Fig. 3. Study protocol of rituximab treatment to reduce the dose of immunosuppressants in steroid-dependent minimal change nephrotic syndrome.
Side Effects of Rituximab Treatment
Rituximab infusion was globally well tolerated. The risk of adverse effects attributed to rituximab varies. With rituximab treatment, the most commonly reported adverse effects are infusion reactions, such as rash and chills; these reactions can be managed by pre-medication or infusion rate adjustments [2]. Each of these reactions is thought to be associated with an underlying disease or to be a result of concomitant immunosuppressive therapy, rather than a direct result of rituximab administration. We have recently assessed the improvement in adverse effects of steroids and the safety of rituximab treatment in adults with steroid-dependent MCNS [18]. A total of 54 adult patients were treated with 4 single-dose 6-monthly infusions of rituximab and the adverse effects with steroids between the first rituximab infusion (baseline) and the end of the 24-month observation period compared. The steroid dose was significantly lower at 24 months than at the baseline. Eight patients with diabetes mellitus showed improved glycemic control at 24 months as compared to that at the baseline. There were no severe adverse effects of rituximab.
Perspectives
Almost all patients whose steroid and other immunosuppressive therapies are withdrawn after rituximab treatment have relapses after the recovery of peripheral B-cell counts. Therefore, further modification of rituximab treatment, including repeated courses of rituximab and adjunct immunosuppressive therapies, may be necessary for maintaining long-term remission. Kimata et al. [19] reported a case series which showed that rituximab administration for 4 times at 3-month intervals induced long-term remission without serious adverse events in children with complicated steroid-dependent MCNS [19]. A case series by Ito et al. [20] suggested that maintenance therapy with mycophenolate mofetil after rituximab administration was effective for maintaining long-term remission in children with complicated frequently relapsing NS/steroid-dependent NS [20]. The efficacy, safety, and cost-effectiveness of various rituximab dosing regimens should be compared to determine an appropriate rituximab treatment regimen for complicated frequently relapsing NS/steroid-dependent NS in adults. Large-scale multicenter cohort studies or multicenter RCTs to compare treatment outcomes after different dosing regimens are required to clarify the optimal dosage of rituximab to use. We have recently shown that treatment with rituximab was possibly superior to previous pharmacological treatments from a health economics perspective [21].
Conclusion
We demonstrated that rituximab treatment was effective and safe in adult patients with steroid-dependent MCNS and dose reduction or discontinuation of the steroid. In addition, rituximab leads to the amelioration of adverse effects of the steroid. Only infusion reactions, such as rash and chills, occurred after single-dose rituximab infusion, and these reactions could be managed by premedication or infusion rate adjustments. Consequently, careful clinical monitoring is mandatory for these patients. The measurement of the peripheral CD19 cell count seems to be a crude monitoring tool, but it is not a reliable means of deciding whether to proceed with rituximab therapy. Controlled randomized trials that include adult patients with steroid-dependent MCNS are required to prove the efficacy and safety of rituximab and to evaluate the cost-effectiveness of rituximab treatment.
References
1Yokoyama H, Sugiyama H, Sato H, et al: Renal disease in the elderly and the very elderly Japanese: analysis of the Japan Renal Biopsy Registry (J-RBR). Clin Exp Nephrol 2012;16:903–920.
2Takei T, Koike M, Suzuki K, et al: The characteristics of relapse in adult-onset minimal-change nephrotic syndrome. Clin Exp Nephrol 2007;11:214–217.
3Shalhoub RJ: Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 1974;2:556–560.
4Araya C, Diaz L, Wasserfall C, et al: T regulatory cell function in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol 2009;24:1691–1698.
5Audard V, Pawlak A, Candelier M, et al: Upregulation of nuclear factor-related kappa B suggests a disorder of transcriptional regulation in minimal change nephrotic syndrome. PLoS One 2012;7:e30523.
6Takei T, Nitta K: Rituximab and minimal change nephrotic syndrome: a therapeutic option. Clin Exp Nephrol 2011;15:641–647.
7Kamei K, Ito S, Nozu K, et al: Single dose of rituximab for refractory steroid-dependent nephrotic syndrome in children. Pediatr Nephrol 2009;24:1321–1328.
8Tobinai K, Kobayashi Y, Narabayashi M, et al: Feasibility and pharmacokinetic study of a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) in relapsed B-cell lymphoma. The IDEC-C2B8 Study Group. Ann Oncol 1998;9:527–534.
9Vieira CA, Agarwal A, Book BK, et al: Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1 safety, pharmacodynamics, and pharmacokinetics. Transplantation 2004;77:542–548.
10Genberg H, Hansson A, Wernerson A, et al: Pharmacodynamics of rituximab in kidney allotransplantation. Am J Transplant 2006;6:2418–2428.
11McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16:2825–2833.
12Sidner RA, Book BK, Agarwal A, et al: In vivo human B-cell subset recovery after in vivo depletion with rituximab, anti-human CD20 monoclonal antibody. Hum Antibodies 2004;13:55–62.
13Radhakrishnan J, Cattran DC: The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines – application to the individual patient. Kidney Int 2012;82:840–856.
14Munyentwali H, Bouachi K, Audard V, et al: Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease. Kidney Int 2013;83:511–516.
15Guitard J, Hebral AL, Fakhouri F, et al: Rituximab for minimal-change nephrotic syndrome in adulthood: predictive factors for response, long-term outcomes