People living with type 1 diabetes have increased risk to develop diabetic nephropathy. No targeted cure exists, but the progression can be slowed down if detected early. We tested whether metabolic biomarkers measured in urine could predict progression of diabetic nephropathy (DN) in the Finnish nationwide FinnDiane Study.
At baseline, 18 urine metabolites were measured with nuclear magnetic resonance metabolomics and scaled relative to urine creatinine. Individuals were followed for DN status for 9.0 years (± 5.1 years) until they progressed to their most severe DN status (334 events) or the latest known DN status for non-progressors. A Bonferroni-corrected P<0.003 was considered significant.
Five out of 18 urine metabolites were robustly associated with risk for DN progression in Cox regression models adjusted for sex, year of diabetes diagnosis as well as baseline age, DN status, BMI and eGFR. Individuals with elevated urinary levels of alanine (Hazard Ratio (HR) = 1.49 [1.26, 1.77] per 1-SD creatinine-scaled metabolite concentration, , P=3×10-6), valine (HR = 1.34 [1.22, 1.48], P=4×10-9), 2–hydroxyisobutyrate (HR = 1.48 [1.30, 1.67], P=1×10-9), cis-Aconitate (HR = 1.17 [1.06, 1.28], P=9×10-4) and pseudouridine (HR = 1.45 [1.24, 1.69], P=4×10-6) showed higher DN progression rate.
We conclude that urinary biomarkers are indicative of kidney disease progression in type 1 diabetes, independently of baseline microalbuminuria and eGFR. The urinary biomarkers span multiple metabolic pathways, including microbial metabolism, citric acid cycle, and amino acids reflecting adiposity and dietary quality.
S. Mutter: None. E.A. Valo: None. V. Aittomäki: Employee; Self; Nightingale Health Ltd. Other Relationship; Self; Nightingale Health Ltd. C. Forsblom: None. P. Groop: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Sanofi, Sanofi. Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medscape, Merck Sharp & Dohme Corp., Mundipharma International. P. Wurtz: Employee; Self; Nightingale Health Ltd. Stock/Shareholder; Self; Nightingale Health Ltd.
Folkhälsan Finland; Novo Nordisk Foundation; Academy of Finland