Encarnación, Montserrat M. Díaz

ABSTRACT Background Membranous nephropathy (MN) associated with phospholipase A2 receptor (PLA2R) antibodies is the most common cause of nephrotic syndrome in non-diabetic adult patients. This study investigated the relationship between clinical phenotypes and renal outcomes in this population, emphasizing the potential for phenotype-based treatment stratification. Methods We conducted a retrospective, multi-center cohort study of PLA2R-positive MN. Unsupervised cluster analysis grouped patients based on clinicopathological characteristics. Primary outcomes included complete or partial remission within 2 years of biopsy and end-stage kidney disease (ESKD) or death during follow-up. Results Among 178 patients, three distinct clusters emerged (n = 89, 70, and 19). Within 2 years of biopsy, 102 patients (57%) achieved complete or partial remission. Cluster 1, characterized by the mildest disease markers, including the lowest body mass index, serum anti-PLA2R titer, serum creatinine, proteinuria, and triglycerides, had the highest remission rate of 72%, compared with 50% in cluster 2 and 54% in cluster 3. Cluster 2 had significantly lower remission compared to cluster 1 (HR 0.64, 95% CI 0.42–0.96, P = .03); results were similar in cluster 3, albeit not statistically significant (HR 0.50, 95% CI 0.23–1.09, P = .08). Elevated anti-PLA2R levels (>100 U/ml) and proteinuria (>8 g/24-hour) predicted reduced remission (HR 0.56, 95% CI 0.36–0.88, P = .01; HR 0.43, 95% CI 0.26–0.73, P = .002, respectively), while high high-density lipoprotein levels were protective (HR 1.01, 95% CI 1.00–1.02, P = .048). Overall, 21 patients (12%) developed ESKD or died. ESKD-free survival differed significantly across clusters (log-rank test P = .04). Conclusions Unsupervised clustering identified distinct clinical phenotypes in PLA2R-positive MN, each associated with different renal prognoses. Phenotype-based risk stratification could enhance treatment precision, improve patient outcomes, and potentially reduce treatment-related adverse effects.

Monocyte chemoattractant protein 1 (MCP-1) is a CC cytokine that fundamentally contributes to the pathogenesis of inflammatory renal disease. MCP-1 is highly expressed in cytokine-stimulated mesangial cells in vitro and following glomerular injury in vivo. Interventions to limit MCP-1 expression are commonly effective in assorted experimental models. Fish oil, an abundant source of n-3 fatty acids, has anti-inflammatory properties, the basis of which remains incompletely defined. We examined potential mechanisms whereby fish oil reduces MCP-1 expression and thereby suppresses inflammatory responses to tissue injury. Cultured mesangial cells were treated with TNF-α in the presence of the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); equimolar concentrations of the n-6 fatty acids LA and OA served as controls. MCP-1 mRNA expression was assessed by Northern blotting, and transcriptional activity of the MCP-1 promoter was assessed by transient transfection. The involvement of the ERK and NF-κB pathways was evaluated through transfection analysis and the use of the MEK inhibitor U0126. DHA and EPA decreased TNF-α-stimulated MCP-1 mRNA expression by decreasing transcription of the MCP-1 gene. DHA and EPA decreased p-ERK expression and nuclear translocation of NF-κB, both of which are necessary for TNF-α-stimulated MCP-1 expression. Both NF-κB and AP-1 sites were involved in transcriptional regulation of the MCP-1 gene by DHA and EPA. We conclude that DHA and EPA inhibit TNF-α-stimulated transcription of the MCP-1 gene through interaction of signaling pathways involving ERK and NF-κB. We speculate that such effects may contribute to the salutary effect of fish oil in renal and vascular disease.