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Precise clinicopathologic findings for application of genetic testing in pediatric kidney transplant recipients with focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome

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Abstract

Background

Establishing a molecular genetic diagnosis of focal segmental glomerulosclerosis (FSGS)/steroid-resistant nephrotic syndrome (SRNS) can be useful for predicting post-transplant recurrence. Monogenic causes are reportedly present in approximately 20–30% of patients with FSGS/SRNS. However, the characteristics of patients who are likely to have a monogenic cause remain to be determined.

Methods

Pediatric recipients with SRNS and/or biopsy-proven FSGS who underwent their first kidney transplantation at our center between 1999 and 2019 were analyzed. Patients with secondary FSGS/SRNS were excluded. The recipients were divided into three groups: familial/syndromic, presumed primary, and undetermined FSGS/SRNS. Patients who met all of the following criteria were categorized as having presumed primary FSGS/SRNS: (i) nephrotic syndrome, (ii) complete or partial remission with initial steroid therapy and/or additional immunosuppressive therapies, and (iii) diffuse foot process effacement on electron microscopy in the native kidney biopsy. All patients underwent genetic testing using next-generation sequencing.

Results

Twenty-four patients from 23 families were analyzed in this study. Pathogenic or likely pathogenic variants in FSGS/SRNS-related genes were identified in four of four families, zero of eight families, and 10 of 11 families with familial/syndromic, presumed primary, and undetermined FSGS/SRNS, respectively. Post-transplant recurrence only occurred in patients with presumed primary FSGS/SRNS.

Conclusions

Our systematic approach based on precise clinicopathological findings including nephrotic syndrome, treatment responses, and diffuse foot process effacement might be useful to differentiate pediatric kidney transplant recipients with FSGS/SRNS who are likely to have a monogenic cause from patients who are not, and to predict post-transplant recurrence.

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A higher resolution version of the Graphical abstract is available as Supplementary information.

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Data availability

The datasets of the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the affected individuals, their families, and their physicians who contributed to this study. The following doctors recruited patients and gathered detailed clinical information for this study: Noriko Sugawara (Tohoku University), Shuichiro Fu**aga (Saitama Children’s Medical Center), Amane Endo (Juntendo University), Takeshi Yanagihara (Nippon Medical School), Daisuke Matsuoka (Shinshu University), Takayuki Miyai (Okayama University), and Mikiya Fujieda (Kochi University). We also thank Professor Kazuho Honda (Showa University) for his kind support in examination of the degree of FPE on EM, and Professor Kandai Nozu (Kobe University) and Dr. Hidenori Sato (Yamagata University School of Medicine) for performing genetic analysis in some patients.

In this research work, we used instruments in the Medical Research Institute (MRI), Tokyo Women’s Medical University.

We thank Georgia Lenihan-Geels, PhD, and Ryan Chastain-Gross, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was supported in part by Grants-in-Aid Scientific Research (C) (JP21K07829 [KM] and JP21K07857 [NK]) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Pediatric Nephrology, Tokyo Women’s Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, Japan

    Kenichiro Miura, Naoto Kaneko, Taeko Hashimoto, Kiyonobu Ishizuka, Yoko Shirai, Hiroko Chikamoto, Yuko Akioka, Shoichiro Kanda & Motoshi Hattori

  2. Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan

    Taeko Hashimoto

  3. Department of Nephrology, Chiba Children’s Hospital, Chiba, Japan

    Masataka Hisano

  4. Department of Pediatrics, Saitama Medical University, Saitama, Japan

    Yuko Akioka

  5. Department of Pediatrics, The University of Tokyo, Tokyo, Japan

    Shoichiro Kanda & Yutaka Harita

  6. Institute of Medical Genetics, Tokyo Women’s Medical University, Tokyo, Japan

    Toshiyuki Yamamoto

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  1. Kenichiro Miura
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  2. Naoto Kaneko
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Contributions

K.M. and N.K. participated in research design, data analysis, and writing the manuscript. T.H., Y.H., and T.Y. participated in genetic analysis and comprehensive editing of the manuscript. K.I. and Y.S. participated in data acquisition and genetic analysis. M.Hi., H.C., Y.A., and S.K. participated in data acquisition and comprehensive editing of the manuscript. M.Ha. participated in research design and comprehensive editing of the manuscript.

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Correspondence to Motoshi Hattori.

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Miura, K., Kaneko, N., Hashimoto, T. et al. Precise clinicopathologic findings for application of genetic testing in pediatric kidney transplant recipients with focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. Pediatr Nephrol 38, 417–429 (2023). https://doi.org/10.1007/s00467-022-05604-3

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