Anti-CD20 therapy is increasingly being used in the treatment of various patterns of nephrotic syndrome in adults and children. However, its use is still based largely on observational studies and expert opinion. Well-designed randomized controlled trials are urgently needed to define the role of this expensive therapy.
In a recent observational trial, Ruggenenti and colleagues investigated the effect of rituximab—a B-cell depleting anti-CD20 monoclonal antibody—on relapse rate in 30 adults and children with steroid-responsive nephrotic syndrome.1 The pathological features in those who had undergone renal biopsy were minimal change disease (MCD; n = 19), mesangial proliferative glomerulonephritis (n = 3) and focal segmental glomerulosclerosis (FSGS; n = 3). At the time of rituximab therapy, the nephrotic syndrome had remained steroid-dependent or frequently relapsing in 25 patients despite at least one course of an immunosuppressive steroid-sparing agent and continued use of steroids (in all but one patient).
Over the 12-month study period, a significant reduction in the frequency of relapses was reported, but four patients had no response. Compared with the period before rituximab treatment, these patients required less ongoing immunosuppressive therapy and lower doses of steroids to achieve remission in subsequent relapses. Although a striking reduction in relapse rate was reported, rituximab seemed to be suppressive rather than curative in some—40% of patients still needed other therapy at 1 year to maintain remission, although dosage was reduced compared with pre-rituximab relapses. The reduced exposure to steroids and other immunosuppressive agents following rituximab therapy might reduce treatment-related toxicity. However, the only measurable benefits in the study by Ruggenenti et al.1 were an improved growth velocity and a modest reduction in systolic blood pressure in the children, presumably a consequence of lower steroid exposure.
“... why did these centres not coordinate and execute the RCTs that are so desperately needed?”
The encouraging findings in this study along with other published data suggest that rituximab might have a role in the management of the important minority of patients with steroid-responsive nephrotic syndrome who frequently relapse or are steroid-dependent despite conventional approaches with recurrent steroid courses and a variety of steroid-sparing agents. Rituximab has found wide favour among nephrologists treating glomerular disease over the past decade. It is widely regarded as a safe, well-tolerated therapy with a favourable adverse effects profile that renders it superior to a number of other available immunomodulating agents, including cyclophosphamide and calcineurin inhibitors. In patients with steroid-responsive nephrotic syndrome and membranous nephropathy, rituximab is now frequently used and multiple dosing is increasingly being proposed. Expert opinion and observational studies supporting this view have been widely discussed, and the strategy is regarded by many as an established part of the therapeutic armamentarium in glomerular disease.2
On the other hand, evidence from randomized controlled trials (RCTs) assessing the efficacy of rituximab is very limited, presumptions about its long-term safety have been challenged, its likely mode of action in a number of conditions is unknown and its cost makes its use prohibitive in many parts of the world. So, where is the balance in this debate? RCTs are often projected as being too difficult and too expensive to conduct. Ruggenenti and colleagues defend their study design, pointing out that a longitudinal design with intrapatient comparisons in a well characterized population with high event rates generates statistical power in a situation (uncommon disease, high-cost intervention) that makes RCTs difficult to deliver.1 The strength of their case, however, depends on the presumption that relapse rates would not spontaneously change during the study such that the change in clinical behaviour of each patient can be attributed to rituximab. This is a unsound assumption even in patients with nephrotic syndrome who have regularly relapsed for some time; spontaneous changes in relapse rate are well recognized in clinical practice. One small, open-label RCT in children with steroid-dependent nephrotic syndrome3 supports the conclusions of Ruggenenti and colleagues,1 but additional RCTs are mandatory to confirm these encouraging findings before the role of rituximab can be agreed on. Additionally, the use of rituximab in steroid-resistant nephrotic children also had a growing popularity, but a small RCT showing no benefit4 will have damped enthusiasm.
The rationale for the use of rituximab to deplete B cells in patients with nephrotic syndrome due to membranous nephropathy is clear given the pathogenic role of circulating antibodies against phospholipase A2 receptors (PLA2Rs).5 Rituximab has been used in children with nephrotic syndrome who have not undergone renal biopsy to determine whether MCD or FSGS is the prevailing pathology. Debate continues about differing pathogenesis between MCD and FSGS, but the basis for rituximab therapy in either case is fragile; little evidence supports the hypothesis that B cells or autoantibodies have a key pathogenic role.6 Some recent evidence suggesting that rituximab might have direct effects on podocytes independent of its B-cell depleting effects7 will be welcome to clinicians who have previously used rituximab without a clear pathogenic justification.
Despite a decade of experience with rituximab in nephrotic syndrome, only two RCTs have been reported among many observational studies (Table 1). This reality is particularly disappointing given the high cost of rituximab; most health economies urgently need an evidence base to evaluate the justification for use of this drug. The relative rarity of these patterns of nephrotic syndrome is often cited as a reason for the lack of RCTs. However, among the many observational studies are single reports with substantial numbers of cases—why did these centres not coordinate and execute the RCTs that are so desperately needed? This scenario highlights the disappointing lack of effective national and international networks for the study of therapies for glomerular diseases. By contrast, the clinical trials networks for lupus nephritis and renal vasculitis have been effective in the past decade, with a series of high-quality RCTs changing practice through the efforts of multinational consortia. In both conditions, anti-CD20 therapy has been tested in RCTs and, despite optimism for its use, was not shown to be superior to conventional therapies in terms of safety and efficacy for prespecified primary end points.8,9
Although long-term safety data on anti-CD20 therapy are broadly reassuring, a mortality rate of 3% has been reported in the 3 years following its initiation in patients with a variety of autoimmune diseases,10 mainly due to infection. Of course, the concomitant use of other immunosuppressive therapies makes direct attribution of cause and effect uncertain; nevertheless, use of anti-CD20 therapy in children and adults with nephrotic syndrome has been associated with progressive multifocal leukoencephalopathy, fulminant viral myocarditis requiring heart transplantation, fatal Pneumocystis pneumonia and pulmonary fibrosis.
The publication of more observational studies will not inform this debate. Sufficiently powered RCTs that provide data on the efficacy, safety and health-care costs of anti-CD20 therapy in patterns of glomerular injury causing nephrotic syndrome are instead urgently needed. The international nephrology community has a poor track record in assembling RCTs, and often seems to prefer the easier option of guidance by expert opinion based on observational studies. It is the responsibility of nephrologists working in this field to develop the multinational clinical networks to initiate and complete RCTs. In my judgement, we have the capacity to do this.
Ruggenenti, P. et al. Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2013030251.
Kattah, A. G., Fervenza, F. C. & Roccatello, D. Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases. Autoimmun. Rev. 12, 854–859 (2013).
Ravani, P. et al. Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial. Clin. J. Am. Soc. Nephrol. 6, 1308–1315 (2011).
Magnasco, A. et al. Rituximab in children with resistant idiopathic nephrotic syndrome. J. Am. Soc. Nephrol. 23, 1117–1124 (2012).
Glassock, R. J. The pathogenesis of membranous nephropathy: evolution and revolution. Curr. Opin. Nephrol. Hypertens. 21, 235–242 (2012).
Cara-Fuentes, G. et al. Rituximab in idiopathic nephrotic syndrome: does it make sense? Pediatr. Nephrol. http://dx.doi.org/10.1007/s00467-013-2534-4.
Chan, A. C. Rituximab's new therapeutic target: the podocyte actin cytoskeleton. Sci. Transl. Med. 3, 85ps21 (2011).
Gregersen, J. W. & Jayne, D. R. B-cell depletion in the treatment of lupus nephritis. Nat. Rev. Nephrol. 8, 505–514 (2012).
Specks, U. et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N. Engl. J. Med. 369, 417–427 (2013).
Tony, H. P. et al. Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID). Arthritis Res. Ther. 13, R75 (2011).
The author declares no competing financial interests.
About this article
Cite this article
Feehally, J. Is there a role for rituximab in nephrotic syndrome?. Nat Rev Nephrol 10, 245–247 (2014). https://doi.org/10.1038/nrneph.2014.37
Autoimmunity Reviews (2017)
Nature Reviews Nephrology (2017)
The Clinical Course of Minimal Change Nephrotic Syndrome With Onset in Adulthood or Late Adolescence: A Case Series
American Journal of Kidney Diseases (2017)
Journal of the American Society of Nephrology (2016)