Current understanding of adult nephrotic syndrome: Minimal change disease

Abstract

The underlying molecular changes that result in minimal change disease (nephrotic syndrome) require an in-depth analysis. Current molecular studies have shown the involvement of zinc fingers and homeobox transcriptional factors in its pathogenesis. The application of therapeutic drugs relies on understanding the cascade of molecular events to determine their efficacy in managing the clinical condition.

Key Words: Minimal change disease; Nephrotic syndrome; Hyposialylation; Podocytes; Albuminuria

Core Tip: Minimal change disease (MCD) represents a unique type of nephrotic syndrome in adults. MCD pathogenesis has been previously attributed to several mechanisms, though they did not explain all of the features and therapeutic implications of MCD. The recent identification of zinc fingers and homeobox transcriptional factors has provided a new dimension to understand and provide better management in MCD.

TO THE EDITOR

Minimal change disease (MCD) represents a small percentage (10%-20%) of the adult population suffering from nephrotic syndrome. The etiology of MCD is suspected to be immunologically driven. Triggers such as insect bites, pollen, and certain foods that initiate allergic reactions can induce MCD. These factors also account for multiple relapses. MCD patients are known to have a relatively higher incidence of atopic dermatitis and elevated immunoglobulin E levels. Together, these data have led to the hypothesis that atopy and MCD are closely linked. More than the causation, the underlying dysregulation of immune mechanisms in both must be appreciated[1].

Pathogenesis

In the kidney, podocytes form an essential part of the glomerular filtration barrier. Podocyte foot processes are integral to maintaining the barrier, and damaging them results in the typical clinical manifestations of MCD, namely albuminuria. Upon upregulation of the Zinc fingers and Homeoboxes (ZHX) and Angiopoietin like 4 (ANGPTL4) pathway, hyposialylated ANGPTL4 is released, inducing microcellular level injury to podocytes. Certain genetic defects involving ZHX2 place podocytes at risk of injury caused by cytokine storms from the common cold. The cytokine storm displaces ZHX1 from the podocyte membrane to the nucleus, leading to the ANGPTL4 upregulation. This cascade results in the secretion of hyposialylated ANGPTL4 protein, ultimately damaging the glomerulus through podocyte foot process effacement and loss of glomerular basement membrane charge (Figure 1). Hence, the current focus in understanding MCD is on ZHX and ANGPTL4 [2].

Figure 1 Podocyte foot process effacement and loss of glomerular basement membrane charge. Normal versus minimal change disease (MCD) illustration showing proteins getting repelled by intact podocyte foot processes with negative charge (normal). In MCD, proteins leak due to the effaced podocyte foot processes with loss of charge. MCD: Minimal change disease.

Earlier animal model studies proposed that MCD pathogenesis was associated with the administration of specific proteins, podocyte structural alterations, alternate pathways and T-cell-mediated damage. T cell dysfunction is known to be a component in MCD, but whether it plays a causative role is unclear. Through their ability to activate B cells and cytotoxic T8 cells and to release cytokines, T4 helper contribute to the autoimmune mechanism involved in targeting podocytes. T4 regulator cells, which help restore normalcy, are reduced in numbers in MCD, resulting in immune dysregulation and an exaggerated inflammatory response[3]. The complex interactions between the T cell and B cell are significant in pathogenesis. However, the available studies have failed to elucidate the exact sequence of events orchestrating the disease process of MCD. In addition, the multiple MCD relapses were attributable to the complex interactions of many proteins rather than a single protein[2,4,5]. The B lymphocyte dysregulator Telitacicept prevents its differentiation and maturation in recalcitrant MCD and has been demonstrated to elicit a therapeutic response, reserving its use in select cases[6].

The key component of the ZHX and ANGPTL4 pathway in MCD is the depletion of sialic acid due to podocyte injury. The management strategy of steroid use can rescue the ANGPTL4 upregulation, decreasing the chances of its hyposialylation and thus eliciting a favorable clinical response[5].

MCD AND FSGS

Although MCD and focal segmental glomerulosclerosis (FSGS) represent the extremes along a spectrum, they are both steroid-responsive. The differences in molecular mechanisms underlying MCD and FSGS deserve attention. ZHX2 expression is reduced in both, but there is an increase in nuclear ZHX1 in MCD, and an increase in nuclear ZHX2 and ZHX3 in FSGS. The former (rise in nuclear ZHX1) leads to disturbance in the podocyte body, whereas the latter (rise in nuclear ZHX2, ZHX3) results in altered podocyte foot processes[2].

Anti-nephrin antibodies

Newer studies have been investigating the role of anti-nephrin autoantibodies in MCD pathogenesis, which is considered immune-mediated podocytopathy. Nephrin is an integral component of podocyte architecture, and it plays a central role in cellular signaling. Autoantibodies against Nephrin display a good correlation with disease activity and are also etiological in the evolution of the disease process. Rituximab, a B cell-targeted agent, can induce clinical remission by exhausting the anti-nephrin antibodies. Pharmacological agents aimed at the anti-nephrin antibodies are potential future targets in the management of MCD[7,8].

Interestingly, the degree of proteinuria severity does not appear to influence MCD outcomes. However, elevated 24-hour albumin clearance levels are predictive of MCD recurrence. The impaired charge barrier at the glomerular level directly affects albumin clearance and is the basis for the utility of albumin clearance value in prognosis[9,10].

CONCLUSION

Targeted molecular interventions, or personalized precision nephrology, are recent developments that help identify MCD patients with unconventional outcomes, such as poor responders. Customizing the therapeutic approach to suit the individual patient with inputs from the disease progression, genetics, and other personal factors defines how personalized precision nephrology works. A typical example is tumor necrosis factor, identified by markers such as monocyte chemoattractant protein-1 and tissue inhibitor of metalloproteinases-1 and known to be associated with a subtype of poor responders amongst MCD. Such an individualized approach represents a significant move towards recognizing those with poor prognosis upfront and planning suitable therapeutic strategies for better outcomes[11].

The documentation of MCD by Shakeel et al[12], including the clinicopathologic characteristics, treatment response and outcome evaluation, offers an institutional viewpoint. In addition, the various aspects of MCD, such as the presentation and management approach, can be understood from the background of a single center perspective.