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KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD

2013; Elsevier BV; Volume: 62; Issue: 5 Linguagem: Inglês

10.1053/j.ajkd.2013.06.008

1523-6838

Alan S. Kliger, Robert N. Foley, David S. Goldfarb, Stuart L. Goldstein, Kirsten L. Johansen, Ajay Singh, Lynda A. Szczech,

Iron Metabolism and Disorders

The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for Anemia in Chronic Kidney Disease provides clinicians with comprehensive evidence-based recommendations to improve patient care. In this commentary, we review these recommendations and the underlying evidence. Most recommendations are well reasoned. For some, the evidence is unclear and recommendations require some qualification. While the KDIGO guideline stresses the potential risks of intravenous iron therapy, withholding iron might have its own risks. The recommendation to avoid hemoglobin levels falling below 9 g/dL sets a lower bound of “acceptability” that may increase blood transfusion. Given the lack of research supporting the optimal transfusion strategy for end-stage renal disease patients, it is difficult to weigh the risks and benefits of red blood cell transfusion. We find a paucity of evidence that hemoglobin concentration targeted between 11 and 11.5 g/dL is associated with a safety risk. Although the evidence that erythropoiesis-stimulating agent use improves patient quality of life is poor, it is possible that the instruments used to measure quality of life may not be well attuned to the needs of chronic kidney disease or dialysis patients. Our last section focuses specifically on the recommendations to treat anemia in children. The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for Anemia in Chronic Kidney Disease provides clinicians with comprehensive evidence-based recommendations to improve patient care. In this commentary, we review these recommendations and the underlying evidence. Most recommendations are well reasoned. For some, the evidence is unclear and recommendations require some qualification. While the KDIGO guideline stresses the potential risks of intravenous iron therapy, withholding iron might have its own risks. The recommendation to avoid hemoglobin levels falling below 9 g/dL sets a lower bound of “acceptability” that may increase blood transfusion. Given the lack of research supporting the optimal transfusion strategy for end-stage renal disease patients, it is difficult to weigh the risks and benefits of red blood cell transfusion. We find a paucity of evidence that hemoglobin concentration targeted between 11 and 11.5 g/dL is associated with a safety risk. Although the evidence that erythropoiesis-stimulating agent use improves patient quality of life is poor, it is possible that the instruments used to measure quality of life may not be well attuned to the needs of chronic kidney disease or dialysis patients. Our last section focuses specifically on the recommendations to treat anemia in children. The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for anemia in chronic kidney disease (CKD) was published in 2012.1KDIGO Anemia Work GroupKDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease.Kidney Int Suppl. 2012; 2: 279-335Crossref Scopus (721) Google Scholar An international group of experts, led by John J.V. McMurray and Patrick S. Parfrey, with the assistance of an evidence review team from Tufts Medical Center in Boston, created comprehensive, evidence-based guidance for the treatment of anemia in CKD, tempered by the substantial judgment of experienced clinicians. Our NKF-KDOQI (National Kidney Foundation–Kidney Disease Outcomes Quality Initiative) commentary group, selected as independent experts in this field, has reviewed these KDIGO recommendations and comments on this up-to-date and well-considered guideline. Clinical practice is driven by many forces: best clinical evidence, patient and physician preferences, financial conditions, and regulatory requirements. For anemia management in particular, the United States has seen much recent activity that has impacted on anemia treatment: the US Food and Drug Administration (FDA) has changed the labeling of erythropoiesis-stimulating agents (ESAs) to reflect the risks of targeting hemoglobin (Hb) concentrations at or close to normal levels, in light of the relatively sparse evidence that ESAs improve the quality of life (QoL) for patients with CKD. In addition, the Centers for Medicare & Medicaid Services (CMS), the major payor for CKD care in the United States, has changed the method of payment for the dialysis procedure to now include ESAs and parenteral iron in the “bundle” of care reimbursed under this capitated system, effectively removing these medications as profit centers for dialysis centers. Although these regulatory and payment changes have had a substantial effect on prescribing patterns and affect how anemia in CKD is managed, we make few comments on these forces in this commentary, focusing primarily on the evidence and clinical judgment required for best medical care. The evidence-gathering strategies for the KDIGO guideline are based on studies published through March 2012 and appear to be comprehensive, systematic, and unbiased. Using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) template, guideline recommendations are codified by strength of the recommendation (Levels 1 and 2) and quality of the supportive evidence (Grades High [A], Moderate [B], Low [C], and Very Low [D]). In this scheme, a Level 1 Grade A treatment would generate a statement beginning with “We recommend” (based on a Level of 1), most patients should receive the recommended action (also based on Level of 1), and the quality of evidence is High because raters are confident that the true and estimated effects of the studies lie in close numerical proximity. However, subjectivity is inevitable, even when individual studies provide clear and consistent results. Statements beginning with “We recommend” should be examined very carefully. For example, when treatments produce large effects on a clinically relevant primary outcome in well-designed, generalizable, randomized trials, making statements beginning with “We recommend …” should be straightforward and unlikely to generate controversy or debate. In contrast, it is more difficult to come to a single recommendation when study results are not as straightforward (eg, similar event rates for primary outcomes but differences in important secondary outcomes or prespecified patient subgroups). Intuitively, one would expect that Level 1 or “We recommend” statements would usually be accompanied by Grade A or High-quality evidence. It is interesting, then, that although 40.5% of the 37 recommendations were graded as Level 1, only 5.4% had an A grade for quality of evidence. Rather, some recommendations are “not graded,” suggesting that these statements are based largely on expert opinion rather than on objective evidence. Finally, there were several instances in which statements implying strength of effect were used without quantifying effect size and confidence intervals in the supporting text of the KDIGO document. This approach is inherently subjective and should lead us to scrutinize these recommendations with particular care. In the following, numbered text within horizontal rules is quoted directly from the KDIGO document, using the same numbering scheme as in the original. Not all guideline statements are included; only those that the work group thought required comment or qualification are reproduced here. All material is reproduced with permission of KDIGO. Frequency of testing for anemia1.1.1: For CKD patients without anemia (as defined … in Recommendation 1.2.1 for adults and Recommendation 1.2.2 for children), measure Hb concentration when clinically indicated and (Not Graded): •at least annually in patients with CKD 3•at least twice per year in patients with CKD 4-5ND•at least every 3 months in patients with CKD 5HD and CKD 5PD1.1.2: For CKD patients with anemia not being treated with an ESA, measure Hb concentration when clinically indicated and (Not Graded): •at least every 3 months in patients with CKD 3-5ND and CKD 5PD•at least monthly in patients with CKD 5HD[See Recommendations 3.12.1-3.12.3 for measurement of Hb concentration in patients being treated with ESA.]Investigation of anemia1.3: In patients with CKD anemia (regardless of age and CKD stage), include the following tests in initial evaluation of the anemia (Not Graded): •Complete blood count (CBC), which should include Hb concentration, red cell indices, white blood cell count and differential, and platelet count•Absolute reticulocyte count•Serum ferritin level•Serum transferrin saturation (TSAT)•Serum vitamin B12 and folate levels Frequency of testing for anemia 1.1.1: For CKD patients without anemia (as defined … in Recommendation 1.2.1 for adults and Recommendation 1.2.2 for children), measure Hb concentration when clinically indicated and (Not Graded): •at least annually in patients with CKD 3•at least twice per year in patients with CKD 4-5ND•at least every 3 months in patients with CKD 5HD and CKD 5PD 1.1.2: For CKD patients with anemia not being treated with an ESA, measure Hb concentration when clinically indicated and (Not Graded): •at least every 3 months in patients with CKD 3-5ND and CKD 5PD•at least monthly in patients with CKD 5HD [See Recommendations 3.12.1-3.12.3 for measurement of Hb concentration in patients being treated with ESA.] Investigation of anemia 1.3: In patients with CKD anemia (regardless of age and CKD stage), include the following tests in initial evaluation of the anemia (Not Graded): •Complete blood count (CBC), which should include Hb concentration, red cell indices, white blood cell count and differential, and platelet count•Absolute reticulocyte count•Serum ferritin level•Serum transferrin saturation (TSAT)•Serum vitamin B12 and folate levels KDIGO made recommendations for testing of Hb concentration for patients with CKD with and without anemia and for diagnostic studies to be used in anemic adults and children with CKD. Not unexpectedly, no randomized trials were available to inform this section of the guideline. Nevertheless, most of the recommendations were similar to previous guideline documents and unlikely to generate much controversy. One notable exception, however, was the recommendation to measure Hb concentration at least annually in all patients with CKD stage 3. In practice, one could argue about the necessity of this among patients with nonprogressive or slowly progressive early-stage CKD. For example, the case for annual Hb measurement in an adult without anemia, with a stable glomerular filtration rate of 59 mL/min/1.73 m2 but no albuminuria, is hardly compelling. KDIGO continued to recommend the use of serum ferritin concentration and transferrin saturation (TSAT) to define iron stores and iron availability. For all their imperfections, these metrics remain our best routinely-available tools to assess iron status and manage iron supplementation. In the absence of superior, cost-effective, and easily applicable alternatives, this approach seems reasonable. 2.1.1: When prescribing iron therapy, balance the potential benefits of avoiding or minimizing blood transfusions, ESA therapy, and anemia-related symptoms against the risk of harm in individual patients (e.g., anaphylactoid and other acute reactions, unknown long-term risks). (Not Graded)2.1.2: For adult CKD patients with anemia not on iron or ESA therapy we suggest a trial of IV iron (or in CKD ND patients alternatively a 1-3 month trial of oral iron therapy) if (2C): •an increase in Hb concentration without starting ESA treatment is desired* and•TSAT is ≤ 30% and ferritin is ≤ 500 ng/ml (≤500 μg/l)2.1.3: For adult CKD patients on ESA therapy who are not receiving iron supplementation, we suggest a trial of IV iron (or in CKD ND patients alternatively a 1-3 month trial of oral iron therapy) if (2C): •an increase in Hb concentration** or a decrease in ESA dose is desired*** and•TSAT is ≤ 30% and ferritin is ≤ 500 ng/ml (≤ 500 μg/l)*Based on patient symptoms and overall clinical goals, including avoidance of transfusion, improvement in anemia-related symptoms, and after exclusion of active infection.**Consistent with Recommendations #3.4.2 and 3.4.3.***Based on patient symptoms and overall clinical goals including avoidance of transfusion and improvement in anemia-related symptoms, and after exclusion of active infection and other causes of ESA hyporesponsiveness. 2.1.1: When prescribing iron therapy, balance the potential benefits of avoiding or minimizing blood transfusions, ESA therapy, and anemia-related symptoms against the risk of harm in individual patients (e.g., anaphylactoid and other acute reactions, unknown long-term risks). (Not Graded) 2.1.2: For adult CKD patients with anemia not on iron or ESA therapy we suggest a trial of IV iron (or in CKD ND patients alternatively a 1-3 month trial of oral iron therapy) if (2C): •an increase in Hb concentration without starting ESA treatment is desired* and•TSAT is ≤ 30% and ferritin is ≤ 500 ng/ml (≤500 μg/l) 2.1.3: For adult CKD patients on ESA therapy who are not receiving iron supplementation, we suggest a trial of IV iron (or in CKD ND patients alternatively a 1-3 month trial of oral iron therapy) if (2C): •an increase in Hb concentration** or a decrease in ESA dose is desired*** and•TSAT is ≤ 30% and ferritin is ≤ 500 ng/ml (≤ 500 μg/l) *Based on patient symptoms and overall clinical goals, including avoidance of transfusion, improvement in anemia-related symptoms, and after exclusion of active infection. **Consistent with Recommendations #3.4.2 and 3.4.3. ***Based on patient symptoms and overall clinical goals including avoidance of transfusion and improvement in anemia-related symptoms, and after exclusion of active infection and other causes of ESA hyporesponsiveness. Among patients with CKD, iron therapy has the potential to increase Hb concentration or decrease ESA dose when TSAT is ≤30% and should be considered. However, the guideline recommendation for iron therapy is more complex when TSAT and serum ferritin are high, but Hb is low. The KDIGO guideline recommendations point out that in most patients with TSAT >30% or serum ferritin >500 ng/mL, any erythropoietic response to iron supplementation alone will be small, and the safety of giving additional iron has been assessed in very few patients: “It is the consensus of the Work Group that additional IV iron should not routinely be administered in patients with serum ferritin levels that are consistently >500 ng/ml.” The DRIVE (Dialysis Patients' Response to Intravenous Iron With Elevated Ferritin) Study2Coyne D.W. Kappoian T. Suki W. et al.DRIVE Study GroupFerric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) Study.J Am Soc Nephrol. 2007; 18: 975-984Crossref PubMed Scopus (350) Google Scholar showed that intravenous (IV) iron administered to patients with ferritin concentrations >500 ng/mL reduced ESA doses and subsequent health care costs. While the limited power afforded by the sample size of the DRIVE trial should be acknowledged, we believe that it still merits consideration when balancing potential risks of IV iron administration against ESA dose, transfusions, and costs. KDIGO suggests that, for selected patients, “a therapeutic trial of additional iron (i.e., a single course of up to 1,000 mg of iron over a period of several weeks which can be repeated as needed) may be undertaken in patients with serum ferritin > 500 ng/ml after due consideration of potential acute toxicities and long-term risks.” The KDIGO guideline recommendations repeatedly express concern about the risks of IV iron administration. They state, for example, that “It is important that the short and long-term safety of oral and intravenous (IV) iron agents, when known, be carefully considered when iron therapy is prescribed, and that the potential for as yet undiscovered toxicities also be taken into account.” Although we understand that concern about possible long-term risks has not been eliminated by adequately powered studies, we also underscore that there are currently no data available that suggest long-term IV iron administration in moderate doses causes worse outcomes. Furthermore, withholding IV iron could have unintended consequences. In focusing exclusively on caution related to potential risks associated with iron administration, the KDIGO guideline statements do not adequately emphasize that withholding IV iron might have its own risks. We encourage research to evaluate the long-term safety of iron administration. We believe that the degree of caution expressed by KDIGO is not supported by the available evidence and could have negative effects, such as sustained iron deficiency anemia, higher ESA dose requirements, and increased blood transfusions. The guideline repeatedly includes cost as a variable influencing the choices made by treating physicians regarding treatment of anemia. However, we note that no formal assessments of the literature analyzing costs have been reviewed in the guideline. Whether physicians are practicing in the “bundled” payment environment of the US End-Stage Renal Disease (ESRD) Program or in similar or dissimilar payor environments, we agree that cost is an important determinant of treatment decisions, particularly when relative risks and benefits of different strategies are equivalent or unclear. Although no formal cost assessment has been done, Pizzi and colleagues3Pizzi L.T. Bunz T.J. Coyne D.W. Goldfarb D.S. Singh A.K. Ferric gluconate yields cost savings in patients with high ferritin and low TSAT.Kidney Int. 2008; 74: 1588-1595Crossref PubMed Scopus (22) Google Scholar showed that IV iron administration in patients with high ferritin and low TSAT yielded cost savings. More iron may be less expensive than more ESAs and safer than higher doses of ESAs. We therefore believe that a therapeutic trial of IV iron (or in non–dialysis-dependent CKD patients [denoted as CKD ND in the guideline], a trial of oral iron therapy) could be considered when TSAT is low (≤30%), even if ferritin concentration is above 500 ng/mL. There is insufficient evidence upon which to base a recommendation for an upper ferritin limit above which IV iron must be withheld. A decision to administer iron in the setting of high ferritin would require weighing potential risks and benefits of persistent anemia, ESA dosage, comorbid conditions, and health-related QoL. In accordance with KDIGO recommendations, Hb response to iron therapy, TSAT, and ferritin should be monitored closely and further iron therapy titrated accordingly. 2.1.4: For CKD ND patients who require iron supplementation, select the route of iron administration based on the severity of iron deficiency, availability of venous access, response to prior oral iron therapy, side effects with prior oral or IV iron therapy, patient compliance, and cost. (Not Graded)2.1.5: Guide subsequent iron administration in CKD patients based on Hb responses to recent iron therapy, as well as ongoing blood losses, iron status test (TSAT and ferritin), Hb concentration, ESA responsiveness and ESA dose in ESA treated patients, trends in each parameter, and the patient's clinical status. (Not Graded) 2.1.4: For CKD ND patients who require iron supplementation, select the route of iron administration based on the severity of iron deficiency, availability of venous access, response to prior oral iron therapy, side effects with prior oral or IV iron therapy, patient compliance, and cost. (Not Graded) 2.1.5: Guide subsequent iron administration in CKD patients based on Hb responses to recent iron therapy, as well as ongoing blood losses, iron status test (TSAT and ferritin), Hb concentration, ESA responsiveness and ESA dose in ESA treated patients, trends in each parameter, and the patient's clinical status. (Not Graded) The KDIGO guideline says, “The consensus of the Work Group is that a clearly defined advantage or preference for IV compared to oral iron was not supported by available evidence in CKD ND patients.” Although we agree with this statement, we note that the guidelines issued by the European Renal Association and European Dialysis and Transplant Association recommend IV iron for non–dialysis-dependent CKD patients. A recent review of the randomized controlled trials performed to investigate this question noted that relevant studies reported inconsistent results and were too short to conclude whether the duration of oral iron administration was sufficient to answer the question definitively.4Liles A.M. Intravenous versus oral iron for treatment of iron deficiency in non-hemodialysis-dependent patients with chronic kidney disease.Am J Health Syst Pharm. 2012; 69: 1206-1211Crossref PubMed Scopus (12) Google Scholar However, IV iron consistently achieved higher TSAT and ferritin values than oral iron. It is possible, then, that in the long run, IV iron may be superior to oral iron as a route of administration. The economic implications of choosing oral versus IV iron are complex and not easily resolved without a prospective and interventional study design. IRON STATUS EVALUATION2.2.1: Evaluate iron status (TSAT and ferritin) at least every 3 months during ESA therapy, including the decision to start or continue iron therapy (Not Graded)2.2.2: Test iron status (TSAT and ferritin) more frequently when initiating or increasing ESA dose, when there is blood loss, when monitoring response after a course of IV iron, and in other circumstances where iron stores may become depleted. (Not Graded)CAUTIONS REGARDING IRON THERAPY2.3: When the initial dose of IV iron dextran is administered, we recommend (1B) and when the initial dose of IV non-dextran iron is administered, we suggest (2C) that patients be monitored for 60 minutes after the infusion, and that resuscitative facilities (including medications) and personnel trained to evaluate and treat serious adverse reactions be available. IRON STATUS EVALUATION 2.2.1: Evaluate iron status (TSAT and ferritin) at least every 3 months during ESA therapy, including the decision to start or continue iron therapy (Not Graded) 2.2.2: Test iron status (TSAT and ferritin) more frequently when initiating or increasing ESA dose, when there is blood loss, when monitoring response after a course of IV iron, and in other circumstances where iron stores may become depleted. (Not Graded) CAUTIONS REGARDING IRON THERAPY 2.3: When the initial dose of IV iron dextran is administered, we recommend (1B) and when the initial dose of IV non-dextran iron is administered, we suggest (2C) that patients be monitored for 60 minutes after the infusion, and that resuscitative facilities (including medications) and personnel trained to evaluate and treat serious adverse reactions be available. We note that the guideline statements do not discriminate among different IV iron preparations, instead referring only to iron dextran and nondextran iron. Although head-to-head comparisons of the safety and short-term side effects related to the administration of these different preparations do not exist, there is evidence that high-molecular-weight preparations, ie, high-molecular-weight iron dextran, are associated with more adverse effects, specifically more acute reactions.5Auerbach M. Ballard H. Clinical use of intravenous iron: administration, efficacy, and safety.Hematology Am Soc Hematol Educ Program. 2010; 2010: 338-347Crossref PubMed Scopus (223) Google Scholar We therefore suggest that high-molecular-weight iron dextran should be avoided. We also note that product labeling for all IV iron preparations recommends having personnel and therapies immediately available for treatment of anaphylaxis and other hypersensitivity reactions. We believe this recommendation is consistent with the possibility of significant reactions with any nondextran irons, and therefore we also recommend resuscitative facilities be available when administering any formulation of IV iron. 2.4: Avoid administering IV iron to patients with active systemic infections. (Not Graded) 2.4: Avoid administering IV iron to patients with active systemic infections. (Not Graded) Although there is theoretical evidence that iron overload stimulates bacterial growth,6Sunder-Plassmann G. Patruta S.I. Horl W.H. Pathobiology of the role of iron in infection.Am J Kidney Dis. 1999; 34: S25-S29Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar definitive evidence from randomized controlled trials showing that IV iron administration exacerbates infection is lacking. Therefore, while we agree with the statement in the KDIGO guideline that “current evidence cannot provide a clear answer” about whether IV iron increases the risk for infection or for having a worse outcome with infection, we believe the potential risk of iron-induced worsening of infection outcomes must be weighed against the theoretical evidence that iron deficiency may itself impair response to infection.7Oppenheimer S.J. Iron and its relation to immunity and infectious disease.J Nutr. 2001; 131: 616S-635SPubMed Google Scholar, 8Cu Y. Zhang Z.N. Li R.S. Influence of latent iron deficiency on generation of oxygen species in polymorphonuclear leukocytes.Chin Med J (Engl). 1990; 103: 642-646PubMed Google Scholar We agree with the KDIGO statement: “Clinical judgment is necessary in each individual patient to assess whether there is an immediate need for IV iron (as opposed to delaying treatment until resolution of an infection), likelihood of achieving benefit from a dose of IV iron in the setting of an active infection, and the severity of an infection.” In addition, although the association of transfusion with infection has not been specifically studied among patients with CKD, transfusion has been clearly associated with increased risk of infection in hospitalized surgical and nonsurgical patients.9Carless P.A. Henry D.A. Carson J.L. Hebert P.P. McClelland B. Ker K. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion.Cochrane Database Syst Rev. 2010; 10 (CD002042)PubMed Google Scholar Therefore we make no recommendation about the use or avoidance of IV iron in the setting of infection. 3.2: In initiating and maintaining ESA therapy, we recommend balancing the potential benefits of reducing blood transfusions and anemia-related symptoms against the risks of harm in individual patients (e.g., stroke, vascular access loss, hypertension). (1B)3.3: We recommend using ESA therapy with great caution, if at all, in CKD patients with active malignancy—in particular when cure is the anticipated outcome—(1B), a history of stroke (1B), or a history of malignancy (2C).3.4.1: For adult CKD ND patients with Hb concentration ≥10.0 g/dl ( ≥100 g/l) we suggest that ESA therapy not be initiated. (2D)3.4.2: For adult CKD ND patients with Hb concentration < 10.0 g/dl (<100 g/l) we suggest that the decision whether to initiate ESA therapy be individualized based on the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anemia. (2C)3.4.3: For adult CKD 5D patients, we suggest that ESA therapy be used to avoid having the Hb concentration fall below 9.0 g/dl (90 g/l) by starting ESA therapy when the hemoglobin is between 9.0-10.0 g/dl (90-100 g/l). (2B)3.4.4: Individualization of therapy is reasonable as some patients may have improvements in quality of life at higher Hb concentration and ESA therapy may be started above 10.0 g/dl (100 g/l). (Not Graded)ESA MAINTENANCE THERAPY3.5.1: In general, we suggest that ESAs not be used to maintain Hb concentration above 11.5 g/dl (115 g/l) in adult patients with CKD. (2C)3.5.2: Individualization of therapy will be necessary as some patients may have improvements in quality of life at Hb concentration above 11.5 g/dl (115 g/l) and will be prepared to accept the risks. (Not Graded)3.6: In all adult patients, we recommend that ESAs not be used to intentionally increase the Hb concentration above 13 g/dl (130 g/l). (1A) 3.2: In initiating and maintaining ESA therapy, we recommend balancing the potential benefits of reducing blood transfusions and anemia-related symptoms against the risks of harm in individual patients (e.g., stroke, vascular access loss, hypertension). (1B) 3.3: We recommend using ESA therapy with great caution, if at all, in CKD patients with active malignancy—in particular when cure is the anticipated outcome—(1B), a history of stroke (1B), or a history of malignancy (2C). 3.4.1: For adult CKD ND patients with Hb concentration ≥10.0 g/dl ( ≥100 g/l) we suggest that ESA therapy not be initiated. (2D) 3.4.2: For adult CKD ND patients with Hb concentration < 10.0 g/dl (<100 g/l) we suggest that the decision whether to initiate ESA therapy be individualized based on the rate of fall of Hb concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of symptoms attributable to anemia. (2C) 3.4.3: For adult CKD 5D patients, we suggest that ESA therapy be used to avoid having the Hb concentration fall below 9.0 g/dl (90 g/l) by starting ESA therapy when the hemoglobin is between 9.0-10.0 g/dl (90-100 g/l). (2B) 3.4.4: Individualization of therapy is reasonable as some patients may have improvements in quality of life at higher Hb concentration and ESA therapy may be started above 10.0 g/dl (100 g/l). (Not Graded) ESA MAINTENANCE THERAPY 3.5.1: In general, we suggest that ESAs not be used to maintain Hb concentration above 11.5 g/dl (115 g/l) in adult patients with CKD. (2C) 3.5.2: Individualization of therapy will be necessary as some patients may have improvements in quality of life at Hb concentration above 11.5 g/