Anemia develops as a frequent complication of chronic kidney disease (CKD) with an incidence and severity that are proportional to the degree of renal dysfunction.1 Correction of anemia and maintenance of stable hemoglobin levels using erythropoiesis-stimulating agents (ESA) is an important aspect of disease management.1,2 In clinical studies, moderate increase in hemoglobin concentration is associated with relief from symptoms of anemia, improved quality of life, and decreased blood transfusion rate.3,4 The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend target hemoglobin levels in the range 11 to 12 g/dl, whereas hemoglobin >13 g/dl should be avoided.5 Several recent randomized clinical trials showed targeting hemoglobin levels >13 g/dl to “normalize” hemoglobin in CKD may be associated with poor clinical outcomes,6–10 and recent expert review by the Food and Drug Administration has left the target range between 10 and 12 g/dl unchanged.11
Although average hemoglobin levels have steadily increased since the introduction of ESA, until recently, approximately 15 to 20% of maintenance dialysis patients had average hemoglobin levels <11 g/dl.12 The standard deviation (SD) of hemoglobin in maintenance dialysis populations in the United States is 1.1 to 1.3 g/dl,12,13 which may explain the relatively high frequency of hemoglobin level outside the recommended range of 11 to 12 g/dl. Whereas hemoglobin levels are generally higher for patients who receive ESA treatment, evidence from various clinical trials as well as the US Renal Data System (USRDS) suggests many patients who receive ESA experience fluctuations in hemoglobin over time, with a great degree of variability above and below the target range.14–17 Recent analyses of USRDS data also suggest that considerably higher amounts of ESA are prescribed in for-profit dialysis care providers, leading to higher hemoglobin levels than other dialysis centers.14,18,19 This may be related to the high profit margin from the ESA trades and utilization or simply a natural trend in patient care.20
DEFINITION AND CLINICAL EVIDENCE OF HEMOGLOBIN VARIABILITY
Hemoglobin variability is the fluctuation of hemoglobin above or below the target range over time. Hence, hemoglobin variability is the extent to which multiple measured hemoglobin values differ from each other within a given time span, whereas the calculated mean of all hemoglobin levels may still remain within the target range.21 ESA therapy may produce short, intermittent, nonbiologic bursts of plasma erythropoietin availability. The result can be a rising and falling of hemoglobin in a cyclic pattern that varies from patient to patient. This is in contrast to untreated, healthy individuals, in whom during homeostasis hemoglobin levels are maintained within a narrow range by close regulation of oxygen sensing, erythropoietin-producing, and erythropoietic systems.1
A 2-yr study by Ofsthun et al.22 showed that of 41,919 dialysis patients, >50% spent >1.2 to 6.0 mo at hemoglobin levels <11 g/dl. A longitudinal analysis that was conducted by Lacson et al.23 and involved >65,000 dialysis patients showed only approximately 38% had hemoglobin levels within the range of 11 to 12 g/dl. Despite a mean hemoglobin level of 11.5 g/dl, the average individual patient had a ±1.4-g/dl fluctuation in hemoglobin during the course of 1 yr on the basis of 3-mo rolling average values.23 A 15-mo retrospective study of standard clinical practice conditions demonstrated substantial hemoglobin variability in 987 epoetin-treated hemodialysis patients.24 The range of mean hemoglobin values (10.9 to 11.2 g/dl) that included the middle 50, 80, and 90% of values from a single month were within 1.7, 3.3, and 4.4 g/dl, respectively. One-month hemoglobin values exhibited the greatest degree of variability, with longer rolling intervals being associated with narrower hemoglobin ranges; however, even when a 6-mo rolling average was applied, <50% of hemodialysis patients had hemoglobin values within the KDOQI-recommended 11- to 12-g/dl range. Hemoglobin levels >12 g/dl were predicted to occur approximately 21% of the time.24
The foregoing findings were confirmed by the recent USRDS analysis, in which patients were categorized into one of three baseline hemoglobin cohorts of <11.0 g/dl (23%), 11.0 to 12.5 g/dl (47%), and ≥12.5 g/dl (30%).12 As shown in Figure 1, there was significant movement between and within hemoglobin groups during a 3-mo time period. For example, 14% of patients who started with a hemoglobin level ≥12.5 g/dl fell below 11 g/dl at 3 mo, whereas 25% of patients who started with a hemoglobin level <11 g/dl had a hemoglobin ≥12.5 g/dl at 3 mo. In fact, only 55% of patients who were in the range of 11.0 to <12.5 g/dl stayed within that target range at 3 mo.12
In another USRDS analysis by Ebben et al.,17 hemoglobin fluctuations during a 6-mo period were categorized into a few common patterns: Hemoglobin levels that were consistently <11.0 g/dl (low-hemoglobin group), between 11.0 and 12.5 g/dl (target hemoglobin group), or ≥12.5 g/dl (high-hemoglobin group) for all 6 mo; hemoglobin levels that crossed one boundary, in effect, varied between low and target groups or between high and target groups during the 6 mo; and hemoglobin levels that varied across all three hemoglobin boundaries.17 As illustrated in Figure 2, only 10% of patients maintained hemoglobin levels within a single hemoglobin category during the entire 6-mo period. Overall, 29% of patients experienced hemoglobin fluctuations between the high and target hemoglobin groups, and 21% experienced fluctuations between the low and target hemoglobin groups. In almost 90% of patients, hemoglobin levels were in some degree of flux at any point in time. Fluctuation across all three hemoglobin categories during the 6-mo period was observed in nearly 40% of patients.17
Fishbane et al.16 analyzed the movement of hemoglobin levels over time in 281 individual hemodialysis patients who were treated with epoetin. Hemoglobin cycling, repeated up-and-down undulations of hemoglobin levels, was found in >90% of patients. The patterns were somewhat predictable and were interrupted by periods of illnesses and hospitalizations. Hemoglobin excursions (defined as half of one hemoglobin cycle) occurred at a mean rate of 3.1 ± 1.1 per patient/yr, at a mean amplitude of 2.51 ± 0.89 g/dl, and for a mean duration of 10.3 ± 5.1 wk.16
The foregoing studies reveal the complexity of maintaining stable hemoglobin levels over time and indicate that traditional point-in-time analyses of hemoglobin levels may not accurately reflect anemia management in the clinical setting. Understanding the nature of hemoglobin variability is of particular importance when assessing the incidence of morbidity and mortality in this patient population, particularly because fluctuations in hemoglobin levels are themselves associated with adverse outcomes.25
MEASURING HEMOGLOBIN VARIABILITY
Variability may be assessed within the same patient or between patients in a group. In the context of clinical practice, it is generally the variability within a patient that is important, whereas for quality assurance purposes, variability both within patients (an index of individual stability) and between patients (an index of the extent to which values differ between patients) are relevant.21 Different methods have been used to quantify the degree of hemoglobin variability (Box 1), including the conventional SD; the coefficient of variation, that is, the ratio of the SD to the mean; the proportion of time outside certain thresholds (Figure 2), on the basis of either actual hemoglobin measurement or rolling averages of hemoglobin measurements17; the magnitude of the residual SD or the average of the absolute SD changes25; and the absolute value of the rate of hemoglobin change or trajectory (calculated from curve-fitting computer algorithms) measured in g/dl per month.26 As depicted in Figure 3, however, the linear regression slope may not discriminate between the inter-patient variance, which implies the population level variability, and the intra-patient variability; that is, the variability at the individual level, which is the relevant metric to study hemoglobin variability. More sophisticated repeated measure models may be required to decompose the variability slope into its different individual patient- and population-based components. Because the frequency and the direction of the changes over time are usually relevant in studying variability, methods that more accurately integrate the element of time, such as calculating the slope of the change over smaller periods of time using regression models, seem more desirable.27
CONSEQUENCES OF HEMOGLOBIN VARIABILITY
To the best of our knowledge, the relationship between hemoglobin variability and outcomes in an earlier (predialysis) CKD population has not been well studied. In maintenance dialysis patients, however, hemoglobin variability seems to be associated with increased risk for death according to at least two studies.25,28 In a recent USRDS analysis of 151,000 hemodialysis patients, Gilbertson et al.28 found the 1-yr mortality risk was lowest in the few patients (6.5%) who consistently maintained hemoglobin within 11.0 to 12.5 g/dl. In these patients, both the number of times the hemoglobin level dropped to <11 g/dl and the time spent at <11 g/dl were predictive of mortality risk.28 In another recent retrospective cohort study of 34,963 hemodialysis patients, each 1-g/dl increase in the residual SD was independently associated with a 33% increased death rate.25 Of note in this study, patient characteristics accounted for only a small portion of the variation in this hemoglobin variability metric.25
Because hemoglobin variability seems to be associated with mortality, it is expected that both low and high hemoglobin levels would be associated with increased death risk. Consistent with the foregoing notion, in several recent observational studies, a U-shaped or inverse J-curve relationship was observed between hemoglobin levels and clinical outcomes, whereby a specific range of hemoglobin was associated with greatest survival, rather than an incremental or linear association between hemoglobin and survival.13,29,30 A recent retrospective study of 58,058 maintenance hemodialysis patients also demonstrated an inverse J-curve relationship between hemoglobin levels and adverse outcomes (Figure 4),13 in that hemoglobin levels between 11.5 and 13.0 g/dl were associated with the lowest death risk. A decrease in hemoglobin over time is also associated with a higher risk for death, whereas an increase in hemoglobin over time is associated with a lower death risk, an effect probably due to the overrepresentation by those whose baseline hemoglobin level to start is lower than usual. Improved survival outcomes are observed in dialysis patients using ESA at any dosages, whereas among those who received an ESA, a higher dosage requirement is a surrogate of higher death risk.13
The inconsistency of studies regarding upper hemoglobin threshold is also of clinical interest. Many observational studies indicated a strictly incremental improvement in survival with higher hemoglobin levels without any changing trend of increased death risk in both nondialysis31 and dialysis32 patients with CKD. This is, however, in sharp contradistinction to several recent studies showing increased death risk beyond certain achieved13 or targeted6,8,9 hemoglobin threshold levels, usually approximately or >13 g/dl in the CKD population (Figure 4). The discrepancy between randomized clinical trials and some but not all epidemiologic studies may be related to the observational nature and/or methods used to analyze mortality risk factors in the latter studies.31,32 In particular, physician use of ESA in observational studies is not randomly assigned. Furthermore, although descriptive data can be used to determine correlations, they cannot definitively determine causality; however, there are also several advantages of observational studies, because such data can be more representative of real-world use and outcome of treatments. In contrast, randomized, controlled trials have restrictive inclusion/exclusion criteria and more ideal patterns of patient encounter than occur in usual care.
In addition to associations of blood hemoglobin with mortality and hospitalizations in the CKD population, anemia is associated with fatigue, weakness, shortness of breath, and a decreased health-related quality of life.33,34 Furthermore, hemoglobin overshoot may be associated with various safety concerns, including the development of elevated BP with risk for hypertensive encephalopathy,35 iron deficiency,36 high platelet count,37–39 thrombotic events,40 and accelerated left ventricular dysfunction and hypertrophy.7
FACTORS AFFECTING HEMOGLOBIN VARIABILITY
Minor fluctuations above and below the target range may be normal in any setting; however, wide and/or prolonged fluctuations in hemoglobin are usually associated with several internal and external factors that can influence ESA response and hemoglobin stability. These factors can be grouped into several categories, as listed in Box 2.
Drug-Related Factors
Drug-related factors such as differences in pharmacokinetic and bioavailability parameters among ESA and different routes of administration (intravenous versus subcutaneous41,42) may affect hemoglobin stability in patients with CKD. Longer dosing intervals may lead to less variability in hemoglobin levels over time by producing fewer peaks and troughs and thereby requiring fewer dosage adjustments.43–45 Both epoetin and darbepoetin have been studied over extended intervals beyond the currently approved regimens,27,45,46 and similar data on newer ESA including continuous erythropoietin receptor activator are emerging.43,44 Conversely, it is also possible more frequent dosing with agents with shorter half-lives is associated with better control of hemoglobin variability. Whether extended versus shorter dosing intervals with any of these ESA agents are associated with less variability in hemoglobin levels remains to be confirmed in clinical trials. In addition, medications that modulate hemoglobin synthesis such as iron preparations47,48 or cardiovascular medications such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers49,50 that are commonly used in this patient population, as well as medications for cancer chemotherapy, may lead to hemoglobin variability, especially at the initiation, discontinuation, and dosage titration.
Patient-Related Factors
Hemoglobin levels vary by age, gender, and race. In general, lower hemoglobin levels have been observed with increasing age, in women compared with men, and in black patients compared with white patients.51–53 Although no major differences in ESA response are observed by age, gender, or race in clinical trials, these factors should be considered during ESA dosage selection and adjustment, because treatment may need to be individualized to maintain hemoglobin levels within target ranges. Laboratory variation of hemoglobin measurement amounts to 0.5 g/dl within a given blood sample.54 Normal individuals may exhibit varying hemoglobin by ≥1 g/dl within a short period of time.54 In dialysis patients, blood samples drawn at the beginning of the week may have lower hemoglobin values as a result of hemodilution as compared with midweek draws.55
Additional reasons for hemoglobin variability include acute or chronic comorbidities17; alteration in iron stores56; infection or inflammation57,58; blood loss or transfusion59; dialysis treatment features such as dialysis adequacy60 or water quality61; stage of CKD and residual renal function31; level of parathyroid hormone62; vitamin and mineral status such as vitamin D, B12, or folate deficiencies63; and seasonal effects.61 Hemoglobin variability is more prominent in patients who are younger, have lower albumin or higher serum ferritin levels, or have changes in appetite64 possibly related to alterations in nutritional or inflammatory status57 and higher mean corpuscular hemoglobin.24 Iron supplementation strategies, for example, intravenous iron maintenance versus repletion, may cause different patterns of variations in hemoglobin level.
Factors Related to Medical Care and Reimbursement Policies
Hemoglobin variability is also affected by anemia management practice patterns, which in turn are influenced by clinical practice guidelines, treatment protocols, and, in particular, reimbursement policies.65 Management of CKD, including dialysis treatment, contributes substantially to the economic burden on the US health care system.66 The presence of anemia has been identified as a major driver of health care costs in patients with CKD, and, as a result, anemia management is often a target of various cost-containment policies65; however, formulary restrictions, payment policies, and other cost-containment issues that require clinicians to maintain hemoglobin levels within a certain range increase the likelihood of hemoglobin variability. It is possible the recent debates and hearings on ESA use in patient populations with CKD and cancer by Congress and the Food and Drug Administration67 and the recent inclusion of black box warnings for the currently approved ESA68–70 have some impact on anemia management and hemoglobin variability.
MANAGEMENT OF HEMOGLOBIN VARIABILITY
Because fluctuations in actual or achieved hemoglobin levels above and below the target range are common in clinical practice, there are ongoing efforts to minimize the variability. Box 3 shows proposed strategies that can be used to prevent or manage hemoglobin variability in patients with CKD. Selecting and administrating an ESA and adjusting its dosing, whether initiated by a physician on the basis of clinical judgment or whether used through clinical decision algorithms by nonphysician health care providers, should follow the principles of a “negative-feedback loop.”21 Setting a narrow hemoglobin target of 11 to 12 g/dl may increase the chances of observing actual hemoglobin levels that deviate out of range. It could also be argued that a wider target range would lead to the greater variability by allowing more flexible ESA dosing. Values above or below a certain target range or a trajectory toward such deviations usually leads to an ESA dosage adjustment in the desired direction. The degree of hemoglobin fluctuations as well as occurrence can also be minimized by controlling for many patient-related factors that are manageable and by streamlining anemia practice patterns. In general, the challenge is to anticipate the changes on the basis of recent trends and to adjust the dosage and frequency of ESA, iron, and other medications accordingly, rather than waiting for hemoglobin values to be outside the target zones. Even though many protocols recommend fine-tuned rather than drastic changes in ESA dosage (Box 3), a recent study suggested that discontinuation, rather than reduction, of ESA treatment was more appropriate when hemoglobin level reaches 13 g/dl in hemodialysis patients.71 Changing the ESA dosage or frequency while maintaining the same dosage and frequency of intravenous iron may or may not be appropriate and needs to be examined in clinical studies.
CONCLUSIONS
Minimizing hemoglobin variability can have important short- and long-term clinical consequences. In the short run, fewer fluctuations above 12 g/dl may minimize the occurrence of serious cardiovascular events associated with high hemoglobin levels, whereas fewer fluctuations below 11.0 g/dl provide improved symptomatic relief and maximize survival. Increased hemoglobin stability also means better performance in meeting audit targets, because in some jurisdictions, exceeding upper hemoglobin thresholds may have reimbursement implications.21,72 The traditional desire to maximize the fraction of patients with CKD and with a blood hemoglobin level >11 g/dl along with recent efforts to minimize the proportion of patients with hemoglobin level >12 g/dl contributes to some of the challenges in the management of hemoglobin variability. Hemoglobin target ranges could be recommended on the basis of clinical or scientific data to indicate the ranges shown to be associated with the optimal combination of quality and length of life.21 Targets that require least frequent ESA dosage adjustment and yet meet the criteria set forth by regulatory or consensus bodies should be pragmatically selected. Because the foregoing purposes may be distinct, the optimal hemoglobin target range for each may differ.21 Future studies need to examine extended versus more frequent ESA dosing strategies, algorithms based on hemoglobin trends,73 or neural network based on reinforcement learning74–76 or iron supplementation strategies.
DISCLOSURES
KKZ's contributions were supported by the National Institute of Health grant R01DK078106. K.K.Z. has received honoraria or grants from or has served as consultant for Abbott, AMAG, Amgen, DaVita, Genzyme, Ortho-Biotech, Roche, Shire, Vifor, and Watson; has had research grants from the National Institutes of Health, American Heart Association, National Kidney Foundation, Abbott, Amgen, DaVita, Watson, and philanthropist Mr. Harold Simmons; and is the medical director of Harbor-UCLA/MFI DaVita dialysis clinic in Long Beach, California. G.R.A. has received honoraria, served on advisory boards, or performed funded research for American Regent, Amgen, Ortho-Biotech, and Roche.
;)
Figure 1: Fluctuations in hemoglobin levels over 3 mo. Although hemoglobin (Hb) distribution among the three groups remained consistent, only 33% of patients starting in the low-Hb group, 55% of patients starting in the mid-Hb group, and 43% of patients starting in the high-Hb group were still in those groups after 3 mo. Adapted from United States Renal Data System.
12Patterns of fluctuations in Hb levels during a 6-mo period (
n = 152,846). Hb values were divided into three groups. Only 6.5% of the patients remained within the range of 11.0 to 12.5 g/dl for 6 mo. (A) During 6 mo, 51.2% strayed outside their initial Hb groups into the next closest group (B), and 39.5 varied across two groups (C). Adapted from Ebben
et al. 17Schematic representation of the hemoglobin variability over time representing both population and individual slopes.
Figure 4: Hazard ratio for all-cause mortality on the basis of time-dependent hemoglobin levels that change quarterly (
i.e., every 13 wk) over 8 calendar quarters (July 2001 through June 2003). The greatest overall survival occurred for patients with hemoglobin values between 11.5 and 12.9 g/dl. Adapted from Regidor
et al. 13Measures of hemoglobin variability
Box 2: Potential contributors to hemoglobin variability in patients with CKDa
Box 3: Strategies for reduction of hemoglobin variability
KKZ's contributions were supported by the National Institute of Health grant R01DK078106. We acknowledge Dr. Devanshi Amin and Dr. Deborah L. Regidor for review and recommendations.
Published online ahead of print. Publication date available at www.jasn.org.
References
1. Weiss G, Goodnough LT: Anemia of chronic disease. N Engl J Med 352 : 1011– 1023, 2005
2. Aronoff GR, Duff DR, Sloan RS, Brier ME, Maurice B, Erickson B, Golper TA: The treatment of anemia with low-dose recombinant human erythropoietin. Am J Nephrol 10[Suppl 2] : 40– 43, 1990
3. Moreno F, Sanz-Guajardo D, Lopez-Gomez JM, Jofre R, Valderrabano F: Increasing the hematocrit has a beneficial effect on quality of life and is safe in selected hemodialysis patients. Spanish Cooperative Renal Patients Quality of Life Study Group of the Spanish Society of Nephrology. J Am Soc Nephrol 11 : 335– 342, 2000
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 22 : 1929– 1937, 2006
5. KDOQI: Clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease—2007 update of hemoglobin target. Am J Kidney Dis 50 : 471– 530, 2007
6. 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 339 : 584– 590, 1998
7. Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D: Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol 16 : 2180– 2189, 2005
8. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355 : 2085– 2098, 2006
9. Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A: Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355 : 2071– 2084, 2006
10. Phrommintikul A, Haas SJ, Elsik M, Krum H: Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: A meta-analysis. Lancet 369 : 381– 388, 2007
11. FDA Panel Votes against Anemia Drug Restrictions. Gaithersburg, MD, Renal Business, 2007. Available at:
http://www.renalbusiness.com/hotnews/79h14962958311.html. Accessed September 5, 2008
12. United States Renal Data System: United States Renal Data System 2006 Annual Data Report Atlas of Chronic Kidney Disease & End-Stage Renal Disease in the United States. Am J Kidney Dis 49 : 1– 296, 2007
13. Regidor DL, Kopple JD, Kovesdy CP, Kilpatrick RD, McAllister CJ, Aronovitz J, Greenland S, Kalantar-Zadeh K: Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol 17 : 1181– 1191, 2006
14. Foley RN, Zhang R, Gilbertson DT, Dunning S, Ishani A, Collins AJ: Exceeding hemoglobin target levels in US hemodialysis patients receiving epoetin, 1999 to 2002. Hemodial Int 11 : 333– 339, 2007
15. Fishbane S, Berns JS: Evidence and implications of haemoglobin cycling in anaemia management. Nephrol Dial Transplant 22 : 2129– 2132, 2007
16. Fishbane S, Berns JS: Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney Int 68 : 1337– 1343, 2005
17. Ebben JP, Gilbertson DT, Foley RN, Collins AJ: Hemoglobin level variability: Associations with comorbidity, intercurrent events, and hospitalizations. Clin J Am Soc Nephrol 1 : 1205– 1210, 2006
18. Thamer M, Zhang Y, Kaufman J, Cotter D, Dong F, Hernan MA: Dialysis facility ownership and epoetin dosing in patients receiving hemodialysis. JAMA 297 : 1667– 1674, 2007
19. Collins AJ, Brenner RM, Ofman JJ, Chi EM, Stuccio-White N, Krishnan M, Solid C, Ofsthun NJ, Lazarus JM: Epoetin alfa use in patients with ESRD: An analysis of recent US prescribing patterns and hemoglobin outcomes. Am J Kidney Dis 46 : 481– 488, 2005
20. Coyne DW: Use of epoetin in chronic renal failure. JAMA 297 : 1713– 1716, 2007
21. Brimble KS, Clase CM: Hemoglobin variability in dialysis patients. J Am Soc Nephrol 18 : 2218– 2220, 2007
22. Ofsthun NJ, LaBrecque J, Keen M, Youngson HI, Krishnan M, Lazarus JM: The association of mortality and hospitalization with hemoglobin (Hb) and missed dialysis treatments in stage 5 chronic kidney disease (CKD) patients with and without cardiac comorbidities [Abstract]. Nephrol Dial Transplant 20 : v268 , 2005 . Available at:
http://www.abstracts2view.com/era/view.php?nu=ERA5L_948. Accessed September 7, 2007
23. Lacson E Jr, Ofsthun N, Lazarus JM: Effect of variability in anemia management on hemoglobin outcomes in ESRD. Am J Kidney Dis 41 : 111– 124, 2003
24. Berns JS, Elzein H, Lynn RI, Fishbane S, Meisels IS, Deoreo PB: Hemoglobin variability in epoetin-treated hemodialysis patients. Kidney Int 64 : 1514– 1521, 2003
25. Yang W, Israni RK, Brunelli SM, Joffe MM, Fishbane S, Feldman HI: Hemoglobin variability and mortality in ESRD. J Am Soc Nephrol 18 : 3164– 3170, 2007
26. West RM, Harris K, Gilthorpe MS, Tolman C, Will EJ: Functional data analysis applied to a randomized controlled clinical trial in hemodialysis patients describes the variability of patient responses in the control of renal anemia. J Am Soc Nephrol 18 : 2371– 2376, 2007
27. Agarwal AK, Silver MR, Reed JE, Dhingra RK, Liu W, Varma N, Stehman-Breen C: An open-label study of darbepoetin alfa administered once monthly for the maintenance of haemoglobin concentrations in patients with chronic kidney disease not receiving dialysis. J Intern Med 260 : 577– 585, 2006
28. Gilbertson DT, Ebben JP, Foley RN, Weinhandl ED, Bradbury BD, Collins AJ: Hemoglobin level variability: associations with mortality. Clin J Am Soc Nephrol 3 : 133– 138, 2008
29. Sabatine MS, Morrow DA, Giugliano RP, Burton PB, Murphy SA, McCabe CH, Gibson CM, Braunwald E: Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation 111 : 2042– 2049, 2005
30. Go AS, Yang J, Ackerson LM, Lepper K, Robbins S, Massie BM, Shlipak MG: Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: The Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study. Circulation 113 : 2713– 2723, 2006
31. Kovesdy CP, Trivedi BK, Kalantar-Zadeh K, Anderson JE: Association of anemia with outcomes in men with moderate and severe chronic kidney disease. Kidney Int 69 : 560– 564, 2006
32. Ofsthun N, Labrecque J, Lacson E, Keen M, Lazarus JM: The effects of higher hemoglobin levels on mortality and hospitalization in hemodialysis patients. Kidney Int 63 : 1908– 1914, 2003
33. Macdougall IC: Quality of life and anemia: the nephrology experience. Semin Oncol 25 : 39– 42, 1998
34. Moreno F, Aracil FJ, Perez R, Valderrabano F: Controlled study on the improvement of quality of life in elderly hemodialysis patients after correcting end-stage renal disease-related anemia with erythropoietin. Am J Kidney Dis 27 : 548– 556, 1996
35. Chen J, Gul A, Sarnak MJ: Management of intradialytic hypertension: The ongoing challenge. Semin Dial 19 : 141– 145, 2006
36. Coyne D: Challenging the boundaries of anemia management: A balanced approach to i.v. iron and EPO therapy. Kidney Int Suppl S1– S3, 2006
37. Beguin Y, Loo M, R'Zik S, Sautois B, Lejeune F, Rorive G, Fillet G: Effect of recombinant human erythropoietin on platelets in patients with anemia of renal failure: Correlation of platelet count with erythropoietic activity and iron parameters. Nippon Jinzo Gakkai Shi 36 : 1288– 1295, 1994
38. Streja E, Kovesdy CP, Greenland S, Kopple JD, McAllister CJ, Nissenson AR, Kalantar-Zadeh K: Erythropoietin, iron depletion, and relative thrombocytosis: a possible explanation for hemoglobin-survival paradox in hemodialysis. Am J Kidney Dis 52 : 642– 644, 2008
39. Dahl NV, Henry DH, Coyne DW: Thrombosis with erythropoietic stimulating agents-does iron-deficient erythropoiesis play a role? Semin Dial 21 : 210– 211, 2008
40. Kooistra MP, van Es A, Marx JJ, Hertsig ML, Struyvenberg A: Low-dose aspirin does not prevent thrombovascular accidents in low-risk haemodialysis patients during treatment with recombinant human erythropoietin. Nephrol Dial Transplant 9 : 1115– 1120, 1994
41. Macdougall IC, Robson R, Opatrna S, Liogier X, Pannier A, Jordan P, Dougherty FC, Reigner B: Pharmacokinetics and pharmacodynamics of intravenous and subcutaneous continuous erythropoietin receptor activator (C.E.R.A.) in patients with chronic kidney disease. Clin J Am Soc Nephrol 1 : 1211– 1215, 2006
42. Silverberg DS, Wexler D, Blum M, Tchebiner JZ, Sheps D, Keren G, Schwartz D, Baruch R, Yachnin T, Shaked M, Schwartz I, Steinbruch S, Iaina A: The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrol Dial Transplant 18 : 141– 146, 2003
43. Besarab A, Salifu MO, Lunde NM, Bansal V, Fishbane S, Dougherty FC, Beyer U: Efficacy and tolerability of intravenous continuous erythropoietin receptor activator: A 19-week, phase II, multicenter, randomized, open-label, dose-finding study with a 12-month extension phase in patients with chronic renal disease. Clin Ther 29 : 626– 639, 2007
44. Macdougall IC: CERA (continuous erythropoietin receptor activator): A new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep 4 : 436– 440, 2005
45. Egrie JC, Browne JK: Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer 84[Suppl 1] : 3– 10, 2001
46. Brunkhorst R, Bommer J, Braun J, Haag-Weber M, Gill C, Wagner J, Wagener T: Darbepoetin alfa effectively maintains haemoglobin concentrations at extended dose intervals relative to intravenous or subcutaneous recombinant human erythropoietin in dialysis patients. Nephrol Dial Transplant 19 : 1224– 1230, 2004
47. Aronoff GR: Safety of intravenous iron in clinical practice: Implications for anemia management protocols. J Am Soc Nephrol 15[Suppl 2] : S99– S106, 2004
48. Kalantar-Zadeh K, Regidor DL, McAllister CJ, Michael B, Warnock DG: Time-dependent associations between iron and mortality in hemodialysis patients. J Am Soc Nephrol 16 : 3070– 3080, 2005
49. Hayashi K, Hasegawa K, Kobayashi S: Effects of angiotensin-converting enzyme inhibitors on the treatment of anemia with erythropoietin. Kidney Int 60 : 1910– 1916, 2001
50. Ishani A, Weinhandl E, Zhao Z, Gilbertson DT, Collins AJ, Yusuf S, Herzog CA: Angiotensin-converting enzyme inhibitor as a risk factor for the development of anemia, and the impact of incident anemia on mortality in patients with left ventricular dysfunction. J Am Coll Cardiol 45 : 391– 399, 2005
51. Maraldi C, Ble A, Zuliani G, Guralnik JM, Mussi C, Fellin R, Volpato S: Association between anemia and physical disability in older patients: Role of comorbidity. Aging Clin Exp Res 18 : 485– 492, 2006
52. Powers JS, Krantz SB, Collins JC, Meurer K, Failinger A, Buchholz T, Blank M, Spivak JL, Hochberg M, Baer A, et al.: Erythropoietin response to anemia as a function of age. J Am Geriatr Soc 39 : 30– 32, 1991
53. Warnock DG, McClellan W, McClure LA, Newsome B, Campbell RC, Audhya P, Cushman M, Howard VJ, Howard G: Prevalence of chronic kidney disease and anemia among participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort Study: Baseline results. Kidney Int 68 : 1427– 1431, 2005
54. Gaillard HM, Hamilton GC: Hemoglobin/hematocrit and other erythrocyte parameters. Emerg Med Clin North Am 4 : 15– 40, 1986
55. Lundsgaard-Hansen P, Doran JE, Blauhut B: Is there a generally valid, minimum acceptable hemoglobin level? Infusionstherapie 16 : 167– 175, 1989
56. Gotloib L, Silverberg D, Fudin R, Shostak A: Iron deficiency is a common cause of anemia in chronic kidney disease and can often be corrected with intravenous iron. J Nephrol 19 : 161– 167, 2006
57. Kalantar-Zadeh K, McAllister CJ, Lehn RS, Lee GH, Nissenson AR, Kopple JD: Effect of malnutrition-inflammation complex syndrome on EPO hyporesponsiveness in maintenance hemodialysis patients. Am J Kidney Dis 42 : 761– 773, 2003
58. Priyadarshi A, Shapiro JI: Erythropoietin resistance in the treatment of the anemia of chronic renal failure. Semin Dial 19 : 273– 278, 2006
59. Yabana M, Ikeda Y, Kihara M, Kurita K, Toya Y, Tamura K, Takagi N, Onishi T, Umemura S: Good response of endogenous erythropoietin to blood loss in persistently improving renal anemia after discontinuation of erythropoietin treatment. Nephron 81 : 111– 112, 1999
60. Ifudu O, Feldman J, Friedman EA: The intensity of hemodialysis and the response to erythropoietin in patients with end-stage renal disease. N Engl J Med 334 : 420– 425, 1996
61. Pyo HJ, Kwon YJ, Wee KS, Kwon SY, Lee CH, Kim S, Lee JS, Cho SH, Cha CW: An outbreak of Heinz body positive hemolytic anemia in chronic hemodialysis patients. Korean J Intern Med 8 : 93– 98, 1993
62. Rao DS, Shih MS, Mohini R: Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med 328 : 171– 175, 1993
63. Witte KK, Desilva R, Chattopadhyay S, Ghosh J, Cleland JG, Clark AL: Are hematinic deficiencies the cause of anemia in chronic heart failure? Am Heart J 147 : 924– 930, 2004
64. Kalantar-Zadeh K, Block G, McAllister CJ, Humphreys MH, Kopple JD: Appetite and inflammation, nutrition, anemia and clinical outcome in hemodialysis patients. Am J Clin Nutr 80 : 299– 307, 2004
65. Ofsthun NJ, Lazarus JM: Impact of the change in CMS billing rules for erythropoietin on hemoglobin outcomes in dialysis patients. Blood Purif 25 : 31– 35, 2007
66. Klahr S: Anemia, dialysis, and dollars. N Engl J Med 334 : 461– 463, 1996
67. Mitka M: New limits advised for anemia drugs. JAMA 297 : 2464 , 2007
68. Singh AK: The FDA black box for EPO: What should nephrologists do? Nephrol News Issues 21 : 55– 56, 58–59, 2007
69. Fishbane S, Nissenson AR: The new FDA label for erythropoietin treatment: How does it affect hemoglobin target? Kidney Int 72 ; 806– 813, 2007
70. FDA Public Health Advisory: Erythropoiesis-stimulating agents (ESAs), 2007. Available at:
http://www.fda.gov/cder/drug/InfoSheets/HCP/RHE200711HCP.htm. Accessed September 5, 2008
71. Weiner DE, Miskulin DC, Seefeld K, Ladik V, Zager PG, Singh AK, Johnson HK, Meyer KB: Reducing versus discontinuing erythropoietin at high hemoglobin levels. J Am Soc Nephrol 18 : 3184– 3191, 2007
72. Berns JS, Fishbane S, Elzein H, Lynn RI, Deoreo PB, Tharpe DL, Meisels IS: The effect of a change in epoetin alfa reimbursement policy on anemia outcomes in hemodialysis patients. Hemodial Int 9 : 255– 263, 2005
73. Tolman C, Richardson D, Bartlett C, Will E: Structured conversion from thrice weekly to weekly erythropoietic regimens using a computerized decision-support system: A randomized clinical study. J Am Soc Nephrol 16 : 1463– 1470, 2005
74. Gaweda AE, Muezzinoglu MK, Aronoff GR, Jacobs AA, Zurada JM, Brier ME: Individualization of pharmacological anemia management using reinforcement learning. Neural Netw 18 : 826– 834, 2005
75. Gabutti L, Lotscher N, Bianda J, Marone C, Mombelli G, Burnier M: Would artificial neural networks implemented in clinical wards help nephrologists in predicting epoetin responsiveness? BMC Nephrol 7 : 13 , 2006
76. Gaweda AE, Jacobs AA, Aronoff GR, Brier ME: Model predictive control of erythropoietin administration in the anemia of ESRD. Am J Kidney Dis 51 : 71– 79, 2008
