Oxidative Stress in Uremia: The Role of Anemia Correction
Vicente Lahera*,
Marian Goicoechea,
Soledad García de Vinuesa,
Pilar Oubiña*,
Victoria Cachofeiro*,
Francisco Gómez-Campderá,
Raquel Amann and
José Luño
* Department of Physiology, School of Medicine, Universidad Complutense, and Department of Nephrology, Hospital General Universitario Gregorio Marañon, Madrid, Spain
Address correspondence to: Dr. Vicente Lahera, Department of Physiology, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain. Phone: +34-91-394-2287; Fax: +34-91-394-1628; E-mail: vlahera{at}med.ucm.es
Patients with chronic kidney disease (CKD) are prone to developcardiovascular disorders. Numerous reports have shown the associationbetween uremia and oxidative stress, which increases patients’risk for cumulative injury to multiple organs. Anemia is a commonand disabling feature of CKD and seems to be a main cause ofoxidative stress; correction of anemia represents an effectiveapproach to reduce oxidative stress and, consequently, cardiovascularrisk. There is increasing evidence that correction of anemiawith erythropoiesis-stimulating agents could protect from oxidativestress in patients with CKD and ESRD. However, iron deficiencyfrequently complicates anemia in patients with CKD, and ferrousiron cation is a co-factor that is needed for hydroxyl radicalproduction, which can promote cytotoxicity and tissue injury.This has raised a justifiable concern that prescription of intravenousiron may exacerbate oxidative stress and, hence, endothelialdysfunction, inflammation, and progression of cardiovasculardisease, which are widely known consequences of CKD. Correctionof anemia represents an effective approach to reduce oxidativestress and, consequently, cardiovascular risk. Iron deficiencyis a common cause of resistance to erythropoiesis-stimulatingagents, and the overall risk-benefit ratio favors use of intravenousiron to treat iron deficiency in patients with CKD. Consecutiveor combined treatment with intravenous iron and erythropoiesis-stimulatingagents clearly is beneficial for patients with CKD and irondeficiency, and anemia and could contribute to prevent the riskfor cardiovascular events in these patients.
Oxidative stress can be considered an imbalance between reactiveoxygen species (ROS) production and antioxidant defense. Thisimbalance can lead to the oxidation of molecules, resultingin tissue damage. The "oxidant condition" mainly depends onthe oxidative processes inside the organism (1). Alterationsin mitochondrial enzyme complex cytochrome oxidase accountsfor an important part of oxidative processes, because the mitochondriahandles 90% of total oxygen in a human. A fraction of oxygenthat is metabolized in the mitochondria can leak through theelectron transport chain, forming reactive oxygen intermediatesand oxygen free radicals such as superoxide anions and hydrogenperoxide. These ROS can diffuse out of the mitochondria, beingan important source of oxidative stress (1,2). Another sourceof ROS is the NAD(P)H oxidase, which is important in endothelialand phagocytic cells. In addition, xanthine oxidase is a mainsource of oxygen species in occlusion-reperfusion situations.On the other side, a number of enzyme activities such as superoxidedismutase, catalase, glutathione (GSH) reductase (GRed), andGSH peroxidase (GPx) are determinants of antioxidant defense,leading to ROS clearance and buffering (1,3,4). Reduced GSHis a primary antioxidant that has been proposed as a major scavengerof ROS. Levels of GSH are maintained in the cells by the GPx/GRedsystem. GPx catalyzes the reduction of H2O2 to H2O, which iscoupled to the oxidation of GSH to its disulfide form, GSSG.The reduction of GSSG to GSH is coupled to the oxidation ofNADPH to NADP+ through GRed. Erythrocytes play a key role inthe maintenance of both systemic and local redox balance, asa result of their ability to recycle GSH formation through theGPx/GRed system. Therefore, evaluation of GSH system parametersin erythrocyte is considered a reliable method to study redoxstatus (4).
ROS are part of the unspecific defense system of an organism.However, ROS also may affect cells of the host organism, inparticular at sites of inflammation, which plays a role in avariety of renal diseases, such as glomerulonephritis, acuteor progressive renal failure, or tubulointerstitial nephritis(1,3), contributing to proteinuria. ROS also are consideredto contribute to the pathogenesis of ischemia-reperfusion injury(5).
From a vascular point of view, many studies have shown thatatherosclerosis and risk factors for the development of thedisease are associated with an exaggerated production of ROS.Atherosclerosis involves the participation of several cell typesand processes, such as endothelial dysfunction, oxidation, inflammation,and fibrinolytic imbalance (6). ROS are determinants for theoxidation of LDL, which are taken up by macrophages, leadingto the formation of foam cells. In addition, ROS and, specifically,superoxide anions participate in an important manner in theprocesses that are involved in the progression of atherosclerosis.In turn, oxidized LDL also are capable of enhancing generationof ROS via stimulation of NAD(P)H oxidase in endothelial cellsand smooth muscle cells (6). Superoxide anions combine withnitric oxide to form peroxynitrite, thereby contributing toendothelial dysfunction and the subsequent alterations thatare related to the loss of nitric oxide availability. Furthermore,enhanced superoxide formation results in either cell proliferationor apoptotic death of endothelial cells (7). Many data indicatethat ROS contribute to the progression and complications ofatherosclerosis by stimulating various intermediate and transcriptionfactors that lead to the formation of adhesion molecules, cytokines,and metalloproteinases, which participate in the progressionand complications of atherosclerosis (6).
Recent studies have shown that oxidative stress is highly presentin patients with renal disease (1,3). It is known that LDL fromuremic patients present an elevated susceptibility to oxidation,being an indication of accelerated atherosclerosis in thesepatients. Uremic oxidative stress is characterized from a biochemicalpoint of view as a state of reactive aldehyde and oxidized thiolgroup accumulation, together with depletion of reduced thiolgroups, which are particularly important as part of antioxidantdefense. As a consequence of diminished renal catabolism andfunction, uremic oxidant mediators accumulate, favoring vascularcell dysfunction and progression of atherosclerosis. In additionto the mentioned oxidized thiol groups, homocysteine accumulatesin uremic patients and may contribute to atherosclerotic disease(8). Epidemiologic studies have correlated hyperhomocysteinemiawith atherosclerotic disease not only in the general populationbut also in hemodialysis patients. It should be mentioned thatelevated inflammatory markers such as C-reactive protein andcytokines are highly prevalent in patients with ESRD (8). Infact, a linkage among increased oxidative stress, inflammation,and endothelial dysfunction in hemodialysis patients was describedrecently. Furthermore this synergistic linkage could contributeto increased cardiovascular risk in uremic patients (9).
Oxidative stress occurs when ROS exceed antioxidant defense,which is replenished continually by ingestion of nutrients.Malnutrition is relatively common in uremic patients and maycontribute to increased oxidative stress (10). In fact, malnourisheduremic patients present increased markers of oxidative stressthan well-nourished uremic patients (9,10).
Anemia is a common and disabling feature of CKD. There is increasingevidence from epidemiologic studies of an association betweenanemia and cardiovascular mortality. The Atherosclerosis RiskIn Communities (ARIC) study revealed that individuals with anemiahad a worse prognosis than those with normal hemoglobin levelsand demonstrated that anemia was associated independently withan increased risk for cardiovascular disease (11). Several studiesshowed that in patients with ESRD, low hematocrit levels wereassociated with a marked increased in cardiovascular morbidityand mortality (12). There are several reasons to explain therelationship between anemia and adverse cardiac outcomes. First,anemia is a marker of poor cardiac function. Second, it is acausative risk factor for cardiac ischemia, because coronaryartery disease limits the ability to extract oxygen from hemoglobin.Third, the physiologic adaptive response to anemia is an increasein cardiac output. This initial compensatory benefit is limited,because a chronic adaptation to low hemoglobin levels may increaseleft ventricle growth in response to increased myocardial workload.In fact, several studies demonstrated the association betweenanemia and left ventricular hypertrophy in nonrenal patientsand in patients who had CKD, were on dialysis, or received arenal transplant (13).
Uremic patients are characterized by a predominant state ofoxidative stress, and anemia seems to be a main cause for thisredox imbalance (14). Regular supplements of intravenous ironand erythropoiesis-stimulating agents are standard therapiesfor treatment of anemia in patients with CKD. Consequently,correction of anemia in uremic patients, besides its primarybeneficial effects, represents an effective approach to reduceoxidative stress and hence potential cardiovascular risk. Thereis increasing evidence that erythropoiesis-stimulating agentscould protect from oxidative stress in patients who are on hemodialysisor peritoneal dialysis (1,3). Treatment with erythropoiesis-stimulatingagents decreases patient morbidity and mortality, particularlyas a result of cardiovascular disease in patients with ESRD(15). Furthermore, treatment of anemia with erythropoietin hasbeen shown to produce regression of left ventricular hypertrophyin patients with CKD (16).
Intravenous iron supplements are incorporated rapidly into thetransferrin and ferritin system for iron transport and storage.However, large doses of intravenous iron may exceed storagecapacity leading to certain amounts of unbound iron in plasma.Ferric iron can be reduced to the ferrous form, which, via theFenton reaction, can produce the hydroxyl radical, one of themost potent ROS. This has raised a justifiable concern thatintravenous iron may exacerbate oxidative stress and, hence,endothelial dysfunction, inflammation, and progression of cardiovasculardisease (17,18).
Evaluation of redox status in erythrocytes has been used asa reliable method to evaluate oxidative stress and antioxidantdefense in patients with CKD (19,20). We aimed to investigatethe effects of intravenous iron treatment followed by subcutaneous-darbepoetin treatment on erythrocyte redox status in nine nondialysispatients with CKD (Table 1). As expected, hematocrit and hemoglobinincreased after intravenous iron and -darbepoetin treatments.However, none of the treatments modified plasma concentrationsof iron, ferritin, or transferrin or transferrin saturation.The results support the oxidant effect of intravenous iron becauseiron treatment was associated with the elevation of malondialdehydelevels, an index of lipid peroxidation. Erythrocyte GSH/GSSGratio decreased after iron treatment. This was due to a netdecrease of GSH without changes in GSSG. Administration of -darbepoetinreturned malondialdehyde levels to values comparable to thoseobserved before iron treatment and markedly increased GSH/GSSGratio. This was due to an important elevation of GSH by -darbepoetin,without changes in GSSG. Similarly, The changes in GSH thatwere observed seem to be due to a marked increase of GPx activityafter iron and a decrease after -darbepoetin, together withmoderate changes of GRed activity. These effects of the treatmentson erythrocyte redox balance occurred without changes in serumcreatinine, creatinine clearance, C-reactive protein, and homocysteine.This clinical study in a small number of patients with CKD showsthat intravenous iron increases oxidative stress by diminishingerythrocyte antioxidant defense. Administration of -darbepoetinrebalanced GSH/GSSG system, further supporting the clinicalbenefits of anemia correction with erythropoiesis-stimulatingagents on oxidative stress in patients who have CKD and receiveintravenous iron supplements.
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Abstract
Oxidative Stress: Definition and...
-darbepoetin treatment on erythrocyte redox status in nine nondialysis patients with CKD (Table 1). As expected, hematocrit and hemoglobin increased after intravenous iron and 
