Abstract: FR-OR070

Ferric Citrate Administration Reduces FGF23 Production and Improves Renal Function in a Mouse Model of CKD

Session Information

Category: Mineral Disease

  • 1202 Mineral Disease: Vitamin D, PTH, FGF-23

Authors

  • Francis, Connor, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States
  • David, Valentin, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States
  • Courbon, Guillaume, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States
  • Neuburg, Samantha, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States
  • Gerber, Claire, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States
  • Wang, Xueyan, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States
  • Dussold, Corey, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States
  • Qi, Lixin, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University - Feinberg School of Medicine, Chicago, Illinois, United States
  • Wolf, Myles S., Duke University, Durham, North Carolina, United States
Background

Elevated levels of fibroblast growth factor 23 (FGF23) are strongly associated with cardiovascular disease, mortality, and progression of chronic kidney disease (CKD). Hyperphosphatemia and iron deficiency are powerful stimuli of FGF23 production. This suggests that reducing dietary phosphate intake or absorption and increasing serum iron may lower FGF23 levels and improve clinical outcomes in CKD.

Methods

We tested the hypotheses that ferric citrate treatment will simultaneously correct iron deficiency and also bind to dietary phosphate in the Col4a3ko mouse model of progressive CKD. We fed 4 week-old wild-type (WT) and Col4a3ko (CKD) mice, a control (Ctr) or a 5% Ferric Citrate enriched (FC) diet for 6 weeks and performed biochemical, molecular and histological analyses.

Results

At ten weeks, Ctr-CKD animals displayed a decline in renal function, as shown by a 8 fold increase in Blood Urea Nitrogen (BUN) and urinary albumin, signs of iron deficiency anemia, evidenced by low serum iron (99±12 vs 128±5 mg/dL) and hemoglobin (15±1 vs 19±1 g/dL), as well as a 2 fold increase in serum phosphate (p<0.05 vs WT). This was concomitant with a marked increase in both total (tFGF23, which includes intact and cleaved proteins) and intact FGF23 (iFGF23) serum levels, compared to WT (11426±2623 vs. 433±32 and 7312±1749 vs. 207±57 pg/mL respectively, p<0.05). In addition, serum 1,25 Vitamin D levels were low (34±7 vs 143±45 pg/mL) in Ctr-CKD animal (p<0.05, vs. Ctr-WT).
Ferric citrate increased serum iron levels by 1.6 fold in CKD mice and resulted in a 1.5 fold serum phosphate reduction (p<0.05, vs. Ctr-CKD). In addition, tFGF23 and iFGF23 were reduced by 4 and 3 fold respectively and serum 1,25 Vitamin D levels increased by 2 fold in FC-CKD mice (p<0.05 vs. Ctr-CKD). Interestingly, the FC diet also decreased BUN (127±21 vs. 218±24 mg/dL) and 24h urine albumin (101±69 vs. 586±91 µg) (p<0.05 vs. Ctr-CKD). Reductions in interstitial fibrosis and tubular dystrophy were also evident by histology in FC-CKD animals compared to Ctr-CKD group.

Conclusion

Our data show that ferric citrate administration in CKD mice reduces the magnitude of FGF23 increase and slows disease progression. This suggests that ferric citrate might mitigate renal injury.

Funding

  • Commercial Support