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Racial Disparities in Hemoglobin Concentration in Children With CKD
Racial Disparities in Hemoglobin Concentration in Children With CKD Related Article, p. 1009
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umerous large-scale studies have conclusively established that African Americans have lower serum hemoglobin concentrations than whites.1 In the general US population, the average hemoglobin level in African Americans is 0.7 g/dL (7 g/L) lower than in whites, even after adjusting for possible iron deficiency or hemoglobinopathies that may be more common in African Americans.2 Although racial disparity with regard to anemia is well described in adults with chronic kidney disease (CKD),3,4 a similar analysis in children had not been reported. In this issue of the American Journal of Kidney Diseases, Atkinson et al5 describe a higher prevalence of anemia in African American children with CKD in the large carefully conducted Chronic Kidney Disease in Children (CKiD) Study. After adjusting for relevant patient characteristics, maternal education, glomerular filtration rate (GFR), iron use, and erythropoietinstimulating agent (ESA) administration, average hemoglobin levels for African American children were estimated to be 0.6 g/dL (6 g/L [95% confidence interval, ⫺0.9 to ⫺0.2]) lower than in white children. The investigators noted further widening of hemoglobin levels at lower GFRs. The study’s particular strengths are its large patient cohort, the careful completion of the CKiD Study, and uniform measurement of GFR using a gold-standard method. A robust reference population was chosen (Third National Health and Nutrition Examination Survey [NHANES III]). The cross-sectional nature of the study precluded a conclusion about the cause of kidney disease based on the reported associations. It is debatable whether lower hemoglobin levels in African Americans result from genetic predisposition or emanate from a different set of environmental conditioning and comorbid condition spectrum in this population.1 The current literature supports the latter and suggests that the ethnic difference in hemoglobin levels is the consequence of a combination of overall nutrition, iron status, and inflammation.6 African American children enrolled in the study by Atkinson et al5 had significantly higher body mass index z scores, which can decrease hemoglobin
levels through an increase in iron demand. Low serum albumin levels in the African American children again suggested the contribution of environmental factors. Hypoalbuminemia could reflect relatively poor nutrition, which could induce iron deficiency and low hemoglobin levels. Low serum albumin levels also may indicate a high inflammatory state, resulting in a decrease in hemoglobin levels caused by lower iron availability and higher resistance to erythropoietin. Unlike in the non-CKD population, the proinflammatory potential of CKD complicates the interpretation of hematologic indices. Ferritin levels can be increased despite underlying iron deficiency. Interpretation of iron store status and ESA use becomes complex in the presence of inflammatory states. An acute-phase increase in ferritin levels secondary to inflammation may mask iron deficiency and a high ESA dose can reflect variable resistance to ESAs secondary to inflammation, rather than better medical care.7 With the emerging literature for lower hemoglobin levels in children with CKD of African American descent, it is important to discuss how this information may be used clinically. Should the reference intervals for hemoglobin levels for African American children be different from those for white children?8 This is an important clinical issue and warrants a careful look at the way anemia should be defined in African American children with CKD. Unlike in adults, children undergo developmental changes in hematologic parameters and age- and sex-specific reference intervals have to be used. That adds a component of age dependency to the interpretation of hemoglobin targets in children, an aspect that was not considered in the first set of Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines.9 z Score calculations can account for an age-dependent change in hemoglobin levels and can allow for comparison of hemoglobin Address correspondence to Guido Filler, MD, PhD, FRCPC, Department of Pediatrics, University of Western Ontario, Children’s Hospital, London Health Science Centre, 800 Commissioners Rd E, London, ON, Canada N6A 5W9. E-mail: guido. [email protected] © 2010 by the National Kidney Foundation, Inc. 0272-6386/10/5506-0003$36.00/0 doi:10.1053/j.ajkd.2010.03.003
American Journal of Kidney Diseases, Vol 55, No 6 (June), 2010: pp 981-983
981
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Figure 1. Number of children (total 351 with chronic kidney disease [CKD], described in10) that are anemic using Kidney Disease Outcomes Quality Initiative (KDOQI) definitions and age- and sex-specific reference intervals. P ⫽ 0.001.
levels across various ages.10 Use of an agedependent hemoglobin z score can even categorize the degree of anemia differently than classifications based on hemoglobin levels10 (Fig 1). Applying previously reported reference intervals to the anemic children of African American descent from the study by Atkinson et al,5 the proportion of anemic children may be similar to that observed in whites. Similar accounting for age dependency also needs to be applied when interpreting iron status in children with CKD.11 In light of the observations suggesting lower hemoglobin concentrations in African American children, the important question emerges whether correcting anemia to the published KDOQI guidelines in these children improves clinical outcomes. Overall, the appropriate target hemoglobin level for children with CKD is poorly defined. Currently, the recommended hemoglobin target is largely opinion based and is broadly guided by similar studies of adults with CKD.12 In adults, there is a reasonable degree of evidence that correcting severe anemia with ESAs results in lower transfusion rates.13 However, correcting mild anemia does not offer much benefit in terms of decreasing the incidence of cardiovascular events.14 On the contrary, correcting anemia to the reference range could even aggravate cardiovascular events. The recent Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) did not show a decrease in death or cardiovascular events, but showed an increase in stroke incidence with hemoglobin correction close
Filler, Huang, and Sharma
to 13 g/dL using darbepoetin alfa in 4,038 adults with diabetes who had associated CKD and moderate anemia and were not undergoing dialysis.14 Other large trials, including Cardiovascular Risk Reduction by Early Anemia Treatment With Epoetin Beta (CREATE) and Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR), conveyed a similar impression of neutral or increased cardiovascular events by hemoglobin level correction to the reference range, with no added benefit from achieving higher hemoglobin targets.15,16 Evidence of increased hospitalization risk with hematocrits ⬍33% also is based on only retrospective data.17 With this evidence, the debate about cost consideration, given the higher ESA needs in African American adults, may initiate similar discussions about using ESAs in children with CKD.18 In the absence of strong evidence to suggest otherwise, it would seem intuitive to adopt principles and hemoglobin targets for children with CKD similar to those for adults. However, this issue can be looked at from a different perspective when one considers the onset of CKD in childhood rather than in adulthood. Because of an early onset, atherosclerotic changes in children are expected to be much less pronounced. This could mean there is a window to attain normal physiologic hemoglobin targets without the risks associated with attaining normal hemoglobin levels in adults. Because cardiovascular events in children are relatively uncommon, attaining normal hemoglobin levels in children likely will not increase the risk of these events. Childhood onset of CKD also involves much longer exposure of target organs to a deranged uremic milieu than in adult-onset CKD. With this combination of factors, full correction of anemia in children with CKD theoretically could have a preventative role in avoiding target-organ damage secondary to mild, but prolonged, duration of ischemic injury. Growth and school performance are additional considerations unique to children that can guide the appropriateness of a hemoglobin target in children. The low likelihood of cardiovascular events in children and relatively low prevalence of CKD in children as such makes these assumptions hard to test in a rigorous scientific manner. Identifying appropriate surrogate markers in children can guide fu-
Editorial
983
ture research for establishing appropriate hemoglobin targets in children with CKD. In summary, the study by Atkinson et al5 shows a difference in hemoglobin levels in children with CKD that equals that in the general population (about 0.6 g/dL [6 g/L]). Targeting the same hemoglobin levels in African American children as outlined in the KDOQI guidelines15 will be associated with higher cost. Future studies are required to derive evidence-based hemoglobin targets with optimized outcome and cost analysis in children with CKD. Guido Filler, MD, PhD, FRCPC Shih-Han Susan Huang, MD, FRCPC Ajay P. Sharma, MD, FRCPC University of Western Ontario Ontario, Canada
ACKNOWLEDGEMENTS Financial Disclosure: The authors declare they have no relevant financial interests.
REFERENCES 1. Kent S. Interpretations of differences in population hemoglobin means: a critical review of the literature. Ethn Dis. 1997;7(2):79-90. 2. Beutler E, West C. Hematologic differences between African-Americans and whites: the role of iron deficiency and alpha-thalassemia on hemoglobin levels and mean corpuscular volume. Blood. 2005;106:740-745. 3. Sehgal AR. Impact of quality improvement efforts on race and sex disparities in hemodialysis. JAMA. 2003;289: 996-1000. 4. Collins AJ, Kasiske B, Herzog C, et al. Excerpts from the United States Renal Data System 2006 Annual Data Report. Am J Kidney Dis. 2007;49(suppl 1):S16-296. 5. Atkinson MA, Pierce CB, Zack RM, et al. Hemoglobin differences by race in children with CKD. Am J Kidney Dis. 2010;55(6):1009-1017.
6. Pan Y, Jackson RT. Insights into the ethnic differences in serum ferritin between black and white US adult men. Am J Hum Biol. 2008;20(4):406-416. 7. Lacson E, Rogus J, Teng M, Lazarus JM, Hakim RH. The association of race with erythropoietin dose in patients on long-term hemodialysis. Am J Kidney Dis. 2008;52:11041114. 8. Robins EB, Blum S. Hematologic reference values for African American children and adolescents. Am J Hematol. 2007;82(7):611-614. 9. National Kidney Foundation. KDOQI update 2000 website (2000). Guideline 1. When to initiate the work-up of anemia. New York. http://www.kidney.org/professionals/ kdoqi/guidelines_updates/doqiupan_i.html#1. Accessed October 10, 2005. 10. Filler G, Mylrea K, Feber J, Wong H. How to define anemia in children with chronic kidney disease? Pediatr Nephrol. 2007;22(5):702-707. 11. Ooi CL, Lepage N, Nieuwenhuys E, Sharma AP, Filler G. Pediatric reference intervals for soluble transferrin receptor and transferrin receptor-ferritin index. World J Pediatr. 2009;5(2):122-126. 12. National Kidney Foundation. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007;50(3):471-530. 13. Bennett WM. A multicenter clinical trial of epoetin beta for anemia of end-stage renal disease. J Am Soc Nephrol. 1991;1(7):990-998. 14. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032. 15. Drüeke TB, Locatelli F, Clyne N, et al; CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071-2084. 16. Singh AK, Szczech L, Tang KL, et al; CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085-2098. 17. Staples AO, Wong CS, Smith JM, et al. Anemia and risk of hospitalization in pediatric chronic kidney disease. Clin J Am Soc Nephrol. 2009;4(1):48-56. 18. Ishani A, Guo H, Arneson TJ, et al. Possible effects of the new Medicare reimbursement policy on African Americans with ESRD [published online ahead of print on April 23, 2009]. J Am Soc Nephrol. 2009;20:1607-1613.
N
umerous large-scale studies have conclusively established that African Americans have lower serum hemoglobin concentrations than whites.1 In the general US population, the average hemoglobin level in African Americans is 0.7 g/dL (7 g/L) lower than in whites, even after adjusting for possible iron deficiency or hemoglobinopathies that may be more common in African Americans.2 Although racial disparity with regard to anemia is well described in adults with chronic kidney disease (CKD),3,4 a similar analysis in children had not been reported. In this issue of the American Journal of Kidney Diseases, Atkinson et al5 describe a higher prevalence of anemia in African American children with CKD in the large carefully conducted Chronic Kidney Disease in Children (CKiD) Study. After adjusting for relevant patient characteristics, maternal education, glomerular filtration rate (GFR), iron use, and erythropoietinstimulating agent (ESA) administration, average hemoglobin levels for African American children were estimated to be 0.6 g/dL (6 g/L [95% confidence interval, ⫺0.9 to ⫺0.2]) lower than in white children. The investigators noted further widening of hemoglobin levels at lower GFRs. The study’s particular strengths are its large patient cohort, the careful completion of the CKiD Study, and uniform measurement of GFR using a gold-standard method. A robust reference population was chosen (Third National Health and Nutrition Examination Survey [NHANES III]). The cross-sectional nature of the study precluded a conclusion about the cause of kidney disease based on the reported associations. It is debatable whether lower hemoglobin levels in African Americans result from genetic predisposition or emanate from a different set of environmental conditioning and comorbid condition spectrum in this population.1 The current literature supports the latter and suggests that the ethnic difference in hemoglobin levels is the consequence of a combination of overall nutrition, iron status, and inflammation.6 African American children enrolled in the study by Atkinson et al5 had significantly higher body mass index z scores, which can decrease hemoglobin
levels through an increase in iron demand. Low serum albumin levels in the African American children again suggested the contribution of environmental factors. Hypoalbuminemia could reflect relatively poor nutrition, which could induce iron deficiency and low hemoglobin levels. Low serum albumin levels also may indicate a high inflammatory state, resulting in a decrease in hemoglobin levels caused by lower iron availability and higher resistance to erythropoietin. Unlike in the non-CKD population, the proinflammatory potential of CKD complicates the interpretation of hematologic indices. Ferritin levels can be increased despite underlying iron deficiency. Interpretation of iron store status and ESA use becomes complex in the presence of inflammatory states. An acute-phase increase in ferritin levels secondary to inflammation may mask iron deficiency and a high ESA dose can reflect variable resistance to ESAs secondary to inflammation, rather than better medical care.7 With the emerging literature for lower hemoglobin levels in children with CKD of African American descent, it is important to discuss how this information may be used clinically. Should the reference intervals for hemoglobin levels for African American children be different from those for white children?8 This is an important clinical issue and warrants a careful look at the way anemia should be defined in African American children with CKD. Unlike in adults, children undergo developmental changes in hematologic parameters and age- and sex-specific reference intervals have to be used. That adds a component of age dependency to the interpretation of hemoglobin targets in children, an aspect that was not considered in the first set of Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines.9 z Score calculations can account for an age-dependent change in hemoglobin levels and can allow for comparison of hemoglobin Address correspondence to Guido Filler, MD, PhD, FRCPC, Department of Pediatrics, University of Western Ontario, Children’s Hospital, London Health Science Centre, 800 Commissioners Rd E, London, ON, Canada N6A 5W9. E-mail: guido. [email protected] © 2010 by the National Kidney Foundation, Inc. 0272-6386/10/5506-0003$36.00/0 doi:10.1053/j.ajkd.2010.03.003
American Journal of Kidney Diseases, Vol 55, No 6 (June), 2010: pp 981-983
981
982
Figure 1. Number of children (total 351 with chronic kidney disease [CKD], described in10) that are anemic using Kidney Disease Outcomes Quality Initiative (KDOQI) definitions and age- and sex-specific reference intervals. P ⫽ 0.001.
levels across various ages.10 Use of an agedependent hemoglobin z score can even categorize the degree of anemia differently than classifications based on hemoglobin levels10 (Fig 1). Applying previously reported reference intervals to the anemic children of African American descent from the study by Atkinson et al,5 the proportion of anemic children may be similar to that observed in whites. Similar accounting for age dependency also needs to be applied when interpreting iron status in children with CKD.11 In light of the observations suggesting lower hemoglobin concentrations in African American children, the important question emerges whether correcting anemia to the published KDOQI guidelines in these children improves clinical outcomes. Overall, the appropriate target hemoglobin level for children with CKD is poorly defined. Currently, the recommended hemoglobin target is largely opinion based and is broadly guided by similar studies of adults with CKD.12 In adults, there is a reasonable degree of evidence that correcting severe anemia with ESAs results in lower transfusion rates.13 However, correcting mild anemia does not offer much benefit in terms of decreasing the incidence of cardiovascular events.14 On the contrary, correcting anemia to the reference range could even aggravate cardiovascular events. The recent Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) did not show a decrease in death or cardiovascular events, but showed an increase in stroke incidence with hemoglobin correction close
Filler, Huang, and Sharma
to 13 g/dL using darbepoetin alfa in 4,038 adults with diabetes who had associated CKD and moderate anemia and were not undergoing dialysis.14 Other large trials, including Cardiovascular Risk Reduction by Early Anemia Treatment With Epoetin Beta (CREATE) and Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR), conveyed a similar impression of neutral or increased cardiovascular events by hemoglobin level correction to the reference range, with no added benefit from achieving higher hemoglobin targets.15,16 Evidence of increased hospitalization risk with hematocrits ⬍33% also is based on only retrospective data.17 With this evidence, the debate about cost consideration, given the higher ESA needs in African American adults, may initiate similar discussions about using ESAs in children with CKD.18 In the absence of strong evidence to suggest otherwise, it would seem intuitive to adopt principles and hemoglobin targets for children with CKD similar to those for adults. However, this issue can be looked at from a different perspective when one considers the onset of CKD in childhood rather than in adulthood. Because of an early onset, atherosclerotic changes in children are expected to be much less pronounced. This could mean there is a window to attain normal physiologic hemoglobin targets without the risks associated with attaining normal hemoglobin levels in adults. Because cardiovascular events in children are relatively uncommon, attaining normal hemoglobin levels in children likely will not increase the risk of these events. Childhood onset of CKD also involves much longer exposure of target organs to a deranged uremic milieu than in adult-onset CKD. With this combination of factors, full correction of anemia in children with CKD theoretically could have a preventative role in avoiding target-organ damage secondary to mild, but prolonged, duration of ischemic injury. Growth and school performance are additional considerations unique to children that can guide the appropriateness of a hemoglobin target in children. The low likelihood of cardiovascular events in children and relatively low prevalence of CKD in children as such makes these assumptions hard to test in a rigorous scientific manner. Identifying appropriate surrogate markers in children can guide fu-
Editorial
983
ture research for establishing appropriate hemoglobin targets in children with CKD. In summary, the study by Atkinson et al5 shows a difference in hemoglobin levels in children with CKD that equals that in the general population (about 0.6 g/dL [6 g/L]). Targeting the same hemoglobin levels in African American children as outlined in the KDOQI guidelines15 will be associated with higher cost. Future studies are required to derive evidence-based hemoglobin targets with optimized outcome and cost analysis in children with CKD. Guido Filler, MD, PhD, FRCPC Shih-Han Susan Huang, MD, FRCPC Ajay P. Sharma, MD, FRCPC University of Western Ontario Ontario, Canada
ACKNOWLEDGEMENTS Financial Disclosure: The authors declare they have no relevant financial interests.
REFERENCES 1. Kent S. Interpretations of differences in population hemoglobin means: a critical review of the literature. Ethn Dis. 1997;7(2):79-90. 2. Beutler E, West C. Hematologic differences between African-Americans and whites: the role of iron deficiency and alpha-thalassemia on hemoglobin levels and mean corpuscular volume. Blood. 2005;106:740-745. 3. Sehgal AR. Impact of quality improvement efforts on race and sex disparities in hemodialysis. JAMA. 2003;289: 996-1000. 4. Collins AJ, Kasiske B, Herzog C, et al. Excerpts from the United States Renal Data System 2006 Annual Data Report. Am J Kidney Dis. 2007;49(suppl 1):S16-296. 5. Atkinson MA, Pierce CB, Zack RM, et al. Hemoglobin differences by race in children with CKD. Am J Kidney Dis. 2010;55(6):1009-1017.
6. Pan Y, Jackson RT. Insights into the ethnic differences in serum ferritin between black and white US adult men. Am J Hum Biol. 2008;20(4):406-416. 7. Lacson E, Rogus J, Teng M, Lazarus JM, Hakim RH. The association of race with erythropoietin dose in patients on long-term hemodialysis. Am J Kidney Dis. 2008;52:11041114. 8. Robins EB, Blum S. Hematologic reference values for African American children and adolescents. Am J Hematol. 2007;82(7):611-614. 9. National Kidney Foundation. KDOQI update 2000 website (2000). Guideline 1. When to initiate the work-up of anemia. New York. http://www.kidney.org/professionals/ kdoqi/guidelines_updates/doqiupan_i.html#1. Accessed October 10, 2005. 10. Filler G, Mylrea K, Feber J, Wong H. How to define anemia in children with chronic kidney disease? Pediatr Nephrol. 2007;22(5):702-707. 11. Ooi CL, Lepage N, Nieuwenhuys E, Sharma AP, Filler G. Pediatric reference intervals for soluble transferrin receptor and transferrin receptor-ferritin index. World J Pediatr. 2009;5(2):122-126. 12. National Kidney Foundation. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007;50(3):471-530. 13. Bennett WM. A multicenter clinical trial of epoetin beta for anemia of end-stage renal disease. J Am Soc Nephrol. 1991;1(7):990-998. 14. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032. 15. Drüeke TB, Locatelli F, Clyne N, et al; CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071-2084. 16. Singh AK, Szczech L, Tang KL, et al; CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085-2098. 17. Staples AO, Wong CS, Smith JM, et al. Anemia and risk of hospitalization in pediatric chronic kidney disease. Clin J Am Soc Nephrol. 2009;4(1):48-56. 18. Ishani A, Guo H, Arneson TJ, et al. Possible effects of the new Medicare reimbursement policy on African Americans with ESRD [published online ahead of print on April 23, 2009]. J Am Soc Nephrol. 2009;20:1607-1613.