FC 009CIRCULATING BIOMARKERS OF COLLAGEN TURNOVER ARE ASSOCIATED WITH DISEASE SEVERITY IN PATIENTS WITH ADPKD
Authors: Sparding Nadja , Genovese Federica , A. Karsdal Morten , Heida Judith E , Meijer Esther , Gansevoort Ronald , G. K. Rasmussen Daniel 
Published: May 2021

Abstract

Background and Aims
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited kidney disease characterized by development and growth of cysts leading to loss of kidney function. In patients with ADPKD, fibrosis has been associated with the expansion of cysts and with an increased rate of progression to end-stage kidney disease (ESKD). Fibrosis is characterized by an imbalanced turnover of extracellular matrix (ECM) components such as collagens. Existing biomarkers of ADPKD have limited prognostic ability and the ECM can be a source of novel biomarkers of disease progression. In the current study, we investigated the cross-sectional association of collagen biomarkers with markers of disease severity in patients with ADPKD.

Method
Collagen type I, III and VI formation as well as collagen type III degradation were assessed with the PRO-C1, PRO-C3, PRO-C6 and C3M enzyme-linked immunosorbent assays (ELISAs). The four biomarkers were measured in serum from 311 patients with ADPKD from the DIPAK-1 (NCT01616927) study at baseline. Biomarker levels were compared with levels in serum of 38 healthy controls matched for sex and age. The difference between the ADPKD and the control group was assessed by Kruskal-Wallis test. The association of the collagen biomarkers with kidney function (eGFR) and height adjusted total kidney volume (htTKV) was assessed with uni- and multivariate regression analysis. Data was log-transformed if appropriate.

Results
Biomarker levels in the ADPKD patients (age, median (IQR): 49 (43-54) years; sex: 53% female) were compared with levels in matched healthy controls (age, median (IQR): 49 (43-56) years; sex: 53% female). In patients with ADPKD both PRO-C3 and PRO-C6 levels were increased compared to healthy controls (ADPKD vs controls, PRO-C3 median (IQR): 12.8 (10.5-15.8) vs 8.4 (7.5-10.1) ng/mL; P&lt;0.0001; PRO-C6 median (IQR): 11.3 (9.4-13.7) vs 6.8 (5.4-8.8) ng/mL; P&lt;0.0001). PRO-C1 levels were decreased in patients with ADPKD compared to controls (ADPKD vs controls, PRO-C1 median (IQR): 47.1 (31.9-65.0) vs 110.9 (83.0-176.4) ng/mL; P&lt;0.0001) l, whereas there was no difference in C3M levels between the two groups (ADPKD vs controls, C3M median (IQR): 11.4 (9.7-13.7) vs 10.3 (8.7-12.5) ng/mL; P=0.11). None of the investigated biomarkers was associated with TKV, whereas PRO-C3 and PRO-C6 were associated with eGFR in univariate regression analysis (PRO-C3, P&lt;0.01; PRO-C6, P&lt;0.001) but not with htTKV (PRO-C3, P=0.49; PRO-C6, P=0.32). In a multivariate regression analysis adjusting for sex, age, htTKV and PKD mutation, both PRO-C3 and PRO-C6 showed a significant negative association with eGFR (both P&lt;0.001).

Conclusion
While biomarkers of tubulointerstitial fibrosis (PRO-C3 and PRO-C6) were elevated in circulation in ADPKD patients, possibly reflecting an elevated fibrosis activity in the kidneys, levels of collagen type I formation (PRO-C1) were lower, possibly reflecting a suppressed bone turnover previously observed in patients with ADPKD. Both PRO-C3 and PRO-C6 showed an independent association with eGFR, but not with htTKV, when adjusting for known determinants of disease severity. Such biomarkers deserve further investigation in this patient population, especially concerning their prognostic abilities, as fibrosis is acknowledged as a driving force in progression to ESKD.