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Kidney Week

Abstract: SA-PO987

High Phosphate Diet Induces the Development of Tertiary Lymphoid Structures and Fibrosis in Murine Kidneys

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Richter, Beatrice, Hannover Medical School, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover, Germany
  • Weingärtner, Nina, Hannover Medical School, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover, Germany
  • Vogt, Isabel, Hannover Medical School, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover, Germany
  • Kapanadze, Tamar G., Hannover Medical School, Department of Nephrology and Hypertension, Hannover, Germany
  • Haffner, Dieter, Hannover Medical School, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover, Germany
  • Leifheit-Nestler, Maren, Hannover Medical School, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover, Germany
Background

Tertiary lymphoid structures (TLS) are immune cell aggregates found in non-lymphoid organs, including the kidneys, and are associated with chronic inflammation. Similar to secondary lymphatic organs, TLS can initiate adaptive immune reactions. Among others, TLS are described in aging kidneys as well as in autoimmune diseases including IgA nephropathy, ANCA-associated glomerulonephritis and lupus nephritis. Recently, the role of vascular endothelial cells is discussed for the initiation of TLS. Here, we identify for the first time a chronically high phosphate load as a novel trigger for TLS formation in kidneys from mice.

Methods

C57BL/6N male mice received a 2% high phosphate diet (HPD) for 1-6 months and were compared to animals on a 0.8% normal phosphate diet (NPD). Renal tissue was collected for histology, flow cytometry, gene expression analyses and cytokine array.

Results

Starting after 2 months, in renal tissue from mice on HPD larger immune cell aggregates were found. In parallel, the renal mRNA levels for venous markers and cell adhesion molecules were significantly elevated. Distinctive TLS occurred in mice on HPD after 3 months. At the later time points, perivascular TLS formation in the corticomedullary junction and renal cortex was found for all mice on HPD. No TLS were detected in renal tissue derived from NPD controls. Flow cytometry analysis and histological staining showed a significant increase of CD3+ T cells and CD45R+ B cells starting after 3 months of HPD. Furthermore, an increased accumulation of collagen 3, podoplanin+ fibroblastic reticular cell networks, LYVE+ lymphatic vessel, and Cxcr4+ cells were found. F4/80+ macrophages accumulated in the periphery of TLS. Cluster of proliferating B cells, the presence of plasma cells and detection of IgG secretion in month 4 pointed to the existence of phosphate-induced mature TLS. The induction of Cxcl13, an important chemokine for recruitment and differentiation of B cells, was found in histology and confirmed by cytokine array.

Conclusion

Our results indicate that chronically increased phosphate intake leads to de novo formation of fully mature perivascular TLS in kidneys of mice, which was associated with significant interstitial fibrosis.