Letter to the Editor / Reply Published online: February 6, 2014
Blood Purif 2014;37:47 DOI: 10.1159/000357395
Comment on the Paper: Hospitalization and Mortality in Hemodialysis Patients: Association with Hemoglobin Variability G. Imamovic School of Medicine, Tuzla University, Tuzla, Bosnia and Herzegovina
Dear Editor, I read with great interest the paper published in your journal by Handelman et al. [1]. The authors concluded that the number of excursions below the range appeared to have the most influence on mortality, whereas time below range, area below range, and measures of amplitude have the most effect on hospitalization. They also specified that this variability is linked to outcomes of hospitalization and mortality, with the most impact coming from measures below the target range. However, the observational study design that the authors applied cannot account for such conclusions because it was not a randomized controlled trial to infer causality. The authors performed the epidemiological study instead and applied mul-
tivariate logistic regression analysis using hypertension and coronary artery disease as covariates. However, those covariates do not meet the criteria for confounder’s definition since they are on a causal path between the predictor and the outcome [2], which means the higher hemoglobin, the higher blood pressure [3], and the higher hemoglobin, the worse coronary artery disease [4]. Above all, the authors entered in the model all covariates and observed what would come up as the result. Thus, they were testing a prognostic and not an etiological model, so there was no room for the inferences made, but only for the probabilities for the outcomes specified [5].
References 1 Handelman GJ, Kotanko P, Cisternas MG, Hoenich N, Usvyat L, Kuhlmann M, Levin NW: Hospitalization and mortality in hemodialysis patients: association with hemoglobin variability. Blood Purif 2013;35:247–257. 2 Jager K, Zoccali C, MacLeod A, Dekker FW: Confounding: what it is and how to deal with it. Kidney Int 2008;73:256–260. 3 Strippoli GF, Craig JC, Manno C, Schena FP: Hemoglobin targets for the anemia of chronic kidney disease: a meta-analysis of randomized, controlled trials. J Am Soc Nephrol 2004; 15:3154. 4 Besarab A, Bolton WK, Browne JK, et al: 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;339:584. 5 Tripepi G, Jager K, Dekker FW, Zoccali C: Testing for causality and prognosis: etiological and prognostic models. Kidney Int 2008; 74:1512–1515.
Reply Garry J. Handelman, for all co-authors University of Massachusetts, Lowell, Mass., USA
We appreciate the thoughtful comments of Dr. Imamovic on our study. Dr. Imamovic is concerned that we have drawn inferences about causality without the use of a randomized trial design. Our study is a study of association and indicates negative outcomes associated with hemoglobin going below target range and positive outcomes with excursions above the target
range. Therefore, we conclude that a prudent clinician would give special attention to a patient going below the target hemoglobin range, which might be an early warning indicator of impending problems. This conclusion uses the same reasoning as the use of fever and elevated white count as indicators of infection, and severe edema as indicative of congestive heart failure. While
© 2014 S. Karger AG, Basel 0253–5068/14/0371–0047$39.50/0 E-Mail [email protected] www.karger.com/bpu
high hemoglobin may be associated in some studies with hypertension and heart disease, especially when targets were in the 12–14 g/dl range, the hemoglobin increases observed were only transient, the target was 11.5 g/dl, and clinic protocols promptly decreased the dose of ESA and intravenous iron to keep patients within the target range.
G. Imamovic Centar za dijalizu Sime Perića 2 75400 Zvornik (Bosnia and Herzegovina) E-Mail goran.imamovic @fmc-ag.com
Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Blood Purif 2014;37:47 DOI: 10.1159/000357395
Comment on the Paper: Hospitalization and Mortality in Hemodialysis Patients: Association with Hemoglobin Variability G. Imamovic School of Medicine, Tuzla University, Tuzla, Bosnia and Herzegovina
Dear Editor, I read with great interest the paper published in your journal by Handelman et al. [1]. The authors concluded that the number of excursions below the range appeared to have the most influence on mortality, whereas time below range, area below range, and measures of amplitude have the most effect on hospitalization. They also specified that this variability is linked to outcomes of hospitalization and mortality, with the most impact coming from measures below the target range. However, the observational study design that the authors applied cannot account for such conclusions because it was not a randomized controlled trial to infer causality. The authors performed the epidemiological study instead and applied mul-
tivariate logistic regression analysis using hypertension and coronary artery disease as covariates. However, those covariates do not meet the criteria for confounder’s definition since they are on a causal path between the predictor and the outcome [2], which means the higher hemoglobin, the higher blood pressure [3], and the higher hemoglobin, the worse coronary artery disease [4]. Above all, the authors entered in the model all covariates and observed what would come up as the result. Thus, they were testing a prognostic and not an etiological model, so there was no room for the inferences made, but only for the probabilities for the outcomes specified [5].
References 1 Handelman GJ, Kotanko P, Cisternas MG, Hoenich N, Usvyat L, Kuhlmann M, Levin NW: Hospitalization and mortality in hemodialysis patients: association with hemoglobin variability. Blood Purif 2013;35:247–257. 2 Jager K, Zoccali C, MacLeod A, Dekker FW: Confounding: what it is and how to deal with it. Kidney Int 2008;73:256–260. 3 Strippoli GF, Craig JC, Manno C, Schena FP: Hemoglobin targets for the anemia of chronic kidney disease: a meta-analysis of randomized, controlled trials. J Am Soc Nephrol 2004; 15:3154. 4 Besarab A, Bolton WK, Browne JK, et al: 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;339:584. 5 Tripepi G, Jager K, Dekker FW, Zoccali C: Testing for causality and prognosis: etiological and prognostic models. Kidney Int 2008; 74:1512–1515.
Reply Garry J. Handelman, for all co-authors University of Massachusetts, Lowell, Mass., USA
We appreciate the thoughtful comments of Dr. Imamovic on our study. Dr. Imamovic is concerned that we have drawn inferences about causality without the use of a randomized trial design. Our study is a study of association and indicates negative outcomes associated with hemoglobin going below target range and positive outcomes with excursions above the target
range. Therefore, we conclude that a prudent clinician would give special attention to a patient going below the target hemoglobin range, which might be an early warning indicator of impending problems. This conclusion uses the same reasoning as the use of fever and elevated white count as indicators of infection, and severe edema as indicative of congestive heart failure. While
© 2014 S. Karger AG, Basel 0253–5068/14/0371–0047$39.50/0 E-Mail [email protected] www.karger.com/bpu
high hemoglobin may be associated in some studies with hypertension and heart disease, especially when targets were in the 12–14 g/dl range, the hemoglobin increases observed were only transient, the target was 11.5 g/dl, and clinic protocols promptly decreased the dose of ESA and intravenous iron to keep patients within the target range.
G. Imamovic Centar za dijalizu Sime Perića 2 75400 Zvornik (Bosnia and Herzegovina) E-Mail goran.imamovic @fmc-ag.com
Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
