An updated view of the pathogenesis of steroid-sensitive nephrotic syndrome

Abstract

Idiopathic nephrotic syndrome is the most common childhood glomerular disease. Most forms of this syndrome respond to corticosteroids at standard doses and are, therefore, defined as steroid-sensitive nephrotic syndrome (SSNS). Immunological mechanisms and subsequent podocyte disorders play a pivotal role in SSNS and have been studied for years; however, the precise pathogenesis remains unclear. With recent advances in genetic techniques, an exhaustive hypothesis-free approach called a genome-wide association study (GWAS) has been conducted in various populations. GWASs in pediatric SSNS peaked in the human leukocyte antigen class II region in various populations. Additionally, an association of immune-related CALHM6/FAM26F, PARM1, BTNL2, and TNFSF15 genes, as well as NPHS1, which encodes nephrin expressed in podocytes, has been identified as a locus that achieves genome-wide significance in pediatric SSNS. However, the specific mechanism of SSNS development requires elucidation. This review describes an updated view of SSNS pathogenesis from immunological and genetic aspects, including interactions with infections or allergies, production of circulating factors, and an autoantibody hypothesis.

Keywords: Autoantibody; HLA class II; Immune system; NPHS1; Podocyte disorders; Steroid-sensitive nephrotic syndrome.

Fig. 1

Molecules possibly involved in the pathogenesis of SSNS. The molecules identified in the genome-wide association studies are highlighted in red. HLA class II molecules present antigens mainly in APCs and B cells, but they are also expressed in podocytes. BTNL2 shares a common structure with CD 80/86 and may be involved in T cell regulation. CALHM6 is expressed in various lymphocytes and releases cytokines such as IFN-γ. TNFSF15 interacts with death receptor 3 and activates immune cells. Nephrin is a key component of the slit diaphragm in podocytes. APC, antigen-presenting cell; TCR, T cell receptor; Treg, regulatory T cell; BTNL2, butyrophilin-like 2; CTLA4, cytotoxic T-lymphocyte-associated-4; IFN-γ, interferon-gamma; TNFSF15, tumor necrosis factor superfamily member 15; DR3, death receptor 3; Flash, some signals related to T cell differentiation