Faculty Profiles - MIZUNO, Masashi

Eculizumab for pediatric dense deposit disease: A case report and literature review. Reviewed International journal

Katsuaki Kasahara, Yoshimitsu Gotoh, Hisakazu Majima, Asami Takeda, Masashi Mizuno

Clinical nephrology. Case studies Vol. 8 page： 96 - 102 2020

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

Dense deposit disease (DDD), a subtype of complement component 3 (C3) glomerulopathy (C3G), results from alternative complement pathway hyperactivity leading to membrane attack complex formation. DDD treatment strategies are limited. We report a case of a 13-year-old girl diagnosed with DDD at 9 years of age, with nephritic and nephrotic syndrome and C3 nephritic factor-negative alternative complement pathway activation. Initial treatment with prednisolone, methylprednisolone pulses (MPs), and mizoribines was effective for 3 years, after which she relapsed. Despite MP treatment followed by prednisolone and mycophenolate mofetil (MMF), her kidney function and proteinuria deteriorated with a high soluble (s)C5b-9 level; she also developed dyspnea and pleural effusion (PE). Three days after the first eculizumab (ECZ) infusion, urine volume increased, respiratory condition improved, PE resolved, and proteinuria decreased in 1 month. Serum creatinine level decreased, and kidney function completely normalized within 7 weeks. The sC5b-9 level normalized, and although proteinuria decreased, nephrotic range proteinuria persisted during ECZ treatment with MMF for 53 weeks, even with increased treatment interval. Thus, complement activation pathway-targeted therapy may be useful for rapidly progressing DDD. Our data support the role of complement pathway abnormalities in C3G with DDD.

DOI： 10.5414/CNCS110309

Safety and effectiveness of eculizumab for adult patients with atypical hemolytic-uremic syndrome in Japan: interim analysis of post-marketing surveillance. Reviewed International journal

Hideki Kato, Yoshitaka Miyakawa, Yoshihiko Hidaka, Norimitsu Inoue, Shuichi Ito, Shoji Kagami, Shinya Kaname, Masanori Matsumoto, Masashi Mizuno, Takahisa Matsuda, Akihiko Shimono, Shoichi Maruyama, Yoshihiro Fujimura, Masaomi Nangaku, Hirokazu Okada

Clinical and experimental nephrology Vol. 23 ( 1 ) page： 65 - 75 2019.1

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

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

Safety and effectiveness of eculizumab for pediatric patients with atypical hemolytic-uremic syndrome in Japan: interim analysis of post-marketing surveillance. Reviewed International journal

Shuichi Ito, Yoshihiko Hidaka, Norimitsu Inoue, Shinya Kaname, Hideki Kato, Masanori Matsumoto, Yoshitaka Miyakawa, Masashi Mizuno, Hirokazu Okada, Akihiko Shimono, Takahisa Matsuda, Shoichi Maruyama, Yoshihiro Fujimura, Masaomi Nangaku, Shoji Kagami

Clinical and experimental nephrology Vol. 23 ( 1 ) page： 112 - 121 2019.1

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

BACKGROUND: In 2013, eculizumab was approved for treatment of the atypical hemolytic-uremic syndrome (aHUS) in Japan, which was defined as a thrombotic microangiopathy (TMA) excluding Shiga toxin-producing Escherichia coli-HUS and thrombotic thrombocytopenic purpura. Simultaneously, post-marketing surveillance was started to assess its safety and effectiveness. In 2016, Japanese clinical guide redefined terms to limit the use of "aHUS" to complement-mediated HUS only. Accordingly, TMA with other causes was defined as secondary TMA. Here we report the interim analysis of post-marketing surveillance of pediatric patients with aHUS and secondary TMA. METHODS: Pediatric patients treated with eculizumab from approval to 15 March 2017 were included in this observational real-world study. Clinical endpoints of effectiveness were TMA event-free status, complete TMA response, platelet count normalization, and improvement of estimated glomerular filtration rate (eGFR). Adverse reactions to eculizumab were also analyzed. RESULTS: In 27 pediatric patients with aHUS, median age at diagnosis was 4 years. Complement genes' variants were detected in 14 of 21 patients (66.7%). Median time from diagnosis to eculizumab initiation was 2.0 days. TMA event-free status, complete TMA response, platelet normalization, and improvement in eGFR were achieved in 85.2, 36.4, 78.3, and 75.0% of patients, respectively. Three patients with aHUS died. Twenty-four and 10 adverse reactions were reported in 31 aHUS patients and 17 secondary TMA patients, respectively; however, no eculizumab-related death or meningococcal infection was reported. CONCLUSIONS: This interim analysis confirmed that eculizumab is well-tolerated and effective for Japanese pediatric patients with aHUS in a real-world setting.

DOI： 10.1007/s10157-018-1610-2

Increase of Eosinophil in Dialysate During Induction of Peritoneal Dialysis. Reviewed International journal

Shigemoto E, Mizuno M, Suzuki Y, Kobayashi K, Sakata F, Kariya T, Katsuno T, Maruyama S, Ito Y

Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis Vol. 39 ( 1 ) page： 90 - + 2019.1

Complement regulation and kidney diseases: recent knowledge of the double-edged roles of complement activation in nephrology Invited Reviewed International journal

Masashi Mizuno, Yasuhiro Suzuki, Yasuhiko Ito

Clinical and Experimental Nephrology Vol. 22 ( 1 ) page： 3 - 14 2018.2

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

Mesangial proliferative glomerulonephritis in murine malaria parasite, Plasmodium chabaudi AS, infected NC mice Reviewed International journal

Akihito Yashima, Masashi Mizuno, Yukio Yuzawa, Koki Shimada, Norihiko Suzuki, Hideo Tawada, Waichi Sato, Naotake Tsuboi, Shoichi Maruyama, Yasuhiko Ito, Seiichi Matsuo, Tamio Ohno

CLINICAL AND EXPERIMENTAL NEPHROLOGY Vol. 21 ( 4 ) page： 589 - 596 2017.8

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

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

High Levels of Soluble C5b-9 Complex in Dialysis Fluid May Predict Poor Prognosis in Peritonitis in Peritoneal Dialysis Patients Reviewed International coauthorship International journal

Masashi Mizuno, Yasuhiro Suzuki, Keiko Higashide, Yumi Sei, Daiki Iguchi, Fumiko Sakata, Masanobu Horie, Shoichi Maruyama, Seiichi Matsuo, B. Paul Morgan, Yasuhiko Ito

PLOS ONE Vol. 12 ( 1 ) page： e0169111 2017.1

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

Recent analysis of status and outcomes of peritoneal dialysis in the Tokai area of Japan: the second report of the Tokai peritoneal dialysis registry Reviewed International journal

Masashi Mizuno, Yasuhiko Ito, Yasuhiro Suzuki, Fumiko Sakata, Yosuke Saka, Takeyuki Hiramatsu, Hirofumi Tamai, Makoto Mizutani, Tomohiko Naruse, Norimi Ohashi, Hirotake Kasuga, Hideaki Shimizu, Hisashi Kurata, Kei Kurata, Satoshi Suzuki, Satoko Kido, Yoshikazu Tsuruta, Teppei Matsuoka, Masanobu Horie, Shoichi Maruyama, Seiichi Matsuo

CLINICAL AND EXPERIMENTAL NEPHROLOGY Vol. 20 ( 6 ) page： 960 - 971 2016.12

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

Expression of membrane complement regulators, CD46, CD55 and CD59, in mesothelial cells of patients on peritoneal dialysis therapy Reviewed International coauthorship International journal

Yumi Sei, Masashi Mizuno, Yasuhiro Suzuki, Masaki Imai, Keiko Higashide, Claire L. Harris, Fumiko Sakata, Daiki Iguchi, Michitaka Fujiwara, Yasuhiro Kodera, Shoichi Maruyama, Seiichi Matsuo, Yasuhiko Ito

MOLECULAR IMMUNOLOGY Vol. 65 ( 2 ) page： 302 - 309 2015.6

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

Long-Term Effects of Spironolactone in Peritoneal Dialysis Patients Reviewed International journal

Ito Yasuhiko, Mizuno Masashi, Suzuki Yasuhiro, Tamai Hirofumi, Hiramatsu Takeyuki, Ohashi Hiroshige, Ito Isao, Kasuga Hirotake, Horie Masanobu, Maruyama Shoichi, Yuzawa Yukio, Matsubara Tatsuaki, Matsuo Seiichi

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Vol. 25 ( 5 ) page： 1094 - 1102 2014.5

Anti-C5a complementary peptide ameliorates acute peritoneal injuries induced by neutralization of Crry and CD59. Reviewed

Mizuno T, Mizuno M, Imai M, Suzuki Y, Kushida M, Noda Y, Maruyama S, Okada H, Okada N, Matsuo S, Ito Y.

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Vol. 305 ( 11 ) page： F1603 - F1616 2013

Exploiting the Nephrotoxic Effects of Venom from the Sea Anemone, Phyllodiscus semoni, to Create a Hemolytic Uremic Syndrome Model in the Rat Invited Reviewed International coauthorship International journal

Masashi Mizuno, Yasuhiko Ito, B. Paul Morgan

MARINE DRUGS Vol. 10 ( 7 ) page： 1582 - 1604 2012.7

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

Membrane complement regulators protect against fibrin exudation increases in a severe peritoneal inflammation model in rats Reviewed International coauthorship International journal

Masashi Mizuno, Yasuhiko Ito, Tomohiro Mizuno, Claire L. Harris, Yasuhiro Suzuki, Noriko Okada, Seiichi Matsuo, B. Paul Morgan

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Vol. 302 ( 10 ) page： F1245 - F1251 2012.5

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

Peritonitis is still an important factor for withdrawal from peritoneal dialysis therapy in the Tokai area of Japan Reviewed International journal

Masashi Mizuno, Yasuhiko Ito, Akio Tanaka, Yasuhiro Suzuki, Hideki Hiramatsu, Midoriko Watanabe, Yoshikazu Tsuruta, Teppei Matsuoka, Isao Ito, Hiroshi Tamai, Hirotake Kasuga, Hideaki Shimizu, Hisashi Kurata, Daijo Inaguma, Takeyuki Hiramatsu, Masanobu Horie, Tomohiko Naruse, Shoichi Maruyama, Enyu Imai, Yukio Yuzawa, Seiichi Matsuo

CLINICAL AND EXPERIMENTAL NEPHROLOGY Vol. 15 ( 5 ) page： 727 - 737 2011.10

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

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

Specific collaboration between rat membrane complement regulators Crry and CD59 protects peritoneum from damage by autologous complement activation. Reviewed

Mizuno T, Mizuno M, Morgan BP, Noda Y, Yamada K, Okada N, Yuzawa Y, Matsuo S, Ito Y

Nephrol Dial Transplant Vol. 26 ( 6 ) page： 1821-1830 2011.6

Zymosan, but Not Lipopolysaccharide, Triggers Severe and Progressive Peritoneal Injury Accompanied by Complement Activation in a Rat Peritonitis Model Reviewed International coauthorship International journal

Masashi Mizuno, Yasuhiko Ito, Natalie Hepburn, Tomohiro Mizuno, Yukihiro Noda, Yukio Yuzawa, Claire L. Harris, B. Paul Morgan, Sefchi Matsuo

JOURNAL OF IMMUNOLOGY Vol. 183 ( 2 ) page： 1403 - 1412 2009.7

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

Zymosan, but not lipopolysaccharide, triggers severe and progressive peritoneal injury accompanied by complement activation in a rat peritonitis model. Reviewed

Mizuno M, Ito Y, Hepburn N, Mizuno T, Noda Y, Yuzawa Y, Harris CL, Morgan BP, Matsuo S.

J Immunol Vol. 183 page： 1403-1412 2009

A protein toxin from the sea anemone Phyllodiscus semoni targets the kidney and causes a severe renal injury with predominant glomerular endothelial damage. Reviewed International coauthorship International journal

Mizuno, M; Nozaki, M; Morine, N; Suzuki, N; Nishikawa, K; Morgan, BP; Matsuo, S

AMERICAN JOURNAL OF PATHOLOGY Vol. 171 ( 2 ) page： 402 - 414 2007.8

High levels of complement C3a receptor in the glomeruli in lupus nephritis Reviewed International coauthorship International journal

Masashi Mizuno, Stephanie Blanchin, Philippe Gasque, Kazuhiro Nishikawa, Seiichi Matsuo

AMERICAN JOURNAL OF KIDNEY DISEASES Vol. 49 ( 5 ) page： 598 - 606 2007.5

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

Immunization with autologous CD46 generates a strong autoantibody response in rats that targets spermatozoa Reviewed International coauthorship International journal

Masashi Mizuno, Claire L. Harris, B. Paul Morgan

JOURNAL OF REPRODUCTIVE IMMUNOLOGY Vol. 73 ( 2 ) page： 135 - 147 2007.4

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

CD55 expression in rat male reproductive tissue: Differential expression in testis and expression of a unique truncated isoform on spermatozoa. Reviewed International coauthorship International journal

Mizuno M, Donev RM, Harris CL, Morgan BP

Mol. Immunol. Vol. 44 page： 1624-1633 2006

A review of current knowledge of the complement system and the therapeutic opportunities in inflammatory arthritis. Invited Reviewed

Mizuno M

Curr Med Chem Vol. 13 ( 14 ) page： 1707-1717 - 1717 2006

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.

CD46 plays a key role in tailoring innate immune recognition of apoptotic and necrotic cells Reviewed International coauthorship International journal

Elward, K; Griffiths, M; Mizuno, M; Harris, CL; Neal, JW; Morgan, BP; Gasque, P

JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 280 ( 43 ) page： 36342 - 36354 2005.10

Expression of CD46 in developing rat spermatozoa: Ultrastructural localization and utility as a marker of the various stages of the seminiferous tubuli Reviewed International coauthorship International journal

M Mizuno, CL Harris, N Suzuki, S Matsuo, BP Morgan

BIOLOGY OF REPRODUCTION Vol. 72 ( 4 ) page： 908 - 915 2005.4

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

Nucleic acids and CD46 are key regulators in innate immune recognition and the finely tuned removal of “danger-self". Reviewed

Elward K, Griffiths M., Mizuno M., Harris CL., Neal JW., Morgan BP., Gasque P.

J Biol Chem Vol. 280 page： 36342-36354 2005

Rat membrane cofactor protein (MCP; CD46) is expressed only in the acrosome of developing and mature spermatozoa and mediates binding to immobilized activated C3 Reviewed International coauthorship International journal

M Mizuno, CL Harris, PM Johnson, BP Morgan

BIOLOGY OF REPRODUCTION Vol. 71 ( 4 ) page： 1374 - 1383 2004.10

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

Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis Reviewed International coauthorship International journal

AS Williams, M Mizuno, PJ Richards, DS Holt, BP Morgan

ARTHRITIS AND RHEUMATISM Vol. 50 ( 9 ) page： 3035 - 3044 2004.9

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

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

CD59a is the primary regulator of membrane attack complex assembly in the mouse Reviewed International coauthorship International journal

S Baalasubramanian, CL Harris, RM Donev, M Mizuno, N Omidvar, WC Song, BP Morgan

JOURNAL OF IMMUNOLOGY Vol. 173 ( 6 ) page： 3684 - 3692 2004.9

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

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.

The possibilities and pitfalls for anti-complement therapies in inflammatory diseases. Invited Reviewed International coauthorship International journal

Mizuno M, Morgan BP

Current Drug Targets Inflammation & Allergy Vol. 3 page： 85-94 2004

Generation of a recombinant, membrane-targeted form of the complement regulator CD59 - Activity in vitro and in vivo Reviewed International coauthorship International journal

DA Fraser, CL Harris, AS Williams, M Mizuno, S Gallagher, RAG Smith, BP Morgan

JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 278 ( 49 ) page： 48921 - 48927 2003.12

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

Generation of a recombinant, membrane-targeted form of the complement regulator, CD59: activity in vitro and in vivo. Reviewed

Fraser DA., Harris CL., Williams AS., Mizuno M., Gallagher S., Smith RAG., Morgan BP.

J. Biol. Chem. Vol. 278 page： 48921-48927 2003

Membrane complement regulators protect against the development of type II collagen-induced arthritis in rats Reviewed International coauthorship International journal

M Mizuno, K Nishikawa, OB Spiller, BP Morgan, N Okada, H Okada, S Matsuo

ARTHRITIS AND RHEUMATISM Vol. 44 ( 10 ) page： 2425 - 2434 2001.10

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

CD59 protects rat kidney from complement mediated injury in collaboration with Crry Reviewed International coauthorship International journal

M Watanabe, Y Morita, M Mizuno, K Nishikawa, Y Yuzawa, N Hotta, BP Morgan, N Okada, H Okada, S Matsuo

KIDNEY INTERNATIONAL Vol. 58 ( 4 ) page： 1569 - 1579 2000.10

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

Acute renal failure after a sea anemone sting Reviewed International journal

M Mizuno, K Nishikawa, Y Yuzawa, T Kanie, H Mori, Y Araki, N Hotta, S Matsuo

AMERICAN JOURNAL OF KIDNEY DISEASES Vol. 36 ( 2 ) page： art. no. - E10 2000.8

Authorship：Lead author,　Corresponding author 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

Comparison of the suppressive effects of soluble CR1 and C5a receptor antagonist in acute arthritis induced by anti-rat CD59 antibody. Reviewed International coauthorship

Mizuno M, Nishikawa K, Morgan B.P, Matsuo S

Clin. Exp. Immunol. Vol. 119 page： 368-375 2000

The effects of functional suppression of a membrane-bound complement regulatory protein, CD59, in the synovial tissue in rats Reviewed International coauthorship International journal

M Mizuno, K Nishikawa, RM Goodfellow, SJ Piddlesden, BP Morgan, S Matsuo

ARTHRITIS AND RHEUMATISM Vol. 40 ( 3 ) page： 527 - 533 1997.3

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

Successfully treated C3 glomerulopathy in which protein and genetic analyses were useful for diagnosis. Reviewed International journal

Kanzaki M, Kurahashi M, Watanabe K, Nishikawa M, Fukuoka K, Shimada N, Mizuno M, Asano K

CEN case reports 2024.9

Pathophysiological Mechanisms of Peritoneal Fibrosis and Peritoneal Membrane Dysfunction in Peritoneal Dialysis. Reviewed International journal

Yasuhiko Ito, Ting Sun, Mitsuhiro Tawada, Hiroshi Kinashi, Makoto Yamaguchi, Takayuki Katsuno, Hangsoo Kim, Masashi Mizuno, Takuji Ishimoto

International journal of molecular sciences Vol. 25 ( 16 ) 2024.8

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

The characteristic feature of chronic peritoneal damage in peritoneal dialysis (PD) is a decline in ultrafiltration capacity associated with pathological fibrosis and angiogenesis. The pathogenesis of peritoneal fibrosis is attributed to bioincompatible factors of PD fluid and peritonitis. Uremia is associated with peritoneal membrane inflammation that affects fibrosis, neoangiogenesis, and baseline peritoneal membrane function. Net ultrafiltration volume is affected by capillary surface area, vasculopathy, peritoneal fibrosis, and lymphangiogenesis. Many inflammatory cytokines induce fibrogenic growth factors, with crosstalk between macrophages and fibroblasts. Transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF)-A are the key mediators of fibrosis and angiogenesis, respectively. Bioincompatible factors of PD fluid upregulate TGF-β expression by mesothelial cells that contributes to the development of fibrosis. Angiogenesis and lymphangiogenesis can progress during fibrosis via TGF-β-VEGF-A/C pathways. Complement activation occurs in fungal peritonitis and progresses insidiously during PD. Analyses of the human peritoneal membrane have clarified the mechanisms by which encapsulating peritoneal sclerosis develops. Different effects of dialysates on the peritoneal membrane were also recognized, particularly in terms of vascular damage. Understanding the pathophysiologies of the peritoneal membrane will lead to preservation of peritoneal membrane function and improvements in technical survival, mortality, and quality of life for PD patients.

DOI： 10.3390/ijms25168607

学校検尿でみつかった、電顕像にて電子密度の異なる沈着物を認めるDense Deposit Diseaseの13歳女児例

特集補体と腎疾患:温故知新腎疾患における補体と病態生理膜性増殖性糸球体腎炎/C3腎症 Invited

水野正司

腎と透析 Vol. 97 ( 1 ) page： 82 - 87 2024.7

Effectiveness of additional topical antibiotics for recurrent or refractory exit-site infection: a case series Reviewed International journal

Asai, N; Suzuki, Y; Asai, A; Kinashi, H; Kamiya, K; Hagita, J; Matsuoka, N; Kawamura, S; Fukui, S; Kim, H; Yamaguchi, M; Katsuno, T; Mizuno, M; Ishimoto, T; Ito, Y

RENAL REPLACEMENT THERAPY Vol. 10 ( 1 ) 2024.6

Rationale and design of the Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study Reviewed International journal

Kurasawa, S; Kato, S; Ozeki, T; Akiyama, S; Ishimoto, T; Mizuno, M; Tsuboi, N; Kato, N; Kosugi, T; Maruyama, S

CLINICAL AND EXPERIMENTAL NEPHROLOGY Vol. 28 ( 5 ) page： 431 - 439 2024.5

Durvalumab plus carboplatin-etoposide treatment in a patient with small-cell lung cancer on hemodialysis: a case report and literature review. Reviewed International journal

Ushijima F, Hase T, Yamashita Y, Kim H, Shimokata T, Kondo C, Sato T, Baba T, Watanabe S, Futamura K, Ando Y, Mizuno M, Ishii M

International cancer conference journal Vol. 13 ( 2 ) page： 88 - 92 2024.4

Role of endothelial hyaluronan in peritoneal membrane transport and disease conditions during peritoneal dialysis Reviewed International coauthorship International journal

Kamiya, K; Hatayama, N; Tawada, M; Asai, A; Yamauchi, M; Kinashi, H; Kunoki, S; Yamaguchi, M; Mizuno, M; Suzuki, Y; Banshodani, M; Ishimoto, T; Naito, M; Kawanishi, H; Ito, Y

SCIENTIFIC REPORTS Vol. 14 ( 1 ) page： 7412 2024.3

A Case of C3 Nephritis With a Rare Variant of the CFHR5 Gene Reviewed International journal

Kamido, H; Yamamoto, S; Yokoi, H; Mizuno, M; Yanagita, M

CUREUS JOURNAL OF MEDICAL SCIENCE Vol. 16 ( 2 ) page： e55102 2024.2

今月の特集2 補体をめぐる話題注目の補体異常症 C3腎症

金恒秀, 水野正司

臨床検査 Vol. 68 ( 1 ) page： 88 - 92 2024.1

特集補体revisited--抗補体療法はどこまで進んだか? 非典型溶血性尿毒症症候群 Invited

水野正司

医学のあゆみ Vol. 287 ( 10 ) page： 757 - 761 2023.12

遺伝性血管性浮腫(Hereditary angioedema:HAE)診療ガイドライン改訂2023年版

堀内孝彦, 大澤勲, 宮田敏行, 赤津裕康, 今井優樹, 大谷克城, 奥健志, 関根英治, 塚本浩, 中尾実樹, 西村純一, 水野正司, 村上良子, 井上徳光, 一般社団法人日本補体学会HAEガイドライン作成委員会

補体 Vol. 60 ( 1 ) page： 23 - 23 2023.8

手塚優子, 新野亮治, 木内拓海, 岡本健太郎, 村上至孝, 松田修, 澤井俊宏, 水野正司, 清水章

日本小児腎臓病学会雑誌 Vol. 36 ( Suppl. ) page： 179 - 179 2023.5

Inhibition of Transglutaminase 2 Reduces Peritoneal Injury in a Chlorhexidine-Induced Peritoneal Fibrosis Model. Reviewed International journal

Shunnosuke Kunoki, Hideki Tatsukawa, Yukinao Sakai, Hiroshi Kinashi, Tetsuyoshi Kariya, Yasuhiro Suzuki, Masashi Mizuno, Makoto Yamaguchi, Hiroyuki Sasakura, Masashi Ikeno, Kosei Takeuchi, Takuji Ishimoto, Kiyotaka Hitomi, Yasuhiko Ito

Laboratory investigation; a journal of technical methods and pathology Vol. 103 ( 4 ) page： 100050 - 100050 2023.4

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

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

Nutritional Assessment and Nutrient Supplement in Patients with Chronic Kidney Disease

Video-assisted thoracoscopic surgery for pleuroperitoneal communication International journal

Tsubouchi, H; Nakamura, S; Fukui, T; Kadomatsu, Y; Ueno, H; Ozeki, N; Fukumoto, K; Mizuno, M; Chen-Yoshikawa, TF

ASIAN JOURNAL OF ENDOSCOPIC SURGERY Vol. 16 ( 2 ) page： 262 - 265 2023.4

Mizuno, M

NUTRIENTS Vol. 15 ( 8 ) 2023.4

特集 Genetics in CKD 疾患編補体関連遺伝子の異常と腎疾患

金恒秀, 水野正司

腎と透析 Vol. 94 ( 3 ) page： 405 - 410 2023.3

Case report: Thrombotic microangiopathy concomitant with macrophage activation syndrome in systemic lupus erythematosus refractory to conventional treatment successfully treated with eculizumab Reviewed International journal

Makoto Yamaguchi, Masashi Mizuno, Fumiya Kitamura, Shiho Iwagaitsu, Hironobu Nobata, Hiroshi Kinashi, Shogo Banno, Akimasa Asai, Takuji Ishimoto, Takayuki Katsuno, Yasuhiko Ito

Frontiers in Medicine Vol. 9 page： 1097528 2023.1

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

ASSISTED PD：Problems and Countermeasures Based on Home-Visit Nursing Station Surveys Reviewed

Recurrent Cerebrovascular Complications under Enzyme Replacement Therapy in a Patient with Fabry Disease on Peritoneal Dialysis Reviewed International journal

Muto Reiko, Suzuki Yasuhiro, Shimizu Hideaki, Yasuda Kaoru, Ishimoto Takuji, Maruyama Shoichi, Ito Yasuhiko, Mizuno Masashi

Internal Medicine Vol. 62 ( 3 ) page： 565 - 569 2023

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

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.

DOI： 10.2169/internalmedicine.0185-22

Takai Nami, Nakabayashi Kichio, Kawashima Shoichi, Mizuno Masashi, Koide Shigehisa, Kasuga Hirotake, Saka Yosuke, Sakai Emiko, Inaguma Daijo, Ito Yasuhiko

Nihon Toseki Igakkai Zasshi Vol. 56 ( 11 ) page： 401 - 409 2023

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

[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.

DOI： 10.4009/jsdt.56.401

Long-term peritoneal dialysate exposure modulates expression of membrane complement regulators in human peritoneal mesothelial cells Reviewed International journal

Kobayashi Kazuma, Ozeki Toshikazu, Kim Hangsoo, Imai Masaki, Kojima Hiroshi, Iguchi Daiki, Fukui Sosuke, Suzuki Masafumi, Suzuki Yasuhiro, Maruyama Shoichi, Ito Yasuhiko, Mizuno Masashi

FRONTIERS IN MEDICINE Vol. 9 page： 972592 2022.12

Interleukin-6 blockade reduces salt-induced cardiac inflammation and fibrosis in subtotal nephrectomized mice. Reviewed International journal

Hiroya Tanaka, Ting Sun, Hiroshi Kinashi, Keisuke Kamiya, Makoto Yamaguchi, Hironobu Nobata, Fumiko Sakata, Hangsoo Kim, Masashi Mizuno, Shunnosuke Kunoki, Yukinao Sakai, Akiyoshi Hirayama, Tomoyoshi Soga, Kazuhiro Yoshikawa, Takuji Ishimoto, Yasuhiko Ito

American journal of physiology. Renal physiology Vol. 323 ( 6 ) page： F654 - F665 2022.12

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

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

A case of C3 glomerulopathy with nephritis-associated plasmin receptor positivity without a history of streptococcal infection Reviewed International journal

Asano, M; Oda, T; Mizuno, M

CEN CASE REPORTS Vol. 11 ( 2 ) page： 259 - 264 2022.5

Expression of a Crry/p65 is reduced in acute lung injury induced by extracellular histones. Reviewed International journal

Fumihiko Nagano, Tomohiro Mizuno, Masaki Imai, Kazuo Takahashi, Naotake Tsuboi, Shoichi Maruyama, Masashi Mizuno

FEBS open bio Vol. 12 ( 1 ) page： 192 - 202 2022.1

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

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

Complement activation and C3 glomerulopathy

A novel model mouse for type 2 diabetes mellitus with early onset and persistent hyperglycemia Reviewed International journal

Ohno Tamio, Miyasaka Yuki, Yoshida Kanta, Kobayashi Misato, Horio Fumihiko, Yokoi Norihide, Mizuno Masashi, Ikegami Hiroshi

Experimental Animals Vol. 71 ( 4 ) page： 510 - 518 2022

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

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-Tyr+,Ay) in which a spontaneous mutation of the agouti yellow (Ay) 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 (Ay/a) males with normal black (a/a) 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-Tyr+,Ay 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.

DOI： 10.1538/expanim.22-0061

Mizuno Masashi

Japanese journal of pediatric nephrology Vol. 35 ( 1 ) page： 5 - 12 2022

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society for Pediatric Nephrology

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.

DOI： 10.3165/jjpn.rv.2022.0002

Low-GDP, pH-neutral solutions preserve peritoneal endothelial glycocalyx during long-term peritoneal dialysis. Reviewed International coauthorship International journal

Naoya Sugiyama, Mitsuhiro Tawada, Ting Sun, Yasuhiro Suzuki, Hiroshi Kinashi, Makoto Yamaguchi, Takayuki Katsuno, Jan Aten, Carmen A Vlahu, Toin H van Kuppevelt, Yoshifumi Takei, Takuji Ishimoto, Shoichi Maruyama, Masashi Mizuno, Yasuhiko Ito

Clinical and experimental nephrology Vol. 25 ( 9 ) page： 1035 - 1046 2021.9

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

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

生体腎移植術を安全に施行できた著明な血小板減少症を合併するEpstein症候群の一例

安田宜成, 岡崎雅樹, 菱田学, 田中章仁, 斎藤尚二, 加藤規利, 鈴木康弘, 小杉智規, 水野正司, 藤田高史, 加藤真史, 藤元昭一, 此元隆雄, 丸山彰一

移植 Vol. 56 ( 総会臨時 ) page： P1 - 50 2021.9

Vasculopathy plays an important role during the development and relapse of encapsulating peritoneal sclerosis with conventional peritoneal dialysis solutions. Reviewed International coauthorship International journal

Mitsuhiro Tawada, Yasuhiko Ito, Masataka Banshodani, Masahiro Yamashita, Sadanori Shintaku, Ting Sun, Yasuhiro Suzuki, Hiroshi Kinashi, Yoko Kubo, Masahiko Ando, Makoto Yamaguchi, Takayuki Katsuno, Masashi Mizuno, Hideki Kawanishi

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Vol. 36 ( 8 ) page： 1519 - 1526 2021.8

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

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

A case of temporary metastatic pulmonary calcification in a patient with hyperparathyroidism on peritoneal dialysis. Reviewed International journal

Kota Kawase, Kimiaki Takagi, Masashi Mizuno, Masanobu Horie

Clinical nephrology Vol. 95 ( 3 ) page： 161 - 165 2021.3

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

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

腎障害への補体の関与 Invited

金恒秀, 水野正司

腎臓内科 Vol. 13 ( 3 ) page： 361 - 367 2021.3

Oral Antibiotics are Effective for Preventing Colonoscopy-associated Peritonitis as a Preemptive Therapy in Patients on Peritoneal Dialysis Reviewed International journal

Suzuki Yasuhiro, Mizuno Masashi, Kojima Hiroshi, Sato Yuka, Kim Hangsoo, Kinashi Hiroshi, Katsuno Takayuki, Ishimoto Takuji, Maruyama Shoichi, Ito Yasuhiko

Internal Medicine Vol. 60 ( 3 ) page： 353 - 356 2021

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

Objective 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. Methods 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. Results We observed no incidence of colonoscopy-associated peritonitis. Conclusion 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.

DOI： 10.2169/internalmedicine.5092-20

Refractory Hypotension Caused by Selenium Deficiency in a Patient on Peritoneal Dialysis Reviewed International journal

Ryuge Akihiro, Kim Hangsoo, Suzuki Yasuhiro, Okazaki Masaki, Kojima Hiroshi, Saito Shoji, Kato Noritoshi, Ishimoto Takuji, Kosugi Tomoki, Maruyama Shoichi, Mizuno Masashi

Internal Medicine Vol. 60 ( 15 ) page： 2461 - 2464 2021

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

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.

DOI： 10.2169/internalmedicine.6632-20

Impact on survival of urgent dialysis initiation in patients with end-stage renal disease: a case-control study. Reviewed International journal

Kimiaki Takagi, Masashi Mizuno, Kota Kawase, Kenichi Minoshima, Masayoshi Yamaha, Masanobu Horie

Clinical and experimental nephrology Vol. 24 ( 12 ) page： 1154 - 1161 2020.12

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

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

遺伝性血管性浮腫(Hereditary angioedema:HAE)診療ガイドライン改訂2019年版 Reviewed

堀内孝彦, 大澤勲, 今井優樹, 大谷克城, 関根英治, 塚本浩, 中尾実樹, 西村純一, 水野正司, 村上良子, 山本哲郎, 木下タロウ, 大井洋之, 井上徳光, 若宮伸隆, 野々山恵章, 一般社団法人日本補体学会, 厚生労働省難治性疾患等政策研究事業「原発性免疫不全症候群の診断基準・重症度分類および診療ガイドラインの確立に関する研究」研究班

補体 Vol. 57 ( 1 ) page： 3 - 22 2020.12

補体活性異常とC3腎症 Invited Reviewed

水野正司

日本小児腎臓病学会雑誌 Vol. 33 ( 1Suppl. ) page： 51 - 51 2020.12

ANALYSIS OF FREQUENCY AND KINDS OF ALARM HISTORIES OF HOME PD SYSTEM KAGUYA DURING THE INTRODUCTION: PERIOD IN A SINGLE CENTRE

Hiramatsu Tetsuaki, Mizuno Masasi, Suzuki Yasuhiro, Nomori Sumiyo, Suzuki Masafumi, Shiga Yoshiko, Sato Yuka, Nakamura Tomohiro, Ishimoto Takuji, Kosugi Tomoki, Maruyama Shoichi, Koyama Tomio

NEPHROLOGY Vol. 25 page： 77 - 78 2020.10

CASES OF ACUTE APPENDICITIS IN PATIENTS ON PERITONEAL DIALYSIS (PD) IN A SINGLE CENTRE DURING 15 YEARS

Mizuno, M; Suzuki, Y; Kojima, H; Sato, Y; Kinashi, H; Katsuno, T; Maruyama, S; Ito, Y

NEPHROLOGY Vol. 25 page： 82 - 82 2020.10

The effectiveness and safety of computed tomographic peritoneography and video-assisted thoracic surgery for hydrothorax in peritoneal dialysis patients: A retrospective cohort study in Japan. Reviewed International coauthorship International journal

Naoya Matsuoka, Makoto Yamaguchi, Akimasa Asai, Keisuke Kamiya, Hiroshi Kinashi, Takayuki Katsuno, Takaaki Kobayashi, Hirofumi Tamai, Takatoshi Morinaga, Takaaki Obayashi, Kichio Nakabayashi, Shigehisa Koide, Michimasa Nakanishi, Katsushi Koyama, Yasuhiro Suzuki, Takuji Ishimoto, Masashi Mizuno, Yasuhiko Ito

PloS one Vol. 15 ( 9 ) page： e0238602 2020.9

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

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

CD55 EXPRESSION CHANGES IN MESOTHELIAL CELLS OF PATIENTS ON PERITONEAL DIALYSIS (PD) THERAPY

補体からみたC3腎症とaHUS Invited

水野正司

日本小児腎臓病学会雑誌 Vol. 33 ( 1 ) page： 59 - 60 2020.4

Successful Introduction of Peritoneal Dialysis in an End-stage Renal Failure Patient with Idiopathic Aplastic Anemia Reviewed International journal

Suzuki Yasuhiro, Mizuno Masashi, Sakata Fumiko, Kojima Hiroshi, Sato Yuka, Kishimoto Mayuko, Suzuki Nobuaki, Kinashi Hiroshi, Saito Shoji, Katsuno Takayuki, Kosugi Tomoki, Maruyama Shoichi, Murata Makoto, Kiyoi Hitoshi, Ito Yasuhiko

Internal Medicine Vol. 59 ( 5 ) page： 683 - 687 2020

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

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.

DOI： 10.2169/internalmedicine.3775-19

Dietary salt restriction during conservative therapy may prevent declines in residual renal function for the first year after starting peritoneal dialysis in patients with end-stage renal diseases Invited Reviewed International journal

Tetsuaki Hiramatsu, Masashi Mizuno, Yasuhiro Suzuki, Sumiyo Nomori, Yoshiko Shiga, Ting Sun, Takako Ishii, Hiroshi Kojima, Takayuki Katsuno, Tomohiro Nakamura, Tomoki Kosugi, Shoichi Maruyama, Tomio Koyama, Satoshi Noguchi, Yasuhiko Ito

Integrative Food, Nutrition and Metabolism Vol. 7 ( 1 ) 2020

Excessive salt intake increases peritoneal solute transport rate via local tonicity-responsive enhancer binding protein in subtotal nephrectomized mice. Reviewed International journal

Sun T, Sakata F, Ishii T, Tawada M, Suzuki Y, Kinashi H, Katsuno T, Takei Y, Maruyama S, Mizuno M, Ito Y

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Vol. 34 ( 12 ) page： 2031 - 2042 2019.12

Ozeki Toshikazu, Mizuno Masashi, Kobayashi Kazuma, Iguchi Daiki, Sei Yumi, Suzuki Yasuhiro, Kojima Hiroshi, Fukui Sosuke, Yamashita Ryoko, Kinashi Hiroshi, Imai Masaki, Maruyama Shoichi, Ito Yasuhiko

MOLECULAR IMMUNOLOGY Vol. 114 page： 422 - 422 2019.10

Connective tissue growth factor is correlated with peritoneal lymphangiogenesis. Reviewed International coauthorship International journal

Hiroshi Kinashi, Naohiro Toda, Ting Sun, Tri Q Nguyen, Yasuhiro Suzuki, Takayuki Katsuno, Hideki Yokoi, Jan Aten, Masashi Mizuno, Shoichi Maruyama, Motoko Yanagita, Roel Goldschmeding, Yasuhiko Ito

Scientific reports Vol. 9 ( 1 ) page： 12175 - 12175 2019.8

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

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

C4著明低値を示した抗H因子抗体陽性C3腎炎の1例

田中寿弥, 木谷昂志, 塩津弥生, 砂原康人, 山内紘子, 中村格, 山下紀行, 草場哲郎, 益澤尚子, 小西英一, 澤井俊宏, 水野正司, 玉垣圭一

日本腎臓学会誌 Vol. 61 ( 6 ) page： 877 - 877 2019.8

Mouse NC/Jic strain provides novel insights into host genetic factors for malaria research International journal

Ohno Tamio, Miyasaka Yuki, Kuga Masako, Ushida Kaori, Matsushima Miyoko, Kawabe Tsutomu, Kikkawa Yoshiaki, Mizuno Masashi, Takahashi Masahide

Experimental Animals Vol. 68 ( 3 ) page： 243 - 255 2019.7

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

Malaria is caused by Plasmodium 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 P. falciparum 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.

DOI： 10.1538/expanim.18-0185

Effects of long-term treatment with low-GDP, pH-neutral solutions on peritoneal membranes in peritoneal dialysis patients. Reviewed International journal

Tawada M, Hamada C, Suzuki Y, Sakata F, Sun T, Kinashi H, Katsuno T, Takei Y, Maruyama S, Honda K, Mizuno M, Ito Y

Clinical and experimental nephrology Vol. 23 ( 5 ) page： 689 - 699 2019.5

Differences in peritoneal solute transport rates in peritoneal dialysis. Reviewed

Marina Asano, Takako Ishii, Akiyoshi Hirayama, Masashi Mizuno, Yasuhiro Suzuki, Fumiko Sakata, Shin-Ichi Akiyama, Shoichi Maruyama, Tomoyoshi Soga, Hiroshi Kinashi, Takayuki Katsuno, Yasuhiko Ito

Clinical and experimental nephrology Vol. 23 ( 1 ) page： 122 - 134 2019.1

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

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

Peritoneal expression of membrane complement regulators in peritoneal dialysis patients with fungal peritonitis

HIV-associated Immune Complex Kidney Disease with C3-dominant Deposition Induced by HIV Infection after Treatment of IgA Nephropathy Reviewed International journal

Kawakita Chieko, Kinomura Masaru, Otaka Nozomu, Kitagawa Masashi, Sugiyama Hitoshi, Kusano Nobuchika, Mizuno Masashi, Wada Jun

Internal Medicine Vol. 58 ( 20 ) page： 3001 - 3007 2019

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

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.

DOI： 10.2169/internalmedicine.2439-18

Investigation on the benefits of mycophenolate mofetil and therapeutic drug monitoring in the treatment of Japanese patients with lupus nephritis Reviewed International journal

Takayuki Katsuno, Takenori Ozaki, Takaya Ozeki, Asaka Hachiya, Hangsoo Kim, Noritoshi Kato, Takuji Ishimoto, Sawako Kato, Tomoki Kosugi, Naotake Tsuboi, Masashi Mizuno, Yasuhiko Ito, Shoichi Maruyama

Clinical and Experimental Nephrology Vol. 22 ( 6 ) page： 1341 - 1350 2018.12

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

Anti-C5a complementary peptide mitigates zymosan-induced severe peritonitis with fibrotic encapsulation in rat pretreated with methylglyoxal. Reviewed International journal

Iguchi D, Mizuno M, Suzuki Y, Sakata F, Maruyama S, Okada A, Okada H, Ito Y

American journal of physiology. Renal physiology Vol. 315 ( 6 ) page： F1732 - F1746 2018.12

Fukui Sosuke, Suzuki Yasuhiro, Tawada Mitsuhiro, Matsukawa Yoshihisa, Imai Masaki, Maruyama Shoichi, Ito Yasuhiko, Mizuno Masashi

MOLECULAR IMMUNOLOGY Vol. 102 page： 152 - 152 2018.10

Extracellular histones decrease the expression of membrane complement regulators Reviewed International journal

Mizuno Tomohiro, Nagano Fumihiko, Mizuno Masashi, Iwata Ayumi, Takahashi Kazuo, Tsuboi Naotake, Maruyama Shoichi, Nagamatsu Tadashi, Imai Masaki

MOLECULAR IMMUNOLOGY Vol. 102 page： 189-189 2018.10

Comprehensive analysis of complement proteins and genes in thrombotic microangiopathy in Japan

Hidaka, Y; Inoue, N; Ohtani, K; Ohtsuka, Y; Sawai, T; Miyata, T; Ohsawa, I; Okada, H; Kinoshita, T; Sekine, H; Tsukamoto, H; Nakao, M; Mizuno, M; Murakami, Y; Horiuchi, T; Wakamiya, N

MOLECULAR IMMUNOLOGY Vol. 102 page： 163 - 163 2018.10

SODIUM RESTRICTED DIET DURING CONSERVATIVE THERAPY IN PATIENTS WITH END-STAGE RENAL DISEASES (ESRD) MAY RESCUE RESIDUAL RENAL FUNCTION (RRF) FOR THE FIRST YEAR AFTER STARTING PERITONEAL DIALYSIS (PD)

Hiramatsu Tetsuaki, Mizuno Masashi, Nomori Sumiyo, Sakata Fumiko, Suzuki Yasuhiro, Maruyama Shoichi, Yasuhiko Ito, Noguchi Satoshi

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 33 page： . 2018.5

高齢腹膜透析患者の地域連携における現状と課題

伊藤恭彦, 水野正司, 鈴木康弘, 杉山斉, 深水圭, 猪阪善隆

医工学治療 Vol. 30 ( Suppl. ) page： 161 - 161 2018.3

TGF-beta 1-VEGF-A pathway induces neoangiogenesis with peritoneal fibrosis in patients undergoing peritoneal dialysis Reviewed International journal

Kariya Tetsuyoshi, Nishimura Hayato, Mizuno Masashi, Suzuki Yasuhiro, Matsukawa Yoshihisa, Sakata Fumiko, Maruyama Shoichi, Takei Yoshifumi, Ito Yasuhiko

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Vol. 314 ( 2 ) page： F167 - F180 2018.2

Current Status of Peritoneal Dialysis in Japan. Reviewed International coauthorship International journal

Ito Y, Tawada M, Tine S, Mizuno M, Suzuki Y, Katsuno T

Contributions to nephrology Vol. 196 page： 123 - 128 2018

Peritoneal eosinophils increase during induction of peritoneal dialysis and may be related to production of C3a in peritoneal dialysate

Mizuno Masashi, Shigemoto Emi, Kobayashi Kazuma, Iguchi Daiki, Sakata Fumiko, Suzuki Yasuhiro, Maruyama Shoichi, Ito Yasuhiko

MOLECULAR IMMUNOLOGY Vol. 89 page： 193-193 2017.9

Establishment of a complement examination system for complement-related diseases by the Japanese Association for Complement Research (JACR)

Yoshihiko Hidaka, Norimitsu Inoue, Yasufumi Ohtsuka, Toshihiro Sawai, Toshiyuki Miyata, Isao Osawa, Katsuki Ohtani, Hidechika Okada, Taroh Kinoshita, Hideharu Sekine, Hiroshi Tsukamoto, Miki Nakao, Masashi Mizuno, Yoshiko Murakami, Takahiko Horiuchi, Nobutaka Wakamiya

MOLECULAR IMMUNOLOGY Vol. 89 page： 192 - 192 2017.9

Hexamerization-enhanced CD20 antibody mediates complement-dependent cytotoxicity in serum genetically deficient in C9 Reviewed International coauthorship International journal

Ronald P. Taylor, Margaret A. Lindorfer, Erika M. Cook, Frank J. Beurskens, Janine Schuurman, Paul W. H. I. Parren, Clive S. Zent, Karl R. VanDerMeid, Richard Burack, Masashi Mizuno, B. Paul Morgan

CLINICAL IMMUNOLOGY Vol. 181 page： 24 - 28 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

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

Apoptosis inhibitor of macrophage ameliorates fungus-induced peritoneal injury model in mice Reviewed International journal

Takako Tomita, Satoko Arai, Kento Kitada, Masashi Mizuno, Yasuhiro Suzuki, Fumiko Sakata, Daisuke Nakano, Emiri Hiramoto, Yoshifumi Takei, Shoichi Maruyama, Akira Nishiyama, Seiichi Matsuo, Toru Miyazaki, Yasuhiko Ito

SCIENTIFIC REPORTS Vol. 7 ( 1 ) page： 6450 2017.7

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

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

Sodium chloride promotes tissue inflammation via osmotic stimuli in subtotal-nephrectomized mice Reviewed International coauthorship International journal

Fumiko Sakata, Yasuhiko Ito, Masashi Mizuno, Akiho Sawai, Yasuhiro Suzuki, Takako Tomita, Mitsuhiro Tawada, Akio Tanaka, Akiyoshi Hirayama, Akihiro Sagara, Takashi Wada, Shoichi Maruyama, Tomoyoshi Soga, Seiichi Matsuo, Enyu Imai, Yoshifumi Takei

LABORATORY INVESTIGATION Vol. 97 ( 4 ) page： 432 - 446 2017.4

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

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<0.001), heart (P<0.05) and para-aortic tissues (P<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

Therapeutic effects of a C5a antagonist, AcPepA, for severe peritoneal injuries associated with fungal infection in a rat model

Tetracycline Reduces Kidney Damage Induced by Loxosceles Spider Venom Reviewed International coauthorship International journal

Okamoto, CK; Van den Berg, CW; Masashi, M; Gonçalves-de-Andrade, RM; Tambourgi, DV

TOXINS Vol. 9 ( 3 ) 2017.3

Complement component 5 promotes lethal thrombosis International journal

Mizuno Tomohiro, Yoshioka Kengo, Mizuno Masashi, Shimizu Mie, Nagano Fumihiko, Okuda Tomoyuki, Tsuboi Naotake, Maruyama Shoichi, Nagamatsu Tadashi, Imai Masaki

SCIENTIFIC REPORTS Vol. 7 page： 42714 2017.2

PDのエビデンス

多和田光洋, 鈴木康弘, 水野正司, 伊藤恭彦

日本透析医学会雑誌 Vol. 50 ( 11 ) page： 685 - 691 2017

Masashi Mizuno, Daiki Iguchi, Emi Shigemoto, Kazuma Kobayashi, Fumiko Sakata, Yasuhiro Suzuki, Alan Okada, Hidechika Okada, Seiichi Matsuo, Yasuhiko Ito

IMMUNOBIOLOGY Vol. 221 ( 10 ) page： 1212 - 1212 2016.10

C5 promotes histone-induced lethal thromboembolism Reviewed

Tomohiro Mizuno, Kengo Yoshioka, Masashi Mizuno, Naotake Tsuboi, Shoichi Maruyama, Tadashi Nagamatsu, Masaki Imai

IMMUNOBIOLOGY Vol. 221 ( 10 ) page： 1140 - 1141 2016.10

Complement promote releasing transglutaminase 2 from cytoplasm Reviewed International journal

Hara Kaori, Mizuno Tomohiro, Takahashi Kazuo, Mizuno Masashi, Kato Akihiro, Onouchi Takanori, Tsutsumi Yutaka, Tatsukawa Hideki, Nagamatsu Tadashi, Hitomi Kiyotaka, Yuzawa Yukio

IMMUNOBIOLOGY Vol. 221 ( 10 ) page： 1142 - 1142 2016.10

TGF-beta-VEGF-A PATHWAY INDUCES NEOANGIOGENESIS IN PERITONEAL FIBROSIS OF PERITONEAL DIALYSIS

Tetsuyoshi Kariya, Yasuhiko Ito, Masashi Mizuno, Yasuhiro Suzuki, Fumiko Sakata, Takeshi Terabayashi, Takako Ishii, Mitsuhiro Tawada, Daiki Iguchi, Shoichi Maruyama, Seiichi Matsuo

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 31 page： 35 - 35 2016.5

APOPTOSIS INHIBITOR OF MACROPHAGE PROTEIN AMELIORATES FUNGUS-INDUCED PERITONEAL INJURY IN MICE BY UPREGULATION OF CLEARANCE OF NECROTIC DEBRIS

Takako Tomita, Yasuhiko Ito, Kento Kitada, Masashi Mizuno, Yasuhiro Suzuki, Fumiko Sakata, Daisuke Nakano, Shoichi Maruyama, Satoko Arai, Toru Miyazaki, Akira Nishiyama, Seiichi Matsuo

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 31 page： 1503 - 1503 2016.5

Vascular Endothelial Cell Injury Is an Important Factor in the Development of Encapsulating Peritoneal Sclerosis in Long-Term Peritoneal Dialysis Patients. Reviewed International journal

Tawada M, Ito Y, Hamada C, Honda K, Mizuno M, Suzuki Y, Sakata F, Terabayashi T, Matsukawa Y, Maruyama S, Imai E, Matsuo S, Takei Y

PloS one Vol. 11 ( 4 ) page： e0154644 2016.4

Depression of complement regulatory factors in rat and human renal grafts is associated with the pregress of acute T-cell medicated rejection. Reviewed

Yamanaka K., Kakuta Y., Miyagawa S., Nakazawa S., Kato T., Abe T., Imamura R., Okumi M., Maeda A., Mizuno M., Nonomura N.

PlosOne Vol. 11 ( 2 ) page： e0148881 2016

Rat Models of Acute and/or Chronic Peritoneal Injuries Including Peritoneal Fibrosis and Peritoneal Dialysis Complications

Mizuno Masashi, Ito Yasuhiko

KIDNEY RESEARCH: EXPERIMENTAL PROTOCOLS, 2ND EDITION Vol. 1397 page： 35 - 43 2016

Increase of Antimyeloperoxidase Antineutrophil Cytoplasmic Antibody (ANCA) in Patients with Renal ANCA-associated Vasculitis: Association with Risk to Relapse. Reviewed International journal

Yamaguchi M, Ando M, Kato S, Katsuno T, Kato N, Kosugi T, Sato W, Tsuboi N, Yasuda Y, Mizuno M, Ito Y, Matsuo S, Maruyama S

The Journal of rheumatology Vol. 42 ( 10 ) page： 1853 - 1860 2015.10

Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury Reviewed International journal

Takeshi Terabayashi, Yasuhiko Ito, Masashi Mizuno, Yasuhiro Suzuki, Hiroshi Kinashi, Fumiko Sakata, Takako Tomita, Daiki Iguchi, Mitsuhiro Tawada, Ryosuke Nishio, Shoichi Maruyama, Enyu Imai, Seiichi Matsuo, Yoshifumi Takei

LABORATORY INVESTIGATION Vol. 95 ( 9 ) page： 1029 - 1043 2015.9

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

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<0.05) and day 50 after reduction of inflammation (P<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<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

A case of difficult hemodialysis induction in a patient with acute intermittent porphyria

Development of encapsular peritoneal sclerosis (EPS)-like peritonitis in rat and complement activation International journal

Daiki Iguchi, Masashi Mizuno, Emi Shigemoto, Fumiko Sakata, Yasuhiro Suzuki, Alan Okada, Hidechika Okada, Shoichi Maruyama, Seiichi Matsuo, Yasuhiko Ito

MOLECULAR IMMUNOLOGY Vol. 67 ( 1 ) page： 145 - 146 2015.9

Calcified Amorphous Tumor in the Left Atrium in a Patient on Long-term Peritoneal Dialysis Reviewed International journal

Tanaka Akihito, Mizuno Masashi, Suzuki Yasuhiro, Oshima Hideki, Sakata Fumiko, Ishikawa Hideaki, Tsukushi Saori, Ito Yasuhiko

Internal Medicine Vol. 54 ( 5 ) page： 481 - 485 2015

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.

DOI： 10.2169/internalmedicine.54.2967

The efficacy of tolvaptan as a diuretic for chronic kidney disease patients. Reviewed

Tanaka A., Katsuno T., Ozaki T., Sakata F., Kato N., Suzuki Y., Kosugi T., Kato S., Tsuboi N., Sato W., Yasuda Y., Mizuno M., Ito Y., Matsuo S., Maruyama S.

Vol. 70 page： 217-223 2015

Smoking is a risk factor for the relapse of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

Yamaguchi M., Ando M., Kato S., Katsuno T., Kato N., Kosugi T., Sato W., Tsuboi N., Yasuda Y., Mizuno M., Ito Y., Matsuo S., Maruyama S

J Rheumatology page： in press 2015

Vasuclar endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury.

Terabayashi T, Ito Y, Mizuno M, Suzuki Y, Kinashi H, Sakata F, Tomita T, Iguchi D, Tawada M, Nishio R, Maruyama S, Imai E, Matsuo S, Takei Y.

Lab Invest page： in press 2015

Successful Treatment of Cryptococcus laurentii Peritonitis in a Patient on Peritoneal Dialysis International journal

Asano Marina, Mizutani Makoto, Nagahara Yasuko, Inagaki Koji, Kariya Tetsuyoshi, Masamoto Daijiro, Urai Makoto, Kaneko Yukihiro, Ohno Hideaki, Miyazaki Yoshitsugu, Mizuno Masashi, Ito Yasuhiko

Internal Medicine Vol. 54 ( 8 ) page： 941 - 944 2015

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 Cryptococcus species. Based on antifungal susceptibility testing, the treatment was changed to voriconazole and continued for 3 months. A genetic analysis identified the isolate as Cryptococcus laurentii (C. laurentii). This patient was diagnosed with C. laurentii PD-related peritonitis and was successfully treated with voriconazole and removal of the PD catheter.

DOI： 10.2169/internalmedicine.54.3586

Kojima Keitaro, Mizuno Masashi, Hattori Shinichi, Minoshima Kenichi, Yamaha Masayoshi, Horie Masanobu

Nihon Toseki Igakkai Zasshi Vol. 48 ( 7 ) page： 437 - 441 2015

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

腹膜透析排液中の補体活性化産物測定により、腹膜炎の予後を予想できるか?

Patient Age and the Prognosis of Idiopathic Membranous Nephropathy Reviewed International journal

Yamaguchi Makoto, Ando Masahiko, Yamamoto Ryohei, Akiyama Shinichi, Kato Sawako, Katsuno Takayuki, Kosugi Tomoki, Sato Waichi, Tsuboi Naotake, Yasuda Yoshinari, Mizuno Masashi, Ito Yasuhiko, Matsuo Seiichi, Maruyama Shoichi

PLOS ONE Vol. 9 ( 10 ) page： e110376 2014.10

Level of soluble C5b-9 complex in dialysis fluid may be a predictor of poor prognosis in peritonitis in peritoneal dialysis patients, especially in culture negative peritonitis International coauthorship International journal

Masashi Mizuno, Yasuhiko Ito, Keiko Higashide, Yumi Sei, Daiki Iguchi, Fumiko Sakata, Yasuhiro Suzuki, Isao Ito, Masanobu Horie, B. Paul Morgan, Seiichi Matsuo

MOLECULAR IMMUNOLOGY Vol. 61 ( 2 ) page： 225 - 225 2014.10

水野正司, 伊藤恭彦, 東出慶子, 清祐実, 井口大旗, 坂田史子, 鈴木康弘, 堀江正宣, Morgan B. Paul, 松尾清一

補体 Vol. 51 ( 1 ) page： 93 - 94 2014.8

Smoking is a risk factor for the progression of idiopathic membranous nephropathy Reviewed International journal

Makoto Yamaguchi, Masahiko Ando, Ryohei Yamamoto, Shinichi Akiyama, Sawako Kato, Takayuki Katsuno, Tomoki Kosugi, Waichi Sato, Naotake Tsuboi, Yoshinari Yasuda, Masashi Mizuno, Yasuhiko Ito, Seiichi Matsuo, Shoichi Maruyama

PLoS ONE Vol. 9 ( 6 ) page： e100835 2014.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Public Library of Science

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

ASSOCIATION OF ANKLE BRACHIAL INDEX AND PROTEIN-ENERGY WASTING WITH MORTALITY IN PATIENTS ON HEMODIALYSIS International journal

Keiko, K; Hirotake, K; Ryo, T; Chieko, M; Kiyohito, K; Hirohisa, K; Masashi, M; Yasuhiro, S; Shouichi, M; Yasuhiko, I; Seiichi, M

NEPHROLOGY Vol. 19 page： 178 - 179 2014.5

LYMPHANGIOGENESIS DEVELOPS DURING PERITONEAL FIBROSIS IN RAT PERITONITIS MODELS

Takeshi, T; Yasuhiko, I; Hiroshi, K; Masashi, M; Yasuhiro, S; Fumiko, S; Takako, T; Mitsuhiro, T; Yumi, S; Daiki, I; Seiichi, M

NEPHROLOGY Vol. 19 page： 193 - 193 2014.5

IMPROVEMENT OF PREVALENCE OF PERITONEAL DIALYSIS (PD) THERAPY IN END-STAGE RENAL DISEASE (ESRD) PATIENTS FROM 2010 TO 2012 IN THE TOKAI AREA OF JAPAN. - FIVE YEARS AFTER THE PREVIOUS STUDY

Mizuno Masashi, Ito Yasuhiko, Suzuki Yasuhiro, Saka Yosuke, Hiramatsu Takeyuki, Tamai Hirofumi, Mizutani Makoto, Naruse Tomohiko, Ohashi Norimi, Kasuga Hirotake, Shimizu Hideaki, Kurata Hisashi, Kurata Kei, Suzuki Satoshi, Maruyama Shoichi, Matsuo Seiichi

NEPHROLOGY Vol. 19 page： 113 - 113 2014.5

EXPRESSION OF MEMBRANE COMPLEMENT REGULATORS IN MESOTHERIAL CELLS OF PATIENTS' PERITONEUM ON PERITONEAL DIALYSIS THERAPY

Yumi, S; Masashi, M; Yasuhiro, S; Masaski, I; Keiko, H; Fumiko, S; Daiki, I; Noriko, O; Seiichi, M; Yasuhiko, I

NEPHROLOGY Vol. 19 page： 151 - 151 2014.5

Rat adipose tissue-derived stem cells attenuate peritoneal injuries in rat zymosan-induced peritonitis accompanied by complement activation Reviewed International journal

Kim Hangsoo, Mizuno Masashi, Furuhashi Kazuhiro, Katsuno Takayuki, Ozaki Takenori, Yasuda Kaoru, Tsuboi Naotake, Sato Waichi, Suzuki Yasuhiro, Matsuo Seiichi, Ito Yasuhiko, Maruyama Shoichi

CYTOTHERAPY Vol. 16 ( 3 ) page： 357 - 368 2014.3

Long-term effects of spironolactone in peritoneal dialysis patients. Reviewed

Ito Y., Mizuno M., Suzuki Y., Tamai G., Hiramatsu T.,Ohashi H., Ito I., Kasuga H., Horie M., Maruyama S., Yuzawa Y., Matsubara T., Matsuo S, Nagoya Spiro Study Group.

J Am Soc Nephrol page： in press 2014

Smoking is a risk factor for the progression of idiopathic membranous nephropathy. Reviewed

Yamaguchi M., Ando M., Yamamoto R., Akiyama S., Kato S., Katsuno T., Kosugi T., Sato W., Tsuboi N., Yasuda Y., Mizuno M., Ito Y., Matsuo S., Maruyama S.

PloS One Vol. ９ ( ６ ) page： e100835 2014

Patient age and the prognosis of idiopathic membrane nephropathy. Reviewed

Yamaguchi M., Ando M., Yamamoto R., Akiyama S., Kato S., Katsuno T., Kosugi T., Sato W., Tsuboi N., Yasuda Y., Mizuno M., Ito Y., Matsuo S., Maruyama S.

ProsOne Vol. 9 ( 10 ) page： e110376 2014

Future Expectations of Diagnostic Approaches for Treating Endogenous Peritonitis in Patients on Peritoneal Dialysis Reply International journal

Masashi Mizuno, Yasuhiro Suzuki, Yasuhiko Ito

INTERNAL MEDICINE Vol. 53 ( 6 ) page： 647 - 647 2014

Expression of membrane complement regulators in patients on peritoneal dialysis therapy International coauthorship International journal

Sei, Y; Mizuno, M; Imai, M; Suzuki, Y; Higashide, K; Okada, N; Harris, C; Matsuo, S; Ito, Y

MOLECULAR IMMUNOLOGY Vol. 56 ( 3 ) page： 277 - 278 2013.12

Anti-C5a complementary peptide ameliorates acute peritoneal injury induced by neutralization of Crry and CD59 Reviewed International journal

Tomohiro Mizuno, Masashi Mizuno, Masaki Imai, Yasuhiro Suzuki, Mayu Kushida, Yukihiro Noda, Shoichi Maruyama, Hidechika Okada, Noriko Okada, Seiichi Matsuo, Yasuhiko Ito

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Vol. 305 ( 11 ) page： F1603 - F1616 2013.12

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

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

An autopsy case of Clostridium perfringens peritonitis on CAPD related to malignant mesothelioma Reviewed

TGF-β1 promotes lymphangiogenesis during peritoneal fibrosis.

Kinashi H, Ito Y, Mizuno M, Suzuki Y, Terabayashi T, Nagura F, Hattori R, Matsukawa Y, Mizuno T, Noda Y, Nishimura H, Nishio R, Maruyama S, Imai E, Matsuo S, Takei Y

Journal of the American Society of Nephrology : JASN Vol. 24 ( 10 ) page： 1627 - 42 2013.10

Low serum cultured adipose tissue-derived stromal cells ameliorate acute kidney injury in rats. Reviewed

Katsuno T., Osaki T., Saka Y., Furuhashi K., Kim H., Yasuda K., Yamamoto T., Sato W., Tsuboi N., Mizuno M., Ito Y., Imai E., Matsuo S., Maruyama S.

Cell Transplant Vol. 22 ( 2 ) page： 287-297 2013

TGF-β1 promotes lymphangiogenesis during peritoneal fibrosis. Reviewed

Kinashi H, Ito Y, Mizuno M, Suzuki Y, Terabayashi T, Nagura F, Hattori R, Matsukawa Y, Mizuno T, Noda Y, Nishimura H, Nishio R, Maruyama S, Imai E, Matsuo S, Takei Y.

Journal of American Society of Nephrology Vol. 24 ( 10 ) page： 1627-1642 2013

Perforative peritonitis caused by appendicitis in a patient on peritoneal dialysis. Reviewed

Mizuno M, Suzuki Y, Nonaka K, Sei Y, Maruyama S, Matsuo S, Ito Y.

Internal Medicine Vol. 52 ( 11 ) page： 1177-1181 2013

Asano Marina, Inagaki Koji, Kariya Tetsuyoshi, Asano Shuichi, Masamoto Daijiro, Mizutani Makoto, Takahashi Yohei, Mizuno Masashi, Ito Yasuhiko

Nihon Toseki Igakkai Zasshi Vol. 46 ( 9 ) page： 949 - 954 2013

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. Clostridium perfringens and Streptococcus mitis 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

Low Serum Cultured Adipose Tissue-Derived Stromal Cells Ameliorate Acute Kidney Injury in Rats Reviewed International journal

Katsuno Takayuki, Ozaki Takenori, Saka Yosuke, Furuhashi Kazuhiro, Kim Hangsoo, Yasuda Kaoru, Yamamoto Tokunori, Sato Waichi, Tsuboi Naotake, Mizuno Masashi, Ito Yasuhiko, Imai Enyu, Matsuo Seiichi, Maruyama Shoichi

CELL TRANSPLANTATION Vol. 22 ( 2 ) page： 287 - 297 2013

Perforative Peritonitis caused by Appendicitis in a Patient on Peritoneal Dialysis Reviewed International journal

Mizuno Masashi, Suzuki Yasuhiro, Nonaka Keisuke, Sei Yumi, Maruyama Shoichi, Matsuo Seiichi, Ito Yasuhiko

INTERNAL MEDICINE Vol. 52 ( 11 ) page： 1177 - 1181 2013

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.

DOI： 10.2169/internalmedicine.52.9196

Rat adipose tissue-derived stromal cells in a low serum medium attenuate peritoneal injuries in rat zymosan-induced peritonitis Reviewed

Hangsoo Kim, Masashi Mizuno, Kazuhiro Furuhashi, Takayuki Katsuno, Takenori Ozaki, Kaoru Yasuda, Naotake Tsuboi, Enyu Imai, Seiichi Matsuo, Yasuhiko Ito, Shoichi Maruyama

IMMUNOBIOLOGY Vol. 217 ( 11 ) page： 1197 - 1197 2012.11

Short-term Administration of Diclofenac Sodium Affects Renal Function After Laparoscopic Radical Nephrectomy in Elderly Patients Reviewed International journal

Mizuno Tomohiro, Ito Kazuma, Miyagawa Yasuhiro, Ishikawa Kazuhiro, Suzuki Yasuhiro, Mizuno Masashi, Ito Yasuhiko, Funahashi Yasuhito, Hattori Ryohei, Gotoh Momokazu, Yamada Kiyofumi, Noda Yukihiro

JAPANESE JOURNAL OF CLINICAL ONCOLOGY Vol. 42 ( 11 ) page： 1073 - 1078 2012.11

C5a is a target to prevent peritoneal tissue damage in acute peritoneal injury in rats

Tomohiro Mizuno, Masashi Mizuno, Masaki Imai, Yasuhiro Suzuki, Mayu Kushida, Kiyofumi Yamada, Yukihiro Noda, Shoichi Maruyama, Hidechika Okada, Noriko Okada, Seiichi Matsuo, Yasuhiko Ito

IMMUNOBIOLOGY Vol. 217 ( 11 ) page： 1144 - 1144 2012.11

A rare case of acute kidney injury associated with autoimmune hemolytic anemia and thrombocytopenia after long-term usage of oxaliplatin Reviewed International journal

ITO Isao, ITO Yasuhiko, MIZUNO Masashi, SUZUKI Yasuhiro, YASUDA Kaoru, OZAKI Takenori, KOSUGI Tomoki, YASUDA Yoshinari, SATO Waichi, TSUBOI Naotake, MARUYAMA Shoichi, IMAI Enyu, MATSUO Seiichi

Vol. 16 ( 3 ) page： 490 - 494 2012.6

A rare case of acute kidney injury associated with autoimmune hemolytic anemia and thrombocytopenia after long-term usage of oxaliplatin Reviewed International journal

Isao Ito, Yasuhiko Ito, Masashi Mizuno, Yasuhiro Suzuki, Kaoru Yasuda, Takenori Ozaki, Tomoki Kosugi, Yoshinari Yasuda, Waichi Sato, Naotake Tsuboi, Shoichi Maruyama, Enyu Imai, Seiichi Matsuo

CLINICAL AND EXPERIMENTAL NEPHROLOGY Vol. 16 ( 3 ) page： 490 - 494 2012.6

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

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

Asymptomatic diverticulosis identified by computed tomography is not a risk factor for enteric peritonitis International journal

Susumu Toda, Yasuhiko Ito, Masashi Mizuno, Yasuhiro Suzuki, Isao Ito, Hideki Hiramatsu, Takenori Ozaki, Naotake Tsuboi, Waichi Sato, Shoichi Maruyama, Enyu Imai, Seiichi Matsuo

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 27 ( 6 ) page： 2511 - 2516 2012.6

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

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

Transforming growth factor-beta induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction International journal

Suzuki Yasuhiro, Ito Yasuhiko, Mizuno Masashi, Kinashi Hiroshi, Sawai Akiho, Noda Yukihiro, Mizuno Tomohiro, Shimizu Hideaki, Fujita Yoshiro, Matsui Katsuyuki, Maruyama Shoichi, Imai Enyu, Matsuo Seiichi, Takei Yoshifumi

KIDNEY INTERNATIONAL Vol. 81 ( 9 ) page： 865 - 879 2012.5

Atrial natriuretic peptide ameliorates peritoneal fibrosis in rat peritonitis model Reviewed International journal

Hiroshi Kato, Tomohiro Mizuno, Masashi Mizuno, Akiho Sawai, Yasuhiro Suzuki, Hiroshi Kinashi, Fumiko Nagura, Shoichi Maruyama, Yukihiro Noda, Kiyofumi Yamada, Seiichi Matsuo, Yasuhiko Ito

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 27 ( 2 ) page： 526 - 536 2012.2

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

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

Renal impairment after laparoscopic radical nephrectomy affects hypoglycaemic therapy Reviewed International journal

Mizuno T., Ito K., Miyagawa Y., Kimura K., Suzuki Y., Mizuno M., Ito Y., Funahashi Y., Hattori R., Gotoh M., Noda Y., Yamada K.

JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS Vol. 37 ( 1 ) page： 49 - 52 2012.2

Aliskiren-Induced Chyloperitoneum in a Patient on Peritoneal Dialysis Reviewed International journal

Y. Saka, H. Tachi, H. Sakurai, M. Tawada, A. Sawai, Y. Shimamura, M. Mizuno, S. Maruyama, S. Matsuo, Y. Ito

PERITONEAL DIALYSIS INTERNATIONAL Vol. 32 ( 1 ) page： 111 - U123 2012.1

Aliskiren-induced chyloperotoneum in a patient on peritoneal dialysis. et al. A case report. Reviewed

Saka Y, Tachi H, Sakurai H, Tawada M, Sawai A, Shimamura Y, Mizuno M, Maruyama S, Matsuo S, Ito Y.

Perit Dial Int Vol. 32 page： 111-113 2012

Guideline for hereditary angioedema (HAE) 2010 by the Japanese association for complement research. Invited Reviewed

Horiuchi T., Ohi H., Ohsawa I., Fujita T., Matsushita M., Okada N., Seya T., Yamamoto T., Endo Y., Hatanaka M., Wakamiya N., Mizuno M., Nakao M., Okada H., Tsukamoto H., Matsumoto M., Inoue N., Nonaka M., Kinoshita T.

Allergol Int Vol. 61 ( 4 ) page： 559-562 2012

Short-term administration of diclofenac sodium affects renal function after laparoscopic radical nephrectomu in elderly patients. Reviewed

Mizuno T., Ito K., Miyagawa Y., Ishikawa K., Suzuki Y., Mizuno M., Ito Y., Funabashi Y., Hattori R., Gotoh M., Yamada K., Noda Y.

Jpn J Clin Oncol Vol. 42 ( 11 ) page： 1073-1078 2012

Exploiting the nephrotoxic effects of venom from the sea anemone, Phyllodiscus semoni, to create a hemolytic uremic syndrome model in the rat. Invited Reviewed

Mizuno M., Ito Y, Morgan BP.

Marine Drugs Vol. 10 page： 1582-1604 2012

Combined values of serum albumin, C-reactive protein and body mass index at dialysis initiation accurately predicts log-term mortality. Reviewed

Takahashi R., Ito Y., Takahashi H., Ishii H., Kasuga H., Mizuno M., Suzuki Y., Yuzawa Y., Maruyama S., Murohara T., Imai E., Matsuo S.

Am J Nephrol Vol. 36 page： 136-143 2012

A rare case of acute kidney injury associated with autoimmune hemolytic anemia and thrombocytopenia after long-term usage of oxaliplatin. Reviewed

Ito I., Ito Y., Mizuno M., Suzuki Y., Yasuda K., Ozaki T., Kosugi T., Yasuda Y., Sato Y., Tsuboi N., Maruyama S., Imai E., Matsuo S.

Clin Exp Nephrol Vol. 16 page： 490-494 2012

Membrane complement regulators protect against fibrin exudation in a severe peritoneal inflammation model in rats. Reviewed

Mizuno M., Ito Y., Mizuno T., Suzuki Y., Harris CL., Okada N, Matsuo S, Morgan BP.

Am J Physil Renal Physiol Vol. 302 page： F1245-F1251 2012

Transforming growth factor-β induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction. Reviewed

Suzuki Y., Ito Y., Mizuno M., Kinashi H., Sawai A., Noda Y., Mizuno T., Shimizu H., Fujita Y., Matsui K., Maruyama S., Imai E., Matsuo S., Takei Y.

Kidney Int. Vol. 81 page： 865-879 2012

Renal impairment after laparoscopic radical nephrectomy affects hypoglycemic therapy. Reviewed

Mizuno T., Ito K., Miyagawa Y., Kimura K., Suzuki K., Mizuno M., Ito Y., Funabashi Y., Hattori R., Gotoh M., Noda Y., Yamada K.

J. Clin Pharm Therapy Vol. 37 page： 49-52 2012

Atrial natriuretic peptide ameliorates peritoneal fibrosis in a rat peritonitis model. Reviewed

Kato H., Mizuno T., Mizuno M., Sawai A., Suzuki Y., Kinashi H., Nagura F., Maruyama S., Noda Y., Yamada K., Matsuo S., Ito Y.

Nephrol. Dial. Transplant. Vol. 27 page： 526-536 2012

各論２　腹膜透析ガイドライン, 3. 腹膜炎管理 ISPDガイドラインを本邦の実地臨床にいかに活用するか？本邦のガイドラインをいかにすべきか？ Invited

伊藤恭彦、水野正司、鈴木康弘、清祐実、平松英樹、松尾清一

臨床透析 Vol. 28 page： 856-864 2012

至摘透析・体液管理, 腹膜透析における小・中・大分子量物質除去と腹膜機能の関連性

5. 平松英樹、伊藤恭彦、水野正司、鈴木康弘、戸田晋、坪井直毅、伊藤功、佐藤和一、丸山彰一、今井圓裕、林裕樹、松尾清一

腎と透析 2012 （腎と透析　別冊） Vol. 73 page： 235-236 2012

IV. 課題と対策（２）腹膜炎 - 名古屋大学関連施設レジストリーからみたPD腹膜炎の問題点. Invited

伊藤恭彦、水野正司、鈴木康弘、他

臨床と透析 Vol. 28 page： 571-577 2012

腹膜組織における補体活性化の観点からみた、現在の透析液の問題

水野正司、伊藤恭彦、鈴木康弘、松尾清一

腎と透析 2012 （腎と透析　別冊） Vol. 73 page： 109-110 2012

遺伝子組換えヒトエリスロポエチンによる赤血球造血刺激因子製剤療法低反応性腹膜透析患者の持続型赤血球層血刺激因子製剤Darbepoetin Alfa投与の効果 Reviewed

平松英樹、林祐樹、水野正司、鈴木康弘、戸田晋、伊藤功、丸山彰一、伊藤恭彦、松尾清一

日本透析医学会会誌 Vol. 45 page： 247-253 2012

Guideline for Hereditary Angioedema (HAE) 2010 by the Japanese Association for Complement Research - Secondary Publication International journal

Horiuchi Takahiko, Ohi Hiroyuki, Ohsawa Isao, Fujita Teizo, Matsushita Misao, Okada Noriko, Seya Tsukasa, Yamamoto Tetsuro, Endo Yuichi, Hatanaka Michiyo, Wakamiya Nobutaka, Mizuno Masashi, Nakao Miki, Okada Hidechika, Tsukamoto Hiroshi, Matsumoto Misako, Inoue Norimitsu, Nonaka Masaru, Kinoshita Taroh

Allergology International Vol. 61 ( 4 ) page： 559 - 562 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Allergology

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

Adequate administration of darbepoetin alfa improves renal anemia in Japanese peritoneal dialysis patients for whom the maximum dose of recombinant human erythropoietin did not fully achieve improved anemia International coauthorship

Hiramatsu Hideki, Hayashi Hiroki, Mizuno Masashi, Suzuki Yasuhiro, Toda Susumu, Ito Isao, Maruyama Shoichi, Ito Yasuhiko, Matsuo Seiichi

Nihon Toseki Igakkai Zasshi Vol. 45 ( 3 ) page： 247 - 253 2012

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 serumβ2 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

Combined Values of Serum Albumin, C-Reactive Protein and Body Mass Index at Dialysis Initiation Accurately Predicts Long-Term Mortality Reviewed International journal

Takahashi Ryo, Ito Yasuhiko, Takahashi Hiroshi, Ishii Hideki, Kasuga Hirotake, Mizuno Masashi, Suzuki Yasuhiro, Yuzawa Yukio, Maruyama Shoichi, Murohara Toyoaki, Imai Enyu, Matsuo Seiichi

AMERICAN JOURNAL OF NEPHROLOGY Vol. 36 ( 2 ) page： 136 - 143 2012

腹膜組織における補体活性化の観点からみた、現在の透析液の問題

水野正司, 伊藤恭彦, 鈴木康弘, 松尾清一

腎と透析 2012 （腎と透析別冊） Vol. 73 page： 109-110 2012

平松英樹, 林祐樹, 水野正司, 鈴木康弘, 戸田晋, 伊藤功, 丸山彰一, 伊藤恭彦, 松尾清一

日本透析医学会会誌 Vol. 45 page： 247-253 2012

各論２腹膜透析ガイドライン, 3. 腹膜炎管理 ISPDガイドラインを本邦の実地臨床にいかに活用するか？本邦のガイドラインをいかにすべきか？ Invited

伊藤恭彦, 水野正司, 鈴木康弘, 清祐実, 平松英樹, 松尾清一

臨床透析 Vol. 28 page： 856-864 2012

A case of perforative peritonitis caused by a piece of bamboo in a patient on peritoneal dialysis Reviewed International journal

SUZUKI Yasuhiro, MIZUNO Masashi, NAKASHIMA Ryoko, HIRAMATSU Hideki, TODA Susumu, SATO Waichi, TSUBOI Naotake, ITO Isao, MARUYAMA Shoichi, IMAI Enyu, MATSUO Seiichi, ITO Yasuhiko

Vol. 15 ( 6 ) page： 962 - 965 2011.12

A case of perforative peritonitis caused by a piece of bamboo in a patient on peritoneal dialysis Reviewed International journal

Yasuhiro Suzuki, Masashi Mizuno, Ryoko Nakashima, Hideki Hiramatsu, Susumu Toda, Waichi Sato, Naotake Tsuboi, Isao Ito, Shoichi Maruyama, Enyu Imai, Seiichi Matsuo, Yasuhiko Ito

CLINICAL AND EXPERIMENTAL NEPHROLOGY Vol. 15 ( 6 ) page： 962 - 965 2011.12

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

Peritonitis is still an important factor for withdrawal from peritoneal dialysis therapy in the Tokai area of Japan

MIZUNO Masashi, ITO Yasuhiko, TANAKA Akio, SUZUKI Yasuhiro, HIRAMATSU Hideki, WATANABE Midoriko, TSURUTA Yoshikazu, MATSUOKA Teppei, ITO Isao, TAMAI Hiroshi, KASUGA Hirotake, SHIMIZU Hideaki, KURATA Hisashi, INAGUMA Daijo, HIRAMATSU Takeyuki, HORIE Masanobu, NARUSE Tomohiko, MARUYAMA Shoichi, IMAI Enyu, YUZAWA Yukio, MATSUO Seiichi

Clinical and experimental nephrology Vol. 15 ( 5 ) page： 727 - 737 2011.10

Non-physiological osmolarity and pH in peritoneal dialysis fluid impair complement regulation in rat peritoneal mesothelial cells International coauthorship International journal

Mizuno, M; Mizuno, T; Ito, Y; Suzuki, Y; Kinashi, H; Noda, Y; Yamada, K; Okada, N; Morgan, BP; Matsuo, S

MOLECULAR IMMUNOLOGY Vol. 48 ( 14 ) page： 1690 - 1690 2011.8

Peritoneal macrophage infiltration is correlated with baseline peritoneal solute transport rate in peritoneal dialysis patients. Reviewed

Sawai A, Ito Y, Mizuno M, Suzuki Y, Toda S, Ito I, Hattori R, Matsukawa Y, Gotoh M, Takei Y, Yuzawa Y, Matsuo S

Vol. 26 ( 7 ) page： 2322-2332 2011.7

Peritoneal macrophage infiltration is correlated with baseline peritoneal solute transport rate in peritoneal dialysis patients Reviewed International journal

Sawai Akiho, Ito Yasuhiko, Mizuno Masashi, Suzuki Yasuhiro, Toda Susumu, Ito Isao, Hattori Ryohei, Matsukawa Yoshihisa, Gotoh Momokazu, Takei Yoshifumi, Yuzawa Yukio, Matsuo Seiichi

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 26 ( 7 ) page： 2322 - 2332 2011.7

Specific collaboration between rat membrane complement regulators Crry and CD59 protects peritoneum from damage by autologous complement activation Reviewed International coauthorship International journal

Tomohiro Mizuno, Masashi Mizuno, B. Paul Morgan, Yukihiro Noda, Kiyofumi Yamada, Noriko Okada, Yukio Yuzawa, Seiichi Matsuo, Yasuhiko Ito

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 26 ( 6 ) page： 1821 - 1830 2011.6

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' 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

A case of fulminant peritonitis caused by Streptococcus mitis in a patient on peritoneal dialysis. Reviewed

Mizuno M., Ito Y, Masuda T, Toda S, Hiramatsu H, Suzuki Y, Ozaki T, Yasuda Y, Ito I, Tsuboi N, Sato W, Maruyama S, Imai E, Matsuo S.

Intern Med Vol. 50 page： 471-474 2011

Lymphangiogenesis develop during tubulo-interstitial fibrosis via TGF-beta VEGF-C pathway in rat unilateral ureteral obstruction. Reviewed

Suzuki Y, Ito Y, Mizuno M, Sawai A, Kinashi H, Noda Y, Kato H, Shimizu H, Fujita Y, Matsui K, Imai E, Yuzawa Y, Matsuo S, Takei Y.

Kidney Int Vol. ??? in press page： ???????? 2011

Asymptomatic diverticulosis identified by computed tomography is not a risk factor for enteric peritonitis. Reviewed

Toda S, Ito Y, Mizuno M, Suzuki Y, Ito I, Hiramatsu H, Ozaki T, Tsuboi N, Sato W, Maruyama S, Imai E, Matsuo S.

Nephrol Dial Transplant Vol. ?? page： ?????? in press 2011

A case of perforative peritonitis by a piece of bamboo in a patient on peritoneal dialysis. Reviewed

Suzuki Y., Mizuno M., Nakashima R., Hiramatsu H., Toda S., Sato W., Tsuboi N., Ito I., Maruyama S., Imai E., Matsuo S., Ito Y.

Clin Exp Nephrol Vol. 15 page： 962-965 2011

A case of acute renal failure caused by cholesterol embolization after carotid artery stenting that was improved by peritoneal dialysis. Reviewed

Mizuno M., Ito Y., Hayasaki T., Suzuki Y., Hiramatsu H., Toda S., Tatematsu M., Ozaki T., Sato W., Tsuboi N., Ito I., Marumaya S., Imai E., Matsuo S.

Intern Med Vol. 50 page： 1719-1723 2011

A case of acute renal failure caused by cholesterol embolization after carotid artery stenting that was improved by peritoneal dialysis. Reviewed

Mizuno M., Ito Y., Hayasaki T., Suzuki Y., Hiramatsu H., Toda S., Tatematsu M., Ozaki T., Sato W., Tsuboi N., Ito I., Marumaya S., Imai E., Matsuo S.

Intern Med Vol. 50 page： 1719-1723 2011

腹膜透析にかかわる腹膜組織障害における補体の関与 Invited

水野正司、伊藤恭彦、松尾清一

医学のあゆみ Vol. 239 page： 779-783 2011

残腎機能を有する腹膜透析患者に対するシナカルセト投与時のMg、K代謝に及ぼす影響 Reviewed

柴田佳菜子、伊藤恭彦、水野正司、鈴木康弘、平松英樹、伊藤功、戸田晋、丸山彰一、中尾誠、松尾清一

日本透析医学会会誌 Vol. 44 page： 1007-1013 2011

A Case of Fulminant Peritonitis Caused by Streptococcus mitis in a Patient on Peritoneal Dialysis Reviewed International journal

Mizuno Masashi, Ito Yasuhiko, Masuda Tomohiro, Toda Susumu, Hiramatsu Hideki, Suzuki Yasuhiro, Ozaki Takenori, Yasuda Yoshinari, Ito Isao, Tsuboi Naotake, Sato Waichi, Maruyama Shoichi, Imai Enyu, Matsuo Seiichi

Internal Medicine Vol. 50 ( 5 ) page： 471 - 474 2011

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 Streptococcus mitis (S. mitis), part of the normal flora of oral cavity, intestine, female genial tract and upper respiratory tract. S. mitis shows pathogenicity for diseases such as endocarditis, brain abscesses and sepsis in children with malignancy or transplantation. However, S. mitis rarely shows severe pathogenic responses in adults. We report herein a case of fulminant peritonitis caused by S. mitis in an adult PD patient.

DOI： 10.2169/internalmedicine.50.4122

Effects of cinacalcet on magnesium and potassium metabolism in peritoneal dialysis patients with residual renal function International journal

Shibata Kanako, Ito Yasuhiko, Mizuno Masashi, Suzuki Yasuhiro, Hiramatsu Hideki, Ito Isao, Toda Susumu, Maruyama Shoichi, Matsuo Seiichi

Nihon Toseki Igakkai Zasshi Vol. 44 ( 10 ) page： 1007 - 1013 2011

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

A Case of Acute Renal Failure Caused by Cholesterol Embolization after Carotid Artery Stenting that was Improved by Peritoneal Dialysis International journal

Mizuno Masashi, Ito Yasuhiko, Hayasaki Takahiro, Suzuki Yasuhiro, Hiramatsu Hideki, Toda Susumu, Mizuno Tomohiro, Tatematsu Miho, Ozaki Takenori, Yasuda Yoshinari, Sato Waichi, Tsuboi Naotake, Ito Isao, Maruyama Shoichi, Imai Enyu, Matsuo Seiichi

Internal Medicine Vol. 50 ( 16 ) page： 1719 - 1723 2011

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.

DOI： 10.2169/internalmedicine.50.5358

Asymptomatic diverticulosis identified by computed tomography is not a risk factor for enteric peritonitis. Reviewed International journal

Toda S, Ito Y, Mizuno M, Suzuki Y, Ito I, Hiramatsu H, Ozaki T, Tsuboi N, Sato W, Maruyama S, Imai E, Matsuo S

Nephrol Dial Transplant Vol. ?? page： ?????? in press 2011

残腎機能を有する腹膜透析患者に対するシナカルセト投与時のMg、K代謝に及ぼす影響 Reviewed

柴田佳菜子, 伊藤恭彦, 水野正司, 鈴木康弘, 平松英樹, 伊藤功, 戸田晋, 丸山彰一, 中尾誠, 松尾清一

日本透析医学会会誌 Vol. 44 page： 1007-1013 2011

Pathological changes in chronic eosinophilic peritonitis in peritoneal dialysis patient. Reviewed International journal

Yuzawa Y, Ito Y, Mizuno M, Sawai A, Matsuo S

NDT plus Vol. 3 ( 4 ) page： 372 - 5 2010.8

Membrane complement regulators may protect against encapsular peritoneal sclerosis (EN) in a chronic proliferative peritoneal inflammation model of zymosan peritonitis in the rat International coauthorship International journal

Masashi Mizuno, Yasuhiko Ito, Tomohiro Mizuno, Yasuhiro Suzuki, Yukihiro Noda, Kiyofumi Yamada, Claire L. Harris, Noriko Okada, B. Paul Morgan, Seiichi Matsuo

MOLECULAR IMMUNOLOGY Vol. 47 ( 13 ) page： 2270 - 2270 2010.8

[Recent knowledge of complement system and the protective roles]. Invited

Mizuno M, Matsuo S

Nihon rinsho. Japanese journal of clinical medicine Vol. 68 Suppl 6 page： 49 - 52 2010.6

Connective tissue growth factor (CTGF/CCN2) is increased in peritoneal dialysis patients with high peritoneal solute transport rate Reviewed International coauthorship International journal

Mizutani Makoto, Ito Yasuhiko, Mizuno Masashi, Nishimura Hayato, Suzuki Yasuhiro, Hattori Ryohei, Matsukawa Yoshihisa, Imai Masaki, Oliver Noelynn, Goldschmeding Roel, Aten Jan, Krediet Raymond T., Yuzawa Yukio, Matsuo Seiichi

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Vol. 298 ( 3 ) page： F721 - F733 2010.3

Recent knowledge of complement system and the protective roles. Invited

Mizuno M, Matsuo S.

Nippon Rinsho Vol. 68 page： 49-52 2010

Acute kidney injury presenting a feature of leukemic infiltration during therapy for chronic myelogenous leukemia. Reviewed

Yuzawa Y, Sato W, Masuda T, Hamada Y, Tatematsu M, Yasuda Y, Ozaki T, Ito I, Mizuno M, Maruyama S, Ito Y, Matsuo S.

Intern Med Vol. 49 page： 1139-1142 2010

Connective tissue growth factor (CTGF/CCN2) is increased in peritoneal dialysis patients with high peritoneal solute transport rate. Reviewed

Mizutani M, Ito Y, Mizuno M, Nishimura H, Suzuki Y, Hattori R, Matsukawa Y, Imai M, Oliver N, Goldschmeding R, Aten J, Krediet RT, Yuzawa Y, Matsuo S.

Am J Physiol Renal Physiol Vol. 298 ( F721-F733 ) 2010

名大腎不全システム研究会レジストリによる東海地区13施設の３年間（2005～2007）解析から得た、現在の腹膜透析療法の傾向と問題点

2. 水野正司、伊藤恭彦、田中章郎、平松英樹、渡辺緑子、稲熊大城、戸田晋、檀原敦、玉井宏史、倉田久嗣、春日弘毅、志水英明、松岡哲平、鶴田吉和、堀江正宣、成瀬友彦、平松武幸、伊藤功、丸山彰一、湯澤由紀夫、松尾清一

腎と透析 2010 （腎と透析別冊） Vol. 69 page： 638-640 2010

基礎カンファレンス　腹膜線維化に関する基礎研究の進歩, 腹膜線維症・機能不全と成長因子　特にTGF-β/CTGF/VEGFからの検討

3. 伊藤恭彦、水野正司、水谷真、西村勇人、鈴木康弘、澤井晶穂、鬼無洋、湯澤由紀夫、松尾清一

腎と透析 2010（腎と透析　別冊） Vol. 69 page： 128-131 2010

IX.免疫学的検査C.補体および関連物質 Invited Reviewed

水野正司, 松尾清一

日本臨床 Vol. Vol.68 page： 49 - 52 2010

名大腎不全システム研究会レジストリによる東海地区13施設の3年間(2005～2007)解析から得た、現在の腹膜透析療法の傾向と問題点 Reviewed

水野正司, 伊藤恭彦, 松尾清一

腎と透析2010 Vol. Vol.69 page： 638 - 640 2010

基礎カンファレンス腹膜線維化に関する基礎研究の進歩、腹膜線維症・機能不全と成長因子

伊藤恭彦, 水野正司, 松尾清一

腎と透析2010 Vol. Vol.69 page： 128 - 131 2010

Acute Kidney Injury Presenting a Feature of Leukemic Infiltration during Therapy for Chronic Myelogenous Leukemia International journal

Yukio Yuzawa, Waichi Sato, Tomohiro Masuda, Yuzuru Hamada, Miho Tatematsu, Yoshinari Yasuda, Takenori Ozaki, Isao Ito, Masashi Mizuno, Shoichi Maruyama, Yasuhiko Ito, Seiichi Matsuo

INTERNAL MEDICINE Vol. 49 ( 12 ) page： 1139 - 1142 2010

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

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

基礎カンファレンス腹膜線維化に関する基礎研究の進歩, 腹膜線維症・機能不全と成長因子特にTGF-β/CTGF/VEGFからの検討

伊藤恭彦, 水野正司, 水谷真, 西村勇人, 鈴木康弘, 澤井晶穂, 鬼無洋, 湯澤由紀夫, 松尾清一

腎と透析 2010（腎と透析別冊） Vol. 69 page： 128-131 2010

名大腎不全システム研究会レジストリによる東海地区13施設の３年間（2005～2007）解析から得た、現在の腹膜透析療法の傾向と問題点

水野正司, 伊藤恭彦, 田中章郎, 平松英樹, 渡辺緑子, 稲熊大城, 戸田晋, 檀原敦, 玉井宏史, 倉田久嗣, 春日弘毅, 志水英明, 松岡哲平, 鶴田吉和, 堀江正宣, 成瀬友彦, 平松武幸, 伊藤功, 丸山彰一, 湯澤由紀夫, 松尾清一

腎と透析 2010 （腎と透析別冊） Vol. 69 page： 638-640 2010

Tissue-type plasminogen activator deficiency attenuates peritoneal fibrosis in mice Reviewed International journal

Kei Kurata, Shoichi Maruyama, Sawako Kato, Waichi Sato, Jun-ichiro Yamamoto, Takenori Ozaki, Atsumi Nitta, Toshitaka Nabeshima, Yoshiki Morita, Masashi Mizuno, Yasuhiko Ito, Yukio Yuzawa, Seiichi Matsuo

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Vol. 297 ( 6 ) page： F1510 - 7 2009.12

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

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

Specific collaboration between rat membrane complement regulators, Crry and CD59, protects peritoneum from damage by autologous complement activation in peritoneal dialysate fluid

Tomohiro Mizuno, Masashi Mizuno, B. Paul Morgan, Noriko Okada, Yukihiro Noda, Yukio Yuzawa, Seiichi Matsuo, Yasuhiko Ito

MOLECULAR IMMUNOLOGY Vol. 46 ( 14 ) page： 2859 - 2860 2009.9

Lymphatic vessels develop during tubulointerstitial fibrosis Reviewed International journal

Sakamoto Izumi, Ito Yasuhiko, Mizuno Masashi, Suzuki Yasuhiro, Sawai Akiho, Tanaka Akio, Maruyama Shoichi, Takei Yoshifumi, Yuzawa Yukio, Matsuo Seiichi

KIDNEY INTERNATIONAL Vol. 75 ( 8 ) page： 828 - 838 2009.4

Tissue-type plasminogen activator deficiency attenuates peritoneal fibrosis in mice. Reviewed

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.

Am J Physiol Renal Physiol Vol. 297 ( F1510-1517 ) 2009

Lymphatic vessels develop during tubulointerstitial fibrosis. Reviewed

Sakamoto I, Ito Y, Mizuno M, Suzuki Y, Sawai A, Tanaka A, Maruyama S, Takei Y, Yuzawa Y, Matsuo S.

Kidney Int Vol. 75 page： 828-838 2009

The role of membrane complement regulators in the normal peritoneal cavity

Tomohiro Mizuno, Masashi Mizuno, Yasuhiko Ito, Seiiti Matsuo, Yukihiro Noda

JOURNAL OF PHARMACOLOGICAL SCIENCES Vol. 109 page： 59P - 59P 2009

Zymosan, but not LPS, triggers severe and progressive peritoneal injury accompanied by complement activation in a rat peritonitis model initiated by mechanical scraping Reviewed International coauthorship International journal

Masashi Mizuno, Yasuhiko Ito, Tomohiro Mizuno, Claire L. Harris, B. Paul Morgan, Natalie Hepburn, Hayato Nishimura, Seiichi Matsuo

MOLECULAR IMMUNOLOGY Vol. 45 ( 16 ) page： 4153 - 4154 2008.10

Mineralocorticoid receptor blockade ameliorates peritoneal fibrosis in new rat peritonitis model Reviewed International journal

Nishimura Hayato, Ito Yasuhiko, Mizuno Masashi, Tanaka Akio, Morita Yoshiki, Maruyama Shoichi, Yuzawa Yukio, Matsuo Seiichi

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Vol. 294 ( 5 ) page： F1084 - F1093 2008.5

The mouse complement regulator CD59b is significantly expressed only in testis and plays roles in sperm acrosome activation and motility. Reviewed

Donev RM., Sivasankar B., Mizuno M., Morgan BP.

Mol. Immunol. Vol. 45 page： 534-542 2008.1

The mouse complement regulator CD59b is significantly expressed only in testis and plays roles in sperm acrosome activation and motility (Retracted article. See vol. 58, pg. 150, 2014) Reviewed International coauthorship International journal

Rossen M. Donev, Baalasubrarnanian Sivasankar, Masashi Mizuno, B. Paul Morgan

MOLECULAR IMMUNOLOGY Vol. 45 ( 2 ) page： 534 - 542 2008.1

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

\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

Immunisation with CD46 generates a strong autoantibody response targeting the spermatozoal acrosome in rat

Mineralocorticoid receptor blockade ameliorates peritoneal fibrosis in new rat peritonitis model. Reviewed

Nishimura H, Ito Y, Mizuno M, Tanaka A, Morita Y, Maruyama S, Yuzawa Y, Matsuo S.

Am J Physiol Renal Physiol Vol. 294 page： F1084-F1093 2008

『特集　アシドーシスとアルカローシス』代謝性酸塩基平衡異常における治療の基本とその方法 Invited

伊藤恭彦、水野正司

薬局 Vol. 59 page： 42-47 2008

本邦のCAPD療法の現況　–　CAPD療法に対する取り組み　大学・教育病院の役割 Invited

伊藤恭彦、水野正司、丸山彰一、湯澤　由紀夫、松尾清一

臨床透析 Vol. 24 page： 205-210 2008

Complement C3a receptor was highly found in the glomeruli of inflamed human lupus nephritis International coauthorship International journal

Mizuno, M; Blanchin, S; Gasque, P; Nishikawa, K; Matsuo, S

MOLECULAR IMMUNOLOGY Vol. 44 ( 16 ) page： 3953 - 3953 2007.9

CD59b is abundantly expressed only in testis and plays a role in acrosome activation and spermatozoal motility Reviewed International coauthorship International journal

Donev, RM; Sivasankar, B; Mizuno, M; Morgan, BP

MOLECULAR IMMUNOLOGY Vol. 44 ( 16 ) page： 3956 - 3956 2007.9

A protein toxin from the sea anemone Phyllodiscus semoni targets the kidney and causes a renal injury resembling haemolytic uremic syndrome. Reviewed

Mizuno M., Nozaki M., Morine N., Suzuki N., Nishikawa K., Morgan BP., Matsuo S.

Am. J. Pathol. Vol. 171 page： 402-414 2007.8

Authorship：Lead 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.

CD55 in rat male reproductive tissue: Differential expression in testis and expression of a unique truncated isoform on spermatozoa International coauthorship International journal

Mizuno, M; Donev, RM; Harris, CL; Morgan, BP

MOLECULAR IMMUNOLOGY Vol. 44 ( 7 ) page： 1613 - 1622 2007.3

Mizuno, M; Harris, CL; Morgan, BP

MOLECULAR IMMUNOLOGY Vol. 44 ( 1-3 ) page： 216 - 216 2007.1

High levels of complement C3a receptor in the glomeruli of inflamed human lupus nephritis. Reviewed

Mizuno M., Blanchin S., Gasque P., Nishikawa K., Matsuo S.

Am. J. Kidney Dis. Vol. 49 page： 598-606 2007

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

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.

よく使う利尿薬について習熟する　スピロノラクトン Invited

水野正司、伊藤恭彦

Medicina Vol. 44 page： 359-342 2007

Immunization with autologous CD46 in rats generates a strong autoantibody response that targets spermatozoa. Reviewed

Mizuno M., Harris CL., Morgan BP.

J. Reprod. Immunol. Vol. 73 page： 135-147 2007

【特集:これだけは知っておきたい分子腎臓学2007】 C5a. Invited

水野正司、湯澤由紀夫、松尾清一

腎と透析 Vol. 63 page： 580-582 2007

Complement membrane attack is required for endplate damage and clinical disease in passive experimental myasthenia gravis in Lewis rats Reviewed International coauthorship International journal

J. Chamberlain-Banoub, J. W. Neal, M. Mizuno, C. L. Harris, B. P. Morgan

CLINICAL AND EXPERIMENTAL IMMUNOLOGY Vol. 146 ( 2 ) page： 278 - 286 2006.11

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

The membrane attack pathway of complement drives pathology in passively induced experimental autoimmune myasthenia gravis in mice Reviewed International coauthorship International journal

B. P. Morgan, J. Chamberlain-Banoub, J. W. Neal, W. Song, M. Mizuno, C. L. Harris

CLINICAL AND EXPERIMENTAL IMMUNOLOGY Vol. 146 ( 2 ) page： 294 - 302 2006.11

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

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

Spermatogenic cells distal to the blood-testis barrier in rats lack C3 convertase regulators and may be at risk of complement-mediated injury.

Mizuno M, Harris CL, Morgan BP

Journal of reproductive immunology Vol. 69 ( 1 ) page： 23 - 34 2006.2

Complement and complement regulators in the male reproductive system Reviewed International coauthorship International journal

CL Harris, M Mizuno, BP Morgan

MOLECULAR IMMUNOLOGY Vol. 43 ( 1-2 ) page： 57 - 67 2006.1

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

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

Stage-specific expression of CD55 isoforms during spermiogenesis in the rat

Mizuno, M; Harris, CL; Donev, RM; Spiller, OB; Morgan, BP

MOLECULAR IMMUNOLOGY Vol. 43 ( 1-2 ) page： 156 - 156 2006.1

The membrane attack pathway of complement drives pathology in experimental autoimmune myasthenia gravis in mice. Reviewed

Morgan BP., Chamberlain-Banoub J., Neal JW.,Song W., Mizuno M., Harris CL.

Clin Exp Immunol Vol. 146 page： 294-302 2006

Complement and complement regulators in the male reproductive system. Invited Reviewed

Harris CL., Mizuno M., Morgan BP.

Mol Immunol Vol. 43 page： 57-67 2006

Complement membrane attack is required for endplate damage and clinical disease in experimental myasthenia gravis in Lewis rats. Reviewed

Chamberlain-Banoub J., Neal JW., Mizuno M., Harris CL., Morgan BP.

Clin Exp Immunol Vol. 146 page： 278-286 2006

CD55 expression in rat male reproductive tissue: Differential expression in testis and expression of a unique truncated isoform on spermatozoa. Reviewed

Mizuno M., Donev RM., Harris CL., Morgan BP.

Mol. Immunol. Vol. 44 page： 1624-1633 2006

A review of current knowledge of the complement system and the therapeutic opportunities in inflammatory arthritis. Invited Reviewed

Mizuno M.

Curr Med Chem Vol. 13 page： 1707-1717 2006

Unique expression patterns of membrane complement regulators and C3 in rat testes and spermatozoa delineate the blood-testis barrier and suggest distinct functional roles in germ cell development. Reviewed

Mizuno M., Harris CL., Morgan BP.

J Reprod Immunol Vol. 69 page： 23-34 2006

Mizuno M, Harris CL, Morgan BP

J Reprod Immunol Vol. 69 page： 23-34 2006

Shiga toxin 1causes direct renal injury in rats Reviewed International journal

Yamamoto ET, Mizuno M, Nishikawa K, Miyazawa S, Zhang LS, Matsuo S, Natori Y

INFECTION AND IMMUNITY Vol. 73 ( 11 ) page： 7099 - 7106 2005.11

Novel C5a regulators in inflammatory disease Invited Reviewed International journal

M Mizuno, DS Cole

EXPERT OPINION ON INVESTIGATIONAL DRUGS Vol. 14 ( 7 ) page： 807 - 821 2005.7

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

Inummohistochemical analysis of membrane complement regulatory proteins in rat testis: unique roles for DAF and MCP in spermatozoal function?

Expression of CD46 in developing rat spermatozoa: ultrastructural localisation and utility as a marker of the various stages of the seminiferous tubuli. Reviewed

Mizuno M., Harris CL., Suzuki N., Matsuo S., Morgan BP.

Biol Reprod Vol. 72 page： 908-915 2005

Shiga toxin-1 causes direct renal injury in rats. Reviewed

Yamamoto ET., Mizuno M., Nishikawa K., Miyazawa S., Zhang L., Matsuo S., Natori Y.

Infect Immun Vol. 73 page： 7099-7106 2005

Novel C5a regulators in inflammation. Invited Reviewed

Mizuno M., Cole DS.

Expert Opin Investig Drugs Vol. 14 page： 807-821 2005

CD59a is the primary regulator of membrane attack complex assembly in the mouse.

Baalasubramanian S, Harris CL, Donev RM, Mizuno M, Omidvar N, Song WC, Morgan BP

Journal of immunology (Baltimore, Md. : 1950) Vol. 173 ( 6 ) page： 3684 - 92 2004.9

Mizuno, M; Harris, CL; Morgan, BP

MOLECULAR IMMUNOLOGY Vol. 41 ( 2-3 ) page： 280 - 280 2004.6

The possibilities and pitfalls for anti-complement therapies in inflammatory diseases. Invited Reviewed

Mizuno M., Morgan BP.

Current Drug Targets Inflammation & Allergy Vol. 3 page： 85-94 2004

CD59a is the primary regulator of membrane attack complex assembly in the mouse. Reviewed

Baalasubramanian S., Harris CL., Donev RM., Mizuno M., Omidvar N., Song W., Morgan BP.

J. Immunol. Vol. 173 page： 3684-3692 2004

Rat membrane cofactor protein (MCP; CD46) is expressed only in the acrosome of developing and mature spermatozoa and mediates binding to immobilized activated C3. Reviewed

Mizuno M., Harris CL., Johnson PM., Morgan BP.

Biol Reprod Vol. 71 page： 1374-1383 2004

Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis. Reviewed

Williams AS., Mizuno M., Richards PJ., Holt DS., Morgan BP

Arthritis Rheum Vol. 50 page： 3035-3044 2004

In two patients on long-term hemodialysis, Etidronate Disodium improved their discomfort and extremities' blood flow associated with severe abnormal arterial wall calcification. Reviewed

Mizuno M., Kashima N., Kato K., Ito A, Matsuo S.

Clin Drug Invest Vol. 24 page： 365-371 2004

Improvement in Discomfort and Decreased Blood Flow Associated with Severe Arterial Wall Calcification following Etidronic Acid. Reviewed International journal

Mizuno M, Kashima N, Kato K, Ito A, Matsuo S

Clinical drug investigation Vol. 24 ( 6 ) page： 365 - 71 2004

Implication of the complement system in the induction of antiglomerular basement membrane glomerulonephritis in WKY rats Reviewed International journal

SHIKE Tatsuhiko, ISOME Masato, MIZUNO Masashi, SUZUKI Junzo, MATSUO Seiichi, YAMAMOTO Tadashi, SUZUKI Hitoshi

Pathol Int Vol. 53 ( 11 ) page： 757 - 761 2003.11

Implication of the complement system in the induction of anti-glomerular basement membrane glomerulonephritis in WKY rats.

Shike T, Isome M, Mizuno M, Suzuki J, Matsuo S, Yamamoto T, Suzuki H

Pathology international Vol. 53 ( 11 ) page： 757 - 61 2003.11

The nephrotoxicity of Aristolochia manshuriensis in rats is attributable to its aristolochic acids

LIU Man-Chang, MARUYAMA Shoichi, MIZUNO Masashi, MORITA Yoshiki, HANAKI Shigeru, YUZAWA Yukio, MATSUO Seiichi

Clinical and experimental nephrology Vol. 7 ( 3 ) page： 186 - 194 2003.9

The nephrotoxicity of Aristolochia manshuriensis in rats is attributable to its aristolochic acids Reviewed International journal

Man-Chang Liu, Shoichi Maruyama, Masashi Mizuno, Yoshiki Morita, Shigeru Hanaki, Yukio Yuzawa, Seiichi Matsuo

Clinical and Experimental Nephrology Vol. 7 ( 3 ) page： 186 - 194 2003.9

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

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

Scopus

Membrane cofactor protein (MCP; CD46) in the rat is expressed only in male germ cells and precursors

Mizuno, M; Harris, CL; Morgan, BP

MOLECULAR IMMUNOLOGY Vol. 40 ( 2-4 ) page： 202 - 203 2003.9

Characterization of the mouse analogues of CD59 using novel monoclonal antibodies: tissue distribution and functional comparison.

Harris CL, Hanna SM, Mizuno M, Holt DS, Marchbank KJ, Morgan BP

Immunology Vol. 109 ( 1 ) page： 117 - 26 2003.5

Characterization of the mouse analogues of CD59 using novel monoclonal antibodies: tissue distribution and functional comparison Reviewed International coauthorship International journal

CL Harris, SM Hanna, M Mizuno, DS Holt, KJ Marchbank, BP Morgan

IMMUNOLOGY Vol. 109 ( 1 ) page： 117 - 126 2003.5

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.

The use of polysulfone hemodialysis membrane may improve hyperlipemia in patients receiving long-term maintenance hemodialysis Reviewed

Non-dipping is a potent predictor of cardiovascular mortality and is associated with autonomic dysfunction in haemodialysis patients Reviewed International journal

Liu MC, Takahashi H, Morita Y, Maruyama S, Mizuno M, Yuzawa Y, Watanabe M, Toriyama T, Kawahara H, Matsuo S

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 18 ( 3 ) page： 563 - 569 2003.3

Non-dipping is a potent predictor of cardiovascular mortality and is associated with autonomic dysfunction in haemodialysis patients. Reviewed

Liu M., Takahashi H., Morita Y., Maruyama S., Mizuno M., Yuzawa Y., Watanabe M., Toriyama T., Kawahara H., MatsuoS.

Nephrol Dial Transplant. Vol. 18 page： 563-569 2003

Implication of the complement system in the induction of anti-glomerular basement membrane glomerulonephritis in WKY rats. Pathol. Reviewed

Shike T., Isome M., Mizuno M., Suzuki J., Matsuo S., Yamamoto T., Suzuki H.

Pathol. Int. Vol. 53 page： 757-761 2003

The nephrotoxicity of Aristolochia manshuriensis in rats is attributable to its aristolochic acids. Reviewed

Liu MC., Maruyama S., Mizuno M., Morita Y., Hanaki S., Yuzawa Y., Matsuo, S.

Clin Exp Nephrol Vol. 7 page： 186-194 2003

Characterization of the mouse analogues of CD59 using novel monoclonal antibodies: tissue distribution and functional comparison. Reviewed

Harris CL., Hanna SM., Mizuno M., Holt DS., Marchbank KJ., Morgan BP.

Immunology Vol. 109 page： 117-126 2003

Nephrogenic diabetes insipidus associated with hemochromatosis Reviewed International journal

Okumura A, Kondo K, Hirai C, Nishimura H, Tamai H, Kawarazaki F, Ichikawa M, Mizuno M, Oiso Y, Yamamoto M

AMERICAN JOURNAL OF KIDNEY DISEASES Vol. 40 ( 2 ) page： 403 - 406 2002.8

P-selectin-dependent macrophage migration into the tubulointerstitium in unilateral ureteral obstruction Reviewed International journal

Naruse T, Yuzawa Y, Akahori T, Mizuno M, Maruyama S, Kannagi R, Hotta N, Matsuo S

KIDNEY INTERNATIONAL Vol. 62 ( 1 ) page： 94 - 105 2002.7

MIZUNO Masashi, KOBAYASHI Kaoru, NAKATA Atsuhiro, WATANABE Midoriko, TORIYAMA Takanobu, KAWAHARA Hirohisa, MATSUO Seiichi

Vol. 35 ( 1 ) page： 43 - 49 2002.1

Soluble complement receptor type 1 protects rats from lethal shock induced by anti-Crry antibody following lipopolysaccharide priming

Mizuno M, Nishikawa K, Okada N, Matsuo S, Okada H

INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY Vol. 127 ( 1 ) page： 55 - 62 2002.1

Soluble complement receptor type 1 protects rats from lethal shock induced by anti-Crry antibody following lipopolysaccharide priming.

Mizuno M, Nishikawa K, Okada N, Matsuo S, Okada H

International archives of allergy and immunology Vol. 127 ( 1 ) page： 55 - 62 2002.1

高脂血症を伴う長期維持血液透析患者におけるポリスルフォン膜(PS-UW)の有用性について Reviewed

水野正司、小林薫、中田淳博、渡辺緑子、鳥山高伸、川原弘久、松尾清一

日本透析医学会雑誌 Vol. 35 page： 43-49 2002

二次性副甲状腺機能亢進症に対するmaxacalcitorol（オキサロールＲ）静注パルス療法の効果 ―早期低用量使用の試みー Reviewed

渡辺緑子、中田敦博、八島影人、河出恭雅、佐藤悌、小杉智規、鳥山高伸、河原弘久、水野正司、森田良樹、松尾清一

日本透析医学会誌 Vol. 35 page： 1193-1250 2002

Soluble CR1 protects rats from lethal shock induced by anti-Crry antibody following LPS priming. Reviewed

Mizuno M., Nishikawa K., Okada N., Mastuo S., Okada H.

Internal. Arch. Allergy Immunol. Vol. 127 page： 55-62 2002

Nephrogenic diabetes insipidus associated with hemochromatosis. Reviewed

Okumura A., Kondo K., Hirai C., Nishimura H., Tamai H., Kawarazaki F., Ichikaraki M., Mizuno M., Oiso Y., Yamamoto M.

Am J Kidney Dis Vol. 40 page： 403-406 2002

P-selectin-dependent macrophage migration into the tubulointerstitium in unilateral ureteral obstruction. Reviewed

Naruse T., Yuzawa Y., Akahori T, Mizuno M., Maruyama S., Kannagi R., Hotta S., Matsuo S.

Kidney Int. Vol. 62 page： 94-105 2002

The effects of low-dose intravenous maxacalcitol therapy on mild secondary hyperparathyroidism. Reviewed

Watanabe Midoriko, Nakata Atsuhiro, Yashima Akihito, Kawade Yasumasa, Sato Yasushi, Kosugi Tomoki, Toriyama Takanobu, Kawahara Hirohisa, Mizuno Masashi, Morita Yoshiki, Matsuo Seiichi

Nihon Toseki Igakkai Zasshi Vol. 35 ( 8 ) page： 1193 - 1198 2002

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

The use of polysulfone hemodialysis membrane may improve hyperlipemia in patients receiving long-term maintenance hemodialysis. Reviewed

Mizuno Masashi, Kobayashi Kaoru, Nakata Atsuhiro, Watanabe Midoriko, Toriyama Takanobu, Kawahara Hirohisa, Matsuo Seiichi

Nihon Toseki Igakkai Zasshi Vol. 35 ( 1 ) page： 43 - 49 2002

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. 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. 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

高脂血症を伴う長期維持血液透析患者におけるポリスルフォン膜(PS-UW)の有用性について Reviewed

水野正司, 小林薫, 中田淳博, 渡辺緑子, 鳥山高伸, 川原弘久, 松尾清一

日本透析医学会雑誌 Vol. 35 page： 43-49 2002

二次性副甲状腺機能亢進症に対するmaxacalcitorol（オキサロールＲ）静注パルス療法の効果 ―早期低用量使用の試みー Reviewed

渡辺緑子, 中田敦博, 八島影人, 河出恭雅, 佐藤悌, 小杉智規, 鳥山高伸, 河原弘久, 水野正司, 森田良樹, 松尾清一

日本透析医学会誌 Vol. 35 page： 1193-1250 2002

Blockage of complement regulators in the conjunctiva and within the eye leads to massive inflammation and iritis Reviewed

DS Bardenstein, CJ Cheyer, C Lee, E Cocuzzi, M Mizuno, N Okada, ME Medof

IMMUNOLOGY Vol. 104 ( 4 ) page： 423 - 430 2001.12

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.

The role of C5a in the development of thrombotic glomerulonephritis in rats

Kondo C, Mizuno M, Nishikawa K, Yuzawa Y, Hotta N, Matsuo S

CLINICAL AND EXPERIMENTAL IMMUNOLOGY Vol. 124 ( 2 ) page： 323 - 329 2001.5

The role of C5a in the development of thrombotic glomerulonephritis in rats. Reviewed International journal

Kondo C, Mizuno M, Nishikawa K, Yuzawa Y, Hotta N, Matsuo S

Clinical and experimental immunology Vol. 124 ( 2 ) page： 323 - 9 2001.5

Glomerulocystic kidney associated with subacute necrotizing-encephalomyelopathy International journal

T Yamakawa, F Yoshida, T Kumagai, H Watanabe, A Takano, M Mizuno, H Ikeguchi, Y Morita, G Sobue, S Matsuo

AMERICAN JOURNAL OF KIDNEY DISEASES Vol. 37 ( 2 ) page： E14 2001.2

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

【Innate immunity】　臨床　補体制御因子と疾患 Reviewed

松尾清一, 水野正司

現代医療 Vol. 33 page： 1011-1016 2001

【尿蛋白と尿細管障害】　尿中補体成分と尿細管障害 Invited

松尾清一, 森田良樹, 水野正司

細胞 Vol. 33 page： 12-15 2001

Glomerulocystic Kidney Associated With Subacute Necrotizing-Encephalomyelopathy. Reviewed

Yamakawa T., Yoshida H., Kumagai T., Watanabe H., Takano A., Mizuno M., Ikeguchi H., Morita Y., Sobue G., Matsuo S.

Am. J. Kidney Dis. Vol. 37 page： E14 2001

Blockage of complement regulators in the conjunctiva and within the eye leads to massive inflammation and iritis. Reviewed

Bardenstein SD., Cheyer JC, Lee C., Cocuzzi E., Mizuno M., Okada N., Medof EM.

Immunology Vol. 104 page： 423-430 2001

Membrane complement regulators protect against the development of type II collagen-induced arthritis (CIA) in rats. Reviewed

Mizuno M., Nishikawa K., Spiller OB., Morgan BP., Okada N., Okada H., Matsuo S.

Arthritis Rheum. Vol. 44 page： 2425-2434 2001

The effects of a new synthetic selectin blocker in an acute rat thrombotic glomerulonephritis. Reviewed

Ito I., Yuzawa Y., Mizuno M., Nishikawa K., Jomori T., Tashita A., Hotta N., Matsuo S.

Am. J. Kidney Dis. Vol. 38 page： 265-273 2001

The Role of C5a in The Development of Thrombotic Glomerulonephritis in Rats. Reviewed

Kondo C., Mizuno M., Nishikawa K., Yuzawa Y., Hotta N., Matsuo S.

Clin. Exp. Immunol. Vol. 124 page： 323-329 2001

【尿蛋白と尿細管障害】尿中補体成分と尿細管障害 Invited

松尾清一, 森田良樹, 水野正司

細胞 Vol. 33 ( 1 ) page： 12-15 - 15 2001

Abolition of anti-glomerular basement membrane antibody-mediated glomerulonephritis in FcRgamma-deficient mice. Reviewed International journal

Wakayama H, Hasegawa Y, Kawabe T, Hara T, Matsuo S, Mizuno M, Takai T, Kikutani H, Shimokata K

European journal of immunology Vol. 30 ( 4 ) page： 1182 - 90 2000.4

Comparison of the suppressive effects of soluble CR1 and C5a receptor antagonist in acute arthritis induced in rats by blocking of CD59 Reviewed International coauthorship

Mizuno M, Nishikawa K, Morgan BP, Matsuo S

CLINICAL AND EXPERIMENTAL IMMUNOLOGY Vol. 119 ( 2 ) page： 368 - 375 2000.2

Comparison of the suppressive effects of soluble CR1 and C5a receptor antagonist in acute arthritis induced in rats by blocking of CD59. Reviewed International coauthorship International journal

Mizuno M, Nishikawa K, Morgan BP, Matsuo S

Clinical and experimental immunology Vol. 119 ( 2 ) page： 368 - 75 2000.2

A case report of acute renal failure following a sting presumedly by a sea anemone. Reviewed

Mizuno M., Nishikawa K., Yuzawa Y., Kanie T., Mori H., Araki Y., Hotta N., Matsuo S.

Am. J. Kidney Dis. Vol. 36 page： E10 2000

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

【腎臓病の分子生物学】　腎障害のメディエータ　補体制御による進行性腎疾患治療の可能性

松尾清一, 水野正司

医学のあゆみ Vol. 193 page： 32-35 2000

【急性腎不全の全て-2000】　病因・病態　急性腎不全とサイトカイン Invited

松尾清一, 水野正司

腎と透析 Vol. 49 page： 373-376 2000

Comparison of the suppressive effects of soluble CR1 and C5a receptor antagonist in acute arthritis induced by anti-rat CD59 antibody. Reviewed

Mizuno M., Nishikawa K., Morgan B.P., Matsuo S.

Clin. Exp. Immunol. Vol. 119 page： 368-375 2000

The role of complement in the progression of renal fibrosis: a clinical study. Invited Reviewed

Matsuo S., Morita Y., Mizuno M., Nishikawa K., Yuzawa Y.

Nephrol. Dial. Transplant. Vol. 15 page： 53-54 2000

CD59 protects kidneys from complement mediated injury in collaboration with Crry in rats. Reviewed

Watanabe M., Morita Y., Mizuno M., Nishikawa K., Yuzawa Y., Hotta N., Morgan B.P., Okada N., Okada H., Matsuo S.

Kidney Int. Vol. 58 page： 1569-1579 2000

Abolition of anti-glomerular basement membrane antibody-mediated glomerulonephritis in FcRgamma-deficient mice. Reviewed

Wakayama H., Hasegawa Y., Kawabe T., Hara T., Matsuo S., Mizuno M., Takai T., Kikutani H., Shimokata K.

Eur. J. Immunol. Vol. 30 page： 1182-1190 2000

The role of complement in the progression of renal fibrosis: a clinical study Invited Reviewed International journal

S Matsuo, Y Morita, M Mizuno, K Nishikawa, Y Yuzawa

NEPHROLOGY DIALYSIS TRANSPLANTATION Vol. 15 page： 53 - 54 2000

A case report of acute renal failure following a sting presumedly by a sea anemone. Reviewed

Mizuno M, Nishikawa K, Yuzawa Y, Kanie T, Mori H, Araki Y, Hotta N, Matsuo S

Am. J. Kidney Dis. Vol. 36 page： E10 2000

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

Direct Gram staining of blood culture sample enabled the early diagnosis of brain abscess due to Listeria monocytogenes Reviewed

The role of complement in the progression of renal fibrosis: a clinical study. Reviewed International journal

Matsuo S, Morita Y, Mizuno M, Nishikawa K, Yuzawa Y

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Vol. 15 Suppl 6 page： 53 - 4 2000

TAKANO Akemi, ADACHI Hiroaki, MIZUNO Masashi, KAWAMURA Kumiko, SOBUE Gen

Rinsho Shinkeigaku (Clin Neurol) Vol. 39 ( 11 ) page： 1164 - 1167 1999.11

Inhibition of a membrane complement regulatory protein by a monoclonal antibody induces acute lethal shock in rats primed with lipopolysaccharide Reviewed International journal

M Mizuno, K Nishikawa, N Okada, S Matsuo, K Ito, H Okada

JOURNAL OF IMMUNOLOGY Vol. 162 ( 9 ) page： 5477 - 5482 1999.5

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.