Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis

Abstract

The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated. However, a growing body of evidence emphasizes the pivotal role of the immune system in both initiating and perpetuating the disease. Extensive investigations, encompassing both experimental models and patient studies, have implicated T cells, B cells, and complement as crucial actors in the pathogenesis of primary FSGS, with various molecules being proposed as potential “circulating factors” contributing to the disease and its recurrence post kidney-transplantation. In this review, we critically assessed the existing literature to identify essential pathways for a comprehensive characterization of the pathogenesis of FSGS. Recent discoveries have shed further light on the intricate interplay between these mechanisms. We present an overview of the current understanding of the engagement of distinct molecules and immune cells in FSGS pathogenesis while highlighting critical knowledge gaps that require attention. A thorough characterization of these intricate immune mechanisms holds the potential to identify noninvasive biomarkers that can accurately identify patients at high risk of post-transplant recurrence. Such knowledge can pave the way for the development of targeted and personalized therapeutic approaches in the management of FSGS.

Post-Transplant Glomerulonephritis: Challenges and Solutions

“…It is characterized by the deposition of extracellular matrix, which leads to the obliteration of a portion of the glomerular tuft in some glomeruli. 33 , 34 FSGS can occur at any age, and it is present in approximately 20% to 30% of adults with nephrotic syndrome, more frequent in male and black patients. 34 FSGS can be classified into primary, genetic, or secondary forms, including maladaptive, virus-associated, and drug-induced FSGS.…”

“… 34 FSGS can be classified into primary, genetic, or secondary forms, including maladaptive, virus-associated, and drug-induced FSGS. 33 , 34 Primary FSGS is an immunological disease caused by serum molecules known as circulating factors, which selectively target and damage the glomerular barrier, especially podocytes. 33 , 34 Several factors have been considered as biomarkers of podocyte injury because of their ability to induce podocyte cytoskeleton reorganization in vitro and induce albuminuria in animal model studies.…”

“… 33 , 34 Primary FSGS is an immunological disease caused by serum molecules known as circulating factors, which selectively target and damage the glomerular barrier, especially podocytes. 33 , 34 Several factors have been considered as biomarkers of podocyte injury because of their ability to induce podocyte cytoskeleton reorganization in vitro and induce albuminuria in animal model studies. Some of these biomarkers include serum urokinase plasminogen activator receptor (suPAR), urine apolipoprotein A-1b, cardiotrophin-like cytokine-1 (CLC-1), anti-angiotensin II type 1 receptors (AT1R-Ab), anti-CD40, and interleukin-13.…”

“… 35 Genetic FSGS is associated with gene mutations in podocyte development and structural protein-encoding. 33 In all FSGS forms, injured podocytes are detached from the basement membrane, leaving it uncovered and allowing the interaction of capillary loops and parietal epithelial cells. The remaining podocytes suffer hypertrophy, and intracapillary hypertension results in changes in podocyte, endothelial, and mesangial cells, with progressive focal and segmental sclerosis.…”

“… 34 Spontaneous remission is rare in primary FGSG, occurring in about 5% of the cases. 33 About 40–70% of patients with FSGS course with ESKD despite treatment within 10 to 20 years after diagnosis. 36 …”