Circulating Activin A, Kidney Fibrosis, and Adverse Events

Abstract

Background Identification of reliable biomarkers to assess kidney fibrosis severity is necessary for patients with CKD. Activin A, a member of the TGF-β superfamily, has been suggested as a biomarker for kidney fibrosis. However, its precise utility in this regard remains to be established. Methods We investigated the correlation between plasma activin A levels, kidney fibrosis severity, and the incidence of major adverse kidney events in patients who underwent native kidney biopsies at a tertiary medical center. We performed RNA sequencing and histological analyses on kidney biopsy specimens to assess activin A expression. In vitro experiments were also conducted to explore the potential attenuation of TGF-β–induced fibroblast activation through activin A inhibition. Results A total of 339 patients with biopsy-confirmed kidney diseases were enrolled. Baseline eGFR was 36 ml/min per 1.73 m2, and the urine protein/creatinine ratio was 2.9 mg/mg. Multivariable logistic regression analysis revealed a significant association between plasma activin A levels and the extent of tubulointerstitial fibrosis. Our RNA sequencing data demonstrated a positive correlation between kidney INHBA expression and plasma activin A levels. Furthermore, the histological analysis showed that myofibroblasts were the primary activin A–positive interstitial cells in diseased kidneys. During a median follow-up of 22 months, 113 participants experienced major adverse kidney events. Cox proportional hazards analysis initially found a positive association between plasma activin A levels and kidney event risk, but it became insignificant after adjusting for confounders. In cultured fibroblasts, knockdown of activin A significantly attenuated TGF-β–induced fibroblast–myofibroblast conversion. Conclusions Plasma activin A levels correlate with kidney fibrosis severity and adverse outcomes in various kidney disorders.

Association of Serum Activin Levels with Allograft Outcomes in Patients with Kidney Transplant: Results from the KNOW-KT

“…However, we could not establish a significant association between serum activin levels and graft rejection. This lack suggests that the main mechanism by which activin adversely affects kidney allografts might be profibrotic effects [15, 33, 34]. However, we cannot exclude the possibility of an association between local activin A levels in grafts and rejection, as a previous study reported that activin A was upregulated mainly in the allograft and there was no change in serum activin levels after transplantation and ischemia-reperfusion injury [18].…”

“…In contrast, many studies have suggested that activin A may act as a pathogenetic factor [31]. Activin A is a potent TGF-βmediated profibrotic substance, is expressed dominantly in myofibroblasts, and has attracted attention as a pathogenetic factor and a therapeutic target in CKD [15,[32][33][34]. Activin has also been linked to immunity and inflammation [35].…”

Associations of urinary fetuin-A with histopathology and kidney events in biopsy-proven kidney disease

“…Its primary goal is to study kidney transcriptomic profiles and discover new circulating biomarkers for CKD. Tissue specimens were processed per standard procedures and interpreted by an experienced nephropathologist [ 26 , 27 ]. Blood and urine samples were collected on the biopsy day.…”