A Novel Marker of Collagen Type VI Formation Is Prognostic for Cardiovascular Disease, All-Cause Mortality, and Deterioration of Kidney Function in Patients with Type 2 Diabetes with Microalbuminuria

Background Type 2 diabetes is a common risk factor for the development of renal fibrosis and chronic kidney disease (CKD). Recent findings have shown that type VI collagen (COL VI) is markedly upregulated during fibrosis. The role of COL VI has been sparsely investigated in fibrosis onset and progression. We evaluated a novel biomarker of COL VI formation as a prognostic marker for cardiovascular events, all-cause mortality, and decline in eGFR in patients with type 2 diabetes with microalbuminuria and without symptoms of coronary artery disease. Methods The cohort included 200 participants followed for 6.1 years. COL VI formation was assessed with the Pro-C6 assay, detecting a specific fragment of COL VI released upon deposition in the extracellular matrix. Pro-C6 levels were measured in serum at baseline. Endpoints included: 1) a composite of cardiovascular events (n=40); 2) all-cause mortality (n=26); and 3) decline in eGFR of >30% (n=42). Cox models were unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA1c, creatinine and urinary albumin excretion rate). Pro-C6 was assessed per doubling in the analysis. To assess if Pro-C6 improved risk prediction beyond traditional risk factors we calculated relative integrated discrimination improvement (rIDI). Results Levels of Pro-C6 were associated with an increased risk of cardiovascular events (unadjusted HR 2.65, 95% CI 1.47-4.79, p=0.0013; adjusted HR 2.32, 95% CI 1.08-5.01, p=0.032), all-cause mortality (unadjusted HR 3.95, 95% CI 1.98-7.86, p=0.0001; adjusted HR 6.98, 95% CI 3.06-15.9, p<0.0001), and decline in eGFR (unadjusted HR 3.00, 95% CI 1.72-5.21, p=0.0001; adjusted HR 2.67, 95% CI 1.21-5.89, p=0.015). Addition of Pro-C6 to a model containing traditional risk factors improved the rIDI by 14.5% (p=0.04) for cardiovascular events, 64.3% (p<0.001) for all-cause mortality, and 19.8% (p=0.007) for decline in eGFR. Conclusion In conclusion, Pro-C6 was associated with cardiovascular events, all-cause mortality, and decline in eGFR in patients with type 2 diabetes and microalbuminuria.