Abstract: SA-PO805

Levels of the EPO-Responsive Hormone Erythroferrone in Mice and Humans with CKD

Session Information

Category: Dialysis

  • 605 Dialysis: Anemia and Iron Metabolism

Authors

  • Hanudel, Mark R., Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Rappaport, Maxime, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Gabayan, Victoria Rivka, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Salusky, Isidro B., Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Ganz, Tomas, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Nemeth, Elizabeta, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
Background

We previously demonstrated that, in mice with normal kidney function, erythropoietin (EPO) stimulates erythroblasts to secrete the hormone erythroferrone (ERFE), which acts to suppress production of the iron-regulatory hormone hepcidin. ERFE-mediated hepcidin suppression increases iron availability for RBC production. ERFE has not been assessed in humans or in the setting of CKD.

Methods

We measured serum ERFE levels in wild type mice, with and without adenine diet-induced CKD, after administration of a single EPO dose. We also measured serum ERFE in adults with normal kidney function after EPO treatment, as well as in 161 adult and pediatric healthy controls, 82 adult and pediatric non-dialysis CKD patients, and 101 adult and pediatric dialysis patients.

Results

In mice with normal kidney function, serum ERFE levels, undetectable at baseline, increased in response to EPO, peaking 6h post-injection. In mice with CKD, serum ERFE levels increased to a similar degree, but peaked later, at 24h post-injection. In both groups, serum hepcidin was decreased at 48h. In four adults with normal kidney function injected with a single EPO dose, serum ERFE increased 2.2-fold from baseline by 48-72h post injection. Concurrently, serum hepcidin levels decreased 2.3-fold from baseline by 48-72h hours post injection.

Median serum ERFE did not differ between non-dialysis CKD and control patients (6.1 vs. 7.8 ng/ml), but was significantly elevated in dialysis patients (15.7 ng/ml, p<0.05). In the non-dialysis CKD patients, serum EPO correlated positively with ERFE (Spearman r=0.59, p<0.001), but ERFE did not correlate with hepcidin. Hepcidin correlated with TSAT (Spearman r=0.34, p=0.004), but not with CRP or eGFR. Similarly, in the dialysis patients, rhEPO dose correlated positively with ERFE (Spearman r=0.44, p<0.001), but ERFE did not significantly correlate with hepcidin. Hepcidin did not correlate with TSAT or CRP.

Conclusion

In humans with normal kidney function, EPO administration increases ERFE and suppresses hepcidin. In CKD patients, ERFE correlates with serum EPO or rhEPO dose, but not hepcidin. These data suggest that ERFE is responsive to EPO in humans and mice regardless of kidney function, but that regulation of hepcidin in CKD is multifactorial, masking the hepcidin suppressive effects of ERFE.

Funding

  • NIDDK Support