Novel urinary protein biomarkers predicting the development of microalbuminuria and renal function decline in type 1 diabetes

Jan. 11, 2012

OBJECTIVE To define a panel of novel protein biomarkers of renal disease.

RESEARCH DESIGN AND METHODS Adults with type 1 diabetes in the Coronary Artery Calcification in Type 1 Diabetes study who were initially free of renal complications (n = 465) were followed for development of micro- or macroalbuminuria (MA) and early renal function decline (ERFD, annual decline in estimated glomerular filtration rate of ≥3.3%). The label-free proteomic discovery phase was conducted in 13 patients who progressed to MA by the 6-year visit and 11 control subjects, and four proteins (Tamm-Horsfall glycoprotein, α-1 acid glycoprotein, clusterin, and progranulin) identified in the discovery phase were measured by enzyme-linked immunosorbent assay in 74 subjects: group A, normal renal function (n = 35); group B, ERFD without MA (n = 15); group C, MA without ERFD (n = 16); and group D, both ERFD and MA (n = 8). RESULTS In the label-free analysis, a model of progression to MA was built using 252 peptides, yielding an area under the curve (AUC) of 84.7 ± 5.3%. In the validation study, ordinal logistic regression was used to predict development of ERFD, MA, or both. A panel including Tamm-Horsfall glycoprotein (odds ratio 2.9, 95% CI 1.3-6.2, P = 0.008), progranulin (1.9, 0.8-4.5, P = 0.16), clusterin (0.6, 0.3-1.1, P = 0.09), and α-1 acid glycoprotein (1.6, 0.7-3.7, P = 0.27) improved the AUC from 0.841 to 0.889.

CONCLUSIONS A panel of four novel protein biomarkers predicted early renal damage in type 1 diabetes. These findings require further validation in other populations for prediction of renal complications and treatment monitoring.

Figure Significant differences were observed between groups A and D for THP (Figure A) and progranulin (Figure B). Both THP and progranulin followed a stepwise pattern, with the lowest levels in those patients who maintained normal renal function and normoalbuminuria (Group A), increasing non-significantly in those patients with either ERFD (Group B) or MA (Group C), and significantly increased in patients with both ERFD and MA (Group D).

Results from: Schlatzer D, Maahs DM, Chance MR, Dazard JE, Li X, Hazlett F, Rewers M, Snell-Bergeon JK. Diabetes Care. 35(3):549-55, 2012. PMID: 22238279