Roles of the complement system to develop peritoneal inures in PD

• Project/Area Number: 18K08206
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Nagoya University
• Principal Investigator: Mizuno Masashi 名古屋大学, 医学系研究科, 特任教授 (20303638)
• Co-Investigator(Kenkyū-buntansha): 鈴木 康弘 名古屋大学, 医学系研究科, 特任講師 (20584676) ; 伊藤 恭彦 愛知医科大学, 医学部, 教授 (60402632)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 人工透析 / 腹膜透析 / 補体活性化 / 補体制御 / 腹膜傷害 / 腹膜炎 / 人工透析学 / 補体 / 真菌性腹膜炎

Outline of Final Research Achievements

①We clarified the protective effects of C1 inhibitor, which is currently used as an anti-complement (C) in patients with HAE, on peritoneal injury in an animal model of peritoneal dialysis (PD)-related fungal peritonitis. We are also proceeding to investigate any roles of the C terminal pathway in the process from peritoneal injury to encapsulated peritoneal sclerosis (EPS) using genetically modified animals of C-related proteins and neutralizing antibodies in the animal model.
②Using human PD effluent, we reported increase of peritoneal eosinophils due to enhanced activation of the C system when PD was introduced with neutralized PD fluid. We also observed that the expression of membrane C regulatory proteins was at least increased during PD treatment 3 years periods in primary cultures of peritoneal mesothelial cells (HMPC) of PD effluent of PD patients.

Academic Significance and Societal Importance of the Research Achievements

PDとCの関連性の探求は、世界に先駆けて我々が開拓進めている研究分野である。今回の我々の研究成果は、PDが腹膜のC活性および制御系に与えることを証明し、腹膜炎による腹膜傷害に抗C薬が治療の選択肢となる可能性を示した。また、腹膜炎や腹膜傷害とEPS 発症進展に対して抗C薬の治療選択の糸口となり、更に腹膜傷害進展の証明や、腹膜傷害とEPS進展を予想するC関連のバイオマーカーの発見が、より長期に安全な PD の実現につながる可能性を示唆する。

Research Products

• [Journal Article] Refractory Hypotension Caused by Selenium Deficiency in a Patient on Peritoneal Dialysis (2021)
  • Author(s): Ryuge A, Kim H, Suzuki Y, Okazaki M, Kojima H, Saito S, Kato N, Ishimoto T, Kosugi T, Maruyama S, Mizuno M.
  • Journal Title: Internal Medicine Volume: 60 Issue: 15 Pages: 2461-2464
  • DOI: 10.2169/internalmedicine.6632-20
  • NAID: 130008070597
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-08-01
  • Peer Reviewed
• [Journal Article] Oral Antibiotics are Effective for Preventing Colonoscopy-associated Peritonitis as a Preemptive Therapy in Patients on Peritoneal Dialysis (2021)
  • Author(s): Suzuki Y, Mizuno M, Kojima H, Sato Y, Kim H, Kinashi H, Katsuno T, Maruyama S, Ito Y.
  • Journal Title: Internal Medicine Volume: 60 Issue: 3 Pages: 353-356
  • DOI: 10.2169/internalmedicine.5092-20
  • NAID: 130007979708
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-02-01
  • Peer Reviewed
• [Journal Article] A case of temporary metastatic pulmonary calcification on peritoneal dialysis accompanied with ectopic hyperparathyroidism. (2021)
  • Author(s): Kawase K, Takagi K, Mizuno M, Horie M.
  • Journal Title: Clin Nephrol. Volume: 95 Issue: 3 Pages: 161-165
  • DOI: 10.5414/cn110337
  • Peer Reviewed
• [Journal Article] Safety and utility of the alpha replacer for treatment of intraluminal obstruction of peritoneal catheters by fibrin clots. (2021)
  • Author(s): Asai A, Kinashi H, Suzuki Y, Kojima H, Sato Y, Matsuoka N, Asai N, Kuroyanagi Y, Yamaguchi M, Nobata H, Katsuno T, Ishimoto T, Mizuno M, Ito Y.
  • Journal Title: Clin Exp Nephrol. Volume: 25 Issue: 4 Pages: 418-427
  • DOI: 10.1007/s10157-020-02001-8
  • Peer Reviewed
• [Journal Article] C1 inhibitor mitigates peritoneal injury in zymosan-induced peritonitis. (2021)
  • Author(s): Ozeki T, Mizuno M, Iguchi D, Kojima H, Kim H, Suzuki Y, Kinashi H, Ishimoto T, Maruyama S, Ito Y.
  • Journal Title: Am J Physiol Renal Physiol. Volume: － Issue: 6 Pages: F1123-F1132
  • DOI: 10.1152/ajprenal.00600.2020
  • Peer Reviewed
• [Journal Article] Successful Introduction of Peritoneal Dialysis in an End-stage Renal Failure Patient with Idiopathic Aplastic Anemia (2020)
  • Author(s): 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
  • Journal Title: Internal Medicine Volume: 59 Issue: 5 Pages: 683-687
  • DOI: 10.2169/internalmedicine.3775-19
  • NAID: 130007804622
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-03-01
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Vasculopathy plays an important role during the development and relapse of encapsulating peritoneal sclerosis with conventional peritoneal dialysis solutions (2020)
  • Author(s): 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
  • Journal Title: Nephrol Dial Transplant Volume: ー Issue: 8 Pages: 1-9
  • DOI: 10.1093/ndt/gfaa073
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impact on survival of urgent dialysis initiation in patients with end-stage renal disease: a case-control study. (2020)
  • Author(s): Takagi K, Mizuno M, Kawase K, Minoshima K, Tamada M, Horie M.
  • Journal Title: Clin Exp Nephrol. Volume: 24 Issue: 12 Pages: 1154-1161
  • DOI: 10.1007/s10157-020-01931-7
  • Peer Reviewed
• [Journal Article] 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 (2020)
  • Author(s): Matsuoka N, Yamaguchi M, Asai A, Kamiya K, Kinashi H, Katsuno T, Kobayashi T, Tamai H, Morinaga T, Obayashi T, Nakabayashi K, Koide S, Nakanishi M, Koyama K, Suzuki Y, Ishimoto T, Mizuno M, Ito Y.
  • Journal Title: Plos One Volume: Sep 3; 15(9) Issue: 9 Pages: e0238602-e0238602
  • DOI: 10.1371/journal.pone.0238602
  • Peer Reviewed / Open Access
• [Journal Article] Eculizumab for pediatric Dense Deposit Disease: a case report and literature review. (2020)
  • Author(s): Kasahara K, Gotoh Y, Majima H, Takeda A, Mizuno M.
  • Journal Title: Clin Nephrol. Case Studies Volume: 8 Issue: 01 Pages: 96-120
  • DOI: 10.5414/cncs110309
  • Peer Reviewed
• [Journal Article] 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. (2020)
  • Author(s): Hiramatsu T, Mizuno M, Suzuki Y, Nomori S, Shiga Y, Sun T, Ishii T, Hiroshi Kojima H, Katsuno T, Nakamura T, Kosugi T, Maruyama S, Koyama T, Noguchi S, Ito Y.
  • Journal Title: Integr Food Nutr Metab, Volume: - Issue: 1
  • DOI: 10.15761/ifnm.1000276
  • Peer Reviewed
• [Journal Article] Diffrences in peritoneal solute transport rates in peritoneal dialysis. (2019)
  • Author(s): Asano M, Ishii T, Hirayama A, Mizuno M, Suzuki Y, Sakata F, Akiyama S, Maruyama S, Soga T, Kinashi H, Katsuno T, Ito Y.
  • Journal Title: Clin Exp Nephrol. Volume: 23 Issue: 1 Pages: 122-134
  • DOI: 10.1007/s10157-018-1611-1
  • Peer Reviewed / Open Access
• [Journal Article] Increase of eosinophil in dialysate during induction of peritoneal dialysis. (2019)
  • Author(s): Shigemoto E, Mizuno M, Suzuki Y, Kobayashi K, Sakata F, Kariya T, Katsuno T, Maruyama S, Ito Y.
  • Journal Title: Perit Dial Int. Volume: 39 Issue: 1 Pages: 90-92
  • DOI: 10.3747/pdi.2017.00205
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effects of long-term treatment with low-GDP, pH-neutral solutions on peritoneal membranes in peritoneal dialysis patients. (2019)
  • Author(s): Tawada H, Hamada C, Suzuki Y, Sakata F, Sun T, Kinashi H, Katsuno T, Takei Y, Maruyama S, Honda K, Mizuno M, Ito Y.
  • Journal Title: Clin Exp Nephrol. Volume: 23 Issue: 5 Pages: 689-699
  • DOI: 10.1007/s10157-018-1679-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Excessive salt intake increases peritoneal solute transport rate via local tonicity-responsive enhancer binding protein in subtotal nephrectomized mice (2019)
  • Author(s): Sun Ting、Sakata Fumiko、Ishii Takako、Tawada Mitsuhiro、Suzuki Yasuhiro、Kinashi Hiroshi、Katsuno Takayuki、Takei Yoshifumi、Maruyama Shoichi、Mizuno Masashi、Ito Yasuhiko
  • Journal Title: Nephrology Dialysis Transplantation Volume: 34 Issue: 12 Pages: 2031-2042
  • DOI: 10.1093/ndt/gfz045
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Connective tissue growth factor is correlated with peritoneal lymphangiogenesis (2019)
  • Author(s): Kinashi Hiroshi、Toda Naohiro、Sun Ting、Nguyen Tri Q.、Suzuki Yasuhiro、Katsuno Takayuki、Yokoi Hideki、Aten Jan、Mizuno Masashi、Maruyama Shoichi、Yanagita Motoko、Goldschmeding Roel、Ito Yasuhiko
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 12175-12175
  • DOI: 10.1038/s41598-019-48699-9
  • NAID: 120006958096
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Complement regulation and kidney diseases: recent knowledge of the double-edged roles of complement activation in nephrology. (2018)
  • Author(s): Mizuno M, Suzuki Y, Ito Y.
  • Journal Title: Clinical Experimental Nephrology Volume: 22 Issue: 1 Pages: 3-14
  • DOI: 10.1007/s10157-017-1405-x
  • Peer Reviewed
• [Journal Article] TGF-β1-VEGF-A pathway induces neoaniogenesis with peritoneal fibrosis in patients undergoing pertoneal dialysis. (2018)
  • Author(s): Kariya T., Nishimura H., Mizuno M., Suzuki Y, Matsukawa Y., Sakata F., Maruyama S., Takei Y., Ito Y.
  • Journal Title: Am J Physiol Renal Physiol. Volume: 314 Issue: 2 Pages: F167-F180
  • DOI: 10.1152/ajprenal.00052.2017
  • Peer Reviewed / Open Access
• [Journal Article] Investigation on the benefits of mycophenolate mofetil and therapeutic drug monitoring in the treatment of Japanese patients with lupus nephritis. (2018)
  • Author(s): Katsuno T, Ozaki T, Ozeki T, Hachiya A, Kim H, Kato N, Ishimoto T, Kato S, Kosugi T, Mizuno M, Ito Y, Marutama S.
  • Journal Title: Clin Exp nephrol. Volume: 22 Issue: 6 Pages: 1341-1350
  • DOI: 10.1007/s10157-018-1590-2
  • NAID: 120006627981
  • Peer Reviewed
• [Journal Article] Current Status of Peritoneal Dialysis in Japan. (2018)
  • Author(s): Ito Y, Tawada M, Tine S, Mizuno M, Suzuki Y, Katsuno T.
  • Journal Title: Contrib Nephrol. Volume: 196 Pages: 123-128
  • DOI: 10.1159/000485711
  • ISBN: 9783318062977, 9783318062984
  • Peer Reviewed
• [Journal Article] Anti-C5a complementary peptide mitigates zymosan-induced severe peritonitis with fibrotic encapsulation in rat pretreated with methylglyoxal. (2018)
  • Author(s): Iguchi D, Mizuno M, Suzuki Y, Sakata Y, Maruyama Y, Okata A, Okada H, Ito Y.
  • Journal Title: Am J Physiol Renal Physol. Volume: 315 Issue: 6 Pages: F1732-F1746
  • DOI: 10.1152/ajprenal.00172.2018
  • Peer Reviewed
• [Presentation] Analysis of frequency and kinds of alarm histories of Home PD system「Kaguya」during the introduction period in a single center. (2020)
  • Author(s): Hiramatsu T, Mizuno M, Suzuki Y, Nomori S, Suzuki M, Shiga Y, Sato Y, Kojima H, Nakamura T, Maruyama S, Koyama T.
  • Organizer: APCN 2020
  • Int'l Joint Research
• [Presentation] Cases of acute appendicitis in patients on peritoneal dialysis (PD) in a single center during 15 years. (2020)
  • Author(s): Mizuno M, Suzuki Y, Kojima H, SatoY, Kinashi H, Katsuno T, Kosugi T, Maruyama S, Ito Y.
  • Organizer: APCN 2020
  • Int'l Joint Research
• [Presentation] ラット腹膜炎モデルにおいてC1-inhibitorは腹膜傷害の軽減に有効である (2020)
  • Author(s): 尾関俊和、水野正司、鈴木康弘、小島博、福井聡介、山下良子、神谷知明、丸山彰一、伊藤恭彦
  • Organizer: 第65回日本透析医学会学術集会
• [Presentation] Educational conference 1: Case discussion on management of PD related infection. (2019)
  • Author(s): Ito Y, Szeto CC, Mizuno M, Li PKT.
  • Organizer: APCM-ISPD2019
  • Int'l Joint Research / Invited
• [Presentation] Innate immunity in peritoneal cavity in peritoneal dialysis (PD) ～Peritoneal injuries and roles of the complement system in PD～ (2019)
  • Author(s): Mizuno M, Suzuki Y, Ito Y.
  • Organizer: APCM-ISPD2019
  • Int'l Joint Research / Invited
• [Presentation] Differences in peritoneal solute: transport rates of small-seized molecules in peritoneal dialysis. (2019)
  • Author(s): Asano M, Ishii T, Mizuno M，Suzuki Y，Sakata F，Akiyama S，Maruyama S，Kinashi H，Katsuno T，Ito Y.
  • Organizer: APCM-ISPD2019
  • Int'l Joint Research
• [Presentation] Peritoneal expression of membrane complement regulators in peritoneal dialysis patients with fungal peritonitis. (2019)
  • Author(s): Fukui S，Suzuki Y，MTawada M， Kojima H，Yuka Sato Y，Sugiyama N， Ting S，Yamashita R，Ozeki T， Kamiya T，Matsukawa Y，Imai M，Maruyama S，Ito Y，Mizuno M
  • Organizer: APCM-ISPD2019
  • Int'l Joint Research
• [Presentation] Effects of Long-term Treatment with Neutral Solutions on Peritoneal Membranes in Peritoneal Dialysis Patients. (2019)
  • Author(s): Tawada M, Ito Y, Hamada C, Mizuno M, Suzuki Y, Sun T, Kinashi H, Katsuno T, Honda K, Maruyama S
  • Organizer: APCM-ISPD2019
  • Int'l Joint Research
• [Presentation] Dietary salt restriction may be related to prevent declines in residual renal function (RRF) for the first year after starting peritoneal dialysis (PD) therapy. (2019)
  • Author(s): Hiramatsu T, Mizuno M, Suzuki Y, Nomori S, Shiga Y, Ishii T, Kojima H, Nakamura T, Maruyama S, Ito Y, Koyama T.
  • Organizer: APCM-ISPD2019
  • Int'l Joint Research
• [Presentation] TGF-β1-VEGF-A pathway and neoangiogenesis in patients of peritoneal dialysis. (2019)
  • Author(s): Kariya T, Nishimura H, Mizuno M, Suzuki Y, Matsukawa Y, Sakata F, Maruyama S, Takei Y, Ito Y.
  • Organizer: APCM-ISPD2019
  • Int'l Joint Research
• [Presentation] CD55 expression changes in mesothelial cells of patients on peritoneal dialysis (PD) therapy. (2019)
  • Author(s): 15.Ozeki T, Mizuno M, Kobayashi K, Iguchi D, Sei Y, Suzuki Y, Kojima H, Fukui S, Yamashita R, Kinashi H, Imai M, Maruyama S, Ito Y.
  • Organizer: 17th European meeting of complement in human disease
  • Int'l Joint Research
• [Presentation] C5 plays some roles to develop severe peritoneal injuries of a zymosan-induced peritonitis pretreated with methylglyoxal in rat. (2018)
  • Author(s): Mizuno M, Iguchi D, Shigemoto E, Kobayashi K, Sakata F, Kinashi H, Suzuki Y, Maruyama S, Ito Y
  • Organizer: 2018 ISPD
  • Int'l Joint Research
• [Presentation] Induction of peritoneal dialysis in an end stage renal failure patient with aplastic anemia. (2018)
  • Author(s): Suzuki Y, Mizuno M, Sakata F, Katsuno T, Maruyama S, Ito Y
  • Organizer: 2018 ISPD
  • Int'l Joint Research
• [Presentation] Apoptosis inhibitor of macrophage promoted engulfment of necrotic debris by macrophages and mesothelial cell. (2018)
  • Author(s): Ito Y, Tomita T, Suzuki Y, Sakata F, Arai S, Miyazaki T, Maruyama S, Mizuno M
  • Organizer: 2018 ISPD
  • Int'l Joint Research
• [Presentation] High salt intake increases baseline peritoneal solute transport rate in nephrectotomized mice. (2018)
  • Author(s): Sun T, Mizuno M, Suzuki C, Sakata F, Tomita T, Maruyama S, Ito Y
  • Organizer: 2018 ISPD
  • Int'l Joint Research
• [Presentation] Sodium restricted diet during conservative therapy in patients with end-stage renal diseases may rescue residual renal function for the first year after starting peritoneal dialysis. (2018)
  • Author(s): Hiramatsu H, Mizuno M, Nomori S, Sakata F, Suzuki Y, Kosuhi T, Maruyama S, Ito Y, Noguchi S
  • Organizer: 55th ERA-EDTA congress
  • Int'l Joint Research
• [Presentation] Comprehensive analysis of complement proteins and genes in thrombotic microangiopathy by the Japanese Association for Complement Research (JACR). (2018)
  • Author(s): 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
  • Organizer: The 27th International complement workshop
  • Int'l Joint Research
• [Presentation] Peritoneal expression of membrane complement regulators in peritoneal dialysis patients with fungal peritonitis. (2018)
  • Author(s): Fukui S, Suzuki Y, Tawada M, Matsukawa Y, Imai M, Maruyama S, Ito Y, Mizuno M
  • Organizer: The 27th International complement workshop
  • Int'l Joint Research
• [Presentation] Extracellular histones decrease the expression of membrane complement regulators. (2018)
  • Author(s): Mizuno T, Nagano F, Mizuno M, Iwata A, Takahashi K, Tsuboi N, Maruyama S, Nagamatsu T, Imai M
  • Organizer: The 27th International complement workshop
  • Int'l Joint Research
• [Presentation] Safety and effectiveness of eculizumab for adult patients with atypical hemolytic uremic syndrome in Japan: interim analysis of post-marketing surveillance. (2018)
  • Author(s): Okada H, Kato H, Miyakawa Y, Hidaka Y, Inoue N, Ito S, Kagami S, Kaname S, Matsumoto M, Mizuno M, Matsuda T, Shimono A, Maruyama S, Fujimura Y, Nangaku M.
  • Organizer: ASN kidney week 2018
  • Int'l Joint Research
• [Presentation] High Salt Intake Increases Baseline Peritoneal Transport Rate Through Local TonEBP Activation in Subtotal Nephrectomized Mice. (2018)
  • Author(s): Sun T, Mizuno M, Suzuki Y, Tomita T, Sakata F, Maruyama S, Katsuno T, Kinashi H, Ito Y
  • Organizer: ASN kidney week 2018
  • Int'l Joint Research
• [Presentation] Connective Tissue Growth Factor Is Correlated with Peritoneal Lymphangiogenesis. (2018)
  • Author(s): Kinashi H, Yanagita M, Goldschmeding R, Ito Y, Toda N, Nguyen TQ, Suzuki Y, Katsuno T, Yokoi H, Aten J, Mizuno M, Maruyama S.
  • Organizer: ASN kidney week 2018
  • Int'l Joint Research