Non-alcoholic Fatty Liver Disease (NAFLD) causes Erythropoietin Hyporesponsiveness

Abstract

<b>Abstract ID 18842</b> <b>Poster Board 55</b> Treatment with recombinant human erythropoietin (rHuEPO) may correct anemia in patients with chronic kidney disease. However, up to 10% of these patients exhibit EPO resistance or hyporesponsiveness. Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease with a high prevalence in CKD patients. NAFLD could result in TPO deficiency, iron homeostasis disorder and inflammation, which may restrict the response to EPO. Therefore, we hypothesized CKD patients with NAFLD need a higher dose of EPO to achieve the target hemoglobin levels in comparison with CKD patients without NAFLD. To test our hypothesis, pharmacokinetic (PK) and pharmacodynamic (PD) studies of rHuEPO were performed in healthy rats and high-fat and high-calorie (HFHC) diet-induced NAFLD rats. Hematological response, endogenous hormone concentration, erythroid cells in bone marrow, inflammation biomarkers, and iron status were measured. The results demonstrated moderate anemia and EPO hyporesponsiveness in HFHC-NAFLD rats. During the 12-week HFHC diet feeding, steady decreases in mean corpuscular hemoglobin (MCH) concentration and the mean corpuscular volume (MCV) were observed in the HFHC-NAFLD rats from week 3. At the end of the feeding, the MCH (15.5 vs 18.2 pg/cells), MCV (44.3 vs 55.2 μm³), hemoglobin concentration (139.5 vs 149.3 g/L) and hematocrit levels (39.5% vs 42.7%) in HFHC-NAFLD rats were significantly lower than that in healthy rats, respectively. Then, both healthy and HFHC-NAFLD rats received rHuEPO administration (450 IU/kg, thrice weekly) for two weeks. HFHC-NAFLD rats showed significantly lower responses in hemoglobin (452.2% vs 591.8%), hematocrit (501.2% vs 651.9%), and MCV (198.7% vs 263.3%) than that in the healthy rats, respectively. Furthermore, we investigated the underlying mechanism of EPO hyporesponsiveness in HFHC-NAFLD rats. The results showed that iron deficiency and inflammation in NAFLD caused EPO hyporesponsiveness by inhibiting erythroid progenitor cell production. Hepcidin, ferritin, and transferrin and white blood cell concentration in HFHC-NAFLD rats are 12.8, 16.4, 2.51 and 1.40-fold higher than that in healthy rats, respectively. There is no difference in the pharmacokinetics of rHuEPO, endogenous EPO and endogenous TPO concentrations between healthy and HFHC-NAFLD rats. While the number of burst-forming unit-erythroid and colony-forming unit-erythroid progenitor cells in the bone marrow of HFHC-NAFLD rats is only 74.7% and 77.7% of that in healthy rats, respectively. Also, assessed by flow cytometry, the number of erythroid precursor cells in HFHC-NAFLD rats was less than that in healthy rats. In conclusion, our study found EPO hyporesponsiveness caused by iron deficiency and inflammation in HFHC-NAFLD rats, and it suggested NAFLD could be a covariate on EPO response in CKD patients. This work was supported by research grants from the Hong Kong Research Grants Council, Early Career Scheme (24103120).