Association of urinary post-translationally modified fetuin-A fragments with diabetic kidney disease risk stratification in Japanese patients with type 2 diabetes

Abstract

Aims Conventional biomarkers such as estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (uACR) primarily reflect glomerular damage and often fail to detect early tubular injury. Consequently, patients with “non-albuminuric diabetic kidney disease (DKD)” may be overlooked. This study evaluated the independent association between urinary post-translationally modified fetuin-A fragments (uPTM-FetA) and DKD risk stratification in Japanese patients with type 2 diabetes. Methods We conducted a cross-sectional study of 219 outpatients with type 2 diabetes between November 2023 and February 2024 at Edogawa Hospital. First-morning urine samples were analyzed for uPTM-FetA and urinary liver-type fatty acid-binding protein (uL-FABP) using enzyme-linked immunosorbent assays. DKD risk was classified into four categories based on the KDIGO guidelines. The association between uPTM-FetA and higher DKD-risk (categories 2 + 3 + 4) was assessed using multiple logistic regression and restricted cubic spline (RCS) analyses, validated by bootstrapping. Results The optimal cutoff value for uPTM-FetA was determined to be 11.76 ng/mgCr. Multivariable analysis adjusted for potential confounders revealed that high uPTM-FetA levels were significantly and independently associated with DKD-risk categories 2 + 3 + 4 (adjusted odds ratio: 3.88; 95% CI: 2.02–7.45; P < 0.01). RCS analysis indicated a significant non-linear association (P = 0.04). Notably, high uPTM-FetA was detected in 38.8% of patients with normoalbuminuria and 42.0% of those with preserved eGFR. A striking discrepancy was observed compared to uL-FABP: while high uL-FABP was completely absent (0.0%) in patients within the low-to-moderate risk categories (categories 1 and 2), high uPTM-FetA was observed in 34.0% and 60.8% of these patients, respectively. Conclusions uPTM-FetA is independently associated with DKD severity and is elevated in a substantial proportion of patients with early-stage disease where conventional markers remain normal. Unlike uL-FABP, which increases predominantly in advanced stages, uPTM-FetA appears to identify tubular stress earlier. Thus, uPTM-FetA serves as a valuable complementary biomarker to uACR for refining DKD risk stratification.