CKD: Anemia (2001)

Citation:
 
Study Design:
Class:
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Quality Rating:
Research Purpose:

The purpose of this consensus statement is to guide practitioners in providing care for patients of all age groups with anemia of chronic kidney disease (CKD).  CKD is used to describe patients with chronically reduced kidney function, including those with chronic allograft dysfunction, and those in kidney failure who are dialysis dependent.  The same pathophysiology underlies this anemia in all such patients. 

When untreated, the anemia of CKD is associated with a number of physiologic abnormalities, including decreased tissue oxygen delivery and utilization, increased cardiac output, cardiac enlargement, ventricular hypertrophy, angina, congestive heart failure, decreased cognition and mental acuity, altered menstrual cycles, decreased nocturnal penile tuescence, and imparied immune responsiveness.  In addition, anemia may play a role in growth retardation and decreased intellectual performance in pediatric patients.  These abnormalities reduce quality of life and opportunities for rehabilitation of CKD patients and decrease patient survival.

Inclusion Criteria:

The Anemia Work Group reviewed only peer-reviewed studies that compared baseline Hgb/Hct levels of 10 to 11 g/dL/30% to 33% (which is the current target level in the US and most other countries). 

Methods for inclusion criteria for the other guidelines were not discussed.
Exclusion Criteria:

Not discussed.

Description of Study Protocol:

Recruitment:  Methods of study inclusion not described. 

Design: Consensus Statement

Blinding used (if applicable):  not applicable

Intervention (if applicable):  not applicable

Statistical Analysis:

  • When recommendations are based on evidence, a rationale and supporting literature references are indicated.
  • When recommendations are based on opinion in the absence of published evidence, the rationales for the recommendations are described.
  • In some instances, recommendations are based in whole or in part on the opinion of the Work Group members.
Data Collection Summary:

Timing of Measurements:  not applicable

Dependent Variables:  not applicable

Independent Variables: not applicable

Control Variables:  not applicable

 

 

Description of Actual Data Sample:

Initial N: 393 references included

Attrition (final N): 393 references

Age: not mentioned

Ethnicity: not mentioned

Other relevant demographics:

Anthropometrics: 

Location: Worldwide studies

 

Summary of Results:

Other Findings:

Guideline 1: When to Initiate the Work-Up of Anemia

  • Hgb less than 11 g/dL (Hct is less than 33%) in pre-menopausal females and pre-pubertal patients (Evidence)
  • Hgb less than 12 g/dL (Hct is less than 37% in adult males and post-menopausal females (Evidence)

Guideline 2:  Anemia Evaluation

Evaluation of anemia should consist of measurement of at least the following (Evidence):

  • Hgb and/or Hct
  • Red blood cell indices
  • Reticulocyte count
  • Iron parameters:
    • Serum iron
    • Total Iron Binding Capacity (TIBC)
    • Percent transferrin saturation (serum iron x 100 divided by TIBC)
    • Serum ferritin
  • Test for occult blood in stool
  • This work-up should be performed before Epoetin therapy is begun. (Opinion)

Guideline 3:  Erythropoietin Deficiency

  • If no cause for anemia other than CKD is detected, based on the work-up outlined in Guideline 2:  Anemia Evaluation, and the serum creatinine is greater than or equal to 2 mg/dL, anemia is most likely due to EPO deficiency. (Evidence)

Target Hemoglobin/Hematocrit

  • The Work Group reviewed only peer-reviewed studies that compared baseline Hgb/Hct levels of 10-11 g/dL/30-33% (which is the current target level in the United States and most other countries) to higher values.
  • Review of the literature (predialysis and dialysis patients) indicate that patients with chronic kidney disease function better at Hct levels that are near normal or normal and that improvement is continuous as the Hgb/Hct increases above 10 g/dL/30% to normal levels.
  • Most of the initial physiologic and quality of life studies of patients with anemia (predialysis and dialysis) treated with rHuEPO in the US had target Hct values of 36%.
  • Virtually all of the studies have shown improvements with increased hct:
    • Oxygen utilization (VO2) 
    •  Muscle strength & function
    • Cognitive and brain electrophysiological function
    • Cardiac function
    • Sexual function
    • Quality of life
  • One study sponsored by Amgen that involved >1,200 subjects on hemodialysis with documented heart disease. The study was discontinued when it appeared that those patients randomized to a target Hct of 42%+/-3% were experiencing a greater incidence (30%, with a confidence interval of 0.9 to 1.9) of non-fatal MI or death than the control group randomized to a target Hct of 30%+/-3%. The differences were not statistically significant at the time the study was terminated, however.

Guideline 4:  Target Hemoglobin/Hematocrit for Epoetin Therapy

  • Target range for hemoglobin (hematocrit) should be Hgb 11 g/dL (33%) to Hgb 12 g/dL (36%). (Evidence)
  • This target is for Epoetin therapy and is not an indication for blood transfusion therapy. (Opinion)
  • Survival of dialysis patients decreases below a range of 30% to 33% Hct. In one study, mortality decreased at higher Hct levels; in 200 patients who achieved and maintained a normal Hct for 6 months, mortality decreased to ~15%/year, vs. 40% per year in those who maintained an Hct of 30%.
  • Left ventricular hypertrophy (LVH) is more likely in CKD with anemia (Hct <33%); EPO treatment resulted in partial regression of LVH in dialysis-dependent patients.
  • Quality of life increases as the Hgb/Hct increase above 10 to 12 g/dL and 30% to >36%.
  • In hemodialysis patients, exercise capacity (VO2) increases when Hct increases from 30% to 35% to 40%.
  • In hemodialysis patients, the incidence of hospitalization was lower when the Hct was 33% to 36% in comparison to patients with lower Hct.
  • The only published investigation relating EPO therapy to increase CVD is from Okinawa, Japan.
    • The authors reported that the annual incidence of stroke and acute MI increased following the use of EPO in patients with CKD.
    • However, these findings differ from the recent European data, in which CVD morbidity and mortality were decreased by 15% to 20% after 2 years of EPO treatment in CKD patients.

Iron Support

Several important issues related to iron deficiency and its management in the CKD patient, particularly in patients receiving Epoetin therapy should be considered:

  • Iron (blood) losses are high, particularly in the hemodialysis patient.
  • Oral iron usually cannot maintain adequate iron stores, particularly in the hemodialysis patient treated with Epoetin.
  • Epoetin, by stimulating erythropoiesis to greater than normal levels, often leads to functional iron deficiency.
  • Prevention of functional (and absolute) iron deficiency by regular use of intravenous iron (i.e. small doses, weekly, to replace predicted blood losses) improves erythropoiesis.
  • The serum iron, total iron binding capacity, and serum feritin are the best indicators of iron available for erythropoiesis and iron stores, but they do not provide absolute criteria for either iron deficiency or iron overload.

Guideline 6:  Target Iron Level

  • CKD patients should have sufficient iron to achieve and maintain an Hgb/Hct of 11 to 12 g/dL (33% to 36%).  (Evidence)
  • To achieve and maintain this target Hgb/Hct, sufficient iron should be admisinstered to maintain a TSAT of greater than or equal to 20%, and a serum ferritin level of greater than or equal to 100 ng/mL.  (Evidence)
  • CKD patients are unlikely to respond with a further increase in Hgb/Hct and/or a further reduction in Epoetin dose required to maintain a given Hgb/Hct if the TSAT increases to greater than or equal to 50% and/or the serum ferritin level increases to greater than or equal to 800 ng/mL.  (Evidence)

Guideline 7:  Monitoring Iron Status

  • During the initiation of Epoetin therapy and while increaseing the Epoetin dose in order to achieve an increase in Hgb/Hct, the TSAT and the serum ferritin should be checked every month in patients not receiving itravenous iron, and at least once every 3 months in patients receiving intravenous iron, until target Hgb/Hct is reached.  (Opinion)
  • Following attainment of the target Hgb/Hct, TSAT and serum ferritin should be determined at least once every 3 months.  (Opinion)
  • Intravenous iron therapy, if given in amounts of 100 to 125 mg or less per week, does not need to be interrupted in order to obtain accurate measurements of iron parameters.  (Evidence)
  • In CKD patients not treated with Epoetin and whose TSAT is greater than or equal to 20% and serum ferritin is greater than or equal to 100 ng/mL, the iron status should be monitored every 3 to 6 months (Opinion).

Guideline 8:  Administration of Supplemental Iron

  • Supplemental iron should be administered to prevent iron deficiency and to maintain adequate iron stores so that CKD patients can achieve and maintain an Hgb 11 to 12 g/dL (Hct 33% to 36%) in conjunction with Epoetin therapy.  (Evidence)
  • If oral iron is given, it should be administered at a daily dose of at lest 200 mg of elemental iron for adults and 2 to 3 mg/kg for pediatric patients.  (Evidence)
  • The adult CKD patient may not be able to maintain adequate iron status with oral iron.  (Evidence).
  • Most patients will achieve an Hgb 11 to 12 g/dL (Hct of 33% to 36%) with TSAT and serum ferritin levels less than 50% and less than 800 ng/mL, respectively.  (Evidence)
  • Oral iron is not indicated for the CKD patient who requires maintenance doses of IV iron.  (Opinion)

Guideline 9:  Administration of a Test Dose of IV Iron

  • Prior to initiating IV iron dextran therapy, a one-time test dose of 25 mg (in adults) should be given IV.
  • For pediatric patients weighing less than 10 kg, the test dose should be 10 mg.
  • For pediatric patients weighing 10 to 20 kg, the test dose should be 15 mg.  (Opinion)
  • Acute adverse reactions may be seen with administration of IV iron dextran and IV iron gluconate.  In addition, delayed reactions may be seen with the use of IV iron dextran.  Severe acute reactions resembling anaphyylaxis with dyspnea, hypotension, chest pain, angioedema or uticaria are uncommon.  Anaphylaxis-like reactions occur in fewer than 1% of iron dextran or iron gluconate adminstration.

Guideline 10:  Oral Iron Therapy

  • When oral iron is used, it should be given as 200 mg of elemental iron per day, in 2 to 3 divided doses in the adult patient, and 2 to 3 mg/kg/day in the pediatric patient.  Oral iron is best absorbed when ingested without food or other medications.  (Evidence)
  • When food is eaten within 2 hours before or 1 hour after an oral iron supplement, the food will reduce iron absorption by as much as one half.
  • Ascorbic acid does not improve ferrous iron absorption.
  • Oral iron should be in the form of one of the ionic iron salts, such as iron sulfate, fumarate, or gluconate, because they are the cheapest and provide known amounts of elemental iron.

Guideline 11:  Route of Administration of Epoetin

  • Epoetin should be administered subcutaneously in CKD patients. (Opinion)

Guideline 12:  Initial Epoetin Administration

  • When Epoetin is given SC to adult patients, the dose should be 80 to 120 units/kg/wk (typically 6,000 units/wk) in 2 to 3 dose per week. (Evidence)
  • Pediatric patients less than 5 years old frequently require higher doses (300 units/kg/wk) than older pediatric patients and adults.  (Evidence)

Guideline 13:  Swithcing From Intravenous to Subcugtaneous Epoetin -skipped

Guideline 14:  Strategies for Initiating and Converting to Subcutaneous Epoetin Administration- skipped

Guideline 15:  Monitoring of Hemoglobin/Hematocrit During Epoetin Therapy

  • For purposes of monitoring response to Epoetin, Hgb/Hct should be measured every 1 to 2 weeks following initiation of treatment or following a dose increase or decrease, until a stable target Hgb/Hct and Epoetin dose have been achieved.  Once a stable target Hgb/Hct and Epoetin dose have been achieved, Hgb/Hct should be monitored every 2 to 4 weeks.  (opinion)

Guideline 16:  Titration of Epoetin Dosage- skipped

Guideline 17:  Inability to Tolerate Subcutaneous Epoetin; IV Epoetin Dose- skipped

Guideline 18:  Intraperitoneal Epoetin Administration-skipped

Guideline 19:  Epoetin Dosage Perioperatively or During Intercurrent Illness-skipped

Guideline 20:  Causes for Inadequate Response to Epoetin

  • The most common cause of an incomplete response to Epoetin is iron deficiency.
  • In the iron-replete patient with an inadequate response to Epoetin, the following conditions should be evaluated and treated, if reversible:  (Evidence)
    • Infection/inflammation
    • Chronic blood loss
    • Osteitis fibrosa
    • Aluminum toxicity
    • Hemoglobinopathies (e.g. alpha and beta thalasssemias, sickle cell anemia)
    • Folate or vitamin B12 deficiency
    • Multiple myeloma
    • Malnutrition
    • Hemolysis
  • Folic acid and vitamin B12 are essential for optimal Hgb synthesis.  While most of the available literature suggests that effective Epoetin therapy does not requre concomitant vitamin B12 and folate supplementation, the latter is water soluble and dialysate losses may exceed intake in poorly nourished patients.
  • Low serum albumin is associated with low Hgb among dialysis patients.  About one third of CKD patients have low albumin.  While malnutrition is common in this population, any acute or chronic inflammatory condition may result in a low serum albumin.  The effect of nutritional status on Epoetin responsiveness in ESRD patients has received little attention.  Theoretically, protein and/or calorie malnutirion may result in the unavailability of needed substrate for protein synthesis in hematopoietic cells.

Guideline 21:  When to Obtain a Hematology Consultation- skipped

Guideline 22:  Epoetin-Resistant Patients

  • Anemia in Epoetin-resistant patients should be treated in a manner similar to that in which dialysis patients were treated before recombinant human erythropoietin was available.  (Opinion)

Guideline 24:  Possible Adverse Effects Related to Epoetin Therapy:  Hypertension

  • Blood pressure should be monitored in all patients with CKD, particularly during initiation of Epoetin therapy. 
  • Initiation of anti-hypertensive therapy or an increase in anti-hypertensive medicaion, and reduction in Epoetin dose if there has been a rapid rise in Hgb/Hct, may be required to control an increase in blood pressure related to Epoetin therapy.  (Evidence)

Guideline 25:  Possible Adverse Effects Reslated toEpoetin Therapy:  Seizures- skipped

Guideline 26:  Possible Adverse Effects Related to Epoetin Therapy:  Increased Clotting Tendency- skipped- all related to dialysis patients

Guideline 27:  Possible Adverse Effects Related to Epoetin Therapy:  Hyperkalemia- skipped- all related to dialysis patients

 

 

 

 

Author Conclusion:
  • The primary cause of anemia in patients with CKD is insufficient production of erythropoietin by the diseased kidneys.
  • Recombinant human erythropoietin (rHuEPO) has been used in the treatment of anemia of CKD since 1986.  In the U.S., this is available from manufacturers as Epoetin alfa and Procrit.
  • The iron status of the patient with CKD must be assessed and adequate iron stores should be available before Epoetin therapy is initiated.
  • In most cases, intravenous iron will be required to achieve and/or maintain adequate iron stores.
  • Effective treatment of the anemia of CKD improves survival, decreases morbidity, and increases quality of life.
  • Some of the practices recommended in these guidelines are at avariance with current policy of the Health Care Financing Administration (HCFA) and with information contained in the package inserts for Epoetin and iron dextran.  In these instances, the Anemia Work Group believes there is sufficient published scientific data to justify its recommendations.
  • Based on the currently available data, the Anemia Work Group recommends that the Hgb/Hct be maintained between 11 and 12 g/dL (33% to 36%).
  • In striving to reach this target range, Hgb/Hct is likely to rise above this range. The reason why some patients will have increases above this range are unknown, however, it is probably the result of an interplay between IV iron supplementation and EPO therapy that can be unpredictable.
  • As of January, 2000, HCFA will continue to provide reimbursement for the cost of EPO even if Hgb/Hct temporarily increases above the target range, as long as the rolling 3-month average Hgb/Hct is <12.5 g/dL (37.5%). Medical justification is needed for maintaining the Hgb (Hct) above 12 g/dL (36%).
Funding Source:
Reviewer Comments:
Appears to be a very thorough review of the topic.
Quality Criteria Checklist: Review Articles
Relevance Questions
  1. Will the answer if true, have a direct bearing on the health of patients? Yes
  2. Is the outcome or topic something that patients/clients/population groups would care about? Yes
  3. Is the problem addressed in the review one that is relevant to dietetics practice? Yes
  4. Will the information, if true, require a change in practice? ???
 
Validity Questions
  1. Was the question for the review clearly focused and appropriate? Yes
  2. Was the search strategy used to locate relevant studies comprehensive? Were the databases searched and the search termsused described? Yes
  3. Were explicit methods used to select studies to include in the review? Were inclusion/exclusion criteria specified andappropriate? Wereselectionmethods unbiased? Yes
  4. Was there an appraisal of the quality and validity of studies included in the review? Were appraisal methodsspecified,appropriate, andreproducible? Yes
  5. Were specific treatments/interventions/exposures described? Were treatments similar enough to be combined? Yes
  6. Was the outcome of interest clearly indicated? Were other potential harms and benefits considered? Yes
  7. Were processes for data abstraction, synthesis, and analysis described? Were they applied consistently acrossstudies and groups? Was thereappropriate use of qualitative and/or quantitative synthesis? Was variation in findings among studies analyzed? Were heterogeneity issued considered? If data from studies were aggregated for meta-analysis, was the procedure described? No
  8. Are the results clearly presented in narrative and/or quantitative terms? If summary statistics are used, are levels ofsignificance and/or confidence intervals included? Yes
  9. Are conclusions supported by results with biases and limitations taken into consideration? Are limitations ofthe review identified anddiscussed? Yes
  10. Was bias due to the review's funding or sponsorship unlikely? Yes