Anemia and anemia correction: surrogate markers or causes of morbidity in chronic kidney disease?

Abstract

Observational studies have shown a strong positive correlation between the severity of anemia and the risk of poor outcomes in patients with chronic kidney disease (CKD). This observation was initially taken to imply that adverse outcomes in CKD are caused by anemia. However, the assumption of causality ignores the possibility that anemia and adverse outcomes might be unrelated and that both are caused by underlying inflammation, oxidative stress and comorbid conditions. Randomized clinical trials of anemia correction have revealed an increased risk of adverse cardiovascular outcomes in patients assigned to normal, rather than subnormal, hemoglobin targets. As a result, correction of anemia is now considered potentially hazardous in patients with CKD. Notably, individuals who did not reach the target hemoglobin level in the clinical trials, despite receiving high doses of erythropoietin and iron, experienced a disproportionately large share of the adverse outcomes. These observations point to overdose of erythropoietin and iron, rather than anemia correction per se, as the likely culprit. This Review explores the reasons for the apparent contradiction between the findings of observational studies and randomized clinical trials of anemia treatment in CKD. I have focused on data from basic and translational studies, which are often overlooked in the design and interpretation of clinical studies and in the formulation of clinical guidelines.

The Relationship between Hemoglobin Levels and Endothelial Functions in Diabetes Mellitus

“…However, recent studies have shown that full anemia correction in stage 3 to 4 CKD patients may be harmful (1,2). Such an effect is currently attributed to the deleterious action of high doses of erythropoietin imposed by erythropoietin resistance in patients with systemic illness and inflammation (3). Even though a recent secondary analysis of one of these studies (4) offers solid support to this hypothesis, other mechanisms also may be at play (3).…”

“…Such an effect is currently attributed to the deleterious action of high doses of erythropoietin imposed by erythropoietin resistance in patients with systemic illness and inflammation (3). Even though a recent secondary analysis of one of these studies (4) offers solid support to this hypothesis, other mechanisms also may be at play (3). Because Hb is a well recognized carrier and buffer of nitric oxide (NO), which modulates the bioavailability of this compound at tissue level (5), disturbed regulation of endothelial function secondary to changes in Hb concentration appears to be a relevant pathophysiologic pathway whereby changes in red cell mass may exert adverse cardiovascular events (6).…”

Doença renal crônica: frequente e grave, mas também prevenível e tratável

“…A anemia se associa com evolução adversa da DRC, incluindo hospitalização, doença cardiovascular, mortalidade e diminuição da qualidade de vida dos pacientes. 23 A principal causa de anemia na DRC é a deficiência de produção da eritropoietina pelos fibroblastos peritubulares renais. 24 Contudo, é importante mencionar que outros fatores podem determinar a ocorrência de anemia nesses pacientes, particularmente a deficiência de ferro.…”

Safety Issues in Iron Treatment in CKD

“…This trend could potentially be harmful because iron could 6 amplify oxidative stress and inflammation, which are constant features of CKD/ESRD. [7][8][9][10] The potential role of high doses of ESA in the pathogenesis of cardiovascular disease (CVD), thromboembolic disorders, and other complications has been reviewed previously 11,12 and will not be addressed here. This article provides an overview of the potential safety concerns with use of iron preparations.…”