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Synergistic effect of obesity on hypertensive renal arteriosclerosis in individuals without chronic kidney disease: A zero-hour biopsy-based cohort study

Hypertension Research (2026)Cite this article

Abstract

Nephrosclerosis, influenced by aging and elevated blood pressure (BP), including prehypertensive levels, is a major contributor to end-stage kidney disease. However, the relationship between these risk factors and early renal pathological alterations remains insufficiently characterized. This study aimed to examine age- and BP-related renal pathology in individuals without chronic kidney disease (CKD). We analyzed zero-hour biopsies from 520 living kidney donors without CKD at Kyushu University Hospital (2008–2018). Donors were stratified by BP (Normal, Stage I, Stage II) and age ( < 40, 40–49, 50–59, 60–79 years). The primary outcomes were arteriolosclerotic change, specifically arteriolar hyalinization (AH), atherosclerotic change, characterized by intimal thickening of small- to medium-sized arteries (IT) and global glomerulosclerosis. All lesions increased with age and BP. Adjusted odds ratios (ORs) for AH were 1.25 [0.74–2.12] for Stage I and 1.63 [1.02–2.61] for Stage II hypertension (vs. normal BP). IT was significantly increased in individuals aged 50–59 (OR 3.56 [1.27–9.98]) and 60–79 years (OR 5.61 [1.81–17.41]) compared to those <40 years. A significant interaction between BP and obesity was observed for AH (p = 0.03): among obese individuals, both Stage I and Stage II hypertension were associated with AH (ORs 3.72 [1.06–13.1] and 4.05 [1.38–11.85], respectively), but not among non-obese individuals. In conclusion, subclinical nephrosclerosis begins in middle age, primarily driven by age-related vascular changes. Obesity significantly enhances BP-related arteriolar damage, even at prehypertensive levels. These findings support stratified hypertension management based on both BP and metabolic status.

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References

  1. Japanese Society of Nephrology, ed. CKD Clinical Practice Guide 2024. Tokyo Igakusha, Tokyo, 2024.

  2. Japanese Society of Nephrology. (2023). Evidence-based CKD Clinical Practice Guidelines 2023. Tokyo: Igaku-sha.

  3. Nagata D, Hishida E. Elucidating the complex interplay between chronic kidney disease and hypertension. Hypertens Res. 2024;47:3409–22.

    Article  PubMed  Google Scholar 

  4. Hanafusa N, Abe M, Joki N, Hoshino J, Wada A, Kikuchi K, et al. Japanese Society for Dialysis Therapy (JSDT). 2022 Annual Dialysis Data Report, JSDT Renal Data Registry. 2023.

  5. Manual for pathological diagnosis of diabetic nephropathy and hypertensive nephrosclerosis. Nihon Jinzo Gakkai Shi. 2015;57:649–725.

  6. Kohagura K, Zamami R, Oshiro N, Shinzato Y, Uesugi N. Heterogeneous afferent arteriolopathy: a key concept for understanding blood pressure-dependent renal damage. Hypertens Res. 2024;47:3383–96.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Suenaga T, Satoh M, Murakami T, Hirose T, Obara T, Nakayama S, et al. Cross-classification by systolic and diastolic blood pressure levels and chronic kidney disease, proteinuria, or kidney function decline. Hypertens Res. 2023;46:1860–9.

    Article  CAS  PubMed  Google Scholar 

  8. Vikse BE, Aasarød K, Bostad L, Iversen BM. Clinical prognostic factors in biopsy-proven benign nephrosclerosis. Nephrol Dial Transpl. 2003;18:517–23.

    Article  CAS  Google Scholar 

  9. Furuichi K, Shimizu M, Yuzawa Y, Hara A, Toyama T, Kitamura H, et al. Nationwide multicenter kidney biopsy study of Japanese patients with hypertensive nephrosclerosis. Clin Exp Nephrol. 2018;22:629–37.

    Article  PubMed  Google Scholar 

  10. Takebayashi S, Kiyoshi Y, Hisano S, Uesugi N, Sasatomi Y, Meng J, et al. Benign nephrosclerosis: incidence, morphology and prognosis. Clin Nephrol. 2001;55:349–56.

    CAS  PubMed  Google Scholar 

  11. Dasgupta I, Porter C, Innes A, Burden R. Benign” hypertensive nephrosclerosis. Qjm. 2007;100:113–9.

    Article  CAS  PubMed  Google Scholar 

  12. Liang S, Le W, Liang D, Chen H, Xu F, Chen H, et al. Clinico-pathological characteristics and outcomes of patients with biopsy-proven hypertensive nephrosclerosis: a retrospective cohort study. BMC Nephrol. 2016;17:42.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ninomiya T, Kubo M, Doi Y, Yonemoto K, Tanizaki Y, Tsuruya K, et al. Prehypertension increases the risk for renal arteriosclerosis in autopsies: the Hisayama Study. J Am Soc Nephrol. 2007;18:2135–42.

    Article  PubMed  Google Scholar 

  14. Shiraishi N, Kitamura K, Kohda Y, Iseki K, Tomita K. Prevalence and risk factor analysis of nephrosclerosis and ischemic nephropathy in the Japanese general population. Clin Exp Nephrol. 2014;18:461–8.

    Article  CAS  PubMed  Google Scholar 

  15. Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015;373:2103–16.

    Article  CAS  PubMed  Google Scholar 

  16. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:1269–324.

    Article  CAS  PubMed  Google Scholar 

  17. Ohya Y, Sakima A, Arima H, Fukami A, Furuhashi M, Ishida M, et al. Key highlights of the Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and hypertension 2025 (JSH2025). Hypertens Res. 2025;48:2500–11.

  18. Lewis CE, Fine LJ, Beddhu S, Cheung AK, Cushman WC, Cutler JA, et al. Final Report of a Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2021;384:1921–30.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Munkhaugen J, Lydersen S, Widerøe TE, Hallan S. Prehypertension, obesity, and risk of kidney disease: 20-year follow-up of the HUNT I study in Norway. Am J Kidney Dis. 2009;54:638–46.

    Article  PubMed  Google Scholar 

  20. Zheng L, Xie Y, Zheng J, Guo R, Wang Y, Dai Y, et al. Associations between ideal blood pressure based on different BMI categories and stroke incidence. J Hypertens. 2020;38:1271–7.

    Article  CAS  PubMed  Google Scholar 

  21. Ataka E, Matsukuma Y, Ueki K, Tsuchimoto A, Okabe Y, Masutani K, et al. Cumulative smoking dose is associated with subclinical renal injury: a pathological study in individuals without chronic kidney disease. Nephrol Dial Transpl. 2023;38:2799–808.

    Article  CAS  Google Scholar 

  22. Kashiwagi A, Kasuga M, Araki E, Oka Y, Hanafusa T, Ito H, et al. International clinical harmonization of glycated hemoglobin in Japan: From Japan Diabetes Society to National Glycohemoglobin Standardization Program values. J Diab Investig. 2012;3:39–40.

    Article  Google Scholar 

  23. Hata Y, Mabuchi H, Saito Y, Itakura H, Egusa G, Ito H, et al. Report of the Japan Atherosclerosis Society (JAS) Guideline for Diagnosis and Treatment of Hyperlipidemia in Japanese adults. J Atheroscler Thromb. 2002;9:1–27.

    Article  PubMed  Google Scholar 

  24. Ogawa W, Hirota Y, Miyazaki S, Nakamura T, Ogawa Y, Shimomura I, et al. Definition, criteria, and core concepts of guidelines for the management of obesity disease in Japan. Endocr J. 2024;71:223–31.

    Article  PubMed  Google Scholar 

  25. Horio M, Imai E, Yasuda Y, Watanabe T, Matsuo S. Modification of the CKD epidemiology collaboration (CKD-EPI) equation for Japanese: accuracy and use for population estimates. Am J Kidney Dis. 2010;56:32–8.

    Article  PubMed  Google Scholar 

  26. Loupy A, Haas M, Solez K, Racusen L, Glotz D, Seron D, et al. The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology. Am J Transpl. 2017;17:28–41.

    Article  CAS  Google Scholar 

  27. Denic A, Lieske JC, Chakkera HA, Poggio ED, Alexander MP, Singh P, et al. The Substantial Loss of Nephrons in Healthy Human Kidneys with Aging. J Am Soc Nephrol. 2017;28:313–20.

    Article  PubMed  Google Scholar 

  28. Sethi S, D’Agati VD, Nast CC, Fogo AB, De Vriese AS, Markowitz GS, et al. A proposal for standardized grading of chronic changes in native kidney biopsy specimens. Kidney Int. 2017;91:787–9.

    Article  PubMed  Google Scholar 

  29. Rule AD, Amer H, Cornell LD, Taler SJ, Lieske JC, Melton LJ 3rd, et al. Glomerular Sclerosis and Interstitial Fibrosis in Healthy Kidney Donors. Ann Intern Med. 2010;152:561–9.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lhotta K, Rumpelt HJ, König P, Mayer G, Kronenberg F. Cigarette smoking and vascular pathology in renal biopsies. Kidney Int. 2002;61:648–54.

    Article  PubMed  Google Scholar 

  31. Head T, Daunert S, Goldschmidt-Clermont PJ. The Aging Risk and Atherosclerosis: A Fresh Look at Arterial Homeostasis. Front Genet. 2017;8:216.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Nishigaki D, Yamamoto R, Shinzawa M, Kimura Y, Fujii Y, Aoki K, et al. Body mass index modifies the association between frequency of alcohol consumption and incidence of hypertension in men but not in women: a retrospective cohort study. Hypertens Res. 2020;43:322–30.

    Article  CAS  PubMed  Google Scholar 

  33. Thethi T, Kamiyama M, Kobori H. The link between the renin-angiotensin-aldosterone system and renal injury in obesity and the metabolic syndrome. Curr Hypertens Rep. 2012;14:160–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hall ME, do Carmo JM, da Silva AA, Juncos LA, Wang Z, Hall JE. Obesity, hypertension, and chronic kidney disease. Int J Nephrol Renovasc Dis. 2014;7:75–88.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Rule AD, Amer H, Cornell LD, Taler SJ, Cosio FG, Kremers WK, et al. The association between age and nephrosclerosis on renal biopsy among healthy adults. Ann Intern Med. 2010;152:561–7.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kremers WK, Denic A, Lieske JC, Alexander MP, Kaushik V, Elsherbiny HE, et al. Distinguishing age-related from disease-related glomerulosclerosis on kidney biopsy: the Aging Kidney Anatomy study. Nephrol Dial Transpl. 2015;30:2034–9.

    Article  Google Scholar 

  37. Myasoedova VA, Ravani AL, Frigerio B, Moschetta D, Valerio V, Massaiu I, et al. Age and Sex Differences in Carotid Intima-Media Thickness: A Systematic Review and Meta-Analysis. Life. 2024;14.

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Acknowledgements

The authors thank Phoebe Chi, MD, from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript.

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Authors and Affiliations

  1. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3–1–1 Maidashi, Higashi–ku, Fukuoka, 812–8582, Japan

    Hirofumi Okamoto, Yuta Matsukuma, Eri Ataka, Kenji Ueki, Akihiro Tsuchimoto, Kosuke Masutani, Shunsuke Yamada, Toshiaki Nakano & Tetsuro Ago

  2. Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814–0180, Japan

    Kosuke Masutani

  3. Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3–1–1 Maidashi, Higashi–ku, Fukuoka, 812–8582, Japan

    Hiroshi Noguchi, Keizo Kaku & Masafumi Nakamura

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  1. Hirofumi Okamoto
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  2. Yuta Matsukuma
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Contributions

Drafted the manuscript: HO Study design: HO, YM, AT Data acquisition: HO, EA, YM, KU, AT Operation performance and data collection: HN, KK Pathological evaluation: HO, EA, YM Statistical analysis: HO, YM Critically revised the manuscript: KU, YM, AT, HN, KK, MN, KM, TN, TA All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

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Correspondence to Yuta Matsukuma.

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Okamoto, H., Matsukuma, Y., Ataka, E. et al. Synergistic effect of obesity on hypertensive renal arteriosclerosis in individuals without chronic kidney disease: A zero-hour biopsy-based cohort study. Hypertens Res (2026). https://doi.org/10.1038/s41440-026-02553-4

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