Detailed Pathophysiology of Minimal Change Disease: Insights into Podocyte Dysfunction, Immune Dysregulation, and Genetic Susceptibility

Abstract

Minimal Change Disease (MCD) is a predominant cause of idiopathic nephrotic syndrome in the pediatric population, yet presents significant clinical challenges due to its frequent relapses and steroid resistance. Despite its relatively benign histological appearance, MCD is characterized by severe proteinuria, hypoalbuminemia, and edema, which may affect patient outcomes. Current treatment strategies primarily rely on corticosteroids, which are effective in inducing remission but are associated with high relapse rates, steroid resistance, and numerous long-term side effects, underscoring the need for more targeted and effective therapeutic approaches. This narrative review synthesizes current knowledge on the pathophysiological mechanisms underlying MCD, focusing on the following three critical areas: podocyte dysfunction, immune dysregulation, and genetic susceptibility. Podocyte dysfunction, particularly involving alterations in nephrin, plays a central role in the breakdown of the glomerular filtration barrier, leading to the characteristic proteinuria observed in MCD. Immune dysregulation, including the presence of autoantibodies against nephrin and other podocyte components, exacerbates podocyte injury and contributes to disease progression, suggesting an autoimmune component to the disease. Genetic factors, particularly mutations in the NPHS1 and NPHS2 genes, have been identified as significant contributors to disease susceptibility, influencing the variability in treatment response and overall disease severity. Understanding these mechanisms is crucial for developing targeted therapies that address the underlying causes of MCD rather than merely managing its symptoms. This review highlights the need for further research into these pathophysiological processes to pave the way for more personalized and effective treatment strategies, ultimately improving patient outcomes and reducing reliance on corticosteroids.

Keywords: biomarker; glomerular diseases; minimal change nephropathy; nephrin; nephrotic syndrome; podocin.

Figure 1

Pathophysiological mechanisms in Minimal Change Disease (MCD). Genetic mutations in NPHS1 and NPHS2 genes resulting in the synthesis of nephrin and podocin, essential for podocyte integrity. Inflammatory cytokines (e.g., IL-4 and IL-13) and anti-nephrin antibodies contributing to podocyte apoptosis and cytoskeletal damage, disrupting the glomerular filtration barrier. Activation of B-cells and Th2 immune response pathways further exacerbating podocyte injury and proteinuria [23,24,25,26,27,28,29,30,31,33,37,38,39,40,50,58,93,95].