Higher Hb Levels are Important to CKD Patients’ Quality of Life

The use of erythropoietic-stimulating agents (ESAs) in patients with chronic kidney disease (CKD) remains controversial. In fact, recent findings by the Food and Drug Administration (FDA) have suggested that hemoglobin (Hb) targets over 12 g/dL in patients with CKD offer no benefit and may actually increase morbidity and mortality. However, many nephrologists feel that the quality of life (QOL) of patients with CKD is improved with ESA treatment, but few controlled studies demonstrate an improvement in health-related QOL measures. Therefore, a recent study examined the relationship between health-related QOL and anemia severity in a cohort of CKD patients. The CKD Renalsoft Informatics Observational Study (CRIOS) is a prospective study designed to collect data on clinical care practices for renal replacement therapy and health-related QOL assessments.

In the study, 1,186 CKD patients completed the Kidney Disease Quality of Life Short Form Questionnaire (KDQOL-SF), a reliable survey widely used in the assessment of patients with kidney disease. Patients were bracketed into their respective stages of CKD, and Hb levels were grouped into four categories (<11 g/dL, 11 to <12 g/dL, 12 to <13 g/dL, and ≥13 g/dL). In all Hb categories and stages of CKD, significant improvements in QOL domains were observed with increasing Hb levels when only Hb levels were accounted for in the analysis. Also, after adjusting for age, race, gender, stage of CKD, history of iron and ESA use, and the presence or absence of diabetes, a significant association remained in all four physical components of the KDQOL-SF. Furthermore, no significant interactions were found between Hb levels and the use of ESAs, indicating that the association between QOL and Hb levels was independent of ESA use.

The results of this study offer some new understanding to the current controversy over ESA use in CKD patients. While some studies show adverse effects from increasing Hb levels, this study shows significant improvements in QOL in CKD patients. This observation has important implications for the treatment of CKD patients, since currently approved FDA claims do not reflect the QOL improvements observed in this study. However, given the small scale of the study, the findings may not be generalizable to the broader population of CKD patients, and therefore, further prospective trials are needed to analyze the QOL domain changes that occur with ESA use.

Finkelstein FO, Story K, Firanek C, Mendelssohn D, Barre P, Takano T, Soroka S, Mujais S. Health-Related Quality of Life and Hemoglobin Levels in Chronic Kidney Disease Patients. Clin J Am Soc Nephrol. 2008 Nov 5.

NAAC Expert Commentary:
There has been much debate and discussion over the last two years about the QOL impact of ESA use in CKD patients. Much of this discussion was sparked by the CHOIR study,¹ which found no QOL benefit from higher Hb levels, and the simultaneously published CREATE study, which did find a QOL benefit.² While other prospective studies have also suggested a QOL benefit with higher Hb levels,³ the sustainability of QOL improvement with ESA treatment has not been proven. Although this study by Finkelstein et al further supports the concept that higher Hb levels are associated with better QOL in CKD patients, the study leaves other important questions unanswered. These findings are similar to those of Lefebvre et al,⁴ who also reported higher QOL scores across the Hb spectrum and showed dramatically better QOL scores as Hb levels increased from about 9 to 11 g/dL. However, the “dose-response” relationship was considerably less pronounced for most QOL components above 9-11 g/dL.

Several points must be kept in mind when considering this study. For example, the study did not assess changes in QOL scores associated with increasing the Hb level in individual patients; rather, Hb level and QOL scores were examined at single time points. Consequently, we cannot conclude that raising Hb levels causes an increase in QOL. Additionally, since many patients were not on ESA therapy, we should not draw conclusions about any relationship between ESA use and QOL. One problem with all of our studies of anemia management is the lumping together of all CKD patients; it seems likely that this may obscure important differences that might be observed, otherwise. The QOL improvement with higher Hb levels may be very different in a younger, more active individual who works full time in a demanding job, as compared with an older, more sedentary individual with other major comorbidities that could be more critical determinants of QOL.

For now, this study supports prior conclusions and clinical judgment that (1) an Hb level of 11-13 g/dL, with or without ESA treatment, is associated with better QOL and greater physical function, compared to lower Hb levels, and that (2) even higher Hb levels are associated with continued, but perhaps, less improvement in QOL. Nevertheless, this improvement may by offset by an increase in morbidity or mortality.^1,5 Furthermore, a secondary analysis of the CHOIR study suggests that factors other than higher Hb levels may have been important determinants of the outcomes observed in that study.⁶

Still unanswered is whether better QOL is due to higher Hb levels or whether better QOL and higher Hb levels are simply co-occurring in healthier patients. What is currently needed are prospective studies looking more closely at (1) QOL parameters within the Hb range of 10-13 g/dL, (2) the sustainability of changes in QOL, and (3) a closer examination of QOL in different subsets of CKD patients.

References

1. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D; CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006 Nov 16;355(20):2085-98.
2. Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A; CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006 Nov 16;355(20):2071-84.
3. Canadian Erythropoietin Study Group. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ. 1990 Mar 3;300(6724):573-8.
4. Lefebvre P, Vekeman F, Sarokhan B, Enny C, Provenzano R, Cremieux PY. Relationship between hemoglobin level and quality of life in anemic patients with chronic kidney disease receiving epoetin alfa. Curr Med Res Opin. 2006 Oct;22(10):1929-37.
5. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998 Aug 27;339(9):584-90.
6. Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, Patel UD, Singh AK. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int. 2008 Sep;74(6):791-8.

Rheumatoid Arthritis Treatment May Improve Anemia Without Symptom Relief

Rheumatoid arthritis (RA) patients with anemia often experience reduced quality of life as measured by pain, fatigue, and health assessment scores. While most causes of RA-associated anemia (impaired iron delivery and utilization by erythroid progenitors) are consistent with anemia of chronic disease, production of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor alpha (TNFα) are also contributing factors of RA-associated anemia pathogenesis. Mounting evidence has shown that treating anemia can lead to improvement in quality of life in RA patients, and some studies have shown that treatment with TNFα inhibitors, such as infliximab, can elevate hemoglobin (Hb) levels in RA patients with anemia. Recently, a novel study by Doyle et al evaluated the effects TNFα inhibition by pooling data from three prospective, randomized, double-blind, placebo-controlled clinical trials.

In these three trials – ATTRACT,¹ ASPIRE,² and START³ – RA patients with anemia were randomly assigned to receive a combination of methotrexate (MTX) therapy and infliximab or placebo for 22 weeks. Anemia was defined as Hb levels of <12 g/dL, and the overall primary endpoint was the percentage of treated patients with an anemic baseline who had at least a 1 g/dL increase at week 22. Among anemic patients, infliximab plus MTX treatment showed a significantly greater mean increase at week 22 than in patients who received the placebo. These same results were observed in the severe anemia category (Hb levels <10 g/dL). Regression analysis also showed that infliximab treatment was independently associated with greater improvement in Hb levels after adjusting for demographics and improvement in disease activity. In addition, vitality scores showed a positive correlation between Hb and fatigue. Significant improvements in Hb levels and quality of life scores after infliximab and MTX treatment were seen across all three studies, both collectively and individually.

Although the pathophysiology of anemia in RA is not well understood, these results support evidence that the inhibitory effects of TNFα and other cytokines may be an underlying mechanism. However, the authors concluded further study is needed to elucidate the underlying mechanisms of anemia in RA. For instance, in this study, variables such as the concomitant treatment with anti-ulcer therapies may have contributed to the improvement in Hb levels, as well as a reduction in non-steroidal anti-inflammatory drugs. Furthermore, patients with more severe anemia (Hb levels <8.5 or <8.0 g/dL) were excluded from the study, and thus the results may not be generalizable to patients in these categories.

Doyle MK, Rahman MU, Han C, Han J, Giles J, Bingham CO 3rd, Bathon J. Treatment with Infliximab plus Methotrexate Improves Anemia in Patients with Rheumatoid Arthritis Independent of Improvement in Other Clinical Outcome Measures-A Pooled Analysis from Three Large, Multicenter, Double-Blind, Randomized Clinical Trials. Semin Arthritis Rheum. 2008 Sep 27.

NAAC Expert Commentary:
Without question, the greatest advance in the last decade of rheumatology therapeutics has been the introduction of TNFα blockade. Three medications are currently available, with two more medications to follow in the near future. About half of RA patients treated with these agents improve by at least 50% (a “major response”), and about 20% of patients improve dramatically to a point of “minimal disease activity”.

A post-hoc analysis of the ATTRACT trial⁴ several years ago demonstrated that, even in those patients who did not enjoy symptomatic improvement with infliximab treatment, the rate of radiographic progression was reduced in infliximab-treated patients compared to placebo. Thus, it was recognized that there is a “disconnect” or discordance between symptomatic improvement and prevention of bone and cartilage damage as evidenced by radiographs.

In a similar fashion, the study by Doyle et al demonstrated that treatment of RA with infliximab resulted in improvement of anemia even in patients who did not improve clinically. The authors stated, “Multiple regression analysis indicated that the effect of infliximab plus MTX on anemia was independent of improvement in disease activity.” In other words, a therapy targeting a major proinflammatory cytokine, produced improvement in anemia, but did so independently of a reduction in joint pain.

The major lessons we can take from this study are that (1) specifically targeted therapies can result in major hematologic benefit, as we have learned from recombinant agents such as erythropoietin and filgrastim, and that (2) reducing “inflammation” in a chronic disease can result in hematologic benefit, even if symptomatic improvement does not occur.

References

1. St Clair EW, Wagner CL, Fasanmade AA, Wang B, Schaible T, Kavanaugh A, Keystone EC. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002 Jun;46(6):1451-19.
2. Smolen JS, Van Der Heijde DM, St Clair EW, Emery P, Bathon JM, Keystone E, Maini RN, Kalden JR, Schiff M, Baker D, Han C, Han J, Bala M; Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) Study Group. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum. 2006 Mar;54(3):702-10.
3. Westhovens R, Yocum D, Han J, Berman A, Strusberg I, Geusens P, Rahman MU; START Study Group. The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum. 2006 Apr;54(4):1075-86.
4. Smolen JS, Han C, Bala M, Maini RN, Kalden JR, van der Heijde D, Breedveld FC, Furst DE, Lipsky PE; ATTRACT Study Group. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum. 2005 Apr;52(4):1020-30.

Dilutional Anemia, Hb Levels and Blood Volume in Heart Failure Patients

Patients with heart failure (HF) often experience anemia as a comorbidity. Although anemia is typically diagnosed by measuring hemoglobin (Hb) levels, anemia can also be diagnosed using red cell deficit or hemodilution with plasma volume expansion. Nearly half of patients with advanced HF and low ejection fractions (HFLEF) have anemia based on hemodilution with normal red cell volumes. However, it is unclear whether this relationship also exists in patients with HF and preserved ejections (HFPEF). Thus, a study by Abramov et al examined whether (1) patients with anemia and HFPEF have a similar prevalence of dilutional anemia as patients with HFLEF, and whether (2) a correlation exists between Hb values and red cell volume in patients with anemia and HF.

In the study, 46 patients – aged 21 years or older – with HF were divided into an HFLEF group (22) and an HFPEF group (24). Anemia was defined by the World Health Organization criteria of Hb level <13 g/dL in men and <12 g/dL in women. Blood volume and red blood cell volume were compared to normal values after being calculated by plasma volume, measured hematocrit for trapped plasma, and mean body hematocrit in the study patients. Although Hb levels were similar, excess plasma volume was more frequent in HFLEF patients (100%) than in HFPEF patients (71%). Also, HFLEF patients experienced less red blood cell deficit compared to HFPEF patients, but the incidence of dilutional anemia was greater (41% versus 12%, respectively). Finally, in all HF patients, no significant association was found between Hb levels and the percentage of red cell volume deviation from baseline values. The poor correlation of Hb levels and red cell volume was likely observed because of the confounding effects of alterations in plasma volume, secondary to the underlying disease or diuretic therapy.

This study's results point to some important implications in the treatment of anemic patients with HF. Two popular treatments – intravenous iron and erythropoietic stimulators – have shown mixed results, and few studies have considered dilutional anemia as a reason for these ambiguous outcomes. Specifically, treatment with erythropoietic stimulators has often resulted in reductions in plasma volume. Therefore, the authors contend diuresis may be a safer approach in the treatment of anemic patients with HF. Further study is needed to determine if these results are generalizable to the overall HF population, as this trial was restricted to only patients with severe HF at tertiary care centers.

Abramov D, Cohen RS, Katz SD, Mancini D, Maurer MS. Comparison of blood volume characteristics in anemic patients with low versus preserved left ventricular ejection fractions. Am J Cardiol. 2008 Oct 15;102(8):1069-72.

NAAC Expert Commentary:
This article relied on the indirect assessment of red blood cell (RBC) volume by the I-131 labeled albumin method in heart failure patients with preserved and low ejection fraction. The authors found plasma volume excess in 41% of low EF patients and 12% in preserved EF patients. The authors purport that the anemia in heart failure patients may be due to dilutional anemia and should be treated with diuretics.

There are numerous assumptions made when estimating blood volume indirectly from an estimate of plasma volume rather than estimating blood volume by directly measuring the blood volume via labeling the red blood cells with a chromium marker. These assumptions include using a nomogram for estimating plasma volume, assuming the ratio of total body hematocrit to venous hematocrit is constant (i.e. the f ratio), and assuming the translocation of plasma volume across the arteriolar capillaries is similar in patients with and without heart failure. It is known that the actual plasma volume is dependent on the amount of lean muscle mass in an individual. We do not know if these relationships are valid in patients with heart failure.

In individual patients, the f ratio has a coefficient of variation of ±5%, which can translate into a ±10% change in blood volume estimates.¹ The correct f ratio in patients with heart failure remains unknown as this has not been evaluated. In heart failure patients the permeability diffusion is increased, leading to an increase in extracellular fluid, but no increase in plasma volume.² Since the authors did not correct for this increased capillary permeability, it is uncertain if the estimated plasma volume also included some extracellular volume. Direct measurement of blood volume using the chromium labeled standard had a R² of 0.83 relative to the indirect method of estimating blood volume with iodine labeled albumin.³ It is important to note that none of the comparison studies were performed in anemic heart failure patients where all of the assumptions may be invalid.

The authors have previously reported that although the patients were clinically euvolemic, the mean pulmonary capillary wedge pressure (PCWP) was markedly elevated at 26 mm Hg in the patients with hemodilutional anemia.⁴ Treatment with erythropoiesis-stimulating agents (ESAs) in the patients with hemodilutional anemia increased the RBC mass and reduced the plasma volume.⁵ The increase in hemoglobin and peak oxygen consumption was similar in patients with hemodilutional and true anemia.

The validity of the indirect measurement used to determine blood volume in this study remains unknown for heart failure patients who may have leaky capillaries. In such patients, leaky capillaries can lead to a loss of albumin to the interstitial space, causing an overestimation of the plasma volume and subsequently, an overestimation of the red cell volume. If this occurred, there may be problem with the indirect method used to estimate RBC mass. The results of this analysis would be more compelling if the authors had used a direct measurement of red cell volume or if the indirect method had been validated in heart failure patients.

We know that Hb levels correlate with oxygen delivery, increased cardiac output, cytokine activation, and mortality in heart failure patients with both preserved and low EF. We do not have any data to suggest that any of these measurements vary in patients with a true blood deficit versus dilutional anemia. Other authors have noted that anemia can resolve over time in heart failure patients. It is certainly reasonable to diurese patients with low EF to achieve a euvolemic state. However, if the anemia persists, appropriate treatment of these patients remains uncertain. The results of trials using intravenous iron or ESAs are ongoing and we await the results.

References

1. Retzlaff JA, Tauxe WN, Kiely JM, Stroebel CF. Erythrocyte volume, plasma volume, and lean body mass in adult men and women. Blood. 1969 May;33(5):649-61.
2. Galatius S, Bent-Hansen L, Wroblewski H, Kastrup J. Plasma clearance of polyfructosan and extracellular body fluid distribution in idiopathic dilated cardiomyopathy and after heart transplantation. Am J Cardiol. 2000 Apr 1;85(7):843-48.
3. Balga I, Solenthaler M, Furlan M. Should whole-body red cell mass be measured or calculated? Blood Cells Mol Dis. 2000 Feb;26(1):25-31.
4. Androne AS, Katz SD, Lund L, LaManca J, Hudaihed A, Hryniewicz K, Mancini DM. Hemodilution is common in patients with advanced heart failure. Circulation. 2003 Jan 21;107(2):226-29.
5. Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A, Androne AS. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation. 2003 Jan 21;107(2):294-99.