Effect of rituximab in MCNS: a role for IL-13 suppression?

We read with great interest the article by Aditi Sinha and Arvind Bagga (Rituximab therapy in nephrotic syndrome: implications for patients' management. Nat. Rev. Nephrol. 9, 154–169; 2013).¹ These authors reported the beneficial effects of rituximab treatment in patients with nephrotic syndrome and speculated that rituximab might cause apoptosis via complement-dependent cytotoxicity and antibody-dependent cytotoxicity, leading to rapid depletion of B cells.¹ Furthermore, rituximab is reported to induce T-regulatory and B-regulatory cell populations, restore immune tolerance, and attenuate the downregulation of sphingomyelinase-like phosphodiesterase 3b in podocytes.¹

We would like to add another possible mechanism that may explain the beneficial effect of rituximab on minimal-change nephrotic syndrome (MCNS). Although rare, some reports have shown that Th2 cytokines, such as interleukin (IL)-13, may play an important role in the pathogenesis of MCNS.^2,3,4 Yap et al. reported that CD4⁺ and CD8⁺ IL-13 mRNA expression was increased in patients with nephrotic relapse compared with those in remission, healthy individuals, and patient controls (children with viral infections, but without idiopathic nephrotic syndrome; P <0.008) and that this finding was related to an increase in expression of cytoplasmic IL-13 in phorbol myristate acetate/ionomycin-activated CD3⁺ cells (6.66 ± 3.39%) in patients with nephrotic relapse compared with expression in patients in the remission phase (2.59 ± 1.35%, P <0.0001).² Yap et al. speculated that IL-13 may act on monocytes to produce vascular permeability factors involved in the pathogenesis of proteinuria in patients with relapse of nephrotic syndrome.² Cheung et al. also showed that the percentage of CD3⁺ IL-13-producing cells was significantly increased in children with nephrotic relapse, and correlated with serum IgE levels during the active phase of the disease (r = 0.90, P <0.001).³

In addition, Lai et al. have demonstrated that IL-13-transfected rats (n = 41) show a minimal-change-like nephropathy (characterized by increased proteinuria, hypoalbuminaemia and hypercholesterolaemia) compared with control rats (n = 17).⁴ In their study, the glomeruli of rats transfected with IL-13 showed no significant histologic changes, but electron microscopy findings showed that up to 80% of podocyte foot processes showed fusion and that glomerular gene expression of B7-1, IL-4Rα and IL-13Rα2 were upregulated, whereas those of nephrin, podocin and dystroglycan were downregulated.⁴

Although not in the setting of MCNS, another study has shown that rituximab could reduce levels of IL-13 expressing T cells.⁵ Simon et al. showed that the numbers of cytokine-expressing CD4⁺ and CD8⁺ T cells were reduced with a relative decrease in the mRNA expression of IL-5 (mean 53%) and IL-13 (mean 83%) after rituximab therapy in patients with moderate to severe atopic dermatitis not responding to topical corticosteroid and/or calcineurin inhibitor therapy.⁵

So there is a possibility that rituximab might be beneficial in MCNS by suppression of IL-13, which could be involved in the development of MCNS, in addition to depletion of B cells. However, further studies are necessary to evaluate serial changes in levels of IL-13 after rituximab treatment in MCNS and to elucidate the exact role of IL-13 in the pathogenesis of MCNS.