Low-Dose Rituximab in the Treatment of Primary Membranous Nephropathy – A Systematic Review and Meta-Analysis

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Gerry George Mathew

DOI: 10.69097/41-05-2024-04

Gerry George Mathew1, Shanmugam Sundaramurthy2, Prakash Muthuperumal3, V Jayaprakash4

1 Department of Nephrology, SRM Medical College Hospital And Research Centre, Kattankulathur, Tamil Nadu, India-603203
2 Department of Computing technologies, SRM Institute of science and Technology, Kattankulathur, Tamil Nadu, India-603203
3 School of Public Health, Division of Health Data Science, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India
4 Department of Nephrology, SRM Medical College Hospital and Research Centre, Kattankulathur, Tamil Nadu, India-603203

Corresponding author:
Gerry George Mathew
Associate Professor Department of Nephrology, SRM Medical College Hospital and Research Centre, Chennai, Tamil Nadu, India-603203
Mobile: +91-8291077361
Fax: 044-24742845
E-mail: gerrygeorge007@gmail.com

 

Abstract

Introduction. Rituximab (RTX) holds promise as a treatment for idiopathic membranous nephropathy (IMN). While effective in standard regimens, the application of RTX is hampered by cost burdens and severe side effects. To address these issues, low-dose RTX has been proposed as an intervention strategy. Yet, the efficacy of this approach in treating IMN remain subject of debate. This systematic review and meta-analysis seek to examine the effectiveness of low-dose RTX in adult patients with IMN.
Methodology. A literature search was conducted using PubMed, Wiley Online Library, ScienceDirect, Cochrane Library, Springer and other sources, published between 2004 and 2024. Specifically, articles reporting the intravenous application of RTX at doses lower than four weekly infusions of 375 mg/m² or two infusions of 1 gram each on day 0 and day 15 were considered for inclusion. The primary outcomes were complete response (CR) and partial response (PR) rates at last follow-up. Secondary endpoints included serum creatinine levels, serum albumin levels, 24-hour proteinuria levels, protein-creatinine ratio (PCR), estimated glomerular filtration rate (eGFR) and anti-PLA2R antibody levels.
Results. Sixteen articles were included in this meta-analysis. The pooled analysis of odds ratios (OR) revealed that both main-line (OR = 0.48, 95% CI = 0.30-0.75, p = 0.001) and second-line (OR = 0.27, 95% CI = 0.11-0.67, p = 0.005) RTX treatments induced complete remission (CR) in IMN patients. At the last follow-up, patients treated with both main-line (mean difference [MD] = 1.45, 95% CI = 1.00-1.91, p < 0.00001) and second-line (MD = 0.88, 95% CI = 0.23-1.53, p < 0.00001) RTX treatments showed a significant increase in serum albumin levels. Conversely, in the analysed second line RTX therapy patients, low eGFR trend was noted in the post treatment arm compared to baseline levels (MD = 10.57, 95% CI = 0.30-20.83, p = 0.04). Moreover, RTX was found to be effective in reducing PCR (MD = 24.10, 95% CI= 1.07 to 47.13, p = 0.04) and depleting PLA2R antibody levels (MD = 127.36, 95% CI = 14.90-239.81, P = 0.03). However, RTX might be less effective in lowering proteinuria and serum creatinine levels in patients with nephrotic syndrome. Conclusion. Rituximab in a low-dose regimen is quite effective in treating adult patients with IMN. Therefore, it can be considered a promising treatment for both main-line and rescue therapy. More randomized controlled trials and research on optimizing the low-dose regimen, based on various health factors, are warranted.

Keywords: Low-dose rituximab, primary membranous nephropathy, systematic review, proteinuria, creatinine

Introduction

Membranous nephropathy (MN) is an immune-mediated disorder that negatively affects the kidney glomerulus of humans [1]. Approximately 80% of MN occurs due to unidentifiable reasons, termed as either primary MN (PMN) or idiopathic MN (IMN) [2]. In the remaining 20% of individuals, MN develops secondarily due to various clinical conditions, such as bacterial or viral infections (hepatitis B and C, syphilis), malignancies, drug toxicities (penicillamine, gold salts) and other rheumatological or immunological diseases (rheumatoid arthritis, systemic lupus erythematosus) [3]. Annual prevalence rates vary globally, with higher incidences reported in North America and Europe [4], indicating greater tendencies among Caucasians followed by Asians, Blacks and Hispanics [5]. Although membranous glomerulopathy can affect individuals of any age, it predominantly manifests in adults than in children [6], with the average age occurring between 50 and 60 years [7]. Studies suggest a male preponderance in IMN cases, with a male-to-female ratio of 2:1, though the underlying reasons remain elusive [8].

PMN is characterized by B-cell abnormalities and the accumulation of immune complexes along the glomerular capillary walls, leading to membranous thickening [4, 9]. Several potential immunological mechanisms proposed include entrapment of preformed immune complexes in the subepithelial space, localization or implantation of circulating antigens in the subepithelial sites and binding of autoantibodies to podocyte membrane antigens (leading to the subepithelial deposition of immune complexes) [10]. Immune deposits consist of several components, including the immunoglobulin G (IgG) subclass of antigens and the membrane attack complex (MAC) formed from the complement components to create C5b–9 [11]. Figure 1 elaborates the treatment targets and immunological mechanisms in primary membranous nephropathy.

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