes persisted throughout study period in most patients. Compared with the baseline values, the following measures confirmed sustained outcome improvements after a 10-year treatment: SLEDAI, 1.7 ± 2.0; serum C3 level, 83.8 ± 16.1 mg/dL; CH50, 45.6 ± 10.9 U/mL (all p < .01) and Up/cr, 0.16 ± 0.18 and serum anti-dsDNA antibody titre, 25.8 ± 28.8 IU/mL (both p < .05). Serum creatinine level and eGFR remained within the normal range in all study participants except for one patient who experienced several flare-ups. No serious adverse effects were observed. Our results suggest that long-term Tac-based immunosuppressive treatment as maintenance therapy is beneficial and has low cytotoxicity. Therefore, it represents an attractive option for the treatment of selected patients with paediatric-onset LN in a real-world setting.

Efficacy and safety of telitacicept in patients with lupus nephritis.

Although telitacicept is a promising drug for treating systemic lupus erythematosus, there are limited studies on its efficacy and safety in patients with lupus nephritis in China. This lack of research data restricts its potential for broader application and acceptance on a global scale. The present study aimed to determine the efficacy and safety of telitacicept in patients with lupus nephritis (LN) in China. Using a self-controlled before-after comparison method, patients with LN were recruited at Lishui Central Hospital between February 2022 and April 2023, who received telitacicept weekly as part of the standard treatment. Data on the systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K), glucocorticoid dosing and the quantity of immunosuppressive medicines prescribed was collected. Additionally, serum complements, erythrocyte sedimentation rate (ESR), urinary protein levels, immunoglobulin concentrations, serum creatinine levels, plasma albumin concentrations, platelet counts and renal function parameters were documented throughout the study. A total of 13 patients were enrolled in the trial, comprising 11 women and two men. Following 12-48 weeks of treatment with telitacicept (80 or 160 mg per week), 84.6% (n=11) of all patients experienced symptom relief and their SLEDAI-2K score was reduced by more than four points. By the observation endpoint, the median glucocorticoid dosage of the 13 patients was decreased from 15 to 2.5 mg/d, and six patients discontinued their glucocorticoids. Furthermore, 46.1% of patients (n=6) reduced their dose and number of immunosuppressive medicines, while 15.4% (n=2) stopped their immunosuppressive medicines. Minimal changes were observed in serum creatinine, platelet count, C3 levels and C4 levels among patients. Immunoglobulin levels (IgG, IgA and IgM) remained stable or showed an upward trend. Plasma albumin levels remained within the normal range in three patients and increased in ten patients. It increased to the normal range in three of these ten patients. At the endpoint, ESR levels decreased in all patients. Additionally, three patients displayed varying degrees of renal function improvement, and their estimated glomerular filtration rate (ml/min/l.73 m2) increased from 127.8 to 134.2, 95.1 to 123.1 and 61.5 to 67.3, respectively. Urinary protein levels decreased in all patients. It decreased >0.5 g/l in seven patients and reached the normal levels in three patients. The adverse events of telitacicept were manageable. Among the patients infected with COVID-19, three patients had fever, 10 patients remained asymptomatic and none of them exhibited severe respiratory syndromes. In this study, telitacicept effectively stabilized LN activity and alleviated the clinical symptoms of most patients. Furthermore, it reduced the dose of glucocorticoid and immunosuppressive medicines. Therefore, telitacicept may be a promising treatment option for individuals with lupus nephritis.

Gross hematuria and congestive heart failure – two sides of the same coin

Poststreptococcal glomerulonephritis (PSGN) is an immune-mediated disease following infection with nephritogenic strains of group A β-hemolytic Streptococcus (GAS), affecting children aged of 2 to 10. We report 2 different presentations of PSGN from “Grigore Alexandrescu” Hospital. Case 1: A 5 years old girl was admitted for gross hematuria. Investigations revealed: anemia, inflammatory syndrome, mild nitrogen retention syndrome, elevated ASO and low levels of serum C3, nephritic-range proteinuria and severe hematuria. she received antibiotic treatment with initial improvement. A relapse occurred in one week, a second course of antibiotic and corticosteroids was necessary. Case 2: A 15-year-old girl was admitted for acute cardiac failure, hypertension and oliguria. Investigations revealed anemia, nitrogen retention, dyslipidemia, inflammatory syndrome, high ASO titers, low serum C3, microscopic hematuria, nephrotic-range proteinuria. She had fluid build-up in both lungs and pericardium. The diagnosis was PSGN and congestive heart failure (volume overload). She received antibiotics, diuretics and ACE inhibitors. PSGN is re-emerging in pediatric practice due to the resurgence of streptococcal infections within children's communities. The clinical presentation might be highly variable, ranging from hematuria to heart failure. Clinicians should be aware and actively consider this diagnosis.

Dietary Clostridium butyricum metabolites mitigated the disturbances in growth, immune response and gut health status of Ctenopharyngodon idella subjected to high cottonseed and rapeseed meal diet

Cottonseed meal and rapeseed meal exhibit a potential for fishmeal substitute in grass carp feed, while their excessive use contribute to growth decline and weakening immunity of aquatic animals. Clostridium butyricum metabolites (CBM) was recognized as a functional additive due to its antioxidant properties and maintenance of intestinal microbiota balance. CBM was added to a high of cottonseed and rapeseed meal diet to determine its effects on growth, immunity, and intestinal microbiota alterations of grass carp (Ctenopharyngodon idella) over 56 days. Eight hundred grass carp (mean weight, around 50 g) were randomized to five treatments and fed with the basic diet (CON), CBM0 diet (28 % cottonseed and 27 % rapeseed meal), and CBM diets (CBM0.5, CBM1, and CBM2, namely CBM0 diet supplemented with 500, 1000, and 2000 mg kg−1 CBM). The results indicated that compared to CBM0, The ingestion of 1000 mg kg−1 CBM diet by grass carp significantly promoted growth as measured by intestinal lipase activity, villus height, and muscle thickness. Moreover, accompanied by a decrease in intestine MDA content, and enhance antioxidant capacity by activating Keap1/Nrf2 signaling pathway to increase enzyme activities (SOD, CAT and T-AOC) and corresponding gene expression (mnsod, cat, gsto and gpx1) in the intestine of grass crap fed CBM1 diet. The dietary CBM1 diet increased serum levels of C3 and IgM, increased ACP activity and expression of the corresponding anti-inflammatory factors (tgf-β1 and il-15), and suppressed the expression of pro-inflammatory factors (tnf-α and il-12β), resulting in enhanced immunity. The dietary CBM1 diet up-regulates gene expression of tight junction proteins (zo-1, occludin, occludin7a and occludin-c), coupled with the decreases in DAO and D-lactate contents, implying that the decreased mucosal permeability could be observed in the gut. The dietary CBM1 diet largely altered the intestinal microbial community, especially reducing the relative abundance of intestinal pathogenic bacteria (Streptococcus and Actinomyces). And it significantly increased the content of short-chain fatty acids (acetic acid, butyric acid, isobutyric acid, propionic acid and isovaleric acid). Taken above, dietary CBM supplementation improved growth in grass carp and attenuated the intestinal oxidative stress, inflammation and microflora dysbacteriosis caused by high proportions of cottonseed and rapeseed meal diets.

Correlation of Serum Immunoglobulin A and Immunoglobulin A / Complement 3 Ratio with IgA Nephropathy: One Year Prospective Study

Background: IgA nephropathy is the most prevalent primary glomerulonephritis worldwide, characterized by the mesangial deposition of IgA immune complexes.Its clinical course is highly variable, ranging from indolent to rapidly progressive forms, and it represents a significant challenge in nephrology. The diagnostic potential of the IgA/C3 ratio, can provide valuable insights into the underlying immunological processes. Materials and Methods: This is a one year prospective study done in the department of renal pathology at Pratham pathology private limited during the period of 1st November 2021-30th October 2022. Data of all patients were evaluated for the histopathological diagnosis. Report of all cases were reviewed for prebiopsy report of serum IgA and C3 level. All cases of which serum IgA and C3 done were included for the study. Those cases, which didn’t perform serum IgA and C3, were excluded from the study. Results: A total of 182 cases of kidney biopsies were received for evaluation during this period. Out of it 22 cases (12.08 %) were those of IgA Nephropathy. Of which, 13 patients had done a blood level of IgA and C3. There was no statistical difference between serum C3 level, IgA and/or IgA/C3 between IgA nephropathy and non IgA nephropathy. Conclusion: There is no significance variation between serum IgA, C3 and /or IgA/C3 level between IGA nephropathy and other glomerular diseases.

Profiling dendritic cells subsets in renal tissue of patients with crescentic glomerulonephritis.

Dendritic cells (DCs) have been speculated to be involved in the pathogenesis of glomerular diseases. However, the numbers and distribution of DC subsets in the kidneys of patients with crescentic glomerulonephritis (CrGN) have not been clearly elucidated. A total of 26 patients with biopsy-proven CrGN were enrolled. Indirect immunofluorescence staining was used to quantify DC subsets in renal specimens. Double staining of HLA with CD11C, BDCA2 and CD209 respectively was performed to detect DC subsets. The correlation between DC subsets infiltrated in the kidney and clinical and pathological parameters was investigated. DC subsets were predominantly present in the kidney interstitium, particularly in the peri-glomerular area. The numbers of CD11C+DCs, BDCA2+DCs and CD209+DCs increased in the patients with CrGN and varied among different types of CrGN. Though significant correlation between DC subsets and the percentage of crescents had not been identified, a notable increase in the number of CD11C+DCs were observed with the chronic development of crescents. Furthermore, patients with severe tubulointerstitial injury exhibited significantly more infiltrations of CD11C+DCs, BDCA2+DCs and CD209+DCs. Moreover, the numbers of CD11C+DCs and BDCA2+DCs were found to correlate with the level of serum C3. Patients with CrGN showed increased kidney infiltration of DC subsets, primarily localized in the renal interstitium and peri-glomerular region. The correlation between DC subsets and fibrosis of crescent and severe tubulointerstitial injury implied a potential involvement of DCs in the development of CrGN.

Role of serum complement C3 and C4 on kidney outcomes in IgA nephropathy

IgA Nephropathy (IgAN) is the most prevalent glomerular disease worldwide. Complement system activation is crucial in its pathogenesis. Few studies correlated serum C3 and C4 with disease activity and prognosis. This retrospective study investigated the prognostic value of serum complement at the time of diagnosis in patients with IgAN. Specifically we evaluated whether adding serum C3 and C4 levels to established predictive models-one based on variables related to chronic kidney disease (CKD) progression and another incorporating variables from the International IgA Prediction Tool (IntIgAPT)-enhances the accuracy of outcome prediction. A composite renal outcome was defined as 50% decline in eGFR or onset of kidney failure. 101 patients were stratified according to baseline C3 levels in three groups (Low, Medium and High). During a median follow-up of 54 months, the Low group exhibited higher incidence of primary outcome (16.3 events vs 2.9 and 1.7 events × 100 pts/year, p = 0.0026). Model-1 (M1), consisting of CKD progression variables, and Model-3 (M3), comprising IntIgANPT variables, were implemented with baseline C3 and C4 to create Model-2 (M2) and Model-4 (M4), respectively. M2 demonstrated better predictive performance over M1, showing higher discrimination (lower AIC and BIC, higher C-index and NR2). Similarly, M4 outperformed M3, showing enhanced outcome prediction when C3 and C4 levels were added. Implementation of serum C3 and C4 can enhance prediction accuracy of already-validated prognostic models in IgAN. Lower C3 and higher C4 levels were associated with poorer prognosis, highlighting a more 'Complement-Pathic' subset of patients.

Replacement of the massive amino acid losses induced by hemodialysis: A new treatment option proposal for a largely underestimated issue

BackgroundA series of interesting literature reports acknowledges the notable loss of essential and non-essential amino acids (EAAs and NEAAs) during hemodialysis sessions. These losses may exceed 800 g/year, thus contributing towards accelerating the onset of malnutrition in hemodialysis patients (HD). ObjectiveA novel tailored amino acid formula for oral administration was developed to replace total amounts of each individual amino acid lost during dialysis diffusive/convective HD strategies, monitoring the effects produced on nutritional and hematological status. MethodsA three-month randomized double-blind study was conducted on 30 subjects over the age of 70 years extrapolated from a total population of 86 hemodialysis patients. The 30 patients were randomly assigned to two groups: a treatment group of 15 HD patients (TG) to whom a novel mixture containing 5.4 g of AAs was administered solely on interdialytic days, and a control group of 15 HD patients (CG) who received no amino acid supplementation. The AAs mixture was administered post-dialysis at an extended interval from the end of solute and compartmental rebound to replace AA losses and optimize their role in protein anabolism. ResultsThe results obtained highlighted a significant improvement in protein intake g/kg/day (Protein Catabolic Rate, p= 0.014), and increased IgG (p=0.008) and C3 serum levels (p=0.003) in the TG group alone. Fat mass losses were initially confirmed by means of bioelectrical impedance analysis (BIA) (p=0.011) and plicometry (p<0.001) in the CG group alone, although the main objective was to preserve nutritional status and, particularly, muscle mass. The study was extended to investigate the effects produced on anemia, yielding evidence of continued positive effects three months after the end of the study in the TG group alone based on an increase in Hb levels from 11.2+0.6 to 12.1+0.6 (p=0.004) associated with a reduced demand for erythropoietin i.v. from 12928+9033 to 9286+ 5398 U.I/week (p=0.012) and iron i.v. from 75.9+55 to 71.4+33.4 mg/week (p=0.045). ConclusionsThe results obtained following oral administration of this novel tailored AA replacement mixture aimed at reinstating the high AA losses produced during hemodialysis suggest the mixture should be prescribed as a standard procedure to all HD patients.

Low serum complements in idiopathic inflammatory myositis: clinical features and impact on the prognosis

This study investigated the clinical features and prognostic relevance of decreased serum complement levels in patients with idiopathic inflammatory myositis (IIM). The clinical information of IIM patients with less than normal serum complement levels (L-Com) and that of those with normal serum complement levels (N-Com) was compared. In patients with interstitial lung disease (ILD), regression analyses were used to investigate the implication of L-Com in their PaO2/FiO2 (P/F) ratio. Prognostic outcomes of ILD were evaluated using the log-rank test. Of 94 IIM patients, 26 with L-Com (median age, 56.0 years) and 68 with N-Com (56.5 years) were included. The prevalence of women was significantly higher in patients with L-Com (92.3%) than in those with N-Com (67.6%). ILD was observed in 17 (65.4%) patients with L-Com and in 46 (67.6%) with N-Com. Among patients with ILD, the P/F ratio was significantly lower in those with L-Com than in those with N-Com. Serum C3 levels were correlated with decreased P/F ratio. Inferior prognosis of ILD was significantly demonstrated in patients with L-Com, especially in those positive for anti-melanoma differentiation-associated protein 5 antibody. L-Com may be implicated in reduced arterial oxygen levels and a poorer prognosis in patients with IIM-related ILD.

The Effects of Dietary Pterostilbene on the Immune Response, Antioxidant Function, and Jejunal Structure of Broilers.

This experiment was carried out to investigate the effect of pterostilbene (PTE) supplementation in feed on Arbor Acres broilers in terms of serum biochemical parameters, immune and inflammatory responses, antioxidant status, and intestinal morphological structure. For a duration of 42 days, a total of 480 1-day-old Arbor Acres broilers were randomly divided into four groups. Each group was assigned to receive either the basal diet or the basal diet supplemented with 200, 400, or 600 mg/kg of PTE. Each treatment consisted of eight replicates, with 15 chicks per replicate. In comparison with the control group, three PTE treatments significantly increased the lymphocyte transformation rate in the spleen of broilers. The automated biochemical analysis, enzyme-linked immunosorbent assay, and RT-qPCR analysis kits found that 400 mg/kg of PTE significantly increased the serum levels of complement C3, IL-4, and iNOS; reduced the serum levels of IL-6, TNF-α, and mRNA levels of the genes IL-6, IL-8, TNF-α, NLRP3, and IFN-γ; significantly improved the activities of antioxidant enzymes including CAT, GSH-Px, and T-SOD in the jejunum; and significantly reduced the MDA contents in the serum and jejunum of broilers. Nikon microscope observations and ImagePro Plus 6.0 measure results found that 400 mg/kg of PTE supplementation significantly reduced the relative length and weight of the jejunum and improved the jejunal villi structure, resulting in increased intestinal villi, deepened crypt, and an enhanced ratio of villi height to crypt depth (VH/CD). RT-qPCR and Western blot found that dietary PTE also resulted in increased mRNA levels of the genes Claudin-2, Occludin, ZO-1, and Sirt1, and decreased NF-κB protein levels in the jejunum. The results of this study demonstrated that dietary PTE improved the immune function and intestinal health of broilers by reducing inflammation and increasing the antioxidant capacity of the animals.

Serum IgA/C3 ratio: a useful marker of disease activity in patients with IgA nephropathy.

High serum IgA and low serum C3 levels resulting from lectin and alternative pathway activation might be related to IgA nephropathy (IgAN) progression and exacerbation. This study examined whether the serum IgA/C3 ratio can serve as an IgAN progression marker. (1) This nationwide multicenter retrospective study in Japan included 718 patients with biopsy-confirmed IgAN. The patients whose serum creatinine levels at the time of renal biopsy had doubled were defined as having disease progression. (2) Furthermore, to investigate the pathological significance of a reduction in serum IgA/C3 ratio, we reviewed 63 patients whose serum IgA and C3 data at the end of the observation period were obtained. (1) A Kaplan-Meier analysis of the patients with IgAN revealed that the group with a high serum IgA/C3 (≥ 3.3) had a significantly worse renal outcome. In a multivariate analysis of eGFR ≥ 60mL/min per 1.73m2 at the time of biopsy, poor renal outcome was significantly predicted by a serum IgA/C3 ratio of ≥ 3.3. (2) A 15% reduction in the change of serum IgA/C3 ratio was associated with a significantly higher percentage of complete remission of proteinuria. Among the four groups divided by treatment, both the serum IgA/C3 ratio and proteinuria were reduced only in the tonsillectomy and steroid pulse group. The serum IgA/C3 level might reflect the disease activity and be a potent surrogate marker of therapeutic efficacy in patients with IgAN.

#1793 Association of low serum complement C3 with reduced renal survival in ANCA associated vasculitis

Abstract Background and Aims ANCA-associated vasculitis (AAV) is a condition that remains poorly understood. Recent data suggest the existence of a complement alternative pathway activation in the pathogenesis of this disease. And recent studies have correlated low complement levels to unfavourable outcomes. Our study aimed to determine whether low serum C3 levels could be used to estimate the severity of AAV and predict renal survival. Method Our study enrolled 26 patients diagnosed with AAV between January 2013 and January 2023. C3 levels were assessed at the time of diagnosis, and patients were categorized into two groups: those with low serum C3 levels and those with normal serum C3 levels (0.9–1.8 g/l). We examined the correlation between serum C3 levels and the severity of AAV at the time of diagnosis, as well as renal survival. Results The average age at diagnosis was 52.5 years, with 15 male patients (57.69%). All patients had kidney involvement, 30% of patients had respiratory symptoms (mostly due to diffuse alveolar hemorrhage) 42% had Ear Nose Throat system involvement 15% had nervous symptoms and 38% had skin signs. The mean Birmingham Vasculitis Activity Score (BVAS) at presentation was 20, and the average serum creatinine level was 360 µmol/l. The mean serum C3 and C4 levels were 108.3 and 24.5 mg/dL, respectively. Forty-two percent of the patients (eleven patients) had a low serum C3 level at presentation. Low C3 level was significantly correlated with poor renal survival (p: 0.031) and relapse after 6 months of immunosuppressive treatment (p: 0.02). Furthermore, remission at 6 months was significantly more frequent in patients with normal C3 levels. Conclusion The assessment of C3 level in AAV can be a valuable tool to predict the disease severity. Hypocomplementemia can predict worse renal outcome. This phenotype may confer a poor response to usual immunosuppressive approaches. Corresponding patients may greatly benefit from complement-targeting therapy.

#145 Subgroup and secondary endpoint evaluation of a phase 2 randomized placebo-controlled trial of ravulizumab in IgA nephropathy

Abstract Background and Aims The pathogenesis of IgA nephropathy (IgAN) involves immune complex deposition and activation of the complement system, causing formation of the terminal pathway components C5a and C5b-9, leading to inflammation and glomerular damage. Elevated levels of activated C3 in plasma are associated with proteinuria and renal function decline in patients with IgAN [1]; mesangial C3 deposition is also associated with progression of disease [2]. Ravulizumab is a humanized monoclonal antibody that immediately and completely inhibits complement component C5. Primary endpoint (week 26) data from the phase 2 randomized controlled trial (RCT) (NCT04564339) were previously reported and demonstrated a 30% and 33% treatment effect of ravulizumab compared to placebo on 24-hour urine protein and 24-hour urine protein-to-creatinine ratio (UPCR) reduction, respectively [3]. This analysis reports prespecified subgroup and secondary endpoints as well as post hoc exploration of treatment response by baseline serum C3 and C4 quartiles through week 26. Method The SANCTUARY RCT evaluated ravulizumab (IV; weight-based dosing Q8W) vs placebo in adults with primary IgA nephropathy. Randomized patients (2:1) were stratified by mean proteinuria (1–2 vs &amp;gt;2 g/day). Patients (18–75 years) with biopsy-confirmed IgA nephropathy, proteinuria ≥1g/day, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, and on stable maximally tolerated renin angiotensin inhibition were enrolled. The primary endpoint was proteinuria reduction at week 26 based on 24-hour urine collection. Secondary endpoints at week 26 included the proportion of patients with &amp;gt;50% reduction in proteinuria (absolute urine protein) and the percentage with &amp;lt;1g/day proteinuria. The percentage change in proteinuria (absolute urine protein) among subgroups of sex, race, duration of disease, baseline proteinuria and eGFR, and baseline serum C3 and C4 levels were also evaluated, as were safety data. Results 66 patients entered the 26-week initial evaluation period (n = 43, ravulizumab arm; n = 23, placebo arm); 71.2% were White and 21.2% were Asian. Overall, 41.5% and 18.2% of ravulizumab- and placebo-treated patients, respectively, achieved &amp;gt;50% proteinuria reduction (Fig. 1). Proteinuria reduction to &amp;lt;1g/day was achieved in 26.8% and 18.2% in the ravulizumab and placebo arms, respectively. Subgroup analysis indicated a treatment effect across subgroups of sex, race, disease duration, and baseline proteinuria and eGFR (Fig. 2). With ravulizumab, there were reductions of 41.9% and 41.0% in proteinuria for those with the lowest quartile of baseline serum C3 and C4, respectively. Similarly, reductions of 40.4% and 40.8% were observed in those with baseline serum C3 and C4 levels above the lowest quartile. In the ravulizumab arm, two patients had low serum C3 at baseline and there were no patients with low serum C4 at baseline; there was no change in mean serum C3 and C4 levels over time. Treatment with ravulizumab was well-tolerated. Conclusion In this phase 2 trial of ravulizumab in IgAN, proteinuria was significantly reduced with ravulizumab vs placebo through week 26. A reduction in proteinuria was also observed across subgroups of patients. As is typical in IgAN, serum C3 and C4 levels at baseline were normal, and there was no difference in proteinuria reduction by baseline serum C3 and C4 levels with ravulizumab through 6 months.

#1486 Looking for a new role of known players: the additional value of plasmatic C3 and C4 in predicting IgA Nephropathy prognosis, an observational study

Abstract Background and Aims IgA Nephropathy (IgAN) is the most common glomerular disease worldwide [1]. Complement system activation through the alternative and lectin pathways is crucial in its pathogenesis and leads to worse outcome, eliciting the need for (new) biomarkers to assess risk of disease progression and potential response to new targeted treatments [2, 3]. Only few works have correlated serum C3 and C4 with disease activity and prognosis [4, 5]. Our work explores the potential advantages of incorporating serum C3 and C4 levels into a standardized prognostic model to assess kidney outcome in IgAN. Method This retrospective study, conducted at Sant'Orsola University Hospital in Bologna, investigated the prognostic value of serum complement C3 and C4 in patients with IgAN. The primary outcome was defined as a 40% decline in eGFR or the onset of kidney failure. The study aimed to evaluate whether the addition of serum C3 and C4 to an established predictive model, incorporating variables from the International IgA Prediction Tool (IntIgAPT), enhances the accuracy of outcome prediction. We computed the measures of goodness of fit for each model: Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC), Nagelkerke R2 test (NR2) that depicts the% explained variation of the outcome based on the set of variables included, and Likelihood Ratio Test (LRT); discrimination with the c-index. Furthermore, we aimed to evaluate the characteristics of patients stratified by baseline serum C3 levels (Low &amp;lt;90 mg/dl, Medium 90-140 mg/dl, High &amp;gt;140 mg/dl). Results 101 patients were included in the cohort. 90% were Caucasian and 65.3% were male with a mean age of 42.6 years. As reported in Table 1, mean eGFR and median proteinuria levels at baseline were 70.4 ml/min/1.73 m² and 1.04 g/24 h respectively. Mean serum C3 was 114.9 mg/dL. The Low group had lower values of eGFR at baseline (47.0 vs 75.67 and 68.64 ml/min/1.73 m², p = 0.015), while the Medium group had lower values of uProt (0.75 vs 1.81 and 1.46 g/24 h, p = 0.004). During a median 54.28 months follow-up, the Low group exhibited significantly higher primary outcome incidence (16.3 events vs 2.9 and 1.7 events x 100 pts/year, p = 0.003). We computed a first model (M1) based upon IntIgAPT variables and then a second model (M2) as the same of M1 plus serum C3 and C4 at baseline (Table 2). C3 showed a negative association with outcome (OR 0.88, CI 0.78 to 0.99, p = 0.05) whereas C4 had a positive one (OR 1.21, CI 1.02 to 1.48, p = 0.05). M2 had an improved prediction accuracy than M1, as evidenced by lower AIC (49.1 vs 53.8), higher c-index (0.74 vs 0.65), and NR2 (0.76 vs 0.65). Likelihood ratio test was significant between the two (p = 0.008). Conclusion The inclusion of serum C3 and C4 in a validated prognostic model enhances prediction accuracy and improves the percentage of events explained, highlighting complement's inherent informativeness. In our population lower C3 and higher C4 levels were associated with poorer prognosis in IgAN, characterizing a more ‘Complement-Pathic’ subset of patients. This result expands the current evidence, for the first time to our knowledge, in a Caucasian-prevalent study population.

#933 Serum and kidney complement and severity of ANCA associated vasculitis in the kidney

Abstract Background and Aims Kidney involvement in ANCA associated vasculitis (AAV) is commonly described as pauci-immune based on histological characteristics. However, we now know that the complement system is activated and contributes to the pathogenesis of AAV – with Avacopan (C5a inhibitor) demonstrating superior efficacy in maintenance of remission over Prednisolone in the ADVOCATE trial. Our aim was to evaluate if there is an association between kidney disease severity and the presence of serum and histological complement activation markers. Method Retrospective cohort study of 59 patients with AAV diagnosed between November 2015 and May 2019. Complement activation markers were serum complements (C3 and C4) levels and presence of complement (C3, C1q and C4) in glomerular capillary walls in immunofluorescence with intensity of 2+ and 3+. Kidney disease severity markers were peak serum creatinine value at presentation, anti-MPO or anti-PR3 levels, and number and proportion of glomeruli with crescents on kidney biopsy. Associations were evaluated using Spearman correlation or Mann Whitney U test as appropriate Results Among 59 patients with biopsy-proven AAV in the kidney, the median (25th percentile, 75th percentile) age was 68.8 (60.7, 73.4) years, serum creatinine was 263 (156, 560) µmol/L, and anti-MPO and anti-PR3 levels were 100.0 (81.5, 199.2) and 128.8 (22.9, 200) in 41 and 7 patients, respectively. respectively. The number and proportion of glomeruli with crescents were 6 (3, 12) and 33.3% (12.0%, 42.6%), respectively. Serum C3 and C4 were performed in 41 patients and the median levels were 1.00 (0.83, 1.14) and 0.24 (0.18, 0.31), respectively. Serum C3 level did not correlate with serum creatinine, anti-MPO or anti-PR3 titers, and number and proportion of glomeruli with crescents. Serum C4 level was negatively correlated with anti-MPO titer (34 patients; r = −0.393, p = 0.02) but did not correlate with serum creatinine or number or proportion of crescents. Complement in the glomerular capillary wall was present in 8 patients (13.6%): C3, C1q and C4 were present in 8, 3 and 1 patients, respectively. Serum creatinine [median 299 (IQR 133, 998) µmol/L versus 261 (156, 359) µmol/L, p = 0.39], anti-MPO titer [100 (88.3, 200) IU/ml versus 100 (79.4, 198) IU/ml, p = 0.74], number of crescents [14 (4, 21) versus 5 (3, 12), p = 0.90] and proportion of crescents [38.9% (12.5%, 42.3%) versus 31.3% (11.1%, 44.3%), p = 0.59] were not different in those with and without complement in the kidney biopsy. Conclusion The presence of complement activation markers was not associated with kidney disease severity in AAV. However, the detection of clinically significant associations may have been limited by our cohort size.

#752 Ponatinib exacerbates renal damage in MRL/lpr lupus model mice through the lipid metabolism pathway

Abstract Background and Aims The role of tyrosine kinase inhibitors (TKIs) in lupus nephritis is controversial. Ponatinib is a third-generation tyrosine kinase inhibitor that targets multiple receptors. This study aims to explore the effect of ponatinib in lupus nephritis, with the hope of providing insights for the clinical application of ponatinib. Method At 8 weeks of age, mice were randomly divided into four groups. One group received no treatment, while the other three groups were respectively administered Ponatinib, prednisolone acetate, and a combination of Ponatinib and prednisolone acetate. The treatment was concluded when the mice reached 16 weeks of age. ELISA was employed to measure the levels of anti-dsDNA IgG, ANA, and C3 in mouse serum. DEGs and DELs were identified using the DESeq2 package in R. Pathway and gene ontology enrichment analyses were performed using the MetaCore database. Results Compared to the negative control, those mice receiving ponatinib showed a significant increase in the urinary protein/creatinine ratio (P &amp;lt; 0.01), along with notable elevations in blood creatinine and blood urea nitrogen. Pathological examination of kidney tissue suggested predominant acute lesions, including transparent thrombi, cellulose-like necrosis, cellular/fibrous crescents, and interstitial inflammation. Interestingly, serum testing in MRL/lpr mice revealed no significant differences in lupus activity-related indicators, including autoantibodies ANA, double-stranded DNA, and complement C3, between the negative control group and the ponatinib group. Furthermore, it was discovered that the kidney damage caused by ponatinib in MRL/lpr mice could be reversed by prednisone. RNA-Seq of kidney tissue from MRL/lpr mice showed a total of 44 differentially expressed genes when comparing the negative control with mice receiving ponatinib, including 23 upregulated and 21 downregulated genes. Pathway analysis revealed that the top four pathways were all related to lipid metabolism. Conclusion Ponatinib significantly exacerbated kidney damage in MRL/lpr mice and did not induce changes in lupus activity.

#1360 SARS-COV-2 protein in renal tissue enhanced activation of complement system in MN patients with COVID-19 infection

Abstract Background and Aims Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Complement plays an important role in the pathogenesis of MN. COVID-19 infection has been reported to be associated with the occurrence and recurrence of MN. Only few kidney biopsies from COVID-19 patients demonstrate the presence of SARS-CoV-2 in the tissue. The clinical and pathological characteristics and complement system activation of patients with SARS-COV2 in renal tissue are unclear, needing to further study. Method From December 2022 to June 2023, patients with renal biopsy-proven MN at Beijing Anzhen hospital who had experienced COVID-19 infection before proteinuria onset and renal biopsy were enrolled. One hundred patients with primary MN diagnosed from December 2018 to June 2019 (with no COVID-19) were enrolled as control. Patient medical records were reviewed for clinical and pathological data. We performed immunofluorescence and in situ hybridization assays for detection of the SARS-COV2. Glomerular staining for factor H, FHR-5 and MAC were detected by immunohistochemical. Serum C5b-9 were detected by enzyme-linked immunosorbent assay. Clinicopathological and immunological features between MN patients with and without SARS-COV2 infection were analyzed. Results A total of 38 MN patients was proteinuria onset after COVID-19 infection, including 11 patients had SARS-COV protein positive staining along capillary loops in glomerular deposits or in cytoplasm of tubular epithelial cells. The immunofluorescence result shows strong colocalization of SARS-COV2 and IgG, which suggests that SARS-COV protein participated in the formation of immune complex. Compared with primary MN patients, the serum albumin level of 38 MN patients with COVID-19 infection were lower (p = 0.011). However, the clinical manifestations of 11 MN patients with SARS-COV2 renal positive staining were obviously serous. Compared with primary MN patients, urinary protein and serum creatine levels significantly increased (p = 0.027 and p = 0.005), while serum albumin levels decreased (p = 0.014) and the proportion of nephrotic syndrome (p = 0.037) was higher. There was no significant difference in pathological manifestations between MN patients with or without COVID-19 infection. In follow-up, the proportion of patients with urinary protein decreased greater than 50% in MN patients with COVID-19 infection was lower than that in primary MN patients. of urinary protein level Serum level of complement C3 (p = 0.007) and MAC (P = 0.001) in MN patients with COVID-19 infection was significantly higher than that of primary MN patients, especially MN patients with renal tissue positive staining of SARS-COV2 protein (p = 0.002 and p = 0.007). In 38 MN patients with COVID-19 infection, compared with patients with renal tissue negative for SARS-COV2 protein, patients with renal tissue positive for SARS-COV2 protein presented with stronger intensity of MAC deposition (p = 0.023) and factor H deposition (p = 0.002). Conclusion The clinical manifestation of MN patients who was onset after COVID-19 infection with renal tissue positive for SARS-COV2 protein were not only significantly worse than those of primary MN patients, but also worse than patients without tissue SARS-COV2 positive MN patients. We speculate that the reason is the enhanced activation of the complement system in renal tissue.

#1707 Antiphospholipid antibodies in lupus nephritis

Abstract Background and Aims Antiphospholipid antibodies (aPL) constitute a heterogeneous family of antibodies against anionic phospholipids or phospholipid-binding proteins. They may occur in association with autoimmune diseases, infections, and sometimes in the general population. Lupus nephritis (LN) is a major manifestation of systemic lupus erythematosus (SLE). The aim of this study was to investigate the association of aPL with clinical activity, renal damage, renal activity and outcomes in patients with LN. Method A total of 157 patients (11 male, 146 female, age between 17 and 58 years) with LN were included in this study. The International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of LN was used to classify the patients into LN subsets. Histopathological renal activity and damage were estimated using the Activity Index (AI) and Chronicity Index (CI), respectively. Levels of anticardiolipin (aCL) antibodies, anti-β2-glycoprotein I (anti-β2-GPI) antibodies and lupus anticoagulant (LAC) were measured, and other clinical and pathological data were also obtained. Long-term renal outcome was determined by the estimated glomerular filtration rate (eGFR) and the Chronic Kidney Disease stage, after a median follow-up of 20,5 ± 8, 7 years, counting from the occasion of the first renal biopsy. Renal and extra-renal symptoms were analyzed. Patients which have more than one class LN features, were excluded from the study. The treatment includes standard treatment for LN, inhibitors of the angiotensin system in patients with hypertension and proteinuria, steroids, anticoagulants, cyclophosphamide, mycophenolate mofetil, azathioprine. Results LN patients were classified according to the baseline renal biopsies as patients with: minimal mesangial LN (4), mesangial-proliferative LN (30), focal proliferative LN (31), diffuse proliferative LN (48), membranous LN (44). aPL antibodies were detected in 89 (56,69%) patients, aCL antibodies – in 72 (45,86%), anti-β2-GPI antibodies – in 58 (36,94%) and LAC were detected in 46 (29,30%) patients. None of these patients had a concomitant diagnosis of antiphospholipid syndrome nephropathy. Follow-up was similar between aPL-positive and aPL-negative patients. LN patients with positive aPL antibodies had significantly higher SLEDAI (p &amp;lt; 0,05), anti-dsDNA levels (p &amp;lt; 0,05), anti-ribosomal-P antibodies levels (p &amp;lt; 0,05), anti-C1q antibodies (p &amp;lt; 0,05), lower serum C3 (p &amp;lt; 0,005) and C4 (p &amp;lt; 0,05) levels, and higher intensity of complement C3 (p &amp;lt; 0,05) deposits in kidney tissue than the aCL antibody–negative LN patients. aPL-seropositivity was associated with more rapid decline in eGFR (–1,06 mL/min/year compared to –0,45 mL/min/year in aPL-seronegative patients) and showed inferior patient survival (89,8% and 67,9% at 10 and 15 years, respectively, compared to 97,3% and 76% in aPL-seronegative patients). No significant correlation was found between serum aPL antibodies levels and activity or chronicity index scores in renal biopsies at baseline, ANA levels, or age. Conclusion We concluded that aPL-seropositivity are correlated with clinical activity in patients with LN and are associated with inferior long-term patient survival.