The pathogenesis of primary FSGS is still unclear, and its recurrence after renal transplant remains a predicament. Proposed mechanisms include abnormalities in the immune system including T-cell dysfunction/dysregulation, abnormal cross-talk between T and B cells, cytokines, and an unidentified circulating glomerular permeability factor [28
]. Recently, Wei et al. have identified serum soluble urokinase receptor (suPAR) as a circulating factor that may cause recurrent FSGS [29
]. As a result, intensive therapies like plasmapheresis in combination with oral cyclophosphamide or high-dose cyclosporine are commonly prescribed but are not always successful and accelerated allograft failure ensues.
Rituximab, a chimeric monoclonal antibody against CD20, was initially approved for the treatment of B-cell Non-Hodgkin lymphoma and is now used for the treatment of other hematological malignancies and autoimmune disorders. There have been multiple reports of patients with steroid-dependent and steroid-resistant nephrotic syndrome as well as posttransplant FSGS who have been treated with rituximab (for review see [30
Overall, our data show that the response to rituximab is variable and less effective in posttransplant FSGS as compared to idiopathic nephrotic syndrome in the native kidney, where response rates are higher [30
]. This finding could be explained by the fact that a large proportion of steroid-dependent and some of the steroid-resistant patients in the above studies had renal histology consistent with minimal change disease and not FSGS. The first prospective study evaluating rituximab in idiopathic nephrotic syndrome was performed by Guigonis et al. [31
]. The study included 22 patients, 3 with histologic changes of FSGS. Two of the patients were treated with rituximab after remission had been achieved and one during relapse. The patient that was actively nephrotic failed to respond to therapy. Two other patients, actively nephrotic, did not benefit from rituximab. The investigators concluded that disease activity may impact the efficacy of rituximab. By definition, in posttransplant FSGS, all patients have active disease and heavy proteinuria which may explain why response to rituximab is lower than in primary FSGS. In addition, the study by Guigonis also noted that rituximab was more effective in patients on a combination of corticosteroids and a calcineurin inhibitor [31
]. However, our analysis revealed that the type of immunosuppressive agent was not predictive of response to therapy.
The short-term effects of rituximab in children with steroid-dependent nephrotic syndrome were evaluated by Ravani and colleagues in an open-label randomized controlled trial [32
]. This study included mostly patients with renal histology consistent with minimal change disease, but 25% of patients in the intervention arm that received rituximab had a diagnosis of FSGS. At 3 months followup, children who received rituximab had less proteinuria, were receiving lower prednisone and calcineurin inhibitor doses, and had lower risk of relapse. However, patients with steroid-resistant or with steroid-dependent nephrotic syndrome on high-prednisone doses were excluded from this study. Furthermore, the outcomes were not analyzed based on renal histology making it even more difficult to extrapolate the data to the posttransplant FSGS patient population.
In our present analysis, we did find that patients with a normal serum albumin at the time of recurrent FSGS diagnosis were more likely to achieve remission. The normal serum albumin level was documented prior to initiating plasmapheresis with albumin replacement. There are several possible reasons for this association. A normal serum albumin level may imply an earlier stage of disease, when rituximab may have a better chance of working. Alternatively, it may imply a milder disease phenotype. It is important to mention that patients with FSGS secondary to an underlying immune defect and patients with FSGS due to mutations in podocyte proteins may have different response to therapy. Furthermore, there have been an increasing number of podocyte-expressed genes associated with steroid-resistant nephrotic syndrome in both children and adults. In the current cohort, NPHS2 mutation analysis was performed and found to be negative in only 4 patients. Analyses for other slit-diaphragm-associated proteins were not carried out in these or any other of the reported patients. Hence, it is possible that some of the patients may have carried an unidentified podocyte protein mutation.
In the initial reports by Nozu and Pescovitz, rituximab induced complete remission of nephrotic syndrome in a patient with PTLD and another who developed Epstein-Barr-virus-driven diffuse large cell lymphoma. Follow-up investigators reported treatment failure with rituximab in patients without PTLD. In the existing reports, there are only 3 patients treated for malignancy with rituximab. Complete remission of proteinuria was induced in two and partial remission in one of the patients. We found no association between the presence of PTLD and response to rituximab therapy.
So, how could rituximab be effective in some cases of recurrent FSGS? It could be assumed that CD20+ cells play some role in the pathogenesis of posttransplant FSGS. For instance, Dantal et al. treated four patients with relapse of focal glomerulosclerosis after transplantation using an (non-protein A) anti-Ig affinity column and a protein A column [7
]. The two procedures were effective in depleting the relapsing patients' plasma of the factor capable of altering the albumin permselectivity of isolated glomeruli in vitro. The investigators concluded that immunoglobulins have a role in the recurrence of nephrotic syndrome and suggested that the responsible factor may be bound to an immunoglobulin. Furthermore, CD20 is expressed in a fraction of T cells and this population could be targeted with rituximab as well with a resulting alteration in T-cell and B-cell cross-talk [33
]. Rituximab can also inhibit nuclear factor kappa B (NF-κ
B) pathway in CD20+ cells [34
B regulates cytokine expression which was reported by Sahali et al. to be altered in patients with nephrotic syndrome. A recent study suggests that rituximab may act through a B-lymphocyte-independent mechanism by directly regulating podocyte activation [35
]. Investigators found that rituximab binds to sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) in podocyte lipid rafts and prevents its downregulation when exposed to sera from patients with recurrent FSGS. Rituximab also preserved acid sphingomyelinase enzymatic activity at normal levels, essential for the organization of receptors and signaling molecules in the podocyte. Furthermore, rituximab appears to prevent podocyte actin remodeling through stabilization of SMPDL-3b.
In summary, multiple immunological mechanisms or even a direct podocyte effect could be involved in the response following rituximab administration in some patients. Overall, complete remission of the proteinuria was achieved in 17/39 (43.5%) of patients reported to date and this may be an overestimation. The efficacy of rituximab in recurrence of FSGS cannot be estimated based on the current published reports due to possible publication bias, as patients without response may not have been reported in the literature and due to the lack of controlled prospective trials. Also, remission of proteinuria was induced in some patients several months after rituximab administration, while they were still receiving other interventions.
In summary, adjuvant therapy with rituximab for recurrence of FSGS may be beneficial in only some patients and the response will likely be evident after the initial medication doses. A younger age at transplant and a normal serum albumin level at the time of recurrence seem to predict response to treatment. Clearly, prospective controlled trials are needed to prove efficacy and safety of rituximab in posttransplant FSGS.