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Nephrology Dialysis Transplantation 2007 22(Supplement 4):iv10-iv18; doi:10.1093/ndt/gfm161
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. for Permissions, please email: journals.permissions@oxfordjournals.org

Maintaining control over haemoglobin levels: optimizing the management of anaemia in chronic kidney disease

Peter Bárány1 and Hans-Joachim Müller2

1Division of Renal Medicine, Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden and 2Medizinische Klinik III, Klinikum Fulda, Fulda, Germany

Correspondence and offprint requests to: Peter Bárány, MD, PhD, Department of Renal Medicine, K56, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden. Email: Peter.Barany{at}klinvet.ki.se



   Abstract
Top
 Abstract
Introduction
 Haemoglobin targets
 Haemoglobin control over time...
 Factors impacting Hb variability...
 Criteria for defining...
 Conclusions
 References
 
The introduction of erythropoiesis-stimulating agents radically advanced the management of anaemia associated with chronic kidney disease (CKD). The European Best Practice Guidelines recommend that most patients with CKD achieve a target haemoglobin (Hb) ≥11 g/dl to reduce the risk of adverse outcomes. The optimal upper Hb level has not been determined and will likely vary among CKD patient populations. Recently reported studies show evidence that normalising Hb (~14 g/dl) in CKD may increase the risk of adverse events and puts attention to the importance of the upper Hb target. Most patients can achieve target Hb levels with proper treatment. However, recent studies have demonstrated that while average Hb levels may fall within desired targets, the Hb levels of many patients are not being adequately controlled, i.e. their Hb levels are not consistently maintained within a specified target range over time. Furthermore, data indicate that failing to control Hb levels over time may increase the risk of adverse outcomes, including mortality. This review will discuss the challenges in controlling Hb in the CKD patient population, particularly in haemodialysis patients. Factors that affect Hb control over time will be considered, as well as the clinical criteria for its assessment. Although challenging, control of Hb is manageable and has potential clinical benefits.

Keywords: anaemia; chronic kidney disease; erythropoiesis stimulating agents; haemoglobin



   Introduction
Top
 Abstract
 Introduction
Haemoglobin targets
 Haemoglobin control over time...
 Factors impacting Hb variability...
 Criteria for defining...
 Conclusions
 References
 
The European Best Practice Guidelines (EBPGs) [1] and the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQITM) [2] recommend the use of erythropoiesis-stimulating agents (ESAs) for treating anaemia in patients with chronic kidney disease (CKD). Currently, the guidelines recommend treating anaemia to a target haemoglobin (Hb) at or above 11 g/dl [1,2]. Since the introduction of ESAs, studies have shown that the majority of patients in many European countries and the USA achieve Hb above this target when averaged over time [3]. However, it is now recognized that while many patients achieve the Hb target on average, many have difficulty achieving Hb control, defined as consistently maintaining Hb levels within a specified target range over time [4,5]. Studies indicate an association between Hb fluctuations, or deviation outside a specified target range, and a higher risk of adverse outcomes [6].

Recent advances in ESA and iron treatment have led to higher average Hb levels, while fluctuations in Hb levels remain common [3,5]. Achieving control of Hb levels over time is challenging because of several factors. These factors include a too narrow Hb target range and the frequent dose changes that are often required to maintain the patient's Hb levels within this range [5], comorbid conditions that cause variability in the individual's response to different ESAs and iron formulations and Hb variation due to fluctuations in fluid status and sampling conditions. In order to further advance the management of renal anaemia, the clinical relevance of the degree of achieved control over Hb must be investigated more rigorously, and innovative approaches are needed to better control Hb levels and possibly improve patient outcomes. This review discusses the challenges in achieving Hb control and the resulting potential clinical benefits in the CKD patient population. The review focuses on the haemodialysis (HD) population because a substantial volume of data have been published on Hb control in HD patients and only very limited data are available for CKD patients not receiving dialysis or receiving peritoneal dialysis (PD). Factors that affect Hb control are considered, as well as criteria for assessing Hb control.



   Haemoglobin targets
Top
 Abstract
 Introduction
 Haemoglobin targets
Haemoglobin control over time...
 Factors impacting Hb variability...
 Criteria for defining...
 Conclusions
 References
 
Guidelines for managing anaemia in patients with CKD agree on many treatment issues. However, there are also important differences that may be relevant in achieving Hb control in individual patients. The revised EBPGs recommend a lower Hb target of at least 11 g/dl but state that exact targets >11 g/dl should be defined according to patient characteristics, including sex, age, ethnicity, physical activity and comorbidities [1]. It has previously been suggested that normalising Hb would have beneficial effects on cardiac function and patient's wellbeing. Although it has been shown that normalising Hb in CKD is associated with significant effects on some quality of life parameters, it may in fact increase the risk of adverse outcomes [7,8]. In HD patients, Hb concentrations that are >14 g/dl immediately before receiving the dialysis treatment are not desirable due to the risks associated with the effects arising from post-dialysis haemoconcentration. Hb concentrations >12 g/dl are not recommended in patients with severe cardiovascular disease and should be approached with caution in patients with diabetes until more data become available [1]. The 2006 NKF-K/DOQITM guidelines recommend a Hb target of >11 g/dl and not exceeding 13 g/dl regardless of comorbidities or dialysis status [2].

Several cross-sectional and prospective studies have investigated the proportion of patients achieving recommended Hb targets. The international Dialysis Outcomes and Practice Patterns Study (DOPPS) analysed nationally representative samples of HD patients between 2002 and 2003 and found that in seven European countries, the proportion of patients achieving Hb ≥11 g/dl ranged from 55% to 77% (Figure 1) [3]. The Hb target set by the UK Renal Association Guidelines is ≥10 g/dl, and the proportion of patients achieving this target steadily improved from 1997 to 2002 (Figure 2) [9]; in 2002, 82% of HD patients and 88% of PD patients achieved the target Hb level [9]. Improvements in Hb levels over time have also been observed in other European countries [10,11].


Figure 1
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  		Fig. 1. Percentage of HD (>180 days) patients with Hb in target range ≥11 g/dl from 2002 to 2003 [3].

 

Figure 2
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  		Fig. 2. Percentages of UK dialysis patients at a single centre achieving the target Hb of >10 g/dl by year. Error bars are 95% confidence intervals. Reprinted with permission from UK Renal Registry 2003 [9].

 
Despite the improved numbers of patients achieving Hb targets in recent years, data from DOPPS and others also indicate that a substantial proportion of patients do not achieve the recommended Hb targets [3,9,11]. Furthermore, Hb levels do not appear to be well controlled over time in a large proportion of patients. Data from DOPPS showed large intrapatient fluctuations in Hb levels in HD patients during a 4-month interval, varying by baseline Hb, with SD of 1.30 for a baseline Hb <10 g/dl, 0.95 for Hb = 10–10.99 g/dl, 0.82 for Hb = 11–11.99 g/dl and 1.15 for Hb ≥12 g/dl [3]. The UK Renal Association also examined the change in Hb levels in dialysis patients over the course of a year [4]. As shown in Figure 3, Hb levels for a substantial proportion of UK patients fluctuated over the course of 1998, with levels in many patients dropping below 10 g/dl [4].


Figure 3
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  		Fig. 3. Change in Hb in UK HD patients from the first to fourth quarters of 1998. Shading pattern indicates the make up of each Hb range in the fourth quarter according to patients’ first quarter Hb value. Adapted from UK Renal Registry 1999 [4].

 
In the USA, two retrospective studies of large databases tracked dialysis patients’ Hb levels over the course of a 1-year period. Evaluating more than 65 000 patients, in the first quarter of 2000, the 3-month rolling average Hb level followed a Gaussian distribution [5]. More than 60% of patients had a Hb level outside the 2001 NKF-K/DOQITM recommended target range of 11–12 g/dl during this period. Over the course of the year, most patients moved from inside to outside the target Hb range or vice versa. Despite a steady improvement in mean Hb levels between 1995 and 2000 from below to within the target range, the SD for Hb levels remained unchanged, ranging from 1.3 to 1.5 g/dl [5]. Another retrospective, 1-year study of more than 41 000 dialysis patients found that <22% of patients consistently achieved Hb levels ≥11 g/dl [6].

Clinical significance of Hb thresholds
Several studies have observed an association between an increased risk of morbidity and mortality in patients with CKD and low Hb levels. In patients receiving dialysis, Hb levels <11 g/dl are associated with an increased risk of mortality, left ventricular dilatation, and de novo and recurrent cardiac failure [10,12,13]. The DOPPS II group estimated that Hb levels <8 g/dl in HD patients were associated with a 26% increase in the risk of mortality and a 55% increase in the risk of hospitalization compared with the reference group (11.0–11.99 g/dl) [3]. The mortality risk associated with low Hb levels is particularly evident in patients ≤65 years of age (Figure 4). The DOPPS I group estimated that patients between the ages of 18 and 65 years with Hb levels <10 g/dl had a 51% increase in the risk of death compared with those with Hb levels between 11.0 and 11.9 g/dl, and a non-significant 11% risk increase was observed in patients more than 65 years old [10]. In the USA, similar findings have been reported. A longitudinal study by Ofsthun and colleagues [13] using a large database of a dialysis services provider showed that US patients with Hb <9 g/dl were more than twice as likely to die compared with those with Hb levels ≥11 and <12 g/dl. Increased mortality risk has also been observed in patients with a haematocrit (Hct) <30%, particularly in patients with diabetes, with optimum levels between 33% and 36% [14].


Figure 4
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  		Fig. 4. Risk of death by Hb level and age in HD patients from five European countries. Reprinted with permission from Locatelli et al. 2004 [10].

 
The desirable upper Hb limit is still under debate [15–19]. Correcting anaemia to a normal Hb level in CKD patients with or without dialysis has so far not shown any substantial benefits: modest improvements in quality of life parameters and brain function have been reported, but this correction has no or negative effects on mortality and no or minor effects on cardiac function and left ventricular hypertrophy.

Overshooting an upper Hb target may have clinical consequences for some patients. Studies have observed an increased risk of mortality or morbidity for higher Hb targets (>13 g/dl) compared with lower targets, particularly in patients with cardiovascular disease [17,20–22]. Besarab and colleagues [21] randomized 1233 HD patients with cardiovascular disease receiving an ESA to a target Hct of 42% (normalized) or 30%. After 29 months, the mortality risk ratio for the normalized Hct group vs the low Hct group showed a trend of increased risk (risk ratio, 1.3; 95% CI, 0.9–1.9). The incidence of vascular access thrombosis was significantly higher in the normalized Hct group than in the low Hct group (39% vs 29%; P = 0.001). A 96-week randomized study by Parfrey and colleagues [22] compared the cardiac benefit of lower and higher Hb targets in HD patients. A total of 596 HD patients without symptomatic heart disease or left ventricular dilatation were treated with ESA therapy to achieve a Hb target of 9.5–11.5 g/dl or 13.5–14.5 g/dl. Data did not demonstrate a cardiac benefit for the high Hb target over the low Hb target in terms of a change in left ventricular volume index from baseline between the high- and low-target groups (7.6% vs 8.3%). Although there was no significant difference in the mortality rate between groups, the investigators noted a significantly higher incidence of cerebrovascular accidents in the high-target group than in the low-target group (4% vs 1%; P = 0.045).

Results similar to those observed in HD patients have recently been reported in pre-dialysis patients. Studies by Singh and colleagues [7] and Drüeke and colleagues [8] randomized patients with CKD to treatment with ESAs to achieve a low or high Hb target. Over a median follow-up of 16 months, the Singh et al. study observed an increased risk for the primary composite outcome (death, myocardial infarction, hospitalization for congestive heart failure and stroke) in the high-Hb target (13.5 g/dl) group compared with the low-Hb (11.3 g/dl) target group (hazard ratio = 1.34; 95% CI, 1.03–1.74; P = 0.03) [7]. Drüeke et al, on the other hand, did not observe a difference between the high-Hb (13.0–15.0 g/dl) and low-Hb (10.5–11.5 g/dl) target groups for a composite cardiovascular outcome over a 3-year period (hazard ratio, 0.78; 95% CI, 0.53–1.14; P = 0.20), but noted that more patients in the high-target group required start of regular dialysis [8]. The reasons for the apparent discrepancies between these studies are uncertain; however, differences between and limitations of both studies have been noted [23,24].

While these studies indicate that higher Hb targets may be risky, especially in patients with pre-existing cardiovascular disease, most prospective studies have been insufficiently powered to analyse hard clinical endpoints. However, two recent evidence-based systematic literature reviews have been performed. Volkova and Arab [17] concluded that there were insufficient data to generalize the risks or benefits of higher Hb levels in dialysis patients. When including the recent studies in CKD patients, Phrommintikul and colleagues [25] concluded that when treating patients with renal anaemia higher Hb concentrations increase the risk of death and that an upper limit should be considered in future guidelines. Indeed, the Cochrane Renal Group now contend that ‘more trials of haemoglobin target concentrations in patients with chronic kidney disease are no longer required, should be stopped, or at least it should be made fully and publicly explicit what reasons grant their continuation’ [26]. In contrast, other authors still find that studies have not sufficiently determined the optimal Hb concentration in CKD patients or if there is an ideal concentration for the various CKD patient populations [23,24].

Comments
Advances in ESA therapy and iron treatment have resulted in a larger proportion of patients meeting the minimum Hb target recommended by the EBPGs and the NKF-K/DOQITM guidelines (11 g/dl) or the UK Renal Association guidelines (10 g/dl) [5,9,11]. However, a significant proportion of patients with CKD still are not consistently maintaining Hb levels above these recommended thresholds. Although data clearly show that long-term maintenance of Hb >11 g/dl is associated with reduced mortality and morbidity, there are no prospective studies demonstrating a cause-and-effect relationship. It is important to emphasize that observational studies show varying results because of differences in the covariate factors considered in multivariate analyses [17]. For example, after adjusting for albumin level, diabetes, dry weight and sex, Ifudu et al. [27] showed that the effect of low Hb on mortality was not significant. Kovesdy et al. [28] found that the effect of anaemia on mortality in CKD patients was still significant after adjusting for 11 other risk factors, but that the association was much less robust after adjustment. Thus, more prospective data are needed to better elucidate optimal upper Hb levels for CKD patients with anaemia. Tight Hb control (11–12 g/dl) is recommended in patients with certain comorbidities, but the benefits of a higher Hb target for selected individuals are still being debated. Studies in HD patients with cardiovascular disease have demonstrated an association between high Hb levels and increased risk of mortality, and no clinical benefit has been observed for patients with CKD treated to a higher Hb target. Thus, high Hb levels are not currently recommended and should be approached with extreme caution, particularly in patients with comorbidities. The prevalence of many comorbidities differs between European and US patients with CKD (Table 1). Population-based Hb targets are important guides for managing renal anaemia, but a tailored anaemia management approach may be more appropriate for at-risk patients receiving HD.


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  		Table 1. Demographic characteristics and prevalence of comorbid conditions in haemodialysis patients in Europe and the United States. Adapted from Goodkin et al. [57]

 


   Haemoglobin control over time and impact on patient outcomes
Top
 Abstract
 Introduction
 Haemoglobin targets
 Haemoglobin control over time...
Factors impacting Hb variability...
 Criteria for defining...
 Conclusions
 References
 
In view of data demonstrating the risk associated with Hb levels outside recommended targets, it is relevant that the effect of Hb control over time on clinical outcomes be scrutinized further. Data indicate that patients who do not consistently maintain target Hb levels over time are likely to be at greater risk for adverse events. Low Hb levels are associated with left ventricular dilatation and hypertrophy, arrhythmia and myocardial ischaemia; on the other hand, high Hb levels can be associated with hypertension and thrombotic events of the vascular access [16,20,29,30].

A recent retrospective observational study by Ofsthun and colleagues [6] investigated the relationship between morbidity and mortality and Hb levels <11 g/dl over time. The study reviewed the records over a 2-year period of more than 41 000 US dialysis patients. Increased time spent with a Hb level <11 g/dl was associated with a greater mortality risk in comparison to a reference group of patients whose Hb levels did not fall <11 g/dl during the review period (Figure 5), and the rate of hospitalization increased with more time spent at Hb levels <11 g/dl. Overall, patients who spent 1% to 20% of time with Hb levels <11 g/dl had an increased mortality of ~10%, and when patients were stratified based on cardiovascular disease status, a significant increase in mortality risk was evident beginning at 21% of time <11 g/dl in the cardiovascular disease group and 41% of time <11 g/dl in the non-cardiovascular disease group. The reference population for each group comprised the patients within each group who had no Hb levels <11 g/dl during the study period. While these data indicate a clinically significant relationship between low Hb levels and poor outcomes, prospective studies are needed to validate these findings, as a number of confounding factors (e.g. inflammatory disease) may affect both Hb levels and outcomes.


Figure 5
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  		Fig. 5. Risk of mortality with respect to time spent with Hb levels <11.0 g/dl over a 2-year period in a cohort of dialysis patients (N = 41 919) [6]. CI, confidence interval; CVD, cardiovascular disease; Hb, haemoglobin.

 


   Factors impacting Hb variability in CKD patients
Top
 Abstract
 Introduction
 Haemoglobin targets
 Haemoglobin control over time...
 Factors impacting Hb variability...
Criteria for defining...
 Conclusions
 References
 
Several patient factors are associated with Hb variability. These include age, nutritional status, infection, gastrointestinal bleeding, marrow fibrosis and inflammation [4,5,31,32]. Seasonal haematological variations have also been observed in dialysis patients, with Hct varying up to 0.6% over the course of the year [33]. These factors may contribute to patients failing to consistently achieve Hb control over time.

Sampling timing and assay methods may also influence measured Hb levels. Hb levels in HD patients vary during the week because of haemodilution [34]; thus, samples for assessing Hb should be taken at the same time each week in relation to dialysis treatment. Patient position when samples are drawn may affect Hb levels, as may pain or anxiety during sampling, altitude, pregnancy and smoking [34]. Notably, Hct as a measure of anaemia status is not as accurate as Hb and may not reflect the true response to treatment. Hct may be falsely elevated in the presence of hyperglycaemia, and there is greater variability among automated analysers for Hct than for Hb.

Anaemia treatments and physician adjustments
Although many patient factors that affect Hb fluctuations are non-modifiable (e.g. age), ESA therapy and iron supplementation are two major factors involved in maintaining Hb levels that can be controlled by the physician, and >90% of patients respond adequately to standard doses of ESAs. However, the use of ESAs varies. Data from the DOPPS study showed that there was a wide range in the weekly mean ESA dose administered to HD patients across seven European countries [3]. In addition, there is clearly inter- and intrapatient variability in the response to ESAs [1,35,36]. Factors shown to strongly influence the response to ESAs include iron status, nutritional status, type and frequency of dialysis, age, race, sex, comorbidities and other clinical conditions such as inflammation and infections [37,38].

Uraemia is a chronic micro-inflammatory state [39,40]. Inflammatory activity fluctuates in dialysis patients, with most patients having bursts of inflammation in association with comorbid events [40]. The presence of systemic inflammation and elevated levels of inflammatory markers such as C-reactive protein, interleukin-6, and interferon gamma have been associated with erythropoietin resistance [37,39]. In addition, activation of the immune response may accelerate RBC death and divert iron away from erythropoiesis and into storage as ferritin, lactoferrin and haemosiderin, resulting in microcytic and hypochromic RBCs [37,41,42].

Achieving and maintaining a specified target iron level may be more difficult in some patients than in others, and the interaction between iron and ESAs may not be predictable [43]. The EBPGs recommend a wide range of target iron levels for the CKD population (serum ferritin 200–500 mcg/l or transferrin saturation 30% to 40%) in order to achieve recommended minimum criteria (serum ferritin >100 ng/ml or transferrin saturation >20%) [1]. Patients with functional iron deficiency (i.e. adequate or high serum ferritin but low transferrin saturation) may be particularly difficult to treat, as this combination is associated with malnutrition, infection, inflammation and/or ESA resistance [44–46]. It may be impossible to accurately estimate the amount of iron lost during dialysis, and consequently, it may not be possible to estimate the amount of iron supplementation needed in an individual HD patient [47].

One can appreciate the difficulty of maintaining a consistent Hb level in a population of patients with varying comorbidities and clinical conditions. The optimal doses of ESAs and iron may vary over the course of treatment as patients experience infections, inflammation or other changes in physiological status. Because of the lag time between treatment and response, frequent dose changes with ESAs may not be warranted and may be a cause of fluctuations in Hb levels. Erythropoiesis stimulating agents approved for different frequencies of administration may be used, but decisions to alter the dose should be made carefully, using appropriate tools and algorithms, to tailor anaemia management to the individual patient.

Haemoglobin targets and intervention threshold
Hb levels are more variable in patients with CKD than in those without kidney disease. The fluctuation in Hb levels approximates a SD of 0.9 g/dl in people with normal renal function, whereas the fluctuation in Hb levels in dialysis patients approximates a SD of 1.2 g/dl [5]. Despite advances in ESA therapies and iron treatment, the SD of Hb in CKD patients has not improved over the past decade [5]. Thus, the steady improvement in mean Hb over the past decade has been paralleled by an increase in the number of patients with Hb levels >12 g/dl. Lacson and colleagues [5] projected that setting a goal of 90% of patients achieving Hb levels >10 g/dl with current anaemia management practices would result in 26% of patients having Hb levels <11 g/dl, 37% of patients having Hb concentrations = 11–12 g/dl and 37% of patients having Hb levels >12 g/dl.

Maintenance of Hb levels over time within a tight target range for all patients is likely unattainable for a significant proportion of patients without appropriate, tailored anaemia management. Broadening the target range by increasing the upper Hb threshold overall could increase the number of patients with Hb above the 11 g/dl lower limit advocated by both EBPGs and NKF-K/DOQITM. However, because of the desire to avoid overshooting Hb levels in view of the risks that higher Hb levels may entail, effective Hb control with the aid of treatment interventions is essential.

The Hb threshold at which treatment interventions are initiated is a controllable factor affecting Hb control. Will and colleagues showed that there is a distinct association between the target Hb range and median Hb value. In order for 85% of dialysis patients in a given cohort to achieve a minimum Hb level >10 g/dl, for example, would require a median Hb value = 11.5 g/dl, a difference of 1.5 g/dl or approximately the SD observed in dialysis populations [48]. Furthermore, the duration of action of different ESAs makes a narrow range of thresholds necessary to mitigate the degree of Hb variation and maintain Hb levels within a target range.

Tools and treatment algorithms could help guide physicians in differentiating between clinically significant and non-significant changes in Hb levels—changes that warrant or do not warrant treatment intervention [31]. A thorough benefit-to-risk analysis is needed to determine Hb targets for specific patient subgroups, and appropriate tools and treatment algorithms must be implemented to avoid the risk of overshooting. The physician's intervention can be properly guided and tailored to adjust anaemia management as described subsequently.

Comment
The EBPGs offer general recommendations for titrating the ESA dose in relation to Hb levels, but they do not include recommendations on the best way to control Hb over time, including the designation of threshold or ceiling Hb values that would necessitate a change in ESA dose [1]. Interpatient variability with respect to target Hb and ESA response may necessitate individualized dosing changes, but this may be difficult for clinics and dialysis facilities to carry out on a large patient population. Thus, it is clear that management standards and treatment algorithms that can better define Hb targets for the individual patient must be designed, tested, and, if successful, implemented into clinical practice. Treatment intervention by physicians is a controllable factor, and a number of tools and treatment algorithms have been suggested to assist physicians in managing iron and ESA therapy [49–53]. Further evaluation and implementation of these tools and algorithms may significantly improve anaemia management. The benefits of this approach and the use of tools and algorithms in clinical practice are discussed in detail by Will and colleagues [54] in another article in this Supplement.



   Criteria for defining haemoglobin control
Top
 Abstract
 Introduction
 Haemoglobin targets
 Haemoglobin control over time...
 Factors impacting Hb variability...
 Criteria for defining...
Conclusions
 References
 
The majority of studies of renal anaemia treatment have analysed the mean Hb over a short period of time. While this has been useful in defining Hb targets, it does not address the consequences of Hb levels fluctuating outside the target range over a longer time period. The SD of the mean Hb appears to be similar with the various ESAs [55] and also has been used to assess the degree of control over Hb levels [32]. Berns and colleagues assessed Hb deviation in a retrospective observational study of 987 HD patients. The investigators found that the SD was dependent upon the frequency of Hb measurements. The SD of the 1-month rolling average Hb (SD = 1.4 g/dl) was compared with the 3-month rolling average (SD = 1.1 g/dl) as well as the 4-, 5- and 6-month rolling averages (SD = 1.0 g/dl for each) [32]. While this method accounts for fluctuations in Hb levels outside a specified target, it does not take into consideration the amount of time the Hb levels are outside the specified target. To our knowledge, no association between the SD of mean Hb over defined time periods and adverse outcomes has been reported.

The novel approach by Ofsthun et al. [6] as discussed earlier, considers the amount of time spent below a specified Hb target. Their retrospective analysis demonstrated an association between the amount of time that Hb levels were <11 g/dl and the risk of mortality and rate of hospitalization. This is a relevant approach, as the majority of patients in Europe and the USA will be treated to achieve a lower Hb target of 11 g/dl, while the upper Hb target will likely vary according to patient characteristics. As data mature for upper Hb targets, particularly for subgroups of patients with comorbidities, similar analyses should be performed.

Comment
A rational definition of Hb control is the consistent achievement of Hb levels ≥11 g/dl over time. This definition is in accordance with the EBPGs [1] and the NKF-K/DOQITM guidelines [2], and studies suggest that patient outcomes are related to the time spent below this minimum Hb target [6].



   Conclusions
Top
 Abstract
 Introduction
 Haemoglobin targets
 Haemoglobin control over time...
 Factors impacting Hb variability...
 Criteria for defining...
 Conclusions
References
 
Prospective studies evaluating treatment algorithms have demonstrated that Hb levels can be controlled over time with ESA therapy [56]. However, before Hb control over time can be introduced as a primary goal in CKD patients, prospective data are needed to clarify its relationship with patient outcomes. Hb control may very well mitigate the risks of morbidity and mortality in this patient population, but more data are needed to better define its clinical relevance, as there is as yet no evidence that Hb fluctuation is responsible for increased morbidity in CKD patients. The amount of time that Hb levels are at or >11 g/dl appears to be clinically relevant and should be considered a good marker of Hb control. Although debate continues around defining upper Hb limits, it is important to begin to assess the risk associated with the amount of time Hb levels are above upper targets to ensure patient safety.

Achieving Hb control over time is a major challenge because of the various physiological factors that influence the response in individual patients and the potential risk for increased mortality, particularly for patients with comorbidities. Whereas guidelines offer recommendations for the patient population in general, they cannot take into account inter- and intrapatient variations and differences between patient populations (e.g., Europe vs the USA, Table 1) [57,58]. Although Hb control is affected by a number of physiological factors that are not readily modifiable, it can be improved with the proper use of ESAs and iron supplementation. A number of tools and treatment algorithms have been developed to support anaemia management and better control of Hb levels [50,51,53]. These approaches are useful for achieving Hb control in patient populations over time and reducing the risk of over- or undershooting Hb targets. They are also flexible and can be adjusted to fit the needs of individual patients. Computer-based management systems that utilize anaemia-related tools and treatment algorithms have been shown to be effective in managing anaemia in CKD patients and may improve Hb control in this population [51,53,56]. If more efficient Hb control translates into reduced costs and improved patient outcomes with respect to mortality and morbidity, this would represent a significant advance in the management of renal anaemia.



   Acknowledgments
 
We thank Béatrice Benoit and Michael Raffin for their assistance in the preparation of this manuscript. This supplement is sponsored by Amgen Inc.

Conflict of interest statement. P.B. has participated in working groups for the European Best Practice Guidelines and national guidelines for the management of anemia in patients with chronic renal failure. He has received honoraria and reimbursement for lectures, participation in symposia, workshops and educational activities from Roche, Janssen-Cilag and Amgen, and been involved in clinical trials sponsored by these companies. He has also received honoraria for membership of scientific advisory boards for Amgen and Vifor, and has written expert reports for Baxter and Nebo.



   References
Top
 Abstract
 Introduction
 Haemoglobin targets
 Haemoglobin control over time...
 Factors impacting Hb variability...
 Criteria for defining...
 Conclusions
 References
 

  1. Locatelli F, Aljama P, Barany P, et al. Revised European Best Practice Guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant (2004) 19(Suppl 2):ii1–47.[Free Full Text]
  2. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis (2006) 47:S11–145.[CrossRef][Medline]
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  4. UK Renal Association. UK Renal Registry Report 1999. (Accessed 5 January 2006). Available at: http://www.renalreg.com/Report%201999/Cover_1999_Frame.htm.
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