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

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      Yuko Iwabuchi · Takahito Moriyama · Mitsuyo Itabashi · Takashi Takei · Kosaku Nitta

      Department of Medicine, Kidney Center, Tokyo Women’s Medical University, Tokyo, Japan

      ______________________

      Abstract

      Minimal change nephrotic syndrome (MCNS) usually responds to steroids but frequently relapses, requiring additional treatment with immunosuppressive agents. Rituximab is a chimeric murine/human monoclonal immunoglobulin G1 antibody that targets CD20, a B-cell differentiation marker. B-cell recovery begins at approximately 6 months following the completion of treatment. Rituximab has a beneficial effect, with the sustained remission or reduction of proteinuria in patients with steroid-dependent MCNS. Relapses are thought to be associated with an increase in CD19 cells. The mean serum half-life of rituximab was reported to be 10–15 days in patients with steroid-dependent MCNS. Only infusion reactions, such as rash and chills, occurred after single-dose rituximab infusion and can be managed by pre-medication or infusion rate adjustments. Even though severe adverse effects of rituximab are not expected, we must be aware of potentially life-threatening adverse effects. 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. In this review, we highlight recent studies and discuss the effects of these studies on the management of patients with MCNS in adults.

      © 2018 S. Karger AG, Basel

Minimal change nephrotic syndrome (MCNS) accounts for 12.6% of all cases of primary adult nephrotic syndrome in Japan [1]. MCNS usually responds to glucocorticoids (steroids), and the long-term prognosis is generally good. However, 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 СКАЧАТЬ