PHAR 401

PHARMACOTHERAPY OF
CHRONIC KIDNEY DISEASE
- ANEMIA
Alan Lau, Pharm.D.
Professor and Director, Clinical Pharmacy Education
University of Illinois at Chicago
College of Pharmacy

Major complications of CKD:

Anemia
Mineral and bone disorder (MBD)

Kazmi WH, AJKD 38:803, 2001

ANEMIA PREVALENCE BY CKD STAGE

Patients With Anemia* (%)

70

NHANES III
NHANES 1999-2000

60
50
40
30
20
10
0
1

CKD Stage

4-5

*NHANES participants aged 20 y with anemia as defined by WHO criteria: hemoglobin (Hgb)
<12 g/dL for women, and Hgb <13 g/dL for men.
USRDS 2004 Annual Data Report. Available at: www.usrds.org. Accessed 3/28/05.

ANEMIA: ETIOLOGY

Decreased red cell production

Erythropoietin deficiency
Inhibitors of erythropoiesis
Hyperparathyroidism-induced bone marrow fibrosis
Folic acid deficiency
Iron deficiency
Histidine deficiency (?)

Decreased red cell survival

Increased red cell loss
GI, mucosal bleeding
Dialysis loss
Excessive blood sampling

ANEMIA: CLINICAL MANIFESTATIONS

With moderate degrees of renal failure, anemia

is not severe due to compensatory mechanisms
(e.g. cardiac, respiratory) maintain normal body
function

ANEMIA: SIGNIFICANCE

Reduced oxygen delivery to tissues

Impairs patient's ability to function as renal failure worsens
Decrease in Hgb compensated by increased cardiac output
Progressive cardiac damage and progressive renal damage1
Reduced quality of life (QOL)3
Fatigue
Diminished exercise capacity
Reduced cognitive function
Left ventricular hypertrophy (LVH)4
Increased cardiovascular mortality risk2

1. Silverberg et al. Blood Purif. 2003;21:124-130. 2. Collins et al. Semin Nephrol. 2000;20:345-349; 3. The US
Recombinant Human Erythropoietin Study Group. Am J Kidney Dis. 1991;18:50-59; 4. Levin. Semin Dial.
2003;16:101-105.

ANEMIA: LABORATORY FINDINGS

Normochromic, normocyte anemia without

abnormality in white cells or platelets
Low reticulocyte count

ANEMIA: MANAGEMENT

Correct blood loss

Remove drug causes
Correct substrate deficiency
Folate
Iron

(P binders may intestinal absorption)

Transfusion
Risks:

Impair bone marrow RBC synthesis

Secondary hematochromatosis
Hepatitis
AIDS
A valuable resource

ANEMIA: MANAGEMENT
Anabolic steroids
Stimulate red blood cell production, presumably
through an increase of erythropoietin
Androgenic effect does not correlate with
erythropoietic effect
Hematologic response is generally limited
May need 3-6 months of therapy before optimal
response is apparent
Response is generally unsatisfactory in
nephrectomized patients
Adverse effects may include: acne, fluid retention,
virilization, hypertriglyceridemia, hepatotoxicity
Nandrolone is administered intramuscularly

ERYTHROPOIETIN

Mainly produced in the

kidneys in response to need
for tissue oxygenation
Recombinant human
erythropoietin (rHuEPO) is a
polypeptide containing 166
amino acids which is
produced by recombinant
DNA techniques.

RECOMBINANT HUMAN
ERYTHROPOIETIN

Most patients (95%) respond by demonstrating a

clinically significant increase in hematocrit and
hemoglobin
The rate of increase in hemoglobin is dose-dependent
Reticulocyte count may increase after 2-3 doses
The white blood cell count and differential are
unchanged
Virtually all patients are transfusion-independent after 2
months of therapy
Rise in hemoglobin is generally associated with a
reduction in serum ferritin and plasma iron
concentration, even when supplemented with oral iron
therapy. Intravenous iron is often needed.

RECOMBINANT HUMAN
ERYTHROPOIETIN
Most patients experience objective increase in
exercise capacity with subjective improvement of
well-being
CNS functional status and cognitive function
testing are often improved
Increased appetite may improve nutritional status.
Many patients may return to work and live a
productive life

TARGET HGB LEVEL FOR ESA THERAPY

Hgb >13g/dl: heart failure, death, access

thrombosis and declining dialysis efficacy

Increased mortality, serious cardiovascular and thromboembolic

events and tumor progression
CKD patients: Patients experienced greater risk of death and serious
cardiovascular events when administered ESAs to target higher vs lower Hgb
levels (13.5 vs 11.3; 14 vs 10) in two clinical studies. Individual dosing to
achieve and maintain hgb levels within range of 10-12 g/dl

Target (FDA): 10-12 g/dl

KDOQI:

Not >13 g/dl dialysis and non-dialysis patients

Target: 11-12 g/dl

FDA: TARGET HGB LEVEL FOR ESA THERAPY

ESA label:

Warning: ESAs increase the risk of death, myocardial infarction, stroke,

venous thromboembolism, thrombosis of vascular access and tumor
progression or recurrence
Chronic Kidney Disease:

* In controlled trials with CKD patients, patients experienced greater

risks
for death,
serious
adverse
cardiovascular reactions, and stroke
ESA
label
now
recommends:
when administered ESAs to target a hgb level of >11g/dL
* No trial has identified a hgb target level, ESA dose or dosing strategy
that does not increase these risks
* Use the lowest dose sufficient to reduce the need for red blood cell
transfusions

KDIGO ANEMIA TREATMENT GUIDELINES

2012

CKD-ND
Hb10g/dL: ESA may not be initiated
Hb<10g/dL: decision individualized based on rate
of Hb decline, prior response to iron therapy, risk
of needing transfusion, risk of ESA and anemia
symptoms
CKD-5D
ESA initiated when Hb between 9 and 10 g/dL
Individualization of therapy for quality of life
improvement in some patients with Hb >10 g/dL

ROUTE OF EPO ADMINISTRATION

IV:

Commonly given to hemodialysis (HD) patients in US

SC:

Preferred for pre-dialysis and CAPD patients

Bioavailability: 20-30%
Dosage needed reduced by 30% (mean), compared with IV
route
(The initial SC dose should be 2/3 the weekly IV dose when HD
patients are switched from IV to SC after attaining target hgb)
More physiologic serum concentration

IP:

Poor absorption (3-8%, 40% in dry peritoneal cavity)

EPO should be given to dry abdomen (with minimal amount of
dialysate)
Dose requirement > IV or SC, not cost-effective

DARBEPOETIN ALFA AND RHUEPO

rHuEPO

Darbepoetin
Carbohydrate
side chains

Receptor 1

Receptor 2

3 N-linked carbohydrate
chains
Maximum 14 sialic acids
MW ~ 30,400 daltons
40% carbohydrate

Egrie, et al. Br J Cancer. 2001;84(suppl 1):3.

Receptor 1

Additional
carbohydrate side
chains

Receptor 2

5 N-linked carbohydrate
chains
Maximum 22 sialic acids
MW ~ 37,100 daltons
51% carbohydrate

Darbepoetin alfa and rHuEPO

Brit J Cancer 2001; 84(Suppl. 1):3-10

DARBEPOETIN ALFA

The serum half-live 3 times longer (25 hr vs 8.5

hr) than IV rHuEPO
Effective in maintaining hemoglobin with once
weekly administration
In some patients, every other week
administration is sufficient
The less frequent dosing is especially attractive
for patients with chronic kidney disease
Safety profile is similar to rHuEPO

MONITORING OF HEMOATOPOIETIC
EFFECT

Hgb should be measured every 1-2 weeks

following treatment initiation or dosage
change, until target stable hgb and EPO
dose have been achieved
After target stable hgb and EPO dose have
been achieved, hgb should be monitored
every 2-4 weeks

IRON DEFICIENCY IN CKD

In patients beginning ESA treatment, iron

deficiency occurs due to increased iron
consumption during erythropoiesis

Iron deficiency will develop in most dialysis

patients receiving ESAs

Iron deficiency is the most common reason

for resistance to the effect of ESAs

CKD=chronic kidney disease; ESA=erythropoietin-stimulating agent.

National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146.

ASSESSMENT OF IRON STORES

Gold standards:
Bone

marrow iron stores

Liver iron stores (liver biopsy or SQUID*)
*SQUID = superconducting quantum interference device

Serum iron
Diurnal

variation
Does not reflect iron store
May be low in inflammation

ASSESSMENT OF IRON STORES

TSAT (Transferrin saturation)

=

[Serum iron/TIBC] x 100%

TIBC reflects transferrin, the protein to which
virtually all iron in blood is bound.
<20%: absolute iron deficiency, absence of iron in
bone marrow
>50%: risk for iron overload

ASSESSMENT OF
IRON STORES

Ferritin
Storage

form of iron
Does not play a role in iron transport
Gender differences in quantity
Acute phase reactant
Moderately high level may occur in non-iron
related conditions
Low level specific for iron deficiency

ASSESSMENT OF BODY IRON

Therapeutic target:
Transferrin saturation (TSAT, Fe/TIBC):
20%

Ferritin:
200 ng/ml (HD patients)
100 ng/ml (CKD patients)
If TSAT is 50% and/or serum ferritin is
500 ng/ml, further iron therapy is unlikely
to hgb or EPO dose

KDIGO ANEMIA TREATMENT GUIDELINES 2012

CKD patients not receiving iron or ESA therapy: if Hb is
desired without ESA and when TSAT is 30% and ferritin
is 500 ng/ml: (guideline 2.1.2)
Trial of IV iron
ND patients, alternately, 1-3 months trial of PO iron
CKD patients on ESA therapy: if Hb or ESA dose is
desired without ESA and when TSAT is 30% and ferritin
is 500 ng/ml: (guideline 2.1.3)
Trial of IV iron
ND patients, alternately, 1-3 months trial of PO iron

SUPPLEMENTAL IRON ADMINISTRATION: IV

Available as:

Iron dextran (INFed, DexFerrum)

Risk

time

of analphylaxis, 25 mg test dose when given first

Ferric gluconate (Ferrlecit), Iron sucrose (Venofer)

Risk

of allergic reaction
Given in small doses because of hypotension (doserelated)

Ferumoxytol (Feraheme)

FERUMOXYTOL

Superparamagnetic iron oxide nanoparticle

with a polyglucose sorbitol carboxymethylether
coating
Less free iron than other IV preparations
Can be given rapidly at higher doses
510 mg IV injection (30mg/sec),
repeat 3-8 days later
Risk of hypersensitivity and anaphylaxis

RHUEPO: ADVERSE EFFECTS

Development or exacerbation of high blood

pressure

Dialysis patients: 23%

Pre-dialysis patients: 10-20%
Not in anemic patients without renal disease on EPO
therapy
Occurs after 2-16 weeks of therapy
Does not correlate with EPO dose or rate of Hgb
increase
?? Increased risk in severe anemia
Mechanisms:

Increased blood viscosity

Peripheral vascular vasoconstriction
Loss of hypoxia-induced vasodilitation (defective regulation)

Initiate or increase the dose of antihypertensive

medications

RHUEPO: ADVERSE EFFECTS

Seizure (?)
Prior history of seizure is not a
contraindication for EPO use
Thrombosis of arteriovenous fistula
Flu-like syndrome
Reduced dialysis efficiency

RESISTANCE (SUBOPTIMAL RESPONSE)

TO RHUEPO THERAPY

Chronic blood loss

Substrate deficiency

Iron - hemolysis, GI loss, dialysis, phlebotomy, occult

bleeding
Folate
Water-soluble vitamins

Inflammatory conditions

Infections
Malignancy
Surgery
Defective iron transport to site of heme production
Cytokines (IL-1, TNF) may suppress response to EPO

RESISTANCE (SUBOPTIMAL RESPONSE) TO

RHUEPO THERAPY

Febrile illnesses
Inadequate dialysis
Bone marrow suppression from uremia, uremic
toxins
Malnutrition
Hyperparathyroidism (fibrosis)
EPO antibodies
Aluminum toxicity

ALUMINUM TOXICITY

Mechanisms:

Reduces iron utilization (release of transferrin-bound

iron within the erythroid cell)
Altered heme synthesis pathway
Altered cellular maturation
Disruption of intramedullary iron kinetics

May suppress erythropoiesis before skeletal and

CNS effect
Increase EPO dose in patients with moderate
aluminum overload
Chelation therapy will improve EPO response in
severe aluminum toxicity

ASSESSING POTENTIAL FOR RESISTANCE

Fe, TIBC (transferrin saturation), ferritin
Serum folate and B12 concentrations
Occult GI blood loss
Hemolysis
Dialysis related blood loss (dialyzer re-use or
inadequate coagulation)
Recent surgical procedures, infection,
inflammation
PTH (secondary hyperparathyroidism)
Aluminum intoxication, after patient determined
to have adequate iron store and no
inflammatory condition

CERA (CONTINUOUS
ERYTHROPOIESIS
RECEPTOR ACTIVATOR,
MICERA)
Chemistry:
PEGs (polyethylene glycols) are amphiphilic (molecules
containing groups with different properties, such as
hydrophobic and hydrophilic groups) polymers of
ethylene glycols of varying molecular weights that can
be covalently attached to proteins
Pegylated proteins: serum t and immunogenicity
Such effects vary with:
the number of PEG molecules attached
the average MW of the PEG polymer

CERA
Pharmacokinetics:

Serum half-life: CERA > epoetin

Systemic clearance: CERA < epoetin

Postulated mechanism of action:

CERA binds with EPO receptor resulting in erythropoiesis

Rapid dissociation from receptor so that CERA can bind
with another receptor
Extended serum t allows such process to be repeated
Results in continuous stimulation of erythropoiesis

Potential clinical use:

Less frequent administration than rHuEPO

ESA UNDER INVESTIGATION

Hypoxia-inducible factor stabilizers
HIF PH inhibitors inhibitor prolyl hydroxylases
(PH), reducing HIF hydroxylation and
subsequent breakdown, thus prolonging its
presence
AKB-6548