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.

Construction and application of fetal loss risk model in systemic lupus erythematosus patients with mild disease severity.

BACKGROUND: This dynamic nomogram model was developed to predict the probability of fetal loss in pregnant patients with systemic lupus erythematosus (SLE) with mild disease severity before conception. METHODS: An analysis was conducted on 314 pregnancy records of patients with SLE who were hospitalized between January 2015 and January 2022 at Shenzhen People's Hospital, and the Longhua Branch of Shenzhen People's Hospital. Data from the Longhua Branch of the Shenzhen People's Hospital were utilized as an independent external validation cohort. The nomogram, a widely used statistical visualization tool to predict disease onset, progression, prognosis, and survival, was created after feature selection using multivariate logistic regression analysis. To evaluate the model prediction performance, we employed the receiver operating characteristic curve, calibration curve, and decision curve analysis. RESULTS: Lupus nephritis, complement 3, immunoglobulin G, serum albumin, C-reactive protein, and hydroxychloroquine were all included in the nomogram model. The model demonstrated good calibration and discriminatory power, with an area under the curve of 0.867 (95% confidence interval: 0.787-0.947). According to decision curve analysis, the nomogram model exhibited clinical importance when the probability of fetal loss in patients with SLE ranged between 10 and 70%. The predictive ability of the model was demonstrated through external validation. CONCLUSION: The predictive nomogram approach may facilitate precise management of pregnant patients with SLE with mild disease severity before conception.

A cross sectional study assessing steatotic liver disease in patients with systemic lupus erythematosus.

Patients with immune-mediated inflammatory diseases are prone to steatotic liver disease (SLD), which has been observed in patients with psoriasis and hidradenitis suppurativa. We aimed to assess whether systemic lupus erythematosus (SLE) was associated with SLD and to define factors associated with SLD in SLE. This was a cross-sectional study, we included 106 consecutive patients with SLE who were seen in the rheumatology clinic between June 2021 and March 2022 and we chose two sex-paired controls for each SLE. All the participants underwent FibroScan and anthropometric assessments. SLD was defined as a controlled attenuation parameter ≥ 275dB/m. Prevalence of SLD was lower in patients with SLE (21.7% vs 41.5%, p < 0.001). Patients with SLE and SLD had a lower frequency of hydroxychloroquine use (65% vs 84%, p = 0.04), and higher C3 levels [123mg/dl (IQR 102-136) vs 99mg/dl (IQR 78-121), p = 0.004]. Factors associated with SLD in SLE were body mass index (BMI), waist circumference, glucose, and C3; hydroxychloroquine use was a protective factor. On univariate analysis, SLE was associated with a reduced risk of SLD (OR 0.39, 95%CI 0.23-0.67); however, after adjusting for age, BMI, waist, glucose, triglycerides, high-density cholesterol, low-density cholesterol, leukocytes, and hydroxychloroquine, it was no longer associated (OR 0.43, 95%CI 0.10-1.91). In conclusion, the prevalence of SLD in patients with SLE was not higher than that in the general population, and SLE was not associated with SLD. The factors associated with SLD were anthropometric data, glucose, hydroxychloroquine, and C3 levels.

Association of Complement Factors With Disability Progression in Primary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The complement system is known to play a role in multiple sclerosis (MS) pathogenesis. However, its contribution to disease progression remains elusive. The study investigated the role of the complement system in disability progression of patients with primary progressive MS (PPMS). METHODS: Sixty-eight patients with PPMS from 12 European MS centers were included in the study. Serum and CSF levels of a panel of complement components (CCs) were measured by multiplex enzyme-linked immunosorbent assay at a baseline time point (i.e., sampling). Mean (SD) follow-up time from baseline was 9.6 (4.8) years. Only one patient (1.5%) was treated during follow-up. Univariable and multivariable logistic regressions adjusted for age, sex, and albumin quotient were performed to assess the association between baseline CC levels and disability progression in short term (2 years), medium term (6 years), and long term (at the time of the last follow-up). RESULTS: In short term, CC played little or no role in disability progression. In medium term, an elevated serum C3a/C3 ratio was associated with a higher risk of disability progression (adjusted OR 2.30; 95% CI 1.17-6.03; p = 0.040). By contrast, increased CSF C1q levels were associated with a trend toward reduced risk of disability progression (adjusted OR 0.43; 95% CI 0.17-0.98; p = 0.054). Similarly, in long term, an elevated serum C3a/C3 ratio was associated with higher risk of disability progression (adjusted OR 1.81; 95% CI 1.09-3.40; p = 0.037), and increased CSF C1q levels predicted lower disability progression (adjusted OR 0.41; 95% CI 0.17-0.86; p = 0.025). DISCUSSION: Proteins involved in the activation of early complement cascades play a role in disability progression as risk (elevated serum C3a/C3 ratio) or protective (elevated CSF C1q) factors after 6 or more years of follow-up in patients with PPMS. The protective effects associated with C1q levels in CSF may be related to its neuroprotective and anti-inflammatory properties.

Association between circulatory complement activation and hypertensive renal damage: a case-control study.

OBJECTIVE: The aim of this study was to investigate the potential importance of complement system activation, with particular emphasis on the complement alternative pathway (AP), in the pathogenesis of hypertensive renal damage. METHODS: Serum complement C3, complement Factor H (CFH) and AP activation were assessed in 66 participants with established essential hypertension with renal damage (RD). Fifty-nine patients with age- and sex-matched essential hypertension without renal damage (NRD) and 58 healthy participants (normal) were selected. RESULTS: Our study revealed that C3 and AP50 continuously increased from normal to NRD to RD (p < 0.05, respectively), while CFH was significantly lower than that in NRD and healthy participants (p < 0.05, respectively). After multifactorial logistic regression analysis corrected for confounders, elevated serum C3 (p = 0.001) and decreased CFH (p < 0.001) were found to be independent risk factors for hypertension in healthy participants; elevated serum C3 (p = 0.034), elevated AP50 (p < 0.001), decreased CFH (p < 0.001), increased age (p = 0.011) and increased BMI (p = 0.013) were found to be independent risk factors for the progression of hypertension to hypertensive renal damage; elevated serum C3 (p = 0.017), elevated AP50 (p = 0.023), decreased CFH (p = 0.005) and increased age (p = 0.041) were found to be independent risk factors for the development of hypertensive renal damage in healthy participants. CONCLUSION: Abnormal activation of complement, particularly complement AP, may be a risk factor for the development and progression of hypertensive renal damage.

Baseline and end-of-treatment host serum biomarkers predict relapse in adults with pulmonary tuberculosis.

BACKGROUND: There is a need for new tools for monitoring of the response to TB treatment. Such tools may allow for tailored treatment regimens, and stratify patients initiating TB treatment into different risk groups. We evaluated combinations between previously published host biomarkers and new candidates, as tools for monitoring TB treatment response, and prediction of relapse. METHODS: Serum samples were collected at multiple time points, from patients initiating TB treatment at research sites situated in South Africa (ActionTB study), Brazil and Uganda (TBRU study). Using a multiplex immunoassay platform, we evaluated the concentrations of selected host inflammatory biomarkers in sera obtained from clinically cured patients with and without subsequent relapse within 2 years of TB treatment completion. RESULTS: A total of 130 TB patients, 30 (23%) of whom had confirmed relapse were included in the study. The median time to relapse was 9.7 months in the ActionTB study (n = 12 patients who relapsed), and 5 months (n = 18 patients who relapsed) in the TBRU study. Serum concentrations of several host biomarkers changed during TB treatment with IL-6, IP-10, IL-22 and complement C3 showing potential individually, in predicting relapse. A six-marker signature comprising of TTP, BMI, sICAM-1, IL-22, IL-1ß and complement C3, predicted relapse, prior to the onset of TB treatment with 89% sensitivity and 94% specificity. Furthermore, a 3-marker signature (Apo-CIII, IP-10 and sIL-6R) predicted relapse in samples collected at the end of TB treatment with sensitivity of 71% and specificity of 74%. A previously identified baseline relapse prediction signature (TTP, BMI, TNF-ß, sIL-6R, IL-12p40 and IP-10) also showed potential in the current study. CONCLUSION: Serum host inflammatory biomarkers may be useful in predicting relapse in TB patients prior to the initiation of treatment. Our findings have implications for tailored patient management and require prospective evaluation in larger studies.

Prediction model for treatment response of primary membranous nephropathy with nephrotic syndrome.

OBJECTIVE: To investigate the predictors and establish a nomogram model for the prediction of the response to treatment in primary membranous nephropathy (PMN) with nephrotic syndrome (NS). METHODS: The clinical, laboratory, pathological and follow-up data of patients with biopsy-proven membranous nephropathy at the Affiliated Hospital of Qingdao University were collected. A total of 373 patients were randomly assigned into development group (n = 262) and validation group (n = 111). Logistic regression analysis was performed in the development group to determine the predictors of treatment response. A nomogram model was established based on the multivariate logistic regression analysis and validated in the validation group. The C-index and calibration plots were used for the evaluation of the discrimination and calibration performance, respectively. RESULTS: Serum albumin levels (OR = 1.151, 95% CI 1.078-1.229, P < 0.001) and glomerular C3 deposition (OR = 0.407, 95% CI 0.213-0.775, P = 0.004) were identified as independent predictive factors for treatment response in PMN with NS, then a nomogram was established combining the above indicators and treatment regimen. The C-indices of this model were 0.718 (95% CI 0.654-0.782) and 0.789 (95% CI 0.705-0.873) in the development and validation groups, respectively. The calibration plots showed that the predicted probabilities of the model were consistent with the actual probabilities (P > 0.05), which indicated favorable performance of this model in predicting the treatment response probability. CONCLUSIONS: Serum albumin levels and glomerular C3 deposition were predictors for treatment response of PMN with NS. A novel nomogram model with good discrimination and calibration was constructed to predict treatment response probability at an early stage.

Clinical characteristics and risk factors of connective tissue disease complicated with bronchiectasis and pulmonary infection.

The clinical data from 118 CTD patients with bronchiectasis were collected and categorized into two groups: pulmonary infection present (n = 67) and absent (n = 51), for comparative analysis of characteristics and risk factors. Then, we analyzed and compared their demographics, disease characteristics, and risk factors for infection. Among the whole cohort (n = 118), the incidence of pulmonary infections was 56.78%. The occurrence of rheumatoid arthritis, systemic lupus erythematosus, and vasculitis was found to be associated with an increased risk of pulmonary infection. Sputum culture identified Pseudomonas aeruginosa and Klebsiella pneumoniae as the predominant pathogens in the infected group. Notably, symptoms such as joint pains (p = 0.018) and morning stiffness (p = 0.017) were significantly more common in the infected group compared to the noninfected group. Moreover, our findings revealed that elevated levels of C-reactive protein and complement C3, along with bronchial expansion observed on high-resolution computed tomography (HRCT), were significant independent factors in the infection group. Conversely, pulmonary interstitial changes identified through HRCT (OR: 0.135, 95% CI: 0.030-0.612, p = 0.009) were significantly associated with the non-infection group. Overall, this study provides valuable insights into managing CTD patients with bronchiectasis, emphasizing early detection and tailored approaches to prevent and treat pulmonary infections for better outcomes.

Histological reappraisal of IgA nephropathy: the role of glomerular pattern of injury and mesangial complement deposition.

BACKGROUND: There is a clear need to refine the histological assessment in IgA Nephropathy (IgAN). We sought to investigate the clinical significance of the light microscopy (LM) pattern of glomerular injury and of the intensity of mesangial C3 staining in IgAN. METHODS: We conducted a retrospective, observational study that included all patients with biopsy-proven primary IgAN that had at least 12 months of follow-up. The LM pattern of glomerular injury was reevaluated based on a modified HAAS classification. Mesangial C3 deposition by immunofluorescence (IF) staining was scored semi-quantitatively. The study primary composite endpoint was defined as doubling of serum creatinine or ESRD (dialysis, renal transplant or eGFR < 15 ml/min). The secondary study endpoint was eGFR decline per year. RESULTS: This cohort included 214 patients with IgAN (mean age, 41.4 ± 12.6 years), with a mean eGFR and median 24-h proteinuria of 55.2 ± 31.5 ml/min/1.73m2 and 1.5 g/day (IQR:0.8-3.25), respectively. The most frequent LM pattern was the mesangioproliferative (37.4%), followed by the sclerotic (22.5%) and proliferative/necrotizing patterns (21.4%). Regarding the IF findings, mild-moderate and intense mesangial C3 staining was present in 30.6% and 61.1% of patients, respectively. Those with sclerosing and crescentic patterns had the worst renal survival (5-year renal survival of 48.8% and 42.9%) and the highest rate of eGFR change/year (-2.32 ml/min/y and - 2.16 ml/min/y, respectively) compared to those with other glomerular patterns of injury. In addition, those with intense C3 staining reached the composite endpoint more frequently compared to those without intense C3 staining (35.5% vs. 21.4%, p = 0.04). After multivariate adjustment, patients with crescentic and sclerosing patterns had a 3.6-fold and 2.1-fold higher risk for the composite endpoint compared to those with mesangioproliferative pattern, while an intense mesangial C3 deposition being also associated with a worse renal outcome (HR, 3.33; 95%CI, 1.21-9.2). CONCLUSIONS: We have shown that the LM pattern of glomerular injury and the intensity of mesangial C3 deposition might stratify more accurately the renal outcome in patients with IgAN.

Clinical characteristics and outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulopathy in Japanese children.

BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) can be divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G), which includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These conditions result from abnormalities in different complement pathways and may lead to different prognoses. However, there are limited studies describing the respective clinical courses. METHODS: In this study, Japanese pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022 were reclassified as having IC-MPGN or C3G (DDD or C3GN). We retrospectively analyzed the clinical characteristics and outcomes of these patients. RESULTS: Out of 25 patients with MPGN, three (12.0%) were diagnosed with DDD, 20 (80.0%) with C3GN, and two (8.0%) with IC-MPGN. There were 13 (65.0%) patients and one (33.3%) patient in remission after treatment for C3GN and DDD, respectively, and no patients with IC-MPGN achieved remission. The median follow-up period was 5.3 (2.5-8.9) years, and none of the patients in either group progressed to an estimated glomerular filtration rate < 15 ml/min/1.73 m2. Patients with C3GN presenting mild to moderate proteinuria (n = 8) received a renin-angiotensin system inhibitor (RAS-I) alone, and these patients exhibited a significant decrease in the urinary protein creatinine ratio and a notable increase in serum C3 levels at the last follow-up. CONCLUSIONS: Most patients with MPGN were diagnosed with C3GN. The remission rate for C3GN was high, and no patients developed kidney failure during the approximately 5-year follow-up. Additionally, patients with C3GN with mild to moderate proteinuria had good outcomes with RAS-I alone, but continued vigilance is necessary to determine long-term prognosis.

Serum PRO-C3 is useful for risk prediction and fibrosis assessment in MAFLD with chronic kidney disease in an Asian cohort.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is an emerging risk factor for chronic kidney disease (CKD). N-terminal propeptide of collagen type 3 (PRO-C3) is a biomarker of advanced fibrosis in MAFLD and PRO-C3 may be involved in renal fibrosis. We aimed to use PRO-C3 measurements to generate a new algorithmic score to test the prediction of MAFLD with chronic kidney disease (MAFLD-CKD). METHODS: A derivation and independent validation cohort of 750 and 129 Asian patients with biopsy-confirmed MAFLD were included. Serum PRO-C3 concentration was measured and regression analyses were performed to examine associations with MAFLD-CKD. A derivative algorithm for MAFLD-CKD risk prediction was evaluated with receiver operator characteristic (ROC) curve analysis. RESULTS: The study included two Asian cohorts (n = 180 with MAFLD-CKD; mean-eGFR: 94.93 mL/min/1.73 m2; median-urinary albumin-to-creatinine ratio: 6.58 mg/mmol). PRO-C3 was associated with the severity of MAFLD-CKD and independently associated with MAFLD-CKD (adjusted odds ratio = 1.16, 95% confidence interval [CI]: 1.08-1.23, p < .001). A new non-invasive score (termed PERIOD) including PRO-C3 efficiently predicted MAFLD-CKD (AUROC = .842, 95% CI: .805-.875). Accuracy, specificity and negative predictive values were 80.2%, 85.1% and 88.4%, respectively. In the validation cohort, the PERIOD score had good diagnostic performance (AUROC = .807, 95% CI: .691-.893) with similar results in all patient subgroups. In the MAFLD-CKD subgroup, the accuracy for identifying advanced fibrosis was further improved by combining the PRO-C3-based ADAPT with the Agile 3+ scores (AUROC = .90, 95% CI: .836-.964). CONCLUSIONS: The PERIOD score is helpful for accurately predicting the risk of MAFLD-CKD. PRO-C3 can also be used to assess liver fibrosis in people with MAFLD-CKD.

Development of a target concentration intervention to individualize paroxysmal nocturnal hemoglobinuria treatment with pegcetacoplan.

Pegcetacoplan (Aspaveli®/Empaveli™) is a factor C3 inhibitor that is approved for the treatment of paroxysmal nocturnal hemoglobinuria. An individualized dosing strategy might be useful to improve patient-friendliness and cost-effectiveness of this very expensive drug. Therefore, the aim of this study was to develop an individualized treatment regimen for pegcetacoplan based on the pharmacokinetic-pharmacodynamic data of the manufacturer. We conducted a clinical trial simulation with the approved dosing regimen of 1080 mg twice-weekly and a target concentration intervention-based dosing regimen in patients with and without prior eculizumab use. For eculizumab-naïve patients, the target concentration intervention-based dosing regimen resulted in a comparable fraction of patients with LDH normalization (LDH < 226 U/L) and hemoglobulin normalization (> 12 g/dL) compared to the approved regimen (LDH 50.2% and 50.0% respectively and hemoglobulin 45.6% and 44.4%). A modest dose reduction of ~ 5% was possible with target concentration intervention-based dosing. An intensified dosing interval was necessary in 2.3% of the patients however an interval prolongation was possible in 28.2% of the patients. Similar results were obtained for patients prior treated with eculizumab. In this study we show the potential of an individualized dosing regimen of pegcetacoplan with can improve patient friendliness in approximately 30% of the patients and improve therapy in approximately 2% of the patients at slightly reduced costs.

C3 concentrations can be normal in patients with C3 glomerulopathy secondary to C3 nephritic factor.

C3 glomerulopathy (C3G) is a rare kidney disease caused by the glomerular deposition of C3 fragments secondary to alternative pathway complement dysregulation. C3 nephritic factors (C3Nef) are the most common acquired cause, and their detection has treatment and prognostic implications. Although C3 concentration can be normal in the presence of C3Nef, many laboratories will only perform C3Nef testing when C3 is low. We performed a retrospective study of all positive C3Nef results from the authors' laboratory since 2015 and found that two of the four patients with positive C3Nef and biopsy-confirmed C3G had normal C3 concentrations. This may be in part due to limitations in commercial C3 testing methods which use anti-C3c antisera directed against both C3 breakdown products and native C3. A normal C3 concentration should not preclude C3Nef testing in the appropriate clinical context.

Comparison of clinical and laboratory data of adult patients with cutaneous IgA vasculitis and non-IgA vasculitis.

BACKGROUND: Immune complex vasculitides may be subdivided into adult IgA small vessel vasculitis (aIgA-SVV; i.e. adult Henoch-Schönlein purpura) and non-IgA-SVV (hypersensitivity vasculitis, etc.). OBJECTIVES: To evaluate the clinical and laboratory parameters of inpatients fulfilling the diagnostic criteria for aIgA-SVV and non-IgA-SVV. METHODS: Twenty-nine adults aged ≥ 20 years with aIgA-SVV [according to the European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) criteria] and 53 adults with non-IgA-SVV (according to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides) were compared with respect to a variety of clinical and laboratory parameters by uni- and multivariable analyses. RESULTS: Compared with patients with aIgA-SVV, the platelet-to-lymphocyte ratio was significantly higher in patients with non-IgA-SVV. Serum C3 levels and mean corpuscular haemoglobin concentration in patients with non-IgA-SVV were significantly lower compared with patients with aIgA-SVV. Proteinuria and haematuria were significantly more common in patients with aIgA SVV, and were significantly correlated with systemic immune-inflammation biomarkers only in patients with aIgA-SVV. In patients with aIgA-SVV, higher lactate dehydrogenase and C-reactive protein were strong independent predictors for the presence of proteinuria and proteinuria. In patients with non-IgA-SVV, female sex was a protective factor for proteinuria, while skin lesions on the upper extremities proved to be a significant independent predictor of haematuria. CONCLUSIONS: We detected several clinical and laboratory differences between patients with aIgA-SVV and non-IgA-SVV. Distinct predictors for renal involvement were not observed in either group, indicating that aIgA-SVV and non-IgA-SVV are similar conditions but do not appear to represent the same entity.

A large cohort comparison of very late-onset systemic lupus erythematosus with younger-onset patients.

OBJECTIVES: Age has a significant impact on systemic lupus erythematosus (SLE). However, data on very late-onset SLE (vlSLE) are scarce. We have compared the clinical and serological features of vlSLE patients with younger-onset patients. METHODS: We assessed the clinical and laboratory data of all patients fulfilling SLE classification criteria evaluated at a university hospital from 1978 to 2023. Patients were divided into 4 groups according to age at diagnosis: juvenile SLE (jSLE <8 years); adult SLE (aSLE 18-49 years); late SLE (lSLE 50-59 years); vlSLE (≥60 years). RESULTS: 845 patients were enrolled. The jSLE, aSLE, lSLE, and vlSLE groups included 153, 630, 47, and 15 patients, respectively. The vlSLE group tended to have a lower female-to-male ratio (4:1; p=0.282), was mainly Caucasian (93.3%; p<0.001), and had the lowest survival time (20.3 years; p<0.001). vlSLE patients had the lowest prevalence of positive anti-dsDNA antibodies (26.7%; p=0.010) and low C3 levels (13.3%; p<0.001). Although arthritis was less common among vlSLE patients (73.3%; p=0.043), they more commonly developed Sjögren's syndrome (SS 33.3%; p<0.001) and rheumatoid arthritis (RA 13.3%; p<0.001). Infections and malignancy were the main causes of death. CONCLUSIONS: Compared with younger patients, in vlSLE, female predominance is less pronounced. Arthritis, anti-dsDNA antibodies and low C3 levels are less frequent. SS and RA are more common. Despite lower disease activity, vlSLE patients have the lowest survival rate. While uncommon, SLE should not be excluded as a possible diagnosis in the elderly.

Combined Effects of the Serum IgA/C3 Ratio and Glomerular C3 Staining on the Renal Outcome in Adult Immunoglobulin A Nephropathy.

INTRODUCTION: The aim of this study was to evaluate the predictive value of the serum IgA/C3 ratio and glomerular C3 deposits in kidney biopsy in adult IgA nephropathy. METHODS: The study included 718 adult IgAN patients diagnosed based on kidney biopsy. Patients without corticosteroids or immunosuppressive drugs >1 month were regularly followed up for at least 1 year or until the study endpoint. The optimum serum IgA/C3 ratio was calculated by the AUROC-based cutoff ratio. Proteinuria, creatinine, eGFR, serum IgA, and serum C3 were evaluated at baseline. Kidney biopsy was categorized using the Oxford classification, with a calculation of the MEST-C score. The degree of glomerular C3 staining was semiquantitatively determined (grade 0, no or trace; grade 1, mild; grade 2, moderate; grade 3, marked) by immunofluorescence microscopy. The patients were divided into four groups by the serum IgA/C3 ratio and glomerular C3 staining. RESULTS: The baseline data suggested that when the serum IgA/C3 ratio was at the same level, patients with a high glomerular C3 staining score (≥2) always had mesangial proliferation, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis (group 1 vs. group 2; group 3 vs. group 4). When glomerular C3 staining was at the same level, proteinuria was significantly higher in patients with serum IgA/C3<2.806 (group 1 vs. group 3; group 2 vs. group 4), which was contrary to previous studies that have suggested that the serum level of IgA/C3 was associated with disease severity. Hence, this study set out to investigate the combined effects of the serum IgA/C3 ratio and glomerular C3 staining on the renal outcome in adult IgA nephropathy. Renal survival analysis indicated that serum IgA/C3 ≥2.806 and glomerular C3 staining ≥2 (group 1) may be correlated with a poorer prognosis, especially in different clinicopathological characteristics of IgAN patients based on the subgroup analysis. Multivariate Cox analysis demonstrated that hypertension, serum creatinine, CKD stage, T1/2 and C3 staining were independent predictive factors of renal survival. CONCLUSIONS: The combination of serum IgA/C3 and C3 staining may contribute to improved optimization of the prognostic model in IgAN patients, especially patients with different sexes and degrees of disease. However, further study is required for validation in the future.

Serum concentrations of complement C3 and C4 in dogs with idiopathic epilepsy.

BACKGROUND: High concentrations of complement factors are presented in serum of animal epilepsy models and human patients with epilepsy. OBJECTIVES: To determine whether complement dysregulation occurs in dogs with idiopathic epilepsy (IE). ANIMALS: The study included 49 dogs with IE subgrouped into treatment (n = 19), and nontreatment (n = 30), and 29 healthy dogs. METHODS: In this case-control study, the serum concentrations of the third (C3) and fourth (C4) components of the complement system were measured using a canine-specific ELISA kit. RESULTS: Serum C3 and C4 concentrations were significantly higher in dogs with IE (C3, median; 4.901 [IQR; 3.915-6.673] mg/mL, P < .001; C4, 0.327 [0.134-0.557] mg/mL, P = .03) than in healthy control dogs (C3, 3.550 [3.075-4.191] mg/mL; C4, 0.267 [0.131-0.427] mg/mL). No significant differences were observed in serum C3 and C4 concentrations between dogs in the treatment (C3, median; 4.894 [IQR; 4.192-5.715] mg/mL; C4, 0.427 [0.143-0.586] mg/mL) and nontreatment groups (C3, 5.051 [3.702-7.132] mg/mL; C4, 0.258 [0.130-0.489] mg/mL). Dogs with a seizure frequency >3 times/month had significantly higher serum C3 (6.461 [4.695-8.735] mg/mL; P < .01) and C4 (0.451 [0.163-0.675] mg/mL; P = .01) concentrations than those with a seizure frequency ≤3 times/month (C3, 3.859 [3.464-5.142] mg/mL; C4, 0.161 [0.100-0.325] mg/mL). CONCLUSIONS AND CLINICAL IMPORTANCE: Dysregulation of classical complement pathway was identified in IE dogs. Serum C3 and C4 concentrations could be diagnostic biomarkers for IE in dogs with higher seizure frequency.

Morphological and etiological analyses of C3 and non-C3 glomerulonephritis in primary membranoproliferative glomerulonephritis using periodic acid-methenamine silver stain electron microscopy: a retrospective multicentered study.

This study elucidated the etiology of C3 glomerulonephritis (C3GN) and non-C3GN with primary membranoproliferative glomerulonephritis (MPGN) using transmission electron microscopy (TEM) and periodic acid-methenamine silver stain (PAM-EM). Thirty-one primary MPGN cases were analyzed by TEM and PAM-EM to distinguish among MPGN I, MPGN II, MPGN III Burkholder subtype (MPGN IIIB), and Anders and Strife subtype (MPGN IIIA/S). Each case was also classified into C3GN or non-C3GN according to the standard C3GN definition using immunostaining. Four cases of MPGN II met C3 glomerulopathy; whereas, four cases of MPGN IIIB did not meet C3 glomerulopathy. Seven of 11 cases (64%) of MPGN I without GBM disruption and 7 of 12 cases (58%) of MPGN IIIA/S with GBM disruption met the non-C3GN criteria with significant immunoglobulins' deposition. Regardless of the C3GN or non-C3GN diagnosis, the deposits in primary MPGN I and MPGN IIIA/S exhibited ill-defined, amorphous, and foggy characteristics similar to those found in postinfectious GN but were different from immune complex (IC) deposits seen in MPGN IIIB. Not only C3GN but also non-C3GN was due to mechanisms other than IC deposition as found in postinfectious GN. Consequently, GBM disruption of MPGN IIIA/S was not due to IC deposition.

IMMUNOLOGICAL DISORDERS AND COLON DYSBIOSIS IN OBESE PATIENTS WITH HYPOTHYROIDISM.

OBJECTIVE: The aim: To investigate the peculiarities of immunological changes and their relationship with colon dysbiosis in obese patients with HT. PATIENTS AND METHODS: Materials and methods: The examined patients included 48 patients with HT and obesity (group 1) and 34 patients with obesity (group 2). Patients under¬went fecal analysis for dysbiosis. The levels of complement, namely C3 and C4 and the concentration of immunoglobulins (IgA, Ig M, IgG) were determined by means of chromogenic analysis. RESULTS: Results: During the clinical examination, constipation and flatulence were more often diagnosed in patients of group I (58.3% and 66.7%, respectively - p<0.001), while in patients of group 2 with increased BMI without thyroid dysfunction, a tendency to diarrhea was more often found, accompanied by periodic pain along the colon (50.0% and 32.3% of patients, respectively - p<0.001). Changes in the immunological status of patients in both groups were found. In patients with HT and increase of BMI an increase in serum IgA, IgM, IgG levels were found. An increase in serum immunoglobulins (A, M and G) was also diagnosed in group 2 of examined patients too. CONCLUSION: Conclusions: 1. In patients with obesity decrease in the concentration of Bifidobacterium, Lactobacillus and increase in the number of Staphylococcus, Clostridium, Proteus and Klebsiella were detected, which is more pronounced in patients with a combination of obesity and hypothyroidism. 2. Impairment distinct of immu¬nological status in patients with hypothyroidism and obesity was diagnosed, which was manifested by increased levels of immunoglobulins, namly (A, M, G), as well as a decrease in blood serum complements (C3, C4). 3. The level of IgA, G directly depends on the decrese of Bifidobacterium, Lactobacillus and increse of Staphylococcus, Clostridium and Klebsiella in patients with obesity, which is more pronounced in patients with a combination of obesity and hypothyroidism.

The correlation of anxiety and depression with C3 and C4 Levels and systemic lupus erythematosus activity.

BACKGROUND: Anxiety and depression are psychosomatic disorders that are frequently observed in chronic conditions such as systemic lupus erythematosus (SLE). Anxiety and depression can be induced by immunological and neurotransmitter dysregulation, which is characterized by hypothalamic-pituitary-adrenal (HPA) axis dysfunction, production of proinflammatory cytokines, and activation of complement in the blood, such as C3 and C4. The causes of anxiety and depression in SLE are complex, ranging from neuropsychiatric involvement to drug adverse effects. Detecting anxiety and depression symptoms in SLE patients is critical to preventing disability from impacting quality of life. OBJECTIVE: To assess the relationship between anxiety and depression symptomatology, SLE disease activity with levels of C3 and C4 in Cipto Mangunkusumo National Hospital. METHODS: This study used a cross-sectional design. The study included 120 SLE patients from Cipto Mangunkusumo National Hospital, aged 18 to 60 years. All patients were requested to complete a Hospital Anxiety and Depression Scale (HADS) questionnaire to assess their anxiety and depression symptoms. Subjects with anxiety and depression were assessed for disease activity using the Mexican Systemic Lupus Erythematosus Systemic Disease Activity (Mex-SLEDAI), and blood samples were collected to test complement C3 and C4 levels. Spearman's correlation test was used to examine the relationship between HADS scores, Mex-SLEDAI, and C3 and C4 levels. RESULTS: The results of the study showed a very weak statistically significant negative correlation between anxiety symptoms based on HADS and C3 levels (r = -0.189; p = 0.038) and a weak correlation between anxiety symptoms and C4 levels (r = -204; p = 0.026). Depressive symptoms based on HADS revealed a very poor connection and no statistical significance with levels of C3 (r = -0.056; p = 0.546) and C4 (r = -0.068; p = 0.461). Anxiety (r = 0.06; p = 0.173) and depression (r = 0.031; p = 0.753) symptoms have a weak and insignificant positive connection with SLE activity. CONCLUSION: C3 and C4 serum levels appeared to decrease when the presence of anxious symptoms increased. There was no significant correlation in SLE disease activity between anxious and depressed patients.