Collagen Type III Degradation Is Associated with Deterioration of Kidney Function in Patients with Type 2 Diabetes with Microalbuminuria

Background In diabetes one of the main features of the progression to diabetic kidney disease is a pathological deposition of extracellular matrix components triggering renal fibrosis. The main structural component of the fibrotic core is collagen. One of the most prominent collagens is collagen type III (COL III), which is excessively synthesized and incorporated into the fibrotic extracellular matrix. Multiple studies in both humans and mice have suggested that MMP-9 activity is increased in diabetic kidney disease. We investigated whether a neo-epitope fragment of COL III generated by MMP-9 (C3M) was associated with deterioration of kidney function in a well-characterised type 2 diabetic population with microalbuminuria and without symptoms of coronary artery disease. Methods The cohort included 200 participants, followed for 6.1 years. We measured C3M levels in serum (S-C3M) and urine (U-C3M) at baseline. To adjust for urine output levels of U-C3M were normalized for urinary creatinine. The investigated endpoint was a decline in eGFR of >30% (n=42). Cox proportional hazards regression analysis was performed for S-C3M and U-C3M both unadjusted and adjusted for traditional risk factors (sex, age, systolic blood pressure, LDL-cholesterol, smoking, HbA1c, creatinine and urinary albumin excretion rate). To assess whether S-C3M or U-C3M improved risk prediction beyond traditional risk factors we calculated the relative integrated discrimination improvement (rIDI). Results The hazard ratio per doubling of S-C3M was 3.00 (95% CI 1.52-5.90, p=0.002). When adjusted for traditional risk factors the hazard ratio per doubling of S-C3M was 2.84 (95% CI 1.35-5.97, p=0.006). Addition of S-C3M to a model containing traditional risk factors improved the relative discrimination by 19.8 percentage points (p=0.007). U-C3M was not associated with declining eGFR. Conclusion In conclusion, S-C3M was independently associated with decline in renal function, and added significant improved discriminatory power to a model containing traditional risk factors.