Synergistic co-operation between HIF and non-HIF pathways, such as the pro-fibrotic TGF-β1/SMAD3 signaling pathway, may further enhance the expression of HIF-regulated genes in the CKD setting; HIF-1 and TGF-β1 have been shown to co-regulate vascular endothelial growth factor (VEGF) [37], endoglin [38] and EPO [39]. Here, EPO is linked to chronic kidney disease.