Anemia in CKD - ESAs Therapy - Guideline Critique, Evidence base - Dr. Gawad

Mohammed Abdel Gawad
Nephrologist – Alexandria – Egypt
Founder & Chairman of NephroTube
drgawad@gmail.com

More of lectures on
www.NephroTube.com

Why CKD Patients need ESAs?
(Erythropoiesis-Stimulating Agents)

Why CKD Patients need ESAs?
(Erythropoiesis-Stimulating Agents)
Experimental Hematology 2008;36:1573–1584

Anemia of CKD?
Normochromic Normocytic
Hypochromic Microcytic
Normochromic Macrocytic
Presence of other type of anemia may point to
another cause rather than CKD (on top of CKD)

• CHr
• CRP
Primary Evaluation (Prior to ESAs Therapy)
+ other Investigations
To address all correctable causes of anemia
Reticulocyte count :
If > 130,000/µl → look for:
blood loss or hemolysis
(endoscopy, colonoscopy, hemolysis screen)
Fe Deficiency when:
S. Ferritin ≤ 500 ng/ml
S.TSAT ≤ 30%
CHr: Detect iron stores in BM in last 1-2 days
CRP: Exclude infection

Back to Basics
Erythropoiesis & CHr (Reticulocytic Hb Content)

Back to Basics
Erythropoiesis & CHr (Reticulocytic Hb Content)
• The reticulocyte Hb content (CHr) is a
measure of the amount of Hb in the
reticulocytes.
• The amount of Hb in the reticulocytes
is a reasonably good reflection of how
much iron was available to the bone
marrow for incorporation into new red
blood cells a few days before.

ESAs Therapy
Initiation Maintenance
• Q1: When to initiate?
• Q2: What is the dose?
• Q3: How to follow initiation?
• Q1: What is the target Hb level?
• Q2: What is the dose & frequency?
• Q3: How to follow maintenance?

ESAs Therapy
Initiation

ESAs Initiation
Q1: When to Initiate?
Male, 25 years, CKD G4, Hb 10.5g/dl, on maintenance
iron therapy with S.TSAT 35% & S.Ferritin 600 ng/ml:
1. ESAs therapy is mandatory.
2. ESAs therapy may be initiated if anemia symptoms are
present.
3. Never start ESAs therapy.
4. Increase the Fe dose if there is a symptom of anemia

ESAs Initiation
Q1: When to Initiate?

Initiation Dose
EPO α and β
20-50 units/kg 3 times/week
(I.V. dosage must be 20-30% higher than S.C. dosage)
Darbepoetin alfa
0.45 µg/kg once weekly
or
0.75 µg/kg once every two weeks
(S.C. or IV)
Methoxy polyethylene
glycol-epoetin beta
0.6mcg (600ng)/kg every two weeks
(S.C. or IV)
ESAs Initiation
Q2: What is the recommended dosage?

ESAs Initiation
Q2: How to follow initiation?
During the initiation phase of ESA therapy,
measure Hb concentration at least monthly.
(Not Graded)

ESAs Initiation
Q2: How to follow initiation?
Clinical Experience

ESAs Therapy
Maintenance

ESAs - Maintenance
Q1: What is the target Hb level for CKD patients?
1. 11.5 - 13 g/dl.
2. 10 - 11.5 g/dl.
3. 9 - 10 g/dl
4. None of the above.

ESAs Maintenance
Q1: What is the recommended target Hb level?
Higher risk of stroke, all
cause, cardiovascular
morbidity & mortality

RCTs suggest that attempts to
reach higher Hb target are
associated with excess
morbidity & possibly
mortality, especially for cardiac
events.
ESAs Maintenance
Q1: Recommended target Hb level
What is the Evidence ?

ESAs Maintenance

ESAs Maintenance
Vs Placebo
`

ESAs Maintenance
• The only trial on CKD 5HD
(N=110).
• Two different targets (9.5-11 g/dl
and >11 g/dl) vs placebo

ESAs Maintenance
CKD 5HD

ESAs Maintenance
Q2: What is the dosage & frequency of administration?
Dose prescribed must maintain Hb level within
target.
Drug dose can be kept unchanged but
frequency can be reduced.

ESAs Maintenance
Q3: How to follow maintenance?

Don’t forget Individualization

ESAs Therapy
Initial
Subsequent
(Acquired)

1. No increase in Hb
concentration from baseline.
2. After the first month of ESA.
3. On appropriate weight-based
dosing.
1. After treatment with stable doses
of ESA
2. Require 2 increases in ESA doses
up to 50% beyond the dose at
which they had been stable to
maintain a stable Hb
concentration.
Initial
Subsequent
(Acquired)
ESAs Therapy
ESAs Hyporesponsiveness

ESAs Therapy

ESAs Therapy
• CHr
• CRP
+ other Investigations
Time
HbResponse
Plateau Effect
Due to Fe ↓ 2nry to
ESA administration
(functional Fe
deficiency)
Fe ↓
Vit B12/folate ↓
Infection/Inflammation
Blood loss
• Occult blood in stool

ESAs Therapy
ESAs Hyporesponsiveness – Other Causes
↑ Blood loss
dialysis line & filter
Hyperparathyroidism
Hemolysis (high LDH,
unconjugated
bilirubin) & other
hemoglobinopathies
Hypothyroidism
Underdialysis
Serum Alb & Nutrition ACE-I/ARB
(for CKD ND)
BM biopsy
Pure Red Cell Aplasia
(PRCA)
Non-adherence
Malignancy

ESAs Therapy
(PRCA)
EPO α
AlbuminPolysorbate
EPO α
Polysorbate
EPO
receptors on
erythrocyte
precursors
Immune
system

ESAs Therapy
(PRCA)
Polysorbate was used
with Eprex instead of
human serum albumin as a
stabilizing agent
Polysorbate stimulates the
formation of EPO-Ab
• ESA therapy for more than 8 weeks
• Sudden rapid decrease in Hb concentration at the
rate of 0.5 to 1.0 g/dl per week
• OR requirement of transfusions at the rate of
approximately 1 to 2 per week
• Normal platelet and white
cell counts, AND
• Absolute reticulocyte
count less than 10,000/µl
Treatment of PRCA
• Stop ESA therapy
• Peginesatide

ESAs Therapy
(PRCA)
Treatment of PRCA
• Stop ESA therapy
• Peginesatide
Peginesatide
• Formerly called hematide
• Small synthetic peptide that stimulates
erythroid colony growth.
• Its amino acid sequence is unrelated to
erythropoietin, does not cross react with
erythropoietin antibodies

ESAs Therapy
Side Effects
*Bennett WM. J Am Soc Nephrol 1991; 1:990.
** Buur T etal. Clin Nephrol 1990; 34:230.

ESAs Therapy
Side Effects
• 15 % of cases.*
• More common with I.V.
route.**
*Bennett WM. J Am Soc Nephrol 1991; 1:990.
**Watson AJ etal. Am J Med 1990; 89:432.
Therapy of EPO-induced
hypertension begins with
prevention.
The risk of hypertension can be
ameliorated by raising the
hematocrit slowly.

Avoid, when possible, red cell transfusions to minimize
the general risks related to their use.
In patients eligible for organ transplantation, avoid, when
possible, red cell transfusions to minimize the risk of
allosensitization.
Blood Transfusion

Benefits of red cell transfusions may outweigh the risks in
patients in whom:
1.ESA therapy is ineffective (e.g., hemoglobinopathies,
bone marrow failure, ESA resistance)
2.The risks of ESA therapy may outweigh its benefits (e.g.,
previous or current malignancy, previous stroke)
3.If rapid correction is required to stabilize the patient’s
condition (e.g., acute hemorrhage, unstable coronary
artery disease)
4.When rapid pre-operative Hb correction is required
Blood Transfusion

Future ESAs Therapy
Back to Basics - Erythropoietin
Iain C. Macdougall. Am J Kidney Dis. March 2012. 59(3):444-451.

Future ESAs Therapy
Back to Basics - Erythropoietin

Future ESAs Therapy
Hypoxic Inducible factor (HIF) Stabilizer
Iain C. Macdougall. Am J Kidney Dis. 59(3):444-451.Iain C. Macdougall. Am J Kidney Dis. March 2012. 59(3):444-451.

Future ESAs Therapy
Hypoxic Inducible factor (HIF) Stabilizer
HIF Stabilizer
Iain C. Macdougall. Am J Kidney Dis. 59(3):444-451.Iain C. Macdougall. Am J Kidney Dis. March 2012. 59(3):444-451.

Take Home Messages
Anemia of CKD is Normochromic Normocytic
anemia.
Exclude iron deficiency, infection and others causes
of anemia before starting ESAs therapy.
Replete iron stores before starting ESAs therapy.

Randomized controlled studies consistently
demonstrate that normalizing the Hb level of
patients with CKD with ESAs is associated with
poor outcomes , and it is better to get a Hb
target in the 9.0 to 11.5 g/dL range.
Take Home Messages

Take Home Messages
Don’t go fast: don’t target Hb rise at
initiation more than 1-2 g/dl/month

Take Home Messages
ESAs hyporesponsivness requires
rechecking of iron store status, infection
and other associated causes that may
lead to ESAs resistance.

Take Home Messages
It is better to avoid blood transfusion, but
there are some situations that it may be
mandatory.
RISK vs BENIFIT

Anemia in CKD - ESAs Therapy - Guideline Critique, Evidence base - Dr. Gawad

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