A New Candidate Therapeutic Target and Biomarker for Idiopathic Nephrotic Syndrome

In a recent paper published in Science Translational Medicine, researchers from the Kidney and Urinary Tract Center at Nationwide Children’s Hospital present data that challenges the current understanding of idiopathic nephrotic syndrome (INS) as a strictly podocyte disease.

The paper provides evidence for the role of endothelium in disease pathogenesis and points toward endothelial cell-released CD93 as a mediator of podocyte injury and candidate therapeutic and prognostic target for INS.

“INS is considered a podocyte disease triggered by immune-derived factors,” says Gabriel Cara Fuentes, MD, PhD, nephrologist and principal investigator at Nationwide Children’s and senior author of the paper. “We knew that endothelial activation occurred, but its implication was unknown. This study tested, and ultimately supports, the hypothesis that the glomerular endothelium contributes to podocyte injury. This represents a paradigm  shifting in our understand of INS and open new opportunities toward the development of therapies aimed to restore the lining of blood vessels.”

The team studied 460 patients with INS and 150 with other podocyte-related diseases. They analyzed CD93 in kidney tissues, urine and serum in addition to performing cell cultures. The protein was highly expressed by glomerular endothelial cell in tissues from patients with INS. Additionally, the protein was excreted at very high levels in patients during relapse, and in some during remission. Importantly, patients with higher levels, regardless of the disease state, showed worse kidney outcomes over time.

“Identifying a candidate predictive target for INS is especially helpful because the disease is highly heterogeneous and because current therapies are non-targeted immunosuppressive drugs, which are often used arbitrarily and associated with important side effects. Because we can track this marker in urine from these patients, it would provide insights into long term prognosis and potentially into response to therapies. Thus, this would potentially improve our ability to use existing therapies more judiciously, potentially reducing some side effects experienced by patients and improving quality of life,” says Dr. Cara Fuentes, who is also an assistant professor of pediatrics at The Ohio State University College of Medicine.

The research team also tested the effectiveness of blocking CD93 in in vitro and in vivo models of INS. In vitro, blocking CD93 stopped podocyte activation and albumin permeability. In vivo, CD93 blockade prevented glomerulosclerosis and podocyte loss. Additionally, CD93 knockout mice were protected from doxorubicin-induced albuminuria. Collectively, these findings identifying a new role of the glomerular endothelium, and particular CD93, in podocyte injury in INS.

“INS has remained as a mysterious disease for decades. Because there is some underlying immune dysregulation, immunosuppressive drugs have been the standard of care to treat these patients. However, these therapies are mechanistically different and are associated with variable efficacy, unpredictable response, and important side effects,” says Dr. Cara Fuentes “Our study uncovered an unexpected role of the endothelium as contributor of podocyte injury. This provide the rationale to develop therapies aimed to restore the vasculature. Thus, Cd93 seems like a promising candidate therapeutic target for INS. However, additional research is still needed, but we are excited to continue working on this challenging disease.”

Reference:

Bauer C, Piani F, Troost J, Da Sacco S, Rojas-Sanchez G, Davizon-Castillo P, Perin L, Daehn I, Islam MI, Fetsko A, Carrera-Muñoz C, Rovin B, Zhang XL, Banks M, de Lucas-Collantes C, Ordóñez-Álvarez FA, Aparicio-López C,  Lanaspa MA, Andres-Hernando A, Segarra A, Martinez C, Bjornstad P, Lucia MS, Schaefer F, Yilmaz A, Zurowska A, Wang X, McCown PJ, Eddy S, Hartman J, Mariani L, Kretzler M, Zhu Y, Bouts AHM, Levtchenko EN, Dougherty JA, Smoyer WE, Kerlin BA, Kallash M, Soranno DE, Cabrera-Sevilla JE, Gonzalez-Rodriguez JD, Siegele BJ, Tsuji S, Keneko K, Sethna CB, Srivastava T, Bitzer M, O’Conner CL, Dimberg A, Zhao S, Yu L, Thurman JM, Johnson RJ, Cara-Fuentes G. Endothelial-released CD93 contributes to podocyte injury in idiopathic nephrotic syndrome. Science Translational Medicine. 2026;18(832):eadw2206.

Image credit: Nationwide Children’s Hospital