Diabetic kidney disease (DKD) poses a significant health risk to individuals with diabetes, leading to a considerable impact on morbidity and mortality. As kidney function declines, there is an almost exponential increase in the risk of cardiovascular disease (CVD),1 and DKD is the leading cause of end-stage kidney disease (ESKD) in Western countries.2 Therefore, identification of biomarkers that can assess risk of initiation and progression of DKD at an early stage is of utmost importance.

Increased turnover of extracellular matrix (ECM) proteins is an underlying and driving feature of pathogenesis in several diseases, including DKD.3 Collagen is the dominant structural component of ECM and is of major importance in maintaining health and integrity of various tissues. Understanding the regulation of collagen balance and its interactions within the ECM involves exploring various cellular and molecular pathways and is essential for understanding tissue physiology and the development of fibrotic diseases. Dysregulated turnover of ECM proteins, such as collagens, can result in abnormal tissue deposition and accumulation of ECM components. This may lead to fibrogenesis, which is characterized by excessive scarring and stiffening of tissues — consequently impairing organ function.4

During fibrosis progression, proteins reflecting ECM turnover are released into biological fluids. The possibility of detecting fragments of these protein allows for a more sensitive measurement of the ongoing fibrotic process compared to the detection of total protein concentration. Fragments derived from the collagen pro-peptides (pro-collagen), which are released due to post-translational modifications during the formation of the fibrils, reflect active collagen formation (fibrogenesis), while neoepitope fragments of collagens mediated by proteolytic cleavage reflect collagen degradation (fibrolysis). Interestingly, collagens are emerging as more than passive structural proteins, as proteolytic-derived fragments of different collagens can have signaling functions.5

Previous studies have demonstrated that several markers of collagen turnover (i.e., fibrosis), measured in circulation and/or urine, are independently associated with risk of DKD, CVD and mortality in people with diabetes.6., 7., 8., 9., 10., 11. Inflammation plays an important role in fibrosis. A previous study in the same population included in this paper have shown that a degradation product of collagen type III (C3M) was associated with markers of inflammation at baseline and a risk marker for DKD progression.6

In this post-hoc analysis of a prospective study, we investigated whether serum levels of six biomarkers of ECM turnover targeting: 1) tumstatin (TUM), a matrikine of collagen type IV; 2) C1M, a degradation fragment of collagen type I; 3) CTX-III, a degradation fragment of cross-linked collagen type III; 4) PRO-C7, a pro-peptide of collagen type VII; and 5) PRO-C28, the C-terminal of collagen type XXVIII; and 6) an activated form of TGF-β (a fragment of latency-associated protein (LAP)-TGF-β released by plasma kallikrein (PLK)), a known pro-fibrotic cytokine and regulator of collagen synthesis, were risk markers for progression of DKD, development of CVD and mortality in people with T2D and moderately increased albuminuria, but without known cardiac disease. Furthermore, we investigated if the matrix metalloproteinase (MMP)-degraded markers (C1M, CTX-III, TUM) were associated with markers of inflammation at baseline.