1

ANEMIA IN CKD- HOW TO MANAGE IT

7/7/2015

2

TOPICS BEING DISCUSSED

Anemia in CKD

Causes for Anemia in CKD

Reasons for Anemia correction

Therapeutic options for correction in anemia of CKD

7/7/2015

3

ANEMIA IN CKD

• Anemia - WHO recommendations- Hb concentration <13.0 g/dL for adult males and postmenopausal women and an Hb <12.0 g/dL for premenopausal women

• The anemia of chronic kidney disease (CKD)normocytic and normochromic

7/7/2015

4

Causes for Anemia in CKD

• Failure of Erythropoietin (EPO) production by diseased kidney

• Reduction in red cell survival

7/7/2015

57/7/2015

6

Reasons for Anemia Correction

• Deterioration in cardiac function• Decreased cognition and mental acuity• Fatigue• Increased risk of morbidity and mortality

7/7/2015

7

THERAPEUTIC OPTIONS FOR CORRECTION IN ANEMIA OF CKD

RED BLOOD CELL TRANSFUSIONS

ERYTHROPOIETIN-STIMULATING AGENTS (ESAS)

ANDROGENS

7/7/2015

8

RBC TRANSFUSIONS

• Universally successful in increasing Hb levels.• Decreases symptoms & improve health-related

quality of life. • COMPLICATIONSTransfusion-transmitted infectionImmunologic sensitizationIron overload syndromesVolume overloadTransfusion reactions

7/7/2015

9

Androgens

• Androgens (se endogenous EPO production, sensitivity of erythroid progenitors to the effects of EPO, and red blood cell survival) were used regularly in the treatment of anemia in dialysis patients.

• Limited role side effects – IM injection, acne, priapism, hepatitis, LFT abnormalities, and risk of HCC.

7/7/2015

10

ERYTHROPOIETIN-STIMULATING AGENTS (ESAS)

• Initial phase III clinical trial showing that recombinant human EPO was effective and eliminated the need for continued transfusions.

• In this study, 333 dialysis patients with Hb levels <10 g/dL received recombinant human EPO to maintain the hematocrit at 35 % .

• Within 2 months of initiation of therapy, the need for transfusions (1030 within the six months prior to beginning treatment) was eliminated.

• In addition, there was a 40 % reduction in ferritin levels after 6 months among the 68 patients with iron overload.

7/7/2015

11

• They substantially reduced the need for red cell transfusions

• Decrease in risk for transfusion-related complications

• They also help mobilize iron stores, which is particularly beneficial in patients with CKD and iron overload due to previous transfusions

7/7/2015

12

PEGINESATIDE

• Peginesatide is a synthetic peptide that activates the EPO receptor

• Stimulates erythroid colony growth, reticulocyte

count, and hematocrit

• Does not crossreact with EPO antibodies (amino acid sequence is unrelated to EPO)

7/7/2015

137/7/2015

14

• In 2 phase-III studies (PEARL-I and PEARL-II) that compared peginesatide with darbepoetin among non-dialysis CKD patients, there was an increase in cardiovascular events associated with peginesatide.

• FDA approved peginesatide for IV or SC administration to treat anemia in adult dialysis patients only, but not in patients with CKD who are not on dialysis or in patients with cancer-related anemia.

• Serious hypersensitivity reactions reported in approximately 0.2 % of patients following the first dose of IV administration, with death occurring in 0.02 % of patients

7/7/2015

15

Darbepoetin alfa• Used for the treatment of anemia of CKD

• It is a molecule with 165 amino acids that differs from recombinant human EPO in that it contains five N-linked oligosaccharide chains, whereas EPO has only three

• The additional carbohydrate chains result in a half-life that is longer than that for EPO

7/7/2015

16

PRINCIPLES GOVERNING THE ADMINISTRATION OF RECOMBINANT HUMAN ESAS

• The response to EPO is dose-dependent

• The response is dependent on the route of administration (IV Vs. SC ) and the frequency of administration.

• The response may be limited by low iron stores, bone marrow fibrosis, infection, inflammation, inadequate dialysis, and other conditions.

• Stroke, mortality, and hypertension may complicate therapy. This is primarily limited to patients undergoing dialysis.

7/7/2015

17

INDICATIONS OF ESA

• Use in HD patients – Hb level of <10g/dL with consideration specific patient characteristics, such as functional and cognitive status, life-expectancy

• Nondialysis patients with CKD- initiate ESAs when Hb levels are <10 g/dL and try to maintain goal Hb levels between 10.0 and 11.5 g/dL.

• Exceptions- Dialysis patients who have a H/o stroke or malignancy, or an active malignancy.

• ESAs should not be started until iron status has been evaluated

7/7/2015

18

• Reliance upon the hematocrit alone is not the optimal method for assessing the response to ESAs

• Laboratory variability in the measurement of hematocrit is greater than for Hb

• Current Guidelines- Recommend the use of Hb rather than hematocrit, for evaluating & treating anemia in CKD patients

• Route of administration• Large studies – SC dose of EPO required to achieve a target

Hb is approximately 30 % less than that required with IV administration.

7/7/2015

197/7/2015

20

• The 2012 KDIGO guidelines suggest either IV or SC administration for patients on hemodialysis, hemofiltration, or hemodiafiltration, and SC administration for nondialysis CKD patients or patients on peritoneal dialysis

7/7/2015

21

Dose

• Initial dose of EPO baseline Hb level, overall clinical setting, mode of administration & target hemoglobin level

• Numerous studies IV therapy requires 30% more EPO than with the subcutaneous route

• The FDA-recommended starting dose is 50 to 100 units/kg three times per week for both IV and subcutaneous administration

7/7/2015

22

Side effects• Hypertension

• Headache

• Pure red cell aplasia

• Hyporesponsiveness to ESAs

No increase in Hb concentration after 1st month of appropriate weight-based dosing & acquired hyporesponsiveness as requiring two increases in ESA doses up to 50% beyond the dose at which the patient had originally been stable- KDIGO

7/7/2015

23

Causes for resistance to ESA• Absolute iron deficiency external blood losses or

exhaustion of iron stores due to an increase in erythropoiesis caused by ESA treatment

• Bone disease due to secondary hyperparathyroidism• Occult malignancy and unsuspected hematologic disorders• Multiple myeloma/myelofibrosis/myelodysplastic syndrome• HIV infection• Chronic inflammation (with inhibition possibly due to

enhanced cytokine production)

7/7/2015

24

THANK YOU

7/7/2015