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Association between urinary C-megalin levels and progressive kidney dysfunction: a cohort study based on the diabetes distress and care registry at Tenri (DDCRT 24)

Acta Diabetologica volume 60, pages 1643–1650 (2023)Cite this article

Abstract

Aims

The aim of this cohort study was to evaluate the association between urinary levels of C-megalin, a full-length form of megalin, and kidney dysfunction progression and its dependence on the urinary albumin-creatinine ratio (UACR) in individuals with diabetes.

Methods

We enrolled 1,547 individuals with diabetes who visited the ambulatory clinic at Tenri Hospital, a regional tertiary-care hospital in Tenri City, Nara Prefecture, Japan, with an estimated glomerular filtration (eGFR) of ≥ 30 mL/min/1.73 m2. The hazard ratio (HR) and 95% confidence interval (CI) were estimated using Cox proportional hazard models to examine the association between urinary C-megalin levels and eGFR decline by ≥ 40% from baseline.

Results

Urinary C-megalin level was not associated with ≥ 40% eGFR decline in an age-, sex-, eGFR-, systolic blood pressure-, hemoglobin-, and UACR-adjusted model in the 1,547 patients enrolled in the study. However, urinary C-megalin levels were associated with a ≥ 40% decline in eGFR when accounting for the relationship between urinary C-megalin levels and UACR in the model. This association was UACR-dependent.

Conclusions

High urinary C-megalin levels were associated with progressive kidney dysfunction in individuals with diabetes, and this association was attenuated by high UACRs.

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Data availability

The datasets generated during and/or analyzed during the current study are not publicly available due to the need for participant privacy but are available from the corresponding author upon reasonable request.

References

  1. Afkarian M, Zelnick LR, Hall YN et al (2016) Clinical manifestations of kidney disease among US adults with diabetes, 1988–2014. JAMA 316:602–610. https://doi.org/10.1001/jama.2016.10924

    Article  PubMed  PubMed Central  Google Scholar 

  2. Nielsen R, Christensen EI, Birn H (2016) Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease. Kidney Int 89:58–67. https://doi.org/10.1016/j.kint.2015.11.007

    Article  CAS  PubMed  Google Scholar 

  3. Baines RJ, Brunskill NJ (2008) The molecular interactions between filtered proteins and proximal tubular cells in proteinuria. Nephron Exp Nephrol 110:e67-71. https://doi.org/10.1159/000161982

    Article  CAS  PubMed  Google Scholar 

  4. Christensen EI, Birn H (2001) Megalin and cubilin: synergistic endocytic receptors in renal proximal tubule. Am J Physiol Renal Physiol 280:F562–F573. https://doi.org/10.1152/ajprenal.2001.280.4.F562

    Article  CAS  PubMed  Google Scholar 

  5. Reisman SA, Chertow GM, Hebbar S et al (2012) Bardoxolone methyl decreases megalin and activates nrf2 in the kidney. J Am Soc Nephrol 23:1663–1673. https://doi.org/10.1681/ASN.2012050457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nishiwaki H, Niihata K, Kinoshita M et al (2022) Urinary C-megalin as a novel biomarker of progression to microalbuminuria: a cohort study based on the diabetes Distress and Care Registry at Tenri (DDCRT 22). Diabetes Res Clin Pract 186:109810. https://doi.org/10.1016/j.diabres.2022.109810

    Article  CAS  PubMed  Google Scholar 

  7. Iida T, Hosojima M, Kabasawa H et al (2022) Urinary A- and C-megalin predict progression of diabetic kidney disease: an exploratory retrospective cohort study. J Diabetes Complications 36:108312. https://doi.org/10.1016/j.jdiacomp.2022.108312

    Article  CAS  PubMed  Google Scholar 

  8. Levin A, Agarwal R, Herrington WG et al (2020) International consensus definitions of clinical trial outcomes for kidney failure: 2020. Kidney Int 98:849–859. https://doi.org/10.1016/j.kint.2020.07.013

    Article  PubMed  Google Scholar 

  9. Levey AS, Gansevoort RT, Coresh J et al (2020) Change in albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney Foundation in collaboration with the US Food and Drug Administration and European Medicines Agency. Am J Kidney Dis 75:84–104. https://doi.org/10.1053/j.ajkd.2019.06.009

    Article  CAS  PubMed  Google Scholar 

  10. Kurita N, Kinoshita M, Fujimura M et al (2022) Association of urinary C-megalin with albuminuria and renal function in diabetes: a cross-sectional study (Diabetes Distress and Care Registry at Tenri [DDCRT 21]). J Nephrol 35:201–210. https://doi.org/10.1007/s40620-021-00995-2

    Article  CAS  PubMed  Google Scholar 

  11. Hayashino Y, Mashitani T, Tsujii S et al (2014) Serum high-sensitivity C-reactive protein levels are associated with high risk of development, not progression, of diabetic nephropathy among Japanese type 2 diabetic patients: a prospective cohort study (Diabetes Distress and Care Registry at Tenri [DDCRT7]). Diabetes Care 37:2947–2952. https://doi.org/10.2337/dc14-1357

    Article  CAS  PubMed  Google Scholar 

  12. Hayashino Y, Okamura S, Tsujii S et al (2018) Association between diabetes distress and all-cause mortality in Japanese individuals with type 2 diabetes: a prospective cohort study (Diabetes Distress and Care Registry in Tenri [DDCRT 18]). Diabetologia 61:1978–1984. https://doi.org/10.1007/s00125-018-4657-4

    Article  PubMed  Google Scholar 

  13. Ogasawara S, Hosojima M, Kaseda R et al (2012) Significance of urinary full-length and ectodomain forms of megalin in patients with type 2 diabetes. Diabetes Care 35:1112–1118. https://doi.org/10.2337/dc11-1684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Matsuo S, Imai E, Horio M et al (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982–992. https://doi.org/10.1053/j.ajkd.2008.12.034

    Article  CAS  PubMed  Google Scholar 

  15. Miyamoto M, Kurita N, Suemitsu K, Murakami M (2017) Fistula and survival outcomes after fistula creation among predialysis chronic kidney disease stage 5 patients. Am J Nephrol 45:356–364. https://doi.org/10.1159/000466707

    Article  PubMed  Google Scholar 

  16. Sun Y, Goes Martini A, Janssen MJ et al (2020) Megalin: a novel endocytic receptor for prorenin and renin. Hypertension 75:1242–1250. https://doi.org/10.1161/HYPERTENSIONAHA.120.14845

    Article  CAS  PubMed  Google Scholar 

  17. Saito A, Nagai R, Tanuma A et al (2003) Role of megalin in endocytosis of advanced glycation end products: implications for a novel protein binding to both megalin and advanced glycation end products. J Am Soc Nephrol 14:1123–1131. https://doi.org/10.1097/01.asn.0000062962.51879.f8

    Article  CAS  PubMed  Google Scholar 

  18. Hori Y, Aoki N, Kuwahara S et al (2017) Megalin blockade with cilastatin suppresses drug-induced nephrotoxicity. J Am Soc Nephrol 28:1783–1791. https://doi.org/10.1681/ASN.2016060606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Members of the Diabetes Distress and Care Registry at Tenri Study Group: Hitoshi Ishii and Hirohito Kuwata (Department of Diabetology, Nara Medical University); Maki Fujimura, Kiyoko Takano, Satoru Tsujii, Shintaro Okamura, Satoshi Matsunaga, Yasuaki Hayashino, and Masako Kitatani (Department of Endocrinology, Tenriyorozu Hospital); Mako Kitatani (Shirakawa Branch, Tenri Hospital); Satoshi Matsunaga (Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine); Yaeko Kondo (Department of Diabetes and Clinical Nutrition, Kyoto University); Naotaka Fujita (Otsu Red Cross Hospital); Rei Ueda (Second Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus); Rie Kawata (Sawa Hospital); Masami Tanaka (Tokyo Women’s Medical University Medical Center East); Tsuyoshi Mashitani (Mashitani Clinic); and Miyuki Furuya (Furuya Clinic). We would like to thank Yukari Moritsuji, Yuki Fujita, Noriko Nakamura, and Yoko Sakamoto (Department of Endocrinology, Tenri Hospital) for their clerical support. This study was funded by the Manpei Suzuki Diabetes Foundation and the Japan Society for the Promotion of Science (JSPS) KAKENHI [grant numbers 25460641 and 16K08897]. The funders played no role in designing the study; in collecting, analyzing, or interpreting the data; in writing the manuscript; and in the decision to submit the article for publication.

Author information

Author notes

  1. Hiroki Nishiwaki and Kakuya Niihata contributed equally to this work.

  2. Members of the Diabetes Distress and Care Registry at Tenri Study Group are listed in the Acknowledgments.

Authors and Affiliations

  1. Department of Clinical Epidemiology, Graduate School of Medicine, Fukushima Medical University, Fukushima, Fukushima, Japan

    Kakuya Niihata, Hiroki Nishiwaki & Noriaki Kurita

  2. Division of Nephrology, Department of Internal Medicine, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan

    Hiroki Nishiwaki

  3. Showa University Research Administration Center (SURAC), Showa University, Shinagawa, Tokyo, Japan

    Hiroki Nishiwaki

  4. Department of Clinical Laboratory, Tenri Hospital, Nara, Tenri, Japan

    Maki Kinoshita

  5. Department of Endocrinology, Tenri Hospital, Nara, Tenri, Japan

    Kentaro Kurosawa, Yui Sakuramachi, Satoshi Matsunaga, Shintaro Okamura, Satoru Tsujii & Yasuaki Hayashino

  6. Department of Innovative Research and Education for Clinicians and Trainees (DiRECT), Fukushima Medical University Hospital, Fukushima, Fukushima, Japan

    Noriaki Kurita

  7. Center for Innovative Research for Communities and Clinical Excellence (CIRC2LE), Fukushima Medical University, Fukushima, Japan

    Noriaki Kurita

  8. Institute for Health Outcomes and Process Evaluation Research (iHope International), Kyoto, Japan

    Noriaki Kurita

Authors
  1. Kakuya Niihata
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  2. Hiroki Nishiwaki
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  6. Satoshi Matsunaga
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  9. Yasuaki Hayashino
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Consortia

Diabetes Distress and Care Registry at Tenri Study Group

  • Hitoshi Ishii
  • , Hirohito Kuwata
  • , Maki Fujimura
  • , Kiyoko Takano
  • , Satoru Tsujii
  • , Shintaro Okamura
  • , Satoshi Matsunaga
  • , Yasuaki Hayashino
  • , Masako Kitatani
  • , Mako Kitatani
  • , Satoshi Matsunaga
  • , Yaeko Kondo
  • , Naotaka Fujita
  • , Rei Ueda
  • , Rie Kawata
  • , Masami Tanaka
  • , Tsuyoshi Mashitani
  • , Miyuki Furuya
  • , Yukari Moritsuji
  • , Yuki Fujita
  • , Noriko Nakamura
  •  & Yoko Sakamoto

Contributions

Conceptualization: NK; methodology: KN, HN, and NK; investigation: MK, KK, YS, SM, SO, ST, and YH; formal analysis: KN, HN, and NK; writing—original draft preparation: KN, HN, and NK; writing—review and editing: YH and NK; funding acquisition: YH; resources: NK, MK, KK, YS, SM, SO, ST, and YH; supervision: YH and NK.

Corresponding author

Correspondence to Kakuya Niihata.

Ethics declarations

Conflict of interest

Kakuya Niihata, Hiroki Nishiwaki, Maki Kinoshita, Kentaro Kurosawa, Yui Sakuramachi, Satoshi Matsunaga, Shintaro Okamura, Satoru Tsujii, and Yasuaki Hayashino declare that they have no conflicts of interest. Noriaki Kurita has served as a senior scientist at the Institute for Health Outcomes and Process Evaluation Research (iHope International, a non-profit organization), but was not compensated for his contribution to this study. Denka Seiken Co., Ltd., measured urinary C-megalin; however, the company had no role in designing the study; in collecting, analyzing, or interpretating the data; in writing the manuscript; and in the decision to submit the article for publication. Denka Seiken Co., Ltd., contracted this study to iHope International.

Human and animals rights

This study conformed to the tenets of the Declaration of Helsinki and was approved by the institutional review boards of Tenri Hospital (approval no. 785) and Fukushima Medical University (approval no. 2966).

Informed consent

All patients provided informed consent to participate in this study.

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This article belongs to the topical collection Diabetic Nephropathy, managed by Giuseppe Pugliese.

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Niihata, K., Nishiwaki, H., Kinoshita, M. et al. Association between urinary C-megalin levels and progressive kidney dysfunction: a cohort study based on the diabetes distress and care registry at Tenri (DDCRT 24). Acta Diabetol 60, 1643–1650 (2023). https://doi.org/10.1007/s00592-023-02144-6

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  • DOI: https://doi.org/10.1007/s00592-023-02144-6

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