There is an unmet need for high‐quality liquid biomarkers that can safely and reproducibly predict the stage of fibrosis and the outcomes of chronic liver disease (CLD). The requirement for such markers has intensified because of the high global prevalence of diseases such as non‐alcoholic fatty liver disease (NAFLD). In particular, there is a need for diagnostic and prognostic tools, as well as predictive biomarkers that reflect the efficacy of interventions, as described by the BEST criteria (Biomarkers, EndpointS, and other Tools Resource). This review covers the various liver collagens, their functional role in tissue homeostasis and delineates the common nomenclature for biomarkers based on BEST criteria. It addresses the common confounders affecting serological biomarkers, and describes defined collagen epitope biomarkers that originate from the dynamic processes of extracellular matrix (ECM) remodelling during liver injury.

Renal fibrosis is the central pathogenic process in progression of chronic kidney disease (CKD). Collagen type VI (COL VI) is upregulated in renal fibrosis. Endotrophin is released from COL VI and promotes pleiotropic pro-fibrotic effects. Kidney disease severity varies considerably and accurate information regarding CKD progression may improve clinical decisions. We tested the hypothesis that urinary endotrophin derived during COL VI deposition in fibrotic human kidneys is a marker for progression of CKD in the Renal Impairment in Secondary Care (RIISC) cohort, a prospective observational study of 499 CKD patients. Endotrophin localised to areas of increased COL VI deposition in fibrotic kidneys but was not present in histologically normal kidneys. The third and fourth quartiles of urinary endotrophin:creatinine ratio (ECR) were independently associated with one-year disease progression after adjustment for traditional risk factors (OR (95%CI) 3.68 (1.06–12.83) and 8.65 (2.46–30.49), respectively). Addition of ECR quartiles to the model for disease progression increased prediction as seen by an increase in category-free net reclassification improvement (0.45, 95% CI 0.16–0.74, p = 0.002) and integrated discrimination improvement (0.04, 95% CI 0.02–0.06, p < 0.001). ECR was associated with development of end-stage renal disease (ESRD). It is concluded that ECR predicts disease progression of CKD patients.

OBJECTIVE Type 2 diabetes is a common risk factor for the development of chronic kidney disease (CKD). Enhanced de novo collagen type VI (COL VI) formation has been associated with renal fibrosis and CKD. We investigated the hypothesis that PRO-C6, a product specifically generated during COL VI formation, is prognostic for adverse outcomes in patients with type 2 diabetes and microalbuminuria. RESEARCH DESIGN AND METHODS In a prospective, observational study, we measured PRO-C6 in serum (S-PRO-C6) and urine (U-PRO-C6) of 198 patients with type 2 diabetes and microalbuminuria without symptoms of coronary artery disease. Patients were followed for a median of 6.5 years, and end points were a composite of cardiovascular events (n = 38), all-cause mortality (n = 26), and reduction of estimated glomerular filtration rate (eGFR) of >30% (disease progression [n = 42]). Cox models were unadjusted and adjusted for the conventional risk factors sex, age, BMI, systolic blood pressure, LDL cholesterol, smoking, HbA_1c, plasma creatinine, and urinary albumin excretion rate. RESULTS Doubling of S-PRO-C6 increased hazards for cardiovascular events (hazard ratio 3.06 [95% CI 1.31–7.14]), all-cause mortality (6.91 [2.96–16.11]), and disease progression (4.81 [1.92–12.01]). Addition of S-PRO-C6 to a model containing conventional risk factors improved relative integrated discrimination by 22.5% for cardiovascular events (P = 0.02), 76.8% for all-cause mortality (P = 0.002), and 53.3% for disease progression (P = 0.004). U-PRO-C6 was not significantly associated with any of the outcomes. CONCLUSIONS S-PRO-C6 generated during COL VI formation predicts cardiovascular events, all-cause mortality, and disease progression in patients with type 2 diabetes and microalbuminuria.

BackgroundEndotrophin, a collagen type VI–derived peptide, mediates metabolic dysregulation, inflammation, and fibrosis in animal models, but has not been studied in human heart failure (HF... Endotrophin, a Collagen VI–Derived Peptide, in Heart FailureCirculating levels of endotrophin, a collagen type VI–derived peptide, were measured at baseline in patients with human heart failure (HF...

Renal fibrosis is a hallmark of chronic kidney disease (CKD) caused by an imbalance between formation and degradation of extracellular matrix proteins. We investigated the collagen turnover profile of 81 non-dialysis CKD stage 2–5 patients by measuring peptides reflecting formation and degradation of collagen type (COL) I, III, IV, and VI. Based on the collagen turnover profile, we identified four clusters of patients. Cluster 1 contained one patient with prostate cancer, who had a distinct collagen turnover. The other clusters generally had severe (Cluster 2), moderate (Cluster 4), or mild CKD (Cluster 3). Cluster 4 patients were characterized by higher levels of COL III, COL IV, and COL VI (all p < 0.001) degradation fragments in plasma, while patients in Clusters 2 and 4 had higher levels of COL VI formation (p < 0.05). COL IV fragments in plasma were lower in Cluster 2 (p < 0.01). Urinary COL III fragments decreased from Cluster 3 to 4, and from Cluster 4 to 2 (both p < 0.001). We show that patients with similar kidney function have a different collagen remodeling profile, suggesting that different phenotypes exist with different disease activity and potentially disease progression. Biomarkers of collagen remodeling could provide additional information to traditional markers of renal function.