Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The Oxford classification of IgA nephropathy consists of four markers as prognosticators. We retrospectively examined the relevance of extracapillary proliferation involving cellular and fibrocellular crescents (Ex) and arteriolar hyalinosis (A) on the long-term outcome of renal function.
A total of 314 Japanese patients who were diagnosed with IgA nephropathy, with 12 months or more of follow-up period were included in this study. A total of 186 patients were with UP aeyen 0.5 g/day. Patients with diabetes mellitus or severe kidney injury (eGFR < 30 ml/min/1.73 m(2)) were excluded. The presence of Ex and A were scored 0 in the absence, and 1 in the presence, of each lesion. The end point was determined as a 50 % reduction in initial eGFR or end-stage renal disease defined as eGFR < 15 ml/min/1.73 m(2).
In univariate analyses, the kidney survival rate was significantly lower in patients with Ex1 and A1 if UP aeyen 0.5 g/day. In the patients with UP < 0.5/day, none of the clinical and pathological parameters was determined as a risk factor. In the multivariate model including pathological parameters, Ex1 and A1 were independent risk factors for renal outcome if UP aeyen 0.5 g/day. In those patients treated with RAS-blocker or treated before introduction of methylprednisolone pulse therapy, Ex was the only independent risk factor. In multivariate analysis including clinical parameters, eGFR alone was a risk factor, due to strong correlation with other parameters.
Ex and A would be associated with the renal outcome of the patients with UP aeyen 0.5 g/day.

DOI： 10.1007/s10157-015-1185-0

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Leptin and IL-23 production in NTS nephritis.Leptin, one of the typical adipokines, is reported to promote T(h)17 cell responses and to enhance production of proinflammatory cytokines. To clarify the role of leptin in the regulation of the IL-23/IL-17 axis and the development of kidney disease, we used a murine model of nephrotoxic serum (NTS) nephritis (NTN). Sheep NTS was administered in wild-type C57BL/6J mice and food-restricted, leptin-deficient C57BL/6J-ob/ob (FR-ob/ob) mice after preimmunization with sheep IgG. The profile of mRNA expression relevant to T helper lymphocytes in the kidneys was analyzed by quantitative real-time PCR (qRT-PCR). Cultured murine glomerular podocytes and peritoneal exudate macrophages (PEMs) were used to investigate the direct effect of leptin on IL-23 or MCP-1 production by qRT-PCR. Kidney injury and macrophage infiltration were significantly attenuated in FR-ob/ob mice 7 days after NTS injection. The T(h)17-dependent secondary immune response against deposited NTS in the glomeruli was totally impaired in FR-ob/ob mice because of deteriorated IL-17 and proinflammatory cytokine production including IL-23 and MCP-1 in the kidney. IL-23 was produced in glomerular podocytes in NTN mice and cultured murine glomerular podocytes produced IL-23 under leptin stimulation. MCP-1 production in PEMs was also promoted by leptin. Induction of MCP-1 expression was observed in PEMs regardless of Ob-Rb, and the leptin signal was transduced without STAT3 phosphorylation in PEMs. Leptin deficiency impairs the secondary immune response against NTS and down-regulates IL-23 production and T(h)17 responses in the NTN kidney, which is accompanied by decreased MCP-1 production and macrophage infiltration in the NTN kidney.

DOI： 10.1093/intimm/dxv067

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

In order to clarify the interaction between cardiac dysfunction and sodium homeostasis in the kidney, we used a murine model of cardiac dysfunction and investigated the effect on sodium transporters in renal tubular cells.
Cardiac function was deteriorated by abdominal aortic banding, and the gene expression of sodium transporters in the kidneys was evaluated by real-time RT-PCR and compared with that in the kidneys of control mice.
Gene expression of all three variants of the murine prolactin receptor was enhanced by aortic banding. Upregulated prolactin receptor was distributed in the proximal tubular cells of the pars recta in the deep inner cortex and the outer stripe of the outer medulla. Prolactin has been reported to be a natriuretic hormone that inhibits proximal tubular Na+/K+-ATPase activity, resulting in reduced sodium reabsorption and the acceleration of natriuresis. Inhibition of endogenous prolactin secretion by bromocriptine administration decreased the urine sodium excretion in both aortic banding and control mice. On the other hand, excess exogenous prolactin administration enhanced urine potassium excretion in aortic banding mice. Furthermore, a high-sodium diet accelerated urinary sodium excretion, which was also significantly decreased by inhibition of endogenous prolactin secretion in aortic banding mice.
We reported that the prolactin receptor was upregulated by aortic banding treatment. Prolactin-prolactin receptor interaction in the proximal tubular cells of the pars recta should involve a different mechanism of kaliuresis other than inhibition of Na+/K+-ATPase.

DOI： 10.1007/s10157-013-0820-x

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

IgA nephropathy (IgAN) is characterized by mesangial deposition of IgA1 and galactose-deficient IgA1 is expected to play a pathogenic role. However, the identity of the receptor for IgA1 is still controversial. Hence, the aim of this study was to explore the receptor for galactose-deficient IgA1. Human monoclonal IgA1 was treated with exoglycosidase and FITC-conjugated control, asialo- and agalactosyl-IgA1 was used as a probe to detect the receptor in cultured human mesangial cells. Tumor necrosis factor-alpha or transforming growth factor-beta 1 treatment accelerated IgA1-binding on mesangial cells, and these effects were diminished by the addition of dexamethasone, whereas these changes were not dependent on galactose-deficiency of IgA1. According to comprehensive gene expression analysis, we focused on integrin beta 1. Pre-treatment by Mn2+, which activates integrin by changing its structure, enhanced the binding of IgA1 in cultured mesangial cells. Furthermore, pre-incubation with collagens specifically enhanced binding of IgA1 in the cultured human mesangial cells without activation by Mn2+. Collagen type IV distributed in the mesangial region of the glomeruli as well as Bowman's capsule and tubular basal membrane in IgAN patients, and the IgA1 with collagen type IV induced proliferative signals on mesangial cells by phosphorylating extracellular signal-regulated kinase more effectively than the IgA1 alone. Immunoprecipitation assay revealed the binding of IgA1 and integrin alpha 1/beta 1 and alpha 2/beta 1 heterodimer and down-regulation of integrin alpha 1, alpha 2 and beta 1 expression in human mesangial cells induced by each specific small interfering RNA diminished the ability to bind IgA1 probe. Integrin alpha 1/beta 1 and alpha 2/beta 1 would be a candidate receptor for IgA1.

DOI： 10.1093/intimm/dxr125

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC ADVANCEMENT SCIENCE  

Immunoglobulin G (IgG) mediates pro- and anti-inflammatory activities through the engagement of its Fc fragment (Fc) with distinct Fc gamma receptors (Fc gamma Rs). One class of Fc-Fc gamma R interactions generates pro-inflammatory effects of immune complexes and cytotoxic antibodies. In contrast, therapeutic intravenous gamma globulin and its Fc fragments are anti-inflammatory. We show here that these distinct properties of the IgG Fc result from differential sialylation of the Fc core polysaccharide. IgG acquires anti-inflammatory properties upon Fc sialylation, which is reduced upon the induction of an antigen-specific immune response. This differential sialylation may provide a switch from innate anti-inflammatory activity in the steady state to generating adaptive pro-inflammatory effects upon antigenic challenge.

DOI： 10.1126/science.1129594

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROCKEFELLER UNIV PRESS  

Introduction of heterologous anti-glomerular basement membrane antiserum (nephrotoxic serum, NTS) into presensitized mice triggers the production of IgG anti-NTS antibodies that are predominantly IgG2b and the glomerular deposition of pathogenic immune complexes, leading to accelerated renal disease. The pathology observed in this model is determined by the effector cell activation threshold that is established by the coexpression on infiltrating macrophages of the IgG2a/2b restricted activation receptor Fc gamma RIV and its inhibitory receptor counterpart, Fc gamma RIIB. Blocking Fc gamma RIV with a specific monoclonal antibody thereby preventing IgG2b engagement or treatment with high dose intravenous gamma-globulin (IVIG) to down-regulate Fc gamma RIV while up-regulating Fc gamma RIIB, protects mice from fatal disease. In the absence of Fc gamma RIIB, IVIG is not protective; this indicates that reduced Fc gamma RIV expression alone is insufficient to protect animals from pathogenic IgG2b immune complexes. These results establish the significance of specific IgG subclasses and their cognate FcR gamma s in renal disease.

DOI： 10.1084/jem.20051900

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Background. Monocyte chemoattractant protein (MCP)-1 is closely related to the pathogenesis of the progression of various chronic renal diseases, including IgA nephropathy (IgAN), through its chemoattractant effect on macrophages. However, the correlation of MCP-1 gene polymorphism with the long-term prognosis of Japanese patients with IgAN has not been clearly determined yet. Methods. We investigated 277 Japanese patients diagnosed with IgAN based on renal biopsy to clarify the association between the progression of IgAN and MCP-1 gene polymorphism at position A-2518G, which regulates the transcription of the MCP-1 gene. Results. The incidence of endstage renal disease was significantly higher in patients with the AA genotype (47.1%) compared to those with the AG (24.1%) or GG (27.4%) genotype (P = 0.024). Moreover, Kaplan-Meier analysis revealed that the AA genotype significantly facilitated the progression of renal disease (log rank
P = 0.0029), and Cox proportional hazards regression model analysis showed that the AA genotype represented a 2.058-fold risk for the progression of renal disease (P = 0.026) compared to the AG/GG genotype. However, when the patients were treated with angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker, or corticosteroid, homozygosity for the -2518A allele was not associated with a higher rate of incidence of endstage renal disease. Serum MCP-1 levels were higher although not significantly so, in the patients with IgAN possessing the AA genotype. Conclusions. The AA genotype at MCP-1 -2518 was an independent risk factor for the progression of renal disease in Japanese patients with IgAN, and was closely associated with renal survival. © Japanese Society of Nephrology 2005.

DOI： 10.1007/s10157-005-0375-6

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background: Thrombotic occlusion is a frequent complication of central venous catheters used to provide temporary blood access on hemodialysis therapy. Heparin-lock is conventionally used to maintain patency of the catheter, but the necessity of heparin-lock has not been determined yet. Methods: After the immobilized-urokinase double-lumen central venous catheter was inserted into 48 Japanese hemodialysis patients, 22 patients randomized to the heparin group received a 20-ml saline-flush, followed by 2 ml of 1,000 U/ml heparin-lock, and 26 patients randomized to the saline group received only the 20-ml saline-flush once a day for each lumen. Results: Thrombotic occlusion was observed in only 1 out of 22 patients in the heparin group and 1 out of 26 patients in the saline group. No significant difference of the catheter survival was observed between the two groups (p = 0.8599). Conclusions: Natural saline-flush is sufficient for maintaining the patency of an immobilized-urokinase double-lumen central venous catheter. Copyright (C) 2004 S. Karger AG, Basel.

DOI： 10.1159/000081811

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING INC  

Background. Iron deficiency is a frequent cause of recombinant human erythropoietin (rhEPO)-resistant anemia in hemodialysis patients. Both reticulocyte hemoglobin content (CHr) and transferrin saturation (TSAT) have been proposed as markers of iron deficiency, but it is unclear which parameter is superior.
Methods. To compare the efficacy of CHr and TSAT as an indicator for treatment of iron deficiency, we conducted a single-center, open-label, prospective, randomized, controlled trial at the Kidney Center in Shinraku-en Hospital of 197 Japanese patients on chronic hemodialysis. After 4 weeks of run-in period during which iron supplementation was suspended, 100 patients who were randomized to the CHr group received 240 mg iron colloid intravenously over 2 weeks when CHr less than 32.5 pg, and 97 patients who were randomized to the TSAT group received the same doses of iron colloid when TSAT less than 20%. We measured the rhEPO dose needed to maintain prestudy hematocrit levels, hematocrit, CHr, TSAT, serum ferritin, percentage of hypochromic red blood cells, and total iron administered.
Results. Sixteen weeks later, 94 patients in the CHr group and 89 patients in the TSAT group finished the study. The doses of rhEPO required decreased by 35.8% (4081 to 2629 U/week, P < group (4121 to 3606 U/week). Although CHr increased promptly after the iron administration in both groups, TSAT increased only in the TSAT group.
Conclusions. Although CHr reflects the iron status more sensitively, TSAT is a better clinical marker for iron supplementation therapy.

DOI： 10.1046/j.1523-1755.2003.00826.x

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Rat anti-glomerular basement membrane (GBM) nephritis is a model of crescentic glomerulonephritis induced by injection of anti-GBM antiserum. To elucidate the mechanism of glomerular injury, we analyzed the gene expression patterns in the kidneys of anti-GBM nephritis rats using DNA arrays, and found that macrophage metalloelastase/matrix metalloproteinase (MMP)-12 was one of the highly expressed genes in the kidneys on days 3 and 7 after the injection of anti-GBM antiserum. Enhancement of MMP-12 mRNA expression was confirmed by Northern blot analysis, and in situ hybridization revealed that MMP-12 mRNA was expressed in ED-1-positive macrophages and multinuclear giant cells in the glomeruli with crescent. Moreover, these cells were positive with anti-rat rMMP-12 Ab on the section of the kidneys of anti-GBM nephritis rats on day 7. To clarify the role of MMP-12, we conducted a neutralization experiment using anti-rat rMMP-12 Ab, which had an ability to inhibit rMMP-12 activity of degrading natural substrate such as bovine, elastin or human fibronectin in vitro. Anti-rat rMMP-12 Ab or control Ig was injected in each of six rats on days 0, 2, 4, and 6 after the injection of anti-GBM antiserum. Consequently, crescent formation and macrophage infiltration in the glomeruli were significantly reduced in the rats treated with anti-rat rMMP-12 Ab, and the amount of urine protein was also decreased. These results disclosed that MMP-12 played an important role in glomerular injury in a crescentic glomerulonephritis model, and inhibition of MMP-12 may lead to a new therapeutic strategy for this disease.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROCKEFELLER UNIV PRESS  

The administration of concanavalin A (Con A) induces a rapid severe injury of hepatocytes in mice. Although the Con A-induced hepatitis is considered to be an experimental model or human autoimmune hepatitis, the precise cellular and molecular mechanisms that induce hepatocyte injury remain unclear. Here, we demonstrate that V alpha 14 NKT cells are required and sufficient for induction of this hepatitis. Moreover, interleukin (IL)-4 produced by Con A-activated V alpha 14 NKT cells is found to play a crucial role in disease development by augmenting the cytotoxic activity of V alpha 14 NKT cells in an autocrine fashion. Indeed, short-term treatment with IL-4 induces an increase in the expression of granzyme B and Fas ligand (L) in V alpha 14 NKT cells. Moreover, V alpha 14 NKT cells from either perforin knock-out mice or FasL-mutant gld/gld mice fail to induce hepatitis, and hence perforin-granzyme B and FasL appear to be effector molecules in Con A-induced V alpha 14 NKT cell-mediated hepatocyte injury.

DOI： 10.1084/jem.191.1.105

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Human V alpha 24 NKT cells bearing an invariant V alpha 24J alpha Q antigen receptor, the counterpart of the murine V alpha 14 NKT cells, are activated by the specific ligand, alpha-galactosylceramide (alpha-GalCer) in a CD1d-dependent manner. Here, we demonstrate that the alpha-GalCer-activated V alpha 24 NKT cells exert a potent perforin-dependent cytotoxic activity against a wide variety of human tumor cell lines. In addition, we demonstrate that V alpha 24 NKT cells and dendritic cells (DCs) from melanoma patients are functionally normal, even in the tumor-hearing status. The potential use of alpha-GalCer-activated V alpha 24 NKT cells and/or DCs from patients for cancer immunotherapy is discussed.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Murine NKT cells can recognize a-galactosylceramide (alpha-GalCer) in the context of a class Ib CD1d molecule. Here we show that alpha-GalCer can selectively activate freshly isolated human V(alpha)24(+)V(beta)11 (+) cells, functionally defining the human NKT cells. The naive human NKT cell repertoire consisted of cells expressing an invariant V(alpha)24J(alpha)Q chain and a diverse array of beta chains derived from a single V beta 11 gene segment. Stimulation with a-GalCer expanded a polyclonal subset of the human NKT cell repertoire carrying a novel complementarity-determining region (CDR) 3 beta consensus motif that may directly interact with the sugar moiety of a-GalCer, Our data suggest that certain redundancy is allowed for CDR3 beta of NKT antigen receptor to interact with the ligand and provide a first clue to understand the novel protein-carbohydrate interaction mechanisms.

DOI： 10.1093/intimm/11.6.881

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

We have recently identified alpha-galactosylceramide (alpha-GalCer) as a specific ligand for an invariant V alpha 14/V beta 8.2 T cell receptor exclusively expressed on the majority of V alpha 14 NKT cells, a novel subset of lymphocytes. Here, we report that alpha-GalCer selectively activates V alpha 14 NKT cells resulting in prevention of tumor metastasis, The effector mechanisms of the ligand-activated V alpha 14 NKT cells seem to be mediated by natural killer (NK)-like nonspecific cytotoxicity. Indeed, the cytotoxic index obtained by alpha-GalCer-activated V alpha 14 NKT cells was reduced by the addition of cold target tumor cells or by treatment with concanamycin Al which inhibits activation and secretion of perforin, but not by mAbs against molecules involved in the NKT cell recognition and conventional cytotoxicity, such as CD1d, V beta 8, NK1.1, Ly49C, Fas. or Fas ligand, These results suggest that the ligand-activated V alpha 14 NKT cells kill tumor cells directly through a CD1d/V alpha 14 T cell receptor-independent, NK-like mechanism.

DOI： 10.1073/pnas.95.10.5690

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A lymphocyte subpopulation, the V(α)14 natural killer T (NKT) cells, expresses both NK1.1 and a single invariant T cell receptor encoded by the V(α)14 and J(α)281 gene segments. Mice with a deletion of the J(α)281 gene segment were found to exclusively lack this subpopulation. The V(α)14 NKT cell-deficient mice could no longer mediate the interleukin-12 (IL-12)- induced rejection of tumors. Although the antitumor effect of IL-12 was thought to be mediated through natural killer cells and T cells. V(α)14 NKT cells were found to be an essential target of IL-12, and they mediated their cytotoxicity by an NK-like effector mechanism after activation with IL-12.

DOI： 10.1126/science.278.5343.1623

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Natural killer T (NKT) lymphocytes express an invariant T cell antigen receptor (TCR) encoded by the V(alpha)14 and J(alpha)281 gene segments. A glycosylceramide-containing alpha-anomeric sugar with a longer fatty acyl chain (C-26) and sphingosine base (C-18) was identified as a ligand for this TCR. Glycosylceramide-mediated proliferative responses of V(alpha)14 NKT cells were abrogated by treatment with chloroquine-concanamycin A or by monoclonal antibodies against CD1dN(beta)8, CD40/CD40L, or B7/CTLA-4/CD28, but not by interference with the function of a transporter-associated protein. Thus, this lymphocyte shares distinct recognition systems with either T or NK cells.

DOI： 10.1126/science.278.5343.1626

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Abstract

Objectives

We evaluated the association between anti-ribosomal P antibody (anti-RibP) titres and disease activity in Japanese systemic lupus erythematosus (SLE) patients.

Methods

Eighty patients admitted and treated in Niigata University Hospital for new-onset or flare-up of SLE were included in this retrospective cross-sectional study. Clinical data were obtained from medical records at admission. Anti-RibP index, and cytokine and tryptophan metabolite levels were determined by ELISA.

Results

Of the 80 SLE patients, 30 had anti-RibP. Anti-RibP presence was associated with a greater prevalence of skin rash and more severe inflammatory responses, demonstrated by higher inflammatory cytokine levels, hypocomplementemia, and accelerated tryptophan metabolism, in younger patients. The serum anti-RibP index correlated with age at diagnosis, clinical indicators, initial prednisolone dose, and cytokines and tryptophan metabolite levels in univariate analysis. Multivariate analysis showed the anti-RibP index was independently associated with initial prednisolone dose and prevalence of skin rash. Anti-RibP IgG were mainly IgG2 and IgG3 subclasses, and anti-RibP IgG3 was associated with hypocomplementemia, higher disease activity score, accelerated kynurenine pathway activity, and higher proinflammatory cytokine production. The coexistence of anti-dsDNA IgG and anti-RibP IgG2 or IgG3 accompanied higher IL-10 and IFN-α2 levels; furthermore, anti-RibP IgG3 coexistence with anti-dsDNA antibody contributed to the requirement for higher initial prednisolone doses and accelerated kynurenine pathway activity.

Conclusion

Anti-RibP was associated with clinical manifestations and parameters in SLE, and its index might be a useful indicator of disease severity. Anti-RibP IgG3 was the IgG subclass most strongly associated with the pathogenesis of SLE.

DOI： 10.1093/rheumatology/kead402

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Sodium magnetic resonance imaging can non-invasively assess sodium distribution, specifically sodium concentration in the countercurrent multiplication system in the kidney, which forms a sodium concentration gradient from the cortex to the medulla, enabling efficient water reabsorption. This study aimed to investigate whether sodium magnetic resonance imaging can detect changes in sodium concentrations under normal conditions in mice and in disease models such as a mouse model with diabetes mellitus. Methods: We performed sodium and proton nuclear magnetic resonance imaging using a 9.4-T vertical standard-bore super-conducting magnet. Results: A condition of deep anesthesia, with widened breath intervals, or furosemide administration in 6-week-old C57BL/6JJcl mice showed a decrease in both tissue sodium concentrations in the medulla and sodium concentration gradients from the cortex to the medulla. Further, sodium magnetic resonance imaging revealed reductions in the sodium concentration of the medulla and in the gradient from the cortex to the medulla in BKS.Cg-Leprdb+/+ Leprdb/Jcl mice at very early type-2 diabetes mellitus stages compared to corresponding control BKS.Cg-m+/m+/Jcl mice. Conclusions: The kidneys of BKS.Cg-Leprdb+/+ Leprdb/Jcl mice aged 6 weeks showed impairments in the countercurrent multiplication system. We propose the utility of 23Na MRI for evaluating functional changes in diabetic kidney disease, not as markers that reflect structural damage. Thus, 23Na MRI may be a potential very early marker for structures beyond the glomerulus; this may prompt intervention with novel efficacious tubule-targeting therapies.

DOI： 10.34067/KID.0000000000000072

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BACKGROUND: The post-dialysis plasma level of human atrial natriuretic peptide (hANP) reflects the fluid volume in patients on hemodialysis. The threshold hANP level is reportedly 100 pg/mL; however, the clinical usefulness of the threshold hANP level for volume control has not been sufficiently studied. METHODS: We conducted a single-center, retrospective, observational study that included 156 hemodialysis patients without atrial fibrillation. First, we examined the usefulness of the threshold hANP level (100 pg/mL) for predicting hypoxemia due to congestion in a short-term observational study from December 30, 2015 to January 5, 2016. Subsequently, we conducted a 5-year follow-up study wherein the outcomes were hospitalization due to acute heart failure (AHF), development of cardiovascular diseases (CVD), and all-cause death. Finally, we collected echocardiography data to investigate the relationship between cardiac function and hANP. RESULTS: Our short-term observational study showed that patients with an hANP level ≥ 100 pg/mL developed hypoxemia due to congestion (odds ratio, 3.52; 95% confidence interval, 1.06-11.71; P = 0.040). At the 5-year follow-up, patients with an hANP level ≥ 100 pg/mL had significantly higher rates of hospitalization due to AHF, CVD, and all-cause death based on the log-rank test (P = 0.003, P = 0.019, P < 0.001, respectively). Cardiac disfunctions were significantly associated with the high hANP level. CONCLUSIONS: The hANP level is indicative of both fluid volume and cardiac dysfunction. A threshold hANP level of 100 pg/mL can serve as a predictive marker for AHF and a practical indicator for volume control.

DOI： 10.1007/s10157-023-02333-1

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

<sec><title>Objectives</title> Anti-ribosomal P protein autoantibodies (anti-P) specifically develop in patients with systemic lupus erythematosus. Associations of anti-P with lupus nephritis (LN) histological subclass and renal outcome remain inconclusive. We sought to determine the association of anti-P and anti-double-stranded DNA antibody (anti-dsDNA) with renal histology and prognosis in LN patients.

</sec><sec><title>Methods</title> Thirty-four patients with LN, having undergone kidney biopsy, were included. The 2018 revised ISN/RPS classification system was used for pathophysiological evaluation. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate &lt; 60 mL/min/1.73 m² for &gt; 3 months.

</sec><sec><title>Results</title> Six patients (17.6%) were positive for anti-P and 26 (76.5%) for anti-dsDNA. Among the six patients with anti-P, one did not have anti-dsDNA, but did have anti-Sm antibody, and showed a histological subtype of class V. This patient maintained good renal function for over 14 years. The remaining five patients, who had both anti-P and anti-dsDNA, exhibited proliferative nephritis and were associated with prolonged hypocomplementemia, and the incidence of CKD did not differ from patients without anti-P.

</sec><sec><title>Conclusion</title> Although this study included a small number of patients, the results indicated that histology class and renal prognosis associated with anti-P depend on the coexistence of anti-dsDNA. Further studies with a large number of patients are required to confirm this conclusion.

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DOI： 10.1177/0961203320983906

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/0961203320983906

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DOI： 10.1093/ndt/gfaa319

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

<title>Abstract</title>
<sec>
<title>Background</title>
Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by mesangial polymeric IgA1 deposition. IgAN is believed to develop owing to aberrant mucosal immunoreaction against commensals in the tonsils. However, the exact interrelation between pathogenic IgA and mucosal microbiota in IgAN patients is unclear.


</sec>
<sec>
<title>Methods</title>
Biopsy-proven IgAN or recurrent tonsillitis (RT) patients who had undergone tonsillectomy were enrolled. We used 16S ribosomal RNA gene amplicon sequencing with a flow cytometry-based bacterial cell sorting technique) and immunoglobulin repertoire sequencing of the IgA heavy chain to characterize IgA-coated bacteria of the tonsillar microbiota (IgA-SEQ) and their corresponding IgA repertoire. Furthermore, we fractionated patient serum using gel-filtration chromatography and performed flow cytometry-based analysis of IgA binding to bacteria cultured from incised tonsils.


</sec>
<sec>
<title>Results</title>
Tonsillar proliferation-inducing ligand and B-cell activating factor levels were significantly higher in IgAN than in RT patients. IgA-SEQ for tonsillar microbiota revealed the preferential binding ability of IgA to Bacteroidetes in IgAN tonsils compared with those from RT patients. Expression of immunoglobulin heavy (IGH) constant alpha 1 with IGH variable 3–30 was significantly higher in IgAN than that in RT, and positively correlated with the IgA-coated enrichment score of Bacteroidetes. Serum polymeric IgA, comprising high levels of GdIgA1, exhibited considerable binding to Bacteroidetes strains cultured from the tonsils of IgAN patients.


</sec>
<sec>
<title>Conclusions</title>
These findings provide evidence that aberrant mucosal immune responses to tonsillar anaerobic microbiota, primarily consisting of members of the phylum Bacteroidetes, are involved in IgAN pathophysiology.


</sec>

DOI： 10.1093/ndt/gfaa223

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Language：Japanese   Publisher：(有)科学評論社  

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Inorganic polyphosphate (polyP) is a linear polymer of orthophosphate units that are linked by phosphoanhydride bonds and is involved in various pathophysiological processes. However, the role of polyP in immune cell dysfunction is not well-understood. In this study, using several biochemical and cell biology approaches, including cytokine assays, immunofluorescence microscopy, receptor-binding assays with quartz crystal microbalance, and dynamic light scanning, we investigated the effect of polyP on in vitro lipopolysaccharide (LPS)-induced macrophage inflammatory response. PolyP up-regulated LPS-induced production of the inflammatory cytokines, such as tumor necrosis factor α, interleukin-1β, and interleukin-6, in macrophages, and the effect was polyP dose- and chain length-dependent. However, orthophosphate did not exhibit this effect. PolyP enhanced the LPS-induced intracellular macrophage inflammatory signals. Affinity analysis revealed that polyP interacts with LPS, inducing formation of small micelles, and the polyP-LPS complex enhanced the binding affinity of LPS to Toll-like receptor 4 (TLR4) on macrophages. These results suggest that inorganic polyP plays a critical role in promoting inflammatory response by enhancing the interaction between LPS and TLR4 in macrophages.

DOI： 10.1074/jbc.RA119.011763

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Publishing type：Research paper (scientific journal)  

A 60-year-old male presented with accelerated hypertension, renal insufficiency, proteinuria, and hematuria. Percutaneous kidney biopsy revealed membranoproliferative glomerulonephritis (MPGN) without any immunoglobulin and complement deposition. On performing electron microscopy, deposits with a tubular, organized structure and approximately 60 nm in diameter were detected in the glomerular subendothelial spaces and mesangial areas. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) demonstrated the significantly increased deposition of fibrinogen and fibronectin in glomeruli. Immunohistochemistry and immunoelectron microscopy demonstrated that the deposits were composed of fibrinogen. Here we report a case of cryofibrinogen -associated GN in which LC-MS/MS and immunoelectron microscopy were useful for diagnosis. When MPGN with organized deposits without the deposition of immunoglobulins and complements is diagnosed, we considered the cryofibrinogen-associated GN in one of the differential diagnosis, and even skin symptoms cannot be detected.

DOI： 10.1016/j.ehpc.2018.12.002

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Language：English   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：新潟県医師会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

In chronic kidney disease (CKD) patients, accumulation of uremic toxins is associated with cardiovascular risk and mortality. One of the hallmarks of kidney disease-related cardiovascular disease is intravascular macrophage inflammation, but the mechanism of the reaction with these toxins is not completely understood. Macrophages differentiated from THP-1 cells were exposed to indoxyl sulfate (IS), a representative uremic toxin, and changes in inflammatory cytokine production and intracellular signaling molecules including interleukin (IL)-1, aryl hydrocarbon receptor (AhR), nuclear factor (NF)-κ, and mitogen-activated protein kinase (MAPK) cascades as well as the NLRP3 inflammasome were quantified by real-time PCR, Western blot analysis, and enzyme-linked immunosorbent assay. IS induced macrophage pro-IL-1β mRNA expression, although mature IL-1 was only slightly increased. IS increased AhR and the AhR-related mRNA expression
this change was suppressed by administration of proteasome inhibitor. IS promoted phosphorylation of NF-κB p65 and MAPK enzymes
the reaction and IL-1 expression were inhibited by BAY11-7082, an inhibitor of NF-κB. In contrast, IS decreased NLRP3 and did not change ASC, pro-caspase 1, or caspase-1 activation. IS-inducing inflammation in macrophages results from accelerating AhR-NF-κB/MAPK cascades, but the NLRP3 inflammasome was not activated. These reactions may restrict mature IL-1β production, which may explain sustained chronic inflammation in CKD patients.

DOI： 10.3390/toxins10030124

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/aor.12961

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Language：Japanese   Publisher：(公社)日本透析医会  

背景・目的:蛋白結合尿毒症物質(protein-bound uremic toxins;PBUTs)の血中濃度高値は種々の透析関連合併症の原因となる。我々はヘキサデキル基固定セルロースビーズ(hexadecyl-immobilized cellulose bead;HICB)のPBUTsの吸着効果について臨床的に検討した。方法:HICBを含有したカラム(リクセルS-35)を維持血液透析患者に使用した。カラム通過前後と2週間使用前後の血清インドキシル硫酸(indoxyl sulfate;IS)、インドール酢酸(indole acetic acid;IAA)、フェニル硫酸(phenyl sulfate;PhS)、そしてpクレシル硫酸(p-cresyl sulfate;PCS)濃度を質量分析により測定した。結果:リクセルS-35通過後に蛋白結合していない血中フリーIS、IAA、PhSとPCS濃度は34.4±30.0%、34.8±25.4%、28.4±18.0%と34.9±22.1%減少した。しかし、蛋白結合したPBUTsはカラム通過後に有意に減少しなかった。リクセルを2週間使用したが、血中PBUT値は有意に低下しなかった。結論:HICBsはPBUTsを部分的に吸着した。この吸着効果は臨床的に十分でなく、今後PBUTs吸着効果のより優れた血液浄化器の開発が望まれる。(著者抄録)

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Language：English   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(公社)日本透析医会  

腎コロボーマ症候群(RCS)におけるPAX2遺伝子異常が、胎生期のヒト後腎ネフロン前駆細胞への分化に及ぼす影響を調べるため、RCS患者末梢血Tリンパ球から人工多能性幹細胞(induced pluripotent stem cell、iPS細胞)を樹立し、後腎ネフロン前駆細胞への分化の過程で発現する遺伝子群を健常者と比較した。iPS細胞からの分化開始11日目、14日目でみられる発現遺伝子には差がみられず、ヘテロのPAX2変異では後腎ネフロン前駆細胞への分化は影響を受けないと考えられた。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

IgA nephropathy (IgAN) is a chronic glomerular disease that causes end-stage renal disease in 20-40 % of patients within 20 years. The efficacy of tonsillectomy combined with steroid pulse (SP) administration (TSP) for clinical remission of IgAN has been reported. Particularly in Japan, TSP has been performed widely. However, the optimum method for steroid administration in TSP has not been established.
We retrospectively compared clinical remission in IgAN patients treated with tonsillectomy combined with two different steroid administration methods: (1) three courses of SP therapy and oral prednisolone administered on alternate days (group 3A; n = 25); and (2) one course of SP therapy and oral prednisolone administered on consecutive days (group 1C; n = 22).
There was no significant difference in the clinical remission rates between the two groups at 12 (48.0 vs. 40.9 %, P = 0.77) and 24 months after starting treatment (68.0 vs. 72.7 %, P = 0.76) and at the final observation (76.0 vs. 81.8 %, P = 0.73). The mean period from starting treatment to remission of hematuria in group 3A was significantly shorter than that in group 1C (5.7 +/- 4.4 vs. 9.9 +/- 5.9 months, P = 0.03). Dyslipidemic patients treated for the first time with statin after the SP therapy were more present in group 3A at 24 months (P = 0.02).
In IgAN patients, treatment of group 3A may be effective for inducing rapid remission of hematuria. Further studies are needed to establish an appropriate protocol for TSP.

DOI： 10.1007/s10157-016-1282-8

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

A 36-year-old woman who was undergoing dialysis for end-stage kidney disease (ESKD) was admitted to our hospital with consciousness disorder. She was diagnosed with Budd-Chiari syndrome due to antiphospholipid syndrome at the age of 28 years. Her kidney function and leg edema gradually deteriorated. After initiation of hemodialysis (HD), transient loss of consciousness due to hepatic encephalopathy during HD treatment occurred frequently. Her kidney replacement therapy was changed to online hemodiafiltration (HDF), which dramatically improved her hepatic coma. Compared with HD, HDF contributed to the increase in Fischer's ratio and decrease in tryptophan level, which has a high protein-bound property. This case suggests that HDF may be beneficial for hepatic encephalopathy in ESKD patients by modulating the amino acid profile.

DOI： 10.1007/s13730-015-0209-7

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Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：English   Publishing type：Part of collection (book)   Publisher：Springer Japan  

There have been several lines of evidences for familial aggregation of IgA nephropathy (IgAN), as well as mesangial deposition of IgA, suggesting that the susceptibility to this disease is genetically controlled. In our institute, family histories of hematuria, end-stage kidney disease, and glomerulonephritis are observed in about 10 % of cases with IgAN, even in those without any significant hereditary nephritis or kidney diseases. Recent large-scale genome-wide association studies (GWAS) of sporadic IgAN have identified multiple susceptibility loci, providing an insight into the genetic architecture of this disease, although each of their individual impact to the development of the disease is still not enough. It has been recognized that most of these loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. Further elucidation of the role of genetic variants underlying IgAN, and hologenetic views of gene variants and environmental factors, would be necessary to understand the precise pathogenic mechanism of IgAN in more detail.

DOI： 10.1007/978-4-431-55588-9_3

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Language：Japanese   Publisher：(一社)日本内科学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J01159&link_issn=&doc_id=20150918170030&doc_link_id=10.2169%2Fnaika.104.1930&url=https%3A%2F%2Fdoi.org%2F10.2169%2Fnaika.104.1930&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

One of the possible causes of enhanced atherosclerosis in patients with chronic kidney disease (CKD) is the accumulation of uremic toxins. Since macrophage foam cell formation is a hallmark of atherosclerosis, we examined the direct effect of indoxyl sulfate (IS), a representative uremic toxin, on macrophage function. Macrophages differentiated from THP-1 cells were exposed to IS in vitro. IS decreased the cell viability of THP-1 derived macrophages but promoted the production of inflammatory cytokines (IL-1 beta, IS 1.0 mM: 101.8 +/- 21.8 pg/mL vs. 0 mM: 7.0 +/- 0.3 pg/mL, TNF-alpha, IS 1.0 mM: 96.6 +/- 11.0 pg/mL vs. 0 mM: 15.1 +/- 3.1 pg/mL) and reactive oxygen species. IS reduced macrophage cholesterol efflux (IS 0.5 mM: 30.3% +/- 7.3% vs. 0 mM: 43.5% +/- 1.6%) and decreased ATP-binding cassette transporter G1 expression. However, lipid uptake into cells was not enhanced. A liver X receptor (LXR) agonist, T0901317, improved IS-induced production of inflammatory cytokines as well as reduced cholesterol efflux. In conclusion, IS induced inflammatory reactions and reduced cholesterol efflux in macrophages. Both effects of IS were improved with activation of LXR. Direct interactions of uremic toxins with macrophages may be a major cause of atherosclerosis acceleration in patients with CKD.

DOI： 10.3390/toxins7083155

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

A 31-year-old woman with proteinuria, hypocomplementemia, rheumatoid factor, and high serum polyclonal IgM concentration was admitted to our hospital for renal biopsy. She had a past history of two renal biopsies. When she was 12 years old, she developed proteinuria, microscopic hematuria, and hypocomplementemia. She was diagnosed as having 'IgM nephropathy' based on minor glomerular abnormalities as determined by light microscopy and IgM and C3 deposition in the mesangial region by immunofluorescence microscopy at the first biopsy. Despite corticosteroid treatment, her proteinuria did not improve and she discontinued regular outpatient checkups. When she was 29 years old and pregnant, she developed preeclampsia and, after delivery, a second renal biopsy was implemented. She was diagnosed as having progressed 'IgM nephropathy' with endotheliosis induced by preeclampsia. She was treated with angiotensin II receptor blocker and her proteinuria diminished; however, 1 year after the delivery, she developed proteinuria again, along with microscopic hematuria and hypocomplementemia. A third renal biopsy was conducted at 31 years of age and she was diagnosed as having membranoproliferative glomerulonephritis (MPGN) type I on the basis of diffuse mesangial proliferation, endocapillary hypercellularity with double contour of the capillary wall, and lobular formation in glomeruli, as determined by light microscopy. Immunofluorescence staining demonstrated deposits of C3, C4, C1q, and IgM in the mesangial region and capillary wall. She underwent corticosteroid therapy followed by normalization of urinalysis and serum complement level. Although she had initially been diagnosed with 'IgM nephropathy', she was finally diagnosed with secondary MPGN and was successfully treated by corticosteroid therapy.

DOI： 10.1007/s13730-012-0042-1

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Authorship：Lead author,　Corresponding author  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Gastric antral vascular ectasia (GAVE) is currently recognized as an important cause of gastrointestinal bleeding. Chronic kidney disease (CKD) is associated with a high incidence of GAVE. We report 3 patients with CKD who presented with severe anemia and were diagnosed with GAVE; they were resistant to endoscopic argon plasma coagulation. However, remission of anemia and improvement in GAVE lesions were observed after the initiation of hemodialysis. The pathogenesis of GAVE remains largely unknown, but mechanical stress of the antrum could play an important role. This stress may be reduced by hemodialysis through improvement of uremia-associated gastrointestinal symptoms. Therefore, the initiation of hemodialysis might be effective for intractable GAVE in CKD patients.

DOI： 10.1159/000332832

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Language：Japanese   Publisher：新潟医学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J00990&link_issn=&doc_id=20110815110022&doc_link_id=%2Fdg3nigta%2F2011%2F012505%2F022%2F0286-0286%26dl%3D2&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2011%2F012505%2F022%2F0286-0286%26dl%3D2&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_5.gif

Language：Japanese   Publisher：(株)東京医学社  

55歳男。慢性腎不全が進行して51歳時に腹膜透析導入され、以後CAPDを継続していた。今回、便潜血陽性を指摘され、大腸内視鏡検査にて上行結腸肝彎曲よりに0-I sp型の腫瘍性病変を認め、生検で大腸癌、深達度smと診断された。入院時の諸検査より上行結腸癌[A]cSMcN0cH0cM0 cStage Iと術前診断し、腹腔鏡下右半結腸切除術D3郭清を施行した。腫瘍は漿膜面に引きつれを認め、術後診断はMPsN0sH0sP0sM0 sStage Iであった。なお、手術に際しては第3病日より血液透析を週3回併用し、CAPDは手術日早朝に排液した。術後は2日目よりHD週3回を継続し、約2週間でCAPD再開して15日目に退院となった。術後85日目に腹膜機能検査を行ったが、術前と比べ明らかな低下は認めなかった。

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Authorship：Lead author,　Corresponding author  

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Language：Japanese   Publisher：(株)日本医学館  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publisher：AMER SOC NEPHROLOGY  

DOI： 10.2215/CJN.05871108

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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We present here a male patient who had developed nephrotic syndrome 11 yr after kidney transplantation. Nephrotic syndrome suddenly occurred after severe sunburn he got in Hawaii. Such a clinical course seemed very rare in kidney transplantation, and multifactorial etiology was suspected. The histological findings of graft biopsy were intricate. On light microscopy, there were mesangial expansion and endocapillary proliferation with duplication of GBM and crescent formation. Deposits of IgM in mesangium were the most prominent finding on immunofluorescence microscopy, but IgA and C3 deposits were also detected. Electron microscopy revealed paramesangial and a few subepithelial dense deposits. Additionally, small organized deposits were found in the subepithelial space. Based on these findings, a provisional diagnosis of IgA nephropathy superimposed on chronic transplant glomerulopathy was made. However, hepatitis C virus related nephropathy could not be excluded. © 2007 Blackwell Munksgaard.

DOI： 10.1111/j.1399-0012.2007.00715.x

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Language：Japanese   Publisher：(公財)日本腎臓財団  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/sj.ki.5001941

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING INC  

Background. The immunoregulatory activity of ligands for peroxisome proliferator-activated receptors (PPARs) has been recently paid attention. The regulatory effect of bezafibrate (BZF), a ligand for PPAR alpha on glomerulonephritis was investigated using a rat anti-glomerular basement membrane (GBM) glomerulonephritis model.
Methods. The effect on development of anti-GBM glomerulonephritis was examined by treatment with BZF from day -7 to day 7 after intravenous injection of rabbit anti-GBM serum into Wistar Kyoto (WKY) rats. The therapeutic efficacy after onset of the glomerulonephritis was also checked by treatment with BZF from day 3 to 7. On day 7, the condition was evaluated histologically. The expression of a tissue injury molecule, macrophage metalloesterase (MME), was measured by Northern blot analysis. The suppressive effect on immune cells was assessed by proliferation assay with mitogen-stimulated rat spleen cells.
Results. Histopathologic changes induced by anti-GBM in rats treated with BZF (day -7 to day 7) were markedly suppressed in a dose-dependent fashion. Infiltration of ED-1+ macrophages in glomeruli, proteinuria, and mRNA expression of MME in kidneys were diminished in parallel with histologic improvement. Moreover, the disease activity was also attenuated even by the treatment after onset of the glomerulonephritis (day 3 to 7). The mitogen-induced proliferation of spleen cells was down-regulated at concentrations of BZF, which were equivalent to those in sera of BZF-treated rats.
Conclusion. BZF markedly suppresses the activity of rat anti-GBM crescentic glomerulonephritis. Fibrates might serve as a therapeutic option for crescentic glomerulonephritis.

DOI： 10.1111/j.1523-1755.2005.00280.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING INC  

Background. Osteopontin (OPN) is a potent chemoattractant for mononuclear cells that is up-regulated in various inflammatory states of the kidney. The role of OPN and its expression in human renal allograft rejection are unknown.
Methods. We examined by immunohistochemistry and in situ hybridization, renal biopsies from patients with acute rejection (N = 22), protocol biopsies without rejection (N = 9), and perioperative donor biopsies (N = 35) for intrarenal expression of OPN, and its correlation with clinical, laboratory, and histopathologic parameters. In the rejection biopsies, interstitial monocyte/macrophage infiltration, tubulointerstitial cell proliferation/regeneration and apoptosis were investigated.
Results. In the majority of rejection biopsies, OPN expression by proximal tubular epithelium was widespread, and tended to be enhanced in the tubules surrounded by numerous inflammatory cells. Conversely, in patients that did not experience episodes of rejection and in donor biopsies, OPN expression by proximal tubules was nil or weak. OPN mRNA was colocalized with its translated protein in the renal tubular epithelium. OPN expression positively correlated with the degree of interstitial inflammation (P &lt; 0.05), CD68+ monocyte infiltration (P &lt; 0.01), Ki-67+ regenerating tubular and interstitial cells (P &lt; 0.05 and P &lt; 0.005, respectively), but not with terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL)-positive apoptotic tubular cells.
Conclusion. These data suggest that inducible expression of OPN in the tubular epithelium may have a pathogenic role in acute renal allograft rejection by mediating interstitial monocyte infiltration and possibly tubular regeneration.

DOI： 10.1111/j.1523-1755.2005.00153.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Transforming growth factor (TGF)-beta1, a multifunctional cytokine, which regulates proliferation and differentiation of a variety of cell types, has the central role in the development and progression of renal injury in both animal models and human. Although it has been suggested that genetic variations in the TGF-beta1 gene are associated with the activity of the gene product, their clinical significance in glomerular disease is unknown. We investigated whether the polymorphisms of C-509T and T869C in TGF-beta1 account for interindividual variation in manifestations of IgA nephropathy (IgAN) using 626 Japanese subjects including 329 patients with histologically proven IgAN and 297 healthy controls with normal urinalysis. The frequencies of genotypes, alleles, and major haplotypes were similar between the patients and controls. The C-509T and T869C polymorphisms were in tight linkage disequilibrium, and the major haplotypes were C-C and T-T, which accounted for more than 95% of the total. In patients with -509CC and in those with the 869CC, urinary protein excretion was higher than in those with other genotypes, whereas no difference in other clinical manifestations was noted. Moreover, patients with -509CC and those with 869CC genotypes presented with a significant higher score of mesangial cell proliferation than in those with other genotypes. These results suggest that TGF-beta1 gene polymorphisms are specifically associated with heavy proteinuria and mesangial cell proliferation in Japanese patients with IgAN, although they do not confer susceptibility to this disease.

DOI： 10.1111/j.1399-0039.2004.00256.x

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腎糸球体メサンギウム領域への免疫グロブリンA(IgA)沈着を伴う増殖性腎炎を特徴とするIgA腎症は,最も頻度の高い原発性糸球体腎炎であり,慢性腎不全の主要な原疾患でもある.本症におけるIgA沈着機序と腎機能低下速度の個人差の機序は不明であるが,遺伝的な背景が,本症の発症と進行の両者に関与する可能性が,近年指摘されてきた.この遺伝的背景を明らかにできれば,IgA腎症の病態と進行機序をより詳細に理解することが可能となる.最近の著者らによる臨床分子遺伝学的な研究を紹介した

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2004&ichushi_jid=J00990&link_issn=&doc_id=20040519030001&doc_link_id=%2Fdg3nigta%2F2004%2F011803%2F001%2F0149-0153%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2004%2F011803%2F001%2F0149-0153%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Sarcoidosis is a systemic disorder associated with granuloma characterized by an abnormal T(h)1-type cytokine production and accumulation of T(h)1 CD4 T cells in the granuloma lesions, suggesting an importance of T(h)1 responses in sarcoidosis. However, the pathogenesis of sarcoidosis remains to be solved. Here, we investigated the nature of V(alpha)24 NKT cells with immunoregulatory functions in sarcoidosis. Patients with non-remitting sarcoidosis displayed a decrease in the number of V(alpha)24 NKT cells in peripheral blood, but an accumulation of these cells in granulomatous lesions. When stimulated with the specific glycolipid ligand, alpha-galactosylceramide, peripheral blood V(alpha)24 NKT cells from patients with non-remitting disease produced significantly less IFN-gamma than those from healthy volunteers, but normal levels of IL-4. The reduced IFN-gamma production was observed only in V(alpha)24 NKT cells and not conventional CD4 T cells, but was normal in patients with remitting disease, suggesting that non-remitting sarcoidosis involves an insufficient IFN-gamma production of V(alpha)24 NKT cells which is well correlated with disease activity. Thus, these results suggest that V(alpha)24 NKT cells play a crucial role in the disease status of sarcoidosis.

DOI： 10.1093/intimm/dxh020

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

The proximal promoter of Ick directs gene expression exclusively in T cells. To investigate the developmental regulation of the Ick proximal promoter activity and its relationship to T cell lineage commitment, a green fluorescence protein (GFP) transgenic (Tg) mouse in which the GFP expression is under the control of the proximal promoter of Ick was created. In the adult GFP-Tg mice, &gt;90% of CD4(+)CD8(+) and CD4(+)CD8(-) thymocytes, and the majority of CD4(+)CD8(-) and CD4(-)CD8(-) [double-negative (DN)] thymocytes were highly positive for GFP, Slightly lower but substantial levels of expression of GFP was also observed in mature splenic T cells. No GFP(+) cells was detected in non-T lineage subsets, including mature and immature a cells, CD5(+) a cells, and NK cells, indicating a preserved tissue specificity of the promoter. The earliest GFP(+) cells detected were found in the CD44(+)CD25(-) DN thymocyte subpopulation, The developmental potential of GFP(-) and GFP(+) cells in the CD44(+)CD25(-) DN fraction was examined using in vitro culture systems. The generation of substantial numbers of ap and gamma delta T cells as well as NK cells was demonstrated from both GFP(-) and GFP(+) cells. However, no development of B cells or dendritic cells was detected from GFP(+) CD44(+)CD25(-) DN thymocytes. These results suggest that the progenitors expressing Ick proximal promoter activity in the CD44(+)CD25(-) DN thymocyte subset have lost most of the progenitor potential for the a and dendritic cell lineage, Thus, progression of T cell lineage restriction in the earliest thymic population can be visualized by Ick proximal promoter activity, suggesting a potential role of Lck in the T cell lineage commitment.

DOI： 10.1093/intimm/13.1.105

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DOI： 10.1159/000053663

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

J-GLOBAL

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Language：Japanese   Publisher：新潟医学会  

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Other Link： http://search.jamas.or.jp/link/ui/2016151274

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：Japanese   Publisher：(株)日本メディカルセンター  

DOI： 10.19020/J01864.2014064176

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：English   Publisher：NATURE PUBLISHING GROUP  

Incompleteness of O-glycosylation in the IgA1 hinge has been implicated as a central mechanism in the development of IgA nephropathy. Although underglycosylation was reported to be an acquired abnormality, genes for enzymes of O-glycosylation, such as C1GALT1, may be responsible for susceptibility to IgA nephropathy.

DOI： 10.1038/sj.ki.5002139

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：医歯薬出版  

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Other Link： http://search.jamas.or.jp/link/ui/2001168361

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Applicant：ザ ロックフェラー ユニバーシティー

Application no：特願2009-534723  Date applied：2007.7

Announcement no：特表2010-512306  Date announced：2010.4

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Applicant：ザ ロックフェラー ユニバーシティー

Application no：特願2009-504279  Date applied：2007.4

Patent/Registration no：特許第6084761号  Date issued：2017.2

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Applicant：ザ ロックフェラー ユニバーシティ

Application no：特願2009-504279  Date applied：2007.4

Announcement no：特表2009-532477  Date announced：2009.9

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