Identification of two distinct clusters in membranous lupus nephritis patients: recognition of a high-risk profile based on unsupervised analysis

ABSTRACT Background and hypothesis Membranous lupus nephritis (MLN) traditionally includes class V (alone), and may be associated with other classes (III or IV). The clinical, therapeutic, and prognostic relevance of the classification remains controversial. Methods A retrospective cohort of 412 MLN patients from the First Affiliated Hospital of Sun-Yat Sen University was followed for a median of 65.68 (interquartile range 23.13–131.70) months. The primary outcomes were adverse renal events including all-cause death and ESRD. Phenotypes were identified and validated using unsupervised clustering analysis (K-means), principal component analysis and decision tree analysis. Results Distinct clinical and pathological differences were noted between the traditional class IV + V and classes V + III and V, while class V + III and class V exhibited high similarities in clinical features and prognosis (P = 0.074). K-means clustering revealed high-risk (n = 180) and low-risk (n = 232) groups, with significant differences in adverse renal outcomes (9.2% vs 4.1%, P < 0.001). To recognize the high-risk profile of MLN patients, a decision tree based on Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, hemoglobin, serum creatinine, traditional classification, and activity index of renal biopsy accurately clustered patients in the development (95.8% accuracy) and validation (87.1% accuracy) cohorts. Conclusions Two novel phenotypic clusters, more predictive than traditional classifications, enhance high-risk profile identification and prognostic accuracy.