Research on the pathogenesis of INS started with an epoch-making paper entitled “Pathogenesis of lipoid nephrosis: a disorder of T-cell function” by Shalhoub, which appeared in the Lancet in 1974 [6], when no clear distinction was made between MCNS and primary FSGS. In those days, they were considered together as lipoid nephrosis, which is synonymous with INS. However, there is still debate as to whether MCNS and FSGS represent opposite ends of one pathophysiological process or distinct disease entities [7, 8]. Shalhoub proposed that INS was a disorder of T-cell function, resulting in increased plasma levels of lymphocyte-derived permeability factor (Shalhoub’s hypothesis) [6]. This hypothesis was based on the absence of immune complexes in the glomeruli, rapid response to steroid therapy, association of INS with Hodgkin’s disease, and the observation that measles infection often induces remission of INS. Therefore, the massive proteinuria and hypoalbuminemia that characterize INS were thought to result from increased permeability of the glomerular capillary wall due to T-cell activation triggered by stimuli such as viral infection or allergens.

The most compelling evidence also came from experience with renal allografts: NS disappeared when MCNS kidneys were transplanted into patients without NS [9]. The following clinical findings support the concept that vascular permeability factors produced from activated T cells play an important role in MCNS: in patients with MCNS, there is a risk of recurrence of the disease when transplanted [10]; placental transfer of proinflammatory cytokines from a mother to a newborn results in neonatal nephrotic syndrome [11]; and the potential of apheresis monotherapy to induce and maintain complete remission of MCNS suggests that circulating factors have an important role in the pathogenesis of MCNS [12].

Based on Shalhoub’s hypothesis, researchers have tried to identify the circulating factors released from T cells that increase the glomerular permeability to serum proteins, and some have confirmed that the capillary permeability factor is detectable in patients with INS [13, 14]. Among various putative factors increasing the glomerular permeability to serum proteins, cytokines are considered to be the most likely pathogenic factors [4, 15]. Cytokines are small proteins (molecular weight 8–80 kDa) that function as soluble mediators in an autocrine or paracrine manner, which are produced by both immune and nonimmune cells. Relapsed patients with INS (mostly MCNS) were found to have increased levels of various cytokines in the serum or urine including interleukin (IL)-2 [16], soluble IL-2 receptor [16–19], interferon (IFN)-γ [16, 20], IL-4 [20, 21], IL-12 [22], IL-18 [23], tumor necrosis factor (TNF)-α [24], and vascular endothelial growth factor (VEGF) [25]. Isolation of peripheral blood mononuclear cells from patients with INS relapse and measurement of the in vitro mitogen-stimulated production of cytokines in the cultured cell supernatants demonstrate increased production of various cytokines including IL-1 [26], IL-2 [20, 27], IL-4 [20, 21], IL-10 [27], IL-12 [28], IL-18 [23], and TNF-α [29]. Yap et al. also reported increased expression of IL-13 mRNA in patients with MCNS relapse [30]. To date, however, the factor itself has not been identified, among possible capillary permeability factors including cytokines, which cause protein leakage from serum to urine, and the various alterations in cytokine production are not in agreement at all. This disagreement may result from the different immunogenetic characteristics of the patients or the heterogeneity of the stimulated cells in nonphysiological environments. The complex interactions among cytokines also make it difficult to determine which cytokine is increased first. Furthermore, lack of documentation of biopsy findings, inclusion of steroid-treated patients, and differences in methodology make it difficult to determine the factors associated with glomerular permeability. The aberrant populations in T cells in INS have also been vigorously studied with conflicting results, e.g., predominance of T-helper (Th) type 2 cells over Th1 cells [31, 32] based on the high comorbidity of atopy and allergy [33, 34], which are caused by Th2 immunological responses. However, others do not support this hypothesis [15, 35]. Recent clinical reports that there is remission after depletion of B cells using monoclonal antibodies or the anti-CD20 drug rituximab also contradict Shalhoub’s hypothesis, which focuses on the T-cell disorder in INS [36, 37].

A new paradigm for the pathogenesis of INS has emerged since the discovery by Tryggvason et al. in 1998 that mutations in the gene NPHS1, which encodes the podocyte-expressed immunoglobulin superfamily protein nephrin, cause congenital NS in humans [38]. This landmark study led to a substantial increase in our understanding of glomerular biology and physiology and that podocytes (visceral glomerular epithelial cells) have attracted particular attention as a key player in the pathogenesis of INS [39, 40]. Podocytes are terminally differentiated cells that line the outer aspect of the glomerular basement membrane. Podocytes form the final barrier to urinary protein loss by the formation and maintenance of podocyte foot processes (FPs) and the interposed slit diaphragms (SDs) [41]. The SDs are the main selectively permeable barrier in the kidney [42]. Podocyte FPs contain a contractile and dynamic apparatus consisting of actin, myosin II, α-actinin-4, talin, vinculin, and synaptopodin [43, 44]. The FPs are anchored to the glomerular basement membrane via α3β1-integrin [45] and dystroglycans [46]. Our knowledge of SD structure is based on genetic studies of familial NS, which led to the identification of SD proteins such as podocin, nephrin, α-actinin-4, and transient receptor potential channel C6. The genes for these proteins may be mutated in inherited NS [47].

Based on this background, several hypotheses have been proposed in the past decade that focus on the role of the podocyte and the related molecules in the mechanism underlying the proteinuria in INS. The candidate molecules as active factors in INS, other than cytokines, include reactive oxygen species [48], nuclear factor-κB [49], hemopexin [50], CD80 (also known as B7.1) [51, 52], and angiopoietin-like 4 [53, 54]; mammalian target of rapamycin complex 1 in MCNS [55]; cardiotrophin-like cytokine-1 [56] and soluble urokinase-type plasminogen activator receptor [57, 58] in FSGS; and M-type phospholipase A2 receptor [59] and cationic bovine serum albumin in IMN [60]. Furthermore, the recent findings suggest that the molecules expressed by podocytes are therapeutic targets for the immunosuppressive agents used for the treatment of INS such as glucocorticoids, cyclosporin A, and rituximab, although these drugs have been considered to act by correcting lymphocyte dysfunction, especially of T cells [61–64].

The rapid pace of scientific progress occasionally sinks to a state of chaos. Currently, the study of the pathogenesis of INS appears to correspond to such a status. As mentioned above, INS was historically thought to be caused by T-cell dysfunction. However, recent evidence suggests that not only T cells but also other immune cells including those associated with innate immunity and podocytes are involved in the pathogenesis of this condition and that INS develops by interactions between humoral factors and podocytes in most cases. To organize the distinct pathogenesis based on various molecules that are newly identified as active factors, the following questions should be clarified: (1) When and how was the molecule identified as the pathogenetic factor in INS? (2) Could the molecule be a novel biomarker to distinguish the histological differences among INS, i.e., MCNS, FSGS, or IMN? (3) How does the molecule play a role in the pathogenesis of INS? (4) Is it expected that the molecule can be the target for new drugs in INS in future? (5) Is there any possible association of the molecule with other putative pathogenetic molecules reported by other researchers? If these questions are answered clearly, the complex pathogenesis of INS would be unraveled.