Erythropoietic response and outcomes in kidney disease and type 2 diabetes

Scott D. Solomon, Hajime Uno, Eldrin F. Lewis, Kai Uwe Eckardt, Julie Lin, Emmanuel A. Burdmann, Dick De Zeeuw, Peter Ivanovich, Andrew S. Levey, Patrick Parfrey, Giuseppe Remuzzi, Ajay K. Singh, Robert Toto, Fannie Huang, Jerome Rossert, John J V McMurray, Marc A. Pfeffer

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Non-placebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA-associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response. METHODS: We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2%) after the first two standardized doses of the drug. RESULTS: Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78). CONCLUSIONS: A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.)

Original languageEnglish (US)
Pages (from-to)1146-1155
Number of pages10
JournalNew England Journal of Medicine
Volume363
Issue number12
DOIs
StatePublished - Sep 16 2010

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Kidney Diseases
Type 2 Diabetes Mellitus
Hemoglobins
Chronic Renal Insufficiency
Hematinics
Confidence Intervals
Darbepoetin alfa
Anemia
Dialysis
Weights and Measures

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Solomon, S. D., Uno, H., Lewis, E. F., Eckardt, K. U., Lin, J., Burdmann, E. A., ... Pfeffer, M. A. (2010). Erythropoietic response and outcomes in kidney disease and type 2 diabetes. New England Journal of Medicine, 363(12), 1146-1155. https://doi.org/10.1056/NEJMoa1005109

Erythropoietic response and outcomes in kidney disease and type 2 diabetes. / Solomon, Scott D.; Uno, Hajime; Lewis, Eldrin F.; Eckardt, Kai Uwe; Lin, Julie; Burdmann, Emmanuel A.; De Zeeuw, Dick; Ivanovich, Peter; Levey, Andrew S.; Parfrey, Patrick; Remuzzi, Giuseppe; Singh, Ajay K.; Toto, Robert; Huang, Fannie; Rossert, Jerome; McMurray, John J V; Pfeffer, Marc A.

In: New England Journal of Medicine, Vol. 363, No. 12, 16.09.2010, p. 1146-1155.

Research output: Contribution to journalArticle

Solomon, SD, Uno, H, Lewis, EF, Eckardt, KU, Lin, J, Burdmann, EA, De Zeeuw, D, Ivanovich, P, Levey, AS, Parfrey, P, Remuzzi, G, Singh, AK, Toto, R, Huang, F, Rossert, J, McMurray, JJV & Pfeffer, MA 2010, 'Erythropoietic response and outcomes in kidney disease and type 2 diabetes', New England Journal of Medicine, vol. 363, no. 12, pp. 1146-1155. https://doi.org/10.1056/NEJMoa1005109
Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. New England Journal of Medicine. 2010 Sep 16;363(12):1146-1155. https://doi.org/10.1056/NEJMoa1005109
Solomon, Scott D. ; Uno, Hajime ; Lewis, Eldrin F. ; Eckardt, Kai Uwe ; Lin, Julie ; Burdmann, Emmanuel A. ; De Zeeuw, Dick ; Ivanovich, Peter ; Levey, Andrew S. ; Parfrey, Patrick ; Remuzzi, Giuseppe ; Singh, Ajay K. ; Toto, Robert ; Huang, Fannie ; Rossert, Jerome ; McMurray, John J V ; Pfeffer, Marc A. / Erythropoietic response and outcomes in kidney disease and type 2 diabetes. In: New England Journal of Medicine. 2010 ; Vol. 363, No. 12. pp. 1146-1155.
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abstract = "BACKGROUND: Non-placebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA-associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response. METHODS: We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2{\%}) after the first two standardized doses of the drug. RESULTS: Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15{\%} or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95{\%} confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95{\%} CI, 1.12 to 1.78). CONCLUSIONS: A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.)",
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T1 - Erythropoietic response and outcomes in kidney disease and type 2 diabetes

AU - Solomon, Scott D.

AU - Uno, Hajime

AU - Lewis, Eldrin F.

AU - Eckardt, Kai Uwe

AU - Lin, Julie

AU - Burdmann, Emmanuel A.

AU - De Zeeuw, Dick

AU - Ivanovich, Peter

AU - Levey, Andrew S.

AU - Parfrey, Patrick

AU - Remuzzi, Giuseppe

AU - Singh, Ajay K.

AU - Toto, Robert

AU - Huang, Fannie

AU - Rossert, Jerome

AU - McMurray, John J V

AU - Pfeffer, Marc A.

PY - 2010/9/16

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N2 - BACKGROUND: Non-placebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA-associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response. METHODS: We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2%) after the first two standardized doses of the drug. RESULTS: Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78). CONCLUSIONS: A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.)

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