Longitudinal Trajectories of Biomarkers of Kidney Tubular Function in Type 1 Diabetes

Christine P Limonte; Xiaoyu Gao; Ionut Bebu; Jesse C Seegmiller; Gayle M Lorenzi; Bruce A Perkins; Amy B Karger; Valerie L Arends; Andrew Paterson; Mark E Molitch; Ian H de Boer; DCCT/EDIC Research Group

doi:10.1016/j.ekir.2023.11.030

Longitudinal Trajectories of Biomarkers of Kidney Tubular Function in Type 1 Diabetes

Kidney Int Rep. 2024 Feb 18;9(5):1406-1418. doi: 10.1016/j.ekir.2023.11.030. eCollection 2024 May.

Authors

Affiliations

¹ Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA.
² Kidney Research Institute, University of Washington, Seattle, Washington, USA.
³ Biostatistics Center, The George Washington University, Rockville, Maryland, USA.
⁴ Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
⁵ Department of Medicine, University of California, San Diego, La Jolla, California, USA.
⁶ Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁷ Program in Genetics and Genome Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
⁸ Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Abstract

Introduction: Tubular biomarkers may shed insight into progression of kidney tubulointerstitial pathology complementary to traditional measures of glomerular function and damage.

Methods: We examined trajectories of tubular biomarkers in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC Study) of type 1 diabetes (T1D). Biomarkers were measured in a subset of 220 participants across 7 time points over 26 years. Measurements included the following: kidney injury molecule 1 (KIM-1), soluble tumor necrosis factor 1 (sTNFR1) in serum or plasma, epidermal growth factor (EGF), monocyte chemoattractant protein-1 (MCP1) in timed urine, and a composite tubular secretion score. We described biomarker trajectories and examined how these were affected by intensive glucose-lowering therapy and glycemia.

Results: At baseline, participants had a mean age of 28 years, 45% were women, and 50% were assigned to intensive glucose-lowering therapy. The mean estimated glomerular filtration rate (eGFR) was 125 ml/min per 1.73 m² and 90% of participants had a urinary albumin excretion rate (AER) <30 mg/24h. Mean changes in biomarkers over time (percent/decade) were: KIM-1: 27.3% (95% confidence interval [CI]: 21.4-33.5), sTNFR1: 16.9% (14.5-19.3), MCP1: 18.4% (8.9-28.8), EGF: -13.5% (-16.7 to -10.1), EGF-MCP1 ratio: -26.9% (-32.2 to -21.3), and tubular secretion score -0.9% (-1.8 to 0.0), versus -12.0% (CI: -12.9 to -11.1) for eGFR and 10.9% (2.5-20.1) for AER. Intensive versus conventional glucose-lowering therapy was associated with slower increase in sTNFR1 (relative difference in change: 0.94 [0.90-0.98]). Higher HbA1c was associated with faster increases in sTNFR1 (relative difference in change: 1.06 per 1% higher HbA1c [1.05-1.08]) and KIM-1 (1.09 [1.05-1.14]).

Conclusion: Among participants with T1D and normal eGFR at baseline, kidney tubular biomarkers changed significantly over long-term follow-up. Hyperglycemia was associated with larger increases in serum or plasma sTNFR1 and KIM-1, when followed-up longitudinally.

Keywords: KIM-1; biomarkers; diabetic kidney disease; sTNFR1; tubular; type 1 diabetes.