Anemia where we stand

Anemia Treatment In CKD patients:
where we stand ?
By
Alaa Sabry., MD, FACP
Mansoura University, Egypt

Focus Of The Presentation
•Magnitude of the problem.
•Clinical management.
•Future therapy.

• A total of 12,077 adults
participated in the National
Health and Nutrition
Examination Survey (NHANES)
interview and examination
components of the surveys in
2007–2008 and 2009–2010.

The pathogenesis of anemia of chronic kidney disease (CKD)
Jodie L. Babitt, and Herbert Y. Lin JASN 2016.

Quality-of-life Sexual function
Exercise capacity Endocrine function
Immune function
Angina Muscle metabolism
LVH Hospitalizations
Bleeding tendency Transfusions
Brain / cognitive function Nutrition
Depression
Sleep patterns
Anemia Control
Benefits

• in 1835 Richard Bright: first suggestion was
made that the kidney might be involved in
erythropoiesis .
• At the beginning of the twentieth century, Paul
Carnot and Deflandre reported that serum
from an anemic rabbit injected into a normal
rabbit resulted in increased erythropoiesis. (
Hemopoitien)
• Exactly 20 years later, Miyake et al isolated the
hormone from urine of patients with aplastic
anemia and named it EPO.
History

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

Conversion Among ESA
Conversion from Epoetin alfa to
Darbepoetin alfa in patients with
CKD not on dialysis:
The dose conversion depicted in
Table does not accurately
estimate the once monthly dose
of Darbepoetin alfa .

• CHr
• CRP
Primary Evaluation (Prior to ESAs Therapy)
+ other Investigations
To address all correctable causes of anemia
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

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

Iron Markers in CKD
Bahrainwala J. Semin Nephrol. 2016 Mar;36(2):94-8
The following thresholds are used to diagnose iron deficiency:
● Percent HRC >6 percent
● CHr <29 pg
Am J Kidney Dis. 2016 Apr;67(4):548-58

Diagnosing iron deficiency
Absolute deficiency
• TSat
• Flaws related to nutitional
transferrin deficiency
• Ferritin
• Flaws related to inflammation
• Percentage microcytic cells
• Flaws related to cell swelling
• Reticulocyte Hb content
Functional deficiency
• Pathophysiology
• Inflammation, hepcidin, transferrin
deficiency
• Lab diagnosis
• High ferritin, low TSAT
• Clinical
• Therapeutic testing

Iron repletion
Oral
• Poly-medication, side effects
• Interactions
• Poor response in dx patients
• Absorption, target achievement
Parenteral iron
• Repletion
• 1000mg divided in 5-10 sessions
• May be repeated
• Maintenance
• 25-100 mg every 1-2 weeks
• More frequent, every session 6-20
mg

Iron drug interactions
• oral iron formulations interact with multiple drugs.
• These interactions include reduced iron absorption
• 1-Tetracycline antibiotics
• 2- Proton pump inhibitors
• 3- fluoroquinolones
• 4-levothyroxine
• 5- levodopa
• Timing of administration of such drugs
• Brookhart MA, et al. J Am Soc Nephrol. 2013; 24:1151-8.

Semin Nephrol. 2016 Mar;36(2):130-5

This mode of iron delivery provides smaller amounts of iron over hours
compared with supplementation IV, which may help avoid oxidative
toxicity

ESAs Initiation
Caution
(malignancy,
stroke history)
CKD ND
 10 g/dl
(no treatment)
< 10 g/dl
(according)
CKD HD
< 10 g/dl
(treat)
Transfusion!!
Individualization
(treat if > 10 g/dl)
ESAs Initiation

Initiation Dose
EPO α and 
20-50 units/kg 3 times/week
(I.V. dosage must be 20-30% higher than S.C. dosage)
Darbepoetin alfa
0.45 g/kg once weekly
or
0.75 g/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
Route of
administration
CKD ND
SC
CKD 5HD
IV or SC

ESAs Initiation
follow Up
During the initiation phase of ESA therapy, measure
Hb concentration at least monthly. (Not Graded)

ESAs Initiation
Follow Up Serum Hb After 2
weeks of starting
initiation
If Hb increases
>1 g/dL
Decrease dose by
≥25%
If Hb increases
<1 g/dL
Repeat serum Hb
after another 2
weeks
If Hb does not
increase by >1
g/dL
Increase dose by
25%

ESAs Therapy
Maintenance
• The target Hb level.
• The dose & frequency.
• Follow Up.

ESAs Maintenance
Recommended target Hb level?
ESAs
Maintenance
In general
11.5
Individualized
>11.5
In all adults
not >13
Higher risk of stroke, all
cause, cardiovascular
morbidity & mortality

CSN
11-12 g/dL
EBPG
>11 g/dL
(upper limit
not defined)DOQI
11-12 g/dL
CARI
11-12 g/dL CVD
12-14 g/dL no CVD
KDOQI
11-12 g/dL
CARI
>11 g/dL CVD
12-14 g/dL no CVD
UK RA
>10 g/dL
EBPG
>11 g/dL
(upper limit
individualised)
CARI
11-12 g/dL CVD
12-14 g/dL no CVD
CVD=cardiovascular disease EBPG=European Best Practice Guidelines
CSN=Canadian Society Nephrology NICE=National Intitute of Health&Clinical excellance
CARI=Caring for Australian with Renal Impairment
Nephrol Dial Transplant (2009) 24: 348–354
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
KDOQI
≥11 g/dL
(caution >13 g/dL)
Anaemia Management Guidelines and Target Hb
KDOQI
2007 update
11-12 g/dL
(not intentionally >13 g/dL)
UK NICE
10.5-12.5 g/dL
10-12 g/dL in children
<2yr
2008
ERBP 2008
11-12 g/dL

ESAs Maintenance
Are Higher levels better ? CKD -ND

Vs Placebo
`
ESAs Maintenance
Are Higher levels better ?

ESAs Maintenance
follow UP
Hb Follow up During
ESAs Maintenance
CKD ND
At least every
3 months
CKD 5D
At least every
month

Initiation Maintenance
 No increase in Hb concentration
from baseline.
 After the first month of ESA.
 After treatment with stable doses of ESA
 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)

• Epo Dose /Kg/week. ((300 IU/kg/week subcutaneously or
450 IU/kg/week intravenously).
• EPO resistance index (ERI: rHuEPO/ kg/wk divided by hemoglobin
level in g) .
• It is assumed that, this method is more efficient to detect EPO
resistance in HD patients.

ESAs
Hyporesponsiveness
Assessment &
Investigations
Treat the casue
• CHr
• CRP
+ other Investigations
Fe ↓
Vit B12/folate ↓
Infection/Inflammation
Blood loss
• Occult blood in stool

ESAs
Hyporesponsiveness
Assessment &
Investigations
Treat the casue
↑ 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
Side Effects
Influenza-like
syndrome
(affecting 5 %)*
Unknown
etiology**
Respond to anti-
inflammatory
drugs**
Hypertension
*Bennett WM. J Am Soc Nephrol 1991; 1:990.
** Buur T etal. Clin Nephrol 1990; 34:230.

Hypertension
• 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.
ESAs Therapy
Side Effects

• Seizure
• Increased blood clotting
• Slight decrease of Kt/ V
• Hyperkalemia
• Pure Red cell aplasia (PRCA)
ESAs Therapy
Side Effects

Clinical factors that trigger red blood cell transfusions in dialysis ordered by relative
importance
n=305 nephrologists; mean age=46 years; 21%women

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

ESA In Cancer
Bohlius J, et al.Lancet 2009
53 trials (n = 13,933)
Tonelli M, et al. Canadian Medical Association Journal 2009.
52 trials (n = 12,006)

What are the regulatory approved indications
for ESAs?:
• 1- Not indicated in patients receiving hormonal agents, therapeutic
biologic products, or radio-therapy unless receiving concomitant
myelosuppressive chemotherapy.
• 2- In patients with a long life expectancy, the decision to administer ESAs
should be based on a benefit-risk assessment with participation of the
patient. (the type and stage of tumor, degree of anemia, life expectancy,
treatment environment, and known risks of transfusions andESAs.
• 3- Not be initiated at baseline hemoglobin levels ≥100 g/L.
• 4-Should be used at the lowest dose needed to avoid transfusions .
• 5- Hemoglobin levels should be maintained within the range of 100–120
g/L, and an increase in hemoglobin >10 g/L in a2-week period should be
avoided.
• 6- Following completion of chemotherapy ESAs should be discontinued.

• Current EPO analogue therapies rely upon supraphysiologic levels of recombinant
variants of EPO to induce erythropoiesis .
• Intravenous Or subcutaneous, Oral or nasal more convenient but the
bioavailability is insufficient.
• Unstable at Room temperatures , required cold chain from the manufacturing step
till administration .
• Inadequate handling increases the risk of immunization by the drug
• Use of greater doses in CKD patients is associated with worsening hypertension
and increased risk for CV events (myocardial infarction, hospitalization for
congestive heart failure and stroke) .
Szczech LA, al. Kidney Int 2008; 74: 791–798
Zhang Y, et al. Am J Kidney Dis 2004; 44: 866–876
Limitations

Future Erythropoiesis-Stimulating Agents

A- Erythropoietin Mimetic Peptides
PEGINESATIDE

Peginesatide
Phase 3 Clinical Trials

• Was approved by FDA in 2012.
• Unfortunately, soon after launch, unexpected toxicity including
anaphylaxis, which can be life-threatening, or fatal, was identified.
• Approximately 0.02% of patients receiving the first dose of the drug
intravenously died.
• As a consequence Affymax, Inc. and Takeda Pharmaceutical Co. Ltd.,
along with the US FDA are informing the public of a voluntary recall of
the entire lot of peginesatide injections in the user level .
Locatelli F, Del Vecchio L. Expert Opin Pharmacother 2013 ;1277:8-14.
Peginesatide

Regulation of hypoxia inducible factor (HIF) activity.
Abbreviations: EPO, erythropoietin; VHL, von Hippel Lindau protein.

Hb response
Mean change from BL in serum hepcidin

• 1- Stimulating endogenous erythropoietin production without exogenous
ESA therapy.
• 2-These agents are orally active and thus there is potential for a noninjectable
anemia therapy in the future.
• 3-These molecules are able to modulate a number of other genes involved in
erythropoiesis (eg, the erythropoietin receptor, transferrin, transferrin
receptor, ferroportin, and divalent metal transporter in addition to the EPO
gene).
Haase VH. Am J Physiol Renal Physiol. 2010;299:F1-F13.
Advantages of HIF stabilization
therapy.

• The potential ability of these compounds to upregulate vascular
endothelial growth factor (VEGF), which may have the adverse
consequence of causing tumor growth and proliferative diabetic
retinopathy .
Toffoli S, Roegiers A, Feron O, et al. Angiogenesis. 2009;12:47-67
Possible disadvantages

Overview of Hepcidin
Antagonist
1
2 3 4

• A theoretical concern could be that inhibition of hepcidin
might :
• 1- Exacerbate the risk of infections, given its endogenous
antimicrobial properties.
• 1- Stabilization of HIF in some studies enhances tumor growth,
stabilization of HIF in some studies enhances tumor growth
• 3- Interruption of BMP (particularly BMP-6) may result in
calcification of tissues (including peritoneum) .
• A possible solution to this problem could entail the suppression of
hepcidin to appropriate levels without complete inhibition of
hepcidin production.
Sun CC,. Am J Hematol 2012
Hepcidin Modulation

5- ERYTHROPOIETIN
GENE THERAPY

• The basic methodology involved extracting a microbiopsy specimen of dermal cells, harvesting them, and
transducing them with the EPO gene (using an adenovirus vector), and then reimplanting the preparation back into
the mice.
• TARGT (Transducer Autologous Regenerative Gene Therapy) system (formerly known as BioPump) was produced.
ERYTHROPOIETIN GENE THERAPY

Harvesting, ex vivo culturing,
implantation, and after implantation steps
of the Biopump in patients.
hEPO serum levels and reticulocyte counts
in patients who received implants with the
adenovector Biopump.

Kidney International (2014) 86, 676–678.

Despite new drugs, our ‘good old friend’ erythropoietin
stimulating agents are our everyday life in nephrology
practice.

Concerns with use of RBC transfusions?
• 1-Increased risks of venous thrombotic events
• 2-Arterial thrombotic events
• 3-Mortality in hospitalized patients with cancer.
• 4-- increased risks of infectious complications
• 5-Acute respiratory distress syndrome
• 3-Noninfectious adverse events include acute immunemediated reactions
(such as antibody mediated hemolyticreactions, febrile non-hemolytic
reactions, transfusion-related lung injury (TRALI), urticarial reactions, and
anaphylaxis), and
• 6- Nonimmune mediated transfusion reactions(hyperkalemia,
hypocalcemia, hypothermia, and iron over-load) .

Epo Use in Cancer Patients
• In Europe, ESAs are indicated for the treatment of symptomatic CIA in
patients with a hemoglobin ≤100 g/L to increase hemoglobin to ≤120 g/L
[30].
• They are not indicated for patients receiving (a) radiation therapy with a
target hemoglobin of >140 g/L, (b) chemotherapy with a target hemoglobin
of 120–140 g/L, or (c) neither chemo therapy nor radiation therapy with a
target hemoglobin of 120 g/L.
• In some clinical situations RBC transfusions should be the preferred
treatment [30,32,33].
• The U.S. FDA approved labeling is more stringent than the Canadian
labeling, in that it specifies that ESAs should not be used for patients
undergoing chemotherapy with curative intent [34–36].

Health Canada approved indications for ESA
therapy in patients with CIA. 2015

Refrigeration
Room Temperature Shelf Life
0
5
7
31
0 5 10 15 20 25 30 35
Darbepoetin alfa
Epoetin beta
Epoetin alfa
Days
C.E.R.A.

• The Normal Hematocrit Study (NHS), a randomized, prospective,
open-label trial, compared the attainment of hemoglobin
concentration targets of 10 g/dL (low hemoglobin group) or 14 g/dL
(normal hemoglobin group) in hemodialysis patients with coexisting
heart failure or coronary artery disease.
• The composite primary endpoint of all-cause mortality or first non
fatal myocardial infarction was investigated. The study was stopped
early due to safety concerns seen in the normal hemoglobin group.
• Although the primary endpoint was not significant in this interim
analysis (RR, 1.3; 95% CI, 0.9–1.9), a 7% increase in mortality rate in
the normal hemoglobin group was observed.

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

CKD 5HD
ESAs Maintenance
Recommended target Hb level CKD 5D

Pure Red Cell Aplasia
(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/l
Treatment of PRCA
• Stop ESA therapy
• Peginesatide

Epo Preparations
Darbepoietin Mircera

Measuring Hgb content of the reticulocytes

• The World Health Organization (WHO) defines anemia as a blood hemoglobin concentration of <13 g/dL in men and postmenopausal women and of <12 g/dL in women of
childbearing age
• KDIGO guidelines mirror the WHO definition of anemia for patients with CKD.
• Serum Feritin: Main Iron storage protein <100 Absolute Iron deficiency.
• Transferin sat: Glycoprotein secreted from the liver, main iron carrier to the cells.
• Reticulocyte hemoglobin content (equivalent)
• Under normal erythropoietic conditions, young erythrocytes (reticulocytes) are released from the bone marrow into circulation and become mature erythrocytes after
several days.
• Reticulocyte hemoglobin content (CHr),, quantifies hemoglobin mass in reticulocytes, providing information about a short-term change in iron status.
• When measuring CHr (RetHe) in clinical practice, the time delay between blood sample draw and analysis should be taken into account when interpreting the results.
Dialysis organizations in the United States typically use centralized laboratories with specimen shipment times ranging between 24 and 48 hours. Due to the quick
maturation process of reticulocytes, there is a risk that this time delay may introduce measurement bias.
• Percentage hypochromic red cells:
• HRC are erythrocytes with mean cellular hemoglobin concentration (MCHC) less than 28 g/dL.
• Soluble transferrin receptor
• Iron uptake into erythroid precursors occurs through internalizing transferrin bound iron. The transferrin bound iron binds to transferrin receptors present on the surface of
the plasma membrane and is internalized through endosomes ultimately leading to the release of iron. Plasma membrane bound transferrin receptors are released into the
blood in form of a truncated sTfR. Ironrestricted erythropoiesis may cause overexpression of sTfR, as increased number of transferrin receptors may come off the surface of
the erythroblasts and become detectable.53–55
• Hepcidin ?????

Oral iron supplements
200mg elemental iron / day

•Reticulocyte hemoglobin content (equivalent)
• Under normal erythropoietic conditions, young erythrocytes (reticulocytes) are released from the bone marrow
into circulation and become mature erythrocytes after several days.
• Reticulocyte hemoglobin content (CHr),, quantifies hemoglobin mass in reticulocytes, providing information
about a short-term change in iron status.
•Percentage hypochromic red cells:
• HRC are erythrocytes with mean cellular hemoglobin concentration (MCHC) less than 28 g/dL.
•Soluble transferrin receptor
• Iron uptake into erythroid precursors occurs through internalizing transferrin bound iron. The transferrin bound
iron binds to transferrin receptors present on the surface of the plasma membrane and is internalized through
endosomes ultimately leading to the release of iron.
• Plasma membrane bound transferrin receptors are released into the blood in form of a truncated sTfR. Ironr
estricted erythropoiesis may cause overexpression of sTfR, as increased number of transferrin receptors may
come off the surface of the erythroblasts and become detectable.
•Hepcidin ?????

Anemia where we stand

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Anemia where we stand