#5482 circulating biomarkers of collagen remodeling as markers for development of microalbuminuria in type 2 diabetes: the priority trial

Abstract Background and Aims Kidney disease progression is characterized by extensive deposition of extracellular matrix components such as collagen. Therefore, we assessed the effect of spironolactone on collagen remodeling biomarkers and investigated the association between the markers and development of microalbuminuria in serum of persons with type 2 diabetes and normoalbuminuria. Method We measured collagen type III (PRO-C3), VI (PRO-C6; endotrophin), VII (PRO-C7), and XXVIII (PRO-C28) formation, and a fragment of degraded crosslinked collagen type III (CTX-III) in serum of persons with high-risk (stratified by a urinary proteomics classifier, CKD273) for development of microalbuminuria, randomized to either spironolactone 25 mg or placebo. Crude and adjusted Cox models were applied to investigate the association between baseline biomarker levels and development of the primary outcome, persistent microalbuminuria, and development of microalbuminuria in at least one morning void sample, used as a secondary outcome. Results In the PRIORITY trial, spironolactone treatment did not prevent progression to microalbuminuria compared to placebo. All biomarkers were measured in 154 participants at baseline and 117 at end-of-study (week 208). Treatment with spironolactone did not affect serum levels of any of the investigated collagen remodeling biomarkers compared to placebo, and there were no differences in delta-biomarker levels between baseline and end-of-study (p ranging 0.277-0.875). In crude analyses, serum endotrophin was associated with both the primary (n = 44) and secondary outcome (n = 74) (HR per two-fold higher level: 1.58, 95% CI: 1.03-2.44, p = 0.037 and 1.62, 1.12-2.35, p = 0.010), whereas serum PRO-C3 was only associated with the secondary outcome (1.89, 1.19-2.99, p = 0.007). After adjustment for sex, baseline age, systolic blood pressure, estimated glomerular filtration rate, urinary albumin-creatinine ratio, and HbA1c, serum endotrophin and PRO-C3 remained significantly associated with the secondary outcome (1.52, 1.03-2.24, p = 0.036 and 1.73, 1.08-2.78, p = 0.022). Levels of PRO-C7, PRO-C28, and CTX-III were not associated with the specified outcomes. Neither baseline levels of serum endotrophin nor PRO-C3 correlated with baseline CKD273 levels (R: 0.00-0.06, p>0.47). Conclusion Treatment with spironolactone did not change serum levels of collagen remodeling biomarkers. Serum endotrophin, reflecting collagen type VI formation and the pro-fibrotic molecule endotrophin, and PRO-C3, a marker of collagen type III formation, were associated with development of microalbuminuria in at least one urine sample, suggesting that these biomarkers are relevant risk markers for kidney disease development in type 2 diabetes.