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Abstract: FR-PO300

Calcimimetic Treatment Reduces Progression of High Phosphate-Induced Tubular Injury in Mice

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • Leifheit-Nestler, Maren, Hannover Medical School, Hannover, Germany
  • Walles, Franziska, Hannover Medical School, Hannover, Germany
  • Richter, Beatrice, Hannover Medical School, Hannover, Germany
  • Weingärtner, Nina, Hannover Medical School, Hannover, Germany
  • Braesen, Jan H., Hannover Medical School, Hannover, Germany
  • Haffner, Dieter, Hannover Medical School, Hannover, Germany
Background

High phosphate stimulates fibroblast growth factor 23 (FGF23) and both factors are discussed to promote chronic kidney disease progression. Recently, we demonstrated that a high phosphate diet (HPD) in mice leads to increased serum phosphate and Fgf23 levels and a Stat3/Kim-1-mediated proximal tubule injury and tubulointerstitial fibrosis. In parallel, inflammatory processes in the renal parenchyma with induction of MCP-1 (monocyte chemoattractant protein-1; Ccl2) and accumulation of macrophages as well as the development of perivascular tertiary lymphoid structures (TLS) in the medullary-cortical junction could be demonstrated in HPD mice. Calcimimetics show both cardio- and nephroprotective effects. Administration of etelcalcetide in hemodialysis patients results in a reduction of FGF23 and slower progression of left ventricular hypertrophy. Cinacalcet stabilizes podocyte function in mice. We therefore postulated that calcimimetics also have a beneficial effect on the progression of HPD-induced renal damage and the maturation of TLS in mice.

Methods

To investigate whether calcimimetic treatment positively affects kidney health, we induced kidney disease in male C57BL/6 mice by the use of a 2% HPD in comparison to a 0.8% phosphate control diet (Ctrl). After four months of dietary intervention, one HPD-fed group was concomitantly treated with 1 mg/kg body weight/day etelcalcetide (Etl) for further two months. At the end, blood and urine were taken and kidneys were harvested for histological and transcriptional analysis.

Results

Therapy with Etl reduced HPD-induced Fgf23 levels but had no effect on elevated serum phosphate levels. Etl reduced activation of the renal Stat3/Kim-1 signaling cascade and decreased HPD-mediated tubule damage. Furthermore, Etl significantly suppressed mRNA expression of Ccl2 and the macrophage-specific marker Adgre1 compared with the HPD group without therapy. Etl had no effect on the development and maturation of renal TLS in the HPD group, which were characterized by CD3+ T cells, CD45R+ B cell clusters, IgD-secreting cells, CD138+ plasma cells, and podoplanin+ cell networks.

Conclusion

Etl therapy reduces FGF23 levels and slows progression of tubule injury in mice on HPD. Maturation of renal TLS remains unaffected by Etl, which may be attributed to persistent hyperphosphatemia.

Funding

  • Commercial Support – Amgen