Endotrophin, a collagen type VI-derived matrikine, reflects the degree of renal fibrosis in patients with IgA nephropathy and in patients with ANCA-associated vasculitis

Abstract

Background Renal fibrosis is the hallmark of chronic kidney disease (CKD) and characterized by an imbalanced extracellular matrix remodeling. Endotrophin (ETP) is a signaling molecule released from collagen type VI (COL VI). ETP can be measured by the PRO-C6 assay, which quantifies the levels of COL VI formation. ETP levels were previously associated with mortality and disease progression in patients with CKD. We hypothesized that serum and urinary ETP levels correlate with the degree of interstitial fibrosis in kidney biopsies from patients with IgA nephropathy (IgAN) and patients with ANCA-associated vasculitis (AAV). Methods We examined a cohort of 49 IgAN and 47 AAV patients. A validation cohort of 85 IgAN patients was included. ETP was measured in serum (S-ETP) and urine (U-ETP/Cr) samples, taken on the same day before renal biopsy was performed, using the ELISA PRO-C6. The biopsies were evaluated for interstitial fibrosis and tubular atrophy according to the Banff and MEST-C scores. Results S-ETP and U-ETP/Cr levels correlated with kidney function, increased with CKD severity, correlated with the extent of interstitial fibrosis and gradually increased with increasing degree of interstitial fibrosis and tubular atrophy. ETP outperformed the known fibrosis biomarker Dickkopf-3 for discrimination of patients with high fibrotic burden. The association of S-ETP and U-ETP/Cr with the level of kidney fibrosis was confirmed in the validation cohort. Conclusions We demonstrated that high levels of circulating and excreted ETP are not only indicative of lower kidney function, but also reflect the burden of fibrosis in the kidneys.

Circulating Levels of Endotrophin Are Prognostic for Long-Term Mortality after AKI

“…However, this has already been confirmed in IgA nephropathy and kidney transplant patients 14,15 . It is also possible to speculate that there may be utility in identifying patients across the spectrum of fibrosis that have a rapidly progressing disease.…”

“…The PRO-C6 ELISA measures levels of ETP and, therefore, also measures the formation of collagen type VI (12,13). Plasma levels of ETP have previously been shown to directly reflect the extent of fibrosis in the kidneys (14,15) and are associated with adverse outcomes in patients with CKD (12,(16)(17)(18).…”

Biomarkers of fibrosis, kidney tissue injury and inflammation may predict severity and outcome of renal ANCA – associated vasculitis

“…Follow-up clinical data were available at 1 year in 44 patients and at 3 years in 32 patients. Two mentioned biomarkers (DKK3 and PRO-C6) were measured in the same cohort of patients in our previous research study ( 18 ).…”

The kidney matrisome in health, aging, and disease

“…4,61 Furthermore, serum and urinary levels of the signaling molecule endotrophin, which is secreted from type VI collagen, correlate with disease severity in IgA nephropathy. 125 Type VI collagen forms a beaded filament and absence of Col6a1 associates with altered mechanical properties in the pericellular matrix of cartilage and the development of osteoarthritis. 126 Type IV collagen α3α4α5 is highly crosslinked through disulfide bonds intramoleculary between cysteine residues in the noncollagenous NC1 domain.…”