Researchers have identified 10 out of 51 urinary metabolites associated with the progression of diabetic nephropathy in patients with type 1 diabetes, even after adjustment for baseline albuminuria and chronic kidney disease (CKD) stage, as reported in Diabetologia.

The investigators used urinary nuclear magnetic resonance (NMR) metabolomic profiling—also known as metabolomics–in 2670 patients with type 1 diabetes to identify metabolites associated with the risk of progression of diabetic nephropathy.

The participants were from the Finnish Diabetic Nephropathy (FinnDiane) study and were followed for a mean of 9.0 years (SD 5.0 years) until their first sign of progression or their latest albuminuria assessment if disease progression was not apparent.

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From the overall cohort, 355 patients (median age, 39.3 years; 57.8% men) progressed to either a worse albuminuria category or end-stage kidney disease, and there were 2315 nonprogressors (median age, 35.7 years; 49.7% men).

Significant differences were found between the progressors and nonprogressors for 17 metabolites. The progressors had an increased ratio (P < .0001) for 2- hydroxyisobutyrate, dimethylamine, isoleucine, and pseudouridine, as well as a decreased ratio for 3-hydroxyisobutyrate, 3-hydroxyisovalerate, citrate, 4-deoxyerythronic acid, ethanolamine, glycine, glycolic acid, histidine, hypoxanthine, indoxyl sulphate, 1-methylnicotinamide, trans-aconitate, and tyrosine.

When Cox models were used to assess the incidence of progression, 7 urinary metabolites demonstrated a significant association with overall progression after adjustment for sex, age, and diabetes duration, along with baseline glycemic control, albuminuria, and CKD stages.

Leucine, until 10 years of follow-up, had the strongest association of all urinary metabolites with overall progression of diabetic nephropathy among the urinary metabolites, with a hazard ratio (HR) of 1.47 (95% CI, 1.30, 1.66; P = 6.83 × 10−10). The following were also associated with progression of diabetic nephropathy: valine until 10 years of follow-up (1.38 [1.22, 1.56]; P = 2.17 × 10−7 ), isoleucine (1.33 [1.18, 1.50]; P = 5.19 × 10−6 ), 2-hydroxyisobutyrate (1.30 [1.16, 1.45]; P = 2.40 × 10−6 ), threonine until 5 years of follow-up (1.27 [1.11, 1.46]; P = .0007) and pseudouridine (1.25 [1.11, 1.42]; P = .0002). An inverse relationship was observed for urinary citrate (0.84 [0.75, 0.93]; P = .0008).

For progression from normoalbuminuria only, which occurred in 1999 individuals, 2-hydroxyisobutyrate was significantly associated with incident diabetic nephropathy after adjustment for all covariates including baseline glycemic control, albuminuria, and CKD stage, with a HR of 1.56 (1.25, 1.95; P = 9.58 × 10−5 ) and was also associated with overall progression.

Among several study limitations, the associations between urine metabolites and progression did not allow for any causal conclusions. Also, the findings have not been replicated in an independent cohort, and dietary data were not available.

“These results provide new potential urinary biomarkers that were associated with progression beyond the traditional markers of albuminuria and estimated kidney filtration rates,” the investigators commented. “This study highlights the potential of routinely analyzing urinary metabolites on a larger scale as urinary NMR metabolomic profiling is a reliable high-throughput method.”

Disclosure: The FinnDiane study was funded in part by the Novo Nordisk Foundation. . Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Mutter S, Valo E, Aittomäki V, et al. Urinary metabolite profiling and risk of progression of diabetic nephropathy in 2670 individuals with type 1 diabetes. Diabetologia. Published online October 22, 2021. doi:10.1007/s00125-021-05584-3