TY - JOUR
T1 - Genetic Background and Clinicopathologic Features of Adult-onset Nephronophthisis
AU - Fujimaru, Takuya
AU - Kawanishi, Kunio
AU - Mori, Takayasu
AU - Mishima, Eikan
AU - Sekine, Akinari
AU - Chiga, Motoko
AU - Mizui, Masayuki
AU - Sato, Noriaki
AU - Yanagita, Motoko
AU - Ooki, Yuki
AU - Nagahama, Kiyotaka
AU - Ohnuki, Yuko
AU - Hamano, Naoto
AU - Watanabe, Saki
AU - Mochizuki, Toshio
AU - Nagatsuji, Katsushi
AU - Tanaka, Kenichi
AU - Tsukamoto, Tatsuo
AU - Tsushima, Hideo
AU - Shimamoto, Mamiko
AU - Tsuji, Takahiro
AU - Kuyama, Tamaki
AU - Kawamoto, Shinya
AU - Maki, Kenji
AU - Katsuma, Ai
AU - Oishi, Mariko
AU - Yamamoto, Kouhei
AU - Mandai, Shintaro
AU - Kikuchi, Hiroaki
AU - Ando, Fumiaki
AU - Mori, Yutaro
AU - Susa, Koichiro
AU - Iimori, Soichiro
AU - Naito, Shotaro
AU - Rai, Tatemitsu
AU - Hoshino, Junichi
AU - Ubara, Yoshifumi
AU - Miyazaki, Mariko
AU - Nagata, Michio
AU - Uchida, Shinichi
AU - Sohara, Eisei
N1 - Funding Information:
Supported in part by the Grants-in-Aid for Scientific Research (25221306, 16H05314, 19H01049, and 19H03672), the Challenging Exploratory Research (15K15327, 16K15467, and 18K19534), the Research Activity Start-up (17H06657, 20K22926), the Young Scientists (19K17733), and the Early-Career Scientists (19K17730) from the Japan Society of the Promotion of Science; the Health Labor Science Research Grant from the Ministry of Health Labor and Welfare, AMED under Grant Number JP18ek0109304 ; grants from the Yukiko Ishibashi Foundation; the Salt Science Research Foundation (1925, 2030); and low-vacuum scanning electron microscope device support from the LVSEM Study Group of Renal Biopsy and Hitachi High-Technologies Corporation in Japan Grant Number 007.
Funding Information:
TM reports personal fees from honoraria for lectures and personal fees from employment outside the submitted work. JH has received a research grant from Otsuka Pharmaceutical Co. All the other authors declared no competing interests.
Publisher Copyright:
© 2021 International Society of Nephrology
PY - 2021/5
Y1 - 2021/5
N2 - Introduction: Recently, nephronophthisis (NPH) has been considered a monogenic cause of end-stage renal disease (ESRD) in adults. However, adult-onset NPH is difficult to accurately diagnose and has not been reported in a cohort study. In this study, we assessed the genetic background and clinicopathologic features of adult NPH. Methods: We investigated 18 sporadic adult patients who were suspected as having NPH by renal biopsy. We analyzed 69 genes that cause hereditary cystic kidney disease and compared clinicopathologic findings between patients with and without pathogenic mutations in NPH-causing genes. Results: Seven of 18 patients had pathogenic NPH-causing mutations in NPHP1, NPHP3, NPHP4, or CEP164. Compared with patients without pathogenic mutations, those with pathogenic mutations were significantly younger but did not significantly differ in the classic NPH pathologic findings, such as tubular cysts. On the other hand, the number of tubules with thick tubular basement membrane (TBM) duplication, which was defined as >10-μm thickness, was significantly higher in patients with genetically proven adult NPH than in those without pathogenic mutations. α-Smooth muscle actin (α-SMA)-positive myofibroblasts were detected inside thick TBM duplication. Conclusions: In adult patients with NPH, thick TBM duplication was the specific finding. Our analysis also suggested that older patients tended to have no pathogenic mutations, even when they were suspected to have NPH by renal biopsy. These findings could be the novel clinical clue for the diagnosis of NPH in adult patients.
AB - Introduction: Recently, nephronophthisis (NPH) has been considered a monogenic cause of end-stage renal disease (ESRD) in adults. However, adult-onset NPH is difficult to accurately diagnose and has not been reported in a cohort study. In this study, we assessed the genetic background and clinicopathologic features of adult NPH. Methods: We investigated 18 sporadic adult patients who were suspected as having NPH by renal biopsy. We analyzed 69 genes that cause hereditary cystic kidney disease and compared clinicopathologic findings between patients with and without pathogenic mutations in NPH-causing genes. Results: Seven of 18 patients had pathogenic NPH-causing mutations in NPHP1, NPHP3, NPHP4, or CEP164. Compared with patients without pathogenic mutations, those with pathogenic mutations were significantly younger but did not significantly differ in the classic NPH pathologic findings, such as tubular cysts. On the other hand, the number of tubules with thick tubular basement membrane (TBM) duplication, which was defined as >10-μm thickness, was significantly higher in patients with genetically proven adult NPH than in those without pathogenic mutations. α-Smooth muscle actin (α-SMA)-positive myofibroblasts were detected inside thick TBM duplication. Conclusions: In adult patients with NPH, thick TBM duplication was the specific finding. Our analysis also suggested that older patients tended to have no pathogenic mutations, even when they were suspected to have NPH by renal biopsy. These findings could be the novel clinical clue for the diagnosis of NPH in adult patients.
KW - adult-onset kidney disease
KW - chronic kidney disease
KW - human genetics
KW - nephronophthisis
KW - renal cystic disease
KW - renal pathology
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U2 - 10.1016/j.ekir.2021.02.005
DO - 10.1016/j.ekir.2021.02.005
M3 - Article
AN - SCOPUS:85102746673
VL - 6
SP - 1346
EP - 1354
JO - Kidney International Reports
JF - Kidney International Reports
SN - 2468-0249
IS - 5
ER -
