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Anemia management for hemodialysis patients: Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines and Dialysis Outcomes and Practice Patterns Study (DOPPS) findings

2004; Elsevier BV; Volume: 44; Linguagem: Inglês

10.1016/s0272-6386(04)01102-3

1523-6838

Francesco Locatelli, Ronald L. Pisoni, Tadao Akizawa, José Miguel Cruz, Peter B. DeOreo, Norbert Lameire, Philip J. Held,

Dialysis and Renal Disease Management

Background: After recombinant human erythropoietin was introduced into routine nephrologic practice, specific clinical guidelines were developed to optimize the quality of anemia management for patients with chronic kidney disease. Methods: The Dialysis Outcomes and Practice Patterns Study (DOPPS), an international investigation providing patient- and facility-level data on hemodialysis practice, was developed to provide information on various aspects of current practices in hemodialysis management, including treatment of renal anemia. Results: Hemoglobin concentration is strongly associated with both morbidity and mortality in hemodialysis patients. Although some improvements can be documented in anemia management practices in the years after the publication of international guidelines, wide variations in anemia management are still observed among countries. Conclusion: Many efforts are still needed to allow a greater proportion of patients to reach the recommended hemoglobin concentrations. Significantly improved outcomes may therefore be expected by a more widespread reaching of the recommended hemoglobin levels. The results of the DOPPS point to the difficulties in implementing clinical guidelines in the everyday management of individual patients. In specific circumstances, a well-designed observational study may offer credible information and serve as a basic instrument for monitoring the implementation of clinical guidelines in typical clinical practice. Background: After recombinant human erythropoietin was introduced into routine nephrologic practice, specific clinical guidelines were developed to optimize the quality of anemia management for patients with chronic kidney disease. Methods: The Dialysis Outcomes and Practice Patterns Study (DOPPS), an international investigation providing patient- and facility-level data on hemodialysis practice, was developed to provide information on various aspects of current practices in hemodialysis management, including treatment of renal anemia. Results: Hemoglobin concentration is strongly associated with both morbidity and mortality in hemodialysis patients. Although some improvements can be documented in anemia management practices in the years after the publication of international guidelines, wide variations in anemia management are still observed among countries. Conclusion: Many efforts are still needed to allow a greater proportion of patients to reach the recommended hemoglobin concentrations. Significantly improved outcomes may therefore be expected by a more widespread reaching of the recommended hemoglobin levels. The results of the DOPPS point to the difficulties in implementing clinical guidelines in the everyday management of individual patients. In specific circumstances, a well-designed observational study may offer credible information and serve as a basic instrument for monitoring the implementation of clinical guidelines in typical clinical practice. IN THE LAST few decades, several important advances have been made in the treatment of end-stage renal disease,1Port F.K. Orzol S.M. Held P.J. et al.Trends in treatment and survival for hemodialysis patients in the United States.Am J Kidney Dis. 1998; 32: S34-S38Abstract Full Text PDF PubMed Google Scholar among these the management of chronic kidney disease (CKD)-related anemia, which has been associated with patients' morbidity, mortality, and quality of life, has been well documented.2Locatelli F. Conte F. Marcelli D. The impact of hematocrit levels and erythropoietin treatment on overall and cardiovascular mortality and morbidity—The experience of the Lombardy Dialysis Registry.Nephrol Dial Transplant. 1998; 13: 1642-1644Crossref PubMed Scopus (152) Google Scholar, 3Levin 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 (749) Google Scholar, 4Foley R.N. Parfrey P.S. Morgan J. et al.Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy.Kidney Int. 2000; 58: 1325-1335Crossref PubMed Scopus (370) Google Scholar, 5Ma J.Z. Ebben J. Xia H. Collins A.J. Hematocrit level and associated mortality in hemodialysis patients.J Am Soc Nephrol. 1999; 10: 610-619PubMed Google Scholar, 6Xia H. Ebben J. Ma J.Z. et al.Hematocrit levels and hospitalization risks in hemodialysis patients.J Am Soc Nephrol. 1999; 10: 1309-1316PubMed Google Scholar Anemia is a frequent complication of CKD, and its prevalence has been shown to increase with diminishing renal function, so that a large proportion of patients reach the need for dialysis in an anemic state.3Levin 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 (749) Google Scholar, 7Astor 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 (593) Google Scholar Nevertheless, the prevalence of anemia is reported to be substantial even in patients with mildly impaired renal function, which suggests that anemia may develop relatively early in the course of CKD.3Levin 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 (749) Google Scholar, 7Astor 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 (593) Google Scholar The management of renal anemia has been revolutionized over the last 15 years, after recombinant human erythropoietin (rHuEpo) was introduced in 1989, which replaced blood transfusions as the mainstay treatment of this complication.8Collins A.J. Influence of target hemoglobin in dialysis patients on morbidity and mortality.Kidney Int Suppl. 2002; 80: 44-48Crossref PubMed Scopus (76) Google Scholar, 9McMahon L.P. McKenna M.J. Sangkabutra T. et al.Physical performance and associated electrolyte changes after haemoglobin normalization A comparative study in hemodialysis patients.Nephrol Dial Transplant. 1999; 14: 1182-1187Crossref PubMed Scopus (107) Google Scholar, 10Painter P. Moore G. Carlson L. et al.Effects of exercise training plus normalization of hematocrit on exercise capacity and health-related quality of life.Am J Kidney Dis. 2002; 39: 257-265Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 11Moreno F. Sanz-Guajardo D. Lopez-Gomez J.M. et al.Spanish Cooperative Renal Patients Quality of Life Study Group of the Spanish Society of NephrologyIncreasing the hematocrit has a beneficial effect on quality of life and is safe in selected hemodialysis patients.J Am Soc Nephrol. 2000; 11: 335-342PubMed Google Scholar, 12Silverberg D.S. Wexler D. Blum M. et al.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. 2003; 18: 141-146Crossref PubMed Scopus (235) Google Scholar, 13Young E.W. Goodkin D.A. Mapes D.L. et al.The Dialysis Outcomes and Practice Patterns Study (DOPPS) An international hemodialysis study.Kidney Int Suppl. 2000; 74: S74-S81Crossref Scopus (356) Google Scholar, 14Furuland H. Linde T. Ahlmen J. et al.A randomized controlled trial of hemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients.Nephrol Dial Transplant. 2003; 18: 353-361Crossref PubMed Scopus (195) Google Scholar In recent years, specific clinical guidelines have been developed to optimize the quality of anemia management secondary to CKD. As a result, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines and the European Renal Association-European Dialysis and Transplantation Association Best Practice Guidelines have been published in the United States and Europe, respectively.15National Kidney FoundationK/DOQI Clinical Practice Guidelines. 2000 update.Am J Kidney Dis. 2001; 37: S1-S238PubMed Google Scholar, 16European Best Practice Guidelines for the management of anemia in patients with chronic renal failure. Working Party for European Best Practices Guidelines for the Management of Anemia in Patients with Chronic Renal Failure.Nephrol Dial Transplant. 1999; 14: 1-50Crossref Google Scholar, 17Locatelli F. Aljama P. Barany P. et al.Revised European Best Practice Guidelines for the management of anemia in patients with chronic renal failure.Nephrol Dial Transplant. 2004; 19: 1-47PubMed Google Scholar Complementing these efforts, the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective, observational study of nationally representative samples of randomly selected hemodialysis facilities and patients, was developed to provide information on current practices in hemodialysis management, including treatment of renal anemia. By providing results from a very large population of hemodialysis patients, the DOPPS has provided insight into how the development of international guidelines may have helped change the management of CKD-related anemia over the past several years and, more generally, has re-emphasized the primary role that observational studies may play, particularly when designed according to specific methodological criteria to improve scientific knowledge. Currently, much debate exists over the merit of observational studies versus randomized trials. Although observational studies have been essential for gaining knowledge of the causes and pathogeneses of many diseases, randomized controlled trials should provide the most robust estimate of causal effects. Nevertheless, it is a matter of fact that there are strengths in observational studies and limitations to randomized, controlled trials. In particular, the use of very strict inclusion criteria in randomized, controlled trials can lead to results with limited external validity, thus reducing the ability to generalize them to conditions of everyday clinical practice. Considering that clinical trials are expensive in terms of money and time and thus not always feasible, a more careful and thoughtful approach to implementing and interpreting observational studies is therefore needed. In addition, certain clinical practices cannot be tested against placebos, and their role can be ascertained only in observational studies. Observational studies may also represent an essential means to generate and investigate hypotheses, thus helping investigators to select the interventions that will be more appropriately assessed by clinical trials in a subsequent phase. Moreover, in particular circumstances observational studies may have the chance to attain more or less the same benefits and credibility of randomized trials.18Vandenbroucke J.P. When are observational studies as credible as randomised trials?.Lancet. 2004; 363: 1728-1731Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar Restriction in research topics, such as choosing to analyze only those candidate agents with a high probability of being causal factors, may therefore become a methodological requisite of paramount importance. Many improvements in the design and analysis of observational studies have been directed toward appropriate adjustments for potential confounding factors. The importance of measuring confounding variables accurately and precisely is often underappreciated. Another important point is ensuring that covariates are modelled correctly, taking into account their nonlinear associations and interactions. In this context, the DOPPS, a unique observational study in terms of the magnitude of the information prospectively collected from a large, representative sample of hemodialysis patients, and whose analyses have been adjusted for a wide range of case-mix characteristics, represents a striking example of how a well-designed observational study may become a major source of meaningful information aimed at improving clinical practice as well as a randomized, controlled clinical trial. Among several practice patterns and outcomes, the DOPPS has evaluated anemia management with rHuEPO and intravenous iron preparations, as well as the control of anemia over time, based on data collected from 101 representative dialysis facilities in 5 European countries (France, Germany, Italy, Spain, and the United Kingdom) in 1998 to 2000 (DOPPS I)19Locatelli F. Pisoni R.L. Combe C. et al.Anemia in hemodialysis patients of five European Countries Association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Nephrol Dial Transplant. 2004; 19: 121-132Crossref PubMed Scopus (375) Google Scholar and from 309 representative dialysis facilities in 12 countries (Australia, Belgium, Canada, France, Germany, Italy, Japan, New Zealand, Spain, Sweden, the United Kingdom, and United States) from 2002 to 2003 (DOPPS II).20Pisoni R.L. Bragg-Gresham J.L. Young E.W. et al.Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2004; 44: 94-111Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar As the results from the DOPPS suggest, large variations in anemia management may be observed among the different countries. Indeed, the mean hemoglobin concentrations in prevalent hemodialysis patients varied widely across the studied countries, ranging from 10.1 g/dL to 12.0 g/dL (101 g/L to 120 g/L) (Fig 1). The percentage of patients with a hemoglobin value lower than 11 g/dL (110 g/L) (ie, below the target recommended by both the K/DOQI guidelines and the European Best Practice Guidelines) also ranged widely, from 23% to 77%, depending on the country (Fig 2).20Pisoni R.L. Bragg-Gresham J.L. Young E.W. et al.Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2004; 44: 94-111Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar Factors such as female sex, catheter use, and history of cancer or gastrointestinal bleeding were significantly associated with lower hemoglobin levels in prevalent hemodialysis patients.19Locatelli F. Pisoni R.L. Combe C. et al.Anemia in hemodialysis patients of five European Countries Association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Nephrol Dial Transplant. 2004; 19: 121-132Crossref PubMed Scopus (375) Google Scholar, 20Pisoni R.L. Bragg-Gresham J.L. Young E.W. et al.Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2004; 44: 94-111Abstract Full Text Full Text PDF PubMed Scopus (304) Google ScholarFig 2Percentage of patients with hemoglobin <11 g/dL ( 180 days) and incident dialysis patients (within 7 days of first hemodialytic treatment) in DOPPS II. (Data from Pisoni et al.20Pisoni R.L. Bragg-Gresham J.L. Young E.W. et al.Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2004; 44: 94-111Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar)View Large Image Figure ViewerDownload (PPT) Despite the reported differences and large deviations from guidelines observed in some countries, significant improvement has been observed in anemia management in the last few years, given that the overall median hemoglobin of the 5 European DOPPS I countries increased from 10.8 g/dL (108 g/L) in 1998 to 1999 to 11.1 g/dL (111 g/L) in 2000, and the percentage of patients with hemoglobin ≥11.0 g/dL (110 g/L) increased from 46% to 53% over the same period.19Locatelli F. Pisoni R.L. Combe C. et al.Anemia in hemodialysis patients of five European Countries Association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Nephrol Dial Transplant. 2004; 19: 121-132Crossref PubMed Scopus (375) Google Scholar The percentage of prevalent hemodialysis patients being prescribed rHuEpo has increased as well, given that both the lowest value observed in France and the highest value observed in the United Kingdom increased between 2000 and 2002 to 2003 (from 75% to 83% and from 92% to 94%, respectively).19Locatelli F. Pisoni R.L. Combe C. et al.Anemia in hemodialysis patients of five European Countries Association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Nephrol Dial Transplant. 2004; 19: 121-132Crossref PubMed Scopus (375) Google Scholar, 20Pisoni R.L. Bragg-Gresham J.L. Young E.W. et al.Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2004; 44: 94-111Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar Although the majority of prevalent hemodialysis patients receive rHuEpo, the same is not true of patients starting hemodialysis. Indeed, only 21% to 65% of incident hemodialysis patients received rHuEpo during the pre-end stage renal disease period. Correspondingly, their mean hemoglobin concentrations were lower and percentage of patients compliant with the recommendation of the international guidelines was lower at the time of starting hemodialysis, when compared with prevalent dialysis patients (Fig 1, Fig 2). Furthermore, even if time-trend analyses show that a significant increase in both mean hemoglobin concentration and the percentage of rHuEpo use occurs during the first months after beginning hemodialysis, several months are yet required for hemoglobin concentration to rise to the recommended level (Fig 3).19Locatelli F. Pisoni R.L. Combe C. et al.Anemia in hemodialysis patients of five European Countries Association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Nephrol Dial Transplant. 2004; 19: 121-132Crossref PubMed Scopus (375) Google Scholar, 20Pisoni R.L. Bragg-Gresham J.L. Young E.W. et al.Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2004; 44: 94-111Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar Considering that anemia is a relatively early complication of CKD, usually arising some years before the need for renal replacement treatment is reached,3Levin 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 (749) Google Scholar, 7Astor 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 (593) Google Scholar it may therefore be expected that a considerable proportion of patients remain in an anemic state for a prolonged time before the initiation of dialysis. Numerous recent studies have pointed to detrimental pathophysiologic consequences associated with poor anemia control during the early phases of CKD, especially promotion of cardiovascular disease. The percentage of prevalent hemodialysis patients receiving intravenous iron varies greatly among DOPPS countries, ranging from 38% to 89%.19Locatelli F. Pisoni R.L. Combe C. et al.Anemia in hemodialysis patients of five European Countries Association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Nephrol Dial Transplant. 2004; 19: 121-132Crossref PubMed Scopus (375) Google Scholar, 20Pisoni R.L. Bragg-Gresham J.L. Young E.W. et al.Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2004; 44: 94-111Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar In some countries, a large fraction of patients (31%-38%) have indications for iron deficiency, according to the K/DOQI and European Best Practice Guidelines, namely a transferrin saturation of less than 20%.20Pisoni R.L. Bragg-Gresham J.L. Young E.W. et al.Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2004; 44: 94-111Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar DOPPS analyses show that transferrin saturation values seem to be unrelated to the administration of intravenous iron, as large proportions of patients continue to have low levels of transferrin saturation, even in countries with high use of intravenous iron.20Pisoni R.L. Bragg-Gresham J.L. Young E.W. et al.Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2004; 44: 94-111Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar Although additional factors, such as cumulative iron doses, blood losses, and inflammation levels, could be involved in the explanation of these results, they may also suggest that iron supplementation, not just rHuEpo administration, is often inadequate in hemodialysis patients. Overall, the DOPPS data show that, despite the availability of practice guidelines for the treatment of renal anemia, wide variation in anemia management exists as a gap between what is recommended by the guidelines and what is accomplished in everyday clinical practice. Increasing awareness of the recommendations of international practice guidelines has led, however, to considerable changes in anemia management practices during the last few years and has led to large improvements in the control of anemia for hemodialysis patients. These results, therefore, remind us of the importance of implementing clinical guidelines. Compliance with clinical guidelines is an important indicator of quality and efficacy of patient care.21Harr D.S. Balas E.A. Mitchell J. Developing quality indicators as educational tools to measure the implementation of clinical practice guidelines.Am J Med Qual. 1996; 11: 179-185Crossref PubMed Scopus (8) Google Scholar Improvement in patient outcomes can be expected when guidelines are more closely followed. At the same time, their adoption in clinical practice may be mitigated by numerous factors, including clinical expertise, patient preferences, constraints of public health policies, community standards, and budgetary limitations.22Kliger A.S. Haley W.E. Clinical practice guidelines in end-stage renal disease A strategy for implementation.J Am Soc Nephrol. 1999; 10: 872-877PubMed Google Scholar Nevertheless, whereas large efforts have been made to develop practice guidelines, much has still to be done to encourage implementation of the guidelines. As this is the only way to ensure real improvement in health care outcomes, it is therefore mandatory that more emphasis is placed on implementation strategies, including the development of local implementation support systems, clinical audit programs, and methods of feeding back information concerning current practices. Another important contribution of the DOPPS is the finding of a strong association between higher hemoglobin concentrations and improved health outcomes.19Locatelli F. Pisoni R.L. Combe C. et al.Anemia in hemodialysis patients of five European Countries Association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Nephrol Dial Transplant. 2004; 19: 121-132Crossref PubMed Scopus (375) Google Scholar, 20Pisoni R.L. Bragg-Gresham J.L. Young E.W. et al.Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2004; 44: 94-111Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar This confirms the recommendations of clinical guidelines. Lower hemoglobin is associated with significantly higher patient morbidity (as measured by hospitalization) and mortality at least for hemodialysis patients. Indeed, before the publication of the DOPPS results, only a few studies had examined with detailed adjustment for associated comorbidities whether adherence to guidelines for hemoglobin in clinical practice really was associated with better clinical outcomes. Studies have shown considerable differences in the extent of an impact of anemia control and outcomes23Grimshaw J.M. Russell I.T. Effect of clinical guidelines on medical practice A systematic review of rigorous evaluations.Lancet. 1993; 342: 1317-1322Abstract PubMed Scopus (2326) Google Scholar or even their failure in improving patient outcomes when applied in prospective, multimember, and randomized trials.24Ramsay C.R. Campbell M.K. Cantarovich D. et al.Evaluation of clinical guidelines for the management of end-stage renal disease in Europe The EU BIOMED 1 study.Nephrol Dial Transplant. 2000; 15: 1394-1398Crossref PubMed Scopus (11) Google Scholar Although the results of these studies have been somewhat disappointing, the results may have been conditioned by some points of weakness in the studies themselves, not least the fact that many of them were performed on selected populations of patients, thus precluding the generalizability of their results.25Locatelli F. Andrulli S. Del Vecchio L. Difficulties of implementing clinical guidelines in medical practice.Nephrol Dial Transplant. 2000; 15: 1284-1287Crossref PubMed Scopus (13) Google Scholar The DOPPS has properly overcome this limitation, and its analyses have been performed on very large populations of hemodialysis patients, using adjustments for a large number of patient case-mix characteristics. This is particularly important for anemia management, given the substantial differences noted by the DOPPS across countries. Such differences include causes of end-stage renal disease, comorbidities, hospitalization rates, vascular access use, and other hemodialysis practices, which may affect anemia and its management practices.26Goodkin D.A. Bragg-Gresham J.L. Koenig K.G. et al.Association of comorbid conditions and mortality in hemodialysis patients in Europe, Japan, and the United States The Dialysis Outcomes and Practice Patterns Study (DOPPS).J Am Soc Nephrol. 2003; 14: 3270-3277Crossref PubMed Scopus (628) Google Scholar, 27Pisoni R.L. Young E.W. Dykstra D.M. et al.Vascular access use in Europe and the United States Results from the DOPPS.Kidney Int. 2002; 61: 305-316Crossref PubMed Scopus (721) Google Scholar In this context, the DOPPS showed that higher hemoglobin concentrations are associated with better outcomes in hemodialysis patients, independent of potentially confounding factors, with the adjusted risk for mortality and hospitalization, respectively, 4% to 5% and 5% to 6% lower for every 1 g/dL (10 g/L) higher hemoglobin concentration (Fig 4).19Locatelli F. Pisoni R.L. Combe C. et al.Anemia in hemodialysis patients of five European Countries Association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Nephrol Dial Transplant. 2004; 19: 121-132Crossref PubMed Scopus (375) Google Scholar, 20Pisoni R.L. Bragg-Gresham J.L. Young E.W. et al.Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS).Am J Kidney Dis. 2004; 44: 94-111Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar Although the DOPPS results, being observational, cannot prove causality, they do provide additional evidence that supports the validity of the practice guidelines for managing CKD-related anemia. According to a recent analysis of the DOPPS data that assumes causality, it has been estimated that treating all patients in the United States with hemoglobin below 11 g/dL (110 g/L) to bring them within the recommended levels, would result in 23,910 life years potentially gained over a 5-year period.28Port F.K. Pisoni R.L. Bragg-Gresham J.L. et al.DOPPS estimates of patient life years attributable to modifiable hemodialysis practices in the United States.Blood Purif. 2004; 22: 175-180Crossref PubMed Scopus (92) Google Scholar These results suggest that a significant trend toward improved outcomes in hemodialysis patients may be expected by widespread implementation of these guidelines. The international results shown by the DOPPS in the management of anemia secondary to CKD in hemodialysis patients indicate that, although some improvements have occurred in anemia management practices since the publication of international guidelines, significant variations in practice are still observed among countries, and many efforts are still needed for the greater proportion of patients to reach the target hemoglobin concentrations recommended by clinical practice guidelines. The challenge is important to resolve because the results of the DOPPS clearly show that hemoglobin concentration is strongly associated with the risk of hospitalization and death in hemodialysis patients. Significantly improved outcomes may be expected by a more widespread achievement of the recommended hemoglobin levels. Collecting data from a large, representative population of hemodialysis patients from different countries, analyzing it, and adjusting for numerous patient case-mix characteristics, has allowed the DOPPS to show how an observational study, if performed under specific methodological circumstances, may become highly informative and credible, while also proving to be a basic instrument for monitoring the implementation of clinical guidelines in everyday clinical practice.