#1451 Calcimimetics reduce the progression of high-phosphate diet-induced tubular damage

Abstract Background and Aims During chronic kidney disease (CKD) progresses, there is an increased phosphate load and the concentration of the phosphaturic hormones PTH and FGF23 rises. In patients, phosphate and FGF23 are discussed as risk factors for CKD progression. We have recently shown that mice with high phosphate, PTH and FGF23 levels develop Stat3/Kim-1-mediated proximal tubule damage and tubulointerstitial fibrosis associated with increased MCP-1 expression and accumulation of macrophages. Calcimimetics lower PTH and FGF23 levels in hemodialysis patients and are thought to have both cardio- and nephroprotective effects. In a preclinical study, cinacalcet was shown to stabilize podocyte function in proteinuric mice. Therefore, we postulate that calcimimetics also have a positive effect on the progression of tubular damage in mice with high phosphate, PTH and FGF23 levels. Method For the induction of phosphaturic hormones with concomitant tubule damage, male C57BL/6 mice were fed a 2.0% high phosphate diet (HPD) and compared to animals on a 0.8% control phosphate diet (CPD). After four months, one HPD group was additionally treated with 1 mg/kg body weight/day etelcalcetide (KP-2326). Six months after the start of the trial, blood and urine samples as well as kidneys were taken for biochemical, histological and molecular biological examinations. Results KP-2326 treatment reduced HPD-induced PTH and FGF23 levels, but had no effect on increased phosphate excretion or elevated serum phosphate levels. Histologically, tubular damage was not as pronounced in the KP-2326-treated HPD animals as in the HPD group without therapy. The increased BUN levels caused by HPD and the albuminuria were significantly reduced by KP-2326. KP-2326 reduced HPD-mediated activation of Stat3 in proximal tubule cells and decreased Kim-1 synthesis at both mRNA and protein levels. Moreover, KP-2326 significantly reduced the mRNA expression of Ccl2 and the macrophage-specific marker Adgre1 compared to the untreated HPD group, which was histologically reflected in a lower accumulation of F4/80+ macrophages around the damaged tubules. Conclusion Treatment with KP-2326 was able to reduce the progression of HPD-induced tubule damage, at least in part due to the reduction in PTH and FGF23 levels.