Urinary Activin A in Sickle Cell Disease: Correlation with Urinary Biomarkers of Inflammation and Risk of Progression of Chronic Kidney Disease

BACKGROUND: Renal disease is a major complication of sickle cell disease (SCD) that is associated with renal inflammation and immune cell infiltration. We demonstrated recently that urinary orosomucoid (ORM), a glycoprotein that is increased during inflammation, is a biomarker of early-stage chronic kidney disease (CKD) in SCD patients. Activin A is one of the factors of the inflammatory response, that is expressed by renal tubular cells and macrophages. HYPOTHESIS: Activin A may serve as a urinary biomarker for inflammation and CKD in SCD. OBJECTIVES: To determine the urinary levels of Activin A in SCD patients with varying risks of CKD progression and to assess its correlations with ORM. METHODS: We evaluated urine samples from the Registry Study at Howard University Center for SCD (RSHUC, n = 46) collected during clinic visits while patients were in a steady state. The risk of CKD progression was assessed using the online tool from the National Kidney Foundation (NKF). Stages of CKD were determined using the criteria of the NKF. Urinary Activin A concentrations were measured by ELISA (R&D Systems) and normalized to urinary creatinine. Pearson correlation analysis was performed using GraphPad Prism 7 to assess correlations between levels of urinary Activin A and plasma and urinary ORM. Immunohistochemistry (IHC) of renal Activin A was performed in SCD and control (CTR) mice. Activin A levels in activated peripheral blood mononuclear cells (PBMCs) from SCD patients and healthy controls were analyzed using RNA sequencing (Illumina) data. RESULTS: Activin A was undetectable in 90% of SCD patients without renal disease. In contrast, it was detected in the urine of 69.9 % patients with early-stage 1-2 CKD (in 75% of males and 52.6% of females). Urinary Activin-A levels demonstrated a significant correlation with urinary (r=0.3534, R 2 =0.1749, p = 0.0217) but not plasma (r=0.1325, R 2 =0.1757, p=0.4342) levels of ORM. Activin A levels were significantly increased in patients with high or very high risk of CKD progression (median: 2096.4 ng/pg, interquartile range [IQR]: 1368.8–3657.6 ng/pg) compared to individuals with low (0 ng/pg, IQR: 0–789.9 ng/pg, p = 0.011) or moderate (279.3 ng/pg, IQR: 0–992.5 ng/pg, p = 0.011) risk of CKD progression. Activin A levels were similar in kidney homogenates from SCD and CTR mice; however, IHC revealed positive staining in kidney-infiltrating macrophages. Activated human SCD PBMCs showed a threefold higher expression of Activin-A compared to CTR PBMCs (p = 0.0078). CONCLUSIONS: Detection of Activin A in renal infiltrating macrophages suggests that urinary Activin A may originate from the inflamed kidney. Thus, urinary Activin A may serve as a biomarker for monitoring renal inflammation in SCD patients. Elevated urinary Activin A levels may predict a higher risk of CKD progression. This work was supported by NIH grants 1R01HL125005, 5U54MD007597, and 1SC1HL150685. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.