Kei Nagai

Toll-like receptor 4 and MAIR-II/CLM-4/LMIR2 immunoreceptor regulate VLA-4-mediated inflammatory monocyte migration

Inflammatory monocytes play an important role in host defense against infections. However, the regulatory mechanisms of transmigration into infected tissue are not yet completely understood. Here we show that mice deficient in MAIR-II (also called CLM-4 or LMIR2) are more susceptible to caecal ligation and puncture (CLP)-induced peritonitis than wild-type (WT) mice. Adoptive transfer of inflammatory monocytes from WT mice, but not from MAIR-II, TLR4 or MyD88-deficient mice, significantly improves survival of MAIR-II-deficient mice after CLP. Migration of inflammatory monocytes into the peritoneal cavity after CLP, which is dependent on VLA-4, is impaired in above mutant and FcRγ chain-deficient mice. Lipopolysaccharide stimulation induces association of MAIR-II with FcRγ chain and Syk, leading to enhancement of VLA-4-mediated adhesion to VCAM-1. These results indicate that activation of MAIR-II/FcRγ chain by TLR4/MyD88-mediated signalling is essential for the transmigration of inflammatory monocytes from the blood to sites of infection mediated by VLA-4.

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.

Annual decline in estimated glomerular filtration rate is a risk factor for cardiovascular events independent of proteinuria

Chronic kidney disease is a risk factor of the development of cardiovascular disease (CVD). However, it is not clear whether decline of glomerular filtration rate (GFR), not reduced GFR, is a risk factor for the incidence of CVD independent of proteinuria.

Expression and Function of Allergin-1 on Human Primary Mast Cells

Mast cells (MC) play an important role in allergic and non-allergic immune responses. Activation of human MC is modulated by several cell surface inhibitory receptors, including recently identified Allergin-1 expressed on both human and mouse MC. Although Allergin-1 suppresses IgE-mediated, mast cell–dependent anaphylaxis in mice, the expression profile and function of Allergin-1 on human primary MC remains undetermined. Here, we established a seven-color flow cytometry method for assessing expression and function of a very small number of human primary MC. We show that Allergin-1S1, a splicing isoform of Allergin-1, is predominantly expressed on human primary MC in both bronchoalveolar lavage (BAL) fluid and nasal scratching specimens. Moreover, Allergin-1S1 inhibits IgE-mediated activation from human primary MC in BAL fluid. These results indicate that Allergin-1 on human primary MC exhibits similar characteristics as mouse Allergin-1 in the expression profile and function.

Tie2 Signaling Enhances Mast Cell Progenitor Adhesion to Vascular Cell Adhesion Molecule-1 (VCAM-1) through α4β1 Integrin

Mast cell (MC) activation contributes considerably to immune responses, such as host protection and allergy. Cell surface immunoreceptors expressed on MCs play an important role in MC activation. Although various immunoreceptors on MCs have been identified, the regulatory mechanism of MC activation is not fully understood. To understand the regulatory mechanisms of MC activation, we used gene expression analyses of human and mouse MCs to identify a novel immunoreceptor expressed on MCs. We found that Tek, which encodes Tie2, was preferentially expressed in the MCs of both humans and mice. However, Tie2 was not detected on the cell surface of the mouse MCs of the peritoneal cavity, ear skin, or colon lamina propria. In contrast, it was expressed on mouse bone marrow–derived MCs and bone marrow MC progenitors (BM-MCps). Stimulation of Tie2 by its ligand angiopoietin-1 induced tyrosine phosphorylation of Tie2 in MEDMC-BRC6, a mouse embryonic stem cell-derived mast cell line, and enhanced MEDMC-BRC6 and mouse BM-MCp adhesion to vascular cell adhesion molecule-1 (VCAM-1) through α4β1 integrin. These results suggest that Tie2 signaling induces α4β1 integrin activation on BM-MCps for adhesion to VCAM-1.

A case of multicentric Castleman's disease with membranoproliferative glomerulonephritis type 3-like lesion

Renal involvement is a significant complication of multicentric Castlemans disease (MCD) and various glomerular involvements have been reported. A 45‐year‐old Japanese man presented with persistent proteinuria, with lymphadenopathy and hypergammaglobulinemia. He had been diagnosed 4 years previously with MCD. As his renal impairment had progressed to renal failure, he underwent a renal biopsy. Histology revealed diffuse and global membranous lesions with large and heterogeneous epimembranous deposits. In addition, mesangial cell proliferation and focal extracapillary lesions were found. Under immunofluorescence, granular staining for anti‐IgG, IgG1, IgG2 and IgA was strongly positive in the capillary loop, and weakly positive in the mesangium. As such, there was a diversity of histological features. Our perspective with regard to pathogenesis is that the formation of the immune‐complex contributed to the membranoproliferative glomerulonephritis type 3‐like lesion. This histological multiform with MCD is valuable for increasing our understanding of the mechanism for onset of immune‐complex glomerular deposition and cellular proliferation of glomerulonephritis.

Relationship between Estimated Glomerular Filtration Rate and Cardiovascular Mortality in a Japanese Cohort with Long-Term Follow-Up

Background Patients with renal impairment are at risk of not only end-stage kidney disease but also cardiovascular disease (CVD). The current definition of CKD stage G3a is eGFR 45–59 ml/min/1.73 m2 and of G3b is 30–44 ml/min/1.73 m2, and subjects in the CKD 3a category are considered to be at lower risk of mortality than are those in CKD 3b. Methods We evaluated the outcome of 97,043 people (33,131 men and 63,912 women) living in Ibaraki Prefecture who underwent annual community-based health checkups beginning in 1993 at age 40–80 years and who were followed for a mean of 17.1 years. Results The number of all-causes deaths was 20,534 (10,375 men and 10,159 women), of which 5,995 (2,695 men and 3,300 women) were deaths due to CVD. Multivariable-adjusted hazard ratio for CVD death in the eGFR 45–49 ml/min/1.73 m2 category was significantly increased (1.82; 95% confidential interval, 1.23–2.69) in non-elderly men, whereas all-cause mortality and CVD mortality in elderly men with eGFR 45–49 ml/min/1.73m2 were non significant. In contrast, both in non-elderly women and in elderly women with eGFR 45–49 ml/min/1.73 m2 showed small, but significant, increases in the risks of all-cause mortality and CVD. Conclusions We demonstrated proportionate increases in mortality with decreasing eGFR in a Japanese CKD population. Like patients in the CKD G3b subgroup, non-elderly men and women with an eGFR of 45–49 ml/min/1.73 m2 (i.e. a part of CKD G3a) are at considerable risk of CVD mortality. Age dependent and eGFR dependent finer risk recognition were required for CVD prevention in clinical practice with regard to CKD patients.

Quantitative evaluation of proteinuria for health checkups is more efficient than the dipstick method

On behalf of the Steering Committee for “Design of the comprehensive health care system for chronic kidney disease (CKD) based on the individual risk assessment by specific health checkups”.

Birth Weight and End‐Stage Diabetic Nephropathy in Later Life: A Japanese Multicenter Study

Dear Editor, Low birth weight (LBW) of less than 2500 g is a surrogate marker for low nephron number, and emerging evidence suggests that it is an important risk factor for both the progression of renal diseases (1,2) and the incidence of end-stage renal disease (ESRD) (2,3). Individuals with an inborn nephron deficit are susceptible to progressive loss of kidney function due to aging-related glomerular alterations (1). However, most study participants have been younger than 40 (2,3), because little well-organized information on birth weight is available for the old general population as comparison subjects in most countries. Diabetes mellitus is currently the most frequent primary disease of patients receiving dialysis, and the mean age of initiation of RRT in DM nephropathy is over 60 years old in Japan. Furthermore, the effect of generational differences must be considered when analyzing the correlation between birth weight and ESRD (4). Therefore, birth weight for each individual should be compared to the mean birth weight from an age-matched population. In January 2010 in nine centers in Ibaraki and Chiba prefectures in Japan, 1130 Japanese patients undergoing maintenance hemodialysis were identified. We surveyed the patients by using a selfcompleted questionnaire containing questions about birth weight. Data were obtained from 230 patients (20.3%). Mean birth weight in each year from 1903 to 1951 was estimated based on three nationwide surveys held in 1951, 1930 and 1903. Mean birth weight from 1951 to 2010 is available in the Annual Vital Statistics of National Population Dynamics Survey conducted by the Ministry of Health, Labor, and Welfare of Japan. We defined mean birth weight in each patient’s birth year as age-matched mean birth weight. We divided our subjects into those with and without DM and used the age of 60 years old in each group as thresholds to further classify subjects as younger and older. We then compared the actual birth weight provided on the questionnaire to the age-matched mean birth weight in each group. Older patients with DM had significantly lower birth weight than age-matched mean birth weight, whereas no significant differences between them existed in younger patients in the DM group or in any patients in the non-DM group, which consists of 101 patients with chronic glomerulonephritis and 45 with miscellaneous diseases (Fig. 1). Ichikawa et al. reported the dynamics of LBW and ESRD in Japan by using an ecological approach. However, they did not consider the effect of aging or the cause of ESRD in individuals (4). In contrast, we analyzed the effect of them by evaluating birth weight separately in younger and older individuals with or without DM. We considered that older diabetic patients with a small number of glomeruli due to significantly lower birth weight may have more severe long-term nephron damage than older nondiabetic patients. Therefore, we speculated that lower-than-mean birth weight would be a risk for ESRD in patients with DM in later life.

Use of darbepoetin alfa for myelodysplastic syndrome coincident with chronic kidney disease

Darbepoetin alfa (DA) has been used in Japan since the end of 2014 to treat myelodysplastic syndrome (MDS) and is the only way apart from blood transfusion to improve these patients’ anemia. Severe anemia is a suspected risk factor in progression of chronic kidney disease (CKD). It is therefore important to maintain appropriate hemoglobin levels in CKD patients, although it remains unclear whether administration of erythropoiesis-stimulating agents suppresses CKD progression [1]. Here, we show how using DA beyond the maximum dose for renal anemia appeared to improve renal function by maintaining hemoglobin levels in a patient with severe anemia caused by MDS coincident with CKD. An 82-year-old man diagnosed with MDS by bone marrow examination had been treated at a local clinic. A low-dose continuous erythropoietin receptor activator was given, but had been stopped after 6 months because it was considered ineffective in improving his anemia. His serum creatinine level rose from 1.18 to 5.27 mg/dL in the 17 months after MDS diagnosis; he was then referred to our hospital (Fig. 1). We could not find out any exogenous causes to induce acute exacerbation of CKD such as administration of nephrotoxic reagents or clinical manifestation of infections. Although the patient’s bodyweight and fluid volume were stably controlled, he felt general fatigue on mild exercise. We began treating him with highdose DA (240 lg) and blood transfusions, because his hemoglobin level had fallen below 6 g/dL and he was symptomatic. DA had just been approved for use in MDS in Japan; using it, we were able to maintain the patient’s hemoglobin level at about 7 g/dL with infrequent blood transfusions. Interestingly, the patient’s serum creatinine level simultaneously decreased to about 3 mg/dL (Fig. 1). We inferred that progression of the CKD had been suppressed by the aggressive use of DA to activate erythropoiesis. We cannot clearly demonstrate why this man’s renal function improved after DA administration. Urinalysis revealed a contentious, mild proteinuria with little hematuria, suggesting that the renal injury had been caused by