Abstract
It is currently postulated that steroid-sensitive idiopathic nephrotic syndrome (SSNS) and steroid-resistant idiopathic nephrotic syndrome (SRNS), which are not related to the mutation of a gene coding for podocyte structures or for glomerular basement membrane proteins, result from a circulating factor affecting podocyte shape and function. T lymphocytes have for a long time been suspected to be involved in the pathophysiology of these diseases. The successful treatment of steroid-dependant nephrotic syndrome with rituximab suggests a potential role for B lymphocytes. Clinical and experimental data indicate roles for cytokines IL-13, TNFα, circulating cardiotrophin-like cytokine factor 1 (member of the IL-6 family), circulating hemopexin, radical oxygen species, and the soluble urokinase-type plasminogen activator receptor (suPAR) in the development of nephrotic syndrome. Podocyte metabolism modifications—leading to the overexpression of the podocyte B7-1antigen (CD 80), hypoactivity of the podocyte enzyme sphingomyelin phosphodiesterase acid-like 3 b (SMPDL3b), and to the podocyte production of a hyposialylated form of the angiopoietin-like 4 (Angptl4)—are mechanisms possibly involved in the changes in the podocyte cytoskeleton leading to SSNS and or SRNS. Different multifactorial pathophysiological mechanisms can be advocated for SSNS and SRNS. The present paper reviews the experimental and clinical data upon which the different hypotheses are based and reports their possible clinical applications.
Highlights
Idiopathic nephrotic syndrome (INS) is the most frequent form of NS in children, representing more than 90 % of cases between 1 and 10 years of age and 50 % after 10 years of age [1]
The attempts to characterize a circulating factor responsible for INS resulted in the identification of several different molecules that can play a role in FSGS or in MCD
Research on the causes of INS has to be continued with several aims: (1) to distinguish at an early stage sensitive idiopathic nephrotic syndrome (SSNS) from steroid-resistant idiopathic nephrotic syndrome (SRNS) to avoid useless and toxic steroid therapy; (2) to detect FSGS relapses after transplantation at time in order to start plasma exchange before the formation of definitive glomerular lesions; (3) to set up new treatments aimed to antagonize or to prevent the secretion of the causal agent; (4) future studies should focus on intrinsic podocytes features which should make the cells more vulnerable to external triggers
Summary
Idiopathic nephrotic syndrome (INS) is the most frequent form of NS in children, representing more than 90 % of cases between 1 and 10 years of age and 50 % after 10 years of age [1]. The successful treatment of SRNS on native kidney or of SRNS relapse after kidney transplantation with antiTNFα antibodies strongly suggests that TNFα participates to the pathogenesis of some types of INS [31, 32] This hypothesis is supported by high blood levels of TNFα in patients with active disease, normalizing with remission and by an animal model of NS that is controlled by anti-TNFα agents (for a review, see 31, 32). Fornoni et al suggest that targeting SMPDL3b expression in podocyte may prove beneficial in the treatment of FSGS Those authors have shown that rituximab treatment at the moment of transplantation was associated with lower incidence of post-transplant proteinuria and stabilization of the glomerular filtration rate [79]. Those authors suggest that treatment of high-risk patients with rituximab at the time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b-dependent manner [79]
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