Immunosuppressive Agent Options for Primary Nephrotic Syndrome: A Review of Network Meta-Analyses and Cost-Effectiveness Analysis

Abstract

Therapeutic options with immunosuppressive agents for glomerular diseases have widened with refinements to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines from 2012 to 2021. However, international guidelines do not necessarily match the reality in each country. Expensive therapies such as rituximab and calcineurin inhibitors are sometimes inaccessible to patients with refractory nephrotic syndrome due to cost or regulations. Under the Japanese medical insurance system, rituximab is accessible but still limited to steroid-dependent patients who developed idiopathic nephrotic syndrome in childhood. Based on international KDIGO guidelines and other national guidelines, possible applications of immunosuppressive agents for nephrotic syndrome are comprehensively examined in this review. While rituximab has become the mainstay of immunosuppressive therapy for nephrotic syndrome, clinical trials have indicated that options such as cyclophosphamide, calcineurin inhibitors, and mycophenolate mofetil would be preferable. Given the rising number of patients with nephrotic syndrome worldwide, KDIGO guidelines mention the need for further consideration of cost-effectiveness. If the new option of rituximab is to be the first choice in combination with steroids for nephrotic syndrome, its cost-effectiveness should also be verified. Among the few studies examining the cost-effectiveness of treatments for nephrotic syndrome, administration of rituximab to young adults has been shown to be cost-beneficial, at least in Japan. However, further large-scale studies involving multiple facilities are needed to verify such findings. Network meta-analyses have concluded that the efficacy of rituximab remains controversial and confirmation through high-quality studies of large cohorts is needed. To this end, the mechanisms of action underlying immunosuppressive agents, both old and new, need to be understood and experience must be accumulated to evaluate possible effects and side effects.

Immunosuppression for adult steroid-dependent or frequently relapsing nephrotic syndrome: A systematic review and meta-analysis

“…Further studies on adverse effects secondary to the immunosuppressive agents and not disease progression is also necessary to identify the safety profile of immunosuppressive agents used. Only then can the treatment risk be appropriately weighed against the likely benefits according to individual patient factors and drug exposures [ 20 ], including comorbid conditions, age, immunological complications and risk of malignancy.…”

“…With the introduction of immunosuppressants, multiple studies evaluating the efficacy of one agent over the other were established. The use of rituximab for steroid-dependent nephrotic syndrome is increasing, while alternatives such as cyclophosphamide, calcineurin inhibitors, and mycophenolate mofetil have also been recommended as the preferred medications in different clinical trials [ 20 ]. For patients with SDNS/FRNS, a network meta-analysis for children suggests that cyclophosphamide may be preferred initially while chlorambucil and rituximab may be acceptable medications [ 21 ].…”

Proteomic Analysis of Idiopathic Nephrotic Syndrome Triggered by Primary Podocytopathies in Adults: Regulatory Mechanisms and Diagnostic Implications

“…The incidence of NS varies from 0.6 to 1.2 cases per 100,000 adults. 2 Steroids are routinely used for treating NS but with limited success in adult patients. Furthermore, steroid-resistant NS is emerging, usually progressing to end-stage renal disease/renal failure within 5− 10 years.…”

“…Clinically, NS is characterized by heavy proteinuria and hypoalbuminemia, along with edema and hyperlipidemia. The incidence of NS varies from 0.6 to 1.2 cases per 100,000 adults . Steroids are routinely used for treating NS but with limited success in adult patients.…”