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Biomarkers of tubulointerstitial damage and function in type 1 diabetes


Objective To evaluate biomarkers of renal tubulointerstitial damage and function in type 1 diabetes with and without diabetic kidney disease.

Research design and methods Cross-sectional case-control study of Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study participants. Cases (N=43) had incident persistent estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 with urinary albumin excretion >300 mg/24 hour. Controls (N=43) had persistent eGFR >90 mL/min/1.73 m2 and urinary albumin excretion <30 mg/24 hour. Urinary and plasma biomarkers reflecting tubular injury, inflammation, fibrosis, secretion, and synthetic function were measured from stored specimens collected at the first study visit with reduced eGFR (for case participants) or the corresponding study year (for control participants).

Results Mean (SD) age was 51 (9) and 50 (8) years for case and control participants, and mean (SD) duration of diabetes was 30 (6) and 30 (5) years, respectively. Mean (SD) eGFR was 39 (14) and 103 (9) mL/min/1.73 m2 for case and control participants, and mean (SD) albumin excretion rate was 1978 (2914) and 10 (7) mg/day, respectively. Comparing cases with controls, significant differences were observed in each measured biomarker, including urine epidermal growth factor (mean 5.3 vs 21.2 μg/g creatinine for case vs control participants, respectively), urine monocyte chemoattractant protein-1 (596 vs 123 ng/g creatinine), urine galectin-3 (168 vs 52 μg/g creatinine), plasma soluble tubular necrosis factor receptor-1 (3695 vs 1022 pg/mL), plasma galectin-3 (21.3 vs 11.0 ng/mL), urinary clearances of hippurate (70 vs 167 mL/min) and cinnamoylglycine (77 vs 317 mL/min), and plasma arginine-citrulline ratio (5.6 vs 7.7 μg/μg), each P<0.001.

Conclusions Marked abnormalities in biomarkers of kidney tubular injury, inflammation, fibrosis, secretion, and synthetic function accompany reduced eGFR and albuminuria in type 1 diabetes.

Trial registration number NCT00360893, NCT00360815.

  • type 1
  • chronic kidney disease
  • biomarkers

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  • Contributors All authors contributed to the study design, interpreted the data, revised the manuscript critically for important intellectual content, approved the final version of the manuscript and agreed to be accountable for the work. In addition, IHdeB drafted the manuscript; XG and IB and JML performed analyses and ANH, AS and MWS acquired laboratory data.

  • Funding The DCCT/EDIC has been supported by U01 Cooperative Agreement grants (1982-93, 2011-2016), and contracts (1982-2011) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and through support by the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the Genetic Clinical Research Centers Program (1993- 2007) and Clinical Translational Science Center Program (2006-present), Bethesda, Maryland, USA. Industry contributors have had no role in the DCCT/EDIC study, but have provided free or discounted supplies or equipment to support participants’ adherence to the study: Abbott Diabetes Care (Alameda, CA), Animas (Westchester, PA), Bayer Diabetes Care (North America Headquarters, Tarrytown, NY) Becton Dickinson (Franklin Lakes, NJ), CanAm (Atlanta, GA) , Eli Lilly (Indianapolis, IN), Lifescan (Milpitas, CA), Medtronic Diabetes (Minneapolis, MN), Omron (Shelton, CT), OmniPod Insulin Management System (Bedford, MA), Roche Diabetes Care (Indianapolis, IN) and Sanofi-Aventis (Bridgewater, NJ). Dr de Boer’s effort was supported by grants R01DK087726 and R01DK088762 from the NIDDK.

  • Competing interests IHdeB consulted for Boehringer-Ingelheim and Ironwood and received research equipment and supplies from Medtronic and Abbott. BAP has consulted for Neurometrix, Boehringer-Ingelheim, Abbott and Insulet. He has received speaker fees for medical education events from Medtronic, Novo Nordisk, Abbott, Insulet and Janssen. His institution has received support on his behalf for research funded by Boehringer-Ingelheim and Novo Nordisk.

  • Patient consent Obtained.

  • Ethics approval Site IRBs.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data from the DCCT/EDIC cohort are available to the public through the NIDDK Repository.

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