High Phosphate Load Induces De Novo Formation of Tertiary Lymphoid Structures in the Kidney

Tertiary lymphoid structures (TLS) are associated with inflammatory kidney diseases, but their pathogenesis is unclear. A chronic high phosphate diet (HPD) in mice increases serum levels of phosphate and fibroblast growth factor 23 (FGF23) which is associated with progressive tubule damage and fibrosis. We hypothesized that chronic HPD induces TLS in the kidneys and thereby promotes progressive kidney injury. After only 2 months, mice on HPD showed increased tubule damage accompanied by the formation of perivascular immune cell clusters of B and T cells in the corticomedullary zone and in the cortex. In addition, lymphatic vessels were observed, accompanied by increased expression of venous markers and cell adhesion molecules. Further analyses showed a time-dependent induction of the immunofibroblast-derived chemokines and lymphotoxins, which are important for the differentiation of immunofibroblasts into follicular dendritic cells (FDC) and fibroblastic reticular cells (FRC). Already after 4 months of HPD, proliferating B-cell clusters with FDCs, T-cell clusters with FRCs, podoplanin⁺ cellular networks, high endothelial venules, plasma cells and increased IgD synthesis indicated fully mature TLSs, while tubular damage and fibrosis continued to increase up to 6 months of feeding HPD. Genetically modified mice overexpressing FGF23 developed tubular damage, fibrosis, and fully mature TLS only in the presence of HPD-induced hyperphosphatemia. Likewise, hypophosphatemic Hyp mice showed no signs of tubular damage or TLS despite increased FGF23 levels. Our data suggest that high phosphate directly causes chronic inflammation in the kidney leading to the development of fully mature TLS associated with progressive tubular injury.