Abstract
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.
Highlights
Chronic kidney disease (CKD) is a pathological condition that results from a gradual and permanent loss of kidney function over time, usually, months to years
At the end of experimental protocol (12 weeks), a significant decrease (p
Since the introduction of the conceptual model, definition, staging of CKD and establishment of the clinical practice guidelines to treat kidney disease patients, the disease evolved from a life-threatening disorder affecting few people who needed care by nephrologists, to a common disorder of varying severity that deserves the attention of a multidisciplinary team and needs a concerted public health approach for prevention, early detection and management [27,28]
Summary
Chronic kidney disease (CKD) is a pathological condition that results from a gradual and permanent loss of kidney function over time, usually, months to years. The incidence of anemia is less than 2% in CKD stages 1 and 2, about 5% in CKD stage 3, 44% in CKD stage 4 and more than 70% in end-stage renal disease (ESRD) [2] This condition is associated with a decreased quality of life [3], increased hospitalizations [4,5], cardiovascular complications—angina, left ventricular hypertrophy (LVH) and chronic heart failure—and mortality [6,7,8,9]. There are evidences that iron metabolism disturbances increase as the CKD progresses The reasons for this high proportion of CKD patients with iron disturbances are not well clarified; inflammation has been proposed to play an important role. Previous works reported that ESRD patients under hemodialysis present higher hepcidin serum levels, increased markers of inflammation [such as C-reactive protein (CRP) and interleukin (IL)-6] and reduced iron absorption and mobilization, presenting lower levels of iron and transferrin [10,11,12]
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