Article Text
Abstract
Introduction Renal tubular injury contributes to the decline in kidney function in patients with diabetes. Cell type-specific DNA methylation patterns have been used to calculate proportions of particular cell types. In this study, we developed a method to detect renal tubular injury in patients with diabetes by detecting exfoliated tubular cells shed into the urine based on tubular cell-specific DNA methylation patterns.
Research design and methods We identified DNA methylation patterns specific for human renal proximal tubular cells through compartment-specific methylome analysis. We next determined the methylation levels of proximal tubule-specific loci in urine sediment of patients with diabetes and analyzed correlation with clinical variables.
Results We identified genomic loci in SMTNL2 and G6PC to be selectively unmethylated in human proximal tubular cells. The methylation levels of SMTNL2 and G6PC in urine sediment, deemed to reflect the proportion of exfoliated proximal tubular cells due to injury, correlated well with each other. Methylation levels of SMTNL2 in urine sediment significantly correlated with the annual decline in estimated glomerular filtration rate. Moreover, addition of urinary SMTNL2 methylation to a model containing known risk factors significantly improved discrimination of patients with diabetes with faster estimated glomerular filtration rate decline.
Conclusions This study demonstrates that patients with diabetes with continual loss in kidney function may be stratified by a specific DNA methylation signature through epigenetic urinalysis and provides further evidence at the level of exfoliated cells in the urine that injury of proximal tubular cells may contribute to pathogenesis of diabetic kidney disease.
- diabetes complications
- kidney diseases
- renal insufficiency
- chronic
- urinalysis
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Footnotes
Contributors TM and ToF conceived and designed the work. TM, JH, TaF, EA and YK performed analysis. TM, JH, MY, YU, TO, KY, YA, AS and TS acquired data. TM, JH, MN, NA, DH, YK and ToF interpreted data. TM wrote the manuscript. TM and ToF are the guarantors of this work and, as such, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Funding This work was supported by AMED-CREST, Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus (JP18ek0210093) and The Translational Research program; Strategic PRomotion for practical application of INnovative medical Technology, TR-SPRINT from Japan Agency for Medical Research and Development, AMED, JSPS KAKENHI (grant numbers 25461230, 15H05788, 16K15466, 18K19533 and 20K08627), the Kidney Foundation, Japan (JFKB19-16) and Okinaka Memorial Institute for Medical Research.
Competing interests Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo is an endowment department, supported with an unrestricted grant from Asahi Group Holdings, Astellas Pharma, Chugai Pharmaceutical, EA Pharma, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, MSD K.K., Nippon Boehringer Ingelheim, Omron Healthcare, Shionogi & Co. and Toray Industries. TM and ToF are inventors of a patent filed in JP (pending; No.2019-163696) with a title 'A method for evaluation of renal function and discrimination of diabetic patients with renal dysfunction'.
Patient consent for publication Not required.
Ethics approval The protocol of this study was approved by the ethics committees of The University of Tokyo (17-35, 18-32, 18-41, 11289-3), Toranomon Hospital (2014-5), International University of Health and Welfare (2017-8), Eiju General Hospital (2017-8) and Keio University (20180169) (University Hospital Medical Information Network identification number: UMIN000020166). Informed consent was obtained from all the participants before taking part and the procedures fully adhered to the Declaration of Helsinki.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. The data set and resources generated and analyzed in this study are available from the corresponding author on reasonable request.