Anemia is a common complication of
chronic kidney disease (CKD) that develops early and its severity increases as renal function declines. It is mainly due to a reduced production of
erythropoietin (EPO) by the kidneys; however, there are evidences that
iron metabolism disturbances increase as CKD progresses. Our aim was to study the mechanisms underlying the development of
anemia of CKD, as well as renal damage, in the remnant kidney rat model of CKD induced by 5/6
nephrectomy. This model of CKD presented a sustained degree of renal dysfunction, with mild and advanced glomerular and tubulointerstitial lesions.
Anemia developed 3 weeks after
nephrectomy and persisted throughout the protocol. The remnant kidney was still able to produce EPO and the liver showed an increased EPO gene expression. In spite of the increased EPO blood levels,
anemia persisted and was linked to low serum
iron and
transferrin levels, while serum
interleukin (IL)-6 and
high sensitivity C-reactive protein (
hs-CRP) levels showed the absence of systemic
inflammation. The increased expression of duodenal
ferroportin favours
iron absorption; however, serum
iron is reduced which might be due to
iron leakage through advanced kidney lesions, as showed by tubular
iron accumulation. Our data suggest that the persistence of
anemia may result from disturbances in
iron metabolism and by an altered activity/function of EPO as a result of kidney cell damage and a local inflammatory milieu, as showed by the increased gene expression of different inflammatory
proteins in the remnant kidney. In addition, this
anemia and the associated kidney
hypoxia favour the development of
fibrosis, angiogenesis and
inflammation that may underlie a resistance to EPO stimuli and reduced
iron availability. These findings might contribute to open new windows to identify putative therapeutic targets for this condition, as well as for recombinant human EPO (rHuEPO) resistance, which occurs in a considerable percentage of CKD patients.