Rituximab Targets Podocytes in Recurrent Focal Segmental Glomerulosclerosis

Abstract

Focal segmental glomerulosclerosis (FSGS) is a prevalent glomerular disease characterized by proteinuria, progression to end stage renal disease and recurrence of proteinuria after kidney transplantation in approximately one third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab recognizes CD20 on B-lymphocytes but might also bind sphingomyelin-phosphodiesterase-acid-like-3b (SMPDL-3b) and regulates acid-sphyngomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. Incidence of nephrotic-range proteinuria and change in estimated glomerular filtration rate (ΔeGFR) were analyzed. SMPDL-3b immunostaining was performed in post-reperfusion kidney biopsies. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of post-transplant proteinuria and decreased ΔeGFR. The number of SMPDL-3b+ podocytes in post-reperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase downregulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Either SMPDL-3b overexpression or treatment with rituximab prevented disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where the gene encoding SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b–dependent manner.

Recurrent focal segmental glomerulosclerosis after kidney transplantation

“…Pre-clinical studies demonstrate that rituximab binds directly to sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein and regulates acid sphingomyelinase activity in the podocyte. Rituximab treatment in 27 patients with recurrent FSGS was associated with lower incidence of post-transplant proteinuria and stabilization of glomerular filtration rate, an effect that was associated with prevention of SMPDL-3b sphingomyelinase down-regulation in podocytes [79]. These exciting findings provide strong rationale for this therapeutic intervention for recurrent FSGS.…”

Rituximab–cyclophosphamide‐dexamethasone is highly effective in patients with monoclonal Ig deposit‐related glomerulopathy and indolent non‐Hodgkin lymphomas

“…Of note, five of the seven patients reported by Guiard et al did not have an overt haematological malignancy, but without thorough assessment of clonality. Because rituximab may also have a direct anti-proteinuric effect [16], adding this drug to other nonspecific treatments for iNHL may significantly improve renal outcomes. Indeed, we observed a significant reduction in proteinuria following RCD, and two of the four patients that did not reach a complete haematological response had a complete renal response.…”

Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases

“…However, it may be useful in treating posttransplant relapse [93], [94] and [95]. Interestingly, recent research has shown that RTX may have a direct effect on podocytes, regardless of its action on B-cells, and this could explain the beneficial effect of RTX in these nephrotic disorders that are not clearly associated with auto-antibodies [96].…”