Cellular Biomarker in the Urine in Predicting Prognosis of Chronic Kidney Disease, Diabetes and Hypertension
Main Article Content
Abstract
Chronic kidney disease (CKD) is a life-threatening condition originated from renal dysfunction. So far we do not have perfect remedies and therefore prevention of progression draw high interests from both researchers and clinicians. There are a lot of risk factors for its development and its prognosis, among them, hypertension and diabetes are the most common risks. We have been using biomarkers for diabetes and hypertension such as HbA1c, diurnal changes of blood pressure, morphological changes in blood vessels and cardiac functions. Recent advances in chemical analysis proposed several biomarkers from blood and urine samples, such as microalbuminuria, L-FABP and others. Animal and cell experiments also suggest potential biomarkers, however, they are not necessarily applicable in human. Besides those chemical markers, studies on genetic or epigenetic factors such as microRNA have been reported. In addition to those upcoming techniques, we learned a lot from classical cellular morphological examination of urinary sediments.
In the current review, we focus on podocyte and round cell in the urinary sediment and epigenetic markers in the urine as novel biomarkers for CKD and its risk factors those are hypertension and diabetes.
Article Details
How to Cite
YOKOYAMA, Chie; SHUKUYA, Kenichi; SHIMOSAWA, Tatsuo.
Cellular Biomarker in the Urine in Predicting Prognosis of Chronic Kidney Disease, Diabetes and Hypertension.
Medical Research Archives, [S.l.], v. 13, n. 2, feb. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6096>. Date accessed: 16 mar. 2025.
doi: https://doi.org/10.18103/mra.v13i2.6096.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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13. Thongboonkerd V, Kanlaya R. The divergent roles of exosomes in kidney diseases: Pathogenesis, diagnostics, prognostics and therapeutics. Int J Biochem Cell Biol. Aug 2022;149:106262. Doi:10.1016/j.biocel.2022.106262
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15. Gámez-Valero A, Lozano-Ramos SI, Bancu I, Lauzurica-Valdemoros R, Borràs FE. Urinary extracellular vesicles as source of biomarkers in kidney diseases. Front Immunol. 2015;6:6. Doi:10.3389/fimmu.2015.00006
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18. Sun G, Reddy MA, Yuan H, Lanting L, Kato M, Natarajan R. Epigenetic histone methylation modulates fibrotic gene expression. J Am Soc Nephrol. Dec 2010;21(12):2069-80. Doi:10.1681/ASN.2010060633
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20. Chen Z, Satake E, Pezzolesi MG, et al. Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes. Sci Transl Med. May 22 2024;16(748):eadj3385. Doi:10.1126/scitranslmed.adj3385
21. Chu AY, Tin A, Schlosser P, et al. Epigenome-wide association studies identify DNA methylation associated with kidney function. Nat Commun. Nov 03 2017;8(1):1286. Doi:10.1038/s41467-017-01297-7
22. Kim JE, Jo MJ, Cho E, et al. The Effect of DNA Methylation in the Development and Progression of Chronic Kidney Disease in the General Population: An Epigenome-Wide Association Study Using the Korean Genome and Epidemiology Study Database. Genes (Basel). Jul 21 2023;14(7) Doi:10.3390/genes14071489
23. Li KY, Tam CHT, Liu H, et al. DNA methylation markers for kidney function and progression of diabetic kidney disease. Nat Commun. May 15 2023;14(1):2543. Doi:10.1038/s41467-023-37837-7
24. Schlosser P, Tin A, Matias-Garcia PR, et al. Meta-analyses identify DNA methylation associated with kidney function and damage. Nat Commun. Dec 09 2021;12(1):7174. Doi:10.1038/s41467-021-27234-3
25. Smyth LJ, Dahlström EH, Syreeni A, et al. Epigenome-wide meta-analysis identifies DNA methylation biomarkers associated with diabetic kidney disease. Nat Commun. Dec 22 2022;13(1):7891. Doi:10.1038/s41467-022-34963-6
26. Hishikawa A, Hayashi K, Yoshimoto N, Nakamichi R, Homma K, Itoh H. DNA damage and expression of DNA methylation modulators in urine-derived cells of patients with hypertension and diabetes. Sci Rep. Feb 25 2020;10(1):3377. Doi:10.1038/s41598-020-60420-9
27. Marumo T, Hoshino J, Kawarazaki W, et al. Methylation pattern of urinary DNA as a marker of kidney function decline in diabetes. BMJ Open Diabetes Res Care. Sep 2020;8(1) Doi:10.1136/bmjdrc-2020-001501
28. Marumo T, Yoshida N, Inoue N, et al. Aberrant proximal tubule DNA methylation underlies phenotypic changes related to kidney dysfunction in patients with diabetes. Am J Physiol Renal Physiol. Sep 01 2024;327(3):F397-F411. Doi:10.1152/ajprenal.00124.2024
29. Elijovich F, Weinberger MH, Anderson CA, et al. Salt Sensitivity of Blood Pressure: A Scientific Statement From the American Heart Association. Hypertension. Sep 2016;68(3):e7-e46. Doi:10.1161/HYP.0000000000000047
30. Morimoto A, Uzu T, Fujii T, et al. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet. Dec 13 1997;350(9093):1734-7. Doi:10.1016/S0140-6736(97)05189-1
31. Gu D, Zhao Q, Chen J, et al. Reproducibility of blood pressure responses to dietary sodium and potassium interventions: the GenSalt study. Hypertension. Sep 2013;62(3):499-505. Doi:10.1161/HYPERTENSIONAHA.113.01034
32. Mu S, Shimosawa T, Ogura S, et al. Epigenetic modulation of the renal beta-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nature Medicine. MAY 2011 2011;17(5):573-U92. Doi:10.1038/nm.2337
33. Cao N, Lan C, Chen C, et al. Prenatal Lipopolysaccharides Exposure Induces Transgenerational Inheritance of Hypertension. Circulation. Oct 04 2022;146(14):1082-1095. Doi:10.1161/CIRCULATIONAHA.122.059891
34. Kawakami-Mori F, Nishimoto M, Reheman L, et al. Aberrant DNA methylation of hypothalamic angiotensin receptor in prenatal programmed hypertension. JCI Insight. Nov 02 2018;3(21) Doi:10.1172/jci.insight.95625
35. Gildea JJ, Lahiff DT, Van Sciver RE, et al. A linear relationship between the ex-vivo sodium mediated expression of two sodium regulatory pathways as a surrogate marker of salt sensitivity of blood pressure in exfoliated human renal proximal tubule cells: the virtual renal biopsy. Clin Chim Acta. Jun 05 2013;421:236-42. Doi:10.1016/j.cca.2013.02.021
36. Isobe K, Mori T, Asano T, et al. Development of enzyme-linked immunosorbent assays for urinary thiazide-sensitive Na-Cl cotransporter measurement. Am J Physiol Renal Physiol. Nov 01 2013;305(9):F1374-81. Doi:10.1152/ajprenal.00208.2013
37. Xu P, Sudarikova AV, Ilatovskaya DV, et al. Epithelial Sodium Channel Alpha Subunit (αENaC) Is Associated with Inverse Salt Sensitivity of Blood Pressure. Biomedicines. Apr 23 2022;10(5) Doi:10.3390/biomedicines10050981
38. Gildea JJ, Carlson JM, Schoeffel CD, Carey RM, Felder RA. Urinary exosome miRNome analysis and its applications to salt sensitivity of blood pressure. Clin Biochem. Aug 2013;46(12):1131-1134. Doi:10.1016/j.clinbiochem.2013.05.052
2. Bonventre JV, Vaidya VS, Schmouder R, Feig P, Dieterle F. Next-generation biomarkers for detecting kidney toxicity. Nat Biotechnol. May 2010;28(5):436-40. Doi:10.1038/nbt0510-436
3. Inoue K. Urinary Podocyte Biomarkers and Glomerular Histologic Change. Kidney360. Mar 31 2022;3(3):407-409. Doi:10.34067/KID.0008212021
4. Ding F, Gao Q, Tian X, Mo J, Zheng J. Increasing urinary podocyte mRNA excretion and progressive podocyte loss in kidney contribute to the high risk of long-term renal disease caused by preterm birth. Sci Rep. Oct 19 2021;11(1):20650. Doi:10.1038/s41598-021-00130-y
5. Fukuda A, Sato Y, Shibata H, Fujimoto S, Wiggins RC. Urinary podocyte markers of disease activity, therapeutic efficacy, and long-term outcomes in acute and chronic kidney diseases. Clin Exp Nephrol. Jun 2024;28(6):496-504. Doi:10.1007/s10157-024-02465-y
6. Lu J, Hu ZB, Chen PP, et al. Urinary levels of podocyte-derived microparticles are associated with the progression of chronic kidney disease. Ann Transl Med. Sep 2019;7(18):445. Doi:10.21037/atm.2019.08.78
7. Hara M, Yamamoto T, Yanagihara T, et al. Urinary excretion of podocalyxin indicates glomerular epithelial cell injuries in glomerulonephritis. Nephron. 1995;69(4):397-403. Doi:10.1159/000188509
8. Vogelmann SU, Nelson WJ, Myers BD, Lemley KV. Urinary excretion of viable podocytes in health and renal disease. Am J Physiol Renal Physiol. Jul 2003;285(1):F40-8. Doi:10.1152/ajprenal.00404.2002
9. Kriz W, Lemley KV. A potential role for mechanical forces in the detachment of podocytes and the progression of CKD. J Am Soc Nephrol. Feb 2015;26(2):258-69. Doi:10.1681/ASN.2014030278
10. Yokoyama C, Usui J, Kobayashi M, et al. Sustained Appearance of Urinary Podocytes Suggests Poor Renal Prognosis in Kidney Transplant Patients with Focal Segmental Glomerulosclerosis: Case Reports and Review of Literature. Clin Lab. 2015;61(12):1961-6. Doi:10.7754/clin.lab.2015.150515
11. Sternheimer R. A supravital cytodiagnostic stain for urinary sediments. JAMA. Feb 24 1975;231(8):826-32.
12. Shukuya K, Ogura S, Tokuhara Y, et al. Novel round cells in urine sediment and their clinical implications. Clin Chim Acta. Jun 01 2016;457:142-9. Doi:10.1016/j.cca.2016.04.017
13. Thongboonkerd V, Kanlaya R. The divergent roles of exosomes in kidney diseases: Pathogenesis, diagnostics, prognostics and therapeutics. Int J Biochem Cell Biol. Aug 2022;149:106262. Doi:10.1016/j.biocel.2022.106262
14. Sinha N, Kumar V, Puri V, et al. Urinary exosomes: Potential biomarkers for diabetic nephropathy. Nephrology (Carlton). Dec 2020;25(12):881-887. Doi:10.1111/nep.13720
15. Gámez-Valero A, Lozano-Ramos SI, Bancu I, Lauzurica-Valdemoros R, Borràs FE. Urinary extracellular vesicles as source of biomarkers in kidney diseases. Front Immunol. 2015;6:6. Doi:10.3389/fimmu.2015.00006
16. Oba S, Ayuzawa N, Nishimoto M, et al. Aberrant DNA methylation of Tgfb1 in diabetic kidney mesangial cells. Sci Rep. Nov 05 2018;8(1):16338. Doi:10.1038/s41598-018-34612-3
17. Li S, Li W, Wu R, et al. Epigenome and transcriptome study of moringa isothiocyanate in mouse kidney mesangial cells induced by high glucose, a potential model for diabetic-induced nephropathy. AAPS J. Dec 05 2019;22(1):8. Doi:10.1208/s12248-019-0393-z
18. Sun G, Reddy MA, Yuan H, Lanting L, Kato M, Natarajan R. Epigenetic histone methylation modulates fibrotic gene expression. J Am Soc Nephrol. Dec 2010;21(12):2069-80. Doi:10.1681/ASN.2010060633
19. Bell JT, Tsai PC, Yang TP, et al. Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genet. 2012;8(4):e1002629. Doi:10.1371/journal.pgen.1002629
20. Chen Z, Satake E, Pezzolesi MG, et al. Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes. Sci Transl Med. May 22 2024;16(748):eadj3385. Doi:10.1126/scitranslmed.adj3385
21. Chu AY, Tin A, Schlosser P, et al. Epigenome-wide association studies identify DNA methylation associated with kidney function. Nat Commun. Nov 03 2017;8(1):1286. Doi:10.1038/s41467-017-01297-7
22. Kim JE, Jo MJ, Cho E, et al. The Effect of DNA Methylation in the Development and Progression of Chronic Kidney Disease in the General Population: An Epigenome-Wide Association Study Using the Korean Genome and Epidemiology Study Database. Genes (Basel). Jul 21 2023;14(7) Doi:10.3390/genes14071489
23. Li KY, Tam CHT, Liu H, et al. DNA methylation markers for kidney function and progression of diabetic kidney disease. Nat Commun. May 15 2023;14(1):2543. Doi:10.1038/s41467-023-37837-7
24. Schlosser P, Tin A, Matias-Garcia PR, et al. Meta-analyses identify DNA methylation associated with kidney function and damage. Nat Commun. Dec 09 2021;12(1):7174. Doi:10.1038/s41467-021-27234-3
25. Smyth LJ, Dahlström EH, Syreeni A, et al. Epigenome-wide meta-analysis identifies DNA methylation biomarkers associated with diabetic kidney disease. Nat Commun. Dec 22 2022;13(1):7891. Doi:10.1038/s41467-022-34963-6
26. Hishikawa A, Hayashi K, Yoshimoto N, Nakamichi R, Homma K, Itoh H. DNA damage and expression of DNA methylation modulators in urine-derived cells of patients with hypertension and diabetes. Sci Rep. Feb 25 2020;10(1):3377. Doi:10.1038/s41598-020-60420-9
27. Marumo T, Hoshino J, Kawarazaki W, et al. Methylation pattern of urinary DNA as a marker of kidney function decline in diabetes. BMJ Open Diabetes Res Care. Sep 2020;8(1) Doi:10.1136/bmjdrc-2020-001501
28. Marumo T, Yoshida N, Inoue N, et al. Aberrant proximal tubule DNA methylation underlies phenotypic changes related to kidney dysfunction in patients with diabetes. Am J Physiol Renal Physiol. Sep 01 2024;327(3):F397-F411. Doi:10.1152/ajprenal.00124.2024
29. Elijovich F, Weinberger MH, Anderson CA, et al. Salt Sensitivity of Blood Pressure: A Scientific Statement From the American Heart Association. Hypertension. Sep 2016;68(3):e7-e46. Doi:10.1161/HYP.0000000000000047
30. Morimoto A, Uzu T, Fujii T, et al. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet. Dec 13 1997;350(9093):1734-7. Doi:10.1016/S0140-6736(97)05189-1
31. Gu D, Zhao Q, Chen J, et al. Reproducibility of blood pressure responses to dietary sodium and potassium interventions: the GenSalt study. Hypertension. Sep 2013;62(3):499-505. Doi:10.1161/HYPERTENSIONAHA.113.01034
32. Mu S, Shimosawa T, Ogura S, et al. Epigenetic modulation of the renal beta-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nature Medicine. MAY 2011 2011;17(5):573-U92. Doi:10.1038/nm.2337
33. Cao N, Lan C, Chen C, et al. Prenatal Lipopolysaccharides Exposure Induces Transgenerational Inheritance of Hypertension. Circulation. Oct 04 2022;146(14):1082-1095. Doi:10.1161/CIRCULATIONAHA.122.059891
34. Kawakami-Mori F, Nishimoto M, Reheman L, et al. Aberrant DNA methylation of hypothalamic angiotensin receptor in prenatal programmed hypertension. JCI Insight. Nov 02 2018;3(21) Doi:10.1172/jci.insight.95625
35. Gildea JJ, Lahiff DT, Van Sciver RE, et al. A linear relationship between the ex-vivo sodium mediated expression of two sodium regulatory pathways as a surrogate marker of salt sensitivity of blood pressure in exfoliated human renal proximal tubule cells: the virtual renal biopsy. Clin Chim Acta. Jun 05 2013;421:236-42. Doi:10.1016/j.cca.2013.02.021
36. Isobe K, Mori T, Asano T, et al. Development of enzyme-linked immunosorbent assays for urinary thiazide-sensitive Na-Cl cotransporter measurement. Am J Physiol Renal Physiol. Nov 01 2013;305(9):F1374-81. Doi:10.1152/ajprenal.00208.2013
37. Xu P, Sudarikova AV, Ilatovskaya DV, et al. Epithelial Sodium Channel Alpha Subunit (αENaC) Is Associated with Inverse Salt Sensitivity of Blood Pressure. Biomedicines. Apr 23 2022;10(5) Doi:10.3390/biomedicines10050981
38. Gildea JJ, Carlson JM, Schoeffel CD, Carey RM, Felder RA. Urinary exosome miRNome analysis and its applications to salt sensitivity of blood pressure. Clin Biochem. Aug 2013;46(12):1131-1134. Doi:10.1016/j.clinbiochem.2013.05.052