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Summary of the KDIGO guideline on anemia and comment: reading between the (guide)line(s)

      The Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline for anemia in chronic kidney disease (CKD) is designed to assist health-care providers in treating CKD patients with anemia. A guideline is not intended to define a standard of care, and should not be construed as one, nor should it be interpreted as prescribing an exclusive course of management. It is intended to provide information and to allow the practitioner to make an informed decision, based on evidence and expert judgment. Every health-care professional making use of these recommendations is responsible for evaluating the appropriateness of applying them in any particular clinical situation. Owing to the general nature of a guideline, it is sometimes difficult to translate it to an individual patient's condition. As the primary goal is to improve patient care, we have decided to focus on practical clinical aspects of the KDIGO anemia guideline.

      Keywords

      The Kidney Disease Improving Global Outcomes (KDIGO) Clinical practice guideline (CPG) for anemia in chronic kidney disease (CKD) is based upon systematic literature searches last conducted in October 2010, supplemented with additional evidence through March 2012. It is designed to provide information and assist decision making. The potential benefits of CPGs are many. By providing clear recommendation based on current evidence, CPGs can improve the quality of clinical decisions. Evidence-based guidelines support interventions that are of proven benefit while documenting the quality of the supporting data. Further, interventions unsupported by good science have also been reviewed, and call attention to ineffective or even harmful practices. On the flip side, there is also the possibility that CPGs could have negative consequences. In the situation in which only a few studies are of high enough quality, many recommendations made by guideline committees are subjective and ‘opinion based’. Importantly, despite good-quality data, a recommendation may not be suitable for a particular patient.
      • Woolf S.H.
      • Grol R.
      • Hutchinson A.
      • et al.
      Clinical guidelines: potential benefits, limitations, and harms of clinical guidelines.
      Finally, applications of nonmedical values combined with intense pressures on health-care provision can create an environment for guideline misuse.
      • Berger J.T.
      • Rosner F.
      The ethics of practice guidelines.
      Although CPGs have been shown to improve the quality of care,
      • Grimshaw J.M.
      • Russell I.T.
      Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations.
      whether they achieve this in daily practice is less clear.
      • Woolf S.H.
      • Grol R.
      • Hutchinson A.
      • et al.
      Clinical guidelines: potential benefits, limitations, and harms of clinical guidelines.
      In an analysis of 59 CPG evaluations covering a wide range of clinical activities, all but four detected statistically significant improvements in the process of medical care. Moreover, all except 2 of the 11 that also measured the outcome of care reported significant improvements in outcome.
      • Grimshaw J.M.
      • Russell I.T.
      Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations.
      Guidelines that are likely to change medical practice have a few characteristics in common. First, they are likely to be developed internally by the very physicians who are going to use them. Second, appropriate development, dissemination, and implementation strategies are adopted during their introduction. Last, implementation strategies that are operative within the doctor–patient consultation are more likely to be effective.
      • Grimshaw J.M.
      • Russell I.T.
      Achieving health gain through clinical guidelines II: ensuring guidelines change medical practice.

      DEVELOPMENT OF THE KDIGO GUIDELINE FOR ANEMIA

      Guideline development takes time, in general at least 2–3 years. For the KDIGO Anemia Guideline, an international work group was created consisting of clinical experts in the field of interest and an ‘evidence review team’ who are experts in the field of guideline development (using techniques including systematic reviews and meta-analyses). The work group formulated recommendations related to a specific question or topic. Each set of recommendations was followed by a ‘rationale’ section, which summarizes the evidence and the reasoning for each recommendation and explains why specific wording was chosen.

      DO WE NEED A NEW ANEMIA GUIDELINE?

      The optimal management of CKD-related anemia has been a rapidly moving field in the past decade, with results being published of an increasing number of large randomized controlled trials of anemia correction using erythropoiesis-stimulating agents (ESAs). These reports progressively convinced the nephrology community that complete anemia correction in patients with CKD and diabetes might be more harmful than beneficial. ‘TREAT’, by far the largest, placebo-controlled anemia correction trial in CKD, was published in 2009.
      • Pfeffer M.A.
      • Burdmann E.A.
      • Chen C.Y.
      • et al.
      A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.
      It examined the effect of increasing hemoglobin (Hb) levels with an ESA (darbepoetin) to a target of 13g/dl, on cardiovascular and kidney outcomes in over 4000 CKD stage 3–4 patients with diabetes. It failed to demonstrate a benefit of full anemia correction, as compared with placebo with no ESA use unless Hb decreased to a level below 9g/dl. Moreover, it showed a substantial increase in risk of stroke, an increase in venous thromboembolic events, and a signal that normalization of Hb with darbepoetin may be harmful in patients with a history of malignancy.
      Therapeutic decisions of the physician are based on the continuous integration of new observations and the continuing need to balance the risks and benefits of treatment. Because of the outcomes of recent studies of anemia correction with ESAs or intravenous (i.v.) iron use, a new assessment of the state of the art of anemia correction in CKD and an update of recommendations for clinical practice were deemed necessary.
      Note that CPGs such as that of KDIGO are intended to provide guidance, not a strict set of rules. The overarching purpose of the recommendations is to assist in decision-making, not provide a ‘cook book’ for clinical management. This is because a guideline recommendation cannot account for all possible variations of patient, provider, and system factors. Thus, each health-care provider needs to assess the appropriateness of a particular recommendation or suggestion in a specific context. Using examples of CKD-associated anemia, we will attempt to show how the recommendations of the guideline can be applied to the needs of individual patients.

      CLINICAL EXAMPLES OF THE APPLICATION OF THE KDIGO GUIDELINE FOR ANEMIA

       Case 1

      A 68-year-old male patient with CKD and insulin-treated diabetes was referred in January 2012 for correction of severe anemia and symptoms that were considered to be linked to it. The patient had a history of ischemic heart disease, which required the placement of two stents. He also had a history of a transient cerebral ischemic attack and chronic obstructive pulmonary disease, probably at least partially related to long-standing smoking. Finally, the patient also had immunoglobulin G lambda monoclonal gammopathy of undetermined significance, diagnosed 3 years earlier. He was receiving three antihypertensive agents, a statin, and low-dose aspirin. His diabetes was well controlled.
      On examination, his body weight was 95kg, following a loss of 10kg during the preceding 6 months, body mass index was 31kg/m2, and BP was 135/88mmHg. Laboratory examination revealed a serum creatinine level of 230μmol/l (2.6mg/dl) and an estimated glomerular filtration rate of 25ml/min per 1.73m2. His Hb was 9.2g/dl, mean corpuscular volume 95μ3, reticulocyte count 30,000/mm3, white blood cell count 8500/mm3, platelet count 350,000/mm3, serum ferritin 110ng/ml, and serum transferrin saturation (TSAT) 21%.
      First question: what is the cause of the anemia and what is the best treatment? The nephrologist diagnosed possible folate deficiency, based on a relatively high mean corpuscular volume, in association with iron deficiency.
      Here is the corresponding KDIGO recommendation:

       Investigation of anemia

      Guideline 1.3: In patients with CKD and anemia (regardless of age and CKD stage), include the following tests in initial evaluation of the anemia (not graded):
      • Complete blood count, which should include Hb concentration, red cell indices, white blood cell count, and differential and platelet count
      • Absolute reticulocyte count
      • Serum ferritin level
      • TSAT
      • Serum vitamin B12 and folate levels
      It would have been preferable to measure the patient's serum folate level, but this recommendation is based on opinion and therefore has not been graded. The nephrologist opted for folate supplementation without measuring serum folate: 5mg/day for 2 weeks, and subsequently 5mg/week for another 6 weeks.
      Second question: should the patient receive iron supplementation?
      Here are the corresponding KDIGO recommendations.
      Guideline 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 risks of harm in individual patients (e.g., anaphylactoid and other acute reactions, unknown long-term risks) (not graded).
      Guideline 2.1.2: For adult CKD patients with anemia not on iron or ESA therapy, we suggest a trial of i.v. iron (or in CKD non-dialysis (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 ≤500ng/ml (≤500mg/l).
      The answer to the second question is yes. Serum ferritin was below 500ng/ml and TSAT below 30%. The patient had no history of iron intolerance.
      Third question: which is the optimal route of iron administration?
      Here is the corresponding KDIGO recommendation:
      Guideline 2.1.4: For CKD ND patients who require iron supplementation, select the route of iron administration on the basis of the severity of iron deficiency, availability of venous access, response to prior oral iron therapy, side effects with prior oral or i.v. iron therapy, patient compliance, and cost (not graded).
      The nephrologist decided to supplement the patient with both oral folate (see above) and i.v. iron. The iron was administered in a 8-week course: one initial i.v. dose of 500mg and a second dose of 500mg 4 weeks later. Two weeks after the second dose, Hb had increased from 9.2 to 9.6g/dl, serum ferritin to 350ng/ml, and TSAT to 35%, whereas mean corpuscular volume had decreased to 90μ3. The serum folate level was then 20ng/ml (normal, 3–16ng/ml). Serum C-reactive protein was 9mg/l, but there was no overt inflammatory disease.
      The degree of anemia correction was considered to be insufficient. At this point, the options were (i) to proceed to a second course of i.v. iron administration or (ii) to initiate treatment with an ESA.
      Here are the corresponding KDIGO recommendations:
      Guideline 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).
      Guideline 3.4.2: For adult CKD ND patients with Hb concentration <10.0g/dl (<100g/l), we suggest that the decision to initiate ESA therapy be individualized based on the rate of decrease 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).
      The nephrologist opted for ESA therapy. This decision was based on unsatisfactory response to i.v. iron despite a TSAT increase over 30%. However, a second i.v. iron course could have been administered, as serum ferritin was still below 500ng/ml and the patient had a history of transient cerebral ischemia and therefore should be considered at increased risk for stroke when receiving ESA therapy. The problem also was that the patient's veins were difficult to puncture.
      After 4 weeks of ESA therapy given subcutaneously, the Hb increased only from 9.6 to 9.7g/dl, with the serum ferritin level falling from 350 to 300ng/ml and the TSAT from 35 to 31%. Therefore, the diagnosis of ESA hyporesponsiveness was made and the ESA dose was not increased because of the history of stroke and ischemic heart disease.
      The possibility of adjuvant therapy was considered but abandoned.
      The corresponding KDIGO recommendation is the following:

       Adjuvant therapies

      Guideline 3.16.2: We suggest not using adjuvants to ESA treatment including vitamin C, vitamin D, vitamin E, folic acid, L-carnitine, and pentoxifylline (2D).
      The nephrologist then decided not to escalate ESA dosing but to explore various causes of ESA hyporesponsiveness.
      The corresponding KDIGO recommendations are the following:

       Initial ESA hyporesponsiveness

      Guideline 3.13.1: Classify patients as having ESA hyporesponsiveness if they have no increase in Hb concentration from baseline after the first month of ESA treatment on appropriate weight-based dosing (not graded).
      Guideline 3.13.2: In patients with ESA hyporesponsiveness, we suggest avoiding repeated escalations in ESA dose beyond double the initial weight-based dose (2D).

       Management of poor ESA responsiveness

      Guideline 3.15.1: Evaluate patients with either initial or acquired ESA hyporesponsiveness and treat for specific causes of poor ESA response (not graded).
      Many possible causes may lead to relative or absolute resistance to ESA therapy, as shown in the Table 1.
      Table 1Potentially correctable versus non-correctable factors involved in the anemia of CKD, in addition to erythropoietin deficiency
      (reproduced from KDIGO Guideline for Anemia, KI Suppl 2012)
      Easily correctablePotentially correctableImpossible to correct
      Absolute iron deficiencyInfection/inflammationHemoglobinopathies
      Vitamin B12/folate deficiencyUnderdialysisBone marrow disorders
      HypothyroidismHemolysis
      ACEiBleeding
      Non-adherenceHyperparathyroidism
      PRCA
      Malignancy
      Malnutrition
      Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; CKD, chronic kidney disease; PRCA, pure red cell aplasia.
      The search for the underlying cause of ESA hyporesponsiveness stimulated various examinations, including a bone marrow biopsy. It led to the diagnosis of myelodysplastic syndrome, subtype ‘refractory cytopenia with unilineage dysplasia’. The myelodysplastic syndrome is a heterogeneous group of closely related clonal hematopoietic disorders. Patients with monoclonal gammopathy of undetermined significance, as was the case here, have an eightfold higher risk to develop acute myeloid leukemia or myelodysplastic syndrome as compared with the general population.
      • Mailankody S.
      • Pfeiffer R.M.
      • Kristinsson S.Y.
      • et al.
      Risk of acute myeloid leukemia and myelodysplastic syndromes after multiple myeloma and its precursor disease (MGUS).
      Because of the patient's resistance to usually recommended ESA dose, a treatment attempt with ‘hematologic’ ESA doses should be discussed. Indeed, studies in myelodysplastic syndrome have shown that ESA may decrease the need for transfusion and increase survival. This treatment involves the administration of 30,000–60,000IU of epoetin-alfa or epoetin-beta, or 150–300μg of darbepoetin-alfa per week (i.e., 3 to 6 times the weight-based dose for a 95-kg-body-weight person). It requires weekly hematological testing for 12 weeks and treatment reevaluation every 4 weeks. Because of the high vascular risk profile of the patient, the ESA dose was only cautiously increased to three times the weight-based dose. The patient's short-term response was an increase in Hb to 10.2g/dl.
      This approach was not in contradiction to the following KDIGO recommendation:
      Guideline 3.15.2: For patients who remain hyporesponsive despite correcting treatable causes, we suggest individualization of therapy, accounting for relative risks and benefits of (2D):
      • decline in Hb concentration
      • continuing ESA, if needed to maintain Hb concentration, with due consideration of the doses required, and
      • blood transfusions
      However, the very high ESA dose would go against the spirit of the following KDIGO recommendation:
      Guideline 3.13.2: In patients with ESA hyporesponsiveness, we suggest avoiding repeated escalations in ESA dose beyond double the initial weight-based dose (2D).
      The nephrologist chose to give a cautious trial of hematologic ESA doses with modest effect on the Hb. Subsequently, one should probably reduce the ESA dose to about two times the weight-based dose in this high-risk patient if one was to adhere to the opinion of the KDIGO Work Group. Note, however, that in hyporesponsive patients there is no randomized data on the optimal doses of ESA.

       Case 2

      A 50-year-old female patient with CKD due to reflux nephropathy was referred in March 2009 because of progressive worsening of anemia and asthenia. She was clinically stable. She had no symptoms of urinary or other infection. Her medical history was unremarkable.
      On examination, her body weight was 65kg, her body mass index was 26kg/m2, and her BP was 125/80mmHg. Laboratory examination revealed a serum creatinine level of 210μmol/l (2.4mg/dl) and an estimated glomerular filtration rate of 25ml/min × 1.73m2. Her Hb was 9.7g/dl, mean corpuscular volume 88μ3, reticulocyte count 45,000/mm3, white blood cell count 7200/mm3, platelet count 240,000/mm3, serum ferritin 41ng/ml, and TSAT 20%. Serum folate and vitamin B12 levels were normal.
      The nephrologist concluded that iron deficiency was the most probable diagnosis of the anemia in association with CKD stage 4. Should any additional investigations be undertaken?
      Here is the corresponding KDIGO recommendation:

       Investigation of anemia

      Guideline 1.3: In patients with CKD and anemia (regardless of age and CKD stage), include the following tests in initial evaluation of the anemia (not graded):
      • Complete blood count, which should include Hb concentration, red cell indices, white blood cell count, and differential and platelet count
      • Absolute reticulocyte count
      • Serum ferritin level
      • TSAT
      • Serum vitamin B12 and folate levels
      Although all the recommended investigations have been carried out, consideration should be given to the investigation of gastrointestinal bleeding.
      The patient was given a course of i.v. iron, 200mg per week for 3 weeks. The treatment was well tolerated. The Hb rose from 9.7 to 11.3g/dl, the serum ferritin to 306ng/ml, and the TSAT to 32% 2 months later. However, after a further 2 months, the Hb was again down to 9.6g/dl, the ferritin to 238ng/ml, and the TSAT to 25%. Another course of i.v. iron could be contemplated, but the nephrologist decided to initiate ESA therapy. Would this fit the present KDIGO guideline? As the i.v. iron was well tolerated and as there was no particular venous access problem, additional courses of i.v. iron would be the preferred treatment modality at present.
      Here are again the corresponding KDIGO recommendations:
      Guideline 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 risks of harm in individual patients (e.g., anaphylactoid and other acute reactions, unknown long-term risks) (not graded).
      Guideline 2.1.2: For adult CKD patients with anemia not on iron or ESA therapy, we suggest a trial of i.v. 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 ≤500ng/ml (≤500mg/l).
      Would the decision to initiate ESA therapy be incompatible with the present KDIGO recommendations? The answer is no. The patient had no history of malignancy or ongoing, active malignancy and no history of stroke. She suffered from fatigue. She did not wish to have repeated courses of i.v. iron therapy.
      Here are again the corresponding KDIGO recommendations:
      Guideline 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).
      Guideline 3.4.2: For adult CKD ND patients with Hb concentration <10.0g/dl (<100g/l), we suggest that the decision 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).
      ESA treatment consisted of the administration of darbepoetin alfa, 60μgQ2W subcutaneously. Oral ferrous fumarate, 325mg once daily, was prescribed as well. Two months later, the Hb rose to 12.4g/dl, although the ferritin decreased to 169 and the TSAT to 22%. The patient confessed that she had interrupted the oral iron treatment because of gastrointestinal intolerance. She refused new courses of i.v. iron.
      Three months later, she was admitted to the hospital because of fever due to acute left-sided pyelonephritis. She had cloudy urine, with urine culture growing Escherichia coli. Antibiotic treatment with i.v. cephalosporin and gentamicin was started.
      Laboratory examination showed a white blood cell count of 14,500/mm3 and a serum C-reactive protein of 146mg/l. The Hb was 7.8g/dl, serum ferritin was 530ng/ml, and TSAT was 18% despite ongoing ESA therapy. The patient was transfused with 2 units of blood because she felt extremely weak. Would the transfusion be indicated according to the present recommendations?
      Here are the corresponding KDIGO recommendations:

       Use of red cell transfusion in chronic anemia

      Guideline 4.1.1: When managing chronic anemia, we recommend avoiding, when possible, red cell transfusions to minimize the general risks related to their use (1B).
      Guideline 4.1.2: In patients eligible for organ transplantation, we specifically recommend avoiding, when possible, red cell transfusions to minimize the risk of allosensitization (1C).
      Guideline 4.2.1: When managing chronic anemia, we suggest that the benefits of red cell transfusions may outweigh the risks in patients in whom (2C):
      • ESA therapy is ineffective (e.g., hemoglobinopathies, bone marrow failure, ESA resistance)
      • The risks of ESA therapy may outweigh its benefits (e.g., previous or current malignancy, previous stroke)
      Guideline 4.2.2: We suggest that the decision to transfuse a CKD patient with nonacute anemia should not be based on any arbitrary Hb threshold, but should be determined by the occurrence of symptoms caused by anemia (2C).
      Thus, the answer to the question whether blood transfusion would be indicated according to the present recommendations is questionable. Under the condition of acute infections, ESA responsiveness is decreased and may be even entirely lost. In such cases, increasing ESA dose generally does not improve the anemia, and blood transfusion may become necessary. Consequently, one needs to balance the benefit of transfusion in treating the weakness and the risks of allosensitization, particularly as this young woman may need a renal transplant in the future.
      After recovery from acute pyelonephritis, the Hb stayed stable between 11.3 and 12.1g/dl with darbepoetin alfa, 60μgQ2W. Eight months later, a Hb level of 13.7g/dl was reported by the laboratory. The question arose whether the ESA dose should be reduced or even temporarily interrupted. The nephrologist decided to check for this unexpected Hb value first by recalling the patient and having an immediate repeat determination. The Hb value that was obtained the second time was 11.7g/dl. Thus, the high level of 13.7g/dl turned out to be a laboratory error. The request of a second Hb determination would be in line with present recommendations, in particular to take into account clinical circumstances, as there was no reasonable explanation for the observed sudden increase in Hb concentration.
      Here are the corresponding KDIGO recommendations:

       ESA dosing

      Guideline 3.8.2: We recommend that ESA dose adjustments be made based on the patient's Hb concentration, rate of change in Hb concentration, current ESA dose, and clinical circumstances (1B).
      Guideline 3.8.3: We suggest decreasing the ESA dose in preference to withholding ESA when a downward adjustment of Hb concentration is needed (2C).

      CONCLUSION

      We hope that the presentation of these two cases shows the usefulness of the KDIGO CPG for anemia in CKD, in assisting practitioners to manage the anemia of their patients in the most appropriate way. We would like to stress again that KDIGO recommendations are meant to guide the clinician, not to prescribe an exclusive treatment schedule.

      ACKNOWLEDGMENTS

      We acknowledge having received the permission to present Case 1 by Vincent Esnault, Professor of Medicine, Service de Néphrologie, and Thomas Cluzeau, Service d’Hématologie, both at Hôpital Pasteur, Nice Medical School, Nice, France; and Case 2 by Iain Macdougall, Professor of Clinical Nephrology, King's College Hospital, London, UK.

      APPENDIX. Summary of Recommendation Statements

       Chapter 1: Diagnosis and evaluation of anemia in CKD

       TESTING FOR ANEMIA

       Frequency of testing for anemia

      • 1.1.1:
        For CKD patients without anemia (as defined below 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.]

       Diagnosis of anemia

      • 1.2.1:
        Diagnose anemia in adults and children >15 years with CKD when the Hb concentration is <13.0g/dl (<130g/l) in males and <12.0g/dl (<120g/l) in females. (Not Graded)
      • 1.2.2:
        Diagnose anemia in children with CKD if Hb concentration is <11.0g/dl (<110g/l) in children 0.5–5 years, <11.5g/dl (115g/l) in children 5–12 years, and <12.0g/dl (120g/l) in children 12–15 years. (Not Graded)

       Investigation of anemia

      • 1.3:
        In patients with CKD and 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

       Chapter 2: Use of iron to treat anemia in CKD

       TREATMENT WITH IRON AGENTS

      • 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 risks 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 (Based on patient symptoms and overall clinical goals, including avoidance of transfusion, improvement in anemia-related symptoms, and after exclusion of active infection.) and
        • • TSAT is =30% and ferritin is =500ng/ml (=500mg/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 (Consistent with Recommendations #3.4.2 and 3.4.3.) or a decrease in ESA dose is desired (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.) and
        • • TSAT is =30% and ferritin is =500ng/ml (=500mg/l)
      • 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 tests (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)
      • 2.1.6:
        For all pediatric CKD patients with anemia not on iron or ESA therapy, we recommend oral iron (or IV iron in CKD HD patients) administration when TSAT is =20% and ferritin is =100ng/ml (=100µg/l). (1D)
      • 2.1.7:
        For all pediatric CKD patients on ESA therapy who are not receiving iron supplementation, we recommend oral iron (or IV iron in CKD HD patients) administration to maintain TSAT >20% and ferritin >100ng/ml (>100µg/l). (1D)

       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 nondextran iron is administered, we suggest (2C) that patients be monitored for 60minutes after the infusion, and that resuscitative facilities (including medications) and personnel trained to evaluate and treat serious adverse reactions be available.

       Iron during infection

      • 2.4:
        Avoid administering IV iron to patients with active systemic infections. (Not Graded)

       Chapter 3: Use of ESAs and other agents to treat anemia in CKD

       ESA INITIATION

      • 3.1:
        Address all correctable causes of anemia (including iron deficiency and inflammatory states) prior to initiation of ESA therapy. (Not Graded)
      • 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 =10.0g/dl (=100g/l), we suggest that ESA therapy not be initiated. (2D)
      • 3.4.2:
        For adult CKD ND patients with Hb concentration <10.0g/dl (<100g/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 9.0g/dl (90g/l) by starting ESA therapy when the hemoglobin is between 9.0–10.0g/dl (90–100g/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 10.0g/dl (100g/l). (Not Graded)
      • 3.4.5:
        For all pediatric CKD patients, we suggest that the selection of Hb concentration at which ESA therapy is initiated in the individual patient includes consideration of potential benefits (e.g., improvement in quality of life, school attendance/performance, and avoidance of transfusion) and potential harms. (2D)

       ESA MAINTENANCE THERAPY

      • 3.5.1:
        In general, we suggest that ESAs not be used to maintain Hb concentration above 11.5g/dl (115g/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 11.5g/dl (115g/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 13g/dl (130g/l). (1A)
      • 3.7:
        In all pediatric CKD patients receiving ESA therapy, we suggest that the selected Hb concentration be in the range of 11.0 to 12.0g/dl (110 to 120g/l). (2D)

       ESA DOSING

      • 3.8.1:
        We recommend determining the initial ESA dose using the patient's Hb concentration, body weight, and clinical circumstances. (1D)
      • 3.8.2:
        We recommend that ESA dose adjustments be made based on the patient's Hb concentration, rate of change in Hb concentration, current ESA dose and clinical circumstances. (1B)
      • 3.8.3:
        We suggest decreasing ESA dose in preference to withholding ESA when a downward adjustment of Hb concentration is needed. (2C)
      • 3.8.4:
        Re-evaluate ESA dose if (Not Graded):
        • • The patient suffers an ESA-related adverse event
        • • The patient has an acute or progressive illness that may cause ESA hyporesponsiveness (See Recommendations 3.13.1–3.13.2)

       ESA ADMINISTRATION

      • 3.9.1:
        For CKD 5HD patients and those on hemofiltration or hemodiafiltration therapy, we suggest either intravenous or subcutaneous administration of ESA. (2C)
      • 3.9.2:
        For CKD ND and CKD 5PD patients, we suggest subcutaneous administration of ESA. (2C)

       Frequency of administration

      • 3.10:
        We suggest determining the frequency of ESA administration based on CKD stage, treatment setting, efficacy considerations, patient tolerance and preference, and type of ESA. (2C)

       TYPE OF ESA

      • 3.11.1:
        We recommend choosing an ESA based on the balance of pharmacodynamics, safety information, clinical outcome data, costs, and availability. (1D)
      • 3.11.2:
        We suggest using only ESAs that have been approved by an independent regulatory agency. Specifically for ‘copy’ versions of ESAs, true biosimilar products should be used. (2D)

       EVALUATING AND CORRECTING PERSISTENT FAILURE TO REACH OR MAINTAIN INTENDED HEMOGLOBIN CONCENTRATION

       Frequency of monitoring

      • 3.12.1:
        During the initiation phase of ESA therapy, measure Hb concentration at least monthly. (Not Graded)
      • 3.12.2:
        For CKD ND patients, during the maintenance phase of ESA therapy measure Hb concentration at least every 3 months. (Not Graded)
      • 3.12.3:
        For CKD 5D patients, during the maintenance phase of ESA therapy measure Hb concentration at least monthly. (Not Graded)

       Initial ESA hyporesponsiveness

      • 3.13.1:
        Classify patients as having ESA hyporesponsiveness if they have no increase in Hb concentration from baseline after the first month of ESA treatment on appropriate weight-based dosing. (Not Graded)
      • 3.13.2:
        In patients with ESA hyporesponsiveness, we suggest avoiding repeated escalations in ESA dose beyond double the initial weight-based dose. (2D)

       Subsequent ESA hyporesponsiveness

      • 3.14.1:
        Classify patients as having acquired ESA hyporesponsiveness if after treatment with stable doses of ESA, they require 2 increases in ESA doses up to 50% beyond the dose at which they had been stable in an effort to maintain a stable Hb concentration. (Not Graded)
      • 3.14.2:
        In patients with acquired ESA hyporesponsiveness, we suggest avoiding repeated escalations in ESA dose beyond double the dose at which they had been stable. (2D)

       Management of poor ESA responsiveness

      • 3.15.1:
        Evaluate patients with either initial or acquired ESA hyporesponsiveness and treat for specific causes of poor ESA response. (Not Graded)
      • 3.15.2:
        For patients who remain hyporesponsive despite correcting treatable causes, we suggest individualization of therapy, accounting for relative risks and benefits of (2D):
        • • decline in Hb concentration
        • • continuing ESA, if needed to maintain Hb concentration, with due consideration of the doses required, and
        • • blood transfusions

       ADJUVANT THERAPIES

      • 3.16.1:
        We recommend not using androgens as an adjuvant to ESA treatment. (1B)
      • 3.16.2:
        We suggest not using adjuvants to ESA treatment including vitamin C, vitamin D, vitamin E, folic acid, L-carnitine, and pentoxifylline. (2D)

       EVALUATION FOR PURE RED CELL APLASIA (PRCA)

      • 3.17.1:
        Investigate for possible antibody-mediated PRCA when a patient receiving ESA therapy for more than 8 weeks develops the following (Not Graded):
        • • Sudden rapid decrease in Hb concentration at the rate of 0.5 to 1.0g/dl (5 to 10g/l) per week OR requirement of transfusions at the rate of approximately 1 to 2 per week, AND
        • • Normal platelet and white cell counts, AND
        • • Absolute reticulocyte count less than 10,000/ml
      • 3.17.2:
        We recommend that ESA therapy be stopped in patients who develop antibody-mediated PRCA. (1A)
      • 3.17.3:
        We recommend peginesatide be used to treat patients with antibody-mediated PRCA. (1B)

       Chapter 4: Red cell transfusion to treat anemia in CKD

       USE OF RED CELL TRANSFUSION IN CHRONIC ANEMIA

      • 4.1.1:
        When managing chronic anemia, we recommend avoiding, when possible, red cell transfusions to minimize the general risks related to their use. (1B)
      • 4.1.2:
        In patients eligible for organ transplantation, we specifically recommend avoiding, when possible, red cell transfusions to minimize the risk of allosensitization. (1C)
      • 4.1.3:
        When managing chronic anemia, we suggest that the benefits of red cell transfusions may outweigh the risks in patients in whom (2C):
        • • ESA therapy is ineffective (e.g., hemoglobinopathies, bone marrow failure, ESA resistance)
        • • The risks of ESA therapy may outweigh its benefits (e.g., previous or current malignancy, previous stroke)
      • 4.1.4:
        We suggest that the decision to transfuse a CKD patient with non-acute anemia should not be based on any arbitrary Hb threshold, but should be determined by the occurrence of symptoms caused by anemia. (2C)

       URGENT TREATMENT OF ANEMIA

      • 4.2:
        In certain acute clinical situations, we suggest patients are transfused when the benefits of red cell transfusions outweigh the risks; these include (2C):
        • • When rapid correction of anemia is required to stabilize the patient's condition (e.g., acute hemorrhage, unstable coronary artery disease)
        • • When rapid preoperative Hb correction is required

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