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Nephrotic syndrome: Rituximab in childhood steroid-dependent nephrotic syndrome

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Page 1: Nephrotic syndrome: Rituximab in childhood steroid-dependent nephrotic syndrome

562 | OCTOBER 2013 | VOLUME 9 www.nature.com/nrneph

NEWS & VIEWS

NEPHROTIC SYNDROME

Rituximab in childhood steroid-dependent nephrotic syndromeOlivia Boyer and Patrick Niaudet

Ravani et al. report that rituximab is a safe and effective steroid-sparing and calcineurin-inhibitor-sparing agent in 46 children with idiopathic nephrotic syndrome over a median follow-up of 3 years. What is the risk-to-benefit profile of rituximab compared to that of the other available drugs for treating this disease?Boyer, O. & Niaudet, P. Nat. Rev. Nephrol. 9, 562–563 (2013); published online 13 August 2013; doi:10.1038/nrneph.2013.153

In their prospective, noncontrolled study, Ravani et al. examined the long-term effi-cacy and safety of rituximab therapy in 46 children with steroid-dependent and calcineurin- inhibitor-dependent idiopathic nephrotic syndrome.1 The children received 1–5 courses of rituximab during a median follow-up time of 3 years. Calcineurin inhib-itors and steroids were tapered and stopped within 45 days after each infusion. The remission rate at 6 months was 48% after the first infusion and 37% after sub sequent infusions. After 1 year, 20% of patients were still in remission without taking any oral therapy. The probability of remission at 6 months was significantly higher in chil-dren who were older than 9.4 years at diag-nosis than in children who were younger at diagnosis (68% versus 32%). The research-ers also observed that the re appearance of CD20+ lymphocytes correlated with the duration of remission. Although five chil-dren experienced initial bronchospasm and three patients had neutro paenia, the investigators conclude that rituximab is safe and can be used repeatedly in chil-dren with steroid- dependent idiopathic nephrotic syndrome.

Idiopathic nephrotic syndrome is the most frequent glomerular disease in chil-dren, and is defined by the combination of a nephrotic syndrome and nonspecific histologic abnormalities of the kidney including minimal glomerular changes, focal segmental glomerulosclerosis, and diffuse mesangial proliferation. Up to 80% of children respond to corticosteroids,

with complete remission occurring within 30 days. However, 40–50% of the patients who achieve remission experience frequent relapses, either as soon as steroid therapy is stopped (frequent relapsers) or when the dosage of steroids is decreased (steroid-dependent patients). Steroid-dependent patients may have a prolonged disease course. In the long term, the main concerns in children with idiopathic nephrotic syn-drome are the risk of relapse and the adverse effects of the treatments.

Corticosteroids and alkylating agents were the only drugs available for the treatment of idiopathic nephrotic syndrome 30 years ago; however, major changes in the approach for treating this disease have occurred over the past 20 years, with the introduction of levamisole, ciclo sporin, mycophenolate mofetil and—more recently—rituximab. Correspondingly, the adverse effects associ-ated with treatments for this disease have changed over time.

Rituximab is a chimeric monoclonal anti-body directed against the CD20 antigen that is present on pre-B and B lymphocytes. In 2004, rituximab was shown to be effective in a child with relapsing nephrotic syn-drome who developed idiopathic thrombo-cytopenic purpura. Several reports have indicated that most patients with steroid-dependent minimal-change disease respond to rituximab, suggesting a role for B cells in addition to T cells in the pathogenesis of minimal-change disease.2 Rituximab may act by inducing regulatory T lympho-cytes, as has been observed in patients with lupus nephritis.3 Fornoni et al. showed that rituximab also acts directly on podocytes by stabil izing the podocyte cytoskeleton and preventing apoptosis through an interaction with the sphingomyelin phosphodiesterase acid-like 3b protein (SMPDL-3b) that is expressed in podocytes.4

The recent article by Ravani et al. raises several issues that should be discussed. Which patients should receive rituximab? How many rituximab infusions should these children receive? What do we know about the long-term safety of rituximab?

Rituximab has been used as a rescue therapy in patients with difficult-to-treat steroid-dependent nephrotic syndrome.2 The Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group suggested that rituximab should be consid-ered only in children who have continuing relapses despite receiving optimal combi-nations of prednisone and steroid- sparing agents and in patients who have developed calcineurin inhibitor nephrotoxicity.5 In their report, Ravani et al. extend the indications for rituximab treatment. These researchers treated children who had steroid-dependent and calcineurin-inhibitor-dependent idio-pathic nephrotic syndrome, but only 17 of the 46 patients showed patent signs of toxi-city. A considerable number of the patients had been receiving low doses of predniso-lone and calcineurin inhibitors, which were well tolerated without any relapse during the previous year. However, most of the patients experienced relapses during the year follow-ing rituximab treatment and needed further courses of prednisolone and rituximab infu-sions. We believe that the benefit of rituxi-mab is not demonstrated in such patients in this noncontrolled study.

Rituximab does not cure the disease—the efficacy of rituximab for preventing relapses is transient in most patients. Relapses correlate well with the reappearance of

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‘‘…the long-term immunological consequences of repeated rituximab infusions in children are not known’’

© 2013 Macmillan Publishers Limited. All rights reserved

Page 2: Nephrotic syndrome: Rituximab in childhood steroid-dependent nephrotic syndrome

NATURE REVIEWS | NEPHROLOGY VOLUME 9 | OCTOBER 2013 | 563

NEWS & VIEWS

CD19+ cells, although some patients main-tain remission despite CD19 reconstitution. The number of doses that can be repeated in case of relapse is not well defined, since the long-term safety is not known. Ravani et al. propose that rituximab infusions may be repeated up to five times. Maintenance therapy with mycophenolate mofetil has also been shown to be effective in prevent-ing relapse after treatment with rituximab.6 Fujinaga et al. found that ciclosporin was even more effective than mycophenolate mofetil for maintaining remission after a single infusion of rituximab.7

Although rituximab is well tolerated in most patients, it can be associated with adverse effects including infusion-related reactions (such as hypotension, fever, skin rashes, diarrhoea and broncho spasm). Patients may develop serious infec-tions secondary to leuko paenia and/or hypogammaglobulin aemia. Patients with minimal-change disease have a decreased serum IgG level, which is more pronounced during relapses, but persists during remis-sion. Rituximab was recently reported to prolong this IgG depletion.8 Several cases of progressive multifocal leukoencephalo-pathy caused by JC polyomavirus have been reported in patients with haemato-logical disorders or lupus treated with rituximab. In addition, one published case study reported death due to lung fibrosis9 and another reported severe myocarditis requiring heart transplantation10 in two chil-dren with nephrotic syndrome treated with rituximab. Additional severe adverse effects occurring in association with rituximab reported in childhood nephrotic syndrome include Pneumocystis carnii pneumonia and severe immune-mediated ulcerative gastro-intestinal disease. These life-threatening complications may be underestimated in the literature. Moreover, the long-term immuno-logical consequences of repeated rituximab infusions in children are not known.

In conclusion, the strength of Ravani et al.’s paper is that it shows the long-term outcomes of children with steroid- dependent nephrotic syndrome receiving single or repeated rituximab infusion. It shows that patients are not cured but shift from dependency on steroids and calci-neurin inhibitors to dependence on rituxi-mab. Well-defined randomized control studies are mandatory to examine which particular drug has the best risk-to- benefit profile and to better define the place of rituximab in the treatment of childhood steroid-dependent nephrotic syndrome.

Université Paris Descartes, Hôpital Necker‑Enfants Malades, 149 rue de Sèvres, 75015 Paris, France (O. Boyer, P. Niaudet). Correspondence to: P. Niaudet [email protected]

Competing interestsThe authors declare no competing interests.

1. Ravani, P. et al. Rituximab is a safe and effective long‑term treatment for children with steroid and calcineurin inhibitor‑dependent idiopathic nephrotic syndrome. Kidney Int. http://dx.doi.org/10.1038/ki.2013.211.

2. Sinha, A. & Bagga, A. Rituximab therapy in nephrotic syndrome: implications for patients’ management. Nat. Rev. Nephrol. 9, 154–169 (2013).

3. Sfikakis, P. P. et al. Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis. Clin. Immunol. 123, 66–73 (2007).

4. Fornoni, A. et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci. Transl. Med. 3, 85ra46 (2011).

5. Lombel, R. M., Gipson, D. S. & Hodson, E. M. Treatment of steroid‑sensitive nephrotic syndrome: new guidelines from KDIGO. Pediatr. Nephrol. 28, 415–426 (2013).

6. Ito, S. et al. Maintenance therapy with mycophenolate mofetil after rituximab in pediatric patients with steroid‑dependent nephrotic syndrome. Pediatr. Nephrol. 26, 1823–1828 (2011).

7. Fujinaga, S. et al. Cyclosporine versus mycophenolate mofetil for maintenance of remission of steroid‑dependent nephrotic syndrome after a single infusion of rituximab. Eur. J. Pediatr. 172, 513–518 (2013).

8. Delbe‑Bertin, L., Aoun, B., Tudorache, E., Lapillone, H. & Ulinski, T. Does rituximab induce hypogammaglobulinemia in patients with pediatric idiopathic nephrotic syndrome? Pediatr. Nephrol. 28, 447–451 (2013).

9. Chaumais, M. C. et al. Fatal pulmonary fibrosis after rituximab administration. Pediatr. Nephrol. 24, 1753–1755 (2009).

10. Sellier‑Leclerc, A. L., Belli, E., Guérin, V., Dorfmüller, P. & Deschênes, G. Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome. Pediatr. Nephrol. http://dx.doi.org/10.1007/s00467‑013‑2485–9.

CHRONIC KIDNEY DISEASE

Fibrosis and anaemia in CKD —two beasts, one ancestorLiangxiang Xiao and Youhua Liu

Renal fibrosis and anaemia are hallmarks of progressive chronic kidney disease (CKD). New evidence demonstrates that these conditions are intimately connected, as injury triggers the phenotypic transition of renal erythropoietin-producing cells into fibrogenic myofibroblasts. Strategies to reverse such a transition may hold promise to alleviate both anaemia and fibrosis in CKD.Xiao, L. & Liu, Y. Nat. Rev. Nephrol. 9, 563–565 (2013); published online 3 September 2013; doi:10.1038/nrneph.2013.179

Chronic kidney disease (CKD) is charac-terized by a prolonged decline in renal function, the relentless accumulation and deposition of extracellular matrix, and pro-gressive tissue fibrosis. Although anaemia resulting from a deficiency in erythro-poietin production is highly prevalent in patients with CKD,1 whether anaemia and renal fibrosis were somehow linked was poorly understood for many years. Now, a new study by Souma and colleagues shows that these two conditions are intimately connected.2 Using numerous unique and sophisticated mouse models, the research-ers demonstrate that renal erythropoietin- producing cells (REPs) switch from a physiologic, erythropoietin- producing state to a pathologic, matrix-producing pheno-type in response to inflammatory injury.

These new findings, together with earlier data from the same researchers,3 have established a clear mechanistic link between anaemia and fibrosis in the development and progression of CKD.

REPs are a population of peritubular, fibroblast-like, interstitial cells that are located in the juxtamedullary cortex of the adult kidney. These stellate-shaped cells express 5'nucleotidase (CD73) in their plasma membranes and are quiescent in nature. They possess multiple, sometimes

‘‘...REPs originate from extra-renal sites and enter the murine embryonic kidney during nephrogenesis’’

© 2013 Macmillan Publishers Limited. All rights reserved