Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Update on Erythropoietin Treatment: Should Hemoglobin Be Normalized in Patients with Chronic Kidney Disease?
Ernesto Paoletti and
Giuseppe Cannella
Divisione di Nefrologia, Dialisi e Trapianto, Azienda Ospedaliera Universitaria San Martino, Genova, Italy
Address correspondence to: Dr. Ernesto Paoletti, Divisione di Nefrologia, Dialisi e Trapianto, Azienda Ospedaliera Universitaria San Martino, Genova, Italy. Phone: +39-010-555-3878; Fax: +39-010-555-6652; E-mail: ernesto.paoletti{at}hsanmartino.it
The partial correction of ESRD anemia by recombinant human erythropoietin(EPO) has resulted both in generalized improvement in qualityof life and physical activity and in reduced mortality and hospitalizationrate. The question remains as to whether normalizing hemoglobin(Hgb) is desirable in patients with chronic kidney disease (CKD).This review provides an analysis and commentary on the availablereports and, for the most part, randomized, controlled trialson the topic. In dialysis patients, normalization of Hgb isassociated with improved quality of life and exercise capacitybut not with reduced mortality and hospitalization rate. Moreover,no significant changes in the degree of left ventricular hypertrophyhave been demonstrated. By contrast, an increased mortalityrate has been reported for hemodialysis patients with overtcardiovascular disease (CVD) when randomly assigned to normalhematocrit by EPO. Data regarding patients who have CKD butare not yet on renal replacement therapy are scarce, and theeffects of EPO on renal disease progression require furtherelucidation through controlled trials. The conclusion that canbe drawn from the available studies is that Hgb >11 g/dlis the minimum required to achieve improved quality of lifein patients with CKD, whereas values >12 g/dl are not recommendedfor patients with overt CVD. Finally, Hgb normalization mightreasonably be restricted to a selected population of younger,employed, and active individuals, provided that they do nothave CVD.
The partial correction of ESRD anemia by recombinant human erythropoietin(EPO) has resulted in generalized improvement in patients’clinical conditions and outcomes. Indeed, current evidence existsthat a hemoglobin (Hgb) level >11 g/dl is associated withimprovement in quality of life (1), with increase in physicalperformance (2), with reduced risk for hospitalization, andwith lower relative risk for mortality (3–5). Furthermore,partial correction of ESRD anemia has been shown to be effectivein inducing a significant regression and even a renormalizationof the left ventricular hypertrophy (LVH) of uremic anemic patients(6).
Consistent with this body of evidence, the National Kidney FoundationDialysis Outcomes Initiative (K/DOQI) guidelines for the managementof anemia of chronic kidney disease (CKD) recommend Hgb valuesbetween 11 and 12 g/dl (7), whereas the recently updated versionof the European Best Practice Guidelines recommends a minimumtarget Hgb value of 11 g/dl without indicating an upper Hgblevel limit (8). However, the optimal Hgb target level has notbeen elucidated clearly, and debate continues as to whetherHgb should be normalized in patients who have ESRD, with theaim of further improving their general and cardiovascular (CV)outcomes.
Quality of life further improved after normalization or nearnormalization of Hgb (9–11). Moreover, normalization ofHgb has been associated with greater work capacity (12), althougha significant increase in maximum oxygen uptake after exercisewas demonstrated only in trained individuals regardless of thelevel of Hgb, suggesting that factors other than anemia correctionmight play a role in the improvement of physical performance(13).
Hgb values >12 g/dl have been associated with significantdecrease in the risk for death as compared with the 11- to 12-g/dlHgb target values recommended by K/DOQI guidelines, and thesame was observed for the hospitalization rate (14). However,no difference was demonstrated in the mortality rate of patientswith normalized Hgb as compared with patients with Hgb in K/DOQIrange when data were adjusted for covariates such as age, race,gender, body mass index, albumin concentration, urea reductionratio, and the presence of diabetes (14). The number of hospitalizationsalso was not significantly different after adjustment for thesame covariates (14).
Randomized, Controlled Trials Comparing Normal and Subnormal Hgb Levels
A meta-analysis by Strippoli et al. (15) on behalf of the CochraneRenal Group evaluated the randomized, controlled trials thathave compared the effects of normal and subnormal Hgb levelsin renal patients. The authors found four studies in 1949 patientsthat compared subnormal and normalized Hgb and three studiesin 255 patients that compared untreated and EPO-treated patients.The analysis found that relative risk for death from all causeswas actually raised in the group with normalized Hgb as comparedwith lower Hgb, whereas no significant differences were evidentin untreated patients as compared with treated patients. Moreover,no differences in the relative risk for arterial hypertensionwere demonstrated between subnormal and normalized Hgb groups,whereas an increase in the development of hypertension in EPO-treatedpatients emerged from the studies that compared treated anduntreated patients (15). The main source of the meta-analysisdata, with a weighting ranging from 72 to 86% of the total,was the Normal Hematocrit Cardiac Trial published by Besarabet al. (16) in 1998. This trial was designed to ascertain whetherfurther benefit could be gained by normalizing Hgb concentrationin dialysis patients with ischemic heart disease (IHD) or cardiacfailure. The study was interrupted after an interim analysisidentified a borderline higher mortality rate in the group ofpatients who were randomly assigned to normal Hgb. Subsequentanalysis of data, however, failed to demonstrate a causal relationshipbetween the normalization of Hgb and mortality. Furthermore,the analysis of the secondary CV end points of that study, suchas hospitalization for congestive heart failure (CHF) or IHD,nonfatal myocardial infarction, and the incidence of revascularizationprocedures, confirmed that no significant differences existedbetween normalized and lower Hgb groups. Therefore, the conclusionthat can be drawn from study of Besarab et al. (16) is thatachieving an Hgb target of almost 14 g/dl does not confer anyadvantage to patients with ESRD, at least in the case of patientswith CV disease (CVD).
The Scandinavian Multicentric Study, which evaluated >300patients who had ESRD and were on renal replacement therapy(RRT) and 72 patients who had CKD and were not yet on a dialysisregimen, confirmed that achieving near-normal Hgb did not reducethe risk for death from all causes or the risk for cardiac death.The latter risk actually increased slightly, although not significantly,in the group of dialysis patients with normalized Hgb concentration(11).
The Multicenter Canadian Trail evaluated the impact of Hgb normalizationon cardiac outcomes in dialysis patients with asymptomatic cardiomyopathy.The achievement of normal Hgb did not significantly reduce eitherleft ventricular mass or volume as compared with lower Hgb inpatients with either pre-existing concentric LVH or left ventriculardilation (10). Indeed, maintaining subnormal Hgb concentrationby EPO in dialysis patients was enough to obtain a regressionof LVH provided that an adequate BP control and a reductionin pulse pressure were achieved by means of angiotensin-convertingenzyme inhibitors (17).
The great majority of studies that have evaluated the effectsof partial or complete correction of the anemia of ESRD havefocused on patients who were undergoing RRT. By contrast, veryfew data are available on patients with CKD before the startof RRT. In this setting, an unfavorable scenario was demonstratedby a recent survey from the European Dialysis and TransplantAssociation, which showed that <30% of predialysis patientswith CKD had Hgb >11 g/dl, and only 25% were on establishedEPO treatment (18). This report is concerning because patientswho did not receive EPO in the predialysis phase had greaterincidence of both CHF and IHD.
The only randomized, controlled trial of predialysis CKD isthe study by Roger et al. (19), in which the impact on cardiacand renal outcomes of an early treatment with EPO that achievedhigher Hgb levels as compared with late intervention with lowerHgb was evaluated in patients with stages 3 to 4 CKD. Aftera 2-yr observation period, the left ventricular mass did notchange significantly in either group. In another study, Silverberget al. (20) reported a significant improvement in CV outcomeand even a slowing in the progression of renal insufficiencyafter near normalization of Hgb by means of early treatmentwith EPO in both patients with and without diabetes and withCHF and mild renal dysfunction.
Indeed, published reports have proposed some potential benefitsof EPO treatment on renal damage and the progression of renaldisease (21,22), possibly by reducing the degree of tubulardamage and the extent and progression of interstitial fibrosis(23). In one such study, patients who were treated with EPOhad a slower decline of renal function than did untreated patients(21), whereas near normalization of Hgb was associated withlower serum creatinine values after 1 yr of observation in anotherstudy (22). Results from these observational studies, however,are not consistent with data from Roger et al. (19), who foundno difference in the rate of decline of renal function in patientswith Hgb that ranged from 12 to 13 g/dl compared with patientswith Hgb levels of 9 to 10 g/dl.
Although K/DOQI Clinical Practice Guidelines (7) recommend targetHgb levels between 11 and 12 g/dl, this range may be too narrow.Indeed, a great variability exists in Hgb concentration in patientswith ESRD. Many factors that are linked to individual responseto EPO, variability in anemia management, and even in Hgb targetand action threshold are involved. As a consequence, the optimalHgb level and upper limit of the desired range have not beenelucidated clearly. Lacson et al. (24) tracked patients whohad ESRD and who were enrolled in Fresenius Medical Care NorthAmerica and evaluated a 3-mo rolling average Hgb level, withthe aim of quantifying the degree of Hgb variability and thepercentage of patients with Hgb >12 g/dl when patients weretreated to avoid lower Hgb limit. Only 38% of patients had Hgblevels within the K-DOQI range for target Hgb, with >60%having Hgb <11 g/dl or >12 g/dl. Through the subsequent9 mo, a rightward shift was observed in the curve of distributionof Hgb to meet goal. A 23% increase in patients with Hgb >12g/dl and 33% in patients with Hgb >12.5 g/dl was needed toreduce by approximately 20% the number of patients with Hgbbelow the lower limit of 11 g/dl. According to these results,an upper Hgb limit of 13.6 g/dl and a level range of 11 to 13.6g/dl seems reasonable and seems to provide a more realisticoutcome expectation (24).
The strategy of increasing or even normalizing Hgb in renalpatients raises financial issues. In the United States, achievinghigher Hgb has been associated with a large expenditure forEPO, approaching $1.5 to 2.0 billion per year. This expensemay be higher than necessary without resulting in optimal benefitfor patients (25). Indeed, large EPO doses are required mostlyto increase Hgb from 12 to upper levels. However, although thetransition from a subnormal Hgb level to the K/DOQI guidelines’Hgb target is associated with a significant increase in lifeexpectancy, according to a Markov model simulation that evaluatedthe quality-adjusted life years, only a small gain is associatedwith further Hgb increase to 12.5 or even 14 g/dl (26). It isinteresting that the cost per quality-adjusted life year gainedper patient is in the region of $55,000 for transition fromsubnormal Hgb to target level, whereas it approaches $800,000for Hgb normalization. Therefore, a great increase in expendituresresults in only a relatively small increase in life expectancy.
The normalization of Hgb in renal patients seems to be associatedwith further improvement in quality of life and physical activitybut with no significant differences in mortality rate, hospitalizationrate, and the extent of LVH regression. Moreover, normalizingHgb has been associated with a higher incidence of vascularaccess clotting (16), whereas the effect of normalized Hgb inpreserving renal function needs to be clarified. Hgb of 11 g/dlseems to be an appropriate minimum target, whereas it probablyis wise not to recommend Hgb concentration >12 g/dl for patientswith known CVD. The normalization of Hgb may be advisable inselected patients who are younger, employed, and leading anactive life, provided that CVD is absent (27) and taking properaccount of the financial implications. Regardless of whethernormalization of Hgb is desirable, we are convinced that themost stringent goal for renal anemia treatment at the beginningof the third millennium is to ensure the minimum Hgb targetof 11 g/dl for all renal patients, in particular, those withpredialysis CKD, with the aim of effectively improving theirgeneral and CV outcome.
Acknowledgments
We thank Mark Northway for help in the revision of the manuscript.
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Abstract
Introduction
