Platelet and Erythrocyte Extravasation across Inflamed Corneal Venules Depend on CD18, Neutrophils, and Mast Cell Degranulation.

Platelet extravasation during inflammation is under-appreciated. In wild-type (WT) mice, a central corneal epithelial abrasion initiates neutrophil (PMN) and platelet extravasation from peripheral limbal venules. The same injury in mice expressing low levels of the ß2-integrin, CD18 (CD18hypo mice) shows reduced platelet extravasation with PMN extravasation apparently unaffected. To better define the role of CD18 on platelet extravasation, we focused on two relevant cell types expressing CD18: PMNs and mast cells. Following corneal abrasion in WT mice, we observed not only extravasated PMNs and platelets but also extravasated erythrocytes (RBCs). Ultrastructural observations of engorged limbal venules showed platelets and RBCs passing through endothelial pores. In contrast, injured CD18hypo mice showed significantly less venule engorgement and markedly reduced platelet and RBC extravasation; mast cell degranulation was also reduced compared to WT mice. Corneal abrasion in mast cell-deficient (KitW-sh/W-sh) mice showed less venule engorgement, delayed PMN extravasation, reduced platelet and RBC extravasation and delayed wound healing compared to WT mice. Finally, antibody-induced depletion of circulating PMNs prior to corneal abrasion reduced mast cell degranulation, venule engorgement, and extravasation of PMNs, platelets, and RBCs. In summary, in the injured cornea, platelet and RBC extravasation depends on CD18, PMNs, and mast cell degranulation.

Development, Validation, and Comparison of Two Mass Spectrometry Methods (LC-MS/HRMS and LC-MS/MS) for the Quantification of Rituximab in Human Plasma.

Rituximab is a chimeric immunoglobulin G1-kappa (IgG1κ) antibody targeting the CD20 antigen on B-lymphocytes. Its applications are various, such as for the treatment of chronic lymphoid leukemia or non-Hodgkin's lymphoma in oncology, and it can also be used in the treatment of certain autoimmune diseases. Several studies support the interest in therapeutic drug monitoring to optimize dosing regimens of rituximab. Thus, two different laboratories have developed accurate and reproductive methods to quantify rituximab in human plasma: one using liquid chromatography quadripolar tandem mass spectrometer (LC-MS/MS) and the other, liquid chromatography orbitrap tandem mass spectrometer (LC-MS/HRMS). For both assays, quantification was based on albumin depletion or IgG-immunocapture, surrogate peptide analysis, and full-length stable isotope-labeled rituximab. With LC-MS/MS, the concentration range was from 5 to 500 µg/mL, the within- and between-run precisions were <8.5%, and the limit of quantitation was 5 µg/mL. With LC-MS/HRMS, the concentration range was from 10 to 200 µg/mL, the within- and between-run accuracy were <11.5%, and the limit of quantitation was 2 µg/mL. Rituximab plasma concentrations from 63 patients treated for vasculitis were compared. Bland-Altman analysis and Passing-Bablok regression showed the interchangeability between these two methods. Overall, these methods were robust and reliable and could be applied to routine clinical samples.

Hematological and Genetic Markers in the Rational Approach to Patients With HCV Sustained Virological Response With or Without Persisting Cryoglobulinemic Vasculitis.

BACKGROUND AND AIMS: Direct-acting antivirals (DAAs) usually lead to improvement/remission of cryoglobulinemic vasculitis (CV), although symptoms may persist/recur after a sustained virological response (SVR). We evaluated hematological and genetic markers in patients with HCV-SVR vasculitis with and without persisting/recurring symptoms to early predict the CV outcome. APPROACH AND RESULTS: Ninety-eight patients with HCV-CV were prospectively enrolled after a DAA-induced SVR: Group A: 52 with complete clinical response; Group B: 46 with symptom maintenance/recurrence. Monoclonal B-cell lymphocytosis, t(14;18) translocation, and abnormal free light chains κ/λ ratios were detected by flow cytometry or nested-PCR or nephelometry in 4% Group A versus 17% Group B (P = 0.04) patients, 17% Group A versus 40% Group B patients (P = 0.02), and 17% Group A versus 47% Group B (P = 0.003) patients, respectively. At least 1 out of 3 clonality markers was altered/positive in 29% of Group A versus 70% of Group B patients (P < 0.0001). When available, pretherapy samples were also tested for t(14;18) translocation (detected in 12/37 [32%] Group A and 21/38 [55%] Group B) and κ/λ ratios (abnormal in 5/35 [14%] Group A and 20/38 [53%] Group B) (P = 0.0006), whereas at least one clonality marker was detected/altered in 16/37 (43%) Group A and 30/38 (79%) Group B (P = 0.002). CV-associated single-nucleotide polymorphisms were tested by real-time PCR. Among them, notch4 rs2071286 T minor allele and TT genotype showed a higher frequency in Group B versus Group A (46% vs. 29%, P = 0.01, and 17% vs. 2%, P = 0.006, respectively). CONCLUSIONS: Hematological or genetic analyses could be used to foresee the CV clinical response after DAA therapy and could be valuable to assess a rational flowchart to manage CV during follow-up.

The relationship between ambulatory arterial stiffness, inflammation, blood pressure dipping and cardiovascular outcomes.

BACKGROUND: The ambulatory arterial stiffness index (AASI) is an indirect measure of arterial stiffness obtained during ambulatory blood pressuring monitoring (ABPM). Its relationship to nocturnal blood pressure dipping status and major adverse cardiovascular events (MACE) are controversial and its association with vascular inflammation has not been examined. We aimed to investigate the relationship between the AASI, inflammation and nocturnal blood pressure dipping status and its association with MACE. METHODS: Adults (aged 18-80 years) who underwent 24-h ABPM for the diagnosis of hypertension or its control were included. The inflammatory markers measured were the neutrophil-lymphocyte (NLR), platelet-lymphocyte (PLR) and monocyte-lymphocyte ratios (MLR). The primary MACE was a composite of cardiovascular death, acute limb ischaemia, stroke or transient ischaemic attack (TIA) or acute coronary syndrome. RESULTS: A total of 508 patients (51.2% female) aged 58.8 ± 14.0 years were included; 237 (46.7%) were normal-dippers (≥ 10% nocturnal systolic dip), 214 (42.1%) were non-dippers (0-10% dip) and 57 (11.2%) were reverse-dippers (< 0% dip). The AASI was significantly higher among reverse (0.56 ± 0.16) and non-dippers (0.48 ± 0.17) compared with normal dippers (0.39 ± 0.16; p < 0.0001) and correlated with the NLR (r = 0.20; 95% CI 0.11 to 0.29: < 0.0001) and systolic blood pressure dipping % (r = - 0.34; - 0.42 to - 0.26: p < 0.0001). Overall 39 (7.7%) patients had ≥ 1 MACE which included a total of seven cardiovascular deaths and 14 non-fatal strokes/TIAs. The mean follow up was 113.7 ± 64.0 weeks. Increasing NLR, but not AASI or systolic dipping, was independently linked to MACE (overall model Chi-square 60.67; p < 0.0001) and MLR to cardiovascular death or non-fatal stroke/TIA (overall model Chi-square 37.08; p < 0.0001). CONCLUSIONS: In conclusion AASI was associated with blood pressure dipping and chronic inflammation but not independently to MACE. The MLR and NLR were independent predictors of MACE.

Vascular inflammation, atherosclerosis, and lipid metabolism and the occurrence of non-high albuminuria diabetic kidney disease: A cross-sectional study.

AIM: Atherosclerosis involves vascular endothelial damage and lipid metabolism disorder, which is closely related to the occurrence and development of diabetic kidney disease (DKD). However, studies on non-high albuminuria DKD (NHADKD) with an albumin to creatinine ratio (ACR) <30 mg/g are rare. This study is to investigate the relationship between atherogenic factors and the occurrence of NHADKD. METHODS: Serum lipid indicators, lipoprotein-associated phospholipase A2 (Lip-PLA2) and homocysteine levels were measured in 1116 subjects to analyze their relationship with NHADKD. RESULTS: Among all subjects, Lip-PLA2 had the closest but relatively weak correlation with ACR (r = 0.297, p < 0.001) and only homocysteine was moderately correlated with eGFR (r = -0.465, p < 0.001). However, in patients with NHADKD, these atherosclerotic factors were weakly correlated or uncorrelated with eGFR (max. |r| = 0.247). Stratified risk analysis showed that when ACR was <10 mg/g, homocysteine [OR = 6.97(4.07-11.95)], total cholesterol (total-Chol) [OR = 6.04(3.03-12.04)], and high-density lipoprotein cholesterol (HDL-Chol) [OR = 5.09(2.99-8.64)] were risk factors for NHADKD. There was no significant difference of OR between these three factors (Z = 0.430-1.044, all p > 0.05). When ACR was ⩾10mg/g, homocysteine [OR = 17.26(9.67-30.82)] and total-Chol [OR = 5.63(2.95-10.76)] were risk factors for NHADKD, and ORhomocysteine was significantly higher than ORtotal-Chol (Z = 3.023, p < 0.05). CONCLUSIONS: The occurrence of NHADKD may be related to the levels of homocysteine, total-Chol, HDL-Chol, and Lip-PLA2 in blood. Among them, homocysteine may be most closely related to NHADKD.

Blood Biomarkers for Monitoring and Prognosis of Large Vessel Vasculitides.

PURPOSE OF REVIEW: Large vessel vasculitides (LVVs) are inflammatory conditions of the wall of large-sized arteries, mainly represented by giant cell arteritis (GCA) and Takayasu arteritis (TA). The inflammatory process within the vessel wall can lead to serious consequences such as development of aneurysms, strokes and blindness; therefore, early diagnosis and follow-up of LVV are fundamental. However, the arterial wall is poorly accessible and blood biomarkers are intended to help physicians not only in disease diagnosis but also in monitoring and defining the prognosis of these conditions, thus assisting therapeutic decisions and favouring personalised management. The field is the object of intense research as the identification of reliable biomarkers is likely to shed light on the mechanisms of disease progression and arterial remodelling. In this review, we will discuss the role of blood biomarkers in LVVs in the light of the latest evidence. RECENT FINDINGS: In clinical practice, the most widely performed laboratory investigations are the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). However, these indices may be within normal limits during disease relapse and they are not reliable in patients receiving interleukin-6 (IL-6) receptor inhibitors. New biomarkers struggle to gain traction in clinical practice and no molecule with good accuracy has been identified to date. IL-6, a pro-inflammatory cytokine that drives CRP synthesis and increases the ESR, is one of the most promising biomarkers in the field. IL-6 analysis is increasingly performed, and serum levels are more sensitive than ESR for active GCA and might reflect persistent inflammation with high risk of relapse in patients on IL-6 receptor inhibitors. A future with biomarkers that reflect different disease features is an important aspiration. Accordingly, intense effort is being made to identify IL-6-independent inflammatory biomarkers, such as S100 proteins, pentraxin-3 and osteopontin. Moreover, metalloproteinases such as MMP2/9 and angiogenic modulators such as VEGF, YLK-40 and angiopoietins are being studied as markers of arterial remodelling. Lastly, biomarkers indicating organ damage may guide prognostic stratification as well as emergency therapeutic decisions: the most promising biomarkers so far identified are NT-proBNP, which reflects myocardial strain; pentraxin-3, which has been associated with recent optic nerve ischemia; and endothelin-1, which is associated with ischaemic complications. Currently, the use of these molecules in clinical practice is limited because of their restricted availability, lack of sufficient studies supporting their validity and associated costs. Further evidence is required to better interpret their biological and clinical value.

Vasculitic Peripheral Neuropathy, Differences Between Systemic and Non-Systemic Etiologies: A Case Series and Biopsy Report.

BACKGROUND: Vasculitic peripheral neuropathy (VPN) is caused by vessel inflammation leading to peripheral nerve injury of acute-to-subacute onset. When VPN occurs in the context of systemic disease it is classified as Systemic Vasculitic Neuropathy (SVN) and as Non-Systemic Vasculitic Neuropathy (NSVN) when restricted to the nerves. OBJECTIVE: This study aimed to compare the clinical characteristics, biopsy findings and disease outcome in patients with VPN. METHODS: Clinical records of adult patients with VPN diagnosed at our institution between June-2002 and June-2019 were retrospectively reviewed. Demographic characteristics, clinical manifestations, nerve conduction studies, nerve biopsies, treatment and clinical evolution were analyzed in all patients with at least 6 months follow-up. RESULTS: Twenty-five patients with VPN were included (SVN, n = 10; NSVN, n = 15). No significant differences in demographic or clinical features were found between groups. The median delay between symptom onset and nerve biopsy was significantly longer in NSVN patients (10 vs 5.5 months, p = 0.009). Erythrocyte sedimentation rate (ESR) values over 20 mm/h were significantly more common in SVN patients (100% vs. 60%, p = 0.024). Nerve biopsies showed active lesions more frequently in treatment-naive patients compared to those who had received at least 2 weeks of corticosteroids (92% vs 38%; p = 0.03), with a higher proportion of definite VPN cases (92 vs 46%; p = 0.04). CONCLUSIONS: Although the clinical manifestations are similar, ESR is an important tool to help distinguish between both conditions. Early nerve biopsy in untreated patients increases diagnostic accuracy, avoiding misdiagnosis.

CCL20 in psoriasis: A potential biomarker of disease severity, inflammation, and impaired vascular health.

BACKGROUND: Psoriasis is associated with increased cardiovascular risk that is not captured by traditional proinflammatory biomarkers. OBJECTIVE: To investigate the relationship between Psoriasis Area and Severity Index, circulating proinflammatory biomarkers, and vascular health in psoriasis. METHODS: In patients with psoriasis and in age and sex-matched controls, 273 proteins were analyzed with the Proseek Multiplex Cardiovascular disease reagents kit and Inflammatory reagents kit (Olink Bioscience), whereas vascular endothelial inflammation and health were measured via direct transcriptomic analysis of brachial vein endothelial cells. RESULTS: In psoriasis, chemokine ligand 20 (CCL20), interleukin (IL) 6, and IL-17A were the top 3 circulating proinflammatory cytokines. Vascular endothelial inflammation correlated with CCL20 (r = 0.55; P < .001) and less so with IL-6 (r = 0.36; P = .04) and IL-17A (r = 0.29; P = .12). After adjustment for potential confounders, the association between CCL20 and vascular endothelial inflammation remained significant (ß = 1.71; P = .02). In nested models, CCL20 added value (χ2 = 79.22; P < .001) to a model already incorporating the Psoriasis Area and Severity Index, Framingham risk, high-sensitivity C-reactive protein, Il-17A, and IL-6 (χ2 = 48.18; P < .001) in predicting vascular endothelial inflammation. LIMITATIONS: Our study was observational and did not allow for causal inference in the relationship between CCL20 and cardiovascular risk. CONCLUSION: We demonstrate that CCL20 expression has a strong association with vascular endothelial inflammation, reflects systemic inflammation, and may serve as a potential biomarker of impaired vascular health in psoriasis.

Rivaroxaban improves vascular response in LPS-induced acute inflammation in experimental models.

Rivaroxaban (RVX) was suggested to possess anti-inflammatory and vascular tone modulatory effects. The goal of this study was to investigate whether RVX impacts lipopolysaccharide (LPS)-induced acute vascular inflammatory response. Male rats were treated with 5 mg/kg RVX (oral gavage) followed by 10 mg/kg LPS i.p injection. Circulating levels of IL-6, MCP-1, VCAM-1, and ICAM-1 were measured in plasma 6 and 24 hours after LPS injection, while isolated aorta was used for gene expression analysis, immunohistochemistry, and vascular tone evaluation. RVX pre-treatment significantly reduced LPS mediated increase after 6h and 24h for IL-6 (4.4±2.2 and 2.8±1.7 fold), MCP-1 (1.4±1.5 and 1.3±1.4 fold) VCAM-1 (1.8±2.0 and 1.7±2.1 fold). A similar trend was observed in the aorta for iNOS (5.5±3.3 and 3.3±1.9 folds reduction, P<0.01 and P<0.001, respectively), VCAM-1 (1.3±1.2 and 1.4±1.3 fold reduction, P<0.05), and MCP-1 (3.9±2.2 and 1.9±1.6 fold reduction, P<0.01). Moreover, RVX pre-treatment, improved LPS-induced PE contractile dysfunction in aortic rings (Control vs LPS, Emax reduction = 35.4 and 31.19%, P<0.001; Control vs LPS+RVX, Emax reduction = 10.83 and 11.48%, P>0.05, respectively), resulting in 24.5% and 19.7% change in maximal constriction in LPS and LPS+RVX respectively. These data indicate that RVX pre-treatment attenuates LPS-induced acute vascular inflammation and contractile dysfunction.

Platelet-derived calpain cleaves the endothelial protease-activated receptor 1 to induce vascular inflammation in diabetes.

Diabetes mellitus is a major risk factor for cardiovascular disease. Platelets from diabetic patients are hyperreactive and release microparticles that carry activated cysteine proteases or calpains. Whether platelet-derived calpains contribute to the development of vascular complications in diabetes is unknown. Here we report that platelet-derived calpain1 (CAPN1) cleaves the protease-activated receptor 1 (PAR-1) on the surface of endothelial cells, which then initiates a signaling cascade that includes the activation of the tumor necrosis factor (TNF)-α converting enzyme (TACE). The latter elicits the shedding of the endothelial protein C receptor and the generation of TNF-α, which in turn, induces intracellular adhesion molecule (ICAM)-1 expression to promote monocyte adhesion. All of the effects of CAPN1 were mimicked by platelet-derived microparticles from diabetic patients or from wild-type mice but not from CAPN1-/- mice, and were not observed in PAR-1-deficient endothelial cells. Importantly, aortae from diabetic mice expressed less PAR-1 but more ICAM-1 than non-diabetic mice, effects that were prevented by treating diabetic mice with a calpain inhibitor as well as by the platelet specific deletion of CAPN1. Thus, platelet-derived CAPN1 contributes to the initiation of the sterile vascular inflammation associated with diabetes via the cleavage of PAR-1 and the release of TNF-α from the endothelial cell surface.

Serum TNF-α Level Is Associated with Disease Severity in Adult Patients with Immunoglobulin A Vasculitis Nephritis.

BACKGROUND: Tumor necrosis factor-α (TNF-α) is a proinflammatory factor involved in the pathogenesis of immunoglobulin A vasculitis (IgAV). The association between serum TNF-α and disease severity in adult patients with IgAV nephritis (IgAV-N) has been inadequately evaluated. METHODS: Serum TNF-α was measured by chemiluminescence immunoassay in 53 renal biopsy-proved IgAV-N patients, 53 healthy controls, and 53 IgA nephropathy (IgAN) patients. The correlations of clinicopathologic parameters of IgAV-N patients with serum TNF-α were analyzed. RESULTS: In this cross-sectional study, the median age of IgAV-N patients was 29 (25-37) years, and 67.9% were female. Serum TNF-α was significantly higher in the IgAV-N group than in the healthy group [7.4 (5.7-9.4) pg/mL vs. 5.9 (5.0, 7.1) pg/mL, P = 0.001], but comparable with sex, age, and estimated glomerular filtration rate (eGFR) grade-matched IgAN patients. Serum creatinine (P = 0.006) and serum cystatin C (P = 0.001) were positively correlated with serum TNF-α level, while albumin (P = 0.014) and eGFR (P = 0.021) were negatively correlated with serum TNF-α level. Multivariate linear regression analysis revealed that eGFR (P = 0.007) was an independent clinical predictor of serum TNF-α. Patients with higher pathological classification grade also had higher serum TNF-α. CONCLUSIONS: Serum TNF-α is associated with renal function and the pathological classification of adult patients with IgAV-N. TNF-α is a potential biomarker for the assessment of IgAV-N severity.

Viscoelastic testing in benign hematologic disorders: Clinical perspectives and future implications of point-of-care testing to assess hemostatic competence.

Viscoelastic tests (VETs) have been used routinely for liver transplantation, cardiac surgery, and trauma, but only recently have found clinical utility in benign hematologic disorders. Therefore, guidelines for diagnosis and treatment of these disorders based on viscoelastic variables have been adapted from the existing transplant, cardiothoracic surgery, and trauma resuscitation literature. As a result, diagnostic and therapeutic strategies for benign hematologic disorders utilizing VETs are not uniform. Accordingly, even though there has been a recent increase in the utilization of VET for the diagnosis and treatment of such disorders, the literature is still in its early stages. Analysis of point-of-care viscoelastic tracings from benign hematologic disorders has the potential to allow prompt recognition of disease and to guide patient-specific intervention. Here we present a review describing the application of VETs to benign hematologic disorders.

Is adiponectin in children with immunoglobulin A vasculitis a suitable biomarker of nephritis in the course of the disease?

INTRODUCTION: Immunoglobulin A vasculitis (IgAV) is the most common form of vasculitis in children. Nephritis in the course of this disease (IgAVN) is observed in 30-50% of patients and might lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Finding a non-invasive biomarker to distinguish initially between patients with and without nephritis and to facilitate a therapeutic decision to reduce the risk of long-term renal impairment is currently the target of much research. The aim of this study was to evaluate the adiponectin concentration in children with IgAV and estimate whether it might be used as a marker of IgAVN. MATERIAL AND METHODS: The study involved 29 IgAV children and 34 healthy controls. Eleven (38%) patients had renal involvement (IgAV-N) and 18 (62%) did not exhibit nephritis (IgAV-noN). The serum adiponectin level was estimated in children in an acute phase of IgAV and after 2-6 months during a follow-up visit. The relationship between the concentration of adiponectin and anthropometric measurements, epidemiological data and laboratory parameters were evaluated. RESULTS: The concentration of adiponectin in serum was significantly higher in children with acute phase of IgAV as compared to the control group (p < 0.001), and in patients without renal involvement in comparison with IgAV-N children (p < 0.049). In analysis of correlation we found a negative relationship between adiponectin level and serum creatinine concentration (r = -0.437, p = 0.02). The logistic regression evaluation demonstrated that a low adiponectin level increased the risk of nephritis in the course of IgAV. CONCLUSIONS: Our study revealed that the serum adiponectin level increased markedly in patients with IgAV. We also documented that higher risk of nephritis in the course of the disease was associated with lower concentration of this hormone.

IgA vasculitis with nephritis in children.

Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura (HSP), is the most common form of systemic vasculitis in children. Although the first case of IgAV was described more than 200 years ago, its etiology still remains unclear. Nephrological symptoms are observed in 30-50% of children during the course of the disease, and in up to 91% of cases within 6 weeks of the onset of the first symptoms. Whereas other organ manifestations of IgAV are mostly benign and self-limiting, nephritis may lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Appropriate treatment commenced early enough can stop the disease progression. However, even in severe cases there are no evidence-based guidelines, which makes the therapeutic decisions more difficult. In this article, which is the most up-to-date overview regarding IgAV, we discuss the disease's pathogenesis, the clinical forms of renal involvement in the course of the disease, the risk factors for adverse prognosis and treatment options in accordance with current recommendations.

Serological testing in small vessel vasculitis.

Serological analysis has a central role in the diagnostic work-up of patients with suspected small vessel vasculitis, both for establishing a specific diagnosis and for the monitoring of response to therapy. Autoantibodies can be detected in all forms of primary small vessel vasculitis as well as in the most common forms of secondary vasculitis. For primary vasculitis the most important serological test is for ANCA. ANCA can be found in 75-95% of patients with pauci-immune small vessel vasculitis leading to this subgroup of vasculitides being named ANCA associated vasculitis. ANCA levels often follow this disease course, but the value of serial ANCA testing is controversial. Other important autoantibodies in primary small vessel vasculitis are anti-glomerular basement membrane antibodies, anti-C1q, anti-galactose deficient IgA and cryoglobulins. A wide variety of systemic inflammatory diseases and infections can be complicated by small vessel vasculitis and detected by serological testing. Important examples are SLE, rheumatoid arthritis, Hepatitis C and HIV.

Intramuscular Hematoma as a Manifestation of IgA Vasculitis.

We describe an atypical pediatric case of immunoglobulin A vasculitis (IgAV), also referred to as Henoch-Schönlein purpura, in which formation of spontaneous hematoma of the paraspinal muscles developed. Spontaneous or unprovoked hematomas rarely occur in IgAV. These manifestations have not been described specifically in the pediatric literature as coinciding with IgAV. These findings are alarming for nonaccidental trauma, particularly in a patient without underlying blood dyscrasia. Our objective for this report is to highlight the possible association of muscular hematoma formation with IgAV and to help providers consider this association when trauma and hemophilia has been ruled out.

Variation in complement factor H affects complement activation in immunoglobulin A vasculitis with nephritis.

BACKGROUND: Immunoglobulin A (IgA) vasculitis with nephritis (IgAVN) and IgA nephropathy (IgAN) are widely considered as related diseases. Considerable evidences support the notion of involvement of complement activation in both IgAVN and IgAN. Our previous studies identified a genetic variant in complement factor H (CFH), rs6677604, as an IgAN-susceptible variant by genome-wide association study, and further confirmed its linkage to CFHR3-1Δ and proved its influence on complement activation and thereby on IgAN susceptibility. AIM: To explore the role of rs6677604 in complement activation of IgAVN. METHODS: In this study, we enrolled 632 patients with IgAVN, 1178 patients with IgAN and 902 healthy controls. The genotype of rs6677604 was measured by TaqMan allele discrimination assays or was extracted from genome-wide association study data. RESULTS: The frequency of the rs6677604-A allele was significantly higher in IgAVN than in IgAN. However, no significant differences were observed between IgAVN and the controls. Higher complement factor H (FH) levels were observed in IgAVN than IgAN, and positive correlation between circulating FH and C3 levels was present in IgAVN. In both IgAVN and IgAN, rs6677604-A was associated with less intensity of glomerular C3 deposits. In agreement with the higher frequency of rs6677604-A in IgAVN, the glomerular C3 deposits of patients with IgAVN were less intense than those in IgAN. CONCLUSION: Our findings suggest that genetic variation in CFH (rs6677604) is involved in the phenotype of complement activation in both IgAVN and IgAN. Moreover, rs6677604 might contribute to the difference of complement activation intensity between IgAVN and IgAN.