Abstract
Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia and usually responds well to steroids. However, relapses are frequent, which can require multi-drug therapy with deleterious long-term side effects. In the last decades, different hypotheses on molecular mechanisms underlying INS have been proposed and several lines of evidences strongly indicate a crucial role of the immune system in the pathogenesis of non-genetic INS. INS is traditionally considered a T-cell-mediated disorder triggered by a circulating factor, which causes the impairment of the glomerular filtration barrier and subsequent proteinuria. Additionally, the imbalance between Th17/Tregs as well as Th2/Th1 has been implicated in the pathomechanism of INS. Interestingly, B-cells have gained attention, since rituximab, an anti-CD20 antibody demonstrated a good therapeutic response in the treatment of INS. Finally, recent findings indicate that even podocytes can act as antigen-presenting cells under inflammatory stimuli and play a direct role in activating cellular pathways that cause proteinuria. Even though our knowledge on the underlying mechanisms of INS is still incomplete, it became clear that instead of a traditionally implicated cell subset or one particular molecule as a causative factor for INS, a multi-step control system including soluble factors, immune cells, and podocytes is necessary to prevent the occurrence of INS. This present review aims to provide an overview of the current knowledge on this topic, since advances in our understanding of the immunopathogenesis of INS may help drive new tailored therapeutic approaches forward.
Highlights
Idiopathic nephrotic syndrome (INS) is the most frequent glomerular disease in childhood and is caused by damage to podocytes, resulting in foot process effacement that leads to alterations to the selectivity of the glomerular filtration barrier [1]
This review aims to provide an overview of current knowledge on the immune system influencing the course of INS and its response to initial steroid treatment, since advances in our understanding of the pathogenesis of INS may help drive new tailored therapeutic approaches forward
In spite of the numerous experimental and clinical studies performed in the last decades, the immune pathogenesis of the non-genetic, idiopathic nephrotic syndrome is still not completely understood
Summary
Idiopathic nephrotic syndrome (INS) is the most frequent glomerular disease in childhood and is caused by damage to podocytes, resulting in foot process effacement that leads to alterations to the selectivity of the glomerular filtration barrier [1]. An active role of B-cells in INS pathogenesis gains more and more evidence, challenging the standpoint of INS as a disease only driven by T-cell dysfunction and RTX and other anti-CD20 antibodies pose as promising alternatives to other steroid-sparing agents Mononuclear phagocytes and their cytokines In Buffalo/Mna rats, which develop INS spontaneously, the frequency of monocyte–macrophage lineage cells and the expression of macrophage-associated factors (tumor necrosis factor-α [TNF-α], IL-12) were found to be higher in the kidney infiltrate compared to healthy rats [53]. The second hit represents dysfunction of theauto-regulatory mechanisms (secretion of soluble CTLR-4, IL-10, and TGF-β by Tregs or downregulation of CD80 by podocytes itself ), resulting in persistent CD80 expression and proteinuria Another co-stimulatory molecule in the adaptive immunity is CD40 [128, 129], which was observed to be constitutively expressed in human cultured podocytes and in glomerular biopsies of FSGS patients [80]. Other biologicals proposed by basic science experiments are awaiting further investigations in nephrotic patients such as the anti-CD40 blocking antibody lucatumumab, antiIL-13 antibodies or anti-IL-4 antibodies
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