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Synergistic effect of proteinuria on dipstick hematuria-related decline in kidney function: The Japan Specific Health Checkups (J-SHC) Study

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Abstract

Background

The effect of isolated hematuria without proteinuria on kidney function decline, and the modification by the severity of proteinuria in general population are not fully elucidated.

Methods

Participants were included in the Japan Specific Health Checkups Study between 2008 and 2014. The exposure of interest was the frequency of dipstick hematuria during the observation. In each proteinuria frequency category (non-, occasional, persistent), hematuria-related decline in the eGFR rate was examined by analysis of covariance (ANCOVA). eGFR decline trajectories were also assessed using mixed-effects models.

Results

Among the 552,951 participants, 146,753 (26.5%) had hematuria, and 56,021 (10.1%) and 8,061 (1.5%) had occasional and persistent proteinuria, respectively. During the median follow-up of 3.0 years, annual change in eGFR decline in participants with hematuria was significantly faster than in those without hematuria (mean [95% confidence interval]: − 0.95 [− 0.98 to − 0.92] vs − 0.86 [− 0.87 to − 0.84] mL/min/1.73 m2/year; P < 0.001). In ANCOVA, the hematuria-related annual eGFR decline rate increased as proteinuria frequency categories increased (differences in annual eGFR decline rate between participants with and without hematuria: 0.08 [0.06 to 0.09] in participants with non-proteinuria category, 0.17 [0.15 to 0.18] in occasional proteinuria category, and 0.68 [0.65 to 0.71] mL/min/1.73 m2/year in persistent proteinuria category; P for interaction < 0.001). Similar results were obtained by the linear mixed-effect model.

Conclusions

Proteinuria has a synergistic effect on dipstick hematuria-related decline in kidney function. Among the general population without proteinuria throughout the observational period, the “isolated hematuria”-related eGFR decline was statistically significant but the difference was small.

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References

  1. Yamagata K, Iseki K, Nitta K, Imai H, Iino Y, Matsuo S, et al. Chronic kidney disease perspectives in Japan and the importance of urinalysis screening. Clin Exp Nephrol. 2008;12(1):1–8. https://doi.org/10.1007/s10157-007-0010-9.

    Article  PubMed  Google Scholar 

  2. Imai E, Yamagata K, Iseki K, Iso H, Horio M, Mkino H, et al. Kidney disease screening program in Japan: history, outcome, and perspectives. Clin J Am Soc Nephrol. 2007;2(6):1360–6. https://doi.org/10.2215/CJN.00980207.

    Article  PubMed  Google Scholar 

  3. Iseki K, Iseki C, Ikemiya Y, Fukiyama K. Risk of developing end-stage renal disease in a cohort of mass screening. Kidney Int. 1996;49(3):800–5. https://doi.org/10.1038/ki.1996.111.

    Article  CAS  PubMed  Google Scholar 

  4. Yamagata K, Takahashi H, Tomida C, Yamagata Y, Koyama A. Prognosis of asymptomatic hematuria and/or proteinuria in men. Nephron. 2002;91:34–42.

    Article  PubMed  Google Scholar 

  5. Kim H, Lee M, Cha MU, Nam KH, An SY, Park S, et al. Microscopic hematuria is a risk factor of incident chronic kidney disease in the Korean general population: a community-based prospective cohort study. QJM. 2018;111(6):389–97. https://doi.org/10.1093/qjmed/hcy054.

    Article  CAS  PubMed  Google Scholar 

  6. Chadban SJ, Briganti EM, Kerr PG, Dunstan DW, Welborn TA, Zimmet PZ, et al. Prevalence of kidney damage in Australian adults: the AusDiab kidney study. J Am Soc Nephrol. 2003;14(7 Suppl 2):S131–8. https://doi.org/10.1097/01.asn.0000070152.11927.4a.

    Article  PubMed  Google Scholar 

  7. Lee HM, Hyun JI, Min JW, Lee K, Kim YK, Choi EJ, et al. The natural course of biopsy-proven isolated microscopic hematuria: a single center experience of 350 patients. J Korean Med Sci. 2016;31(6):909–14. https://doi.org/10.3346/jkms.2016.31.6.909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yu GZ, Guo L, Dong JF, Shi SF, Liu LJ, Wang JW, et al. Persistent hematuria and kidney disease progression in IgA nephropathy: a cohort study. Am J Kidney Dis. 2020;76(1):90–9. https://doi.org/10.1053/j.ajkd.2019.11.008.

    Article  CAS  PubMed  Google Scholar 

  9. Goto M, Wakai K, Kawamura T, Ando M, Endoh M, Tomino Y. A scoring system to predict renal outcome in IgA nephropathy: a nationwide 10-year prospective cohort study. Nephrol Dial Transplant. 2009;24(10):3068–74. https://doi.org/10.1093/ndt/gfp273.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Le W, Liang S, Hu Y, Deng K, Bao H, Zeng C, et al. Long-term renal survival and related risk factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult population. Nephrol Dial Transplant. 2012;27(4):1479–85. https://doi.org/10.1093/ndt/gfr527.

    Article  CAS  PubMed  Google Scholar 

  11. Sevillano AM, Gutierrez E, Yuste C, Cavero T, Merida E, Rodriguez P, et al. Remission of hematuria improves renal survival in IgA nephropathy. J Am Soc Nephrol. 2017;28(10):3089–99. https://doi.org/10.1681/ASN.2017010108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gutierrez E, Zamora I, Ballarin JA, Arce Y, Jimenez S, Quereda C, et al. Long-term outcomes of IgA nephropathy presenting with minimal or no proteinuria. J Am Soc Nephrol. 2012;23(10):1753–60. https://doi.org/10.1681/ASN.2012010063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tsuruya K, Yoshida H, Nagata M, Kitazono T, Hirakata H, Iseki K, et al. Association of the triglycerides to high-density lipoprotein cholesterol ratio with the risk of chronic kidney disease: analysis in a large Japanese population. Atherosclerosis. 2014;233(1):260–7. https://doi.org/10.1016/j.atherosclerosis.2013.12.037.

    Article  CAS  PubMed  Google Scholar 

  14. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53(6):982–92. https://doi.org/10.1053/j.ajkd.2008.12.034.

    Article  CAS  PubMed  Google Scholar 

  15. Gofrit ON, Katz R, Shapiro A, Yutkin V, Pizov G, Zorn KC, et al. Gross hematuria in patients with prostate cancer: etiology and management. ISRN Surg. 2013;2013:685327. https://doi.org/10.1155/2013/685327.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Rastinehad AR, Ost MC, VanderBrink BA, Siegel DN, Kavoussi LR. Persistent prostatic hematuria. Nat Clin Pract Urol. 2008;5(3):159–65. https://doi.org/10.1038/ncpuro1044.

    Article  PubMed  Google Scholar 

  17. Chan D, Ong A, Schoenberg M. Microscopic hematuria. N Engl J Med. 2003;349(13):1292–3. https://doi.org/10.1056/NEJM200309253491317.

    Article  PubMed  Google Scholar 

  18. Mohr DN, Offord KP, Owen RA, Melton LJ. Asymptomatic microhematuria and urologic disease. A population-based study. JAMA. 1986;256(2):224–9.

    Article  CAS  PubMed  Google Scholar 

  19. Bradley MS, Willis-Gray MG, Amundsen CL, Siddiqui NY. Microhematuria in postmenopausal women: adherence to guidelines in a tertiary care setting. J Urol. 2016;195(4 Pt 1):937–41. https://doi.org/10.1016/j.juro.2015.10.136.

    Article  PubMed  Google Scholar 

  20. Pillalamarri N, Shalom D, Sanidad S, Akerman M, Lind L, Winkler H. The prevalence of microscopic hematuria in a cohort of women with pelvic organ prolapse. Int Urogynecol J. 2015;26(1):85–90. https://doi.org/10.1007/s00192-014-2450-6.

    Article  PubMed  Google Scholar 

  21. Vivante A, Afek A, Frenkel-Nir Y, Tzur D, Farfel A, Golan E, et al. Persistent asymptomatic isolated microscopic hematuria in israeli adolescents and young adults and risk for end-stage renal disease. JAMA. 2011;306(7):729–36. https://doi.org/10.1001/jama.2011.1141.

    Article  CAS  PubMed  Google Scholar 

  22. Iseki K. Evidence for asymptomatic microhematuria as a risk factor for the development of ESRD. Am J Kidney Dis. 2012;60(1):12–4. https://doi.org/10.1053/j.ajkd.2012.01.009.

    Article  PubMed  Google Scholar 

  23. Iseki K, Konta T, Asahi K, Yamagata K, Fujimoto S, Tsuruya K, et al. Higher cardiovascular mortality in men with persistent dipstick hematuria. Clin Exp Nephrol. 2021;25(2):150–6. https://doi.org/10.1007/s10157-020-01971-z.

    Article  PubMed  Google Scholar 

  24. Iseki K, Konta T, Asahi K, Yamagata K, Fujimoto S, Tsuruya K, et al. Association of dipstick hematuria with all-cause mortality in the general population: results from the specific health check and guidance program in Japan. Nephrol Dial Transplant. 2018;33(5):825–32. https://doi.org/10.1093/ndt/gfx213.

    Article  CAS  PubMed  Google Scholar 

  25. Pugia MJ, Lott JA, Wallace JF, Cast TK, Bierbaum LD. Assay of creatinine using the peroxidase activity of copper-creatinine complexes. Clin Biochem. 2000;33(1):63–70. https://doi.org/10.1016/s0009-9120(99)00086-7.

    Article  CAS  PubMed  Google Scholar 

  26. Ikeda K, Abe M, Masamoto I, Ishii C, Arimura E, Ushikai M, et al. Comparison of dipstick and quantitative tests for proteinuria and hematuria in middle-aged, male Japanese employees: a single-center study. Health Sci Rep. 2021;4(2):e267. https://doi.org/10.1002/hsr2.267.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Pirkle JL, Palavecino EL, Freedman BI. Lactobacillus species can cause a false-positive test for hematuria on dipstick urinalysis. Am J Med. 2013;126(1):e3-4. https://doi.org/10.1016/j.amjmed.2012.07.017.

    Article  PubMed  Google Scholar 

  28. Levin K, Engström I. Inadequate hemolysis of erythrocytes on reagent strips at low pH causes false-negative readings. Clin Chem. 1984;30(11):1845–7.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge the contributions of the staff members who collected data and instructed subjects on urinalysis at screening centers in the following regions: Hokkaido, Yamagata, Miyagi, Fukushima, Tochigi, Ibaraki, Chiba, Saitama, Tokyo, Kanagawa, Niigata, Ishikawa, Fukui, Nagano, Gifu, Osaka, Hyogo, Okayama, Tokushima, Kochi, Fukuoka, Saga, Kumamoto, Oita, Miyazaki, and Okinawa. We would like to thank Editage for English language editing.

Funding

This work was supported by Health and Labor Sciences Research Grants for Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment by Specific Health Checkup from the Ministry of Health, Labor, and Welfare of Japan and a Grant-in-Aid for Research on Advanced Chronic Kidney Disease (REACH-J), Practical Research Project for Renal Disease from the Japan Agency for Medical Research and Development (AMED).

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Authors and Affiliations

  1. Department of Nephrology, Nara Medical University, 840 Shijo-Cho, Kashihara, Nara, Japan

    Hikari Tasaki, Masahiro Eriguchi, Takayuki Uemura, Fumihiro Fukata, Masatoshi Nishimoto, Takaaki Kosugi, Masaru Matsui, Ken-ichi Samejima & Kazuhiko Tsuruya

  2. Department of Medical Statistics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan

    Hisako Yoshida

  3. Steering Committee of Research on Design of the Comprehensive Health Care System for Chronic Kidney Disease (CKD) Based on the Individual Risk Assessment By Specific Health Check, Fukushima, Japan

    Kunitoshi Iseki, Koichi Asahi, Kunihiro Yamagata, Tsuneo Konta, Shouichi Fujimoto, Ichiei Narita, Masato Kasahara, Yugo Shibagaki, Toshiki Moriyama, Masahide Kondo, Tsuyoshi Watanabe & Kazuhiko Tsuruya

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  1. Hikari Tasaki
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Contributions

Research idea and study design: HT, ME, HY, TU, FF, MN, TK, MM, KS, KT; data acquisition: HY, KI, CI, KA, KY, TK, SF, IN, MKa, YS, TM, MKo, TW, KT; data analysis/interpretation: HT, ME, KT; statistical analysis: HT, ME, HY; supervision or mentorship: ME, KT. Each author contributed important intellectual content during manuscript drafting or revision and accepted accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work were appropriately investigated and resolved.

Corresponding author

Correspondence to Masahiro Eriguchi.

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The authors have declared that no conflict of interest exists.

Ethical approval and consent to participate

All procedures involving human participants were carried out in accordance with the ethical standards of the institutional research committee at which the studies were conducted (Fukushima Medical University; IRB Approval Number #1485, #2771) and in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was conducted in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects that was enacted by the Ministry of Health, Labour and Welfare of Japan (http://www.mhlw.go.jp/file/06-Seisakujouhou-10600000-Daijinkanboukouseikagakuka/0000069410.pdf). In the context of these guidelines, investigators are not necessarily required to obtain informed consent. Instead, we provided public information concerning the study on our website (http://www.fmu.ac.jp/univ/sangaku/data/koukai_2/2771.pdf) and ensured that there were opportunities for the research participants to refuse the use of their personal information.

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Tasaki, H., Eriguchi, M., Yoshida, H. et al. Synergistic effect of proteinuria on dipstick hematuria-related decline in kidney function: The Japan Specific Health Checkups (J-SHC) Study. Clin Exp Nephrol 27, 990–1000 (2023). https://doi.org/10.1007/s10157-023-02390-6

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