Complement system plays an important role in the pathogenesis of idiopathic membranous nephropathy (IMN), however, the relationship between serum complement 4 (C4) and kidney disease progression in ...IMN is unclear. This study aims to investigate the association of serum C4 level with the risk of kidney disease progression among patients with IMN.
The retrospective cohort assessed 1,254 participants with biopsy-proven IMN from three centers in Xi 'an, Shaanxi Province, China. Baseline serum C4 levels were measured at renal biopsy. The association between baseline serum C4 and the risk of renal function progression, defined as a 30% decline in renal function or end stage renal disease, was evaluated in Cox proportional hazards models.
A total of 328 patients with IMN and nephrotic proteinuria were eligible, and 11.3% (37/328) of them attained the renal function progression events after a median follow-up of 51 months (37-59 months). After adjustment for other confounders, a higher value of serum C4 was independently associated with a higher risk of renal function progression event with a hazard ratio (HR) of 4.76 (95% confidence interval 95% CI, 1.77-12.79) per natural log-transformed C4. In reference to the low level of C4, the adjusted HRs were 2.72 (95% CI, 1.02-7.24) and 3.65 (95% CI, 1.39-9.60), respectively, for the median and high levels of C4 (
for trend=0.008). Additionally, the results were robust and reliable in the sensitivity and subgroup analyses.
Among patients with IMN and nephrotic proteinuria, serum C4 at renal biopsy is an independent predictor for kidney disease progression regardless of other confounders.
Background and Objective
Neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody (MOG-IgG) associated disease (MOGAD) are autoimmune inflammatory ...demyelinating diseases of the central nervous system (CNS). As the clinical features of NMOSD are similar to MOGAD, diagnostic confusion exists between the two diseases. To better discriminate NMOSD from MOGAD, we investigated whether the plasma levels of complement 3 (C3) and complement 4 (C4) are different in NMOSD and MOGAD during the acute attacks of the diseases. We sought to determine whether C3 or C4 has an influence on the features of NMOSD.
Methods
In this observational study, data from 73 aquaporin-4 antibodies (AQP4-IgG) positive NMOSD patients and 22 MOG-IgG positive MOGAD patients were collected retrospectively. Demographics, clinical characteristics, plasma parameters, and cerebrospinal fluid (CSF) findings will be analyzed for comparability between the two groups. Immunoglobulin-G (IgG) and albumin were measured in both plasma and CSF. Plasma levels of C3 and C4 were measured and compared between the NMOSD, MOGAD, and 42 healthy controls (HC). The correlations between plasma C3, C4, and NMOSD clinical parameters were analyzed.
Results
The ages of onset were later in the AQP4-IgG positive NMOSD group and females predominated, which differed from the MOGAD group, whose ages were younger and with a slight male preponderance. The AQP4-IgG positive NMOSD patients presented with the clinical symptoms of optic neuritis (ON) and transverse myelitis (TM), whereas encephalitis symptoms were more prevalent in MOGAD patients. CSF analysis shows that slight but not significantly higher white cell count (WCC) and protein were observed in the MOGAD group than in the AQP4-IgG positive NMOSD group. The plasma levels of IgG in MOGAD patients are significantly lower (
p
= 0.027) than in NMOSD patients. On the contrary, the plasma levels of albumin in MOGAD were higher than in NMOSD, which reached statistical significance (
p
= 0.039). Both the plasma C3 and C4 levels in the NMOSD group were significantly lower than in MOGAD and HC. The receiver operating characteristic (ROC) curve of the prediction model comprises C3 and C4 to distinguish NMOSD from MOGAD area under the curve (AUC): 0.731, 0.645, which are considered to have discriminatory values. The results of Spearman’s analysis revealed that there was a significant positive correlation between the plasma C3 and the CSF WCC (r = 0.383,
p
= 0.040). There was an inverse correlation between plasma C4 and plasma IgG (r = -0.244,
p
= 0.038). Plasma C3 or C4 was significantly positively correlated with CSF albumin and Q-Alb, which is considered a measure of blood-brain barrier (BBB) disruption.
Conclusion
During the acute phase of NMOSD and MOGAD, plasma C3 and C4 may become potential biomarkers for distinguishing the two diseases and reflecting the NMOSD BBB damage.
Schizophrenia (SCZ) is a chronic and severe mental illness with no cure so far. Mendelian randomization (MR) is a genetic method widely used to explore etiologies of complex traits. In the current ...study, we aimed to identify novel proteins underlying SCZ with a systematic analytical approach.
We integrated protein quantitative trait loci (pQTLs) of the brain, cerebrospinal fluid (CSF), and plasma with the latest and largest SCZ genome-wide association study (GWAS) via a systematic analytical framework, including two-sample MR analysis, Steiger filtering analysis, and Bayesian colocalization analysis.
The genetically determined protein level of C4A/C4B (OR = 0.70, p = 1.66E-07) in the brain and ACP5 (OR = 0.42, p = 3.73E-05), CNTN2 (OR = 0.62, p = 2.57E-04), and PLA2G7 (OR = 0.71, p = 1.48E-04) in the CSF was associated with a lower risk of SCZ, while the genetically determined protein level of TIE1 (OR = 3.46, p = 4.76E-05), BCL6 (OR = 3.63, p = 1.59E-07), and MICB (OR = 4.49, p = 2.31E-11) in the CSF were associated with an increased risk for SCZ. Pathway enrichment analysis indicated that genetically determined proteins suggestively associated with SCZ were enriched in the biological process of the immune response.
In conclusion, we identified one protein in the brain and six proteins in the CSF that showed supporting evidence of being potentially associated with SCZ, which could provide insights into future mechanistic studies to find new treatments for the disease. Our results also supported the important role of neuroinflammation in the pathogenesis of SCZ.
Numerous studies have shown that the complement system plays an important role in Alzheimer's disease (AD). However, whether complement 4 (C4) protein in cerebrospinal fluid (CSF) was associated with ...AD pathology, especially in the early stage of AD, is still unclear.
We aimed to explore the association of CSF C4 with AD pathology and cognition in the preclinical AD.
The study included a total of 287 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Based on the A/T scheme, they were divided into four groups to access the changes of CSF C4 in the preclinical AD. Linear regression models were used to test the associations between CSF C4 and AD core biomarkers, namely Aβ42, P-tau, and T-tau.
The level of CSF C4 decreased in the A + T- group compared with the A-T- group (p = 0.04) and it increased in the A-T+ group compared to the A + T- group (p = 0.01). In pooled samples, C4 was significantly associated with AD core biomarkers (all p < 0.05), but only in the A + group after stratification according to the A/T scheme. Furthermore, CSF C4 levels at baseline were associated with longitudinal cognitive changes.
Our results showed that CSF C4 levels changed dynamically in the preclinical AD, and that the responses of CSF C4 to brain Aβ pathology, tau pathology and neurodegeneration were found only in the presence of amyloid plaques, both of which indicates the complex link between C4 and AD.
Hereditary angioedema (HAE) is a rare, life-threatening autosomal dominant disorder. We aimed to investigate the prevalence of HAE in a Chinese population with a decreased Complement 4 (C4) level.
...All the patients present in Tongji Hospital with C4 below lower normal range were included from January 2019 to June 2020. The individual data were extracted from the database and categorized by diagnosis. Patients suspected of HAE were further evaluated by C1 inhibitor level and function test to confirm the HAE diagnosis.
A total of 8226 patients were enrolled in our study, among whom 18 had symptoms similar to HAE and received C1 inhibitor level and function tests. Two (1 male and 1 female) of the 18 patients were identified as HAE patients. This means the prevalence of HAE was 2.43/10 000 among the C4-decreased population and 10.1/10 000 in the C4-decreased population with etiology undetermined. The 2 HAE patients had experienced skin and oropharynx edema attack and received tracheotomy. The female patient had a family history. Laboratory tests showed significant decrease of C4 and C1 inhibitor levels in the 2 patients, both of whom were diagnosed as type 1 HAE.
The prevalence of HAE is low in C4-decreased patients. In a large cohort, C4 level can serve as a practical indicator to screen the HAE patients, but further testing of C1 inhibitor activity and levels is needed to confirm the diagnosis of HAE.
Activation of the complement system may play a role in the pathophysiology of human labor. Yet no unanimous conclusion has been drawn.
To compare the differences in maternal complement components C3 ...and C4 serum levels in cesarean section and the vaginal delivery at term and in the postpartum hemorrhage.
One hundred and sixty six women delivered at term were enrolled in this study. Maternal blood samples were obtained from 47 cases of elective cesarean section and 119 cases of the vaginal delivery. Serum complement levels were measured subsequently by immuno-scatter turbidimetry.
The maternal complement levels declined significantly during delivery by both the cesarean section and the vaginal delivery (p＜0.01) in comparison with the baseline. A much larger drop of C3 serum level was found in the postpartum hemorrhage and in the vaginal delivery, and the incidence of the postpartum hemorrhage has a positive correlation with the complement decline rate.
The complement system may be involved in the delivery process and represents a predictive value in postpartum hemorrhage.
الفترات المرجعية للمتممة 3 والمتممة 4 نادرة، خاصة بالطرق غير المباشرة. تهدف هذه الدراسة إلى إنشاء فترات مرجعية إقليمية للمتممة 3 والمتممة 4 باستخدام الطريقة غير المباشرة بالأساليب الإحصائية المناسبة.
...تم تضمين 12313 نقطة بيانات للمتممة 3 و 12125 نقطة بيانات للمتممة 4 من قاعدة بيانات المستشفى الأول بجامعة جيلين في الصين، وتم توحيدها بواسطة الأساليب الإحصائية. تم استخدام معاملات التجانف - الوسيط – معامل التفاوت لتحديد القيمة الحرجة للعمر، مع اختبار "زي" اللاحق لمقارنة الاختلافات. تم استخدام الطريقة غير المتثابتة لإنشاء الفترات المرجعية.
لم تظهر التراكيز للمتممة 3 والمتممة 4 فروقا ذات دلالة احصائية مع الجنس وأظهرت ارتباطا ضعيفا مع العمر. كما لم يتم العثور على فروق ذات دلالة إحصائية بعد حساب قيمة "زي" للنقاط العمرية على المنحنيات المستخدمة. كانت الفترات المرجعية للمتممة 3 هو 0,83-1,58 جم/لتر وللمتممة 4 هو 0.15-0.40 جم/لتر. اجتازت الفترات المرجعية جميع أدوات التحقق.
تم إنشاء الفترات المرجعية المناسبة للمتممة 3 وللمتممة 4 للسكان المحليين وستفيد في التشخيص السريري. تم إثبات جدوى وعملية الطريقة غير المباشرة.
The establishment of reference intervals (RIs) for complement 3 (C3) and complement 4 (C4) is rare, especially by indirect methods. Therefore, this study aims to establish regional RIs for C3 and C4 by an indirect method, using relevant statistical methods.
Total of 12,313 data points for C3 and 12,125 data points for C4 were obtained from the First Hospital of Jilin University's database in China and standardised using the Tukey and Box–Cox statistical methods. The coefficients of the skewness-median-coefficient of variation curves (LMS) were used to determine the critical value for age, and a subsequent z test used to compare the differences. A non-parametric method was used to establish the RIs.
The C3 and C4 concentrations showed no significant differences by sex, and a weak correlation with age. No significant difference was found after calculating the z value for the age points on the LMS curves. The RIs for C3 and C4 were 0.83–1.58 g/L and 0.15–0.40 g/L, respectively. The RIs all passed verification.
Suitable RIs for C3 and C4 were established for the local population, and will benefit clinical diagnosis. The feasibility and practicability of the indirect method were demonstrated.
Cross-sectional studies have reported strong correlations between plasma levels of complement C3, insulin, and glucose. This prospective study explored whether elevated levels of C3, C4, and other ...inflammation-sensitive plasma proteins (ISPs; fibrinogen, orosomucoid, alpha1-antitrypsin, haptoglobin, and ceruloplasmin) are associated with the development of diabetes. Plasma proteins were measured in 2,815 nondiabetic healthy men, age 38-50 years, who were reexamined after a mean follow-up of 6.1 years. Diabetes development (n = 123) was studied in relation to baseline levels of plasma proteins. After adjusting for age, screening year, and glucose at baseline, the odds ratio (95% CI) for developing diabetes was 1.00, 2.4 (1.1-5.3), 2.9 (1.4-6.0), and 5.6 (2.8-10.9), respectively, for men with C3 in the 1st, 2nd, 3rd, and 4th quartiles (trend: P < 0.00001). Fibrinogen, haptoglobin, C4, and the number of elevated ISPs were also related to future diabetes in this model. Only C3 was significantly associated with diabetes development after further adjustments for potential confounders, including BMI, insulin, and other inflammatory markers. We concluded that the risk of developing diabetes is related to levels of complement C3.
Summary A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against ...metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients. Learning points: A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years. Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed. The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin. Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite. Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.
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