Systemic lupus erythematosus (SLE) is a systemic, autoimmune, inflammatory disease that involves multiple organs and predominantly occurs in reproductive-aged women, with a female-to-male ratio of approximately 9:1 (1). The incidence of SLE varies substantially across regions, with estimates ranging from 3.7 to 49.0 per 100,000 person-years in North America, 1.5 to 7.4 in Europe, 1.4 to 6.3 in South America, and 2.8 to 8.6 in Asia (2). Evidence suggests that genetic predisposition, ultraviolet exposure, high estrogen levels, and infections are implicated in the pathogenesis of SLE. It has been reported that nearly 40% of SLE patients progress to lupus nephritis with clinical manifestations such as hematuria, pyuria, proteinuria, and hypoalbuminemia, and 10%-20% of patients eventually develop end-stage renal disease or die (3). The mechanism of renal injury in SLE patients remains unclear and involves various factors such as genetics, environment, and drugs. Exposure to autoantigens activates B cells to produce large amounts of autoantibodies, and antibody deposition in the kidney is an important cause of renal injury (4, 5).

Anti-phospholipid antibodies (aPL) are autoantibodies targeting an array of negatively charged phospholipids, phospholipid-binding proteins, and their complexes (6). The primary aPL profiles utilized in clinical practice encompass anti-β2-glycoprotein I (aβ2GPI) IgG/IgM antibodies, anti-cardiolipin (aCL) IgG/IgM antibodies, and lupus anticoagulant (LA) (7). The aPL are shown to be related to thrombocytopenia, hemolytic anemia, arteriovenous thrombosis, neuropsychiatric symptoms, and recurrent miscarriages in SLE patients (8–10). In addition to the conventional aPL, SLE patients possess a broad spectrum of non-criteria aPL, such as anti-phosphatidylserine antibodies (aPS), anti-prothrombin antibodies (aPT), and their complex-targeting antibodies (aPS/PT), which also play significant roles in organ damage. Several studies have confirmed that autoantibodies secreted by B cells-not only IgG and IgM but also IgA isotype modulate the progression of SLE through distinct mechanisms (11).

However, a clear consensus is lacking regarding the precise contribution of aPL to SLE-associated renal injury. Some studies have shown a correlation between aPL and renal thrombotic microangiopathy, renal infarction, and chronic renal insufficiency, whereas others have not observed any significant associations (12, 13). The aPL mainly exert their prothrombotic effects by binding to or cross-linking various hemostatic and fibrinolytic proteins (such as plasmin, thrombin), as well as coagulation factor X, thereby disrupting the dynamic balance between coagulation and fibrinolysis and promoting thrombosis. The resulting thrombotic events lead to chronic ischemic and hypoxic injury of nephrons and ultimately impair renal function (14). By binding to phospholipids on the cell membrane, aPL activate endothelial cells, upregulate adhesion molecules, recruit infiltrating neutrophils and macrophages, and stimulate the release of pro−inflammatory cytokines, thus triggering local inflammation (15). In addition, aPL can disrupt the glomerular charge barrier, enhance oxidative stress in podocytes, and promote foot process effacement, thereby damaging the glomerular filtration barrier (16). These mechanisms collectively contribute to renal injury in SLE. In the present study, we systematically retrieved all relevant clinical studies and performed a meta-analysis to quantitatively investigate the association between aPL and the risk of renal injury in SLE.

To elucidate the association between aPL profiles and renal injury in SLE, this meta-analysis evaluated 70 studies involving 12,456 patients. The results collectively provide compelling evidence that aPL seropositivity confers a significantly increased risk of renal injury. These findings carry important implications for clinical practice, suggesting that aPL status may serve as a key indicator for renal injury risk stratification and monitoring in SLE.

Immune complex deposition, complement activation, and recruitment of pro-inflammatory cells are central mechanisms in the pathogenesis of kidney injury in SLE (89). The aPL-associated renal disease represents a heterogeneous group of conditions with various clinical manifestations (90). Vascular involvement in aPL−related renal disease may manifest as thrombosis, stenosis, or infarction. Clinically, these lesions can present with proteinuria, hematuria, hypertension, acute kidney injury, or chronic kidney disease. The mechanisms by which aPL induce renal injury in patients with SLE remain unclear. Chul-Soo Cho et al. found that aCL can stimulate endothelial cells to secrete monocyte chemoattractant protein-1, thereby recruiting monocytes (91). Additionally, aCL cross-reacts with oxidized low-density lipoprotein, promoting increased cholesterol uptake by macrophages and their transformation into foam cells, which contributes to the development of atherosclerosis (92). Shengshi Huang et al. found that aPL bind to extroverted lipids on the surface of platelets, promote platelet activation, participate in coagulation cascades, and cause thrombosis (93). As shown in one of our previous studies, aPS IgG antibodies form PS-IgG immune complexes with PS antigen which stimulate the oxidative stress in macrophages in a LOX-dependent manner, impairs phagocytic activity, and finally results in the lupus nephritis development (94). These findings collectively indicate that aPL primarily promotes nephritis pathogenesis through inducing renal vascular thrombosis and immune dysregulation.

Our findings suggest that aPL may serve as a predictive biomarker for renal injury in lupus. Renal biopsy is generally considered the standard for diagnosing and classifying types of renal injury. However, renal biopsy is an invasive procedure; it is associated with complications such as hematuria, hematoma, back pain, bleeding and fever. A number of laboratory and clinical characteristics were observed to aid in early detection of patients at high risk of developing lupus nephritis. The biomarkers used in the diagnosis process and in the prognosis prediction are: complement, autoantibodies (anti-double−stranded DNA antibodies, anti-chromatin antibodies), cytokines (monocyte chemoattractant protein-1, type I and type II interferons), genetic defects (DNA/RNA clearance, complement pathway, anti-nucleic acid sensing in interferon pathway) (95). SLE patients show immune dysfunction, loss of immune tolerance, exposure of phospholipids on the outer leaflet of the plasma membrane, and hyperactivity of B-cells, which leads to high levels of production of autoantibodies (96). The immune complex development of the antigen-antibody complexes in the kidney results in the release of complement, activation of pro-inflammatory cells, and release of pro-inflammatory cytokines, which cause renal injury (97). Multiple studies have reported that aPL positivity is a major risk factor for kidney injury in patients with SLE. Therefore, coagulation parameters and renal function should be closely monitored in aPL−positive SLE patients.

Substantial heterogeneity was observed across studies (I² > 50%), which justified the use of random−effects models. To explore the cause of this heterogeneity, subgroup analyses showed that the strength of the association between aPL and renal injury is significantly different based on region, period of publication, and type of aPL, suggesting these factors as likely contributors to the heterogeneity. Furthermore, both funnel plot and Egger’s test indicated publication bias. Notwithstanding these issues, sensitivity analysis alongside the trim-and-fill method consistently demonstrated a significant risk increase, affirming the robustness of the primary finding that aPL positivity elevates renal injury risk in SLE patients. In addition, we performed cumulative analyses by sequentially adding each new study according to publication year, sample size, and NOS score, thereby dynamically illustrating the changing trend of the research findings. The results consistently showed a gradual narrowing of the 95% CI of the OR values, suggesting the robustness of the main findings of this study.

An earlier meta-analysis conducted by Vinicius Domingues et al. with 35 studies and 3,035 SLE patients up to 2021 showed that aPL-positive patients had a 3.03-fold increased risk of renal microthrombotic lesions (18). This study conducted a comprehensive literature search up to the association between aPL and renal injury up to September 2025 to compute 70 studies that included 12,456 participants. In aPL positive and aPL negative SLE, the pooled OR of renal microvascular lesions was that 2.09 (1.70–2.58). Some studies have revealed that non-criteria aPL, such as aPS, aPT, and aPS/PT antibodies, are also involved in SLE-associated renal injury (96). The aPL that are tested clinically mainly belong to the IgG and IgM isotypes, but IgA antibodies have also been implicated in SLE pathogenesis (97). Therefore, we also focused on the roles of different antibody isotypes (IgG/IgM/IgA) and non-criteria aPL subtypes in various types of aPL-related kidney involvement (such as lupus nephritis and its different classes, chronic kidney disease, renal microvascular thrombosis, and end-stage renal disease), thereby supplementing and updating current research on aPL-related renal injury. Although the meta-analysis included the novel aPL subtypes described above in the search strategy, only two studies reported on aCL IgA, one study investigated aβ2GPI IgA, and one study examined aPS/PT antibodies. The limited number of studies may explain why no significant association was found between these novel antibodies and renal injury. More clinical and basic studies are required to determine the roles of novel aPL and their different isoforms in kidney injury of SLE patients.

The research has several shortcomings. To begin with, there is a difference in the modes of detection of aPL between the 70 studies. aCL and aβ2GPI levels are typically enzyme-linked immunosorbent assays, whereas LA are typically determined by the activated partial thromboplastin time, diluted Russell viper venom time, or silica clotting time. It is also difficult to establish a diagnostic standard for positive aPL levels due to differences in kits, instruments, and positive cutoff values. These differences in assay methods present challenges for the combination of data from different studies. As expected, significant heterogeneity were observed across the included studies. Second, not all the studies was used because the full text was not available. Thus, this meta-analysis did not involve all possible studies. Moreover, since various study design (cohort, cross-sectional, and case-control studies) were involved in this meta-analysis, we could only use OR as the pooled effect measure. As the meta-analysis assigns different weights to individual studies according to their variance, the pooled OR of 2.09 may deviate to some extent from the true effect. To better reflect the actual magnitude of the association, we thus did another meta-analysis in RR limited to cohort studies. The outcome of 23 cohort studies revealed that the risk of renal impairment was notably greater in the aPL-positive cohort compared to the aPL-negative counterpart with the total RR of 1.71 (1.37–2.13). In addition, the 70 studies involved in this meta-analysis cover a considerable time frame (1981–2024), which inevitably made the diagnosis criteria of SLE not consistent, as it embraced the American College of Rheumatology (ACR; 1971, 1982, 1997, 2009, and 2012), the Systemic Lupus International Collaborating Clinics (SLICC 2012) classification criteria, and the European League Against Rheumatism/American College of Rheumatology (2019 EULAR/ACR) criteria, which may affect the reliability and comparability of the results.

It is worth noting that retrospective studies are inevitably subject to information bias, selection bias, and confounding bias due to the limitations of the type of studies to be included in this study. As such, the meta-analysis can only conclude that patients with SLE who are aPL−positive have a higher risk of kidney injury. In the absence of greater evidence of large perspective randomized controlled trials, whether aPL−positive patients remain at a higher risk of kidney injury despite such treatment and subsequent follow-ups remain open. Moreover, in the absence of cellular and animal experimental data, we were unable to further explore the mechanisms by which aPL mediate renal injury in SLE. In future more clinical trials and experimental experiments would be required to further affirm the role and mechanism of aPL in kidney injury.

SLE patients with positive aPL (LA and aCL) or secondary APS are at significantly higher risk of renal injury than those who are aPL-negative. Risk stratification of different aPL types may facilitate clinical management in patients with SLE.