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Inflammation and resistance to erythropoiesis-stimulating agents - links to oxidative stress and cardiovascular mortality

Peter Bárány MD
Division of Renal Medicine, Department of Clinical Science
Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden


Inflammation predicts poor outcome in chronic kidney disease (CKD). It is multifactorial in its cause and, while it may reflect the underlying cardiovascular disease (CVD), the acute-phase response may also contribute to both oxidative stress and progressive vascular injury. Inflammation and the acute-phase response interact with the haematopoietic system at several levels resulting in reduced erythropoiesis and accelerated destruction of erythrocytes. In patients with CKD, inflammation is often linked to functional iron deficiency and resistance to erythropoiesis-stimulating agents (ESA).

Inflammation is a common feature of CKD

About 30-50% of patients with chronic kidney disease (CKD) have serological evidence of an activated inflammatory response with elevated serum levels of C-reactive protein (CRP)1. Several factors may contribute to systemic inflammation including both disease-related and treatment-related processes.

Inflammation predicts poor outcome in CKD

Non-traditional risk factors, such as oxidative stress and inflammation, may contribute to the high prevalence of CVD in patients with CKD1. Indeed, a strong association between mortality rate and both CRP and IL-6 levels have been reported in HD2 and PD3 patients and it is thought that the acute-phase response play a significant role in the accelerated atherogenesis of CKD.

Inflammation and increased oxidative stress

Patients with CKD are thought to have reduced capacity to handle oxidative stress, as indicated by increased lipid peroxidation4 and decreased levels of antioxidants such as glutathione, vitamin E and C, and superoxide dismutase5, 6. A link between inflammation and oxidative stress was first suggested by Memon et al.7 and recent results suggest that inflammation interacts with oxidative stress in patients with CKD8, 9.

Inflammation and anaemia

Growth factors, including erythropoietin and several cytokines, are necessary for the normal growth and differentiation of erythroid progenitors in the bone marrow. In low concentrations, the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-) and interleukin-1 (IL-1) stimulate growth of early progenitors (burst-forming units-erythroid [BFU-e])10.

Inflammation and the acute-phase response interact with the haematopoietic system at several levels. During the early period of the acute-phase response, haemoglobin (Hb) concentration often drops rapidly. This is due to the accelerated destruction of erythrocytes by inflammatory-activated reticuloendothelial macrophages that efficiently clear the circulation of erythrocytes coated with immunoglobulins or immune complex.11. In patients with normal renal function, an acute decrease in Hb concentration stimulates secretion of erythropoietin for 4-10 days. Importantly, this reactive increase in erythropoietin secretion is blunted by pro-inflammatory cytokines in patients undergoing acute-phase response12.

However, the erythropoiesis-suppressing effect of inflammation is mainly due to inhibitory effects of the pro-inflammatory cytokines on erythroid precursors diminishing their sensitivity to erythropoietin10. In patients with chronic inflammatory disorders and high levels of proinflammatory cytokines, such as rheumatoid arthritis, TNF- blockade has been associated with an increase in Hb levels13. In patients with CKD, the most common causes of ESA resistance are iron deficiency (absolute or functional) and systemic inflammation. Patients with elevated inflammatory markers or high levels of proinflammatory cytokines are less responsive to ESA14-17. The inhibitory effect of TNF- and IL-1 on erythropoiesis can usually be overcome dose-dependently by administering higher doses of recombinant human erythropoietin (ESA).

Inflammation and iron metabolism

Inflammation is often associated with a state of functional iron deficiency with low serum levels of iron and transferrin18. In these cases, delivery of iron from reticuloendothelial cells to haematopoietic cells is inhibited or blocked. During inflammation, lactoferrin-bound iron is taken up by activated macrophages that express specific lactoferrin receptors. This causes iron deprivation of the erythroid precursors, which fail to express lactoferrin receptors10. These inflammatory-induced effects on iron metabolism are thought to comprise part of the host-defence mechanisms against bacterial and viral infection19. Serum ferritin, which acts as an acute-phase protein increases two- to four-fold in response to inflammation20. Inflammation also affects mucosal uptake and transfer of iron, thus reducing absorption of oral iron and further contributing to anaemia21.

Is anaemia related to increased cardiovascular disease mortality in CKD?

Observational studies have associated anaemia with increased cardiovascular disease (CVD) and all-cause mortality both in CKD patients22 and in the general population23. However, so far, only one interventional study has been designed to evaluate the effect of ESA correction of anaemia of CKD in patients with CVD, and this failed to demonstrate a significant effect on mortality24. In light of the strong associations between raised levels of pro-inflammatory cytokines and poor outcome in patients with CKD, the independent role of anaemia in this scenario may be questioned. Evolving suggest that poor response to ESA is itself a predictor of mortality in CKD patients. Lowrie25 postulated that anaemia and malnutrition share the inflammatory response as a common cause.

Indeed, we find associations between anaemia and a poor outcome during dialysis treatment in patients with CKD close to start of regular dialysis treatment26, but the other components of the malnutrition -inflammation - atherosclerosis - syndrome are stronger predictors of outcome. Thus, further studies are needed to elucidate the role of anaemia and ESA resistance as risk factors for increased cardiovascular mortality in patients with CKD.

Does anaemia cause increased oxidative stress?

Although methodology is of concern, several recent studies have addressed the issue whether anaemia in patients with CKD is related to increased oxidative stress. It has been reported that peroxidation of lipids within the red blood cell (RBC) membrane may contribute to shortening RBC life span27 and that anaemia is associated with higher plasma concentrations of lipid peroxidation products in HD-patients28. Moreover, lower plasma levels of a surrogate marker of oxidative stress, malondialdehyde (MDA), have been observed in ESA-treated patients with higher Hb levels29. Why anaemia may be associated with increased oxidative stress is not fully understood, it is possible that treatment of anaemia is associated with an increased availability of gluthathione and other anti-oxidants30.

The treatment of anaemia in CKD patients with inflammation

On average, it has been estimated that the ESA dose required to maintain target Hb level may be increased by 30–70% in inflamed dialysis patients (CRP > 20 mg/l) compared with those with a lower CRP concentration26. Indeed, in severe systemic inflammation, the response to ESA may be totally blunted and blood transfusion may be needed. Obviously, comorbid conditions that may contribute to inflammation, such as persistent infections, chronic heart failure and coronary heart disease should be adequately treated.

As increased oxidative stress may be associated both with inflammation and anaemia, as well as ESA resistance, it could be hypothesized that various anti-oxidative treatment strategies may have ESA-sparing effects.


CKD is characterized by a high mortality rate derived largely from CVD. In patients with CKD, high levels of pro-inflammatory cytokines and increased oxidative stress are common features that may contribute to malnutrition, anaemia, ESA resistance and atherosclerosis by different pathogenetic mechanisms. Inflammation is multifactorial in cause and while it may reflect underlying CVD, the acute-phase response may also contribute to both oxidative stress and progressive vascular injury. Recent findings suggest that anaemia is associated with increased oxidative stress and various anti-oxidant treatment strategies have been associated both with a reduction in oxidative stress and in the required dose of ESA in patients with CKD. Conversely, there may be pro-oxidant effects from treatment of anaemia with ESA and iron. Controlled trials are needed before evidence-based recommendations for the management of inflammation-induced anaemia and ESA resistance can be defined. In particular, the risks and benefits of i.v. iron and the effects of various iron dosage schedules warrant further careful evaluation in prospective studies.


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