Urinary metabolite profiling and risk of progression of diabetic nephropathy in 2670 individuals with type 1 diabetes,Diabetologia

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Urinary metabolite profiling and risk of progression of diabetic nephropathy in 2670 individuals with type 1 diabetes
Diabetologia ( IF 8.4 ) Pub Date : 2021-10-22 , DOI: 10.1007/s00125-021-05584-3
Stefan Mutter _{1,

2,

3} , Erkka Valo _{1,

2,

3} , Viljami Aittomäki ₄ , Kristian Nybo ₄ , Lassi Raivonen ₄ , Lena M Thorn _{1,

2,

3,

5} , Carol Forsblom _{1,

2,

3} , Niina Sandholm _{1,

2,

3} , Peter Würtz ₄ , Per-Henrik Groop _{1,

2,

3,

6}

Affiliation

Aims/hypothesis

This 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.

Methods

We 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.

Results

Seven 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/interpretation

Branched-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

中文翻译：

2670 名 1 型糖尿病患者的尿液代谢物分析和糖尿病肾病进展风险

目标/假设

这项前瞻性、观察性研究通过采用适用于大规模尿液样本收集的自动 NMR 代谢组学技术，检查 51 种尿液代谢物与 1 型糖尿病患者糖尿病肾病进展风险之间的关联。

方法

我们从芬兰糖尿病肾病研究中收集了 2670 名 1 型糖尿病患者的 24 小时尿液样本，并通过 NMR 测量了代谢物浓度。对个体进行了 9.0 ± 5.0 年的随访，直到他们首次出现糖尿病肾病进展、终末期肾病或研究结束的迹象。对整个研究人群（总体进展）、1999 名正常白蛋白尿个体和 347 名基线大量白蛋白尿个体进行 Cox 回归。

结果

在调整基线白蛋白尿和慢性肾脏疾病阶段 ( p < 8 × 10 ^-4 )后，七种尿液代谢物与总体进展相关：亮氨酸 (HR 1.47 [95% CI 1.30, 1.66]/1-SD 肌酐标度代谢物浓度) , 缬氨酸 (1.38 [1.22, 1.56]), 异亮氨酸 (1.33 [1.18, 1.50]), 假尿苷 (1.25 [1.11, 1.42]), 苏氨酸 (1.27 [1.11, 1.46]) 和柠檬酸盐 (0.84 [0.75, 0.93]) . 2-羟基异丁酸与总体进展 (1.30 [1.16, 1.45]) 以及正常白蛋白尿的进展 (1.56 [1.25, 1.95]) 相关。六种氨基酸和焦谷氨酸与大量白蛋白尿的进展有关。