In this study, we focused on adult patients with nephrotic syndrome treated with rituximab. We analyzed the correlation between serum IgM levels and treatment efficacy in these patients, and further examined the factors influencing complete clinical remission in patients with membranous nephropathy and minimal change disease treated with rituximab based on serum IgM levels. We discovered that patients with lower levels of serum IgM often had less favorable baseline characteristics, such as being older, having higher levels of 24-hour urinary protein, or lower glomerular filtration rates (eGFR). In this study, patients with nephrotic syndrome were primarily those with Membranous Nephropathy (MN) and Minimal Change Disease (MCD), totaling 45 cases (66.18%) and 23 cases (33.82%), respectively. Among these, 8 MN patients (17.8%) and 15 MCD patients (65.2%) experienced complete remission. There was a positive correlation between serum IgM levels and the complete remission of adult nephrotic syndrome patients treated with Rituximab (P < 0.005). This relationship remained significant in a Cox regression model adjusted for demographic factors, hemoglobin, serum albumin, eGFR, and urine protein quantification (P < 0.05).
Numerous clinical studies have previously indicated a correlation between the levels of serum IgM and the outcomes of kidney diseases. Research conducted in Japan on children with NS revealed that high levels of serum IgM are indicative of a positive response to initial steroid treatment compared to lower levels. Additionally, low serum IgM levels might also reflect the low selectivity of urinary proteins and the severity of glomerular damage [12]. Through logistic regression analysis, Xing Ming xu et al found that compared to high levels of serum IgM (> 0.81g/L), low levels of serum IgM are associated with the severity of kidney disease. Moreover, it is a risk factor for poor renal prognosis in patients with IgA nephropathy, meaning the lower the level of serum IgM, the worse the renal prognosis for the patient [13]. Similarly, Zhang Huiya's research on IgA nephropathy also concluded that lower IgM levels are an independent risk factor for the progression of IgA nephropathy patients to end-stage kidney disease [14]. Scholars like Vasj have suggested that higher levels of IgM can alleviate the progression of lupus and kidney diseases. This is attributed to IgM's ability to inhibit the pro-inflammatory effects of lupus-related RNA IgG immune complexes [15]. Further studies in the MRL/Ipr mouse experimental model have also shown that IgM antibodies can reduce lupus and glomerulonephritis in mice, and can delay the onset of the disease [16, 17]. However, some studies have reported conflicting results. A report from Egypt, following nephrotic syndrome patients for a year, discovered that the levels of serum IgG and IgM at initial diagnosis were significantly correlated with treatment response and relapse rates [18]. Yet, upon further observation, it was found that a higher IgG/IgM ratio indicated a better response to corticosteroids, while a lower ratio suggested a poorer response to the treatment. Research by Manuela and others has shown that the presence of certain atypical types of IgM (T-cell surface IgM) may lead to poor response to hormone therapy in some children with primary nephrotic syndrome (PNS) who are hormone-sensitive. Additionally, patients with high serum IgM levels have a significantly increased risk of disease relapse [19].
Most studies have primarily focused on the reactivity and recurrence of nephrotic syndrome patients to corticosteroid treatment in relation to serum IgM levels. However, there is a scarcity of research on the effectiveness of Rituximab treatment in nephrotic syndrome (NS) patients and the factors influencing its efficacy. Therefore, we conducted this study. Moreover, while the majority of these studies target children with nephrotic syndrome, our research focuses on adults. Current studies have shown that serum IgM levels can be used as a potential predictive marker to measure the efficacy and prognosis of patients with renal diseases treated with rituximab [20]. Moreover, the role of IgM is not only limited to kidney diseases, but also has important predictive value in systemic lupus erythematosus [21], rheumatoid arthritis [22], Waldenstrom macroglobulinemia [23], atherosclerosis [24], severe infection [25] and other systemic diseases. The results of this study are consistent with the results of previous studies [26]. Currently, it is unclear whether there is a correlation between serum IgM levels and kidney IgM deposits. Previous studies have reported a positive correlation between serum IgM levels and kidney IgM deposits. Moreover, patients with IgM deposits tend to have a higher incidence of refractory nephrotic syndrome and are more prone to renal dysfunction [27]. Unfortunately, this study did not collect data related to glomerular IgM deposits in patients, which will be a direction for our future research.
IgM serves as the first line of defense in organisms and plays a crucial role in the primary immune response. It is secreted by B cells in a pentameric form and can be categorized into natural IgM and antigen-induced IgM [28, 29]. The majority of IgM in circulation is composed of natural IgM antibodies [30], which are vital for maintaining tissue homeostasis [31], preventing infectious [32, 33] and autoimmune diseases [34], and identifying and eliminating precancerous and cancer cells[35]. In patients with nephrotic syndrome, an increase in serum IgM levels and a decrease in serum IgG levels are primarily due to the dysfunction of T lymphocytes [36]. Under normal circumstances, when the human body is attacked by antigens, it may enhance the somatic mutation that increases the affinity of the Fab region for the antigen, leading to the conversion of IgM into IgG or other types of antibodies [37]. However, patients with nephrotic syndrome exhibit abnormalities in serum immunoglobulin levels primarily due to T lymphocyte dysfunction, which prevents the conversion of IgM to IgG. This dysfunction also leads to abnormalities in the number of T lymphocytes, potentially affecting the efficacy of rituximab treatment [38]. Chen et al.[39] proposed that an increase in suppressive T cell activity also results in elevated serum IgM levels and reduced IgG production in children with nephrotic syndrome. Nonetheless, the specific mechanisms require validation through more effective clinical trial data.
Rituximab (RTX) is a human-mouse chimeric anti-CD20 monoclonal antibody, which has been widely used in hematological malignancies and autoimmune diseases, including nephrotic syndrome, rheumatoid arthritis, systemic lupus erythematosus and autoimmune cytopenia [40]. It can specifically react with CD20 antigen expressed on more than 95% of normal and malignant B cells, inducing complement-mediated and antibody-dependent cytotoxicity, thereby maintaining steroid-dependent/frequently relapsing NS. SDNS/FRNS) and alleviated the effects of proteinuria[41]. It is well-known that the effectiveness of Rituximab varies significantly across different primary glomerular diseases, ages, and kidney functions in treating NS. Our study found that in patients with MCD, the level of serum IgM plays a significant role in influencing the clinical complete remission in adult NS patients undergoing Rituximab treatment. There is a positive correlation between serum IgM levels and the occurrence of complete remission (p < 0.05), and this trend is also significant (p < 0.05). To this end, we further compared the prognostic relationship of serum IgM levels in patients with MN and MCD undergoing RTX treatment for adult NS. We found that before adjusting for any confounding factors, there was a positive correlation between serum IgM levels in patients with nephrotic syndrome and complete remission of NS (p < 0.05). After adjusting for demographic factors, hemoglobin, serum albumin, eGFR, and urinary protein quantification, serum IgM levels were positively correlated with complete remission in MCD (p < 0.05). However, in MN, patients with lower serum IgM levels had a higher likelihood of complete remission.
Therefore, it can be concluded that the mechanisms by which serum IgM levels play a role differ between MN and MCD, resulting in different kidney prognosis for patients. Reports indicate that 70–80% of MN patients experience an autoimmune reaction caused by circulating anti-PLA2R on podocytes [42]. A decline or disappearance of anti-PLA2R antibodies is a precursor to a significant clinical improvement, whereas an increase in anti-PLA2R indicates a worsening or prolongation of MN's clinical course [43, 44]. Therefore, Anti-PLA2R is a risk factor affecting the prognosis of MN patients, which aligns with the findings of our study [45]. There is a positive correlation between serum IgM and anti-PLA2R, meaning the higher the level of serum IgM, the lower the likelihood of achieving complete remission in MN patients treated with Rituximab.In clinical work, the majority of MN patients are middle-aged and elderly, up to 58% in adults over 65 years old [46]. The prognosis of membranous nephropathy is relatively poor with older age, which is consistent with the results of this study that the complete remission rate of MCD patients was significantly better than that of MN patients (P < 0.001). It may be due to the decline of physiological renal function, more underlying diseases, more contraindications to treatment and poor absorption of therapeutic drugs in elderly patients.
This study has several significant limitations. Firstly, due to the absence of follow-up data on serum IgM levels, we couldn't confirm the changes in serum IgM during the follow-up period and its correlation with relapse. Secondly, as a retrospective study, the combination or dosage of different therapeutic drugs might affect serum IgM levels and the clinical efficacy of nephrotic syndrome, and this study did not eliminate the interference of drug factors. Thirdly, being a single-center study with a limited number of cases from a single source, and focusing solely from a clinical perspective, the mechanism by which serum IgM is involved in nephrotic syndrome remains uncertain. However, the study's strengths are also noteworthy. Most current literature focuses on the efficacy comparison of glucocorticoids, cytotoxic drugs, or immunosuppressants in NS patients, while our study exclusively targets patients treated with Rituximab alone and further observes the correlations affecting its efficacy. This has significant implications for determining treatment strategies with Rituximab in clinical practice. Future research should consider these factors comprehensively, increase sample sizes, extend follow-up periods, and exclude drug interference factors to clarify the relationship between serum IgM levels and the efficacy of Rituximab in treating nephrotic syndrome, thereby guiding clinical diagnosis and treatment.