Laboratory Tests

Decreased RBC count, Hgb, and Hct

Decreased serum iron level, TIBC, serum ferritin, and TSAT

Decreased erythropoietin levels relative to the degree of hypoxia that is present

® Generally, treatment for anemia of CKD requires a combination of ESA and iron supplementation. The goal of treatment is to maintain Hgb levels between 11 g/dL (110 g/L or 6.8 mmol/L) and 12 g/dL (120 g/L or 7.4 mmol/L)46 The goals for iron supplementation are:

• Serum ferritin levels

• 100 to 500 ng/mL (225-1,123.5 pmol/L) for patients not receiving hemodialysis

• 200 to 500 ng/mL (449.4-123.5 pmol/L) for patients receiving hemodialysis

• Transferrin saturation (TSAT): greater than 20% (0.2).42

The approach to the management of anemia of CKD with ESA and iron supplementation is illustrated in Figures 26-3 and 26-4.

Nonpharmacologic Therapy

Sufficient dietary iron intake must be maintained in patients with anemia of CKD. Approximately 1 to 2 mg of iron is absorbed daily from the diet. This small amount is generally not adequate to preserve adequate iron stores to promote RBC production. RBC transfusions have been used in the past as the primary means to maintain Hgb and Hct levels in patients with anemia of CKD. This treatment is still utilized today in patients with severe anemia or contraindications to ESAs, but is considered a third-line therapy for anemia of CKD.

Pharmacologic Therapy

The first-line treatment for anemia of CKD involves replacement of erythropoietin with ESAs. Erythropoietin-stimulating agents are synthetic formulations of EPO produced by recombinant human DNA technology. Use of ESAs increases the iron demand for RBC production and iron deficiency is common, requiring iron supplementation to correct and maintain adequate iron stores to promote RBC production. Androgens were used extensively before the availability of ESAs but are no longer recom-

mended for the treatment of anemia primarily because of toxicity, namely, hepato-toxicity.

Erythropoiesis-Stimulating Agents. Erythropoietin is a growth factor that acts on erythroblasts formed from stem cells in the bone marrow, stimulating proliferation and differentiation into normoblasts, then reticulocytes, which are released into the bloodstream to eventually mature into erythrocytes (mature RBCs). The ESAs currently available in the United States are:

• Epoetin alfa (distributed as Epogen by Amgen, Inc., Thousand Oaks, CA; and Pro-crit by Ortho Biotech, Johnson & Johnson, Raritan, NJ)

• Darbepoetin alfa (Aranesp by Amgen, Inc.)

Epoetin a and epoetin p, which is available outside the United States, have the same biological activity as endogenous EPO. Darbepoetin alfa differs from epoetin alfa by the addition of carbohydrate side chains that increase the half-life of darbepoetin alfa compared to epoetin alfa and endogenous EPO, allowing for less frequent dosing than that of epoetin alfa. All ESAs are equivalent in their efficacy and have a similar adverse-effect profile.

Hgb less Iran 11 g/üL\ Met less Ihan 33V

r_

Monitor Anemia Sta Lui

ConMcter And In« as ipproprtat*

• Iron deti^iency {see Figure ^6-1:

• Infection, ■fiNa.inrnatory diease

■ HypefpaiaHiyrcKHsm

* Mjmükjni l^fl-íily

* Wilamin B,r Qf1oiRle deficiency

* Myfrirrrnsiüii

' Blood lOSS

» Hemolysis

1 'J

4

Hflb grealer man i2 g'tiL: lld (Jrt^toi Ih.in idf i,'

Wo change repmèn. münilarHgh'Hd i-î limes per nionrn

Ifen erylhrüpMdn mcapyL6 reöwcs IbS (Jose fcy £5%

ir naive la erythropoietic therapy fcpüelm (SC or IV):

5Q-1W unilirtijga-3 finies nçkly

Uaifceptiehn alla (hVor StJ:

Û.-flS mcgfkg once weekly ir an erythropoietic therapy increase dosa by 25%

DSSÍH90 (wtecmos flee in Hgb ! after 2-4 weeks in» in Hctcl t-2 pants peí ^eekbut no rnDiieinan 4 2 weeks)

Hgb 11-12 ^dLHd 33-3^ Femt«n: Itû-SOO n^'TiL «or non-HD 200-500 n^'iïiL tor HD T5JI 2Q-5D=i

Monilor

* K^bUd 1-2 limes per waek umil stable. 1hen 1—Z t'dißs pftr irunilh

* Adjust Brylhrop&eflic doses no more than every

» tren int>;es inonlhlyfor 3<nomhs. (hennery

Figura 26-4

Is thene a poor response

in HgMHet?

Wl

No

1_ _!

Manillar as abova fc 1here a Junctional won aoricy IT&m loss ihO.il armai fernlln)?

Are 1hsre reasons for riwiílan» lo #ryllMj(Kiielie IhBrat^

Manillar as abova

incrBasa dose oi ifylhricipouîlic SStiM t>y

Heat undeflying causey)

'Use Hgbaí primaiy parameter to assess anemia. " Epwiin 3ifa <5í Oaitspoíiin ana.

FIGURE 26-3. Guidelines for erythropoietic therapy in the management of anemia of CKD. (Hgb, hemoglobin; SC, subcutaneous; TSat; transferrin saturation.) (Adapted from Hudson JQ. Chronic kidney disease: Management of complications. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008: 775, with permission.)

FIGURE 26-4. Guidelines for iron therapy in the management of anemia of CKD. (CKD, chronic kidney disease; HD, hemodialysis; Hgb, hemoglobin; PD, peritoneal dialysis; TSat, transferrin saturation.) (Adapted from Hudson, JQ. Chronic kidney disease: Management of complications. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008: 774, with permission.)

FIGURE 26-4. Guidelines for iron therapy in the management of anemia of CKD. (CKD, chronic kidney disease; HD, hemodialysis; Hgb, hemoglobin; PD, peritoneal dialysis; TSat, transferrin saturation.) (Adapted from Hudson, JQ. Chronic kidney disease: Management of complications. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008: 774, with permission.)

The most common adverse effect seen with ESA is increased blood pressure,

which can occur in up to 23% of patients. Antihypertensive agents may be required to control blood pressure in patients receiving ESAs. Caution should be used when initiating an ESA in patients with very high blood pressures (greater than 180/100 mm Hg). If blood pressures are refractory to antihypertensive agents, ESAs may need to be withheld.

Subcutaneous (SC) administration of ESA produces a more predictable and sustained response than IV administration, and is therefore the preferred route of administration for both agents. IV administration is often utilized in patients who have established IV access or are receiving hemodialysis. Starting doses of ESAs depend on the patient's Hgb level, the target Hgb level, the rate of Hgb increase, and clinical circumstances.4 The initial increase in Hgb should be 1 to 2 g/dL (10-12 g/L or 0.62-1.24 mmol/L) per month. The recommended starting dose of epoetin alfa is 50 to 100 units/kg/dose administered SC or IV 2 to 3 times weekly; the starting dose of darbepoetin alfa is 0.45 mcg/kg administered SC or IV once weekly (Table 26-3).

Two recent clinical trials evaluated the target level of Hgb in patients receiving

ESAs. Both studies indicated that targeting Hgb levels greater than 13 g/dL (130 g/L

or 8.07 mmol/L) resulted in more cardiovascular complications or death, compared to target Hgb levels less than 11 g/dL (110 g/L or 6.82 mmol/L). The effect of achiev-

47 48

ing the higher Hgb target on quality of life differed between the two studies. ' A secondary analysis of one study indicated that the inability to achieve the target Hgb level was associated with an increased risk of cardiovascular outcomes and death, regardless of the target Hgb level.49 Further studies are needed to evaluate the appropriate target level for Hgb. Nonetheless, based on the findings of these studies, the FDA recommended a black box warning be added to the product information for all ESAs indicating the maximum target Hgb should be between 10 and 12 g/dL (100 and 120 g/L or 6.21 and 7.45 mmol/L) for patients who are receiving ESAs.

Table 26-3 Estimated Starting Doses of Darbepoetin Alfa Based on Previous Epoetin Alfa Dose

Previous Epoetin Alfa Dose (units/week)

Weekly Darbepoetin A]fa Dose {meg/week}

Less Than 2,500

6.25

2,500-4,999

12.5

5,000-10,999

25

11000-17,999

40

18,000-33,999

60

34,000-59,^99

100

60,000-89,999

150

90,000 or more

200

Iron Supplementation. Use of ESAs can lead to iron deficiency if iron stores are not adequately maintained. If serum ferritin and TSAT fall below the goal levels, iron supplementation is required. Oral iron supplements are less costly than IV supplements and are generally the first-line treatment for iron supplementation for patients with

CKD not receiving hemodialysis. When administering iron by the oral route, 200 mg of elemental iron should be delivered daily to maintain adequate iron stores.

Oral iron supplementation is generally not effective in maintaining adequate iron stores in patients receiving ESAs because of poor absorption and an increased need for iron with ESA therapy, making the IV route necessary for iron supplementation. The IV iron products currently available are:

• Iron dextran (distributed as INFeD by Watson Pharmaceuticals, Inc., Morristown, NJ, and Dexferrum by American Reagent, Inc., Shirley, NY)

• Sodium ferric gluconate (Ferrlecit by Watson Pharmaceuticals, Inc., Corona, CA)

• Iron sucrose (Venofer by American Reagent, Inc., Shirley, NY)

Initiation of IV iron should be based on evaluation of iron stores. A serum ferritin level less than 100 ng/mL (225 pmol/L) in conjunction with a TSAT level less than

20% (0.2) indicates absolute iron deficiency and is a clear indication for the need for

iron replacement. Serum ferritin is an acute phase reactant, which may become elevated with inflammation and stress. Thus, when serum ferritin is normal or elevated in conjunction with TSAT levels less than 20%, treatment should be based on the clinical picture of the patient. Iron supplementation may be indicated if Hgb levels are below the goal level. One clinical trial evaluated the efficacy of IV iron supplementation in patients with high serum ferritin levels (500-1,200 ng/mL [1,123.5-2,696.4 pmol/L]) and low TSAT levels (less than 25% [0.25]). A significant increase in Hgb was noted in patients who received IV supplementation compared to those who did not. Furthermore, more patients achieved an increase in Hgb and the response rate was faster. The authors concluded that serum ferritin alone is not a good marker for iron deficiency.50

When replacing iron stores IV in patients receiving ESA therapy, the general approach to treatment is to give a total of 1 g of IV iron, administered in smaller, sequential doses. Table 26-4 lists the FDA-approved doses of the IV iron products. Because iron stores deplete quickly in patients who do not receive iron supplementation, maintenance doses are often used, particularly in patients receiving hemodialys-is. Maintenance doses consist of smaller doses of iron administered weekly or with each dialysis session (e.g., iron dextran or iron sucrose 20-100 mg/week; sodium ferric gluconate 62.5-125 mg/week).

IV iron preparations are equally effective in increasing iron stores. Iron dextran has been associated with side effects, including anaphylactic reactions and delayed reactions, such as arthralgias and myalgias. A test dose of 25 mg iron dextran should be administered 30 minutes before the full dose to monitor for potential anaphylactic reactions. However, patients should be monitored closely when receiving iron dex-tran, as anaphylactic reactions can occur in patients who safely received prior doses of iron dextran. For this reason, use of iron dextran has decreased dramatically in CKD patients in favor of the newer iron preparations, sodium ferric gluconate and iron sucrose, which are associated with fewer severe reactions. The most common side effects seen with these preparations include hypotension, flushing, nausea, and injection site reactions. A test dose is not required prior to the administration of either sodium ferric gluconate or iron sucrose. Long-term use of IV iron may increase oxidative stress, inflammation, and renal and cardiovascular injury.51

Outcome Evaluation

Evaluate Hgb every 1 to 2 weeks when ESA therapy is initiated or the dose is adjusted until Hgb is between 11 g/dL (110 g/L or 6.8 mmol/L) and 12 g/dL (120 g/L or 7.4 mmol/L). Once goal Hgb is attained, evaluate Hgb every 2 to 4 weeks thereafter. While the patient is receiving ESA therapy, monitor iron stores monthly in patients who are not receiving iron supplements or every 3 months in patients who are receiving iron supplements. When the goal Hgb is reached, monitor iron stores every 3 months.

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