Yun Donghwan, Bae Sohyun, Gao Yuqian, Lopez Lauren, Han Dohyun, Nicora Carrie D, Kim Tae Youn, Moon Kyung Chul, Kim Dong Ki, Fillmore Thomas L, Kim Yon Su, Rosenberg Avi Z, Wang Weijie, Sarder Pinaki, Qian Wei-Jun, Afkarian Maryam, Han Seung Seok
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
Kidney Int Rep. 2025 May 6;10(7):2296-2310. doi: 10.1016/j.ekir.2025.04.061. eCollection 2025 Jul.
Mechanisms underlying diabetic kidney disease (DKD) progression remain incompletely understood. This study used untargeted and targeted mass spectrometry-based proteomics in 2 independent cohorts to capture rapidly progressive DKD.
We conducted untargeted and targeted mass spectrometry on urine samples from Korean patients with type 2 diabetes and biopsy-confirmed diabetic nephropathy (SNUH-DN cohort; = 64) and a DKD subgroup of the Chronic Renal Insufficiency Cohort (CRIC-T2D; = 282), respectively. Urine proteins associated with kidney disease progression (doubling of serum creatinine, ≥ 50% decrease in estimated glomerular filtration rates [eGFRs], or progression to end-stage kidney disease[ESKD]) were identified after adjusting for eGFR, proteinuria, and other clinical variables.
In the SNUH-DN patients, urine proteins clustered into 2 groups, with cluster 1 exhibiting a 4.6-fold higher hazard of disease progression (95% confidence interval [CI]: 1.9-11.5) than cluster 0. Proteins in cluster 1 mapped to 10 pathways, 4 of the top 5 being complement-related. A high complement score, derived from urine complement protein abundance, correlated with histopathologic features of DKD and conferred a 2.4-fold greater hazard of disease progression (95% CI: 1.0-5.4) than a low complement score. In CRIC-T2D, targeted mass spectrometry similarly confirmed that complement score stratified patients into rapid and slow DKD progression groups. In both cohorts, complement score exhibited a linear association with disease progression.
The strong association between complement activation and rapid DKD progression highlights the need to explore complement inhibition as a potential therapeutic strategy for DKD.
糖尿病肾病（DKD）进展的潜在机制仍未完全明确。本研究在两个独立队列中使用非靶向和靶向质谱蛋白质组学来捕捉快速进展性DKD。
我们分别对来自韩国2型糖尿病患者且经活检确诊为糖尿病肾病的患者（SNUH-DN队列；n = 64）以及慢性肾功能不全队列（CRIC-T2D）中的DKD亚组（n = 282）的尿液样本进行了非靶向和靶向质谱分析。在调整了估算肾小球滤过率（eGFR）、蛋白尿和其他临床变量后，确定了与肾病进展（血清肌酐翻倍、估算肾小球滤过率[eGFRs]降低≥50%或进展至终末期肾病[ESKD]）相关的尿液蛋白质。
在SNUH-DN患者中，尿液蛋白质聚为两组，第1组疾病进展风险比第0组高4.6倍（95%置信区间[CI]：1.9 - 11.5）。第1组中的蛋白质映射到10条通路，前5条中有4条与补体相关。由尿液补体蛋白丰度得出的高补体评分与DKD的组织病理学特征相关，且与低补体评分相比，疾病进展风险高2.4倍（95% CI：1.0 - 5.4）。在CRIC-T2D中，靶向质谱同样证实补体评分将患者分为DKD快速进展组和缓慢进展组。在两个队列中，补体评分与疾病进展均呈线性关联。
补体激活与DKD快速进展之间的强关联凸显了探索补体抑制作为DKD潜在治疗策略的必要性。
