Anemia is a common feature of CKD associated with poor outcomes. The current management of patients with anemia in CKD is controversial, with recent clinical trials demonstrating increased morbidity and mortality related to erythropoiesis stimulating agents. Here, we examine recent insights into the molecular mechanisms underlying anemia of CKD. These insights hold promise for the development of new diagnostic tests and therapies that directly target the pathophysiologic processes underlying this form of anemia.

Anemia was first linked to CKD over 170 years ago by Richard Bright. As kidney disease progresses, anemia increases in prevalence, affecting nearly all patients with stage 5 CKD.2 Anemia in CKD is associated with reduced quality of life and increased cardiovascular disease, hospitalizations, cognitive impairment, and mortality.

Anemia in CKD is typically normocytic, normochromic, and hypoproliferative. The demonstration of a circulating factor responsible for stimulating erythropoiesis, and the kidney as the main source of erythropoietin (EPO) in the 1950s engendered the hypothesis that EPO deficiency is a predominant cause of anemia in CKD. Purification and cloning of EPO in the late 1970s and 1980s enabled the development of immunologic assays for quantitating levels of circulating EPO. Although generally normal or slightly increased in anemia of CKD, EPO levels are considered inappropriately low relative to the degree of anemia, because similarly anemic patients with normal kidney function have 10–100 times higher EPO levels. One important limitation of such assays is that they measure all immunogenic EPO fragments, which do not all correlate with biologic activity.

Anemia management was revolutionized in the late 1980s with the introduction of recombinant human EPO. This and related erythropoiesis stimulating agents (ESAs) greatly benefited patients by improving their debilitating symptoms, and freeing them from dependence on blood transfusions with their associated complications (secondary iron overload, infections, and sensitization impeding transplantation). However, even in the initial studies, adverse effects were noted in patients receiving ESAs, including worsening hypertension, seizures, and dialysis access clotting. In addition, ESAs do not reduce adverse outcomes associated with anemia, such as mortality, nonfatal cardiovascular events, left ventricular hypertrophy, hospitalizations, and progression of kidney disease, in prospective randomized controlled trials.

In fact, recent trials in both hemodialysis and predialysis CKD patients demonstrate an increased risk of death, adverse cardiovascular events, and stroke by administering ESAs to target hemoglobin levels >11 g/dl. Secondary analyses of these studies suggest that elevated hemoglobin per se does not confer the increased risk, but rather higher doses of ESAs and relative resistance to ESAs, although this has not been studied directly. In addition, ESAs have been associated with increased progression of malignancy and death in cancer patients.

Journal of Nephrology and Urology is an Open Access peer-reviewed publication that discusses current research and advancements in diagnosis and management of kidney disorders as well as related epidemiology, pathophysiology and molecular genetics.

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Regards
Mercy Eleanor
Editorial Assistant
Journal of Nephrology and Urology