To our knowledge, this is the first study to evaluate hepcidin and GDF-15 as markers of anaemia among Egyptian with non-dialysis CKD. Serum hepcidin and GDF-15 predicted anaemia among patients with CKD, with a predictive value of 72% and 76.47%, respectively. In addition, we showed a negative correlation between hepcidin and eGFR among CKD patients. Our observation agrees with findings by others [16, 17]. However, some authors found a positive correlation between hepcidin and GFR levels [ 18]. This suggests that the relationship between hepcidin and renal function is still unclear. Moreover, renal function playing a minimal role in hepcidin pathways which is largely dependent on ferritin metabolism. The sensitivity of the methods used may also play a role in the differences between our findings and others as we used ELISA, others used mass spectrometry [17, 19]. Our data supports published studies reporting higher levels of hepcidin in CKD [ 20]. In the setting of CKD, increase in serum hepcidin levels compared to controls might be due to inflammatory up regulation and decreased renal clearance of hepcidin which results in reduced availability of plasma iron and anemia [21]. We found that serum ferritin, the primary storage molecule for cellular iron, positively correlated with hepcidin in our CKD patients as previously documented [ 22]. The direct relationship of hepcidin with ferritin may represent a protective effect of hepcidin against iron overload [18]. However, there was correlation between hepcidin and inflammatory markers such as hsCRP this explain that CKD patients are prone to develop IDA due to the presence of persistent low-grade inflammation which induces Hepcidin and thereby mediates reticuloendothelial cell block.
Also, in our study serum GDF-15 are significantly elevated in CKD children than control and strongly correlated to CRP serum levels. There are possible mechanisms that may explain the findings of increased GDF-15 is anaemia .First, GDF-15 may be an important mediator in a negative feedback pathway where it suppress high hepcidin levels in CKD patients with iron deficiency. Another explanation is that iron depletion could independently cause GDF-15 induction in the erythroid precursor cells as a result of iron sequestration in macrophages as GDF15 is a product of macrophages activated by proinflammatory cytokines that present in excess in CKD, Interestingly CRP induces GDF15 expression through the regulation of p53 binding sites in the GDF15 promoter and they are also relevant markers of inflammation [25].
Supporting the relationship of GDF-15 to the inflammatory status, We found a strong correlation between both serum ferritin and CRP with GDF-15. Moreover median serum hepcidin and GDF-15 level is higher and statistically significant among participants with higher ferritin level > 300 µg/l. For every ng/ml increase in serum ferritin level among CKD patients, log hepcidin increased by 0.00251 (β = 0.00251, P-value < 0.0001), In other words, hepcidin levels increased by 100 raised to 0.00389 units for every ng/ml increase in serum ferritin. Log GDF-15 decreased with every unit increase of MCHC (β = 0.0196, P-value = 0.005) this explained by cytokine blocks hepcidin expression and increases iron absorption, thus leading to iron loading in these anemias [24]. Besides, in response to anemia, erythroblasts secretes GDF-15, which in turn suppresses hepcidin expression and decrease iron stores [24]. Yilmaz et al and Wang et al. [25,26], reported a significant correlation between GDF15 and serum ferritin but Li et al. [27], reported no significant correlation.
From our results, the high ferritin levels associated with CRP and GDF-15 may indicate the link between iron homeostasis and the inflammatory response through anemia of inflammation or chronic disease. In our study, the diagnostic performance of GDF-15 as a marker of inflammation in CKD was comparable to CRP and better than ferritin that is mostly elevated by iron overload associating CKD, qualifying GDF-15 as a surrogate marker of inflammatory status in CKD. Similar results were found by Bargenda et al. [28], Thorsteinsdottir et al. [29]
Another important finding in this study is the negative correlation of GDF-15 with haemoglobin in CKD patients. This finding is consistent with others [30, 31], but is in disagreement with findings in non-CKD populations, where GDF-15 was positively correlated with haemoglobin [32–33]. This difference could be explained by racial differences and diversity of ethnicity in the studied population.
We also found that GDF-15 predicted anaemia at a cut-off value < 724 pg/ml with a predictive value of 70.0%, sensitivity of 82.98%, and specificity of 87.11%. In contrast, Tanno et al [34]. found that there was no association between iron deficiency and serum GDF-15 levels. Our study, therefore, suggests that GDF-15 can be a useful diagnostic tool in patients with anaemia. However, inflammation-mediated changes seen in iron homoeostasis may not induce the increased GDF-15 levels in patients with anaemia, as serum ferritin levels did not correlate with GDF-15 levels in this study and as reported by Mast et al. [35]