Abstract
Aims/hypothesisThis prospective, observational study examines associations between 51 urinary metabolites and risk of progression of diabetic nephropathy in individuals with type 1 diabetes by employing an automated NMR metabolomics technique suitable for large-scale urine sample collections.MethodsWe collected 24-h urine samples for 2670 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy study and measured metabolite concentrations by NMR. Individuals were followed up for 9.0 ± 5.0 years until their first sign of progression of diabetic nephropathy, end-stage kidney disease or study end. Cox regressions were performed on the entire study population (overall progression), on 1999 individuals with normoalbuminuria and 347 individuals with macroalbuminuria at baseline.ResultsSeven urinary metabolites were associated with overall progression after adjustment for baseline albuminuria and chronic kidney disease stage (p < 8 × 10−4): leucine (HR 1.47 [95% CI 1.30, 1.66] per 1-SD creatinine-scaled metabolite concentration), valine (1.38 [1.22, 1.56]), isoleucine (1.33 [1.18, 1.50]), pseudouridine (1.25 [1.11, 1.42]), threonine (1.27 [1.11, 1.46]) and citrate (0.84 [0.75, 0.93]). 2-Hydroxyisobutyrate was associated with overall progression (1.30 [1.16, 1.45]) and also progression from normoalbuminuria (1.56 [1.25, 1.95]). Six amino acids and pyroglutamate were associated with progression from macroalbuminuria.Conclusions/interpretationBranched-chain amino acids and other urinary metabolites were associated with the progression of diabetic nephropathy on top of baseline albuminuria and chronic kidney disease. We found differences in associations for overall progression and progression from normo- and macroalbuminuria. These novel discoveries illustrate the utility of analysing urinary metabolites in entire population cohorts.Graphical abstract
Highlights
Type 1 diabetes usually manifests at a young age
We employed a high-throughput NMR platform to analyse 51 metabolite-to-creatinine ratios from 24-h urine samples of 2670 individuals with type 1 diabetes and found that ten ratios were associated with progression of diabetic nephropathy after adjusting for baseline albuminuria category and chronic kidney disease (CKD) stage
Several metabolites point towards a link between insulin resistance and progression of diabetic nephropathy
Summary
Type 1 diabetes usually manifests at a young age. the affected individuals are at an especially high lifetime risk of developing diabetic complications such as diabetic nephropathy, which affects a third of individuals and is the main cause of higher mortality rates in type 1 diabetes [1]. The molecular understanding of diabetic nephropathy is expanding, its exact pathophysiology is still elusive [2]. Diabetologia (2022) 65:140–149 and might offer novel molecular insights into the pathophysiology of diabetic nephropathy. Known as metabolomics, has been successfully used to identify blood metabolites that are involved at different stages of diabetic nephropathy [4]. Urine reflects kidney function, and urinary metabolomics is a attractive tool in the study of kidney disease [5]. These studies have commonly been limited to case–control studies of modest size [7] or focused on a small number of metabolites quantified. Developments in NMR have enabled high-throughput metabolomic profiling of urine from large cohorts [3]
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