Development of a new diagnostic method for pediatric HSPN using urinary biomarkers

2021 Fiscal Year Annual Research Report

• Project/Area Number: 18K07799
• Research Institution: Wakayama Medical University
• Principal Investigator: 島 友子 和歌山県立医科大学, 医学部, 講師 (60433364)
• Co-Investigator(Kenkyū-buntansha): 吉川 徳茂 社会医療法人愛仁会高槻病院(臨床研究センター), 腎臓疾患研究室, 室長 (10158412) ; 中西 浩一 琉球大学, 医学(系)研究科(研究院), 教授 (50336880)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 尿バイオマーカー / 紫斑病性腎炎 / 非侵襲的診断 / 腎生検組織

Outline of Annual Research Achievements

IgA血管炎は、小児全身性血管炎として最多で、20～80%の症例に紫斑病性腎炎（HSPN）を合併し、小児の二次性糸球体腎炎の中で最も頻度が高く、HSPNの重症度がIgA血管炎の予後を左右する最重要因子となっている。
現時点では腎予後と発症早期の組織学的重症度はよく相関するため、病勢の把握及び治療には腎生検による病理組織学的診断が必須であるが、腎生検は侵襲的検査であり，繰り返し行うことも困難な状況がある。また、HSPNの中には無治療自然軽快する症例もあれば、一部に末期腎不全進行症例もあり、腎生検及び治療介入時期の決定が難しい。
そこで尿バイオマーカーを用いたHSPN及び重症度診断が腎生検から得られる結果と同等にになれば非常に有用であるため、腎生検組織診断にて確定診断がついた、HSPN、IgA腎症及び腎疾患のないスクリーニング検査で尿検体を採取した小児から尿検体を採取し、尿中NGAL、KIM－1、L-FABP、IL-18等の測定に加えtotal RNAを抽出し、ｍRNAの検出及び定量を行い、HSPN特有の尿バイオマーカーのパターンや各腎生検組織病変（メサンギウ
ム増殖、管内細胞増多、分節性硬化/癒着、尿細管萎縮/間質線維化、半月体、全節性硬化）との相関を検討して、尿バイオマーカーによるHSPN及びその重症度を診断することを目的とした。
計128検体を収集し、尿バイオマーカーを測定した後解析を行い、メサンギウム増殖を示す腎炎群ではL-FABP1, Megalin, Thy1, Cubilinの発現の低下、IgA腎症及びHSPNのIgA関連腎疾患群ではL-FABP1の発現の低下、Podocinの発現とIL-18の濃度の上昇の所見を得たが、IgA腎症とHSPNとの判別は不能であった。

Research Products

• [Int'l Joint Research] Tronto General Hospital(カナダ)
  • Country Name: CANADA
  • Counterpart Institution: Tronto General Hospital
• [Int'l Joint Research] Regina Margarita Hospital(イタリア)
  • Country Name: ITALY
  • Counterpart Institution: Regina Margarita Hospital
• [Int'l Joint Research] University of Leicester(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: University of Leicester
• [Int'l Joint Research] Cedars-Sinai Medical Center(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Cedars-Sinai Medical Center
• [Int'l Joint Research] Peking University First Hospital(中国)
  • Country Name: CHINA
  • Counterpart Institution: Peking University First Hospital
• [Int'l Joint Research]
  • # of Other Countries: 4
• [Journal Article] Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes (2022)
  • Author(s): Ishiko S, Morisada N, Kondo A, Nagai S, Aoto Y, Okada E, Rossanti R, Sakakibara N, Nagano C, Horinouchi T, Yamamura T, Ninchoji T, Kaito H, Hamada R, Shima Y, Nakanishi K, Matsuo M, Iijima K, Nozu K.
  • Journal Title: Clin Exp Nephrol . Volume: 26 Pages: 140-153
  • DOI: 10.1007/s10157-021-02135-3
  • Peer Reviewed
• [Journal Article] Mycophenolate Mofetil after Rituximab for Childhood-Onset Complicated Frequently-Relapsing or Steroid-Dependent Nephrotic Syndrome (2022)
  • Author(s): Iijima K, Sako M, Oba M, Tanaka S, Hamada R, Sakai T, Ohwada Y, et al
  • Journal Title: J Am Soc Nephrol Volume: 33 Pages: 401-419
  • DOI: 10.1681/ASN.2021050643
  • Peer Reviewed / Open Access
• [Journal Article] A case of membranous nephropathy secondary to asymptomatic Graves' disease (2022)
  • Author(s): Moniwa N, Shioya Y, Gocho Y, Takahashi S, Tanaka M, Furuhashi M, Kuroda S, Hama T, Shima Y, Ogawa Y, Miura T.
  • Journal Title: CEN Case Rep. Volume: - Pages: -
  • DOI: 10.1007/s13730-021-00672-0
  • Peer Reviewed
• [Journal Article] Use of renin-angiotensin system inhibitors as initial therapy in children with Henoch-Schonlein purpura nephritis of moderate severity (2022)
  • Author(s): Nagai S, Horinouchi T, Ninchoji T, Kondo A, Aoto Y, Ishiko S, Sakakibara N, Nagano C, Yamamura T, Kaito H, Tanaka R, Shima Y, Fujimura J, Kamiyoshi N, Ishimori S, Nakanishi K, Yoshikawa N, Iijima K, Nozu K.
  • Journal Title: Pediatr Nephrol. Volume: - Pages: -
  • DOI: 10.1007/s00467-021-05395-z
  • Peer Reviewed
• [Journal Article] Efficacy of combination therapy for childhood complicated focal IgA nephropathy (2022)
  • Author(s): Aoto Y, Ninchoji T, Kaito H, Shima Y, Fujimura J, Kamiyoshi N, Ishimori S, Nakanishi K, Minamikawa S, Ishiko S, Sakakibara N, Nagano C, Horinouchi T, Yamamura T, Nagai S, Kondo A, Inaguma Y, Tanaka R, Yoshikawa N, Iijima K, Nozu K.
  • Journal Title: Clin Exp Nephrol. Volume: - Pages: -
  • DOI: 10.1007/s10157-022-02190-4
  • Peer Reviewed
• [Journal Article] Comprehensive genetic analysis using next-generation sequencing for the diagnosis of nephronophthisis-related ciliopathies in the Japanese population (2022)
  • Author(s): Sakakibara N, Nozu K, Yamamura T, Horinouchi T, Nagano C, Ye MJ, Ishiko S, Aoto Y, Rossanti R, Hamada R, Okamoto N, Shima Y, Nakanishi K, Matsuo M, Iijima K, Morisada N.
  • Journal Title: J Hum Genet. Volume: - Pages: -
  • DOI: 10.1038/s10038-022-01020-5
  • Peer Reviewed
• [Journal Article] Clinicopathological significance of glomerular capillary IgA deposition in childhood IgA nephropathy (2021)
  • Author(s): Shima Y, Nakanishi K, Mukaiyama H, Tanaka Y, Wada T, Tanaka R, Kaito H, Nozu K, Sako M, Iijima K, Yoshikawa N.
  • Journal Title: Pediatric Nephrology Volume: 36 Pages: 899-908
  • DOI: 10.1007/s00467-020-04772-4
  • Peer Reviewed
• [Journal Article] Non-immunosuppressive therapies for childhood IgA nephropathy. (2021)
  • Author(s): Shima Y, Nakanishi K, Yoshikawa N.
  • Journal Title: Pediatric Nephrology Volume: 36 Pages: 3057-3065
  • DOI: 10.1007/s00467-021-04954-8
  • Peer Reviewed
• [Journal Article] Utility of glomerular Gd-IgA1 staining for indistinguishable cases of IgA nephropathy or Alport syndrome (2021)
  • Author(s): Ishiko S, Tanaka A, Takeda A, Hara M, Hamano N, Koizumi M, Ueno T, Hayashi H, Kondo A, Nagai S, Aoto Y, Sakakibara N, Nagano C, Horinouchi T, Yamamura T, Ninchoji T, Shima Y, Nakanishi K, Yoshikawa N, Iijima K, Nozu K.
  • Journal Title: Clin Exp Nephrol. Volume: 25 Pages: 779-787
  • DOI: 10.1007/s10157-021-02054-3
  • Peer Reviewed
• [Journal Article] Clinical and histological features in pediatric and adolescent/young adult patients with renal disease: a cross-sectional analysis of the Japan Renal Biopsy Registry (J-RBR) (2021)
  • Author(s): Urushihara M, Sato H, Shimizu A, Sugiyama H, Yokoyama H, Hataya H, Matsuoka K, Okamoto T, Ogino D, Miura K, Hamada R, Hibino S, Shima Y, Yamamura T, Kitamoto K, Ishihara M, Konomoto T, Hattori M; the Committee for Renal Biopsy and Disease Registry of the Japanese Society of Nephrology.
  • Journal Title: Clin Exp Nephrol. Volume: 25 Pages: 1018-1026
  • DOI: 10.1007/s10157-021-02077-w
  • Peer Reviewed
• [Journal Article] Examination of the predicted prevalence of Gitelman syndrome by ethnicity based on genome database (2021)
  • Author(s): Kondo A, Nagano C, Ishiko S, Omori T, Aoto Y, Rossanti R, Sakakibara N, Horinouchi T, Yamamura T, Nagai S, Okada E, Shima Y, Nakanishi K, Ninchoji T, Kaito H, Takeda H, Nagase H, Morisada N, Iijima K, Nozu K.
  • Journal Title: Sci Rep. Volume: 11 Pages: 16099
  • DOI: 10.1038/s41598-021-95521-6
  • Peer Reviewed / Open Access
• [Journal Article] Systematic Review of Genotype-Phenotype Correlations in Frasier Syndrome (2021)
  • Author(s): Tsuji Y, Yamamura T, Nagano C, Horinouchi T, Sakakibara N, Ishiko S, Aoto Y, Rossanti R, Okada E, Tanaka E, Tsugawa K, Okamoto T, Sawai T, Araki Y, Shima Y, Nakanishi K, Nagase H, Matsuo M, Iijima K, Nozu K.
  • Journal Title: Kidney Int Rep . Volume: 6 Pages: 2585-2593
  • DOI: 10.1016/j.ekir.2021.07.010
  • Peer Reviewed / Open Access
• [Journal Article] Defining renal remission in an international cohort of 248 children and adolescents with lupus nephritis (2021)
  • Author(s): De Mutiis C, Wenderfer SE, Orjuela A, Bagga A, Basu B, Sar T, Aggarwal A, Jain A, Yap HK, Ito S, Ohnishi A, Iwata N, Kasapcopur O, Laurent A, Mastrangelo A, Ogura M, Shima Y, Rianthavorn P, Silva CA, Trindade V, Dormi A, Tullus K.
  • Journal Title: Rheumatology (Oxford) Volume: - Pages: keab746
  • DOI: 10.1093/rheumatology/keab746
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Last Nucleotide Substitutions of COL4A5 Exons Cause Aberrant Splicing (2021)
  • Author(s): Aoto Y, Horinouchi T, Yamamura T, Kondo A, Nagai S, Ishiko S, Okada E, Rossanti R, Sakakibara N, Nagano C, Awano H, Nagase H, Shima Y, Nakanishi K, Matsuo M, Iijima K, Nozu K.
  • Journal Title: Kidney Int Rep. Volume: 7 Pages: 108-116
  • DOI: 10.1016/j.ekir.2021.10.012.
  • Peer Reviewed / Open Access
• [Presentation] 重度の小児IgA腎症に対するプレドニゾロン、ミゾリビン、リシノプリルを用いた3剤併用治療法の有効性の検討 (2022)
  • Author(s): 島友子、向山弘展、田中侑、和田卓三、貝藤裕史、田中亮二郎、野津寛大、飯島一誠、吉川徳茂、中西浩一
  • Organizer: 第45回IgA 腎症研究会学術集会
• [Presentation] 遺伝子解析で診断しえた軽症常染色体劣性多発性嚢胞腎の長期経過 (2022)
  • Author(s): 島友子、向山弘展、田中侑、和田卓三、中西浩一
  • Organizer: 第35回近畿小児科学会
• [Presentation] Efficacy of New Combination Therapy with Prednisolone, Mizoribine, and Lisinopril for Severe Childhood IgA Nephropathy. (2021)
  • Author(s): Shima Y, Mukaiyama H, Tanaka Y, Wada T, Kaito H, R, Tanaka R, Nozu K, Iijima K, Yoshikawa N, Nakanishi K.
  • Organizer: The 54th Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] Two male relatives with OFD1 mutations. (2021)
  • Author(s): Wada T, Shima Y, Tanaka Y, Mukaiyama H, Morisada N, Nozu K, Iijima K, Nakanishi K.
  • Organizer: The 18th Japan-Korea-China Pediatric Nephrology Seminar
  • Int'l Joint Research
• [Presentation] Pediatric IgA Nephropathy. (2021)
  • Author(s): Shima Y
  • Organizer: The 16th congress of Asian Society for Pediatric Reserch
  • Int'l Joint Research / Invited
• [Presentation] Oxford分類を用いた小児IgA腎症、紫斑病性腎炎の臨床病理学的所見の比較 (2021)
  • Author(s): 島友子、中西浩一、田中侑、向山弘展、和田卓三、浜武継、佐藤匡、貝藤裕史、野津寛大、田中亮二郎、飯島一誠、鈴木啓之、吉川徳茂
  • Organizer: 第124回日本小児科学会学術集会
• [Presentation] Oxford 分類による小児 IgA 腎症（IgAN），紫斑病性腎炎（IgAVN）の臨床病理学的検討 (2021)
  • Author(s): 島友子、浜武継、向山弘展、田中侑、野津寛大、田中亮二郎、飯島一誠、吉川徳茂、中西浩一
  • Organizer: 第50回日本腎臓学会学術総会
• [Presentation] IgA腎症Oxford分類を用いた病理学的重症度スコアリングの開発と検証 (2021)
  • Author(s): 島友子、向山弘展、田中侑、和田卓三、野津寛大、田中亮二郎、飯島一誠、吉川徳茂、中西浩一
  • Organizer: 第56回日本小児腎臓病学会
• [Presentation] 遺伝子解析で診断しえた軽症常染色体劣性多発性嚢胞腎の長期経過 (2021)
  • Author(s): 島友子、島袋渡、向山弘展、田中侑、和田卓三、森貞直哉、野津寛大、飯島一誠、中西浩一
  • Organizer: 第29回発達腎研究会