Systemic lupus erythematosus (SLE) is a typical autoimmune disease that affects multiple organs, particularly prevalent in women of childbearing age. Its clinical manifestations are diverse and can involve various organs and systems, including the kidneys, skin, and joints. Lupus nephritis (LN) is one of the most severe target organ damages in SLE, and it is also a major cause of poor prognosis in SLE patients, leading to end-stage renal disease (ESRD). Despite the gradual standardization of LN diagnosis and treatment with the introduction of LN guidelines in recent years, a portion of patients still experience disease progression. Within 10 years of the initial diagnosis of SLE, 5-20% of LN patients will progress to ESRD. Additionally, since 2000, the proportion of LN patients requiring renal replacement therapy has remained unchanged, and studies have shown an increasing trend in the proportion of LN patients requiring such therapy in recent years (1, 2). Currently, the diagnosis and treatment of LN remain challenging. The assessment of the degree of LN damage still relies on kidney biopsy; however, due to its invasive nature and potential complications (such as bleeding, infection, and perinephric hematoma), it is difficult to perform frequently during the treatment process. Therefore, relying solely on kidney biopsy to dynamically assess disease progression and treatment outcomes has certain limitations. To overcome these challenges, there is an urgent need to develop reliable, non-invasive biomarkers.

Lymphocyte-related parameters, including the platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), and monocyte to lymphocyte ratio (MLR), have been confirmed in recent years as important novel indicators for several inflammatory diseases. In addition to serving as diagnostic tools, these lymphocyte-related ratios (PLR, NLR, MLR) also have significant value in the prognosis assessment of various diseases. Studies have shown that they can help predict disease progression and patient survival rates, including in coronary artery disease, various solid tumors, and rheumatoid arthritis (3–5). Apart from some systemic diseases, recent studies have also reported the association of PLR, NLR, and MLR with the phenotype and prognosis of kidney diseases, including chronic kidney disease, acute kidney injury, and rapidly progressive glomerulonephritis (6–8). However, previous studies have shown controversial results regarding the predictive value of PLR, NLR, and MLR for prognosis in LN patients, and more research is needed for confirmation. Therefore, the aim of this study is to evaluate the levels of PLR, NLR, and MLR in lupus nephritis patients and explore their relationship with renal prognosis in lupus nephritis.

Our results show that compared with the healthy control group, LN patients had significantly higher levels of PLR, NLR, and MLR (P < 0.05). Kaplan-Meier curves, without considering covariates, revealed that PLR, NLR, and MLR were closely associated with renal outcomes in LN patients (P < 0.05), suggesting that they may serve as potential predictive factors. ROC curve analysis further indicated that NLR and MLR had better predictive ability than PLR, with NLR and MLR showing similar predictive value. After adjusting for general data, laboratory tests, and renal pathology characteristics in multivariate Cox regression analysis, MLR was found to be a better marker for predicting poor renal outcomes than PLR and NLR, indicating that MLR is the only lymphocyte-related parameter that can serve as an independent risk factor.

Platelet activation is triggered by both innate and adaptive immune stimuli. Once activated, platelets release immune-active molecules and interact with immune cells, promoting inflammation and thrombosis, which leads to organ damage in SLE (13). Experimental studies show that anti-platelet aggregation treatment reduces renal inflammation, complement deposition, anti-cardiolipin antibody levels, and thromboxane B2 levels in MRL/lpr mice, suggesting that platelet activation plays a pathogenic role in LN (14). A cross-sectional study from the United States further confirmed this hypothesis. In SLE, circulating immune complexes activate complement, and the generated complement cleavage products can bind to platelets to form PC4d. They found that PC4d is a biomarker of increased platelet activity (15). Additionally, platelets can shed membrane vesicles, known as microparticles or microvesicles, which carry and spread mitochondrial antigens, complement activation products, and other molecules, playing a role in forming immune complexes and mediating immune damage (16). Finally, platelets and their exosomes are the main source of TGF-β in circulation. Platelets and their exosomes promote renal interstitial fibrosis by releasing TGF-β, thereby exacerbating kidney damage (17). Several studies in adolescent SLE patients have demonstrated that those with elevated PLR are more prone to coagulation abnormalities and cutaneous rash (18). These findings suggest that PLR may serve as a predictive biomarker for both SLE disease activity and rash manifestation. Currently, there is no research proving the association between PLR and renal prognosis in LN patients.

The presence of neutrophil infiltration in renal biopsy specimens suggests that inflammatory peptides and cytokines derived from circulating neutrophils may be involved in the pathogenesis of LN. Dysregulated neutrophil activation plays an important role in the onset and progression of SLE, where impaired apoptosis and NET formation expose proteins and DNA with post-translational modifications, triggering adaptive immune responses (such as interferon release and antibody production), and causing tissue damage either directly or by activating adjacent cells (19). NETs, composed of nuclear and granular components released from activated neutrophil membranes, play a key role in the balance between NET production and clearance in SLE and other autoimmune diseases. Studies show that impaired NET clearance is associated with disease activity in SLE patients. Notably, patients with reduced NET clearance have lower levels of circulating complement components C3 and C4 (20). In SLE, dysregulated apoptosis of neutrophils leads to an increased apoptotic load, which is associated with the production of antinuclear autoantibodies (19). Regarding the relationship between NLR and renal prognosis in LN patients, our study suggests that NLR has some predictive value for poor renal outcomes, but NLR does not appear to be an independent risk factor for renal prognosis. Zhou et al. reported similar findings, where their univariate Cox regression analysis indicated that NLR was a risk factor for renal prognosis in LN patients, but after adjusting for general data and laboratory results, NLR was not an independent risk factor for renal prognosis in LN patients (21). However, Chen et al. obtained different results. They included 122 LN patients and divided them into low, medium, and high NLR groups. They combined the medium and low groups in multivariate Cox regression and found that high NLR levels were an independent risk factor for poor prognosis in LN patients (22). The inconsistency in these results may be due to geographic variations in the samples included and the small sample size, or it may be related to their failure to exclude the effects of glucocorticoids and immunosuppressants.

Lymphocytes are closely associated with adaptive immunity. Lymphopenia, a common complication in SLE, is linked to multiple factors including lymphocytotoxic antibodies, excessive apoptosis, increased susceptibility to complement-mediated lysis, and suppressed lymphopoiesis. Notably, lymphopenia correlates with disease activity and elevated risk of organ damage (23). As early as 2019, a study from Denmark found that lymphopenia was an independent risk factor for the first onset of proteinuria in SLE patients (24). The study found that compared with healthy controls, LN patients had significantly reduced lymphocyte counts, mainly affecting the CD4 cell subset. Renal pathology classification in LN patients was mainly associated with changes in CD4 lymphocytes, with peripheral CD4 cell reduction observed in patients with active and proliferative lesions (25). Additionally, Abraham et al. found that a higher density of B cells at the time of renal biopsy was associated with lower chronic renal tubulointerstitial inflammation scores and better prognosis, suggesting that B cells may have a previously unrecognized protective role in the kidneys (26). Recently, several studies focused on LN microenvironment and used single-cell RNA-seq technique to reveal the role of MLR in LN progression. Chemokine receptors CXCR4 and CX3CR1 were broadly expressed in LN kidney, indicating the potential therapy target of LN on cell trafficking (27). Chen et al. observed the enrichment of CD163 dendritic cells (DC3s) in LN kidneys, which exhibited a positive correlation with the severity of LN. The crosstalk involving DC3s, T cells and tubular epithelial cells within LN kidneys may play a significant role in elucidating disease progression mechanisms and could provide potential therapeutic targets for clinical intervention (28). Single cell sequencing analysis also revealed the overactivation of granzyme K CD8 T cells in the kidney of patients with LN and associated extrafollicular B cell response, which may suggest a potential new intervention target for LN. Lymphopenia seems to be not only a laboratory result of disease activity in SLE patients, but also possibly related to renal involvement in SLE patients. This study found that MLR is an independent risk factor for poor renal prognosis in LN patients. The high MLR group showed higher mean arterial pressure and lower eGFR. In terms of renal pathology, the high MLR group had significantly higher AI and CI indices, and the incidence of capillary endothelial cell proliferation, cellular crescent/fibrocellular crescent formation, and interstitial inflammatory cell infiltration was significantly higher than in the low MLR group. One study found that in SLE patients, MLR was positively correlated with C-reactive protein and negatively correlated with IgM (29). Additionally, Liu et al. reported that compared with healthy controls, MLR levels were significantly increased in LN patients without infection (30), which is consistent with our results. However, to our knowledge, there is currently no research on the relationship between MLR and renal prognosis in LN patients, which is a key difference between our study and previous research. A retrospective study showed that for end-stage kidney disease patients requiring renal replacement therapy for 6 months, MLR at admission had strong predictive ability for all-cause 30-day mortality. Elevated MLR was also associated with longer hospital stays and more dialysis sessions per patient (31). Similar results were found in studies of acute kidney injury patients, where higher baseline MLR was identified as an independent risk factor for predicting 30-day and 90-day mortality. Early increases in MLR were associated with higher 30-day mortality (32). Furthermore, Zhang et al. reported the predictive value of MLR in primary membranous nephropathy, finding that higher MLR was associated with poor renal outcomes (33). Therefore, MLR may be a new tool for predicting poor renal outcomes, and larger-scale studies are needed to confirm our hypothesis.

In type II and IV LN, immune complex deposition in capillaries has been observed, and monocytes expressing FcγRIII (also known as CD16) are considered to be associated with the pathogenesis of this disease. In type IV LN, CD16+ monocytes are found at the sites of capillary immune complex deposition, which is related to the expression of the endothelial cell CX3C chemokine ligand 1 (CX3CL1), which may promote the aggregation of these monocytes, suggesting an important role of monocytes in the pathogenesis of LN (34). Macrophages, derived from monocytes, have shown heterogeneity, with both pro-inflammatory and anti-inflammatory functions. In lupus nephritis, these two functions are imbalanced, leading to chronic inflammation, fibrosis, and renal dysfunction. Monocytes mediate varying immune responses through circulating immune complexes and release proinflammatory mediators, triggering microvascular endothelial injury and increased permeability. This pathogenic cascade accelerates the development of SLE complications, particularly lupus nephritis (35). Therefore, targeted macrophage therapy is a potential new treatment approach for LN (36).

The innovation of this study lies in two aspects: First, PLR, NLR, and MLR can be calculated from routine blood cell counts, offering lower cost and easier accessibility compared to other biomarkers predicting disease activity and prognosis in LN patients. Second, considering these hematological parameters are susceptible to various medications and physicochemical factors, this study—unlike others—excluded patients who had received glucocorticoid or other immunosuppressive treatments within three months prior to renal biopsy. This research also has several potential limitations. Firstly, as a single-center retrospective study with an insufficient sample size, future investigations should adopt multicenter prospective designs with larger cohorts for statistical evaluation and validation. Secondly, although we excluded interference from glucocorticoids and immunosuppressants, PLR, NLR, and MLR may still be influenced by other drugs and physicochemical factors, potentially introducing bias. Finally, data of absolute values for macrophages and long-term follow-up with survival data collection remains necessary to further elucidate the relationship between MLR and LN prognosis.

In conclusion, we have discussed the pathogenic roles of lymphocytes, platelets, neutrophils, and monocytes in LN. However, the increase in PLR, NLR, and MLR does not necessarily reflect an absolute increase in platelet, neutrophil, and monocyte counts, or an absolute decrease in lymphocyte counts. In fact, in SLE patients, the incidence of thrombocytopenia, neutropenia, and lymphopenia is 10-40%, 20-40%, and 15-82%, respectively (37, 38). Although the pathogenesis of lupus nephritis is still not fully understood, current research suggests that autoimmune inflammatory responses are an important pathophysiological mechanism for multi-organ and tissue damage, particularly kidney injury. PLR, NLR, and MLR reflect the ratios of platelets, neutrophils, monocytes to lymphocytes, and as a combination of these cell counts, they have lower sensitivity to physical, biochemical, or physiological factors compared to individual indicators, making them more valuable in predicting inflammation. Therefore, they were selected as testing indicators in our study. However, further studies are needed to clarify whether the ratio between specific cell types provides higher diagnostic accuracy for LN than individual cell populations.