Novel Tubular Biomarkers Predict Renal Progression in Type 2 Diabetes Mellitus: A Prospective Cohort Study

Abstract

Background. Tubulointerstitial injury is both a key feature of diabetic nephropathy and an important predictor of renal dysfunction. Novel tubular biomarkers related to renal injury in diabetic nephropathy could improve risk stratification and prediction. Methods. A total of 303 type 2 diabetic patients were followed up. The baseline urine values of cystatin-C to creatinine ratio (UCCR), angiotensinogen to creatinine ratio (UANG), NGAL to creatinine ratio (UNGAL), and KIM-1 to creatinine ratio (UKIM-1) were measured. The primary outcome was a decline in estimated GFR of ≥25% yearly from baseline. Results. Urine tubular biomarkers of UCCR, UANG, UNGAL, and UKIM-1 were significantly higher according to the degree of albuminuria and all were significantly higher among patients with rapid decline in estimated GFR of ≥25% yearly from baseline. All biomarkers predicted primary outcomes with ROC for UCCR of 0.72; 95% CI 0.64-0.79, for UANG of 0.71; 95% CI 0.63-0.79, for UNGAL of 0.64; 95% CI 0.56-0.72, and for UKIM-1 of 0.71; 95% CI 0.63-0.79. Using multivariate Cox regression analysis, the number of patients with rapid renal progression was higher among those in the upper quartiles of all biomarkers than in those in the lower quartiles. Conclusions. Type 2 diabetic patients with high levels of urine tubular biomarkers had a more rapid decline in renal function.

Figure 1

Urinary levels of tubular biomarkers in the rapid and nonrapid GFR decline groups. (a) Cystatin-C, (b) Angiotensinogen, (c) KIM-1, and (d) NGAL adjusted by urinary creatinine in T2DM patients classified in two groups according to GFR decline: rapid renal progression, nonrapid renal progression. Results are presented as median. UANG: urine angiotensinogen creatinine ratio; UCCR: urine cystatin-C creatinine ratio; UKIM-1: Urine Kidney Injury Molecule-1 creatinine ratio; UNGAL: Urine Neutrophil Gelatinase Associated Lipocalin creatinine ratio. ^∗ P < 0.01 versus GFR decline < 25% per year.

Figure 2

Graph ROC curves showing Area under the Curve (AUC) of each tubular biomarker to predict rapid GFR decline. UACR: urine albumin creatinine ratio; UANG: urine angiotensinogen creatinine ratio; UCCR: urine cystatin-C creatinine ratio; UKIM-1: Urine Kidney Injury Molecule-1 creatinine ratio; UNGAL: Urine Neutrophil Gelatinase Associated Lipocalin creatinine ratio.

Figure 3

Kaplan-Meier survival curves of renal endpoint in patients with UNGAL, UCCR, UANG, and UKIM-1 levels above and below the optimal receiver operating characteristics cut-off level of each tubular biomarker. (a) Patients with UNGAL ≥772 ng/g (P = 0.01, log-rank test), (b) UCCR ≥ 3.429 ng/g (P = 0.005, log-rank test), (c) UANG ≥4.52 mcg/g (P = 0.005, log-rank test), and (d) UKIM-1 ≥95 ng/g (P = 0.001, log-rank test) showed a significantly faster progression to endpoint. UANG: urine angiotensinogen creatinine ratio; UCCR: urine cystatin-C creatinine ratio; UKIM-1: Urine Kidney Injury Molecule-1 creatinine ratio; UNGAL: Urine Neutrophil Gelatinase Associated Lipocalin creatinine ratio.