First, decreased glomerular filtration in CKD may directly lead to an increase in circulating FGF21 because FGF21 is a small molecule protein (approximately 21-kD) which can cross the glomerular capillary.[25] However, FGF21 levels are still elevated in patients undergoing hemodialysis.[16] Second, circulating FGF21 levels are usually elevated in metabolic disorders, including obesity and T2D.[4] This is believed to be a compensatory response to metabolic stress in pathophysiological situations. Here, FGF21 is linked to obesity due to melanocortin 4 receptor deficiency.