Note from the National Guideline Clearinghouse (NGC) and National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI): In September 2007, NKF-KDOQI released an update to its 2006 Clinical Practice Guideline and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease, which updated the sections on hemoglobin targets. The affected sections are "CPG and CPR 2.1 Hemoglobin Target" and "CPR for Pediatrics 2.1 Hemoglobin Target." All other recommendations remain the same.
Description of the grades of recommendation based on levels of evidence for clinical practice guidelines (CPGs) (Strong, Moderately Strong) and clinical practice recommendations (CPRs) (In the Opinion of the Work Group) and the definitions of the evidence grades (High, Moderate, Low, Very Low) are provided at the end of the "Major Recommendations" field.
Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease in Adults
CPR 1.1. Identifying Patients and Initiating Evaluation
Identifying anemia is the first step in evaluating the prognostic, diagnostic, and therapeutic significance of anemia in the patient with CKD.
1.1.1 Stage and cause of chronic kidney disease (CKD): In the opinion of the Work Group, hemoglobin (Hb) testing should be carried out in all patients with CKD, regardless of stage or cause.
1.1.2 Frequency of testing for anemia: In the opinion of the Work Group, Hb levels should be measured at least annually.
1.1.3 Diagnosis of anemia: In the opinion of the Work Group, diagnosis of anemia should be made and further evaluation should be undertaken at the following Hb concentrations:
- <13.5 g/dL in adult males
- <12.0 g/dL in adult females
CPR 1.2.: Evaluation Of Anemia In CKD
Anemia in patients with CKD is not always caused by erythropoietin deficiency alone. Initial laboratory evaluation therefore is aimed at identifying other factors that may cause or contribute to anemia or lead to ESA hyporesponsiveness.
1.2.1 In the opinion of the Work Group, initial assessment of anemia should include the following tests:
1.2.1.1 A complete blood count (CBC) including—in addition to the Hb concentration—red blood cell indices (mean corpuscular hemoglobin [MCH], mean corpuscular volume [MCV], mean corpuscular hemoglobin concentration [MCHC]), white blood cell count, and differential and platelet count.
1.2.1.2 Absolute reticulocyte count.
1.2.1.3 Serum ferritin to assess iron stores.
1.2.1.4 Serum transferrin saturation (TSAT) or content of Hb in reticulocytes (CHr) to assess adequacy of iron for erythropoiesis.
CPG and CPR 2.1. Hemoglobin Target (2007 Addendum)
The Hb target is the intended aim of erythropoiesis-stimulating agent (ESA) therapy for the individual patient with CKD. In clinical practice, achieved Hb results vary considerably from the Hb target.
2.1.1 In the opinion of the Work Group, selection of the Hb target and selection of the Hb level at which ESA therapy is initiated in the individual patient should include consideration of potential benefits (including improvement in quality of life and avoidance of transfusion) and potential harms (including the risk of life-threatening adverse events). (Clinical Practice RECOMMENDATION)
2.1.2 In the opinion of the Work Group, in dialysis and nondialysis patients with CKD receiving ESA therapy, the selected Hb target should generally be in the range of 11.0 to 12.0 g/dL. (Clinical Practice RECOMMENDATION)
2.1.3 In dialysis and nondialysis patients with CKD receiving ESA therapy, the Hb target should not be greater than 13.0 g/dL. (Clinical Practice GUIDELINE – MODERATELY STRONG EVIDENCE)
CPR 3.1. Using ESAs
ESAs are critical components in managing the anemia of CKD. Available ESAs are each effective in achieving and maintaining target Hb levels. Aspects of administration may differ between short-acting and long-acting agents.
3.1.1 Frequency of Hb monitoring:
3.1.1.1 In the opinion of the Work Group, the frequency of Hb monitoring in patients treated with ESAs should be at least monthly.
3.1.2 ESA dosing:
3.1.2.1 In the opinion of the Work Group, the initial ESA dose and ESA dose adjustments should be determined by the patient's Hb level, the target Hb level, the observed rate of increase in Hb level, and clinical circumstances.
3.1.2.2 In the opinion of the Work Group, ESA doses should be decreased, but not necessarily withheld, when a downward adjustment of Hb level is needed.
3.1.2.3 In the opinion of the Work Group, scheduled ESA doses that have been missed should be replaced at the earliest possible opportunity.
3.1.2.4 In the opinion of the Work Group, ESA administration in ESA-dependent patients should continue during hospitalization.
3.1.2.5 In the opinion of the Work Group, hypertension, vascular access occlusion, inadequate dialysis, history of seizures, or compromised nutritional status are not contraindications to ESA therapy.
3.1.3 Route of administration:
3.1.3.1 In the opinion of the Work Group, the route of ESA administration should be determined by the CKD stage, treatment setting, efficacy, safety, and class of ESA used.
3.1.3.2 In the opinion of the Work Group, convenience favors subcutaneous administration in non-hemodialysis-CKD patients.
3.1.3.3 In the opinion of the Work Group, convenience favors intravenous (IV) administration in HD (hemodialysis)-CKD patients.
3.1.4 Frequency of administration:
3.1.4.1 In the opinion of the Work Group, frequency of administration should be determined by the CKD stage, treatment setting, efficacy considerations, and class of ESA.
3.1.4.2 In the opinion of the Work Group, convenience favors less frequent administration, particularly in non-HD-CKD patients.
CPG and CPR 3.2. Using Iron Agents
Anemia therapy in patients with CKD requires effective use of iron agents, guided by appropriate testing of iron status. Efficacy of iron therapy appears not to be limited to patients with evidence of iron deficiency. (See Guideline 1.2 for diagnosis of iron deficiency.) Thus, the goals of iron therapy are to avoid storage iron depletion, prevent iron-deficient erythropoiesis, and achieve and maintain target Hb levels.
3.2.1 Frequency of iron status tests: In the opinion of the Work Group, iron status tests should be performed as follows:
3.2.1.1 Every month during initial ESA treatment.
3.2.1.2 At least every 3 months during stable ESA treatment or in patients with HD-CKD not treated with an ESA.
3.2.2 Interpretation of iron status tests: In the opinion of the Work Group, results of iron status tests, Hb, and ESA dose should be interpreted together to guide iron therapy.
3.2.3 Targets of iron therapy: In the opinion of the Work Group, sufficient iron should be administered to generally maintain the following indices of iron status during ESA treatment:
3.2.3.1 HD-CKD:
- Serum ferritin >200 ng/mL
AND
- TSAT >20%, or CHr >29 pg/cell
3.2.3.2 Non-dialysis dependent (ND)-CKD and peritoneal dialysis-dependent (PD)-CKD:
- Serum ferritin >100 ng/mL
AND
- TSAT >20%
3.2.4 Upper level of ferritin: In the opinion of the Work Group, there is insufficient evidence to recommend routine administration of IV iron if serum ferritin level is greater than 500 ng/mL. When ferritin level is greater than 500 ng/mL, decisions regarding IV iron administration should weigh ESA responsiveness, Hb and TSAT level, and the patient's clinical status.
3.2.5 Route of administration:
3.2.5.1 The preferred route of administration is IV in patients with HD-CKD. (STRONG RECOMMENDATION)
3.2.5.2 In the opinion of the Work Group, the route of iron administration can be either IV or oral in patients with ND-CKD or PD-CKD.
3.2.6 Hypersensitivity reactions: In the opinion of the Work Group, resuscitative medication and personnel trained to evaluate and resuscitate anaphylaxis should be available whenever a dose of iron dextran is administered.
CPG and CPR 3.3. Using Pharmacological and Nonpharmacological Adjuvants to ESA Treatment in HD-CKD
Several pharmacological agents and nonpharmacological manipulations of the HD prescription have been examined for potential efficacy as adjuvants to ESA treatment. Studies are not available to address the use of pharmacological or nonpharmacological adjuvants to ESA treatment in patients with ND-CKD and PD-CKD.
3.3.1 L-Carnitine: In the opinion of the Work Group, there is insufficient evidence to recommend the use of L-carnitine in the management of anemia in patients with CKD.
3.3.2 Vitamin C: In the opinion of the Work Group, there is insufficient evidence to recommend the use of vitamin C (ascorbate) in the management of anemia in patients with CKD.
3.3.3 Androgens: Androgens should not be used as an adjuvant to ESA treatment in anemic patients with CKD. (STRONG RECOMMENDATION)
CPR 3.4.: Transfusion Therapy
Red blood cell transfusions should be used judiciously in patients with CKD, especially because of the potential development of sensitivity affecting future kidney transplantation. However, despite the use of ESA and iron therapy, transfusion with red blood cells occasionally is required, in particular in the setting of acute bleeding.
3.4.1 In the opinion of the Work Group, no single Hb concentration justifies or requires transfusion. In particular, the target Hb recommended for chronic anemia management (see Guideline 2.1) should not serve as a transfusion trigger.
CPR 3.5. Evaluating and Correcting Persistent Failure to Reach or Maintain Intended Hb
Although relative resistance to the effect of ESAs is a common problem in managing the anemia of patients with CKD and is the subject of intense interest, the bulk of available information suggests that – in the absence of iron deficiency – there are few readily reversible factors that contribute to ESA hyporesponsiveness.
3.5.1 Hyporesponse to ESA and iron therapy: In the opinion of the Work Group, the patient with anemia and CKD should undergo evaluation for specific causes of hyporesponse whenever the Hb level is inappropriately low for the ESA dose administered. Such conditions include, but are not limited to:
- A significant increase in the ESA dose requirement to maintain a certain Hb level or a significant decrease in Hb level at a constant ESA dose
- A failure to increase the Hb level to greater than 11 g/dL despite an ESA dose equivalent to epoetin greater than 500 IU/kg/wk
3.5.2 Evaluation for pure red cell aplasia (PRCA): In the opinion of the Work Group, evaluation for antibody-mediated PRCA should be undertaken when a patient receiving ESA therapy for more than 4 weeks develops each of the following:
- Sudden rapid decrease in Hb level at the rate of 0.5 to 1.0 g/dL/wk, or requirement of red blood cell transfusions at the rate of approximately 1 to 2 per week
AND
- Normal platelet and white blood cell counts
AND
- Absolute reticulocyte count less than 10,000/microliter
Clinical Practice Recommendations for Anemia in Chronic Kidney Disease in Children
All statements in the pediatric section of the original guideline document assume the preface In the opinion of the Work Group, and all statements are provided as CPRs because there is insufficient evidence in pediatric patients to support evidence-based guidelines. When, in the opinion of the Work Group, the adult guideline statement applies equally well to adults and children, the statement is accompanied by the following: (FULLY APPLICABLE TO CHILDREN). When, in the opinion of the Work Group, the adult guideline statement needs modification or adjustment for children, the following instruction is given, followed by the pediatric-specific guideline statement: (APPLICABLE TO CHILDREN, BUT NEEDS MODIFICATION).
CPR for Pediatrics 1.1: Identifying Patients and Initiating Evaluation
Identifying anemia is the first step in evaluating the prognostic, diagnostic, and therapeutic significance of anemia in patients with CKD.
1.1.1 Stage and cause of CKD: (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, Hb testing should be carried out in all patients with CKD, regardless of stage or cause.
1.1.2 Frequency of testing for anemia: (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, Hb levels should be measured at least annually.
1.1.3 Diagnosis of anemia: (APPLICABLE TO CHILDREN, BUT NEEDS MODIFICATION)
ADULT CPR
In the opinion of the Work Group, diagnosis of anemia should be made and further evaluation should be undertaken at the following Hb concentrations:
- <13.5 g/dL in adult males
- <12.0 g/dL in adult females
PEDIATRIC CPR
In the opinion of the Work Group, in the pediatric patient, diagnosis of anemia should be made and further evaluation should be undertaken whenever the observed Hb concentration is less than the fifth percentile of normal when adjusted for age and sex.
CPR for Pediatrics 1.2: Evaluation of Anemia in CKD
Anemia in patients with CKD is not always caused by erythropoietin deficiency alone. Initial laboratory evaluation therefore is aimed at identifying other factors that may cause or contribute to anemia or lead to ESA hyporesponsiveness.
1.2.1 In the opinion of the Work Group, initial assessment of anemia should include the following tests: (APPLICABLE TO CHILDREN, BUT NEEDS MODIFICATION)
1.2.1.1 A CBC including-in addition to the Hb concentration-red blood cell indices (MCH, MCV, MCHC), white blood cell count and differential and platelet count.
1.2.1.2 Absolute reticulocyte count.
1.2.1.3 Serum ferritin to assess iron stores.
1.2.1.4 ADULT CPR
Serum TSAT or CHr to assess adequacy of iron for erythropoiesis.
PEDIATRIC CPR
In the pediatric patient, serum TSAT to assess adequacy of iron for erythropoiesis.
CPR for Pediatrics 2.1: Hemoglobin Target (2007 Addendum)
The Hb target is the intended aim of ESA therapy for the individual patient with CKD. In clinical practice, achieved Hb results vary considerably from the Hb target.
2.1.1 (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, selection of the Hb target and selection of the Hb level at which ESA therapy is initiated in the individual pediatric patient should include consideration of potential benefits (including improvement in quality of life, school attendance/performance, and avoidance of transfusion) and potential harms (including the risk of life-threatening adverse events). (Clinical Practice RECOMMENDATION)
2.1.2 (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, in pediatric dialysis and nondialysis patients with CKD receiving ESA therapy, the selected Hb target should generally be in the range of 11.0 to 12.0 g/dL. (Clinical Practice RECOMMENDATION)
2.1.3 (APPLICABLE TO CHILDREN, BUT NEEDS MODIFICATION) In dialysis and nondialysis patients with CKD receiving ESA therapy, the Hb target should not be greater than 13.0 g/dL. (Clinical Practice RECOMMENDATION)
CPR for Pediatrics 3.1: Using ESAs
ESAs are critical components in managing the anemia of patients with CKD. Available ESAs
are each effective in achieving and maintaining target Hb levels. Aspects of administration may differ between short-acting and long-acting agents.
3.1.1 Frequency of Hb monitoring: (FULLY APPLICABLE TO CHILDREN)
3.1.1.1 In the opinion of the Work Group, the frequency of Hb monitoring in patients treated with ESAs should be at least monthly.
3.1.2 ESA dosing: (FULLY APPLICABLE TO CHILDREN)
3.1.2.1 In the opinion of the Work Group, the initial ESA dose and ESA dose adjustments should be determined by the patient's Hb level, the target Hb level, the observed rate of increase in the Hb level, and clinical circumstances.
3.1.2.2 In the opinion of the Work Group, ESA doses should be decreased, but not necessarily held, when a downward adjustment of Hb level is needed.
3.1.2.3 In the opinion of the Work Group, scheduled ESA doses that have been missed should be replaced at the earliest possible opportunity.
3.1.2.4 In the opinion of the Work Group, ESA administration in ESA-dependent patients should continue during hospitalization.
3.1.2.5 In the opinion of the Work Group, hypertension, vascular access occlusion, inadequate dialysis, history of seizures, or compromised nutritional status are not contraindications to ESA therapy.
3.1.3 Route of administration: (APPLICABLE TO CHILDREN, BUT NEEDS MODIFICATION)
3.1.3.1 ADULT CPR
In the opinion of the Work Group, the route of administration should be determined by the CKD stage, treatment setting, efficacy considerations, and the class of ESA used.
PEDIATRIC CPR
In the opinion of the Work Group, in the pediatric patient, the route of administration should be determined by the CKD stage, treatment setting, efficacy considerations, the class of ESA used, and the anticipated frequency and pain of administration.
3.1.3.2 In the opinion of the Work Group, convenience favors subcutaneous administration in non-HD-CKD patients.
3.1.3.3 In the opinion of the Work Group, convenience favors IV administration in patients with HD-CKD.
3.1.4 Frequency of administration: (APPLICABLE TO CHILDREN, BUT NEEDS MODIFICATION)
3.1.4.1 ADULT CPR
In the opinion of the Work Group, frequency of administration should be determined by the CKD stage, treatment setting, efficacy considerations, and class of ESA.
PEDIATRIC CPR
In the opinion of the Work Group, in the pediatric patient, the frequency of administration should be determined by the CKD stage, treatment setting, efficacy considerations, and class of ESA; as well, consideration should be given to the anticipated frequency of, and pain on administration of each agent and their potential effects on the child and family.
3.1.4.2 In the opinion of the Work Group, convenience favors less frequent administration, particularly in non–HD-CKD patients.
CPR For Pediatrics 3.2: Using Iron Agents
Anemia therapy in patients with CKD requires effective use of iron agents, guided by appropriate testing of iron status. Efficacy of iron therapy appears not to be limited to patients with evidence of iron deficiency. (See Guideline 1.2 for diagnosis of iron deficiency.) Thus, the goals of iron therapy are to avoid storage iron depletion, prevent iron-deficient erythropoiesis, and achieve and maintain target Hb levels.
3.2.1 Frequency of iron status tests: (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, iron status tests should be performed as follows:
3.2.1.1 Every month during initial ESA treatment.
3.2.1.2 At least every 3 months during stable ESA treatment or in patients with HD-CKD not treated with an ESA.
3.2.2 Interpretation of iron status tests: (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, results of iron status tests, Hb level, and ESA dose should be interpreted together to guide iron therapy.
3.2.3 Targets of iron therapy: (APPLICABLE TO CHILDREN, BUT NEEDS MODIFICATION) In the opinion of the Work Group, sufficient iron should be administered to generally maintain the following indices of iron status during ESA treatment:
3.2.3.1 ADULT CPR HD-CKD:
- Serum ferritin >200 ng/mL
AND
- TSAT >20%, or CHr >29 pg/cell
PEDIATRIC CPR HD-CKD:
- Serum ferritin >100 ng/mL
AND
- TSAT >20%
3.2.3.2 ND-CKD and PD-CKD:
- Serum ferritin >100 ng/mL
AND
- TSAT >20%
3.2.4 Upper level of ferritin: (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, there is insufficient evidence to recommend routine administration of IV iron if serum ferritin is greater than 500 ng/mL. When ferritin level is greater than 500 ng/mL, decisions regarding IV iron administration should weigh ESA responsiveness, Hb and TSAT level, and the patient's clinical status.
3.2.5 Route of administration: (FULLY APPLICABLE TO CHILDREN)
3.2.5.1 The preferred route of administration is IV in patients with HD-CKD. (STRONG RECOMMENDATION)
3.2.5.2 In the opinion of the Work Group, the route of iron administration can be either IV or oral in patients with ND-CKD and PD-CKD.
3.2.6 Hypersensitivity reactions: (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, resuscitative medication and personnel trained to evaluate and resuscitate anaphylaxis should be available whenever a dose of iron dextran is administered.
CPR for Pediatrics 3.3: Using Pharmacological and Nonpharmacological Adjuvants to ESA Treatment in HD-CKD
Several pharmacological agents and nonpharmacological manipulations of the HD prescription have been examined for potential efficacy as adjuvants to ESA treatment. Studies are not available to address the use of pharmacological or nonpharmacological adjuvants to ESA treatment in patients with ND-CKD and PD-CKD.
3.3.1 L-carnitine: (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, there is insufficient evidence to recommend the use of L-carnitine in the management of anemia in patients with CKD.
3.3.2 Vitamin C: (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, there is insufficient evidence to recommend the use of vitamin C (ascorbate) in the management of anemia in patients with CKD.
3.3.3 Androgens: (FULLY APPLICABLE TO CHILDREN) Androgens should not be used as an adjuvant to ESA treatment in anemic patients with CKD. (STRONG RECOMMENDATION)
CPR for Pediatrics 3.4: Transfusion Therapy
Red blood cell transfusions should be used judiciously in patients with CKD, especially because of the potential development of sensitivity, affecting future kidney transplantation. However, despite the use of ESA and iron therapy, transfusion with red blood cells occasionally is required, in particular in the setting of acute bleeding.
3.4.1 (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, no single Hb concentration justifies or requires transfusion. In particular, the target Hb recommended for chronic anemia management (see Guideline 2.1) should not serve as a transfusion trigger.
CPR for Pediatrics 3.5: Evaluating and Correcting Persistent Failure to Reach or Maintain Intended Hb Level
Although relative resistance to the effect of ESAs is a common problem in managing the anemia of CKD and is the subject of intense interest, the bulk of available information suggests that--in the absence of iron deficiency--there are few readily reversible factors that contribute to ESA hyporesponsiveness.
3.5.1 Hyporesponse to ESA and iron therapy: (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, the patient with anemia and CKD should undergo evaluation for specific causes of hyporesponse whenever the Hb level is inappropriately low for the ESA dose administered. Such conditions include, but are not limited to:
- A significant increase in the ESA dose requirement to maintain a certain Hb level or a significant decrease in Hb levels at a constant ESA dose.
- A failure to increase the Hb level to greater than 11 g/dL despite an ESA dose equivalent to epoetin greater than 500 IU/kg/wk.
3.5.2 Evaluation for PRCA: (FULLY APPLICABLE TO CHILDREN) In the opinion of the Work Group, evaluation for antibody-mediated PRCA should be undertaken when a patient receiving ESA therapy for more than 4 weeks develops each of the following:
- Sudden rapid decline in Hb level at the rate of 0.5 to 1.0 g/dL/wk, or requirement of red blood cell transfusions at the rate of approximately 1 to 2 per week
AND
- Normal platelet and white blood cell counts
AND
- Absolute reticulocyte count less than 10,000/microliter
Clinical Practice Recommendations for Anemia in Chronic Kidney Disease in Transplant Recipients
See the original guideline document for a discussion of anemia in CKD in transplant recipients.
Definitions:
Clinical Practice Guidelines (CPGs)
Strong - Indicates it is strongly recommended that clinicians routinely follow the guideline for eligible patients. There is high quality evidence that the practice results in net medical benefit to the patient.
Moderately Strong - Indicates it is recommended that clinicians routinely follow the guideline for eligible patients. There is at least moderately high quality evidence that the practice results in net medical benefit to the patient.
Clinical Practice Recommendations (CPRs)
In the Opinion of the Work Group - In the absence of strong or moderately strong quality evidence or when additional considerations did not support strong or moderately strong evidence-based guideline recommendations, the Work Group could elect to issue CPRs based on consensus of expert opinions. These recommendations are based on the consensus of the Work Group that following the recommendations might improve health outcomes.
Evidence Grade - Definitions
High - Further research is unlikely to change the Work Group's confidence in the estimate of effect.
Moderate - Further research is likely to have an important impact on the Work Group's confidence in the estimate of effect and may change the estimate.
Low - Further research is very likely to have an important impact on the Work Group's confidence in the estimate of effect and may change the estimate.
Very Low - Any estimate of effect is very uncertain.
