Associations of Kidney Tubular Biomarkers With Incident Macroalbuminuria and Sustained Low eGFR in DCCT/EDIC

Author:

Limonte Christine P.12ORCID,Gao Xiaoyu3,Bebu Ionut3,Seegmiller Jesse C.4,Karger Amy B.4,Lorenzi Gayle M.5,Molitch Mark6ORCID,Karanchi Harsha7,Perkins Bruce A.8,de Boer Ian H.12, ,

Affiliation:

1. 1Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA

2. 2Kidney Research Institute, University of Washington, Seattle, WA

3. 3Biostatistics Center, The George Washington University, Rockville, MD

4. 4Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN

5. 5Department of Medicine, University of California, San Diego, La Jolla, CA

6. 6Northwestern University, Chicago, IL

7. 7Department of Medicine, Medical University of South Carolina, Charleston, SC

8. 8Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Abstract

OBJECTIVE Tubulointerstitial injury contributes to diabetic kidney disease (DKD) progression. We tested tubular biomarker associations with DKD development in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS We performed a case-cohort study examining associations of tubular biomarkers, measured across seven time points spanning ∼30 years, with incident macroalbuminuria (“severely elevated albuminuria,” urinary albumin excretion rate [AER] ≥300 mg/day) and sustained low estimated glomerular filtration rate (eGFR) (persistent eGFR <60 mL/min/1.73 m2) in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. Biomarkers included KIM-1 and sTNFR1 in serum/plasma, MCP-1 and EGF in urine, and a composite tubular secretion score reflecting secreted solute clearance. We assessed biomarkers using single values, as mean values from consecutive time points, and as change over consecutive time points, each as time-updated exposures. RESULTS At baseline, mean diabetes duration was 5.9 years, with mean HbA1c 8.9%, eGFR 125 mL/min/1.73 m2, and AER 16 mg/day. There were 4.8 and 3.5 cases per 1,000 person-years of macroalbuminuria and low eGFR, respectively. Assessed according to single biomarker values, KIM-1 was associated with risk of subsequent macroalbuminuria and low eGFR (hazard ratio [HR] per 20% higher biomarker 1.11 [95% CI 1.06, 1.16] and 1.12 [1.04, 1.21], respectively) and sTNFR1 was associated with subsequent macroalbuminuria (1.14 [1.03, 1.25]). Mean KIM-1 and EGF–to–MCP-1 ratio were associated with subsequent low eGFR. In slope analyses, increases in KIM-1 and sTNFR1 were associated with subsequent macroalbuminuria (per 20% biomarker increase, HR 1.81 [1.40, 2.34] and 1.95 [1.18, 3.21]) and low eGFR (2.26 [1.65, 3.09] and 2.94 [1.39, 6.23]). CONCLUSIONS Serial KIM-1 and sTNFR1 are associated with incident macroalbuminuria and sustained low eGFR in T1D.

Funder

the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the General Clinical Research Centers Program

Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease

NIDDK

Clinical Translational Science Center

Publisher

American Diabetes Association

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