( 수 ) 신장내과 전임의 한선애 TREATING ANEMIA IN CKD

Association of kidney function with anemia

 Reduced oxygen delivery to tissues  ↓in Hb compensated by increased cardiac output  Progressive cardiac damage & progressive renal damage  Reduced quality of life  Fatigue  Diminished exercise capacity  Reduced cognitive function  Left ventricular hypertrophy  Increased mortality risk Consequences of anemia in CKD

 Erythropoietin deficiency  Deficiency states (iron, vitamins, malnutrition)  Blood loss (GI, menstruation, samplings)  Chronic inflammatory state  Inhibition of erythropoiesis: uremic toxins (?)  Shortening of RBC survival (hemolysis)  Hyperparathyroidism/marrow fibrosis  Aluminum overload  Inadequate dialysis treatment Causes of anemia in CKD

 World Health Organization (WHO)  Hb < 13.0g/dL for adult males and postmenopausal women  Hb < 12.0g/dL for premenopausal women  KDIGO 2012  Diagnose anemia in adults and children > 15years with CKD when the Hb concentration is < 13.0g/dL in males and < 12.0g/dL in females When to initiate the work-up

 Assess hemoglobin level  If anemia  CBC including Hb, MCH, MCV, MCHC, WBC count & differential, Platelet  Absolute reticulocyte count  Iron studies for serum ferritin (iron stores), TSAT or content of Hb in reticulocytes  Test for occult GI bleeding as indicated  Medical evaluation of comorbid conditions  Work-up should be performed before EPO treatment Initial work up of anemia

CKD patients without anemia CKD 3At least annually CKD 4-5 NDAt least twice per year CKD 5 HD CKD 5 PD At least every 3 months CKD patients with anemia not being treated with ESA CKD 3-5 ND CKD 5 PD At least every 3 months CKD 5 HDAt least monthly Frequency of testing for anemia

 Iron status and initial evaluation  ESA (Erythropoietin-stimulating agents) therapy Anemia management in CKD

 Iron deficiency is common among CKD  Increased loss of iron  Bleeding diathesis (such as through platelet dysfunction or aspirin use)  GI loss  Repeated blood sampling  Inadequate dietary iron intake or absorption  Use of phosphate binders CKD in Iron deficiency

 Absolute iron deficiency  TSAT < 20%  Serum ferritin < 100ng/mL (predialysis and PD), < 200ng/mL (HD)  Functional iron deficiency  Iron stores are adequate, but cannot be mobilized from macrophages of RES and not enough iron is delivered to the marrow  TSAT < 25%  Serum ferritin > 100ng/mL  Increasing dose of ESA is not as effective (serum ferritin level may decrease) Absolute & Functional iron deficiency

Anaphylactoid and other acute complications Unknown long-term risks Avoid blood transfusions, ESA therapy Anemia Sx. Considerations of prescribing iron therapy

Guidelines KDIGOFerritin ≤ 500 ng/mL TSAT ≤ 30% European Renal Best Practice ESA-naïve ESA-therapy CKD-ND: Ferritin < 200ng/mL, TSAT < 25% CKD-5D: Ferritin < 300ng/mL, TSAT < 25% Ferritin < 300ng/mL, TSAT < 35% Canadian Society of Nephrology CKD-ND, CKD-PD CKD-5D Ferritin < 100ng/mL, TSAT < 20% Ferritin < 200ng/mL, TSAT < 20% KDOQITSAT < 30% Even if ferritin > 500ng/mL Guideline for starting iron therapy

 Oral Iron  Safe, Ease to administration  Gastric intolerance & poor compliance  Iron absorption  Limited from GI tract  Too slow for rapid correction of severe anemia  Interactions with other oral medications  IV iron  Effective  More cost, less convenient administration  Acute allergic reactions  Complications caused by the generation of powerful oxidant species, initiation and propagation of lipid peroxidation Oral vs. IV iron therapy

Iron saltDosage/FormElemental Iron Ferrous fumarateTime-released tablet50mg Ferrous gluconate225mg tablet 324mg tablet Ferrous sulfate325mg tablet 220mg/5mL elixir 325mg/5mL elixir 125mg/mL drops 65mg 44mg/5mL 65mg/5mL 25mg/mL Iron carbonyl50mg tablet50mg Oral Iron supplements

IV iron supplements PreparationDose in HD patientsDose in patients not on HD Iron dextran (Dexeferrum, INFeD) 100mg IV q dialysis * 10 doses100mg IV daily * 10 doses mg slow IV infusion Iron sucrose (Venofer) 100mg IV q dialysis * 10 doses 200mg IV q dialysis * 5 doses 250mg * 5 doses in 14 days 500mg slow IV infusion day 1 and day mg, 300mg, 400mg IV infusion each 14 days apart Sodium ferric gluconate (Ferrlecit) 125mg IV q dialysis * 8 doses250mg slow IV infusion Ferumoxytol (Feraheme) 510mg IV * 2 doses 1-4 weeks apart510mg IV * 2 doses apart

 Should be monitored for 60 minutes after the infusion  Resuscitative facilities (including medications) and personnel trained to evaluate and treat serious adverse reactions be avaliable  Avoid administering IV iron to patients with active systemic infections Cautions for IV iron preparations

 Guide subsequent iron administration in CKD patients based on  Hb responses to recent iron therapy  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 Treatment with iron agents

Considerations of prescribing ESA therapy Stroke Vascular access loss Hypertension Avoid blood transfusions Anemia Sx.

 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) ESA therapy : notes of caution

 3.4.1: For adult CKD ND patients with Hb ≥ 10.0g/dL, we suggest that ESA therapy not be initiated (2D)  3.4.2: For adult CKD ND patients with Hb < 10.0g/dL, we suggest that the decision whether to initiate ESA therapy be individualized based on the rate of fall of Hb, 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 initiation

 3.4.3: For adult CKD 5D patients, we suggest that ESA therapy be used to avoid having the Hb fall below 9.0g/dL by starting ESA therapy when the Hb is between g/dL (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 ESA initiation

 3.5.1: In general, we suggest that ESAs not be used to maintain Hb concentration above 11.5g/dL 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 and will be prepared to accept the risks.  3.6: In all adult patients, we recommend that ESAs not be used to intentionally increase the Hb concentration above 13g/dL ESA maintenance therapy

 3.8.1: We recommend determining the initial ESA dose using the patient’s Hb concentration, body weight, and clinical circumstances  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 ESA dosing: Initial consideration

 Short acting  Epoetin-α or –β: 20~50 IU/kg/Bwt tiw  Medium acting  Darbepoetin-α: 0.45ug/kg/Bwt q 1week, SC or IV (0.75ug/kg/Bwt q 2week, SC)  Long acting  CERA: 0.6ug/kg/Bwt q 2weeks SC or IV (1.2ug/kg/Bwt q 4weeks SC) ESA dosing: clinical practice

 Body weight : 60kg  Epoetin-α or –β: 20~50 IU/kg  = 1200~3000IU ≒ 2000 IU, tiw  Darbepoetin-α: 0.45ug/kg = 27ug q 1week, SC or IV 0.75ug/kg = 45ug q 2week, SC  CERA: 0.6ug/kg/Bwt q 2weeks SC or IV (1.2ug/kg/Bwt q 4weeks SC) ESA dosing: calculations

 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  The patient suffers an ESA-related adverse event  The patient has an acute or progressive illness that may cause ESA hyporesponsiveness ESA dosing: Adjustment

 3.9.1: For CKD 5HD patients and those on hemofiltration or hemodiafitration therapy, we suggest either IV or SC administration of ESA  3.9.2: For CKD ND and CKD 5PD patients, we suggest SC administration of ESA  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. ESA administration

 : During the initiation phase of ESA therapy measure Hb concentration at least monthly  : For CKD ND patients, during the maintenance phase of ESA therapy measure Hb concentration at least every 3 months.  For CKD 5D patients, during the maintenance phase of ESA therapy measure Hb concentration at least monthly Frequency of monitoring

 : Classify as having ESA hyporesponsiveness if they have no increase in Hb from baseline after the 1 st month of ESA treatment on appropriate weight-based dosing  : Classify as having loss of ESA response if after treatment with stable dose of ESA, they require 2X increase in ESA doses up to 50% beyond the dose at which they had been stable in an effort to maintain a stable Hb   Avoid repeated escalations in ESA dose beyond double the dose Initial/Subsequent ESA hyporesponsiveness

Easily correctablePotentially correctableImpossible to correct Absolute iron deficiency Vitamin B12/folate deficiency Hypothyroidism ACEi/ARB Non-adherence Infection/inflammation Underdialysis Hemolysis Bleeding Hyperparathyroidism PRCA Malignancy Malnutrition Hemoglobinopathies Bone marrow disorders Factors involved in the anemia of CKD & ESA deficiency

 : We recommend not using androgens as an adjuvant to ESA treatment  : We suggest not using adjuvants to ESA treatment including vitamin C, vitamin D, vitamin E, folic acid, L-carnitine, and pentoxyfylline Adjuvant therapy

 Rare serious adverse events  Antibody-mediated PRCA when a patient receiving ESA therapy for more than 8 weeks  Sudden rapid decrease in Hb concentration at the rate of 0.5 to 1.0g/dL per week or requirement of transfusions at the rate of approximately 1 to 2 per week  Normal platelet and white cell counts  Absolute reticulocyte count less than 10,000/mL  Bone marrow biopsy (absent/sparse erythroblast)  ESA therapy b estopped in patients who develop antibody- mediated PRCA  Immunosuppressant (CsA, Cylophophamide), Hematide Pure Red Cell Aplasia (PRCA)

 ESA therapy is ineffective  Ex: hemoglobinopathies, bone marrow failure, ESA resistance  The risks of ESA therapy may outweigh its benefits  Ex: previous or current malignancy, previous stroke  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 Red cell transfusion

 Diagnose anemia in adults with CKD when the Hb < 13.0g/dl in males and <12.0g/dL in females  Iron therapy may be considered in CKD patients with anemia when TSAT is <30% and ferritin is < 500ng/mL.  CKD ND patients with Hb < 10.0g/dL, adult CKD 5D patietns with Hb g/dL, ESA therapy should be used  Higher Hb obtained with higher ESAs may lead to increased risk of adverse events  Hb values of 11-12g/dL should be generally sought in the CKD without intentionally exceeding 13g/dL Take home messages