What is the role of the immune system in the pathophysiology of pediatric nephrotic syndrome?

Updated: Mar 04, 2020
  • Author: Jerome C Lane, MD; Chief Editor: Craig B Langman, MD  more...
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Immune system

The hallmark of idiopathic nephrotic syndrome (INS) is massive proteinuria, leading to decreased circulating albumin levels. The initiating event that produces proteinuria remains unknown. However, strong evidence suggests that INS, at least in part, has an immune pathogenesis.

The effect of glucocorticoids on inducing remission in INS implicates the immune system, and particularly T lymphocytes, in the pathogenesis of the condition. Glucocorticoids, primarily acting through the nuclear factor kappa B (NF-κB) transcription pathway, have a variety of effects, including inhibiting cytokine production and inhibiting T-cell production and proliferation.

A variety of studies provide further evidence of the role of T cells in INS. [6] Patients with INS in remission have alterations in the NF-κB pathway compared with healthy control subjects. NF-κB transcription is up-regulated in relapse of INS compared with remission. Additionally, nephrotic syndrome has been reported in patients with Hodgkin lymphoma, a T-cell disease. Other observations in INS include altered thymic regulation of T-cell differentiation and alterations in T-cell subsets in INS patients compared with healthy controls.

In addition to T cells, the reports of remission in INS after treatment with rituximab, an anti-CD20 monoclonal antibody that results in complete depletion of B lymphocytes, implicate a role for B cells in the pathogenesis of INS. [7, 8, 9, 10, 11]

A circulating factor may play a role in the development of proteinuria in INS. This role can be demonstrated by the rapid development of proteinuria in the recurrence of nephrotic syndrome after kidney transplantation, the improvement in nephrotic syndrome in such patients after treatment with plasmapheresis, and the experimental induction of proteinuria in animals by plasma from patients with INS. [12]

The nature of this circulating factor is not known. Various cytokines and molecules have been implicated, including the following [13] :

  • Interleukin (IL)-2, IL-4, IL-12, IL-13, IL-15, IL-18

  • IL-2 receptor

  • Interferon-γ

  • Tumor growth factor (TGF)-β

  • Vascular permeability factor

  • NF-κB

  • Tumor necrosis factor (TNF)-α

Wei et al reported an association between circulating levels of soluble urokinase receptor (suPAR) and focal segmental glomerulosclerosis (FSGS) in children and adults. [14, 15] Treatment of FSGS with immunosuppressive medications led to lower levels of suPAR, and a decline in suPAR levels over 26 weeks of treatment was associated with a reduction in proteinuria. Thus, suPAR might affect glomerular permeability. [14] However, subsequent studies have yielded conflicting data regarding suPAR, and the role of suPAR in the pathogenesis of FSGS and other glomerular diseases remains unclear. [16, 17]

The association of allergic responses with nephrotic syndrome also illustrates the role of the immune system in INS. Nephrotic syndrome has occurred after allergic reactions to bee stings, fungi, poison ivy, ragweed, house dust, jellyfish stings, and cat fur. Food allergy might play a role in relapses of INS; a reduced-antigenic diet was associated with improved proteinuria and complete remission in one study. [18, 19]

Additionally, INS is 3-4 times more likely in children with human leukocyte antigen (HLA)-DR7. Steroid-sensitive INS has also been associated with HLA-B8 and the DQB1 gene of HLA-DQW2. A greater incidence of INS is also observed in children with atopy and HLA-B12. [20]

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