Nephrology Dialysis Transplantation

NDT Advance Access originally published online on December 9, 2007
Nephrology Dialysis Transplantation 2008 23(1):11-17; doi:10.1093/ndt/gfm683

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Rituximab and nephrotic syndrome: a new therapeutic hope?

Muhammad Shahed Ahmed and Christopher F. Wong

Department of Nephrology, Aintree University Hospital Foundation Trust, Lower Lane, Liverpool L9 7AL, UK

Correspondence and offprint requests to: Dr Christopher F. Wong, Department of Nephrology, Aintree University Hospital Foundation Trust, Lower Lane, Liverpool L9 7AL, UK. Tel: +44-1515293356; Fax: +44-1515292420; E-mail: chriswong{at}doctors.org.uk

Keywords: focal segmental glomerulosclerosis; membranous; minimal change glomerulonephritis; nephrotic syndrome; rituximab

	Introduction

Top Introduction Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Idiopathic membranous... Focal segmental... Minimal Change... Conclusion References

 
Nephrotic syndrome (NS) remains a therapeutic challenge to nephrologists, despite trials of different ranges of therapeutic regimens. Treatment of NS secondary to either primary glomerulonephritis (GN) or recurrence in renal transplantation remains controversial, as various immunosuppression and plasma exchange regimes have been advocated, with variable success and risk of severe toxic effects [1–17]. Rituximab (RIT) is a chimeric monoclonal antibody that acts by inhibiting CD20-mediated B-cell proliferation and differentiation. The CD20 antigen is a membranous protein found on B cells as well as on malignant cells such as in non-Hodgkin's lymphoma (NHL). It was first introduced in the late 1990s for the treatment of B cell NHL [18,19]. Since then, it has been used in over half a million patients with haematological malignancies, as first line and maintenance treatment. We reviewed the current literature to investigate the use of RIT in NS.

We searched Pubmed with the key words, ‘rituximab’, ‘nephrotic syndrome’, and ‘glomerulonephritis’. Patients with lupus nephritis and cryoglobulinaemia were excluded. Systematic review was performed to analyse all the articles. Demographics including age, sex, clinical presentation and renal diagnosis; therapeutic regimens used in treating refractory NS and biochemical parameters such as serum albumin, creatinine, immunoglobulins, proteinuria and CD19 count were recorded. Success and side effects of treatment and duration of follow-up were also recorded.

In total there were 13 case reports [3–9,11–13,15,17,20], three case series [10,14,16] and one prospective study [1,2] (see Table 1). RIT was used in NS affecting 20 patients with primary GN and 10 renal transplant patients (all with recurrence of their GN). Of the 20 primary GN, there were 10 idiopathic membranous glomerulonephritis (IMGN), 7 minimal change glomerulonephritis (McGN) and 3 focal segmental glomerulosclerosis (FSGS). Nine out of ten of the recurrence in renal transplantation were secondary to FSGS and one was due to IMGN. All of these patients were treated with RIT: four weekly doses of 375 mg/m² as in the treatment of B cell NHL [18], or a variation of this regimen, apart from Hofstra et al. [9], who used two doses of RIT: 1 g with a two weekly interval as in the trial for RIT in rheumatoid arthritis [21] (see Table 2).

View this table: [in this window] [in a new window]   Table 1. Demographic of reported cases of RIT use in primary and transplant GN

 

View this table: [in this window] [in a new window]   Table 2. Treatment course of reported cases of RIT use in primary and transplant GN

 

	Rituximab in nephrotic syndrome secondary to idiopathic membranous glomerulonephritis

Top Introduction Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Idiopathic membranous... Focal segmental... Minimal Change... Conclusion References

 
In the prospective observational study by Ruggenenti et al. [2], eight patients with IMGN received four weekly RIT treatment, 375 mg/m². Most of these patients had long-term NS for 29.7 ± 13.5 months prior to inclusion in the study. Their baseline median proteinuria was 7 g/day (4.8–16.0). These patients were not treated with any immunosuppression prior to receiving RIT. They were on loop diuretics to control oedema, full dose of angiotensin converting enzyme (ACE) inhibitor therapy combined with beta-blockers and calcium channel blockers, as deemed appropriate to control blood pressure and proteinuria, and statin to control hypercholesterolaemia (see Table 2). Proteinuria significantly improved by month 1 after RIT infusion [1,2]. The CD20 B lymphocytes decreased to undetectable numbers by month 1 after RIT infusion and remained below normal ranges up to end of study. Following RIT treatment, the one year outcome was as follows: two-eights achieved complete remission (proteinuria <0.5 g/day), three-eights had partial remission (proteinuria <3.5 g/day) (see Tables 1 and 3).

View this table: [in this window] [in a new window]   Table 3. Biochemical parameters of reported cases of RIT use in primary and transplant GN

 
Rossi et al. [3] and Cobo et al. [4] reported on the successful use of RIT in patients with IMGN who were refractory to conventional immunosuppressive therapy (Table 2), whereas Gallon et al. [5] described a patient with post-transplant recurrence of IMGN treated successfully with RIT, who remained in remission and stable after 3 years post-transplant. In Rossi et al.'s report, the patient had only received methyprednisolone therapy prior to RIT as opposed to Cobo et al.'s patient, who was intolerant of the Ponticelli regimen. In the former, two immune-mediated diseases, namingly IMGN and autoimmune haemolytic anaemia, both resistant to corticosteroid, were treated successfully with RIT. Interestingly, as similarly noted by Ruggenenti et al., at 1 month after RIT infusion, there was a significant reduction >50% in proteinuria in all the three patients [3–5].

	Rituximab in nephrotic syndrome secondary to minimal change glomerulonephritis

Top Introduction Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Idiopathic membranous... Focal segmental... Minimal Change... Conclusion References

 
Francois et al. [7] reported on an adult patient with multi-relapsing NS secondary to McGN and the successful use of RIT in inducing remission of the NS. One year later, the authors rechallenged the patient with two further weekly doses of RIT 375 mg/m² when the CD19 lymphocytes were detectable at 1%, although the patient was still in complete remission. The patient remained in complete remission during follow-up at 28 months. The previous year, Gilbert et al. [6] reported the successful use of RIT in a paediatric patient with high-dose steroid-dependant McGN and multiple relapses. She remained in remission for 9 months until her CD19 cells reappeared and shortly after she had a relapse. At 16 months, she had two further dosages of RIT with further remission. Smith et al. [8], Bagga et al. [10] and Hofstra et al. [9] recently reported five further cases in total of successful use of RIT in NS secondary to McGN.

	Rituximab in nephrotic syndrome secondary to focal segmental glomerulosclerosis

Top Introduction Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Idiopathic membranous... Focal segmental... Minimal Change... Conclusion References

 
Kamar et al. [16] reported two cases of the use of RIT in adult patients with recurrent FSGS in transplantation. Despite a prophylactic perioperative therapy of plasmapheresis (PE) and intravenous cyclosporine A, one patient developed significant proteinuria 1 day after his first kidney transplantation. After two infusions of RIT (375 mg/m²) he had complete remission. A second relapse, which occurred on day 40, was also successfully treated by PE and one additional infusion of RIT. Ten months after transplantation, he still has complete remission from recurrent NS. The second patient developed significant proteinuria 1 day after his second kidney transplantation, and the NS persisted despite 27 sessions of PE and cyclophosphamide therapy. At 13 months after transplantation, he received four infusions of RIT (375 mg/m²), but this was ineffective. Hristea et al. [15] reported success with RIT in the treatment of recurrence of FSGS in living donor renal transplantation following failure with plasma exchange. RIT was used concurrently with plasma exchange and cyclophosphamide. However, Glossman et al. [17] used RIT alone successfully in a patient with recurrence of FSGS in her second cadaveric renal transplant, without concomitant drugs apart from her transplant immunosuppression and anti-hypertensives. In this issue of Nephrology Dialysis Transplantation, El-Firjani et al. [20] described a case of NS secondary to recurrent FSGS that was refractory to both plasma exchange and RIT.

There are seven reported paediatric cases, four with use of RIT in recurrence of FSGS post-renal transplantation and three native primary FSGS. Benz et al. [11] reported one of the latter cases where the patient had 35 relapses over 15 years on steroid and other refractory immunosuppressive therapy, including cyclophosphamide, ciclosporin and tacrolimus. The patient developed idiopathic thrombocytopenic purpura (ITP) at age 15, and both his ITP and NS responded to standard dosage of RIT. He remained in remission after 13 months follow-up. Nozu et al. [12] and Pescovitz et al. [13] reported one case each of successful use of RIT (Tables 2 and 3) in post-transplant lymphoproliferative disease (PTLD) associated with the recurrence of FSGS-related NS following renal transplantation. In contrast, Marks et al. [14] reported two cases with post-transplant recurrence of FSGS where RIT was unsuccessful. However, one important observation in these two failed cases is that in both patients, the CD19 counts were detectable, 2 and 4% respectively, whereas in the other successful cases, the counts were undetectable. Bagga et al. [10] reported two cases who received concomitant calcineurin inhibitors and steroid therapy.

Overall successful use of RIT in refractory NS achieving complete and partial remission were 8/12 FSGS, 8/11 IMGN and 7/7 McGN.

Rituximab and nephrotic syndrome: a new therapeutic hope? In recent years, RIT has been used successfully in several renal diseases associated with autoimmune pathology, especially where the underlying pathogenesis of renal involvement is a part of systemic disease due to pathological antibody production. The exact mechanism whereby RIT exerts its effects in these conditions still remains unclear and needs further research. There have been randomized controlled trials of its use in RA [21], reported cases and prospective open-label studies in Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis [19], systematic review in cryoglobulinemic GN [21] and a phase 1/11 escalation dose trial in systemic lupus erythematous [23]. The success of RIT in these autoimmune diseases enhances the support of the involvement of B cells in their pathogenesis. In addition to being the source of plasma cells, B cells are involved in the presentation of antigens to T lymphocytes, secrete co-stimulatory signals that are required for T cell activation and secretes inflammatory cytokines [24].

	Idiopathic membranous glomerulonephritis

Top Introduction Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Idiopathic membranous... Focal segmental... Minimal Change... Conclusion References

 
IMGN is an immune-mediated disease involving the deposition of immunoglobulin G (IgG) and complement component in the subepithelial layers of glomerular basement membrane. Subepithelial immune complexes and complement activation lead to functional insufficiency of the glomerulus with proteinuria and impairment of filtration barrier. Immunization against a variety of non-specific podocyte antigens such as megalin [25], neutral endopeptidase [26] and aminopepidase A [27] can induce IMGN in rodents. This has led to an important study by Cohen et al. [28] that demonstrated focal or diffuse interstitial infiltration of B cells in IMGN patients, suggesting that there is a role of B cell involvement in the pathogenesis of IMGN, possibly as antigen presenting cells. In this study, the CD20 mRNA expression was found to be significantly higher in IMGN patients compared to controls (p = 0.017; IMGN n = 31, control groups n = 20). Another elegant study of neutral endopeptidase 1 antigen demonstrated a B-cell-dependent pathway leading to the formation of pathogenic antibodies and full manifestation of human IMGN [29]. Others have shown that IgG4 (Th2-type subclass) predominates in both idiopathic and lupus-associated membranous GN. IgG4 is over-presented in the circulating immune complexes and predominates in serum cryoglobulins in IMGN. These data, although limited, suggest that the initiating glomerular antigen in IMGN initiates Th2-type, predominantly humoral immune response [30]. Biancone et al. [31] observed that the inhibition of B cells and of pathogenic antibodies is associated with beneficial effects in experimental membranous nephropathy. In their experimental observational study, disruption of the CD40–CD40 L co-stimulatory pathway can prevent the development of murine IMGN by suppressing T-cell-dependent antibody production by B cells. They demonstrated that T-cell transmitted activation of B lymphocytes with subsequent antibody production is essential for glomerular immunoglobulin deposits and complement activation. The role of B cells in the pathogenesis in GN is also supported by clinical observations such as that by Kemper et al. [32], who observed T and B cell activation in childhood steroid-sensitive NS, and analyzed this activation by measuring the soluble IL-2 and low-affinity IGE receptors. They demonstrated T and B cell markers during different stages of disease, and found increased levels of both sCD23 (a marker of B-cell activation) and sCD25 (a marker of T-cell activation) during relapse of steroid-sensitive NS. Serum marker of sCD was increased in relapse compared to remission and to controls. Furthermore, in Gallon et al.'s [5] patient, the induction agent Campath1 H could have been linked with the rapid recurrence of IMGN in the renal transplant. It has been reported that B cells tend to repopulate faster than T cells after induction with Campath 1 H. Last but not the least, the clinical success of RIT in inducing remission in NS secondary to IMGN [1–5] is not only encouraging but promising.

	Focal segmental glomerulosclerosis

Top Introduction Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Idiopathic membranous... Focal segmental... Minimal Change... Conclusion References

 
FSGS recurs in 20–40% of patients after kidney transplantation. In the pathogenesis of FSGS, circulatory permeability factor is thought to play a key role, as evident from numerous observations such as induction of proteinuria in rats given plasma from FSGS patients, suggesting that T cell cytokines may induce the development of NS [33], or the role of plasmapheresis in improving proteinuria in patients with FSGS in renal transplants. However, few immune deposits are observed on renal biopsy, and the pathogenesis remains unclear. Nozu et al. [12] and Pescovitz et al. [13] both described a case of post-transplant NS with FSGS, with the onset of diffuse large B cell lymphoma and Epstein Barr virus-driven diffuse large cell lymphoma respectively; the proteinuria decreased immediately after the B cells had disappeared, suggesting an important role of B cells in the pathogenesis of proteinuria. In a recent trial of 46 patients, RIT was effective in the treatment of PTLD [34]. Kamar et al. [16] believe that RIT should be given early in the recurrence of FSGS in renal transplantation, as demonstrated by the two cases described above, which had contrasting responses to RIT. Marks et al. reported two failed treatments with RIT in the recurrence of FSGS in renal transplantation. The authors highlighted the fact that their cases differ, in that they did not have PTLD. More importantly, as previously pointed out, both cases had CD19 above 1%, and they had serious cytomegalovirus infection before RIT, which may have induced and accelerated chronic transplant allograft nephropathy.

El-Firjani et al. [20] have provided us with extra information on the unsuccessful use of RIT in the treatment of NS secondary to recurrent FSGS.

Bagga et al. [10] reported the successful use of RIT in steroid-resistant NS patients in two patients with FSGS and three with McGN. There was another patient with unreported FSGS, who had no response to RIT at four weekly doses of 375 mg/m². Though not yet confirmed, preliminary results suggested that this patient has a mutation in the NPHS2 gene (personal communication from Arvind Bagga). Podocin (NPHS2) is a component of the glomerular slit diaphragm, with major regulatory functions in renal permeability of proteins. The loss of podocin and decrease in resynthesis may influence the outcome of proteinuric renal disease such as FSGS, and promoter functionality plays a key role in this process [35–38].

	Minimal Change Glomerulonephritis

Top Introduction Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Idiopathic membranous... Focal segmental... Minimal Change... Conclusion References

 
The pathogenesis of McGN is also poorly understood. It is believed to be a systemic disease, related to T cell immunity [39–41]. RIT probably acts by inhibiting B cells that have a regulatory function over T cells [15]. Some studies of unstimulated T lymphocytes from McGN patients have shown increased production of interleukin(IL)-13 and elevated expression of IL-13 mRNA [42,43]. IL-13 is one of the cytokines associated with Th2 cells, which in turn is a part of the immune response involving B cells, leading to antibody production and allergic reaction. As in the discussion for IMGN, there is also evidence of B cell activation in childhood-sensitive NS [32].

So far, we have discussed the various hypotheses and experimental observational studies of B cell involvement in the pathogenesis of primary and transplant recurrence of GN, hence, the rationale for the use of RIT in NS, primary and recurrence of transplant GN such as IMGN, FSGS and McGN. The overall successful use of RIT in refractory NS achieving complete and partial remission were as follows: 8/12 FSGS, 8/11 IMGN and 7/7 McGN. These results were reasonably impressive, as most of these patients with NS were refractory to other previous conventional treatments prior to RIT, apart from the Ruggenenti et al.'s group.

With RIT treatment, the most commonly reported infusion-related adverse effects, like hypotension or chills, can be managed by pre-medication and infusion rate adjustments. In our review, only rash and chills were reported by Ruggenenti et al. However, there have been reported cases of serious infections such as Staphylococcal aureus-related thigh abscess, herpes zoster infection and a septic elbow in SLE patients who were treated with RIT [23]; each was thought to be related to the underlying disease or a result of concomitant immunosuppressive therapy, rather than a direct result of RIT. There have been reports of serious infection such as pneumocystis carinii pneumonia (PCP) [44,45] and necrotising fasciitis secondary to group A haemolytic streptococal infection [45]. Therefore one should consider the use of prophylaxis for PCP, as by Bagga et al. [10], or have a high index of suspicion of PCP when a patient is very unwell with shortness of breath and signs of chest infection associated with the use of RIT [45]. Some of these serious infections were associated with lowered immunoglobulin after having received RIT [45,46]. The use of prophylactic intravenous immunoglobulin, when IgG levels fall below normal, has been recommended [19,45,47]. However, there have been recent concerns and reports on viral reactivation and progressive multifocal leukoencephalopathy (PML) in patients with lupus erythematosus who received RIT [48]. Then again, it is difficult to attribute these side effects exclusively to RIT, as patients were previously on other immunosuppressive therapies. The other important aspect is that therapeutic RIT levels can be achieved in haemodialysis patients and dosage adjustment is not necessary [49].

	Conclusion

Top Introduction Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Idiopathic membranous... Focal segmental... Minimal Change... Conclusion References

 
RIT has been used in refractory NS secondary to IMGN, FSGS and McGN with mostly favourable outcome and no serious adverse events. However, in all cases, the follow-up period was relatively short. Therefore, benefit of long-term use and follow-up of RIT in NS and GN need further evaluation and prospective randomized controlled trials.

Conflict of interest statement. None declared.

(See related article by Greg A. Knoll et al. Post-transplant focal segmental glomerulosclerosis refractory to plasmapheresis and rituximab therapy. Nephrol Dial Transplant 2008; 23: 425.)

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Top Introduction Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Rituximab in nephrotic syndrome... Idiopathic membranous... Focal segmental... Minimal Change... Conclusion References

 

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Received for publication: 21. 8.07
Accepted in revised form: 4. 9.07

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