Diabetic Kidney Disease

Biomarkers for diabetic kidney disease (DKD)

Diabetic kidney disease (DKD) is a major complication of diabetes and can progress to kidney failure. Despite advances in treatment, many patients continue to progress due to ongoing, often subclinical, fibrotic injury in the kidney. Conventional clinical markers such as albuminuria and eGFR are limited in detecting early fibrotic changes or reflecting treatment effects.

Kidney fibrosis, a hallmark of DKD, is driven by extracellular matrix (ECM) accumulation and remodeling, which contributes to declining kidney function. ECM-derived biomarkers offer direct insight into active fibrogenesis and fibrolysis, enabling earlier detection of disease progression.

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Nordic ProteinFingerPrint™ biomarkers advance drug development in DKD

Our biomarker assays quantify ECM fragments released into the blood or urine during active fibrogenesis and fibrolysis. These biomarkers provide mechanistic insights into kidney tissue remodeling and fibrotic activity.

This enables earlier detection of disease progression and support MoA and pharmacodynamic evaluation of novel drugs. Integrating ECM biomarkers into DKD clinical trials enhances the ability to identify responders early, reduce trial duration, and increase the likelihood of demonstrating efficacy.

This results in more efficient and targeted drug development, supporting faster and better-informed decision-making across all trial phases.

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Elevated serum levels of type VI collagen formation is an early marker of CKD risk in diabetes, even in patients without CKD

Type VI collagen is located near the basement membrane and has several bindings sites for basement membrane proteins. Upon maturation of new type VI collagen molecules produced by highly activated fibroblasts, a bioactive fragment called Endotrophin is released. Endotrophin has pro-fibrotic, pro-tumorigenic and pro-inflammatory signaling roles. We measure nordicEndotrophin™ and formation of type VI collagen with our biomarker nordicPRO-C6™ (PRO-C6).

In type 2 diabetes (T2D) patients with early kidney disease from the JOSLIN study (n=754) and PROVALID study (n=976), higher PRO-C6 levels demonstrated increased risk of kidney disease defined by composite kidney outcome (a sustained 40% decline in eGFR, sustained 30% increase in albuminuria including a transition in albuminuria stage, or kidney failure). These results indicate that circulating levels of PRO-C6 can work as an early indicator of CKD risk, even in patients who have not yet developed CKD (Figure 1A and 1B).

Figure 1. NordicPRO-C6™ is an early marker of CKD Risk in diabetes, even in Patients without CKD

Our DKD publications

Markers of tissue turnover are modulated by GLP1 receptor agonist treatment in patients with type 2 diabetes

During fibrosis, elevated circulating levels of PRO-C6 and reduced urinary levels of C3M, reflecting type III collagen degradation, are observed.

Patients with DKD treated with dulaglutide in the AWARD-7 trial showed a reversal of this process, by reducing PRO-C6 and increasing C3M (Figure 2A-B).

Figure 2. NordicPRO-C6™ and C3M biomarkers show GLP1 receptor agonist treatment in patients with type 2 diabetes in AWARD-7

NordicPRO-C3™ in patients with type 2 diabetes

During fibrosis, elevated type III collagen formation, as measured by nordicPRO-C3™/PRO-C3, is observed. The data demonstrate that patients in the placebo group experience the greatest increase in PRO-C3 over time, reflecting sustained collagen synthesis and ongoing fibrotic activity.

In contrast, both doses of the SGLT2 inhibitor result in a reduced rise in PRO-C3, with the 300 mg dose showing the strongest suppression. This indicates that collagen turnover is modulated by SGLT2 inhibitor therapy in patients with type 2 diabetes.

The dose-dependent reduction in PRO-C3 suggests a pharmacological effect on pathways linked to tissue remodeling and fibrosis, supporting the concept that SGLT2 inhibitors may slow fibrotic progression in this population.

Figure 3a. Elevated nordicPRO-C3™ modulated by SGLT2 inhibitor in patients with type 2 diabetes in the CANVAS trial

NordicCTX-III™ in patients with type 2 diabetes

During the same fibrotic process we observed with PRO-C3, we have also seen a reduction in type III collagen degradation, as indicated by lower nordicCTX-III™/CTX-III concentrations. This reduced collagen degradation is further highlighted in the placebo group, which exhibits a smaller increase in CTX-III over time. SGLT2 inhibition with canagliflozin (both 100 mg and 300 mg) modulates this process as well, as demonstrated by a dose-dependent increase in CTX-III levels at follow-up.

These results, in the context of the CANVAS trial, indicate that patients treated with canagliflozin show reversal of fibrotic remodeling—not only by reducing type III collagen formation (as seen in Figure 3a) but also by enhancing its degradation (increasing CTX-III, Figure 3b). This dual modulation of collagen turnover provides mechanistic evidence that both of these biomarkers are modulated by SGLT2 inhibitors, targeting key fibrotic pathways in type 2 diabetes.

Figure 3b. Reduced nordicCTX-III™ modulated by SGLT2 inhibitor in patients with type 2 diabetes in the CANVAS trial

About diabetic kidney disease (DKD)

  • Diabetes is the leading cause of CKD and end-stage renal disease in the Western world. About 40% of patients with CKD have diabetes as their primary cause. In the US, more than 8.4 million adults have diabetes and CKD.

  • The first step in treating diabetic nephropathy is to treat and control diabetes and, if necessary, high blood pressure (hypertension). With good control of blood sugar and hypertension, kidney dysfunction and other complications can be prevented or delayed. Because of the reservoir of nephrons, the diagnosis is usually not made until CKD is advanced. Patients who reach end-stage renal disease require dialysis or a kidney transplant. The main treatments for CKD are medications to regulate blood pressure or treat the underlying causes of the disease (e.g. GLP-1 agonists and SGLT2 inhibitors in diabetes, which have a positive effect on kidney health).

  • DKD is defined as CKD with diabetes as the primary cause. Patients are diagnosed with CKD when the concentration of creatinine in the blood and/or protein or albumin in the urine is above a certain threshold. Because serum creatinine increases only after the loss of many nephrons and not all patients have proteinuria or albuminuria, better tools are needed to identify patients at risk of developing CKD.

  • Biomarkers targeting extracellular matrix remodeling, such as nordicPRO-C6™ and nordicPRO-C3™, allow for early detection of fibrotic activity even in patients without clinically diagnosed kidney disease. These biomarkers offer a non-invasive way to assess risk and monitor disease progression.

  • Yes, ECM biomarkers have shown modulation in response to treatments such as GLP-1 receptor agonists and SGLT2 inhibitors. For instance, PRO-C6 and C3M levels change with dulaglutide treatment, while PRO-C3 and nordicCTX-III™ levels respond to canagliflozin, reflecting reduced fibrotic activity and improved tissue remodeling.

  • These biomarkers offer specific, dynamic insights into fibrosis and ECM remodeling, supporting mechanism of action studies and early pharmacodynamic assessments. Their integration into clinical trials helps identify responders, shorten timelines, and improve decision-making throughout drug development.

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