Proteomic analysis identifies DKD progression markers in YT2D

A comprehensive analysis of circulating proteins identifies known and novel proteins associated with the progression of diabetic kidney disease (DKD) in Asians with younger-onset type 2 diabetes (YT2D; T2D onset age <40 years).

“Patients with YT2D have an increased risk for kidney failure compared with those with late onset. However, the mechanism of DKD progression in this high-risk group is poorly understood,” said the researchers.

To identify and validate proteins linked to DKD progression, the overall cohort (n=436) was divided into two sets: discovery (n=296) and validation (n=140). The median age at recruitment was 45 years, while the median age at T2D onset was 34 years. Nearly half of the overall population were men. [J Clin Endocrinol Metab 2025;110:e239-e248]

In the discovery set (98 DKD progressors [cases] and 198 controls), 69 proteins were associated with DKD progression, independent of cardiorenal risk factors, baseline estimated glomerular filtration rate (eGFR), and urine albumin-to-creatinine ratio, at a 10-percent false discovery rate. DKD progression was defined as an eGFR decline of ≥3 mL/min/1.73 m² or 40 percent from baseline.

Of the 69 proteins identified in the discovery set, 42 were significantly associated with DKD progression in the validation set (46 cases and 94 controls). Of these, at least seven (CLMP, TNFRSF1, PTGDS, KIM-1, WFDC2, DSC2, FSTL3) were known biomarkers associated with chronic kidney disease (CKD) in general populations or T2D patients. [Kidney Int 2016;89:226-234; Clin J Am Soc Nephrol 2013;8: 873-881; J Am Soc Nephrol 2021;32:2291-2302; Proc Natl Acad Sci U S A 2020;117:25026-25035]

The strongest associations with DKD progression were seen with increased plasma levels of CLMP (odds ratio [OR], 8.66; p=1.26×10⁻⁵), PODXL2 (OR, 7.43; p=7.48×10⁻⁷), and EPHB4 (OR, 7.04; p=1.19×10⁻⁶).

“All identified proteins had a positive association with DKD progression, with higher levels associated with deteriorating kidney function. Notably, the increased plasma proteins levels preceded the development of CKD, as the median eGFR of the population was 110 mL/min/1.73 m²,” said the researchers.

“Our findings also suggest increased plasma WFDC2 as an early marker for DKD progression in the YT2D population,” they added.

The role of angiogenin

Angiogenin was determined as one of the top DKD progression markers (OR, 5.29; p=4.03×10⁻⁵). In the Mendelian randomization analyses, genetic predisposition for a higher level of plasma angiogenin was associated with an increased odds for DKD progression per unit increase in plasma angiogenin (OR, 4.03; p=0.017).

A secreted ribonuclease, angiogenin has been implicated in the pathophysiology of cardiovascular diseases, cancer, and neurological disorders. [Cardiovasc Diabetol 2024;23:70; Dis Markers 2018;2018:1984718] A study has also shown that plasma angiogenin levels increase with advanced CKD. [Kidney Blood Press Res 2019;44:1166-1178]

“Although gene expression of angiogenin in kidney tissues decreased with eGFR decline and fibrosis in the general population, our observational and MR analyses in YT2D suggest that elevated plasma angiogenin increases the risk of DKD progression,” the researchers said. “Given its importance in angiogenesis, corroboration between our observation and previous findings highlights the importance of angiogenesis for DKD progression.”

Provides groundwork for future studies

However, the researchers noted that the findings may not be generalized to other populations as the study cohort comprised Asian individuals. “[Nonetheless,] we were able to refine biological mechanisms further and focus on a limited number of biological processes, namely inflammation and remodeling.”

“Furthermore, we provide evidence of a potential causal role of plasma angiogenin in promoting DKD progression in YT2D,” they added.

“This discovery work provides directions for future mechanistic and clinical studies to deepen the understanding of the molecular aetiology of DKD, as well as facilitate drug development for DKD,” said the researchers.

Given the exploratory nature of the study, the researchers recommended further investigations in larger cohorts to ascertain the results.