Turnover of type III collagen reflects disease severity and is associated with progression and microinflammation in patients with IgA nephropathy

Renal fibrosis is the hallmark of progression to end-stage kidney disease. Non-invasive biomarkers of renal fibrosis could serve as specific end points in clinical trials and improve monitoring and stratification of patients with chronic kidney disease (CKD). To address this, we measured markers of collagen type III turnover in urine and serum of IgA nephropathy (IgAN) patients. We measured the collagen type III pro-peptide (Pro-C3), representing production, and a neo-epitope fragment (C3M), representing a specific degradation fragment of collagen type III, in urine and serum samples from two cohorts of IgAN patients using newly developed enzyme-linked immunosorbent assays. With increasing CKD stage, urinary C3M gradually decreased (mean C3M/creatinine: 17.3 ng/mg in CKD stage 1, 3.5 ng/mg in CKD stage 5) whereas urinary Pro-C3 gradually increased (mean Pro-C3/creatinine: 4.1 ng/mg in CKD stage 1, 20.8 ng/mg in CKD stage 5). The urinary Pro-C3/C3M ratio, a measure of collagen type III turnover, significantly increased in advanced CKD stages. Serum C3M was not related to CKD stage but was associated with microinflammation. Urinary C3M was significantly lower in patients whose CKD stage subsequently progressed compared with those who did not progress. Our results suggest that the combination of urinary markers of collagen type III turnover, in particular the urinary Pro-C3/C3M ratio, is a potential novel, non-invasive diagnostic and prognostic tool to specifically monitor extracellular matrix (ECM) remodelling in kidney fibrosis.