Recent Advances in the Pathogenesis and Treatment of Kidney Diseases. Группа авторов

up to 50% of MCNS patients frequently relapse, requiring additional treatment with immunosuppressive agents. Frequent relapses may need prolonged treatment with 2 or more immunosuppressive drugs, with the result that these patients develop steroid-dependent nephrotic syndrome as adults [2]. Most cases of MCNS are idiopathic and not directly associated with an underlying disease in adults.

The pathophysiology of MCNS remains poorly understood. Shalhoub proposed that the cause of MCNS is a T cell-secreted circulating factor that damages the glomerular basement membrane [3]. Although this circulating factor has not been identified, a recent study highlights a role of immune dysregulation in MCNS. T-regulatory cells, which attenuate immune response by suppression of T-effector cells, are dysfunctional in humans with MCNS [4]. In contrast to the well-established involvement of T-cells in MCNS, the role of B cells is uncertain. Recently, it was shown that nuclear factor-related kappa B is upregulated during the relapse of MCNS, mainly in CD4+ T cells and B cells, and this induces the activation of AP1 signaling [5]. B-cell biology, however, has attained more attention lately, since treatment with rituximab, a monoclonal antibody directed against CD20 bearing cells, has shown good therapeutic responses in the treatment of MCNS.

      Mechanism of Rituximab Action

CD20 is a hydrophobic transmembrane protein, with a molecular weight of approximately 35 kD, located on pre-B and mature B cells, and is not found on other cell types or free in the circulation [6]. CD20 regulates an early step in the activation process for cell cycle initiation and differentiation and possibly functions as a calcium ion channel. Rituximab is a chimeric murine/human monoclonal immunoglobulin G1 antibody that targets CD20, which is a B-cell differentiation marker.

As shown in Figure 1, 3 different mechanisms have been proposed for the elimination of B cells by rituximab, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and stimulation of the apoptotic pathway. Complement-dependent cytotoxicity is most likely the dominant mechanism in vivo. Rituximab improved abnormalities in B-cell homeostasis, with a decreased proportion of autoreactive memory B cells and reconstitution of the B-cell lineage. Therefore, the rituximab-induced depletion of memory B cells may also prevent the activation of autoreactive T cells through interactions with B cells, resulting in the down-regulation of CD40L on CD4-positive T cells and implying that rituximab may improve the disease course by resetting the immune response (Fig. 2).

Fig. 1. Schematic illustration of the mechanism of rituximab action.

Fig. 2. Rituximab reduces memory B cells and induces the reconstitution of the B-cell lineage, leading to clinical efficacy in inflammatory autoimmune diseases.

      Pharmacokinetics of Rituximab Infusion

Rituximab is composed of 2 heavy chains of 451 amino acids and 2 light chains of 213 amino acids, with a molecular weight of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM. The mean serum half-life of rituximab was reported to be 10–15 days in patients with steroid-dependent nephrotic syndrome [7]. In a single-dose study in subjects with renal failure, the substantial half-life was found to range from 10 to 14 days [8]. In a small, single-dose, dose-escalation study, 50 mg/m² resulted in the same degree and duration of peripheral B-cell suppression and the same effect on the antibody response as 375 mg/m²[9].

In human disease states for which rituximab is administered, circulating B cells are rapidly eliminated. Some preliminary data suggest that a single dose of rituximab can deplete tissue CD20-positive cells in transplant recipients [10]. B-cell recovery begins at approximately 6 months following the completion of treatment [11]. The median B-cell levels return to normal by 12 months after the completion of treatment. Even once the total B-cell count returns to normal, a change in phenotype appears to occur, with the B cells present being relatively deficient in the expression of CD27, a surface marker of memory B cells [12]. This finding suggests that the B cells that do repopulate are primarily naïve, at least as late as 2 years after a single dose.

      Single-Dose Rituximab Therapy for Steroid-Dependent MCNS

Kidney Disease Improving Global Outcomes guidelines recommended the usage of steroids to induce remission in adults with MCNS [13]. However, the evidence for this comes from small randomized controlled trials (RCTs) and observational studies in adults. The recommended dosage of steroids is 1 mg/kg/day for 4–16 weeks, tapered slowly over 6 months. For patients with frequent relapses and steroid resistance, Kidney Disease Improving Global Outcomes guidelines suggest alkylating agents (oral cyclophosphamide 2–2.5 mg/kg/day for 8 weeks). If there are contraindications for alkylating agents, calcineurin inhibitors could be used.

In adults, 2 retrospective analyses described patients with steroid-dependent or frequently relapsing MCNS despite immunosuppressive therapy treated with rituximab [14, 15]. Both case series found an increase in remission in about 60% of patients. We have shown that the first prospective cohort study compared rituximab treatment in 25 patients with steroid-dependent and frequently relapsing MCNS to historical controls and confirmed reduction of relapses in adults with MCNS [16]. As shown in Figure 3, a single dose of rituximab (375 mg/m²; max 500 mg) was administered 4 times every 6 months. For the first 6 months from the first dose of rituximab, the dosage of steroid and immunosuppressants were reduced each month and stopped. Rules for dose reduction of immunosuppressants: steroid reduction by 10 mg every month to discontinuation followed by cyclosporine reduction and discontinuation or Mizoribine reduction and discontinuation. This order can be changed according to the onset of adverse drug effects. A significant reduction in the number of relapses and the total dose and the maintenance dose of steroids administered was observed during the 12-month period after the first rituximab infusion. Complete remission was achieved in all patients undergoing B-cell depletion. A follow-up study to this prospective cohort study showed 8 relapses in 24 months after complete remission compared to 108 episodes in 24 months before rituximab [17]. However, complete remission was maintained in all 20 patients in the rituximab continuation group during the 12-month observation period after the first 4 rituximab infusions. Thus, rituximab may be considered as a radical therapeutic agent for adult patients with MCNS. No RCTs in adults have been conducted comparing rituximab treatment in either frequently relapsing or steroid-dependent patients or as a first-line therapy of MCNS.