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[Preprint]. 2024 Aug 17:2024.08.15.24312080.
doi: 10.1101/2024.08.15.24312080.

Urine complement proteins are associated with kidney disease progression of type 2 diabetes in Korean and American cohorts

Donghwan Yun, Sohyun Bae, Yuqian Gao, Lauren Lopez, Dohyun Han, Carrie D Nicora, Tae Youn Kim, Kyung Chul Moon, Dong Ki Kim, Thomas L Fillmore, Yon Su Kim, Avi Z Rosenberg, Weijie Wang, Pinaki Sarder, Wei-Jun Qian, Maryam Afkarian, Seung Seok Han

Urine complement proteins are associated with kidney disease progression of type 2 diabetes in Korean and American cohorts

Donghwan Yun et al. medRxiv. .

Update in

  • Complement Proteins Identify Rapidly Progressive Diabetic Kidney Disease.
    Yun D, Bae S, Gao Y, Lopez L, Han D, Nicora CD, Kim TY, Moon KC, Kim DK, Fillmore TL, Kim YS, Rosenberg AZ, Wang W, Sarder P, Qian WJ, Afkarian M, Han SS. Yun D, et al. Kidney Int Rep. 2025 May 6;10(7):2296-2310. doi: 10.1016/j.ekir.2025.04.061. eCollection 2025 Jul. Kidney Int Rep. 2025. PMID: 40677326 Free PMC article.

Abstract

Background: Mechanisms of progression of diabetic kidney disease (DKD) are not completely understood. This study uses untargeted and targeted mass spectrometry-based proteomics in two independent cohorts on two continents to decipher the mechanisms of DKD in patients with type 2 diabetes.

Methods: We conducted untargeted mass spectrometry on urine samples collected at the time of kidney biopsy from Korean patients with type 2 diabetes and biopsy-proven diabetic nephropathy at Seoul National University Hospital (SNUH-DN cohort; n = 64). These findings were validated using targeted mass spectrometry in urine samples from a Chronic Renal Insufficiency Cohort subgroup with type 2 diabetes and DKD (CRIC-T2D; n = 282). Urinary biomarkers/pathways associated with kidney disease progression (doubling of serum creatinine, ≥50% decrease in estimated glomerular filtration rates, or the development of end-stage kidney disease) were identified.

Results: SNUH-DN patients had an estimated glomerular filtration rate (eGFR) of 55 mL/min/1.73 m 2 (interquartile range [IQR], 44-75) and random urine protein-to-creatinine ratio of 3.1 g/g (IQR, 1.7-7.0). Urine proteins clustered into two groups, with cluster 2 having a 4.6-fold greater hazard (95% confidence interval [CI], 1.9-11.5) of disease progression than cluster 1 in multivariable-adjusted, time-to-event analyses. Proteins in cluster 2 mapped to 10 pathways, four of the top five of which were complement or complement-related. A high complement score, constructed from urine complement protein abundance, was strongly correlated to 4 of 5 histopathologic DN features and was associated with a 2.4-fold greater hazard (95% CI, 1.0-5.4) of disease progression than a low complement score. Targeted mass spectrometry of the CRIC-T2D participants, who had an eGFR of 42 mL/min/1.73 m 2 (IQR, 37-49) and 24-hr urine protein of 0.48 g (IQR, 0.10-1.87), showed that the complement score similarly segregated them into rapid and slow DKD progression groups. In both cohorts, the complement score had a linear association with disease progression.

Conclusions: Urinary proteomic profiling confirms the association between the complement pathway and rapid DKD progression in two independent cohorts. These results suggest a need to further investigate complement pathway inhibition as a novel treatment for DKD.

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