Urine leucine-rich alpha-2 glycoprotein 1 (LRG1) predicts the risk for progression to end stage kidney disease in patients with type 2 diabetes

Objective: Leucine-rich alpha-2 glycoprotein 1 (LRG1) is recently identified as an amplifier of transforming growth factor (TGF)- beta- induced kidney fibrosis in animal models. We aim to study whether urine LRG1 is associated with risk for progression to end stage kidney disease (ESKD) in individuals with type 2 diabetes. 

Design and Methods: 1837 participants with type 2 diabetes and eGFR above 30 ml/min/1.73m2 were recruited from a regional hospital and a primary care facility. Association of urine LRG1 with risk for ESKD (progression to sustained eGFR < 15 ml/min/1.73m2, dialysis or renal death) was assessed by survival analyses.

Results: 134 incident ESKD events were identified during a median follow-up of 8.6 (IQR 5.8-9.6) years. As compared to the lowest tertile, participants with baseline urine LRG1 in the highest tertile had 1.91 (95% CI 1.04- 3.50) folds increased risk for progression to ESKD after adjustment for cardio-renal risk factors including eGFR and albuminuria. As a continuous variable, one SD increment in urine LRG1 was associated with 1.53 (95% CI 1.19-1.98) folds adjusted risk for ESKD. Of note, the association of urine LRG1 with ESKD was independent of plasma LRG1. Moreover, urine LRG1 was associated with rapid kidney function decline and progression to macroalbuminuria, two common pathways leading to ESKD. 

Conclusions: Urine LRG1, a TGF-beta signalling modulator, predicts risk for progression to ESKD independent of clinical risk factors in patients with type 2 diabetes, suggesting that it may be a novel factor involving in the pathophysiological pathway leading to kidney disease progression.