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Nephrol Dial Transplant (2005) 20 [Suppl 8]: viii2viii7

doi:10.1093/ndt/gfh1109

Inflammation and resistance to erythropoiesis-stimulating agentswhat

do we know and what needs to be clarified?

Jana Smrzova1, Jozsef Balla2 and Peter Ba ra ny3

1Haemodialysis Centre, University Hospital Brno, Brno, Czech Republic, 2Division of Nephrology and

Haemodialysis Unit, University of Debrecen, Debrecen, Hungary and 3Division of Renal Medicine,

Karolinska Institutet, Karolinska University Hospital Huddinge, Sweden

Abstract

Resistance to erythropoiesis-stimulating agents (ESA)in patients with chronic kidney disease (CKD) can beassociated with evidence of enhanced systemic inflam-matory responses. This review considers the inflam-matory mechanisms thought to be involved in thedevelopment and aetiology of anaemia of CKD thatmay help our understanding and management ofpatients with ESA resistance. The potential role ofnutritional support and of anti-inflammatory therapiesin managing resistance to ESA therapy is discussedand explored.

Keywords: anaemia; darbepoetin; epoetin;

hyporesponse; inflammation; resistance

Introduction

Anaemia associated with chronic kidney disease(CKD) develops gradually during progressive declineof renal function and is characterized by a relativedeficiency of erythropoietin secretion from thediseased kidney in relation to the degree of anaemia.More than 90% of patients with anaemia of CKDrespond adequately to erythropoiesis-stimulatingagents (ESAs) at doses of

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amyloid A protein, which can increase as much as 100-to 1000-fold in response to severe infections. Otherpositive acute phase proteins that rise during inflam-mation are complement factors, fibrinogen andhaptoglobin. Negative acute phase proteins such asalbumin decrease during inflammation [1214]. Inclinical practice, measurement of CRP levels is widelyused to monitor inflammation. Assay of CRP offers

a reliable and readily available test that is simple,sensitive and inexpensive. However, it is a non-specificindicator of inflammation that does not differentiateeither between infection and other underlyingcauses of inflammation or between acute and chronicinflammation. Although direct measurement ofother cytokines can be performed using commercialassays, to date high costs and a lack of standardiza-tion have restricted the use of these tests to clinicalstudies.

Mechanisms of inflammatory-inducedESA resistance

Elevated cytokine levels and enhanced oxidativestress are implicated in the development of anaemia.Accumulating evidence suggests that activation ofacute phase responses and the cytokine cascadeoccurs in patients with CKD [9,11,15]. Activation ofthe immune system diverts iron traffic from erythro-poiesis to storage sites within the reticuloendothelialsystem, inhibits erythroid progenitor proliferationand differentiation, suppresses erythropoietin produc-tion, blunts response to erythropoietin and acceleratesdestruction of erythrocytes coated with immunecomplexes or immunoglobulins [16].

Pro-inflammatory cytokines such as interferon-g(IFN-g) and tumour necrosis factor-a (TNF-a)diminish colony formation of burst-forming unit-erythroid cells (BFU-Es) and colony-forming unit-erythroid cells (CFU-Es) [17,18]. IFN-g appears tobe the most potent inhibitor of CFU-E proliferation,probably accounting for the inverse correlationbetween plasma IFN-g levels and reticulocyte count[19]. It has been demonstrated that serum derivedfrom uraemic patients suppresses the normal erythroidcolony-forming responses to erythropoietin in amanner that can be inhibited by antibodies againstIFN-g and TNF-a, suggesting a key role for theseinflammatory mediators in uraemia [20]. It has also

been demonstrated that high circulating levels ofblood soluble receptor p80 for TNF-a are associatedwith ESA resistance in haemodialysis patients [21].These marked inhibitory effects of IFN-g and TNF-aon erythroid progenitor cells might be related tothe ability of these cytokines to generate nitric oxide(NO) [22], a substance that is known to suppress theproliferation of erythroid progenitor cells.

In poor responders to ESA, there is increasedexpression of CRP and of erythropoiesis-inhibitingcytokines such as TNF-a, IFN-g, IL-10 and IL-13 byT cells [20,23]. Data from in vitro studies also support

a relationship between high levels of IFN-g or TNF-aand a need for increased doses of erythropoietin toeffect and restore CFU-E colony formation [24].

Diversion of iron traffic from erythropoiesisto storage in chronic inflammation

Activation of the cytokine cascade and associated

acute phase responses induce alterations in ironmetabolism. Hypoferraemia occurs because ofenhanced iron retention and storage within thereticuloendothelial system during inflammation, andthis limits the availability of iron for erythropoiesis.Studies in mice have shown that pro-inflammatorycytokines derived from Th1 (T-helper 1) lymphocytesprovoke both hypoferraemia and anaemia, andthat recombinant TNF-a and recombinant IL-1 causea significant decrease in serum iron levels [25].In humans, administration of recombinant humanTNF-a or recombinant human IFN-g results inhypoferraemia accompanied by an increase in circulat-

ing ferritin concentration and a decrease in solubletransferrin receptor levels [26,27]. There are alsoin vivodata to suggest that pro-inflammatory cytokinesor lipopolysaccharides (LPS) can alter the regulationof several genes involved in iron uptake, storageand utilization in various cell types [28].

Increased expression of ferritin andenhanced iron sequestration

During development of erythroid and other cells,two iron-regulatory proteins (IRP-1 and IRP-2) actto control the level of the intracellular labile iron.These iron-regulating proteins act at the translationallevel to regulate synthesis of the transferrin receptor(divalent metal transporter 1, which determines ironuptake by the cells) and of ferritin (which determinesintracellular iron sequestration) [29,30].

NO and reactive oxygen species

Recent research supports the concept that cytokine-induced alterations in cellular iron homeostasisare mediated in part by the increased production ofNO [28,3139] and reactive oxygen species [40,41]. Inmacrophages exposed to LPS and IFN-g, a dramaticincrease in ferritin synthesis can be observed [28,37,39],

and several laboratories have reported that NOenhances the IRE (iron response element)-bindingactivity of IRP-1 in various cell types [3136].Moreover, the NO-mediated increase in IRP-1 activityhas been shown by some investigators to be accom-panied by translational repression of ferritin synthesisin macrophages and other cells [3133,35,36]. However,these data are in conflict with many other studiesdemonstrating that inflammatory cytokines, which areknown to induce NO production in macrophages,actually stimulate ferritin synthesis [28,3739]. Theseparadoxical results might be explained by the fact that

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NO exhibits markedly different biological effectsdepending upon its redox state. NO in its reducedform, NO, has high affinity for iron and altersthe [FeS] cluster of IRP-1, resulting in highbinding activity for IRE [31,33,34]. In contrast,the oxidized form of NO (NO, nitrosonium ion)causes S-nitrosylation of thiol groups in IRP-2and IRP-1, thereby markedly decreasing the IRE-

binding activity of IRPs [28,3739], which in turnleads to increased ferritin synthesis. In macrophagesof the reticuloendothelial system, cytokine-induceddegradation of IRP-2 mediated by NO might beresponsible for the dramatic upregulation of ferritinsynthesis and the resulting increased sequestration ofintracellular iron [28].

Pro- and anti-inflammatory processes

It is intriguing to note that not only pro-inflammatorybut also anti-inflammatory cytokines play major rolesin the regulation of intracellular iron homeostasis [36].In activated murine macrophages, IL-4 and IL-13increase ferritin translation by opposing the bindingactivity of IRPs for IRE in the 50-untranslated regionof ferritin mRNAs. These anti-inflammatory cytokinesare thought to suppress NO formation, and mayalso alter its redox state, favouring the formation ofthe oxidized form of NO. Thus, T-helper 2 (Th2)lymphocyte-derived anti-inflammatory cytokines areable to increase iron sequestration in activated macro-phages and may also contribute to the developmentof anaemia [36].

Reactive oxygen species such as O2 (superoxide

anion) and H2O2 (hydrogen peroxide) are potentiallytoxic by-products of aerobic metabolism. Studies in

liver lysates have shown that superoxide anion orhydrogen peroxide alone lack reactivity toward IRP-1,but the combined action of these two reactive speciescan induce reversible inactivation of IRP-1 for IRE [41].

In contrast, an exogenous pulse or an enzymaticsource of hydrogen peroxide has been shown toprovoke a rapid increase in IRP-1 activity in cells ortissues [40]. Data suggest that IRP-2 is also highlysensitive to oxidative modification by endogenousreactive oxygen and is accompanied by proteasome-mediated degradation of this regulatory protein [42].However, the binding activity of IRP-2 is not affectedby exposure to exogenous hydrogen peroxide. Thus,on balance, there is evidence that oxidative stress

during inflammation may alter the expression offerritin synthesis at a translational level and that,under certain conditions, transcriptional mechanismsare also affected [43].

Cytokine-mediated alteration in the IRE-bindingactivity of IRPs, and the diminished availability ofapotransferrin during inflammation, leads to reducediron transport into the portal circulation. Indeed,impaired mucosal absorption of iron is seen inhaemodialysis patients with increased CRP levels [44].

According to recent data, a key factor in thedevelopment of functional iron deficiency may be the

IL-6-induced production of hepcidin in the liver.Hepcidin is a peptide that is a negative regulator ofiron absorption in the small intestine and iron releasefrom macrophages [45]. High levels of hepcidin havebeen found in patients with anaemia of chronic diseasesand in CKD patients with anaemia [46,47].

What are the roles of nutritional support, vitaminsand co-factors in anaemia treatment?

End-stage renal disease patients often have a lowprotein and energy intake, which may affect the level ofnutrients essential to erythropoiesis and also contributeto a shorter erythrocyte life span [48]. In non-renalpopulations, it is known that severe malnutrition isassociated with anaemia, which can be reversed bynutritional intervention [49]. CKD patients with alow body mass index (BMI) are more likely to sufferfrom severe anaemia than obese patients, who appearto have higher leptin levels [5052]. Indeed, obesity

has been associated with reduced ESA needs (per kgbody weight) in the management of anaemia. However,to date, there are no data for anaemic CKD patientsto suggest a direct clinical benefit of managementwith protein- and energy-rich nutritional supplements,although there are early reports that amino acidketoanalogues may help improve anaemia in dialysispatients [53].

Anti-inflammatory and/or anti-oxidative agentswith potential effects on ESA resistance

The body produces a wide array of natural anti-oxidants in an attempt to curtail the harmful effect ofreactive oxygen species. Endogenous enzymatic anti-oxidants include superoxide dismutase, catalase andglutathione peroxidase [54,55]. Each of these enzymesreduces the reactivity of reactive oxygen species;superoxide dismutase catalyses the dismutation of O2to H2O2, catalase reduces H2O2to water, and selenium-containing glutathione peroxidase reduces organiclipid peroxides in the presence of glutathione [55].Other, non-enzymatic anti-oxidative agents, such asglutathione, vitamin E, vitamin C, transferrin andalbumin [54], act as scavengers for reactive species suchas H2O2, OH

(hydroxyl anion) and chlorinated

oxidants, and prevent lipid peroxidation.A number of different observations and studies

attest to the anti-oxidant properties of vitamins.Vitamin E has been shown to reduce CRP andmonocyte IL-6 levels in healthy volunteers and inpatients with diabetes mellitus type 2 [56]; it is alsoknown to inhibit the activation of protein kinase Cand nuclear factor-kB by reactive oxygen species [57].A recent study demonstrated that g-tocopherol andits metabolite may exert a significant anti-oxidativeactivity [58], and coating of dialyser membranes withvitamin E has been shown to reduce oxidative stress

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parameters during dialysis [59,60]. Vitamin E may,together with vitamin C, reduce oxidative stressinduced by i.v. iron administration [61], and treatmentwith vitamin E has been shown to reduce the dosagerequirements for ESA [62].

Vitamin C also appears to be beneficial for liberationof iron from its stores [63], and improves the responseto ESA in iron-overloaded patients [64,65]. However,

although a daily vitamin C dose of 150 mg is usuallyconsidered safe [66], i.v. vitamin C treatment mustbe administered with caution during anaemia sincehigh doses may result in oxalate accumulation(especially in case of vitamin B6deficiency).

Glutathione has anti-oxidant properties and hasbeen reported to prolong erythrocyte survival, improveanaemia and reduce the need for ESA in dialysispatients when used either alone [67,68] or in combina-tion with vitamin E-coated dialysers [69].

Melatonin is thought to prevent defective mito-chondrial oxidative phosphorylation by stimulationof complex I and IV of the electron transport chainenzymes in mitochondria [70]. This endogenoussubstance has been reported to reduce the oxidativestress induced by i.v. iron and ESA therapy [71].Omega-3-fatty acids have not been shown to havea positive effect on anaemia [72]. Other compoundsthat have been studied for their anti-oxidant proper-ties, such as selenium and the statin class of lipid-lowering drugs, have not been tested in the context ofrenal anaemia.

Cytokines or their antagonists have been usedsuccessfully in the management of many inflammatorydiseases and wasting syndromes and, currently,monoclonal antibodies such as anti-TNF-aantibodies,soluble TNF-a receptors, IL-1 and IL-6 receptor

antagonists are available as therapeutic agents.Anti-TNF-a antibodies have been shown to improveanaemia in patients with rheumatoid arthritis [73,74],but to date no data are available on the use of thesenovel therapeutic agents in anaemic CKD patients.

Pentoxifylline is a phosphodiesterase inhibitor usedin the management of peripheral vascular diseasebecause of its anti-platelet effects and influenceson erythrocyte deformability. Recently, anti-cytokineproperties of this drug have been described includ-ing anti-TNF-a, anti-IFN-g, anti-IL-10, anti-oxidantand anti-apoptotic effects [75,76]. Treatment withpentoxifylline induces a drop in TNF-a and IFN-gproduction with a concomitant increase in Hb levels

[75,76]. Once again, the potential of this agent in themanagement of anaemia of CKD has not been fullyexplored.

Anaemia and co-morbidityneed for more study

To date, there has been a lack of well-designedinterventional studies in CKD patients with inadequateresponse to ESA. With the exception of parenteraliron treatment for hyporesponsiveness to ESAs, mostclinical studies conducted in this area have either been

open and uncontrolled in design or have lacked thepower to detect clinically important effects on ESAresponsiveness.

However, before large and well-designed studies canbe performed to investigate the therapeutic potentialof some of the putative anti-inflammatory agentsdescribed in this review, more information regardingthe characteristics of inflammatory hyporesponsiveness

needs to be obtained. Low Hct levels and poor ESAresponsiveness are often linked to inflammation, mal-nutrition and cardiovascular disease [5]. This triad con-stitutes the malnutritioninflammationatherosclerosis(MIA) syndrome and is strongly associated with agreater risk of death in haemodialysis patients [77].Since persisting anaemia in ESA-treated patients isoften associated with significant co-morbidity, increas-ing Hb levels without first attempting to treat under-lying conditions may fail to reduce morbidity andmortality [78]. The results of future basic and clinicalresearch into this intriguing area of clinical medicineare eagerly awaited.

Conflict of interest statement. None declared.

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