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

The complement activation system plays important roles to maintain homeostasis in the host and to fight foreign invaders to protect the host. Therefore, the complement system is considered a core part of innate immunity which also cross-talks to acquired immunity. In the history of nephrology, the complement system is familiar to us, because complement protein or fragment deposition, including C3, C4, C1q, and/or C4d, is routinely estimated by immunohistochemistry to diagnose renal pathologies. The relationships between pathological mechanisms and complement activation have been investigated for renal diseases such as post-infectious glomerulonephritis, lupus nephritis, and primary membranoproliferative glomerulonephritis, which are usually accompanied by hypocomplementemia. However, unregulated complement activation in local areas might be associated with progression of various renal injuries even in the normocomplementemic patient. Recently, attention has focused on dysfunction of complement regulation in various diseases including renal diseases such as atypical hemolytic uremic syndrome and C3 glomerulopathy. Some mechanisms associated with complement activation in these diseases were clarified. In addition, lots of anti-complement agents were developed and some of the agents have become clinically available. Now, anti-complement therapies represent a realistic choice of therapeutic approaches for complement-related diseases. Research on roles of complement activation is proceeding into new stages in the field of nephrology and in other fields involving both basic and clinical research. We herein summarize relationships between the complement activation and regulation systems, their physiological effects and roles in maintenance of homeostasis in the host, and how dysregulation of the complement system triggers disease, especially renal disease.

DOI： 10.1007/s10157-017-1405-x

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Background Malaria is an important tropical disease and has remained a serious health problem in many countries. One of the critical complications of malarial infection is renal injury, such as acute renal failure and chronic glomerulopathy. Few animal models of nephropathy related to malarial infection have been reported. Therefore, we developed and investigated a novel malarial nephropathy model in mice infected by murine malaria parasites.
Methods NC mice and C57BL/6J mice were infected with Ttwo different murine malaria parasites, Plasmodium (P.) chabaudi AS and P. yoelii 17X. After the infection, renal pathology and blood and urinary biochemistry were analyzed.
Results NC mice infected by the murine malaria parasite P. chabaudi AS, but not P. yoelii 17X, developed mesangial proliferative glomerulonephritis with endothelial damage, and decreased serum albumin concentration and increased proteinuria. These pathological changes were accompanied by deposition of immunoglobulin G and complement component 3, mainly in the mesangium until day 4 and in the mesangium and glomerular capillaries from day 8. On day 21, renal pathology developed to focal segmental sclerosis according to light microscopy. In C57BL/6J mice, renal injuries were not observed from either parasite infection.
Conclusion The clinical and pathological features of P. chabaudi AS infection in NC mice might be similar to quartan malarial nephropathy resulting from human malaria parasite P. malariae infection. The NC mouse model might therefore be useful in analyzing the underlying mechanisms and developing therapeutic approaches to malaria-related nephropathy.

DOI： 10.1007/s10157-016-1339-8

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

Background
We searched for indicators to predict the prognosis of infectious peritonitis by measuring levels of complement proteins and activation products in peritoneal dialysis (PD) fluid (PDF) of patients at early stages of peritonitis. We retrospectively analyzed the relationship between the levels of sC5b-9, C3 and C4 in PDF and the subsequent clinical prognosis.
Methods
We measured levels of sC5b-9, C3 and C4 in PDF on days 1, 2 and 5 post-onset of peritonitis in 104 episodes of infectious peritonitis in PD patients from 2008 and retrospectively compared levels with clinical outcomes. Further analysis for the presence of causative microorganisms or to demonstrate bacterial culture negative peritonitis was performed and correlated with change of levels of sC5b-9 in PDF.
Results
When PD patients with peritonitis were divided into groups that either failed to recover from peritonitis and were finally withdrawn from PD (group 1; n = 25) or recovered (group 2; n = 79), levels of sC5b-9, C3 and C4 in PDF were significantly higher in group 1 patients compared to those in group 2 on day5. Analysis of microorganisms showed significantly higher sC5b-9 levels in PDF of peritonitis cases caused by culture negative peritonitis in group 1 compared with group 2 when we analyzed for individual microorganisms. Of note, on day5, the sC5b- 9 levels in PDF were similarly high in peritonitis caused by fungi or other organisms.
Conclusion
Our results suggested that levels of complement markers in PDF, especially sC5b- 9, have potential as surrogate markers to predict prognosis of PD-related peritonitis.

DOI： 10.1371/journal.pone.0169111

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

Early withdrawal within 3 years after starting peritoneal dialysis (PD) and PD-related peritonitis have been major obstacles preventing increases in the population of PD patients. To address these problems, we implemented education programs for medical staff. This study analyzed the recent status and outcomes of PD therapy, focusing on findings such as the incidence and prognosis of peritonitis as of 5 years after our last study.
We investigated background, laboratory data and status of PD therapy, reasons for withdrawal from PD and incidental statements on peritonitis from 2010 to 2012 (R2), and compared findings with those from our last study of 2005-2007 (R1).
Early PD therapy withdrawal in R2 clearly improved to 44.7 %, compared with 50.9 % in R1. Peritonitis incidence improved slightly from once per 42.8 months/patient in R1 to once per 47.3 months/patient in R2. Notably, PD-related peritonitis as a cause of mortality improved markedly in R2, but outcomes of PD-related peritonitis did not change significantly between R1 and R2. In contrast, social problems increased as a reason for withdrawal from PD therapy.
Our efforts at education might have been useful for improving early withdrawal from PD and deaths attributable to PD-related peritonitis. However, since improvements to incidence of PD-related peritonitis were limited by education, further improvement in PD-related peritonitis incidence requires development of new sterilized connecting systems during PD-bag exchanges to decrease PD-related peritonitis opportunities. Construction of medical support systems to address social problems is required to maintain long-term PD therapy.

DOI： 10.1007/s10157-016-1249-9

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We investigated the expression of membrane complement regulators (CRegs), CD46, CD55 and CD59 in human mesothelial cells, and correlated with clinical background and level of complement (C) activation products in peritoneal dialysis (PD) fluids (PDF) to clarify influence of the C activation system in PD patients. Expression of CRegs was assessed on primary cultures of mesothelial cells (HPMC) harvested from PD fluid of 31 PD patients. Because expression of CD55 but not CD46 and CD59 in mesothelial cells was significantly correlated to value of dialysate-to-plasma creatinine concentration ratio (D/P Cre) (p<0.005) as an indicator of peritoneal function, we focused on analysis of CD55 expression of HPMCs in comparison with levels of C activation products in the PDF of the PD patients, and their background factors. When comparing expression of the CRegs between systemic neutrophils and HPMC, no correlation was observed, supporting that change of CRegs' expression in HPMC was independently occurring in the peritoneum. Expression of CD55 protein in HPMC was closely correlated with expression at the mRNA level (p<0.0001) and was inversely correlated with levels of sC5b-9 (p<0.05), but not C3, C4, IL6 and CA125 in the PDF. Complications of diabetes, usage of icodextrin and residual renal function were not correlated with change of CD55 expression in HPMCs.
Our data show that the process of PD therapy modifies expression of CD55 on peritoneal mesothelium and triggers local C activation. These findings support efforts to modify PD therapy to limit effects on activation and regulation of the C system. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.molimm.2015.02.005

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DOI： 10.1681/ASN.2013030273

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

In the natural world, there are many creatures with venoms that have interesting and varied activities. Although the sea anemone, a member of the phylum Coelenterata, has venom that it uses to capture and immobilise small fishes and shrimp and for protection from predators, most sea anemones are harmless to man. However, a few species are highly toxic; some have venoms containing neurotoxins, recently suggested as potential immune-modulators for therapeutic application in immune diseases. Phyllodiscus semoni is a highly toxic sea anemone; the venom has multiple effects, including lethality, hemolysis and renal injuries. We previously reported that venom extracted from Phyllodiscus semoni induced acute glomerular endothelial injuries in rats resembling hemolytic uremic syndrome (HUS), accompanied with complement dysregulation in glomeruli and suggested that the model might be useful for analyses of pathology and development of therapeutic approaches in HUS. In this mini-review, we describe in detail the venom-induced acute renal injuries in rat and summarize how the venom of Phyllodiscus semoni could have potential as a tool for analyses of complement activation and therapeutic interventions in HUS.

DOI： 10.3390/md10071582

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

Mizuno M, Ito Y, Mizuno T, Harris CL, Suzuki Y, Okada N, Matsuo S, Morgan BP. Membrane complement regulators protect against fibrin exudation increases in a severe peritoneal inflammation model in rats. Am J Physiol Renal Physiol 302: F1245-F1251, 2012. First published February 15, 2012; doi:10.1152/ajprenal.00652.2011.-Peritonitis and the rare sequela of encapsulating peritoneal sclerosis (EPS) are serious problems in patients on peritoneal dialysis therapy. Chronic and persistent peritoneal injuries may be a risk factor of EPS. We previously reported that a chronic, proliferative peritonitis developed when zymosan was administered intraperitoneally following scraping injury of rat peritoneum (Mizuno M, Ito Y, Hepburn N, Mizuno T, Noda Y, Yuzawa Y, Harris CL, Morgan BP, Matsuo S. J Immunol 183: 1403-1412, 2009). Peritoneal membrane complement regulators (CRegs), especially Crry and CD59, protected from injury by inhibiting local complement activation, suggesting that CRegs play important roles in maintaining homeostasis in rat peritoneum. Here, we investigated roles of complement in the development of EPS by neutralizing CReg function with monoclonal antibodies (MAbs). Proliferative peritonitis was induced by scraping the peritoneum, followed by daily intraperitoneal administration of zymosan. When either Crry or CD59 alone was neutralized by MAb, the tissue injuries were not significantly changed compared with rats without neutralizing MAb. When both Crry and CD59 were neutralized in this model, severe fibrin exudation was observed on the peritoneal surface on day 5, accompanied by inflammatory cell infiltration, resembling the early stages of development of EPS. Dense peritoneal deposition of C3 fragments and membrane attack complex were observed, along with the fibrin exudates. Intravenous administration of cobra venom factor, which profoundly activates complement, further enhanced these pathological changes. Our results show that complement activation in injured peritoneum drives peritoneal inflammation, and that enhancement of complement activation by inhibiting CReg and/or enhancing systemic activation contributes to the initiation of EPS; therefore, anti-complement agents might be of therapeutic value in humans for the treatment of EPS.

DOI： 10.1152/ajprenal.00652.2011

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Background In Japan, the population of patients on peritoneal dialysis (PD) is <4% of the total number of patients with end-stage renal disease. Few systemic analyses have examined why the number of PD patients has not increased in Japan. We organized a registry to analyze PD patients and retrospectively investigated 561 PD patients (about 5% of all Japanese PD patients) from 13 hospitals in the Tokai area for 3 years from 2005.
Methods We investigated background, physical status, laboratory data, status of PD therapy, and the occurrence of PD-related complications, and analyzed reasons for withdrawal from PD.
Results Nutrition did not change significantly during our observation. Urinary volume showed continued decreases after the introduction period. In contrast, PD fluid demand and ultrafiltration volume were significantly increased. For calcium metabolism, multiple phosphate binders were required after the second year of PD therapy. Early dropout within 3 years after starting PD therapy comprised 50.9% of total withdrawals, with PD-related peritonitis as the most common reason, mainly caused by Gram-positive organisms. Incidence of peritonitis was 42.8 months/patient. Culture-negative results were obtained for 32% of peritonitis cultures. Diabetes affects the prognosis of PD therapy, but not the incidence of peritonitis.
Conclusion We examined clinical status over 3 years in the Tokai area. The results suggest that the incidence of peritonitis needs to be decreased to prevent early withdrawal of PD patients. Education systems to decrease the incidence of peritonitis and techniques to decrease culture-negative results might be important for improving the prognosis of peritonitis.

DOI： 10.1007/s10157-011-0471-8

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

Fungal peritonitis is an important complication in peritoneal dialysis patients; either continuous or recurrent peritonitis may enhance peritoneal damage. Even when the peritoneal dialysis catheter is removed in patients with fungal peritonitis, peritoneal fibrosis can progress and evolve into encapsular peritoneal sclerosis. It is unclear why fungal infections are worse than bacterial in these respects. Zymosan is a cell wall component of yeast that strongly activates the complement system. In this study, we compared the effects of zymosan and bacterial LPS on peritoneal inflammation in a rat peritoneal injury model induced by mechanical scraping. Intraperitoneal administration of zymosan, but not LPS or vehicle, caused markedly enhanced peritonitis with massive infiltration of cells and deposition of complement activation products Cab and membrane attack complex on day 5. In rats administered zymosan and sacrificed on days 18 or 36, peritoneal inflammation persisted with accumulation of ED-1-positive cells, small deposits of Cab and membrane attack complex, exudation of fibrinogen, and capillary proliferation in subperitoneal tissues. When zymosan was administered daily for 5 days after peritoneal scrape, there was even greater peritoneal inflammation with peritoneal thickening, inflammatory cell accumulation, and complement deposition. Inhibition of systemic complement by pretreatment with cobra venom factor or local inhibition by i.p. administration of the recombinant complement regulator Crry-Ig reduced peritoneal inflammation in zymosan-treated rats. Our results show that yeast components augment inflammation in the injured peritoneum by causing complement activation within the peritoneal cavity. Local anticomplement therapy may therefore protect from peritoneal damage during fungal infection of the peritoneum. The Journal of Immunology, 2009, 183: 1403-14.12.

DOI： 10.4049/jimmunol.0804245

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

Envenomation by the sea anemone Phyllodiscus semoni causes fulminant dermatitis and, rarely, acute renal failure in humans. Here, we investigated whether the venom extracted from the nematocysts (PsTX-T) was nephrotoxic when administered intravenously in rats and whether PsTX-T induced activation of the complement system. Although small dose of PsTX-T induced acute tubular necrosis in rats resembling pathology seen in patients, kidneys displayed glomerular injury with glomerular endothelial damage, thrombus formation, mesangiolysis, and partial rupture of glomerular basement membrane, accompanied by severe tubular necrosis at 24 hours after administration of 0.03 mg of PsTX-T per animal, similar to the glomerular findings typical of severe hemolytic uremic syndrome. The early stage injury was accompanied by specific PsTX-T binding, massive complement C3b, and membrane attack complex deposition in glomeruli in the regions of injury and decreased glomerular expression of complement regulators. A pathogenic role for complement was confirmed by demonstrating that systemic complement inhibition reduced renal injury. The isolated nephrotoxic component, a 115-kd protein toxin (PsTX-115), was shown to cause identical renal pathology. The demonstration that PsTX-T and PsTX-115 were highly nephrotoxic acting via induction of complement activation suggests that inhibition of complement might be used to prevent acute renal damage following envenomation by P. semoni.

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Background: Taking into consideration the key role of the complement system in renal diseases, we investigated molecular and cellular properties of the human complement C3a receptor (C3aR) in vitro and in situ, looking at its expression in several human renal pathological states.
Methods: Several antibodies were generated and used for immunohistochemistry and Western blot analyses to address C3aR expression and its regulation in vitro on cell lines of myeloid cells and nonmyeloid cell lineages. Furthermore, C3aR distribution was investigated in control nephrectomized kidneys and 116 biopsy specimens from patients with renal diseases, including lupus nephritis (lupus-N).
Results: C3aR is a highly N-glycosylated protein with an apparent molecular mass of 65 to 95 kd expressed by myeloid and endothelial cells. C3aR is particularly upregulated in response to interferon gamma treatment, but was unaffected by the other inflammatory cytokines, such as tumor necrosis factor alpha and transforming growth factor beta. In normal human kidney, C3aR staining was not observed. However, glomerular C3aR staining was detected in 42.9% of lupus-N specimens in association with immunoglobulin G immune-complex depositions. Staining intensity correlated with disease severity. C3aR was found in the endothelial area of 81.3% of samples classified as World Health Organization class IV with active lesions. Conversely, C3aR was not detected by means of immunohistochemistry in kidneys from patients with other renal diseases.
Conclusion: Our data indicate that C3aR expression is tightly regulated and altered in certain disease conditions. C3aR may be used as a unique biomarker of diagnosis and disease activity in patients with lupus-N.

DOI： 10.1053/j.ajkd.2007.02.271

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

1CD46, a membrane complement regulator, has been implicated as pathogen receptor, T cell activator and contributor to spermatozoa-egg interactions. In man, a role in the fertilization process was suggested by its localization on the acrosome. In rodents, CD46 is expressed only on the spermatozoal acrosome, suggesting an essential role at this site. This restricted expression led us to ask whether immunization with CD46 would generate anti-CD46 antibody responses that might target spermatozoa and influence fertility. We immunized male and female rats with rat CD46. Strong immune responses were generated in all rats and immune sera stained CD46 in testis extracts and in situ in testis and sperm. Incubation of spermatozoa with immune sera caused deposition of immunoglobulin and C3b in an acrosome pattern and reduced motility. We mated immune male rats with naive females and female immune rats with naive males. The incidence of pregnancy and number of fetuses were not different in matings involving immune male or female rats compared to controls. Testis sections from immune rats revealed no immunoglobulin deposition on CD46-positive sperm precursors, suggesting that acrosomal CD46 was inaccessible in this location. A minority of spermatozoa harvested from epididymis of immune rats had immunoglobulin and C3b bound to the acrosome, suggesting that anti-CD46, present in genital tract fluids, bound after acrosome reaction. These data demonstrate that the restricted expression of CD46 allows strong anti-CD46 responses in rats that target spermatozoa in vitro and in vivo. The anti-CD46 response did not influence fertility, perhaps reflecting the considerable redundancy for fertilization in rodents. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.jri.2006.08.001

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Authorship：Lead author,　Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BENTHAM SCIENCE PUBL LTD  

The complement activation system, a key component of the innate immune system, protects the host from microorganisms such as bacteria, and other foreign threats including abnormal cells. However, it is also double-edged in that it can have. negative effects in the host; excessive complement activation damages the host and can even kill in anaphylactic shock and septic shock. Regulation of the complement system is a useful strategy to control inflammatory diseases, including inflammatory arthritis. Rheumatoid arthritis is a common inflammatory disease worldwide. Many medicines are developed to control inflammation, including recently developed biological response modifiers such as anti-TNF and IL-6 agents. Nevertheless, in some patients disease remains difficult to control because of complications, side effects and tolerance of medicines. In inflammatory arthritis, including rheumatoid arthritis, there is abundant evidence implicating complement activation in humans and animal models. Therefore, anti-complement agents might be beneficial as part of clinical treatment. However, at present, there are still no applicable agents for therapeutic regulation of excessive complement activation in chronic disease. Novel agents in development might be useful as a strategy to control complement activation. Here I describe recent knowledge of the complement system in inflammatory arthritis, the recent developments in anti-complement agents and their considerable potential for the future.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC STUDY REPRODUCTION  

Identification of the various stages of the seminal tubule epithelium that are important in spermatogenesis in humans and rodents requires considerable expertise for analysis of ultrastructural appearance under light microscopy. Few good stage-specific markers have been reported to facilitate the process. We recently described characterization of the expression of CD46 (membrane cofactor protein) in the rat using a novel monoclonal antibody. Expression of CD46 was restricted to spermatozoa and their immediate precursors in the testis. In the present study, we used a combination of morphological analyses, known acrosome markers, actin staining, direct nuclear staining, and staining for CD46 to delineate precisely the subcellular location of CD46. Staining of CD46 colocalized with known acrosome markers in late spermatids and mature spermatozoa and was confirmed by electron microscopy to be acrosome-restricted. Expression was first detected in step 7 spermatids, whereas known markers were not expressed until step 9. The CD46 staining pattern differed through spermatid development, and distinct patterns of staining could be identified that, when combined with 4 '-6-diamino-2-phenylindole-2HCl nuclear staining, enabled the accurate staging of the seminiferous tubule epithelium in different profiles. This detailed description of the spatiotemporal expression patterns of CD46 provides a valuable tool for analysis of spermatogenesis in the rat. Furthermore, this information will aid ongoing studies regarding the roles of CD46 in acrosome-related spermatozoal functions.

DOI： 10.1095/biolreprod.104.035485

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC STUDY REPRODUCTION  

The rat analogue of the complement regulator membrane cofactor protein (MCP; CD46) was recently cloned and analysis at the mRNA level suggested that expression was restricted to testis. In light of the proposed roles of human MCP in sperm-egg interaction, we undertook to analyze rat MCP expression at the protein level in order better to address its putative role in fertilization. Recombinant fusion proteins comprising antibody Fc and specific domains of rat MCP were generated and used to develop a monoclonal antibody, MM.1, specific for rat MCP. Immunohistochemistry using these reagents confirmed the reported testis-specific expression of MCP in sexually mature rats and demonstrated that MCP was expressed only by spermatozoa and their immediate precursors in spermiogenesis, spermatids. Prepubertal male rats did not express MCP, and there was no evidence of MCP expression at any site in the embryo. Spermatozoal MCP expression was restricted to the inner acrosomal membrane, exposed only after fixation or induction of the acrosome reaction. Acrosome-reacted but not unreacted spermatozoa bound methylamine-activated C3 immobilized on plastic. The retention of MCP at this subcellular site, which is probably crucial to sperm-egg interaction, and the functional demonstration of binding to activated C3 strengthen suggestions from human studies that MCP may play an important role in fertilization. The reagents and results described here will enable studies of the role of spermatozoal MCP in sperm-egg interaction using a relevant animal model system.

DOI： 10.1095/biolreprod.104.030114

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Objective. To investigate the roles of CD59a in the protection of joint tissue in the context of murine antigen-induced arthritis (AIA).
Methods. AIA was triggered in CD59a-deficient (CD59a(-/-)) mice and in CD59a-sufficient (CD59a(+/+)) controls; the course and severity of disease were compared between groups. The effects on arthritis of restoring CD59 to the joint in CD59a(-/-) mice by use of a membrane-targeted recombinant CD59 were also explored.
Results. Disease, as assessed clinically by measurement of joint swelling on day I (P < 0.0001), day 2 (P < 0.01), and day 7 (P < 0.02) and histologically from indicators of joint damage on day 21 (P < 0.02), was significantly enhanced in CD59a(-/-) mice compared with CD59a(+/+) wild-type controls. Membrane attack complex (MAC) deposition in the arthritic joints of CD59a(-/-) mice was also increased compared with that in the joints of CD59a(+/+) controls. Restitution of CD59 activity in joints of CD59a(-/-) mice was attempted with soluble recombinant rat CD59 (sCD59) or with a novel membrane-targeted rat CD59 derivative (sCD59APT542). Strong immunohistochemical staining of the synovial membrane and subsynovial tissue was apparent in sCD59-APT542-injected joints, but not in joints injected with untargeted sCD59. Intraarticular administration of sCD59-APT542 markedly ameliorated disease severity in CD59a(-/-) mice, knee swelling was significantly reduced over the time course of the disease, and joint damage, assessed histologically, was significantly milder on day 21 (P < 0.05).
Conclusion. These data firmly implicate the MAC of complement as a major effector of joint damage in the murine AIA model of rheumatoid arthritis (RA), and they provide a rationale for the inhibition of MAC assembly as a therapeutic strategy for RA.

DOI： 10.1002/art.20478

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Gene-deleted mice have provided a potent tool in efforts to understand the roles of complement and complement-regulating proteins in vivo. In particular, mice deficient in the membrane regulators complement receptor 1-related gene/protein y, decay-accelerating factor, or CD59 have demonstrated homeostatic relevance and backcrossing between the strains has revealed cooperativity in regulation. In mouse, genes encoding decay-accelerating factor and CD59 have been duplicated and show differential expression in tissues, complicating interpretation and extrapolation of findings to man. The first described form of CD59, CD59a, is broadly distributed and deletion of the cd59a gene causes a mild hemolytic phenotype with increased susceptibility in complement-mediated disease models. The distribution of the second form, CD59b, was originally described as testis specific, but later by some as widespread. Deletion of the cd59b gene caused a severe hemolytic and thrombotic phenotype. To apply data from these mouse models to man it is essential to know the relative distribution and functional roles of these two forms of CD59. We have generated new specific reagents and used them in sensitive quantitative analyses to comprehensively characterize expression of mRNA and protein and functional roles of CD59a and CD59b in wild-type (wt) and CD59a-negative mice. cd59b mRNA was detected only in testis and, at very low levels, in bone marrow. CD59b protein was present on mature spermatozoa and precursors and, in trace amounts, erythrocytes. Erythrocyte CD59b did not inhibit complement lysis except when CD59a was absent or blocked. These data confirm that CD59a is the primary regulator of complement membrane attack in mouse.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Inappropriate activation of complement contributes to pathology in diverse inflammatory diseases. Soluble recombinant forms of the natural cell membrane regulators of complement are effective in animal models and some human diseases. However, their use is limited for reasons related to cost, short half lives, and propensity to cause unwanted systemic effects. Some of these limitations may be overcome by use of bacterial expression systems, specific targeting moieties, and judicious choice of regulator. Here we describe the application of these strategies to the generation of a membrane-targeted form of CD59. A recombinant soluble form of rat CD59, comprising the first 71 residues of the mature protein and missing the membrane-anchoring signal, was expressed in bacteria, purified, and refolded in a fully active form. The protein was coupled through its carboxyl terminus to a short, synthetic address tag that confers membrane binding activity. Attachment of the membrane address tag markedly increased complement-inhibitory activity assessed in vitro in hemolysis assays. Intra-articular administration of the tagged agent markedly suppressed disease in a model of rheumatoid arthritis in Lewis rats. This novel type of agent, termed sCD59-APT542, offers for the first time the prospect of efficient and specific inhibition of membrane attack complex activity in vivo.

DOI： 10.1074/jbc.M302598200

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

Background. As previously reported, the membrane-bound complement regulator at the C3 level (Crry/p65) is important in maintaining normal integrity of the kidney in rats. However, the role of a complement regulator at the C8/9 level (CD59) is not clear, especially when activation of complement occurs at the C3 level. The aim of this work was to elucidate the in vivo role of CD59 under C3 activating conditions.
Methods. Two monoclonal antibodies, 5I2 and 6D1, were used to suppress the function of Crry and CD59, respectively. In order to activate alternative the pathway of complement, the left kidney was perfused with 5I2 and/or 6D1 and was recirculated.
Results. In the kidneys perfused with 5I2 alone, deposition of C3 and membrane attack complex (MAC) was observed in the peritubular capillaries, vasa recta, and tubular basement membranes. Cast formation, tubular dilation and degeneration, and cellular infiltration were observed at days 1 and 4, and they recovered by day 7. Further suppression of CD59 by 6D1 significantly enhanced the deposition of MAC and worsened the already exacerbated tubulointerstitial injury. These effects of 6D1 were dose dependent. Perfusion with 6D1 alone did not induce histologic damage or MAC deposition in the tubulointerstitium.
Conclusions. In rats, CD59 maintains normal integrity of the kidney in collaboration with Crry in rats against complement-mediated damage in vivo.

DOI： 10.1046/j.1523-1755.2000.00318.x

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

Objective. To investigate the roles of CD59 in the synovial tissue by functional suppression of CD59.
Methods. Rats treated with cobra venom factor to deplete complement or untreated rats were injected intraarticularly with 0.3 mg of the F(ab')(2) fraction of a monoclonal antibody, 6D1, that inhibits the function of rat CD59, The circumference of knee joints was measured, and histologic changes in the synovium were studied.
Results. Joint swelling, thickening of the synovial tissues, infiltration of inflammatory cells into the synovium, and deposition of membrane attack complex (MAC) on the synovial surface were observed after intraarticular injection of 6D1, The inflammatory reaction reached its peak at 24 hours after injection, and finally subsided to normal within 3 days, It was suggested that functional suppression of CD59 in the synovium induced MAC formation followed by synovitis, Serum complement depletion did not completely sup press this reaction, This indicates that complement existing in the joint space is important for the formation of MAC on the synovial surface and for induction of synovitis.
Conclusion. The membrane-bound complement regulatory protein, CD59, plays a key role in the protection of joints against MAC-mediated synovial injury and in maintaining the normal integrity of the joint.

DOI： 10.1002/art.1780400319

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DOI： 10.1007/s13691-023-00640-8

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DOI： 10.1038/s41598-024-58148-x

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DOI： 10.1007/s10157-023-02449-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：株式会社医学書院  

DOI： 10.11477/mf.1542203505

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DOI： 10.1093/cei/uxad088

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本補体学会  

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Long-term peritoneal dialysis (PD) is often associated with peritoneal dysfunction leading to withdrawal from PD. The characteristic pathologic features of peritoneal dysfunction are widely attributed to peritoneal fibrosis and angiogenesis. The detailed mechanisms remain unclear, and treatment targets in clinical settings have yet to be identified. We investigated transglutaminase 2 (TG2) as a possible novel therapeutic target for peritoneal injury. TG2 and fibrosis, inflammation, and angiogenesis were investigated in a chlorhexidine gluconate (CG)-induced model of peritoneal inflammation and fibrosis, representing a noninfectious model of PD-related peritonitis. Transforming growth factor (TGF)-β type I receptor (TGFβR-I) inhibitor and TG2-knockout mice were used for TGF-β and TG2 inhibition studies, respectively. Double immunostaining was performed to identify cells expressing TG2 and endothelial-mesenchymal transition (EndMT). In the rat CG model of peritoneal fibrosis, in situ TG2 activity and protein expression increased during the development of peritoneal fibrosis, as well as increases in peritoneal thickness and numbers of blood vessels and macrophages. TGFβR-I inhibitor suppressed TG2 activity and protein expression, as well as peritoneal fibrosis and angiogenesis. TGF-β1 expression, peritoneal fibrosis, and angiogenesis were suppressed in TG2-knockout mice. TG2 activity was detected by α-smooth muscle actin-positive myofibroblasts, CD31-positive endothelial cells, and ED-1-positive macrophages. CD31-positive endothelial cells in the CG model were α-smooth muscle actin-positive, vimentin-positive, and vascular endothelial-cadherin-negative, suggesting EndMT. In the CG model, EndMT was suppressed in TG2-knockout mice. TG2 was involved in the interactive regulation of TGF-β. As inhibition of TG2 reduced peritoneal fibrosis, angiogenesis, and inflammation associated with TGF-β and vascular endothelial growth factor-A suppression, TG2 may provide a new therapeutic target for ameliorating peritoneal injuries in PD.

DOI： 10.1016/j.labinv.2022.100050

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DOI： 10.1111/ases.13127

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DOI： 10.3390/nu15081964

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：東京医学社  

DOI： 10.24479/kd.0000000656

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DOI： 10.1186/s12882-022-03022-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Thrombotic microangiopathy (TMA) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). Macrophage activation syndrome (MAS) is also a rare, life-threatening hyperinflammatory condition that is comorbid with SLE. However, the association between TMA and MAS in patients with SLE has rarely been assessed, and the difficulty of diagnosing these conditions remains prevalent. The efficacy of eculizumab has been reported for SLE patients whose conditions are complicated with TMA. However, no study has investigated the therapeutic efficacy of eculizumab for TMA concomitant with SLE-associated MAS. Herein, we report the first case of TMA concomitant with SLE-associated MAS that was initially refractory to conventional immunosuppressive therapy but showed remarkable recovery after eculizumab treatment. Furthermore, we evaluated serum syndecan-1 and hyaluronan levels, which are biomarkers of endothelial damage. We found that these levels decreased after the administration of eculizumab, suggesting that TMA was the main pathology of the patient. This case illustrates that it is important to appropriately assess the possibility of TMA during the course of SLE-associated MAS and consider the use of eculizumab as necessary.

DOI： 10.3389/fmed.2022.1097528

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

<p>Fabry disease is an X-linked lysosomal storage disorder due to mutations in the alpha-galactosidase A gene, which leads to the accumulation of globotriaosylceramide in various organs. In Fabry disease with end-stage renal disease (ESRD), cerebrovascular events are lethal, even with enzyme replacement therapy (ERT). However, the utility of biomarkers to evaluate the ERT response is unclear. We herein report a case of recurrent cerebrovascular complications under ERT in a Fabry disease patient, progressing to ESRD on peritoneal dialysis. Further studies are warranted, but Fabry disease patients with ESRD receiving ERT might need careful long-term follow-up in cases with cerebrovascular manifestations. </p>

DOI： 10.2169/internalmedicine.0185-22

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Dialysis Therapy  

<p>[Objective] To investigate factors hindering the spread of assisted peritoneal dialysis (PD) to support elderly patients in Japan, a survey of PD acceptance at home nursing stations was administered. [Method] A questionnaire survey was conducted involving 616 home-visit nursing stations in Aichi Prefecture, 368 of which were registered with the Aichi Medical Association or Aichi Council of Home-Visit Nursing Stations. [Results] A total of 132 facilities were surveyed, for a collection rate of 35％. The breakdown was as follows：37 home nursing stations were accepting PD patients, 59 were considering accepting PD patients, and 20 were not considering accepting PD patients. A total of 20％ of the facilities were always involved in PD patient visits. Other facilities had only a few opportunities to see PD patients per year. The most common conditions for acceptance by visiting nurses were："medication management" and "emotional support," followed by "PD-bag exchange" and "exit site care". The most common considerations for acceptance were："preparation of APD cycler" and "monitoring the operation of APD equipment," such as preparation of APD equipment. [Conclusion] In order for home health care nurses, who are key personnel in ASSISTED PD, to be able to accept PD patients without anxiety, collaboration and multidisciplinary cooperation, such as joint visits and sharing of care methods with medical staff at PD treatment facilities, are required.</p>

DOI： 10.4009/jsdt.56.401

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DOI： 10.3389/fmed.2022.972592

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Cardiovascular disease is the most common comorbidity in chronic kidney disease (CKD) patients, affecting both their prognosis and quality of life. Cardiac fibrosis is common in CKD patients with left ventricular diastolic dysfunction, and it is associated with increased risk of heart failure and mortality. Recent evidence suggests that high salt intake activates immune responses associated with local accumulation of sodium. We reported that high salt intake promotes cardiac inflammation in subtotal nephrectomized (Nx) mice. We investigated the effects of administration of MR16-1, a rat anti-mouse monoclonal interleukin (IL)-6 receptor antibody, in Nx mice with salt loading (Nx-salt). Expression of monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-a, IL-1b, and IL-6 mRNAs and macrophage infiltration was significantly reduced in the heart of Nx-salt mice treated with MR16-1 (Nx-salt-MR16-1) as compared with Nx-salt mice treated with control rat immunoglobulin G1 (rat IgG1) (Nx-salt-rat IgG1). Correspondingly, cardiac fibrosis was significantly attenuated in Nx-salt-MR16-1 mice compared with Nx-salt-rat IgG1 mice. Furthermore, in the heart of Nx-salt-MR16-1 mice, expression of mRNA for nicotinamide adenine dinucleotide phosphate oxidase-2, an oxidative stress marker, was significantly downregulated compared with Nx-salt-rat IgG1 mice. Increases in cardiac metabolites including histidine and γ-butyrobetaine were also reversed by IL-6 blockade treatment. In conclusion, IL-6 blockade exerts anti-inflammatory, anti-fibrotic, and partial anti-oxidative effects in the heart of Nx-salt mice.

DOI： 10.1152/ajprenal.00396.2021

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DOI： 10.1007/s13730-021-00662-2

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Acute lung injury (ALI) occurs in patients with severe sepsis and has a mortality rate of 40%-60%. Severe sepsis promotes the release of histones from dying cells, which can induce platelet aggregation, activate coagulation and cause endothelial cell (EC) death. We previously reported that the expression of membrane complement receptor type 1-related gene Y (Crry)/p65, which plays a principal role in defence against abnormal activation of complement in the blood, is reduced in response to peritoneal mesothelial cell injury, and we hence hypothesized that a similar mechanism occurs in pulmonary ECs. In this study, we examined the role of Crry/p65 in histone-mediated ALI using an experimental animal model. In ALI model mice, exposure to extracellular histones induces lung injury and results in a decrease in Crry/p65 expression. The levels of lactic acid dehydrogenase (LDH), a marker of cell damage, were significantly increased in the serum of ALI model compared with vehicle mice. The significant inverse correlation between the expression of Crry/p65 and LDH levels in plasma revealed an association between Crry/p65 expression and cell damage. The levels of complement component 3a (C3a) were also significantly increased in the serum of the ALI model compared with vehicle mice. Notably, a C3a receptor antagonist ameliorated lung injury induced by histones. We hypothesize that extracellular histones induce complement activation via down-regulation of Crry/p65 and that C3a might serve as a therapeutic target for the treatment of ALI.

DOI： 10.1002/2211-5463.13322

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Association for Laboratory Animal Science  

<p> Various mouse models of type 2 diabetes have been established, but few of these show early onset and persistent hyperglycemia. We have established a congenic mouse strain (NSY.B6-<i>Tyr⁺,A^y</i>) in which a spontaneous mutation of the agouti yellow (<i>A^y</i>) gene, which causes obesity by hyperphagia, was introduced into the NSY strain, which shows increased glucose intolerance with age. This strain has been maintained as a segregating inbred strain by mating obese yellow (<i>A^y</i>/<i>a</i>) males with normal black (<i>a</i>/<i>a</i>) females. All yellow males showed marked obesity and hyperglycemia (mean blood glucose level >400 mg/dl) from 10 to 24 weeks of age. The yellow males also showed glucose intolerance and insulin resistance. They provide a potentially valuable model mouse for research into type 2 diabetes, hyperlipidemia, fatty liver, and renal glomerular complications. Yellow female mice also showed marked obesity, but the incidence of diabetes and the severity of various pathological conditions were milder than in yellow males. None of the black mice showed hyperglycemia in either sex. NSY.B6-<i>Tyr⁺,A^y</i> strain has good fertility and does not display inter-male aggression, making them useful as a new model for type 2 diabetes with early onset and persistent hyperglycemia.</p>

DOI： 10.1538/expanim.22-0061

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<p>The classical roles of the complement (C) system are known to contribute in part to innate host immunity. In addition, bridging roles of the C system to adaptive immunity were found in the late 21st Century. Since anti-C agents such as C1-inhibitor and anti-C5 antibodies have started to be used in clinical practice during recent decades, the C system has become more familiar to clinicians. Analyses of aspects of the C system are now starting to clarify pathological mechanisms related to the C system and anti-C agents are under development. In the field of nephrology, unexpected C activation has been associated with the incidence, development and/or progression of glomerular and interstitial injuries. Moreover, atypical hematolytic uremic syndrome and C3 nephropathy were referred to as C-associated diseases. However, issues associated with C3 glomerulopathy, its pathogenesis, etiology and therapeutic approaches remain unclear. This mini-review provides a short summary and discussion of renal pathogeneses associated with the C system and its dysregulation, with particular focus on recent insights into C3 glomerulopathy.</p>

DOI： 10.3165/jjpn.rv.2022.0002

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DOI： 10.1371/journal.pone.0257397

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BACKGROUND: During peritoneal dialysis (PD), solute transport and ultrafiltration are mainly achieved by the peritoneal blood vasculature. Glycocalyx lies on the surface of endothelial cells and plays a role in vascular permeability. Low-glucose degradation product (GDP), pH-neutral PD solutions reportedly offer higher biocompatibility and lead to less peritoneal injury. However, the effects on the vasculature have not been clarified. METHODS: Peritoneal tissues from 11 patients treated with conventional acidic solutions (acidic group) and 11 patients treated with low-GDP, pH-neutral solutions (neutral group) were examined. Control tissues were acquired from 5 healthy donors of kidney transplants (control group). CD31 and ratio of luminal diameter to vessel diameter (L/V ratio) were evaluated to identify endothelial cells and vasculopathy, respectively. Immunostaining for heparan sulfate (HS) domains and Ulex europaeus agglutinin-1 (UEA-1) binding was performed to assess sulfated glycosaminoglycans and the fucose-containing sugar chain of glycocalyx. RESULTS: Compared with the acidic group, the neutral group showed higher CD31 positivity. L/V ratio was significantly higher in the neutral group, suggesting less progression of vasculopathy. Both HS expression and UEA-1 binding were higher in the neutral group, whereas HS expression was markedly more preserved than UEA-1 binding in the acidic group. In vessels with low L/V ratio, which were found only in the acidic group, HS expression and UEA-1 binding were diminished, suggesting a loss of glycocalyx. CONCLUSION: Peritoneal endothelial glycocalyx was more preserved in patients treated with low-GDP, pH-neutral solution. The use of low-GDP, pH-neutral solutions could help to protect peritoneal vascular structures and functions.

DOI： 10.1007/s10157-021-02078-9

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本移植学会  

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BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is an uncommon but life-threatening complication of peritoneal dialysis (PD) therapy. The causative factors of EPS remain unclear. Pathological studies of the peritoneum affected by EPS and relationships with clinical factors including PD solutions remain lacking. The objective of this study was to examine peritoneal samples from EPS patients and to identify the associations of peritoneal pathology with different clinical factors. METHODS: Peritoneal specimens were obtained at the time of surgical enterolysis in Tsuchiya General Hospital from 1993 to 2016. A total of 223 PD patients were enrolled and analyzed. Tissues were fixed with formalin and processed with hematoxylin and eosin and Masson's trichrome staining, as well as immunohistochemical staining for CD31 and CD68. RESULTS: Evaluations could be made in 174 patients who received surgical enterolysis. Conventional or pH-neutral low-glucose degradation product PD solutions were utilized during PD treatment. The conventional PD solution group showed less angiogenesis (P = 0.013) but more severe vasculopathy, in the form of a lower ratio of luminal diameter to vessel diameter (L/V ratio) (P < 0.001) in association with longer PD treatment. Multivariate Cox proportional hazard models revealed that L/V ratio (per 0.1 increase, hazard ratio = 0.88, 95% confidence interval 0.77-0.99, P = 0.047) was significantly associated with a lower incidence of EPS relapse. In contrast, most of the cases in the pH-neutral solution group showed milder vasculopathy. CONCLUSIONS: The pathology of EPS differed between conventional and pH-neutral solution groups. Vasculopathy was related to the development and relapse of EPS in the conventional solution group.

DOI： 10.1093/ndt/gfaa073

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INTRODUCTION: Ectopic calcification is associated with secondary hyperparathyroidism (HPT) in patients with end-stage renal failure (ESRD). Metastatic pulmonary calcification (MPC) is another rare type of ectopic calcification, and there are a few reports on MPC in dialysis patients. CASE PRESENTATION: We report the case of a 52-year-old woman admitted with general fatigue and appetite loss, who was on peritoneal dialysis (PD) for 7 years. Although she was initially suspected of having secondary HPT due to ESRD, we finally diagnosed ectopic HPT that was caused by a cystic mass behind her thyroid gland overlapping with secondary HPT. We carefully observed her under conservative therapy because she refused surgery. On admission, she was diagnosed as having MPC because she had ground-glass-like opacification in her lung fields on high-resolution computed tomography scan, which was caused by a parathyroid tumor complicated by secondary HPT associated with ESRD. After she began intravenous injection of etelcalcetide hydrochloride, serum calcium, and intact parathyroid hormone (iPTH), values were adjusted, and the opacification disappeared. CONCLUSION: In a patient on PD, this is the first case of MPC that developed due to acute hypercalcemia, hyperphosphatemia, and dehydration and in which the ectopic pulmonary calcification clearly decreased with optimization of iPTH.

DOI： 10.5414/CN110337

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(有)科学評論社  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

<p><b>Objective </b>In patients on peritoneal dialysis (PD), it was reported that colonoscopy, but not upper gastrointestinal endoscopy, could cause peritonitis as a complication. A guideline of the International Society for Peritoneal Dialysis recommends preemptive intravenous antibiotics administration of ampicillin and aminoglycoside with or without metronidazole, to prevent colonoscopy-associated peritonitis. In this study, we retrospectively evaluated the effects of preemptive antibiotics therapy by oral administration instead of intravenous administration. </p><p><b>Methods </b>We investigated the incidence of colonoscopy-associated peritonitis in a single center. In 170 patients undergoing PD between January 2010 and December 2019, 50 colonoscopies were performed, including 49 with oral administration of amoxicillin and ciprofloxacin and/or metronidazole as preemptive therapy 1 hour before the colonoscopy procedure, and 1 without. </p><p><b>Results </b>We observed no incidence of colonoscopy-associated peritonitis. </p><p><b>Conclusion </b>Generally, oral administration of preemptive antibiotics is less painful and more convenient than intravenous administration, especially in outpatient procedures, such as a colonoscopy. Our results suggest that oral antibiotic administration might be effective for preventing colonoscopy-associated peritonitis in PD patients. </p>

DOI： 10.2169/internalmedicine.5092-20

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<p>Selenium is essential for human health; its deficiency leads to cardiac dysfunction. We herein report a 79-year-old man on peritoneal dialysis who presented with refractory hypotension caused by selenium deficiency. He was admitted to our hospital with bacterial pneumonia and hypotension and abnormal electrocardiogram (ECG) findings. Despite improvement of pneumonia, his hypotension continued, and intravenous noradrenalin could not be discontinued. His serum selenium level was extremely low, and he was started on intravenous selenium. His hypotension and ECG findings gradually improved, and noradrenalin was discontinued. Physicians should consider selenium deficiency when patients on peritoneal dialysis show refractory hypotension. </p>

DOI： 10.2169/internalmedicine.6632-20

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BACKGROUND: Outcomes of patients with end-stage renal disease at urgent dialysis initiation are varied, but evidence of their long-term prognosis is limited. We aimed to characterize patients undergoing urgent dialysis initiation and analyse its effect on survival outcome. METHODS: We retrospectively identified 208 patients who began haemodialysis from 1 January 2012 to 31 December 2018 at our hospital. In this observational case-control study, the case group comprised patients starting urgent dialysis, and the control group comprised patients starting planned dialysis. We analysed laboratory data, sex, age, smoking history, comorbidities and presence of vascular access and nephrology care that potentially affected the outcome. Data were analysed with Kaplan-Meier curves of early and late period (3 years after dialysis initiation) survival and log-rank tests and with Cox regression analysis. RESULTS: Median age (range) at dialysis initiation was 73 (28-90) years, with 50 (24%) patients in the urgent initiation group. Five (10%) patients in this group had vascular access at dialysis initiation, whereas 21 (42%) had not received adequate pre-dialysis nephrology care. The estimated median overall survival rates of the urgent group and planned initiation group were 42 months and not reached, respectively (P = 0.0011). Multivariable analysis found urgent dialysis initiation to be an independent risk factor for survival (HR 2.36; 95% CI 1.36-4.00; P = 0.02). Survival was not significantly different between the groups for patients who continued chronic dialysis for > 3 years from dialysis initiation (P = 0.1339). CONCLUSION: The prognosis of patients starting dialysis in an urgent condition was poor compared with those who started planned dialysis.

DOI： 10.1007/s10157-020-01931-7

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J06455&link_issn=&doc_id=20210107360001&doc_link_id=%2Fdy7hotai%2F2020%2F005701%2F002%2F0003-0022%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy7hotai%2F2020%2F005701%2F002%2F0003-0022%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本小児腎臓病学会  

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INTRODUCTION: Albeit uncommon, hydrothorax is an important complication of peritoneal dialysis (PD). Due to paucity of evidence for optimal treatment, this study aimed to evaluate the effectiveness and safety of computed tomographic (CT) peritoneography and surgical intervention involving video-assisted thoracic surgery (VATS) for hydrothorax in a retrospective cohort of patients who underwent PD in Japan. METHODS: Of the 982 patients who underwent PD from six centers in Japan between 2007 and 2019, 25 (2.5%) with diagnosed hydrothorax were enrolled in this study. PD withdrawal rates were compared between patients who underwent VATS for diaphragm repair (surgical group) and those who did not (non-surgical group) using the Kaplan-Meier method and log-rank test. RESULTS: The surgical and non-surgical groups comprised a total of 11 (44%) and 14 (56%) patients, respectively. Following hydrothorax diagnosis by thoracentesis and detection of penetrated sites on the diaphragm using CT peritoneography, VATS was performed at a median time of 31 days (interquartile range [IQR], 20-96 days). During follow-up (median, 26 months; IQR, 10-51 months), 9 (64.3%) and 2 (18.2%) patients in the non-surgical and surgical groups, respectively, withdrew from PD (P = 0.021). There were no surgery-related complications or hydrothorax relapse in the surgical group. CONCLUSIONS: This study demonstrated the effectiveness and safety of CT peritoneography and VATS for hydrothorax. This approach may be useful in hydrothorax cases to avoid early drop out of PD and continue PD in the long term. Further studies are warranted to confirm these results.

DOI： 10.1371/journal.pone.0238602

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (conference, symposium, etc.)   Publisher：(一社)日本小児腎臓病学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

<p>A 45-year-old man with idiopathic aplastic anemia required renal replacement therapy (RRT) due to end-stage renal disease (ESRD). We succeeded in inserting the peritoneal dialysis (PD) catheter under cover of frequent red blood cell and platelet infusions because of severe pancytopenia. During the one-year period after starting PD using an ultraviolet-ray sterilization device, he developed severe leukopenia but no PD-related peritonitis or exit site/tunnel infection until he died of pneumonia. This case suggests that PD might be a suitable choice as RRT in ESRD patients with aplastic anemia, even in those with severe pancytopenia. </p>

DOI： 10.2169/internalmedicine.3775-19

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Open Access Text Pvt, Ltd.  

DOI： 10.15761/ifnm.1000276

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DOI： 10.1093/ndt/gfz045

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Lymphatic absorption in the peritoneal cavity may contribute to ultrafiltration failure in peritoneal dialysis (PD). Lymphatic vessels develop during PD-related peritoneal fibrosis. Connective tissue growth factor (CTGF, also called CCN2) is an important determinant of fibrotic tissue remodeling, but little is known about its possible involvement in lymphangiogenesis. In this study, we investigated the relationship between CTGF and peritoneal lymphangiogenesis. A positive correlation was observed between vascular endothelial growth factor-C (VEGF-C), a major lymphangiogenic growth factor, and the CTGF concentration in human PD effluents. CTGF expression was positively correlated with expression of lymphatic markers and VEGF-C in human peritoneal biopsies. We found a positive correlation between the increase in CTGF and the increase in VEGF-C in cultured human peritoneal mesothelial cells (HPMCs) treated with transforming growth factor-β1 (TGF-β1). The diaphragm is a central player in peritoneal lymphatic absorption. CTGF expression was also correlated with expression of VEGF-C and lymphatics in a rat diaphragmatic fibrosis model induced by chlorhexidine gluconate (CG). Furthermore, CTGF gene deletion reduced VEGF-C expression and peritoneal lymphangiogenesis in the mouse CG model. Inhibition of CTGF also reduced VEGF-C upregulation in HPMCs treated with TGF-β1. Our results suggest a close relationship between CTGF and PD-associated lymphangiogenesis.

DOI： 10.1038/s41598-019-48699-9

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<p>Malaria is caused by <i>Plasmodium</i> parasites and is one of the most life-threatening infectious diseases in humans. Infection can result in severe complications such as cerebral malaria, acute lung injury/acute respiratory distress syndrome, and acute renal injury. These complications are mainly caused by <i>P. falciparum</i> infection and are major causes of death associated with malaria. There are a few species of rodent-infective malaria parasites, and mice infected with such parasites are now widely used for screening candidate drugs and vaccines and for studying host immune responses and pathogenesis associated with disease-related complications. We found that mice of the NC/Jic strain infected with rodent malarial parasites exhibit distinctive disease-related complications such as cerebral malaria and nephrotic syndrome, in addition to a rapid increase in parasitemia. Here, we focus on the analysis of host genetic factors that affect malarial pathogenesis and describe the characteristic features, utility, and future prospects for exploitation of the NC/Jic strain as a novel mouse model for malaria research.</p>

DOI： 10.1538/expanim.18-0185

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DOI： 10.1007/s10157-018-1679-7

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BACKGROUND: Ultrafiltration failure associated with peritoneal membrane dysfunction is one of the main complications for patients on long-term peritoneal dialysis (PD). The dialysate-to-plasma concentration ratio (D/P) of creatinine is widely used to assess peritoneal membrane function. However, other small-sized solutes have not been studied in detail as potential indicators of peritoneal permeability. METHODS: We studied the D/Ps of small, middle-sized and large molecules in peritoneal equilibration tests in 50 PD patients. We applied metabolomic analysis of comprehensive small molecular metabolites using capillary electrophoresis time-of-flight mass spectrometry. RESULTS: D/Ps of middle-sized and large molecules correlated positively with D/P creatinine. Most D/Ps of small molecules correlated positively with D/P creatinine. Among 38 small molecules contained in the dialysate, urea, citrulline and choline showed significantly lower ability to permeate than creatinine. In the relationship between D/Ps of creatinine and small molecules, regression coefficients of three molecules were less than 0.3, representing no correlation to D/P creatinine. Five molecules showed negative regression coefficients. Among these molecules, hippurate and 3-indoxyl sulfate showed relatively high teinpro binding rates, which may affect permeability. Serum concentrations of two molecules were higher in the Low Kt/V group, mainly due to high protein binding rates. CONCLUSIONS: D/Ps of some molecules did not correlate with D/P creatinine. Factors other than molecular weight, such as charge and protein binding rate, are involved in peritoneal transport rates. Metabolomic analysis appears useful to analyze small molecular uremic toxins, which could accumulate in PD patients, and the status of peritoneal membrane transport for each molecule.

DOI： 10.1007/s10157-018-1611-1

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BACKGROUND: Eculizumab has been available for the treatment of atypical hemolytic-uremic syndrome (aHUS) in Japan since 2013. To assess safety and effectiveness of eculizumab in adult aHUS patients in the real-life setting, we performed interim analysis of a post-marketing surveillance mandated by Japanese regulations. METHODS: This study enrolled any patient who was diagnosed with TMA excluding Shiga toxin-producing Escherichia coli-HUS or thrombotic thrombocytopenic purpura based on Japanese clinical guide published in 2013 as inclusion criteria and treated with eculizumab. Although the term aHUS was redefined to denote only complement-mediated HUS in the guide revised in 2016, the patients with TMA caused by other causes (secondary TMA) were included. Patient outcomes and safety were evaluated at 6 months, 12 months, and annually thereafter. RESULTS: Thirty-three patients with aHUS and 27 patients with secondary TMA were enrolled. Median treatment duration of aHUS was 24weeks. Complement genes variants were detected in 11 of 18 patients with aHUS (61.1%). Among the 29 aHUS patients with available baseline data, platelet count (PLT), lactic dehydrogenase and serum creatinine (SCr) improved within 1-month after eculizumab initiation. TMA event-free status, complete TMA response, PLT normalization, and SCr decrease were achieved in 67.9% (19/28), 27.8% (5/18), 56.5% (13/23), and 57.1% (16/28) of patients, respectively. Thirty-three and 11 adverse reactions were observed in patients with aHUS (13/33 patients) and secondary TMA (6/27 patients), respectively. CONCLUSIONS: This interim analysis confirmed the acceptable safety profile and effectiveness of eculizumab for Japanese adult aHUS patients in real-world settings.

DOI： 10.1007/s10157-018-1609-8

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<p>A 57-year-old man was diagnosed with IgA nephropathy. Hematuria and proteinuria were improved by tonsillectomy plus methylprednisolone pulse therapy. Lymphadenopathy, hypocomplementemia and pancytopenia were observed six years later, and urinalysis abnormalities recurred. A biopsy revealed mesangial proliferative glomerulonephritis with C3-dominant deposition. Human immunodeficiency virus (HIV) antibody demonstrated positive conversion. He was diagnosed with HIV-associated immune complex kidney disease (HIVICK). The hematuria, proteinuria and hypocomplementemia were improved by reducing the HIV viral load through antiretroviral therapy. When C3-dominant deposition is observed on a renal biopsy, HIVICK must be differentiated. </p>

DOI： 10.2169/internalmedicine.2439-18

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DOI： 10.1152/ajprenal.00172.2018

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

Background: Mycophenolate mofetil (MMF) is recommended as a first-line immunosuppressant to treat lupus nephritis (LN). Prognosis and therapeutic response in LN are known to vary depending on race. We investigated the benefits of MMF and therapeutic drug monitoring (TDM) in the treatment of Japanese LN patients. Methods: In this retrospective cohort study, a total of 20 patients with LN who started MMF treatment were included. Clinical data were collected regularly after MMF administration. We evaluated complete remission (CR) rate as the primary outcome. Predictors of CR were identified using univariate and multivariate analyses. In the research of TDM, the correlation with the area under the curve (AUC) was analyzed at MMF dose, single-point value, treatment response, and adverse events. Results: Overall, 70% of cases showed CR
both flare-ups and refractory cases had favorable results. Cases of LN with nephrotic syndrome (NS) or class III/IV + V showed a significantly lower CR rate (p &lt
0.005). The ratio of maintaining CR after MMF therapy was as high as 85.7%. In multivariate analysis, NS was an independent negative predictor of CR (HR 0.09, 95% confidence interval 0.01–0.81
p = 0.03). The relationship between AUC and MMF dose was low, and AUC correlated with trough level (r = 0.73). AUC tended to be high in the treatment responder (p = 0.09), but did not correlate with adverse events of infection (p = 0.92). Conclusion: MMF is a beneficial treatment option for Japanese LN patients, and further investigation on TDM-based therapy is needed.

DOI： 10.1007/s10157-018-1590-2

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DOI： 10.1016/j.molimm.2018.06.158

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DOI： 10.1016/j.molimm.2018.06.072

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DOI： 10.1016/j.molimm.2018.06.096

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Language：Japanese   Publishing type：Research paper (other academic)   Publisher：(NPO)日本医工学治療学会  

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DOI： 10.1152/ajprenal.00052.2017

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DOI： 10.1159/000485711

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DOI： 10.1016/j.molimm.2017.06.195

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DOI： 10.1016/j.molimm.2017.06.194

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We examined complement-dependent cytotoxicity (CDC) by hexamer formation-enhanced CD20 mAb Hx-7D8 of patient-derived chronic lymphocytic leukemia (CLL) cells that are relatively resistant to CDC. CDC was analyzed in normal human serum (NHS) and serum from an individual genetically deficient for C9. Hx-7D8 was able to kill up to 80% of CLL cells in complete absence of C9. We conclude that the narrow C5b-8 pores formed without C9 are sufficient for CDC due to efficient antibody-mediated hexamer formation. In the absence of C9, we observed transient intracellular increases of Ca2+ during CDC (as assessed with FLUO-4) that were extended in time. This suggests that small C5b-8 pores allow Ca2+ to enter the cell, while dissipation of the fluorescent signal accompanying cell disintegration is delayed. The Ca2+ signal is retained concomitantly with TOPRO-3 (viability dye) staining, thereby confirming that Ca2+ influx represents the most proximate mediator of cell death by CDC. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clim.2017.05.016

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Fungal peritonitis in a patient on peritoneal dialysis (PD) is a refractory injury accompanied by severe inflammation, predisposing patients to a poor prognosis. Defective clearance of necrotic tissue interferes with amelioration of tissue injury and induces abnormal tissue remodeling. In the recent reports, apoptosis inhibitor of macrophage (AIM, also called CD5L) prevents obesity, hepatocellular carcinoma and acute kidney injury. Here, we investigated potential roles of AIM in prevention of progression of fungal peritonitis models. AIM(-/)-mice subjected to zymosan-induced peritonitis exhibited progressive inflammation and sustained peritoneal necrosis tissue on day 28 after the disease induction, whereas there was an improvement in AIM(+/+) mice. This appeared to be caused by deposition of AIM at the necrotic peritoneum in AIM(+/+) mice. In vitro, AIM enhanced the engulfment of necrotic debris by macrophages derived from zymosan-induced peritonitis, M1-and M2a-like bone marrow derived macrophages, as well as by mesothelial cells. In addition, administration of recombinant AIM dramatically ameliorated severe inflammation associated with necrosis in zymosan-induced peritonitis of AIM(-/)-mice. Our observations suggest that AIM appears to be involved in the repair process of zymosan-induced peritonitis, and thus, could be the basis of development of new therapeutic strategies for PD-related fungal peritonitis.

DOI： 10.1038/s41598-017-06824-6

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Chronic inflammation, which is often associated with high all-cause and cardiovascular mortality, is prevalent in patients with renal failure; however, the precise mechanisms remain unclear. High-salt intake was reported to induce lymphangiogenesis and autoimmune diseases via osmotic stimuli with accumulation of sodium or chloride. In addition, sodium was recently reported to be stored in the extremities of dialysis patients. We studied the effects and mechanisms of high salt loading on tissue and systemic inflammation in subtotal-nephrectomized mice (5/6Nx) and in cultured cells. Macrophage infiltration in the peritoneal wall (P&lt;0.001), heart (P&lt;0.05) and para-aortic tissues (P&lt;0.001) was significantly higher in 5/6Nx with salt loading (5/6Nx/NaCl) than in 5/6Nx without salt loading (5/6Nx/Water); however, there were no significant differences in blood pressure and renal function between the groups. Tissue interleukin-6, monocyte chemotactic protein-1 (MCP-1), serum- and glucocorticoid-inducible kinase 1 (Sgk1) and tonicity-responsive enhancer binding protein (TonEBP) mRNA were significantly elevated in the peritoneal wall and heart with 5/6Nx/NaCl when compared with 5/6Nx/Water. Sodium was stored in the abdominal wall, exerting high-osmotic conditions. Reversal of salt loading reduced macrophage infiltration associated with decreased TonEBP in 5/6Nx/NaCl. Macrophage infiltration associated with fibrosis induced by salt loading was decreased in the 5/6Nx/NaCl/CC chemokine receptor 2 (CCR2, receptor of MCP-1)-deficient mice when compared with 5/6Nx/NaCl/Wild mice, suggesting that CCR2 is required for macrophage infiltration in 5/6Nx with NaCl loading. In cultured mesothelial cells and cardiomyocytes, culture media with high NaCl concentration induced MCP-1, Sgk1 and TonEBP mRNA, all of which were suppressed by TonEBP siRNA, indicating that both MCP-1 and Sgk1 are downstream of TonEBP. Our study indicates that high NaCl intake induces MCP-1 expression leading to macrophage infiltration via the TonEBP-MCP-1 pathway in 5/6Nx/NaCl mice, and that TonEBP has a central role in inflammation in patients with renal failure taking high salt.

DOI： 10.1038/labinvest.2017.4

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DOI： 10.3390/toxins9030090

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DOI： 10.1038/srep42714

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：一般社団法人 日本透析医学会  

DOI： 10.4009/jsdt.50.685

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DOI： 10.1016/j.imbio.2016.06.193

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DOI： 10.1016/j.imbio.2016.06.037

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DOI： 10.1016/j.imbio.2016.06.040

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DOI： 10.1371/journal.pone.0154644

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DOI： 10.1371/journal.pone.0148881. eCollection 2016.

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DOI： 10.1007/978-1-4939-3353-2_4

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DOI： 10.3899/jrheum.141622

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Appropriate fluid balance is important for good clinical outcomes and survival in patients on peritoneal dialysis. We recently reported that lymphangiogenesis associated with fibrosis developed in the peritoneal cavity via the transforming growth factor-beta 1-vascular endothelial growth factor-C (VEGF-C) pathway. We investigated whether VEGF receptor-3 (VEGFR-3), the receptor for VEGF-C and -D, might be a new target to improve net ultrafiltration by using adenovirus-expressing soluble VEGFR-3 (Adeno-sVEGFR-3) in rodent models of peritoneal injury induced by methylglyoxal (MGO). We demonstrated that lymphangiogenesis developed in these MGO models, especially in the diaphragm, indicating that lymphangiogenesis is a common feature in the peritoneal cavity with inflammation and fibrosis. In MGO models, VEGF-D was significantly increased in the diaphragm; however, VEGF-C was not significantly upregulated. Adeno-sVEGFR-3, which was detected on day 50 after administration via tail vein injections, successfully suppressed lymphangiogenesis in the diaphragm and parietal peritoneum in mouse MGO models without significant effects on fibrosis, inflammation, or neoangiogenesis. Drained volume in the peritoneal equilibration test using a 7.5% icodextrin peritoneal dialysis solution (the 7.5% icodextrin peritoneal equilibration test) was improved by Adeno-sVEGFR-3 on day 22 (P&lt;0.05) and day 50 after reduction of inflammation (P&lt;0.01), indicating that the 7.5% icodextrin peritoneal equilibration test identifies changes in lymphangiogenesis. The solute transport rate was not affected by suppression of lymphangiogenesis. In human peritoneal dialysis patients, the dialysate to plasma ratio of creatinine positively correlated with the dialysate VEGF-D concentration (P&lt;0.001). VEGF-D mRNA was significantly higher in the peritoneal membranes of patients with ultrafiltration failure, indicating that VEGF-D is involved in the development of lymphangiogenesis in peritoneal dialysis patients. These results indicate that VEGFR-3 is a new target to improve net ultrafiltration by suppressing lymphatic absorption and that the 7.5% icodextrin peritoneal equilibration test is useful for estimation of lymphatic absorption.

DOI： 10.1038/labinvest.2015.87

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

A 66-year-old woman with an 11-year history of peritoneal dialysis (PD) for diabetic nephropathy and renal failure exhibited a movable tumor in the left atrium on echocardiography. Tumor resection was performed due to the difficulty in diagnosing the tumor and the future risk of heart failure and embolization. Light microscopy showed a calcified amorphous tumor (CAT), a rare intracardiac mass characterized by the presence of a pedicle and diffuse calcification. An increased calcium-phosphate product level was suspected as an etiology, although degeneration, inflammation and/or mineral balance disorders may also induce the development of CAT. We herein report the first known case of CAT in a PD patient.<br>

DOI： 10.2169/internalmedicine.54.2967

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

A 32-year-old man on peritoneal dialysis (PD) was hospitalized for seven days due to fever. A diagnosis of yeast-like fungal peritonitis was made by Gram staining. The patient was started on intravenous micafungin and oral fluconazole therapy following removal of the PD catheter. A fungal pathogen was isolated from the peritoneal fluid and identified as <i>Cryptococcus</i> species. Based on antifungal susceptibility testing, the treatment was changed to voriconazole and continued for 3 months. A genetic analysis identified the isolate as <i>Cryptococcus laurentii</i> (<i>C. laurentii</i>). This patient was diagnosed with <i>C. laurentii</i> PD-related peritonitis and was successfully treated with voriconazole and removal of the PD catheter.<br>

DOI： 10.2169/internalmedicine.54.3586

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Dialysis Therapy  

A 45-year-old female with a history of chronic renal disease attended our hospital in 2008 with acute intermittent porphyria (AIP). The following year, her renal function deteriorated, and her general condition, and clinical and laboratory findings fulfilled the Japanese criteria for hemodialysis. The porphyrias are metabolic disorders of heme biosynthesis that are triggered and worsened by a number of different drugs. Hemodialysis was initiated in 2009, and we prescribed amlodipine besylate and epoetin beta, paying particular attention to drug safety. Currently, the patient is on hemodialysis and is still taking the medications mentioned above, without any exacerbation of porphyria.

DOI： 10.4009/jsdt.48.437

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DOI： 10.1371/journal.pone.0110376

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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (conference, symposium, etc.)   Publisher：(一社)日本補体学会  

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Background: Multiple studies have shown cigarette smoking to be a risk factor for chronic kidney disease. However, it is unknown whether smoking similarly increases the risk for progression of membranous nephropathy. Methods: This study used the Nagoya Nephrotic Syndrome Cohort Study (N-NSCS), including 171 patients with idiopathic membranous nephropathy (IMN) from 10 nephrology centers in Japan. The dose-response relationships between cigarette smoking and the outcomes were assessed by using multivariate Cox proportional hazards models adjusted for clinically relevant factors. The primary outcome was a 30% decline in the estimated glomerular filtration rate (eGFR). The secondary outcome was first complete remission (CR) of proteinuria. Results: During the observation period (median, 37 months
interquartile range, 16-71 months), 37 (21.6%) patients developed a 30% decline in eGFR and 2 (1.2%) progressed to ESRD. CR occurred in 103 (60.2%) patients. Multivariate Cox proportional hazards models revealed current smoking (adjusted hazard ratio [HR], 7.81 [95% confidence interval (CI), 3.17- 19.7]), female sex (adjusted HR, 3.58 [95% CI, 1.87-8.00]), older age (adjusted HR, 1.71 [95% CI, 1.13-2.62] per 10 years), the number of cigarettes smoked daily (adjusted HR, 1.61 [95% CI, 1.23-2.09] per 10 cigarettes daily), and cumulative smoking of ≥40 pack-years (adjusted HR, 5.56 [95% CI, 2.17-14.6]) to be associated with a 30% decline in eGFR. However, smoking was not associated with CR. Conclusion: Smoking is a significant and dose-dependent risk factor for IMN progression. All patients with IMN who smoke should be encouraged to quit. © 2014 Yamaguchi et al.

DOI： 10.1371/journal.pone.0100835

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DOI： 10.1016/j.jcyt.2013.10.011

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DOI： 10.2169/internalmedicine.53.1827

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DOI： 10.1016/j.molimm.2013.05.110

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In peritoneal dialysis (PD) therapy, physical stresses such as exposure to peritoneal dialysate, catheter trauma, and peritonitis may induce peritoneal injury that can prevent continued long-term PD therapy. Therefore, protection of the peritoneum is an important target to enable long-term PD therapy in patients with end-stage renal disease. We previously showed that neutralization of the membrane complement regulators (CRegs) Crry and CD59 in rat peritoneum provokes development of acute peritoneal injury due to uncontrolled complement activation. C5a is a key effecter molecule of the complement system released during acute inflammation. Control of C5a has been proposed as a strategy to suppress inflammatory reactions and, because peritoneal injury is accompanied by inflammation, we hypothesized that C5a targeted therapy might be an effective way to suppress peritoneal injury. In the present study we used an established acute peritonitis model induced by neutralization of CRegs to investigate the effects on acute peritoneal injury of inhibiting C5a. Intravenous administration of an anti-C5a complementary peptide (AcPepA) up to 4 h after induction of injury significantly and dose-dependently prevented accumulation of inflammatory cells and reduced tissue damage in the model, accompanied by decreased C3b deposition. We show that C5a contributed to the development of peritoneal injury. Our results suggest that C5a is a target for preventing or treating peritoneal injury in patients undergoing prolonged PD therapy or with infectious complications.

DOI： 10.1152/ajprenal.00681.2012

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DOI： 10.1681/ASN.2012030226

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

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Dialysis Therapy  

A 74-year-old man with nephrosclerosis had been treated with CAPD since 2007, until he passed away in 2011. He was admitted to our hospital three times in June, July, and November 2010 due to bacterial peritonitis. In each episode, he responded to antibiotic treatment. In January 2011, he was again admitted to the hospital due to peritonitis. Abdominal CT showed a tumor mass in the upper pole of the spleen and multiple intra-abdominal nodules. Despite highly suspected malignancy, a biopsy was not performed due to his poor state. In March 2011, he was admitted to the hospital again (his fifth hospital admission) due to peritonitis. His clinical condition deteriorated progressively and he passed away on the day of admission. <I>Clostridium perfringens</I> and <I>Streptococcus mitis</i> were identified as the pathogens of the peritonitis by culture of CAPD fluid. The result of the autopsy proved that multiple intra-abdominal nodules were the peritoneal seeding of malignant mesothelioma. Although bacterial peritonitis was ultimately the cause of his death, malignant mesothelioma may be considered as the proximate cause of the peritonitis. Herewith, we present this case as an interesting and rare case in terms of the pathogenesis.

DOI： 10.4009/jsdt.46.949

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：一般社団法人 日本内科学会  

A 46-year-old man on peritoneal dialysis (PD) was hospitalized due to suspicious PD-related peritonitis. Because the patient's abdominal pain was unimproved by conventional antibiotics and multiple bacteria were identified in a smear-sample of PD fluid, endogenous peritonitis was suspected. Perforated appendicitis was finally diagnosed under exploratory laparotomy. In this patient, perforated appendicitis was difficult to diagnose due to the attenuated clinical symptoms and inconclusive results of abdominal computed tomography (CT), even though the positive predictive value of CT is >95% in non-PD patients. Quickly deciding to perform exploratory laparotomy in patients suspected of having endogenous peritonitis is thus important, even when the origin has not been clarified.<br>

DOI： 10.2169/internalmedicine.52.9196

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DOI： 10.3727/096368912X655019

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This guideline was provided by the Japanese Association for Complement Research targeting clinicians for making an accurate diagnosis of hereditary angioedema (HAE), and for prompt treatment of the HAE patient in Japan. This is a 2010 year version and will be updated according to any pertinent medical advancements.

DOI： 10.2332/allergolint.12-RAI-0471

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DOI： 10.1016/j.imbio.2012.08.194

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DOI： 10.1093/jjco/hys145

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DOI： 10.1016/j.imbio.2012.08.046

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Oxaliplatin is effective in advanced colorectal cancer and is known to have relatively few side effects, such as hemolysis and renal toxicity. We report a case of acute kidney injury (AKI) after treatment with a combination of oxaliplatin, folinic acid and 5-fluorouracil or capecitabine. The patient developed acute renal failure, hemolytic anemia and thrombocytopenia after the 34th course of chemotherapy including oxaliplatin. A positive direct antiglobulin test and detection of immunoglobulin G and complement C3b and C3d on erythrocytes suggested the diagnosis of immune-related severe intravascular hemolytic anemia. She was successfully treated and recovered using plasma exchange, corticosteroids and hemodialysis therapy. Only seven other cases of AKI associated with oxaliplatin use have been reported to date. As in this case, acute hemolysis due to autoimmune mechanisms and subsequent AKI occurred suddenly after frequent use of oxaliplatin in four of those cases. We should be aware that oxaliplatin may cause sudden life-threatening hemolysis by drug-induced antibodies and subsequent AKI, even though oxaliplatin is frequently administered without side effects. This represents the first case report of AKI-related hemolysis due to oxaliplatin in Japan.

DOI： 10.1007/s10157-012-0620-8

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Background. Colonic diverticulitis is an important cause of polymicrobial peritonitis, which requires surgical treatment and cessation of peritoneal dialysis (PD). The aim of this study was to examine whether plain abdominal computed tomography (CT) is useful for evaluating colonic diverticulosis in chronic kidney disease (CKD) patients and to explore whether colonic diverticulosis is a risk factor for enteric peritonitis.
Methods. The subjects consisted of 137 consecutive CKD patients (Stage 4 or 5) who were candidates for PD from February 2005 to November 2009. Abdominal CT without contrast media was performed in all PD candidates.
Results. Diverticula of the colon were detected by plain CT in 57 cases (41.6%). The number of diverticula tended to increase with age. The most common site of involvement of diverticulosis was the ascending colon. In patients treated with PD, the incidence of peritonitis was higher in patients with diverticulosis than in those without diverticulosis (P = 0.004). However, only one episode of enteric peritonitis was observed among patients with diverticulosis. The presence of diverticulosis did not affect cumulative or technical survival. PD was not selected in four cases due to a high frequency of diverticula with episodes of abdominal pain. Two cases developed severe diverticulitis with peritonitis and underwent resection of the colon.
Conclusions. Our study suggests that plain CT examination is useful for detecting diverticulosis in CKD patients. Silent diverticulosis is not a risk factor for enteric diverticulosis-related peritonitis. PD may be contraindicated in cases having frequent diverticulosis with episodes of lower abdominal pain.

DOI： 10.1093/ndt/gfr685

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DOI： 10.1038/ki.2011.464

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Atrial natriuretic peptide (ANP) was recently reported to ameliorate fibrosis in the heart and experimental renal diseases and vascular thickening after balloon injury. Peritoneal fibrosis is an important complication of long-term peritoneal dialysis, and peritonitis is a factor in its onset. In the present study, we investigated the effects of ANP in a rat peritonitis-induced peritoneal fibrosis model.
As pretreatment, an osmotic pump containing vehicle (saline) or ANP (0.15 or 0.3 mu g/min) was inserted through the carotid vein in male Sprague-Dawley rats. ANP or saline was continuously infused using the osmotic pump. Three days after administration of ANP or saline, rats underwent peritoneal scraping in a blind manner and were sacrificed on Day 14. The effects of ANP were evaluated based on peritoneal thickness, immunohistochemistry and real-time polymerase chain reaction. In each experiment, we evaluated messenger RNA (mRNA) expression of the ANP receptor natriuretic peptide receptor A (NPR-A) in the peritoneum after scraping. The effects of ANP were also studied in cultured peritoneal fibroblasts and mesothelial cells.
We observed a significant increase in NPR-A mRNA in the peritoneum. Peritoneal thickness increased with time and peaked on Day 14, but ANP significantly reduced peritoneal thickness. Parameters such as number of macrophages and CD-31-positive vessels and expression of type III collagen/transforming growth factor-beta/plasminogen activator inhibitor-1 (PAI-1)/connective tissue growth factor (CTGF) were significantly suppressed by ANP. In cultured peritoneal fibroblasts and mesothelial cells, ANP suppressed angiotensin II-induced upregulation of CTGF and PAI-1.
Our results suggest that ANP is useful in preventing inflammation-induced peritoneal fibrosis.

DOI： 10.1093/ndt/gfr302

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DOI： 10.1111/j.1365-2710.2011.01247.x

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DOI： 10.3747/pdi.2011.00049

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Authorship：Lead author   Language：Japanese  

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Dialysis Therapy  

Although the maximum approved dosage of recombinant human erythropoietin (rHuEPO) is 24,000IU/month in patients on peritoneal dialysis (PD) therapy in Japan, the improvement of renal anemia is not always satisfactorily maintained at a blood hemoglobin (Hb) level>10.0g/dL. Among 46 patients on PD therapy in our hospital, we investigated the effects of darbepoetin alfa (DA) in 8 patients (DA group) with Hb<10.0g/dL after the administration of rHuEPO at 12,000IU/2 weeks, compared with the 38 other patients (non-DA group) with Hb>10.0g/dL after the administration of rHuEPO at a dose<12,000IU/2 weeks. In terms of background data, the residual renal function was lower and serumβ<SUB>2</SUB> microglobulin level was higher in the DA group, compared with the non-DA group. As an inflammatory marker, the serum C-reactive protein level was also higher in the DA group than in the non-DA group. After 18 weeks of DA administration instead of rHuEPO, the mean (±standard deviation) Hb level increased to 11.0±0.8g/dL. The Hb level eventually reached>10.0g/dL in all patients using DA instead of rHuEPO. Of note, serum ferritin levels in all 46 patients were within the normal range, suggesting that low iron storage was not a direct reason for anemia in this study. The present results suggest that renal anemia in patients on PD therapy who remained inadequately managed using the maximum approved dosage of rHuEPO was caused by an inadequate dosage of rHuEPO, and might be controlled to target levels using an adequate dosage of DA.

DOI： 10.4009/jsdt.45.247

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DOI： 10.1159/000339940

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

We report a case of peritonitis resulting from colon perforation caused by ingestion of a rare foreign body in a patient on peritoneal dialysis (PD). A 72-year-old woman on PD was hospitalized with abdominal pain and cloudy PD fluid (PDF). Although conventional antibiotic therapy was started because of a diagnosis of infectious peritonitis, low-grade fever, abdominal pain and a high number of white blood cells in PDF persisted. On day 3, anaerobic bacteria were recognized on bacterial culture of PDF, suggesting a gastrointestinal etiology. During exploratory laparotomy, sigmoidal perforation by a piece of bamboo, probably resulting from ingestion of contaminated food, was found.

DOI： 10.1007/s10157-011-0529-7

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DOI： 10.1016/j.molimm.2011.06.294

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DOI： 10.1093/ndt/gfq702

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

Background. The peritoneal cavity is isolated from the outside and is usually a sterile environment. Patients on peritoneal dialysis (PD) have PD fluid (PDF) infused into the peritoneal cavity. We previously showed that unregulated complement activation could contribute to the development of peritoneal inflammation in yeast peritonitis in PD therapy. In that situation, suppression of local complement activation is essential to protect the host from further injury. The membrane complement regulators (CRegs), Crry, CD55 and CD59, are expressed in the rat peritoneum, especially along the mesothelial cell layer.
Methods. We investigated CRegs&apos; functional roles in the peritoneal cavity using blocking mAb against each CReg and complement activation in different PDFs.
Results. Blockade of any single CReg did not cause spontaneous peritoneal injury in rat. Combined blockade of Crry and CD59 induced focal peritoneal tissue injury and heavy accumulation of inflammatory cells with peritoneal edema at 24 h. Deposits of C3 and C5b-9 were found on the peritoneal surface after combined blocking of Crry and CD59. Systemic complement depletion by cobra venom factor abrogated these inflammatory changes. When combined blockade of Crry and CD59 was performed with PDF of different pH and glucose concentration in rats, the peritoneal injuries were enhanced with lower pH and higher glucose concentration. These results were confirmed by in vitro experiments using primary rat mesothelial cell culture.
Conclusions. Rat CRegs, Crry and CD59, specifically collaborate to control complement activation in rat peritoneum. During PD, impairment of CReg might contribute to the development of severe peritoneal inflammation.

DOI： 10.1093/ndt/gfq683

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

A 54-year-old woman on peritoneal dialysis (PD) was hospitalized with peritonitis with a high body temperature, abdominal pain and cloudy peritoneal fluid. She progressively fell into septic-like shock within only 6 hours after onset. The causative bacteria were <i>Streptococcus mitis</i> (<i>S. mitis</i>), part of the normal flora of oral cavity, intestine, female genial tract and upper respiratory tract. <i>S. mitis</i> shows pathogenicity for diseases such as endocarditis, brain abscesses and sepsis in children with malignancy or transplantation. However, <i>S. mitis</i> rarely shows severe pathogenic responses in adults. We report herein a case of fulminant peritonitis caused by <i>S. mitis</i> in an adult PD patient.<br>

DOI： 10.2169/internalmedicine.50.4122

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Dialysis Therapy  

Cinacalcet, a calcimimetic agent, binds to the calcium-sensing receptor (CaSR) and effectively decreases parathyroid hormone (PTH) secretion. CaSR is expressed in organs such as the parathyroid, kidneys, and bone. In the kidneys, it is expressed in the thick ascending limb (TAL) and the distal tubule (DT). In the TAL, activation of CaSR inhibits magnesium and calcium resorption by direct or indirect mechanisms. It also inhibits recycling of potassium back into the lumen by potassium channels. Peritoneal dialysis (PD) is thought to preserve the residual renal function (RRF) longer than hemodialysis. RRF is thus an important prognostic factor for PD patients. We investigated the effects on electrolyte balance and safety of cinacalcet. Six PD patients with RRF received once-daily oral cinacalcet at 25mg for two months. We examined the changes in levels of serum iPTH, and serum and urinary excretion of phosphorus, calcium, magnesium, and potassium for two months. Median (interquatile range: IQR) serum iPTH levels decreased significantly from 427.2 (351.2~1,313.3) pg/mL to 234.4 (86.0~721.3) pg/mL. Serum phosphorus levels and urinary excretion of phosphorus also decreased significantly. In contrast, concentrations of serum calcium, magnesium, and potassium, and urinary excretion of calcium, magnesium, and potassium did not change significantly. Serum levels of magnesium and potassium were not significantly altered, and were within the normal ranges (before, median 2.2 (IQR: 1.9~2.3) mg/dL, after, median 2.0 (IQR: 1.8~2.5) mg/dL for Mg; and before, median 4.5 (IQR: 4.4~5.2) mEq/L to 4.6 (IQR: 4.2~4.8) mEq/L for K). Based on these findings regarding the potassium and magnesium balance, cinacalcet appears to be useful and safe for the treatment of secondary hyperparathyroidism in PD patients with RRF.

DOI： 10.4009/jsdt.44.1007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

A 68-year-old man was admitted with acute renal failure caused by cholesterol embolization after undergoing carotid artery stenting. Hemodialysis therapy (HD) was immediately required because of uremia, using nafamostat mesilate as an anticoagulant for HD. However, blue toes and gangrene of the feet worsened. To prevent use of anticoagulants and stabilize BP, HD was changed to peritoneal dialysis (PD). After starting PD, blue toes and gangrene improved markedly. Residual renal function also partially recovered. Although BP was unstable during HD, stability of BP and avoidance of anticoagulants during PD therapy might have contributed to the good results.<br>

DOI： 10.2169/internalmedicine.50.5358

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DOI： 10.1093/ndtplus/sfq080

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DOI： 10.1016/j.molimm.2010.05.214

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DOI： 10.1152/ajprenal.00368.2009

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Chronic myelogenous leukemia (CML) is a myeloproliferative disease that originates in abnormal pluripotent bone marrow stem cells and it is consistently associated with the Philadelphia chromosome and/or BCR/ABL fusion gene. Renal infiltration of leukemic cells is relatively rare in CML and is associated with renal impairment. We describe a patient who developed acute renal failure by tubulointerstitial nephropathy during treatment with imatinib mesylate for CML. The acute kidney injury was subsequently found to be due to direct leukemic infiltration. Treatment with hydroxycarbamide and prednisolone resulted in stabilization of the renal function for approximately 4 months. Leukemic infiltration into the kidney should always be considered when a patient with CML presents with renal impairment, regardless of the clinical stage, as the renal failure often responds well to chemotherapy.

DOI： 10.2169/internalmedicine.48.2747

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Kurata K, Maruyama S, Kato S, Sato W, Yamamoto J, Ozaki T, Nitta A, Nabeshima T, Morita Y, Mizuno M, Ito Y, Yuzawa Y, Matsuo S. Tissue-type plasminogen activator deficiency attenuates peritoneal fibrosis in mice. Am J Physiol Renal Physiol 297: F1510-F1517, 2009. doi:10.1152/ajprenal.90330.2008.-Peritoneal fibrosis (PF) is an important complication of peritoneal dialysis therapy. The present study was performed to examine the mechanisms of PF in view of the plasminogen activator (PA)/plasmin/matrix metalloproteinase (MMP) cascade. PF was induced in tissue-type PA (tPA) deficient mice and wild-type mice by intraperitoneal injection of chlorhexidine gluconate. Mice were killed on day 21, and tissue samples were taken. Histopathological studies were performed. Plasmin activity, gelatinases activity, and the levels of tPA, transforming growth factor-beta 1 (TGF-(sic)1), and MMP-2 mRNA were determined. Protein levels of MMP- 3, tissue inhibitor of metalloproteinases (TIMP)-1, -2, and -3, phospho-Smad3, membrane-type 1 (MT1)-MMP, and MT3-MMP were also studied. On day 21, tPA +/+ mice showed severe PF, whereas tPA -/- mice showed milder change. Submesothelial basement membranes were dissolved in tPA +/+ mice while they were relatively preserved in tPA -/- mice. The levels of macrophage infiltration, staining for alpha-smooth muscle actin (alpha-SMA) and collagen type III, and vascular density were all significantly lower in tPA -/- mice than in tPA +/+ mice. The levels of plasmin activity, pro- and active MMP- 2, mRNA expression of tPA and TGF-beta 1, and phospho-Smad3 protein were also lower in tPA -/- mice. No difference was observed between the two groups concerning the protein levels of MMP-3, TIMP-1, TIMP-2, TIMP-3, MT1-MMP, or MT3-MMP. These results indicate that the presence of tPA enhances inflammation, angiogenesis, and fibrogenesis in the peritoneum of the PF model mice. Activation of the PA/plasmin/MMP cascade may play a pivotal role in the pathogenesis of PF.

DOI： 10.1152/ajprenal.90330.2008

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DOI： 10.1016/j.molimm.2009.05.301

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DOI： 10.1038/ki.2008.661

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE PHARMACOLOGICAL SOC  

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DOI： 10.1016/j.molimm.2008.08.174

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DOI： 10.1152/ajprenal.00565.2007

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\In mouse, genes encoding complement regulators CD55 and CD59 have been duplicated. The first described form of CD59, CD59a, is broadly distributed in mouse tissues, while the later identified CD59b was originally described as testis specific. Subsequent studies have been contradictory, some reporting widespread and abundant expression of CD59b. Resolution of the distribution patterns of the CD59 isoforms is important for interpretation of disease studies utilising CD59 knockout mice. Here we have performed a comprehensive distribution study of the CD59 isoforms at the mRNA and protein levels. These data confirm that expression of CD59b is essentially restricted to adult testis; trace expression in other tissues is a consequence of contamination with blood cells, shown previously to express CD59b at low level. In testis, onset of expression of CD59b coincided with puberty and was predominant on the spermatozoal acrosome. Ligation of CD59b, but not CD59a, markedly reduced spermatozoal motility, suggesting a specific role in reproductive function. (c) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.molimm.2007.05.011

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DOI： 10.1016/j.molimm.2007.06.105

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DOI： 10.1016/j.molimm.2007.06.111

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Envenomation by the sea anemone Phyllodiscus semoni causes fulminant dermatitis and, rarely, acute renal failure in humans. Here, we investigated whether the venom extracted from the nematocysts (PsTX-T) was nephrotoxic when administered intravenously in rats and whether PsTX-T induced activation of the complement system. Although small dose of PsTX-T induced acute tubular necrosis in rats resembling pathology seen in patients, kidneys displayed glomerular injury with glomerular endothelial damage, thrombus formation, mesangiolysis, and partial rupture of glomerular basement membrane, accompanied by severe tubular necrosis at 24 hours after administration of 0.03 mg of PsTX-T per animal, similar to the glomerular findings typical of severe hemolytic uremic syndrome. The early stage injury was accompanied by specific PsTX-T binding, massive complement C3b, and membrane attack complex deposition in glomeruli in the regions of injury and decreased glomerular expression of complement regulators. A pathogenic role for complement was confirmed by demonstrating that systemic complement inhibition reduced renal injury. The isolated nephrotoxic component, a 115-kd protein toxin (PsTX-115), was shown to cause identical renal pathology. The demonstration that PsTX-T and PsTX-115 were highly nephrotoxic acting via induction of complement activation suggests that inhibition of complement might be used to prevent acute renal damage following envenomation by P. semoni.

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DOI： 10.2353/ajpath.2007.060984

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DOI： 10.1016/j.molimm.2006.08.018

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DOI： 10.1016/j.molimm.2006.07.162

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BACKGROUND: Taking into consideration the key role of the complement system in renal diseases, we investigated molecular and cellular properties of the human complement C3a receptor (C3aR) in vitro and in situ, looking at its expression in several human renal pathological states. METHODS: Several antibodies were generated and used for immunohistochemistry and Western blot analyses to address C3aR expression and its regulation in vitro on cell lines of myeloid cells and nonmyeloid cell lineages. Furthermore, C3aR distribution was investigated in control nephrectomized kidneys and 116 biopsy specimens from patients with renal diseases, including lupus nephritis (lupus-N). RESULTS: C3aR is a highly N-glycosylated protein with an apparent molecular mass of 65 to 95 kd expressed by myeloid and endothelial cells. C3aR is particularly upregulated in response to interferon gamma treatment, but was unaffected by the other inflammatory cytokines, such as tumor necrosis factor alpha and transforming growth factor beta. In normal human kidney, C3aR staining was not observed. However, glomerular C3aR staining was detected in 42.9% of lupus-N specimens in association with immunoglobulin G immune-complex depositions. Staining intensity correlated with disease severity. C3aR was found in the endothelial area of 81.3% of samples classified as World Health Organization class IV with active lesions. Conversely, C3aR was not detected by means of immunohistochemistry in kidneys from patients with other renal diseases. CONCLUSION: Our data indicate that C3aR expression is tightly regulated and altered in certain disease conditions. C3aR may be used as a unique biomarker of diagnosis and disease activity in patients with lupus-N.

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

Myasthenia gravis (MG) is a debilitating and potentially fatal neuromuscular disease characterized by the generation of autoantibodies reactive with nicotinic acetylcholine receptors (AChR) that cause loss of AChR from the neuromuscular endplate with resultant failure of neuromuscular transmission. A role for complement (C) in the pathology of human MG has been suggested based upon identification of C activation products in plasma and deposited at the endplate in MG. In the rat model, experimental autoimmune MG (EAMG), C depletion or inhibition restricts clinical disease, further implicating C in pathology. The mechanisms by which C activation drives pathology in MG and EAMG are unclear. Here we provide further evidence implicating C and specifically the membrane attack complex (MAC) in the Lewis rat passive EAMG model of MG. Rats deficient in C6, an essential component of the MAC, were resistant to disease induction and endplate destruction was reduced markedly compared to C6-sufficient controls. After reconstitution with C6, disease severity and endplate destruction in the C6-deficient rats was equivalent to that in controls. The data confirm the essential role of the MAC in the destruction of the endplate in EAMG and raise the prospect of specific MAC inhibition as an alternative therapy in MG patients resistant to conventional treatments.

DOI： 10.1111/j.1365-2249.2006.03198.x

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The human neuromuscular disease myasthenia gravis (MG) is characterized by the generation of autoantibodies reactive with nicotinic acetylcholine receptors (AChR) that cause loss of AChR from the neuromuscular end-plate with resultant failure of neuromuscular transmission. A role for complement (C) in AChR loss has been suggested based uponmorphological identification of C at the end-plate in MG and from the effects of C inhibition in murine models. Here we provide further evidence implicating C, and specifically the membrane attack complex (MAC), in a mouse model of MG. Mice deficient in the C regulators Daf1 and/or Cd59a were tested in the model. Wild-type mice were resistant to disease while mice deficient in Daf1 had mild disease symptoms with evidence of C activation and AChR loss at end-plates. Cd59a-deficient mice had very mild disease with some muscle inflammation and essentially undamaged end-plates. In contrast, mice deficient in both C regulators developed a severe paralytic disease with marked muscle inflammation and loss of end-plates. Inhibition of MAC assembly abrogated clinical disease in these double-deficient mice, demonstrating conclusively that MAC formation was driving pathology in the model. These findings provoke us to suggest that current anti-C therapeutics targeting MAC assembly will be beneficial in MG patients resistant to conventional therapies.

DOI： 10.1111/j.1365-2249.2006.03205.x

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DOI： 10.1016/j.jri.2005.11.002

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Spermatozoa are almost unique among cells in that they must survive transplantation into a foreign host in order to perform their physiological role. The biggest hurdle to overcome is innate immune defence that will target the invaders in the female genital tract. Complement is a major player in innate immunity and is present in the female genital tract. Spermatozoa must therefore evade complement attack if they are to reach their goal. Complement evasion is achieved by the presence of complement regulators both in seminal plasma and on the spermatozoa. Here we discuss the parts played by complement and complement regulators in permitting spermatozoa to survive long enough to reach the oocyte, in clearance of the excess spermatozoa that have outlived their usefulness and in aiding activation of spermatozoa to engage the oocyte. In particular, we focus on the unique distribution patterns of complement regulators on spermatozoa, patterns that strongly suggest roles in spermatozoal development and oocyte binding. An understanding of these roles will inform studies of their contribution to fertility and infertility in man. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.molimm.2005.06.026

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DOI： 10.1128/IAI.73.11.7099-7106.2005

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DOI： 10.1074/jbc.M506579200

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

Complement is part of the innate immune system, acting to protect the host from microorganisms such as bacteria, and other foreign and abnormal cells. Although primarily protective, complement activation can also cause damage to the host. In a number of inflammatory diseases, including rheumatoid arthritis and dermatitis, there is excessive and inappropriate complement activation. Many of the toxic effects seen in these conditions are attributable to the excessive production of the anaphylatoxin C5a, which may contribute to both the initiation and progression of the disease. Therefore, the regulation of C5a production and modulation of its function are good pharmacological targets in these disorders. As yet, there are no effective agents for the therapeutic regulation of C5a in routine clinical practice. This review describes the role of C5a in inflammatory disease, animal models used to study C5a-related effects, and current strategies aimed at regulating C5a. There is also a discussion of the strengths and weaknesses of these approaches, and an outline of the likely progress of this class of drugs in the future.

DOI： 10.1517/13543784.14.7.807

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DOI： 10.4049/jimmunol.173.6.3684

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DOI： 10.2165/00044011-200424060-00006

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DOI： 10.1046/j.1440-1827.2003.01555.x

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Background. Although Aristolochia manshuriensis (AM), which was incriminated in the Japanese variety of Chinese herbs nephropathy, has been recently shown to be nephrotoxic in rats, less is known about whether this toxicity is attributable to its aristolochic acids (AA). We compared the renal effect of AM with that of Akebia quinata (AQ), which has similar components to AM but is free of AA
we also compared this effect of AM with that of pure AA, and studied its possible mechanism. Methods. In study 1, rats were divided into four groups. Each group was orally given either 0.4 g of AM, 4 g of AM, or 4 g of AQ per day, or vehicle, for 5 days. In study 2, rats were given 4 g of AM (which contained 4 mg of AA), or 4 mg of pure AA per day, or vehicle, for 5 days. Renal function, and renal histology were evaluated on day 5 in study 1 and on days 1, 3, 5, and 14 in study 2. In study 2, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) and proliferating cell nuclear antigen (PCNA) staining were also performed. In study 3, rats were treated in the same way as in study 2, but were all killed on day 5. Concentrations of AA (I + II) were measured in serum and urine in study 2, and in the kidney, lung, heart, liver, and spleen in study 3. Results. In study 1, only the rats that received 4 g/day of AM developed tubular necrosis, azotemia, proteinuria, and glucosuria. In study 2, both AM- and AA-treated rats showed progressive tubular damage, decreased renal function, and increased urinary protein excretion. The degree of these alterations was comparable in the AM and AA groups. Moreover, the concentrations of AA (I + II), in serum, urine, and kidney were also comparable in the AM- and AA-treated rats. High levels of AA were detected in the lung and kidney. Apoptotic tubular cells increased on day 5 and had decreased by day 14 after the withdrawal of AM or AA. Meanwhile, proliferating tubular cells progressively increased from day 3 to day 14. Conclusions. Our study indicates that the renal toxicity of AM can be attributed to its AA component. Tubular cell apoptosis might be one of the mechanisms involved in this renal injury.

DOI： 10.1007/s10157-003-0229-z

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DOI： 10.1046/j.1365-2567.2003.01628.x

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

CD59, the sole membrane regulator of the membrane attack complex of complement, is broadly and abundantly expressed in man and other mammals. In mouse, CD59 is encoded by two homologous genes. The expression patterns and functional roles of the proteins encoded by these genes, mCD59a and mCD59b, have not been well characterized. Here we describe the generation of monoclonal and polyclonal antibodies detecting specifically mCD59a and mCD59b. These reagents have been used to study function and to ascertain the cell and tissue distributions of mCD59a and mCD59b. mCD59a was broadly distributed on endothelia, erythrocytes, platelets, and on numerous other cell types in organs, a distribution pattern resembling that of CD59 in other species. In marked contrast, expression of mCD59b was restricted to germ cell elements in the testis and mature spermatozoa. Both mCD59a and CD59b inhibited human and rodent complement with similar efficiency. These findings demonstrate that the broadly distributed mCD59a is the key regulator of the terminal complement pathway in mice whereas CD59b, expressed only in testis and on sperm, probably plays other roles in vivo.

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DOI： 10.1093/ndt/18.3.563

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

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

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DOI： 10.1053/ajkd.2002.34540

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DOI： 10.1046/j.1523-1755.2002.00419.x

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

CiNii Research

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

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DOI： 10.1159/000048169

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

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

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

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

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

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Dialysis Therapy  

This study evaluated the effects of low-dose i. v. maxacalcitol (OXAROL^® OCT) in controlling mild secondary hyperparathyroidism (II° HPT) in chronic hemodialysis patients. Nineteen patients were selected for treatment because of increased parathyroid hormone (PTH) levels de spite administration of vitamin D (VD). The patients consisted of 15 males and 4 females, and were divided into 2 groups based on serum intact-PTH (i-PTH) levels (group I; N=11, 240pg/mL≤i-PTH<360pg/mL, group II; N=8, 360pg/mL≤i-PTH<500pg/mL). After a 2-week wash-out period for oral VD, OCT was given intravenously at a dose of 2.5μg in group I and 5.0μg in group II at the end of dialysis therapy 3 times/week. The dose was adjusted to maintain serum i-PTH levels at 240-500pg/mL and normal calcium (Ca) levels. During the 48-week observation period, serum i-PTH decreased significantly in both groups. Serum Ca levels increased mildly in both groups, but they remained within the normal range. Serum levels of phosphorus, ALP, bone ALP and osteocalcin were not significantly changed in either group. There was no correlation between parathyroid gland volume and i-PTH level. These findings suggest that long-term intravenous treatment with low-dose OCT is a useful strategy for the treatment of mild II° HPT without significant increase of serum Ca.

DOI： 10.4009/jsdt.35.1193

CiNii Research

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for Dialysis Therapy  

Ischemic heart disease, cerebral hemorrhage, and cerebral embolus are severe complications seen in patients on maintenance hemodialysis. Hyperlipidemia is one of the risk factors profoundly associated with these complications. We investigated whether the use of polysulfone (PS) hemodialysis membrane improved serum levels of some lipid components in 6 non-DM patients on long-term maintenance hemodialysis. These 6 non-DM patients (one treated with CTA-membrane, 5 with EVAL-membrane) had hyperlipidemia (total cholesterol (TC) 263±17mg/dL, triglyceride (TG) 176±20mg/dL). Three patients were administered 5mg/day of Pravastatin sodium as an anti-hyperlipidemic drug, and one received 20mg/day of the same drug. We measured serum levels of TC, TG, LDL-C, HDL-C, LDL-TG, HDL-TG, Apo-A1, Apo-C3 and other factors before and 1 week after, then 1, 3, 5 and 6 months after the change in hemodialysis membrane. The serum TC level started to decrease after changing the membrane, and it decreased to 212±8mg/dL 3 months after that. Serum levels of LDL-C, Apo-A1 and Apo-C3 had significantly decreased at 6 months after the use of PS-membrane. However, serum levels of HDL-C and TG saw no change after the use of PS-membrane.<br>In addition, we tried to decrease or stop anti-hyperlipidemic drugs 6 months after the change in hemodialysis membrane when serum levels of TC had decreased and remained under 200mg/dL. One of the subjects did not need any drugs associated with hyperlipidemia. Another needed to have an anti-hyperlipidemic drug readministered about 4 months after the drug had been stopped.<br>In the present study, the PS-membrane might improve the hyperlipidemic profiles in patients on long-term hemodialysis. It was suggested that the use of PS-membrane might be available to decrease the dosage of antihyperlipidemia drugs or stop the administration of these drugs in hyperlipidemic patients on maintenance hemodialysis.

DOI： 10.4009/jsdt.35.43

CiNii Research

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

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

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

The open environment of the eye is continuously subject to an influx of foreign agents that can activate complement. Decay-accelerating factor (DAF), membrane cofactor protein (MCP) and CD59 are regulators that protect self-cells from autologous complement activation on their surfaces. They are expressed in the eye at unusually high levels but their physiological importance in this site is unstudied. In the rat, a structural analogue termed 5I2 antigen (5I2 Ag) has actions overlapping DAF and MCP. In this investigation, we injected F(ab')(2) fragments of 5I2 mAb into the conjunctiva and aqueous humor, in the latter case with and without concomitant blockage of CD59. Massive neutrophilic infiltration of the stroma and iris resulted upon blocking 5I2 Ag activity. Frank necrosis of the iris occurred upon concomitant intraocular blockage of CD59. C3b was identified immunohistochemically, and minimal effects were seen in complement-depleted animals and in those treated with non-relevant antibody. The finding that block-age of 5I2 Ag function in periocular tissues and within the eye causes intense conjunctival inflammation and iritis demonstrates the importance of intrinsic complement regulators in protecting ocular tissues from spontaneous or bystander attack by autologous complement.

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

Objective. To investigate changes in the distribution patterns of membrane complement regulators (MCRs) during the development of type II collagen-induced arthritis (CIA) and to examine the protective effects of these molecules against the augmentation of CIA in the knee joint.
Methods. Immunohistochemistry was used to examine the distribution of the MCRs Crry, DAF, and CD59 in the synovium of knee joints before and 2, 4, and 10 weeks after induction of CIA by immunization with type II collagen. In addition, at 2 or 10 weeks after induction of CIA, rats were injected intraarticularly with anti-Crry and/or anti-CD59 as the F(ab')(2) fraction of monoclonal antibodies (mAb). Knee joint swelling and histologic changes in the synovium were examined 2 weeks after mAb injection.
Results. Synovial expression of Crry, DAF, and CD59 decreased in parallel with increased inflammation. When Crry and CD59 were functionally blocked at 2 weeks after the induction of CIA, swelling of the knee joints was markedly increased. Blocking of either regulator alone had no effect on swelling. Thickening of the synovial surface and proliferation of subsynovial tissue were all increased after blocking Crry and CD59, whereas blocking of either MCR alone had no effect. When both Crry and CD59 were blocked, deposits of membrane attack complex were found in the synovium.
Conclusion. Our findings indicate that in rats with CIA and severely inflamed synovium, local expression of MCR is reduced. The MCRs Crry and CD59 appear to suppress the development of CIA.

DOI： 10.1002/1529-0131(200110)44:10<2425::AID-ART407>3.0.CO;2-4

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DOI： 10.1046/j.1365-2249.2001.01513.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO  

A 22-year-old man with subacute necrotizing-encephalomyelopathy (SNE; Leigh's disease) was diagnosed as having progressive renal dysfunction. The clinical diagnosis of Leigh's disease was obtained by the typical central nervous lesions, abnormalities in other organs, and increased lactate concentrations in blood and cerebrospinal fluid. We performed an open biopsy of the right kidney. Light microscopic studies of the renal specimen showed diffuse glomerulocystic kidney (GCK) with tubulointerstitial damage. Electron microscopic examination showed marked swelling and increase in the number of mitochondria of the renal tubular epithelial cells. Therefore, it is suggested that mitochondrial disease seems to play an important role in developing GCK. (C) 2001 by the National Kidney Foundation, Inc.

DOI： 10.1053/ajkd.2001.21358

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Language：Japanese  

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

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

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

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

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO  

A 27-year-old man suffering from severe swelling and pain in his right arm was referred to our hospital. He showed signs of acute renal failure (ARF) with severe dermatitis of his right arm. Three days before being admitted, he accidentally touched some kind of marine organism with his right hand while snorkeling in the Sulu Sea around Cebu Island. Within a few minutes, he was experiencing severe pain in his right hand. Then his right hand gradually became swollen. The marine creature responsible for this injury was thought to have been a sea anemone, which is a type of coelenterate. Histologic findings of a renal biopsy indicated that acute tubular necrosis (ATN) had caused ARF in this patient's case. Supportive therapies improved renal function of this patient, and steroid pulse therapy attenuated the severe skin discoloration. The ATN was thought to have been caused by the poison from a sea anemone because there were no other conceivable reasons for the patient's condition. This is the first time that a marine envenomation case has been reported in which the sting of a sea anemone has caused ATN without the failure of any other organs. (C) 2000 by the National Kidney Foundation, Inc.

DOI： 10.1053/ajkd.2000.9006

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DOI： 10.1002/(SICI)1521-4141(200004)30:4<1182::AID-IMMU1182>3.0.CO;2-H

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DOI： 10.1046/j.1365-2249.2000.01127.x

PubMed

Language：Japanese  

Language：Japanese  

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

A 27-year-old man suffering from severe swelling and pain in his right arm was referred to our hospital. He showed signs of acute renal failure (ARF) with severe dermatitis of his right arm. Three days before being admitted, he accidentally touched some kind of marine organism with his right hand while snorkeling in the Sulu Sea around Cebu Island. Within a few minutes, he was experiencing severe pain in his right hand. Then his right hand gradually became swollen. The marine creature responsible for this injury was thought to have been a sea anemone, which is a type of coelenterate. Histologic findings of a renal biopsy indicated that acute tubular necrosis (ATN) had caused ARF in this patient's case. Supportive therapies improved renal function of this patient, and steroid pulse therapy attenuated the severe skin discoloration. The ATN was thought to have been caused by the poison from a sea anemone because there were no other conceivable reasons for the patient's condition. This is the first time that a marine envenomation case has been reported in which the sting of a sea anemone has caused ATN without the failure of any other organs.

Language：English  

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

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

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

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

Web of Science

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

A 27-year-old man suffering from severe swelling and pain in his right arm was referred to our hospital. He showed signs of acute renal failure (ARF) with severe dermatitis of his right arm. Three days before being admitted, he accidentally touched some kind of marine organism with his right hand while snorkeling in the Sulu Sea around Cebu Island. Within a few minutes, he was experiencing severe pain in his right hand. Then his right hand gradually became swollen. The marine creature responsible for this injury was thought to have been a sea anemone, which is a type of coelenterate. Histologic findings of a renal biopsy indicated that acute tubular necrosis (ATN) had caused ARF in this patient&#039;s case. Supportive therapies improved renal function of this patient, and steroid pulse therapy attenuated the severe skin discoloration. The ATN was thought to have been caused by the poison from a sea anemone because there were no other conceivable reasons for the patient&#039;s condition. This is the first time that a marine envenomation case has been reported in which the sting of a sea anemone has caused ATN without the failure of any other organs.

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DOI： 10.1093/ndt/15.suppl_6.53

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CiNii Research

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

Rats pretreated with traces of LPS developed acute fatal shock syndrome after i.v. administration of a mAb that inhibits the function of a membrane complement regulatory molecule, Such a shock was not observed after the administration of large amounts of LPS instead of the mAb following LPS pretreatment. The lethal response did not occur in rats depleted of either leukocytes or complement, and a C5a receptor antagonist was found to inhibit the reaction. Furthermore, LPS-treated rats did not suffer fatal shock following the injection of cobra venom factor, which activates complement in the fluid phase so extensively as to exhaust complement capacity, Therefore, complement activation on cell membranes is a requirement for this type of acute reaction.

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PubMed

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