Miho Nagai

Serum Levels of BAFF and APRIL in Myeloperoxidase Anti-Neutrophil Cytoplasmic Autoantibody-Associated Renal Vasculitis: Association with Disease Activity

Background: A proliferation-inducing ligand (APRIL) and the B cell activation factor belonging to the tumor necrosis factor family (BAFF) have proven to be key factors in the selection and survival of B cells, and a higher concentration of BAFF has been shown to contribute to autoreactive B cell survival and elevated autoantibody production. Here, serum BAFF and APRIL levels were investigated to analyze their association with disease activity in myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated renal vasculitis. Methods: APRIL and BAFF levels in serum obtained from 37 patients with MPO-ANCA-associated vasculitis were measured by ELISA. Samples were taken from active vasculitis patients, inactive vasculitis patients and inactive vasculitis patients with infectious complications. Results: Although there was no difference in serum APRIL among the active vasculitis, inactive vasculitis and infectious complication patients, serum BAFF was higher in active vasculitis patients than in inactive vasculitis, infectious complication and control patients (for all, p < 0.001). There was no significant correlation between serum APRIL and ANCA titers, but there was a significant correlation between serum BAFF and ANCA titers (r = 0.465, p < 0.001). Conclusion: Excessive BAFF production in MPO-ANCA-associated vasculitis may be one of the factors for autoimmune B cell tolerance, resulting in MPO-ANCA production.

Vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 in septic shock patients treated with direct hemoperfusion with a polymyxin B-immobilized fiber column.

Abstract:  Sepsis is characterized by a systemic inflammatory response to a microbial pathogen. In sepsis, capillary permeability is a tightly regulated feature of microcirculation in all organ beds and is fundamentally altered. We investigated the vascular endothelial growth factor (VEGF) level as a vascular permeability factor and the soluble fms‐like tyrosine kinase‐1 (Flt‐1) level as an antagonist of the VEGF receptors. Serum VEGF and soluble Flt‐1 levels in 21 patients with septic shock, who were treated with direct hemoperfusion with a polymyxin B‐immobilized fiber column (DHP‐PMX), were measured by enzyme‐linked immunoassay. The VEGF and the soluble Flt‐1 levels were more elevated in patients with septic shock than in controls. Between 14 survivors and 7 non‐survivors, there was no significant difference in VEGF level before the DHP‐PMX therapy, but the soluble Flt‐1 level of survivors was significantly lower than that of non‐survivors. Although there was no significant difference between starting and ending VEGF levels in survivors, in non‐survivors the VEGF level at the end of DHP‐PMX therapy was significantly lower than that at the start. In survivors, the soluble Flt‐1 level at the end of DHP‐PMX therapy was significantly lower than that at the start. On the other hand, in non‐survivors, there was no significant difference between the ending and starting soluble Flt‐1 levels. The soluble Flt‐1 level may be a suitable marker of disease severity and mortality.

Angiopoietin Balance in Septic Shock Patients With Acute Kidney Injury: Effects of Direct Hemoperfusion With Polymyxin B-Immobilized Fiber.

Acute lung injury (ALI) in sepsis is characterized by an increase in microvascular permeability, resulting in pulmonary edema. Several studies have suggested that angiopoietin‐1 and ‐2 play a contributory role in the pathogenesis of ALI. Polymyxin B‐immobilized fiber column hemoperfusion is effective for sepsis‐induced ALI. We investigated the angiopoietin levels before and after direct hemoperfusion with polymyxin B‐immobilized fiber column (PMX) therapy. Enzyme‐linked immunoassay was used to measure the serum angiopoietin‐1 and ‐2 levels in 25 patients with septic shock treated with PMX. Eleven of the 25 patients were diagnosed with ALI. There was a significant positive correlation between the angiopoietin‐1 level and the PaO2/FiO2 ratio, but there was a significant inverse correlation between the angiopoietin‐2 level and the PaO2/FiO2 ratio. The mean angiopoietin‐1 level before PMX therapy in the ALI group was significantly lower and the mean angiopoietin‐2 level was significantly higher than in the non‐ALI group. The mean angiopoietin‐1 level of the ALI patients in response to PMX therapy was increased during PMX therapy, but that of the non‐ALI patients with newly occurring ALI showed a decreased angiopoietin‐1 level. On the other hand, the mean angiopoietin‐2 level of the responders was decreased during PMX therapy, but that of patients with newly occurring ALI showed an increased angiopoietin‐2 level. This result suggested that each angiopoietin‐1 and ‐2 level may play a role in the pathogenesis of ALI and that PMX therapy ameliorates the angiopoietin balance in patients with ALI in sepsis.

Serum ratio of soluble triggering receptor expressed on myeloid cells-1 to creatinine is a useful marker of infectious complications in myeloperoxidase-antineutrophil cytoplasmic antibody-associated renal vasculitis

BACKGROUND The contribution of infections to the mortality of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis patients is important and should induce early and careful control of these events. However, the differentiation of infection from active vasculitis is often difficult. The usefulness of serum-soluble triggering receptor expressed on myeloid cells-1 (TREM-1) for detecting the presence of infectious complications regardless of disease activity was investigated. METHODS Soluble TREM-1 in serum obtained from 41 patients with myeloperoxidase (MPO)-ANCA-associated vasculitis was measured by an enzyme-linked immunosorbent assay. Twenty-nine samples were from active vasculitis patients, 27 samples from inactive vasculitis patients without infection and 17 samples from inactive vasculitis patients with infectious complications. Serum-soluble TREM-1 was also measured in 10 patients with acute pyelonephritis and 30 patients with chronic kidney disease (CKD). RESULTS There was a significant correlation between serum levels of soluble TREM-1 and serum creatinine levels among all patients (r = 0.554, P < 0.0001). The serum-soluble TREM-1/creatinine ratio was higher in inactive vasculitis patients with infectious complications than in active vasculitis, inactive vasculitis without infection and CKD patients (P = 0.0005, P < 0.0001 and P < 0.0001, respectively), but not significantly different to that in acute pyelonephritis patients. On receiver-operating-characteristic curve analysis, a lower-limit value of 9.40 ng/mg for this ratio had a sensitivity of 84.6% and a specificity of 90.8% in differentiating patients with infection from those without infection. CONCLUSIONS The serum ratio of soluble TREM-1 to creatinine may be a useful marker for detection of infectious complications in MPO-ANCA-associated vasculitis.

Angiopoietin balance in septic shock patients treated by direct hemoperfusion with polymyxin b-immobilized fiber.

Capillary permeability is a tightly regulated feature of microcirculation in all organ beds; however, in sepsis this feature is fundamentally altered. We previously reported elevated levels of vascular endothelial growth factor and its receptor (fms‐like tyrosine kinase‐1) in patients with septic shock, then investigated two kinds of angiopoietins in those patients. An enzyme‐linked immunoassay was used to measure serum angiopoietin‐1 and ‐2 levels in 12 patients with septic shock who were treated by direct hemoperfusion with a polymyxin B‐immobilized fiber column (DHP‐PMX). The angiopoietin‐1 level was lower in patients with septic shock (7.01 ± 10.08 ng/mL) than in controls (28.24 ± 11.61 ng/mL, P < 0.001), but the angiopoietin‐2 level was higher in septic shock patients (40.83 ± 30.13 ng/mL vs. 2.47 ± 1.78 ng/mL, P < 0.001). Between seven survivors and five non‐survivors there was no significant difference in angiopoietin‐1 levels before DHP‐PMX therapy. During DHP‐PMX therapy, however, the angiopoietin‐2 level was significantly decreased in survivors (31.52 ± 26.15 ng/mL vs. 17.32 ± 22.46 ng/mL, P = 0.035). Moreover, at the end of the therapy, the angiopoietin‐1 level was significantly lower in non‐survivors (1.14 ± 1.30 ng/mL vs. 10.43 ± 13.56 ng/mL, P = 0.042), but the angiopoietin‐2 level in non‐survivors was significantly higher (70.79 ± 40.47 ng/mL vs. 17.32 ± 22.46 ng/mL, P = 0.019). The angiopoietin‐2 level may be associated with vascular permeability in septic patients, and angiopoietins may be suitable markers of disease severity and mortality.

Serum TNF-Related and Weak Inducer of Apoptosis Levels in Septic Shock Patients

Capillary permeability is a tightly regulated feature of microcirculation in all organ beds. In sepsis, this feature is fundamentally altered. We have previously reported elevated levels of angiopoietin‐2 in patients with septic shock, and have investigated tumor necrosis factor (TNF)‐related and weak inducer of apoptosis (TWEAK), which mediates both angiogenesis and inflammation, in those patients. Enzyme‐linked immunoassay was used to measure serum TWEAK levels in 20 patients with septic shock, all of whom were treated by direct hemoperfusion with a polymyxin B‐immobilized fiber column (DHP‐PMX), and in 20 non‐septic controls. The TWEAK levels were higher in patients with septic shock (192.8 ± 230.5 pg/mL) than in controls (84.1 ± 28.7 pg/mL, P = 0.043). Between 11 survivors and 10 non‐survivors, there was no significant difference in the serum TWEAK levels before the DHP‐PMX therapy. During DHP‐PMX therapy, however, the serum TWEAK levels were significantly increased in non‐survivors (142.2 ± 88.1 pg/mL to 399.0 ± 307.1 pg/mL, P = 0.022). There was a significant correlation between the serum TWEAK levels and white blood cell counts (r = 0.393, P < 0.001), platelet counts (r = 0.418, P < 0.001), or serum CRP levels (r = 0.259, P = 0.029), but there was no correlation between the serum TWEAK levels and blood pressure. The serum TWEAK levels were also correlated with the ratio of angiopoietin‐2 to ‐1 (r = 0.464, P < 0.001). TWEAK may be a suitable marker of disease severity and mortality in septic patients, and TWEAK levels may be associated with vascular permeability via angiopoietin balance.

Soluble Vascular Endothelial‐Cadherin Levels in Patients With Sepsis Treated With Direct Hemoperfusion With a Polymyxin B‐immobilized Fiber Column

Capillary permeability is a tightly regulated feature of microcirculation in all organ beds; however, in sepsis this feature is fundamentally altered. Several molecules are investigated as associated factors with capillary permeability and vascular endothelial (VE)‐cadherin internalization by vascular endothelial growth factor (VEGF)‐induced signaling through VEGF receptors leads to increased vascular endothelial cell detachment and trans‐endothelial permeability. We investigated serum soluble VE‐cadherin levels in septic patients. An enzyme‐linked immunoassay was used to measure serum soluble VE‐cadherin levels in 47 septic patients treated by direct hemoperfusion with a polymyxin B‐immobilized fiber column (DHP‐PMX). The serum soluble VE‐cadherin level of septic patients before PMX‐DHP was 3424.1 ± 2033.0 ng/mL, which was significantly lower than that of the controls (5862.0 ± 1521.2 ng/mL; P < 0.0001). The time course of serum soluble VE‐cadherin levels remained unchanged during PMX‐DHP therapy. There was no significant difference in serum soluble VE‐cadherin levels before PMX‐DHP therapy between survivors and non‐survivors, and there was no significant difference in those levels between the groups at any time after the initiation of PMX‐DHP therapy. There was no correlation between soluble VE‐cadherin levels and clinical data, except white blood cell count (r = −0.277, P = 0.0009). There was no correlation between soluble VE‐cadherin levels and the levels of angiopoietin 1 and 2. In summary, the relationship between VE‐cadherin and capillary permeability in sepsis could not be demonstrated. Soluble VE‐cadherins are not reflected in the balance between intercellular junction plasticity and integrity, but VE‐cadherin stabilization by its phosphorylation or internalization may be associated with capillary permeability.

Serum levels of the soluble haemoglobin scavenger receptor CD163 in MPO-ANCA-associated renal vasculitis

Objectives: The contribution of infections to the mortality of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is important, and early and careful infection control is necessary. We investigated the usefulness of the serum-soluble haemoglobin scavenger receptor CD163 for detecting the presence of infectious complications regardless of disease activity. Method: Soluble CD163 in serum obtained from 45 Japanese patients with myeloperoxidase (MPO)-AAV was measured by an enzyme-linked immunosorbent assay (ELISA). We evaluated 36 samples from active-vasculitis patients, 36 samples from inactive-vasculitis patients without infection, and 19 samples from inactive-vasculitis patients with infectious complications. Serum-soluble CD163 was also measured in 15 infectious patients without vasculitis and in 30 normal controls. Results: The mean serum-soluble CD163 level was higher in the patients with infectious complications than in the active-vasculitis patients, inactive-vasculitis patients, and normal controls. There were significant positive correlations between serum-soluble CD163 levels and white blood cell (WBC) count, serum C-reactive protein (CRP) levels, and serum albumin levels, but only serum CRP levels were correlated with serum-soluble CD163 levels in a multiple regression analysis. On the receiver-operating characteristic (ROC) curve, serum-soluble CD163 levels had 80.6% sensitivity and 86.7% specificity for differentiating patients with infection from those without infection. Among the active-vasculitis patients, the mean serum-soluble CD163 level of the patients with alveolar haemorrhage was significantly lower than that of the patients with interstitial lung diseases and that of the patients without pulmonary lesions. Conclusions: The serum-soluble CD163 level may be a useful marker for the detection of infectious complications in MPO-AAV patients.

Human parvovirus B19-induced acute glomerulonephritis: a case report.

Human parvovirus B19 (HPV B19) infection is well known as a cause of erythema infectiosum in children. Acute glomerulonephritis due to HPVB19 infection is rarely observed in adults. Here, we present the case of a 45-year-old female who showed acute glomerulonephritis induced by HPVB19 infection with various autoantibodies. She had proteinuria (175 mg/g creatinine) and hematuria (20–29 erythrocytes per high-power field) in a urinalysis, and various autoantibodies such as antinuclear antibodies, proteinase-3-antineutrophil cytoplasmic antibodies (PR3-ANCA), antiglomerular basement membrane (GBM) antibodies, and anticardiolipin antibodies in a blood examination. A renal biopsy showed that endocapillary proliferative glomerulonephritis comprised of mononuclear cell infiltration. By using immunofluorescence microscopy, IgG, IgA, IgM, C3, C4, and C1q deposits were detected mainly in glomerular capillaries. Electron-dense deposits were detected in the subendothelial area and mesangial area by using electron microscopy. All symptoms and abnormal laboratory data were self-improved. Our patient’s case may provide a clue to the etiology of ANCA-associated vasculitis or lupus nephritis.

Serum decoy receptor 3 levels are associated with the disease activity of MPO-ANCA-associated renal vasculitis

Type 17 T-helper (Th17) cells have been suggested to be involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Th17 cell proliferation is promoted by tumor necrosis factor (TNF)-like ligand 1A (TL1A), which binds to death receptor 3 (DR3) expressed on Th17 cells. Decoy receptor 3 (DcR3) is known to block the TL1A-DR3 pathway by binding TL1A. To evaluate the Th17-TL1A systems as disease activity markers in AAV, we investigated the serum levels of TL1A and DcR3 in AAV patients. Serum IL-17, IL-23, TL1A, and DcR3 were measured by ELISA in 24 AAV patients with microscopic polyangiitis before the initial treatment, 24 AAV patients during remission, and 20 control subjects. There were no significant differences in serum IL-17, IL-23, and TL1A levels among the active-vasculitis patients, inactive-vasculitis patients, and controls. The mean serum DcR3 level was significantly higher in the active-vasculitis patients than in the inactive-vasculitis patients and controls (P < 0.0001, respectively). There were significant positive correlations between the serum DcR3 levels and Birmingham Vasculitis Activity Score (BVAS), myeloperoxidase (MPO)-ANCA titers, white blood cell counts, serum creatinine levels, and serum C-reactive protein levels. In a multiple regression analysis, there was a significant positive correlation between the serum DcR3 level and BVAS (β = 0.650, P = 0.0462). The mean BVAS level was significantly higher in the active-vasculitis patients with high serum DcR3 levels than in those with the low serum DcR3 levels (P = 0.0202). The serum level of DcR3 may be a useful marker for disease activity in AAV.