The clinicopathological significance and mechanisms of interstitial foam cells formation in patients with primary membranous nephropathy

Accumulation of foam cells (FCs) in interstitium is frequently observed in membranous nephropathy (MN). However, the pathophysiological significance of those cells remains poorly understood. It is generally accepted that interstitial FCs are derived from macrophages with lipid deposits filling the cytoplasm. In this study, we investigate the characteristics of cholesterol homeostasis in interstitial FCs and its association with clinicopathological features in patients with primary MN(PMN). In this retrospective, multi-center cohort study, a total of 126 patients diagnosed with PMN were recruited. Based on the presence of interstitial FCs, participants were categorized into FC positive (FC+, n = 23) and FC negative (FC-, n = 103) groups. Clinicopathological parameters were compared between the two groups, and the immunohistochemical stains were performed to evaluated the expression of lipid droplet associated protein PLIN2 and cholesterol reverse transport pump ABCA1 and ABCG1between two groups. In addition, co-staining of PLIN2, ABCA1 and ABCG1 with CD68 were performed to validate FCs identity. Patients in the FC+ group exhibited significantly higher 24-hour urine protein (24-hUP) and urinary albumin-to-creatinine ratio (UACR) compared to those in the FC- group, whereas serum albumin and total protein levels were significantly lower. No significant differences were observed in age, gender, renal function, lipid profiles or other clinical parameters between the two groups. Serum anti-PLA2R antibody titers were elevated in the FC+ group; however, multivariable regression analysis revealed no independent association with the presence of FCs. In addition, patients with FCs had a higher proportion of long-standing PMN (electron microscope stage III) and greater interstitial fibrosis area. Multivariable regression analysis revealed that 24-hUP, serum albumin, LDL and proportion of interstitial fibrosis were independently correlated with the presence of FCs. Immunohistochemically, PLIN2, ABCA1 and ABCG1 are co-localized with CD68 on FCs, and FCs showed marked upregulation of the lipid droplet coat protein PLIN2, along with a striking loss of the cholesterol efflux transporters ABCA1 and ABCG1. Interstitial FCs are significantly associated with massive proteinuria, advanced pathological stage, and interstitial fibrosis in PMN. The concurrent upregulation of PLIN2 and downregulation of ABCA1 and ABCG1 may contribute to FC formation by promoting intracellular lipid accumulation. Our findings establish a potential pathogenic role of FCs in PMN and warrant further investigation to better understand their contribution to disease progression and to identify potential therapeutic targets.