Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Diabetologia. 2022 Jan;65(1):140-149. doi: 10.1007/s00125-021-05584-3. Epub 2021 Oct 22.
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.
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.
Seven urinary metabolites were associated with overall progression after adjustment for baseline albuminuria and chronic kidney disease stage (p < 8 × 10): 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.
目的/假设：本前瞻性观察研究采用适合大规模尿液样本采集的自动 NMR 代谢组学技术，研究了 1 型糖尿病个体中 51 种尿代谢物与糖尿病肾病进展风险之间的关系。
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 测量代谢物浓度。在随访 9.0±5.0 年后，直到他们出现糖尿病肾病、终末期肾病或研究结束的第一个迹象。对整个研究人群（整体进展）、1999 名基线时正常白蛋白尿和 347 名大量白蛋白尿个体进行 Cox 回归。
在调整基线白蛋白尿和慢性肾脏病分期后，有 7 种尿代谢物与整体进展相关（p<8×10）：亮氨酸（肌酐标化代谢物浓度每增加 1-SD，HR 为 1.47[95%CI 1.30，1.66]）、缬氨酸（1.38[1.22，1.56]）、异亮氨酸（1.33[1.18，1.50]）、假尿嘧啶核苷（1.25[1.11，1.42]）、苏氨酸（1.27[1.11，1.46]）和柠檬酸（0.84[0.75，0.93]）。2-羟基异丁酸与整体进展相关（1.30[1.16，1.45]），也与正常白蛋白尿的进展相关（1.56[1.25，1.95]）。6 种氨基酸和焦谷氨酸与从大量白蛋白尿进展有关。
结论/解释：支链氨基酸和其他尿代谢物与白蛋白尿和慢性肾脏病以外的糖尿病肾病进展相关。我们发现整体进展和从正常白蛋白尿和大量白蛋白尿进展的相关性存在差异。这些新发现说明了分析整个人群队列中尿代谢物的效用。
