Prospective trials on anemia of chronic disease: The Trial to Reduce Cardiovascular Events with Aranesp® Therapy (TREAT): Management of comorbidities in kidney disease in the 21st century: Anemia and bone disease

Abstract

Chronic kidney disease (CKD) is emerging as a major public health problem in the United States. Between 1973 and 1999 there was a more than 30-fold increase in the number of patients enrolled in the Medicare funded end-stage renal disease (ESRD) program, from approximately 10,000 to 340,000 [1.United States Renal Data System Annual Data Report Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2001Google Scholar]. The annual incidence of ESRD has nearly doubled from 48,350 patients (190 per million) in 1991 to 89,252 (317 per million) in 1999. Estimates from the Third National Health and Nutrition Examination Survey (NHANES III), using the glomerular filtration rate (GFR) equation from the Modification of Diet in Renal Disease (MDRD) study [2.Levey A.S. Bosch J.P. Lewis J.B. et al.A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation.Ann Intern Med. 1999; 130: 461-470Crossref PubMed Scopus (12277) Google Scholar, 3.Levey A.S. Greene T. Kusek J.W. Beck G.J. A simplified equation to predict glomerular filtration rate from serum creatinine.J Am Soc Nephrol. 2000; 11: 155AGoogle Scholar], showed that the prevalence of CKD, defined as a GFR <60 mL/min /1.73 m2, was approximately 8.3 million individuals, or 4.7% [4.K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease Evaluation, classification and stratification.Am J Kidney Dis. 2002; 39: S1-S266Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar]. The MDRD Study indicated that 85% of patients with impaired kidney function (GFR <55 mL/min/1.73m2) have progressive losses of kidney function at a rate of 4 mL/min per year [5.Hunsicker L.G. Adler S. Caggiula A. et al.Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study.Kidney Int. 1997; 51: 1908-1919Abstract Full Text PDF PubMed Scopus (574) Google Scholar]. The progressive nature of CKD, and epidemiologic factors that include population aging, increasing prevalence of type II diabetes and hypertension, improved survival of patients on dialysis, and the acceptance of higher risk patients into ESRD programs, explain the ongoing and projected increases in the numbers of patients with ESRD. The increasing incidence and prevalence of ESRD and CKD is a global trend not just confined to the United States [6.Locatelli F. Vecchio L.D. Pozzoni P. The importance of early detection of chronic kidney disease.Nephrol Dial Transplant. 2002; 17: 2-7Crossref PubMed Scopus (101) Google Scholar]. Although incidence rates for the United States and Japan are nearly two-fold higher than those of other industrialized nations, the rates of growth appear to be quite similar, best described by an exponential growth curve at the rate of 7.36% per year [7.Port F.K. End-stage renal disease: Magnitude of the problem, prognosis of future trends and possible solutions.Kidney Int. 1995; 50: S3-6Google Scholar]. The impact of these numbers must be interpreted from both health and economic perspectives. The burden of morbidity and comorbidity and decreased quality of life associated with CKD is considerable; progression to ESRD results in a nearly eight-fold reduction in life span [8.Coresh J. Longenecker J.C. Miller 3rd, E.R. Epidemiology of cardiovascular risk factors in chronic renal disease.J Am Soc Nephrol. 1998; 9: S24-30PubMed Google Scholar, 9.Foley R.N. Parfrey P.S. Sarnak M.J. Epidemiology of cardiovascular disease in chronic renal disease.J Am Soc Nephrol. 1998; 9: S16-23Crossref PubMed Scopus (30) Google Scholar]. The financial burden occupies a disproportionate fraction of national health care costs. In 1999, ESRD patients comprised 1.1% of Medicare beneficiaries, but ESRD patient care in that year consumed 5% of expenditures [10.Centers for Medicare & Medicaid Services: National Health Care Expenditures Projections: 2000–2010 http://cms.hhs.govDate: 2000Google Scholar]. Furthermore, the total cost of the ESRD program in the United States was $17.9 billion in 1999, a 7.2% increase over the previous year [1.United States Renal Data System Annual Data Report Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2001Google Scholar]. The projected number of ESRD patients by the year 2010 is estimated to be 661,330, with an estimated Medicare ESRD cost of over $28 billion [11.United States Renal Data System Annual Data Report Atlas of End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD2000Google Scholar]. Cardiovascular disease (CVD) is the major cause of morbidity in patients with CKD, regardless of the stage of the disease [12.Levin A. Djurdjev O. Barrett B. Cardiovascular disease in patients with chronic kidney disease: Getting to the heart of the matter.Am J Kidney Dis. 2001; 38: 1398-1407Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar]. Fifty percent of deaths in dialysis patients are caused by CVD, and the probability of developing de novo heart failure in the first year after starting dialysis is approximately 80% [13.Foley R.N. Parfrey P.S. Harnett J.D. et al.Clinical and echocardiographic disease in patients starting end-stage renal disease therapy.Kidney Int. 1995; 47: 186-192Abstract Full Text PDF PubMed Scopus (1072) Google Scholar, 14.Parfrey P.S. Foley R.N. Harnett J.D. et al.Outcome and risk factors for left ventricular disorders in chronic uremia.Nephrol Dial Transplant. 1996; 11: 1277-1285Crossref PubMed Scopus (539) Google Scholar]. Mortality rates in dialysis patients one year and five years after acute myocardial infarction (MI) were 59% and 90%, respectively, much higher than that in the general population [15.Herzog C.A. Ma J.Z. Collins A.J. Poor long-term survival after myocardial infarction among patients on long-term dialysis.N Engl J Med. 1998; 339: 799-805Crossref PubMed Scopus (767) Google Scholar]. Unfortunately, cardiac morbidity is already established by the time of initiation of dialysis. A survey found that four out of five of the most prevalent comorbidities at a patient's first visit to a dialysis center were cardiac-related—hypertension (78%), coronary heart disease (23%), cardiac failure (15%), and arrhythmia (8%) [16.Valderrabano F. Horl W.H. Macdougall I.C. et al.Pre-dialysis survey on anaemia management.Nephrol Dial Transplant. 2003; 18: 89-100Crossref PubMed Scopus (105) Google Scholar]. A retrospective study of ESRD patients in France found that 42% of first MIs occurred prior to dialysis [17.Jungers P. Khoa T.N. Massy Z.A. Zingraff et al.Incidence of atherosclerotic arterial occlusive accidents in predialysis and dialysis patients: A multicentric study in the Ile de France district.Nephrol Dial Transplant. 1999; 14: 898-902Crossref PubMed Scopus (77) Google Scholar]. While traditional risk factors explain most of the cardiovascular outcomes in the general population, they only partly account for the high cardiovascular mortality rate in ESRD. Specific uremia-related risk factors have been identified, the most notable of which are anemia, extra-cellular volume expansion, inappropriately elevated angiotensin II levels, hyperhomocysteinemia, and disturbances of calcium-phosphate and parathyroid hormone metabolism. There is increasing evidence that even mild degrees of kidney impairment may increase the risk of cardiovascular death. The National Kidney Foundation Task Force on Cardiovascular Disease recommended that patients with CKD be considered in the highest risk group for cardiovascular events. An observational cohort study found that the overall prevalence of CVD was 46% among patients with CKD [12.Levin A. Djurdjev O. Barrett B. Cardiovascular disease in patients with chronic kidney disease: Getting to the heart of the matter.Am J Kidney Dis. 2001; 38: 1398-1407Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar]. In a single-center study, patients with CKD (creatinine clearance 20-50 mL/min) were found to have a two- to three-fold increase in cardiovascular mortality compared to the general population [18.Jungers P. Massy Z.A. Khoa T.N. et al.Incidence and risk factors of atherosclerotic cardiovascular accidents in predialysis chronic renal failure patients.Nephrol Dial Transplant. 1997; 12: 2597-2602Crossref PubMed Scopus (281) Google Scholar]. The significance of the level of kidney function as an independent risk factor for CVD outcomes has been borne out in a post hoc analysis of the Heart Outcomes and Prevention Evaluation (HOPE) study [19.Mann J.F. Gerstein H.C. Pogue J. et al.Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: The HOPE randomized trial.Ann Intern Med. 2001; 134: 629-636Crossref PubMed Scopus (1207) Google Scholar], and in recently published analyses of data from the NHANES II, Atherosclerosis Risk in Communities (ARIC) studies, and Studies of Left Ventricular Dysfunction (SOLVD) [20.Muntner P. He J. Hamm L. et al.Renal Insufficiency and subsequent death resulting from cardiovascular disease in United States.J Am Soc Nephrol. 2002; 13: 745-753PubMed Google Scholar, 21.Manjunath G. Tighiouart H. Ibrahim H. et al.Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community.J Am Coll Cardiol. 2003; 41: 47-55Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar, 22.Al-Ahmad A. Rand W. Manjunath G. et al.Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction.J Am Coll Cardiol. 2001; 38: 955-962Abstract Full Text Full Text PDF PubMed Scopus (604) Google Scholar]. Patients with serum creatinine levels between 1.4 and 2.3 mg/dL in the HOPE study were 1.4 times at risk of cardiovascular death, MI, or stroke compared to patients with serum creatinine levels <1.4 mg/dL. The NHANES II data provided a representative sample from the United States general population, where Muntner et al[20.Muntner P. He J. Hamm L. et al.Renal Insufficiency and subsequent death resulting from cardiovascular disease in United States.J Am Soc Nephrol. 2002; 13: 745-753PubMed Google Scholar] found that, compared to subjects with estimated GFR openface>90 mL/min, those with estimated GFR of <70 mL/min exhibited a higher risk of death from cardiovascular disease [1.68, 95% confidence interval (CI), 1.33-2.13). The analysis from the ARIC study showed that the level of kidney function was independently associated with a higher risk of atherosclerotic vascular disease (ASCVD). Each 10 mL/min/1.73 m2 lower GFR increased the hazard for ASCVD by 5%. Al-Ahmad et al[22.Al-Ahmad A. Rand W. Manjunath G. et al.Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction.J Am Coll Cardiol. 2001; 38: 955-962Abstract Full Text Full Text PDF PubMed Scopus (604) Google Scholar] examined the SOLVD database and similarly found that each 10 mL/min/1.73 m2 decrement in GFR and 1% decrement in hematocrit was associated with a 1.064 (95% CI, 1.033–1.096) and 1.027 (95% CI, 1.015–1.038) higher risk for mortality, respectively. In contrast, analysis of Framingham data by Culleton et al[23.Culleton B. Larson M. Wilson P. et al.Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency.Kidney Int. 1999; 56: 2214-2219Abstract Full Text Full Text PDF PubMed Scopus (724) Google Scholar] showed that kidney disease was associated with a higher prevalence of CVD and all-cause mortality, but was no longer an independent predictor after adjustment for other risk factors. Similar observations have emerged from analyses of administrative databases. A two-year follow-up study of CKD patients aged 65 years or older showed that 6.4 times more patients died than those who reached dialysis. Among patients who had CKD, congestive heart failure (CHF), and anemia, 7.7 times more patients died compared to those who progressed to ESRD. The addition of anemia to diagnoses of CKD, or both CKD and CHF, increased the risk of death by factors of 1.2 to 2.2 [24.Gilbertson D. Li S. Murray A. et al.The competing risks of death vs. ESRD in Medicare beneficiaries 65+ with chronic kidney disease.J Am Soc Nephrol. 2002; 13: 439AGoogle Scholar]. Thus, at all stages of CKD, the presence of CVD may make death a more likely outcome than renal replacement therapy (RRT), with anemia compounding the worse outcomes. It is therefore evident from the foregoing discussion that CKD patients are at increased risk for developing CVD and are at greater risk for death. Both CKD and CVD are synergistic in compounding the increased mortality rate and adversely affect the prognosis of one another. CVD is also the most common cause of death in kidney allograft recipients, and the presence of graft dysfunction is an independent risk factor for cardiovascular mortality [25.Kasiske B.L. Guijarro C. Massy Z.A. et al.Cardiovascular disease after renal transplantation.J Am Soc Nephrol. 1996; 7: 158-165Abstract Full Text PDF PubMed Scopus (318) Google Scholar, 26.Meier-Kriesche H. Baliga R. Kaplan B. Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation.Transplantation. 2003; 75: 1291-1295Crossref PubMed Scopus (280) Google Scholar]. It is thus apparent that CVD provides a continuum of risk from the early stages of CKD through dialysis and into the post-transplant period. CVD may be broadly divided into disorders of perfusion secondary to atherosclerotic disease and disorders of cardiac structure and function, such as left ventricular hypertrophy (LVH) and left ventricular dysfunction. Both disorders can certainly occur together and exacerbate each other. It is important to note that CVD develops early in the course of CKD [27.Levin A. Prevalence of cardiovascular damage in early renal disease.Nephrol Dial Transplant. 2001; 16: 7-11Crossref Scopus (39) Google Scholar]. Anemia, in itself an early consequence of the loss of kidney function, is another important pathophysiologic stimulus that leads to left ventricular remodeling early in the course of CKD [28.Levin A. Anemia and left ventricular hypertrophy in chronic kidney disease populations: A review of the current state of knowledge.Kidney Int. 2002; 80: 35-38Abstract Full Text Full Text PDF Scopus (110) Google Scholar]. Indeed, timely correction of anemia is being recognized as an important approach to minimize and possibly preempt the cardiovascular damage associated with progressive loss of kidney function [29.Portoles J. The beneficial effects of intervention in early renal disease.Nephrol Dial Transplant. 2001; 16: 12-15Crossref PubMed Scopus (14) Google Scholar]. Anemia develops in most patients with CKD because less erythropoietin is produced by the diseased kidneys [30.Erslev A.J. Besarav A. Erythropoietin in the pathogenesis and treatment of the anemia of chronic renal failure.Kidney Int. 1997; 51: 622-630Abstract Full Text PDF PubMed Scopus (132) Google Scholar]. The decline in hemoglobin (Hb) concentration may start at levels of creatinine clearance of around 70 mL/min among men and 50 mL/min among women [31.Hsu C.-J. McCulloch C. Curhan G. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: Results from the Third National Health and Nutrition Examination Survey.J Am Soc Nephrol. 2002; 13: 504-510Crossref PubMed Scopus (73) Google Scholar] and progress relentlessly. Even at serum creatinine levels of ≤2 mg/dL, 45% of patients have a hematocrit (Hct) concentration of <36%, and 8% have a hematocrit of <30%Figure 1. Hematocrit declined 3% for every 10 mL/min/1.73 m2 decrease in estimated GFR [32.Kazmi W.H. Kausz A.T. Khan S. et al.Anemia—An early complication of chronic renal insufficiency.Am J Kidney Dis. 2001; 38: 803-812Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar]. Astor et al[33.Astor B.C. Muntner P. Levin A. et al.Association of kidney function with anemia: The Third National Health and Nutrition Examination Survey (1988–1994).Arch Intern Med. 2002; 162: 1401-1408Crossref PubMed Scopus (551) Google Scholar] analyzed a population-based sample of 15,419 adult participants included in NHANES III. Below an estimated GFR of 60 mL/min/1.73m2, lower kidney function was strongly associated with increasing prevalence of anemia. Given the high prevalence of CKD and the decline in Hb concentration with even modest reductions in kidney function, anemia of CKD is a substantial public health burden. Indeed, Hsu et al[31.Hsu C.-J. McCulloch C. Curhan G. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: Results from the Third National Health and Nutrition Examination Survey.J Am Soc Nephrol. 2002; 13: 504-510Crossref PubMed Scopus (73) Google Scholar] have recently estimated that 800,000 adults have anemia (defined as Hb <11 g/dL) associated with CKD in the United States. Likewise, applying data on the distribution of hematocrit levels among patients with various degrees of CKD from a Health Maintenance Organization to the 1990 United States population of 248,709,873 (1990 United States Census), we estimated that there were as many as 1.5 million individuals with CKD in the United States who were anemic, as many as 1 million of whom had hematocrit levels <33% [34.Kausz A.T. Steinberg E.P. Nissenson A.R. Pereira B.J.G. Prevalence and management of anemia among patients with chronic kidney disease in a health maintenance organization.Dis Mgmt Health Outcomes. 2002; 10: 505-513Crossref Scopus (10) Google Scholar]. The anemia of early-stage CKD contributes to the development of LVH, an independent determinant of mortality among patients with ESRD. In a cross-sectional study, Levin et al[35.Levin A. Singer J. Thompson C.R. et al.Prevalent left ventricular hypertrophy in the predialysis population: Identifying opportunities for intervention.Am J Kidney Dis. 1996; 27: 347-354Abstract Full Text PDF PubMed Scopus (616) Google Scholar] reported that the prevalence of LVH detected by echocardiography was 26.7% in patients with creatinine clearance>50 mL/min, 30.8% in those with clearances between 25 and 49 mL/min, and 45.2% in those with clearance <25 mL/min, and Foley et al[13.Foley R.N. Parfrey P.S. Harnett J.D. et al.Clinical and echocardiographic disease in patients starting end-stage renal disease therapy.Kidney Int. 1995; 47: 186-192Abstract Full Text PDF PubMed Scopus (1072) Google Scholar] reported a 75% prevalence of LVH in patients starting ESRD therapy. In a multivariate analysis, the independent risk of LVH was 32% higher for every 0.5 g/dL decrease in Hb concentration [36.Levin A. Thompson C.R. Ethier J. et al.Left ventricular mass index increase in early renal disease: Impact of decline in hemoglobin.Am J Kidney Dis. 1999; 34: 125-134Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar]. Foley et al[37.Foley R.N. Parfrey P.S. Harnett J.D. et al.The impact of anemia on cardiomyopathy, morbidity and mortality in end-stage renal disease.Am J Kidney Dis. 1996; 28: 53-61Abstract Full Text PDF PubMed Scopus (651) Google Scholar] also examined the impact of anemia on cardiomyopathy, morbidity, and mortality in a cohort of 432 Canadian dialysis patients who were followed prospectively for an average of 41 months. After adjustments for age, diabetes, ischemic heart disease, blood pressure, and serum albumin level, a decrease in Hb concentration of 1 g/dL was associated with a 49% increased likelihood of left ventricular dilatation, a 55% increased likelihood of poor ejection fraction, and a 14% increased likelihood of death from cardiovascular disease after start of RRT. Anemia was also associated with a three- to six-fold increase in the number of myocardial ischemia events and the incidence of heart failure in dialysis patients [14.Parfrey P.S. Foley R.N. Harnett J.D. et al.Outcome and risk factors for left ventricular disorders in chronic uremia.Nephrol Dial Transplant. 1996; 11: 1277-1285Crossref PubMed Scopus (539) Google Scholar]. Rigatto et al[38.Rigatto C. Foley R. Jeffery J. et al.Electrocardiographic left ventricular hypertrophy in renal transplant recipients: Prognostic value and impact of blood pressure and anemia.J Am Soc Nephrol. 2003; 14: 462-468Crossref PubMed Scopus (160) Google Scholar, 39.Rigatto C. Parfrey P. Foley R. et al.Congestive heart failure in renal transplant recipients: Risk factors, outcomes, and relationship with ischemic heart disease.J Am Soc Nephrol. 2002; 13: 1084-1090PubMed Google Scholar] reviewed data from the transplant population and demonstrated that anemia was an independent risk factor for LVH and CHF. Maintenance of adequate tissue oxygenation in anemia is achieved by both non-hemodynamic and hemodynamic adaptations. Non-hemodynamic adaptations include increases in erythropoietin production and increases in the intra-erythrocytic concentrations of 2,3, diphosphoglycerate (2,3-DPG). Hemodynamic adaptations include an increase in cardiac preload and a decrease in systemic vascular resistance, leading to decreased afterload and resulting in a high cardiac output state. The initial left ventricular dilatation causes increased wall tension and initiates ventricular remodeling through both hypertrophy of existing myofibrils and realignment of sarcomeres, with resultant LVH. While these changes are potentially reversible in a non-uremic milieu, various maladaptive processes in CKD (including volume expansion, hyperparathyroidism, and diabetes contribute to myocardial fibrosis, calcium deposition, LV stiffness, and arteriosclerosis) prevent reversibility and amplify the cardiac consequences of anemia [27.Levin A. Prevalence of cardiovascular damage in early renal disease.Nephrol Dial Transplant. 2001; 16: 7-11Crossref Scopus (39) Google Scholar, 40.Levin A. The role of anemia in the genesis of cardiac abnormalities in patients with chronic kidney disease.Nephrol Dial Transplant. 2002; 17: 207-210Crossref PubMed Scopus (10) Google Scholar]. It is now becoming evident that these abnormalities can be reduced or prevented by appropriate early management of anemia and hypertension. Indeed, several studies have shown that partial correction of anemia leads to partial regression of LVH in both dialysis and predialysis patients [41.Silberberg J. Racine N. Barre P. Sniderman A.D. Regression of left ventricular hypertrophy in dialysis patients following correction of anemia with recombinant human erythropoietin.Can J Cardiol. 1990; 6: 1-4PubMed Google Scholar, 42.Hayashi T. Suzuki A. Shoji T. et al.Cardiovascular effect of normalizing the hematocrit level during erythropoietin therapy in predialysis patients with chronic renal failure.Am J Kidney Dis. 2000; 35: 250-256Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar]. Of note are two recent small studies in patients with CKD, one demonstrating a reduction in left ventricular mass index (LVMI) with normalization of hematocrit [43.Portoles J. Torralbo A. Martin P. et al.Cardiovascular effects of recombinant human erythropoietin in predialysis patients.Am J Kidney Dis. 1997; 29: 541-548Abstract Full Text PDF PubMed Scopus (210) Google Scholar], and another showing that recombinant human erythropoietin (rHuEPO) therapy protected against the development of LVH if anemia correction was instituted before the development of structural left ventricular changes [44.Valderrabano F. Spanish group for the study of anemia and left ventricular hypertrophy in pre-dialysis patients. Improvement and prevention of left ventricular hypertrophy in predialysis patients.Nephrol Dial Transplant. 2000; 15: A115Crossref PubMed Scopus (33) Google Scholar]. The Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) Trial is an initiative to investigate the effect of early anemia correction on cardiovascular risk reduction in patients not yet on RRT [45.Eckardt K. The CREATE trial—Building the evidence.Nephrol Dial Transplant. 2001; 16: 16-18Crossref PubMed Scopus (30) Google Scholar]. This is an open, randomized, parallel-group, multicenter (Europe, Mexico, Taiwan, Thailand) study that looks at change in LVMI after one year and time to first cardiovascular event. The treatment arms include the early intervention group where anemia correction with epoetin beta will be instituted when Hb falls within the range of 11 to 12.5 g/dL to a target of 13 to 15 g/dL, and the late intervention group where anemia correction with epoetin beta will begin once Hb has dropped to <10.5 g/dL, to achieve a target Hb of 10.5 to 11.5 g/dL. In addition to the effect on LVH, correction of the anemia of CKD with rHuEPO has been associated with significant improvements in health-related quality of life, overall well-being, energy level, work capacity, aerobic capacity, cognitive function, sexual function, and immune function [46.Besarab A. Ross R.P. Nasca T.J. The use of recombinant human erythropoietin in predialysis patients.Curr Opin Nephrol Hypertens. 1995; 4: 155-161Crossref PubMed Scopus (26) Google Scholar]. Observational studies in patients with ESRD have shown that higher hematocrit levels (36% to <39%) were associated with decreased hospitalization risk and associated costs; morbidity and mortality were also significantly increased at hematocrit levels <33% [47.Madore F. Lowrie E. Brugnara C. Anemia in hemodialysis patients: Variables affecting this outcome predictor.J Am Soc Nephrol. 1997; 8: 1921-1929PubMed Google Scholar, 48.Khan S. Kazmi W. Abichandani R. et al.Health care utilization among patients with chronic kidney disease.Kidney Int. 2002; 62: 229-236Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 49.Xia H. Ebben J. Ma J. Collins A. Hematocrit levels and hospitalization risk in hemodialysis patients.J Am Soc Nephrol. 1999; 10: 1309-1316PubMed Google Scholar, 50.Ma J. Ebben J. Xia H. Collins A. Hematocrit level and associated mortality in hemodialysis patients.J Am Soc Nephrol. 1999; 10: 610-619PubMed Google Scholar, 51.Collins A. Ebben J. Ma J. Manning W. Hematorcrit levels and associated Medicare expenditures.Am J Kidney Dis. 2000; 36: 282-293Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar]. Despite the availability of rHuEPO for more than a decade, recent studies have shown a high prevalence of anemia among patients with ESRD at initiation of dialysis. In a large cohort of patients who began chronic dialysis in the United States between April of 1995 and June of 1997, 51% of patients had hematocrit levels less than 28% and 67% had hematocrit levels less than 30%Figure 2. Overall, only 23% of patients had received rHuEPO before the initiation of dialysis, and among patients with hematocrit levels less than 28%, only 20% had received rHuEPO [52.Obrador G.T. Ruthazer R. Arora P. et al.Prevalence of and factors associated with sub-optimal care prior to initiation of dialysis in the United States.J Am Soc Nephrol. 1999; 10: 1793-1800PubMed Google Scholar]. Other studies showed a similar pattern of undertreatment of anemia in patients with CKD who have yet to progress to ESRD. For example, in a recent large retrospective chart survey of patients with CKD in the predialysis phase, 59% had Hct <36% and 15% had Hct <30% at their first visit to a nephrologist, but only 8% received rHuEPO. During follow-up by the nephrologist, the proportion of patients with Hct <36% increased to 78%, and the proportion with Hct <30% increased to 39%. Despite the prevalence and severity of anemia, only 30% of patients overall, and 55% of patients with Hct <30% were receiving rHuEPO [32.Kazmi W.H. Kausz A.T. Khan S. et al.Anemia—An early complication of chronic renal insufficiency.Am J Kidney Dis. 2001; 38: 803-812Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar]. Trends in anemia at initiation of dialysis in the United States are equally disturbing Figure 3[53.Obrador G. Roberts T. Peter W.S. et al.Trends in anemia at initiation of dialysis in the United States.Kidney Int. 2001; 60: 1875-1884Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. In 1995, prior to the release of the National Kidney Foundation Dialysis Outcome Quality Initiative (NKF-DOQI) guidelines, the mean hematocrit at initiation of dialysis was only 28.1%, and has shown virtually no improvement since then (mean hematocrit 29.3% in 1999). Consequently, roughly two thirds of patients began RRT at hematocrit levels well below the currently recommended levels. The NKF-DOQI guidelines [54.NKF-DOQI Clinical Practice Guidelines for the Treatment of Anemia of Chronic Renal Failure NKF-DOQI clinical practice guidelines—Vascular access, anemia of chronic renal failure.Am J Kidney Dis. 1997; 30: S192-S224PubMed Google Scholar], the European Best Practice guidelines [55.Cameron J. European best practice guidelines for the management of anemia in patients with chronic renal failure.Nephrol Dial Transplant. 1999; 14: 61-65Crossref PubMed Google Scholar], and the Canadian Medical Association guidelines [56.Clinical practice guidelines of the Canadian Society of Nephrology for treatment of patients with chronic renal failure Clinical practice guidelines for the management of anemia coexistent with chronic renal failure. Canadian Society of Nephrology.J Am Soc Nephrol. 1999; 10: S292-S296PubMed Google Scholar] all recommend a threshold hematocrit level for initiation of rHuEPO therapy of 33% for both patients on dialysis and those with CKD. While mean hematocrits in the United States dialysis population have increased steadily since 1990, particula