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Hemoglobin Variability in Nondialysis Chronic Kidney Disease: Examining the Association with Mortality

Neil C. Boudville^*, Ognjenka Djurdjev, Iain C. Macdougall, Angel L.M. de Francisco, Gilbert Deray^||, Anatole Besarab^¶, Paul E. Stevens^**, Rowan G. Walker, Pablo Ureña, Pablo Iñigo, Roberto Minutolo^||||, Yosef S. Haviv^¶¶, Karen Yeates^***, Marisa L. Agüera^,, Jennifer M. MacRae, and Adeera Levin

^* School of Medicine and Pharmacology, University of Western Australia, and Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia; Department of Medicine, Division of Nephrology, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Department of Renal Medicine, King's College Hospital, London, United Kingdom; Servicio de Nefrologia, Hospital Universitario Valdecilla, Santander, Spain; ^|| Department of Nephrology, Hospitalier Pitié-Salpetrière, Paris, France; ^¶ Department of Medicine, Division of Nephrology and Hypertension, Henry Ford Health System, Detroit, Michigan; ^** Department of Renal Medicine, Kent and Canterbury Hospital, Canterbury, United Kingdom; Department of Nephrology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; Service de Néphrologie Dialyse, Clinique du Landy, Saint Ouen, France; Servicio de Nefrología, Hospital Clinico Universitario "Lozano Blesa," Zaragoza, Spain; ^|||| Department of Nephrology, Second University of Naples, Naples, Italy; ^¶¶ Division of Nephrology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; ^*** Department of Medicine, Queen's University, Kingston, Ontario, Canada; Servicio de Nefrologia, Hospital Univeritario Reina Sofia, Córdoba, Spain; and Division of Nephrology, Foothills Medical Centre, Calgary, Alberta, Canada

Correspondence: Dr. Neil Boudville, School of Medicine and Pharmacology, M503, 4th Floor G Block, Sir Charles Gairdner Hospital, Verdun Street, Nedlands, WA, Australia 6009. Phone: 61-8-9346-3333; Fax: 61-8-9346-2816; E-mail: neil.boudville{at}uwa.edu.au

Background and objectives: Anemia and hemoglobin (Hb) variability are associated with mortality in hemodialysis patients who are on erythropoiesis-stimulating agents (ESA). Our aim was to describe the degree of Hb variability present in nondialysis patients with chronic kidney disease (CKD), including those who were not receiving ESA, and to investigate the association between Hb variability and mortality.

Design, setting, participants, & measurements: Hb variability was determined using 6 mo of "baseline" data between January 1, 2003, and October 31, 2005. A variety of definitions for Hb variability were examined to ensure consistency and robustness.

Results: A total of 6165 patients from 22 centers in seven countries were followed for a mean of 34.0 ± 15.8 mo; 49% were prescribed an ESA. There was increased Hb variability with ESA use; the residual SD of Hb was 4.9 ± 4.4 g/L in patients who were not receiving an ESA, compared with 6.8 ± 4.8 g/L. Hb variability was associated with a small but significantly increased risk for death per g/L residual SD, irrespective of ESA use. Multivariate linear regression model explained only 11% of the total variance of Hb variability.

Conclusions: Hb variability is increased in patients who have CKD and are receiving ESA and is associated with an increased risk for death (even in those who are not receiving ESAs). This analysis cannot determine whether Hb variability causally affects mortality. Thus, the concept of targeting Hb variability with specific agents needs to be examined within the context of factors that affect both Hb variability and mortality.