The therapy strategy of

erythropoietin failure

Chandra Irwanadi Mohani

Introduction
• Anemia is frequent complication of chronic kidney disease, and treatable
• Its primary cause is relatively deficient erythropoietin (EPO) production,
due to diminished erythropoiesis
• Anemia in CKD associated with reduced quality of life and increased
cardiovascular disease, hospitalization, cognitive impairment, and
mortality
• Anemia of CKD is a multifactorial process due to relative EPO deficiency,
uremic induced inhibitors of erythropoiesis, shortened erythrocyte
survival, and disordered iron homeostasis
Fishbane S, Spinowitz B. Am Jkidney Dis 2018;71(3): 423-435
Babitt JL, Lin HY. J Am Soc Nephrol 2012;23:1631-1634
Gupta N, Wish JB. Am J Kidney Dis. 2017;69(6):815-826
Introduction
• KDIGO group defined anemia in adults and children aged >15 years with CKD when the Hb
levels are < 13.0 g/dL in males and < 12.0 g/dL in famales
• Since 1980, anemia management was revolutionized with introduction of recombinant
human EPO, related erythropoiesis stimulating agents (ESAs), reduce the need for blood
transfusion in patients with CKD
• Several EASs are currently available, such as; epoetin alfa or beta, epoetin alfa biosimilar,
and longer acting agents such darbepoietin alfa and methoxy polyethylene glycol-epoetin
beta
• Clinical practice guidelines on the use of ESAs were developed and improved with a focus
on evidence-based medicine
• But, the respond capacity of patients with CKD vary widely, due to the etiology of anemia is
KDIGO National Kidney Foundation. Am J Kidney Dis. 2006;47(Suppl 3):S11-S145
multifactorial El-Achkar TM, Ohmit SE, McCullough PA. Kidney Int. 2005;67:1483-1488
Fishbane S, Spinowitz B. Am J Kidney Dis. 2018;71:423435
Introduction
• The patients with reduced hematopoietic response to ESAs are called ESA resistant
or hyporesponsive
• There is no consensus about the definition for rHuEPO resistance, will be evaluated if
there was increase ≥ 25% in erythropoietin dose or < 1 mg/dL gain in Hb levels after
2-4 weeks of treatment
• The most common causes are iron deficiency, either absolute or functional, and
inflammation
• The pathophysiological mechanisms underlying this condition are not yet fully
understood; how ever the processes that cause anemia of chronic disease play a role
• The true incidence of resistance to ESAs, is not known, since in surveys on the use of
different doses, a considerable percentage of patients were below the target level
of 11 g/dL
Santos EJF, Dias RSC, Lima JFB, et al. Int J Nephrol and Renovasc Dis. 2020;13:231-237
KDIGO. Anemia work group. Kidney Int. 2012;2(4)(Suppl):279-335
 Anemia Prevalence by CKD Stage
70
NHANES III
60 NHANES 1999-2000
Patients With Anemia* (%)

50
40
30
20
10
0
1 2 3 4-5

CKD Stage
*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. The data reported here have been supplied by the USRDS. The interpretation and reporting of these data
are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government.
Available at: www.usrds.org. Accessed 3/28/05.

5
 Common causes of anaemia in
CKD
• Relative erythropoietin deficiency
• Iron deficiency
• Blood loss
• Reduced erythrocyte survival duration
• Inflammation
• Infection
• Underlying hematologic disease
• Hyperparathyroidism (dialysis patients)
• Haemolysis
• Nutritional deficits 1. Ganz T. Blood. 2003;102(3):783-785 4. Babitt JL, Lin HY. J Am Soc Nephrol. 2012:23:1631-1634
2. Fishbane S, Spinowitz B. Am J Kidney Dis. 2018:71:423-435 5. Sato Y, Mizuguchi T, Shigenaga S, et al. Ther Apher Dial. 2012;16:16:522-528
3. Radtke HW, Claussner A, Erbes PM. Blood. 1979;54(4):877-884 6. Richmond TD, Chohan M, Barber DL. Trends Cell Biol. 2005;15(3):146-155
 Mechanisms underlying anemia of
CKD
Anemia in CKD is a multifactorial
process:

- EPO deficiency

- Uremic-induced inhibitors of
erythropoiesis

- Shortened erythrocyte survival

- Disordered iron homeostasis

Iron and hormonal flux

Regulatory process
Activation
Inhibition
In CKD
Babit JL and Lin HY. J Am Soc Nephrol 2012;23:1631-4
Evaluation of anaemia in CKD
• Focused history and physical examination
• Blood testing
- Chemistry
- Complete blood cell count (including red blood cell indexes)
- reticulocyte count
- Serum ferritin
- Transferrin saturation
- Folic acid
- Vitamin B12

Fishbane S, Spinowitz B. AJKD 2018;71(3):423-435

Santos EJF, Dias RSC, Lima JFB, et al. Int J Nephrol and Renov. 2020;13:231-237
KDIGO Anemia work group. Kidney Int. 2012;2(4)(Suppl):279-335
ESA Hyporesponsiveness
Current definitions used for hyporesponsiveness to erythropoietin stimulating agents

K/DOQI 450 u/kg per week IV EPO or 300 u/kg per week subcutaneous EPO

European guidelines 300 u/kg per week of EPO (appr 20,000 u/week) and 1.5 µg/kg per week of
Darbepoietin alfa (approx. 100µg/ week )
KDIGO Initial hyporesponsiveness: no increase in hemoglobin concentration after
the first month of appropriate weight-base dosing
KDIGO Acquired hyporesponsiveness: requiring 2 increases in ESA dose up to 50%
beyond the dose at which the patient had originally been stable
ERI Weight-adjusted weekly ESA dose devided by the hemoglobin value

K/DOQI, NKF-DOQI clinical practice guidelines for anemia of chronic renal failure; EPO, erythroiepoitin;
European guidelines; KDIGO, chapter 1: diagnosis and evaluation of anemia in CKD.
ERI, erythropoietin index
Rosati A, Ravaglia F, Panichi V. Blood Purif 2018;45:139-146
Failure to respond to treatment
• Resistance to ESA therapy is usually relative rather than absolute
• Term hyporesponsiveness is often used
• Need a greater than usual dose of ESA to achieve increasing expected Hb concentration
• The definition of resistance to ESAs is continued need for > 20 000 IU/ week (300
IU/kg/week) or 1.5 µg/kg of darbepoetin alfa ( ~ 100 µg/week)  > 2.5 times the
average ESA dose, or has a continued need for such high dosages to maintain the target
• The most common causes of incomplete response to ESAs are iron deficiency, either
absolute or functional, and inflammatory disoreders (evidence level B)
• The fact, resistance to EPO followed by anemia, increases the risk of that in patien with
CKD, association with increased blood pressure (cardiovascular risk), increased blood
velocity (endothelial stress) and improved platelet function (prothrombotic effect)
Santos EJF, Dias RSC, Lima JFB, et al. Int J Nephrol and Renovasc Dis. 2020;13:231-237
KDIGO. Anemia work group. Kidney Int. 2012;2(4)(Suppl):279-335
Suttorp MM, Hoekstra T, Rotmans JI, etal.BMC Nephrol. 2013;14.200
Alves MT, Vilaca SS, Carvalho MG.Rev>BrasHematol Hemoter 2015;37(3):190-197
 ESA Hyporesponsiveness
• An inadequate response to ESAs among CKD patients is an unfavorable
prognostic factor
• May be present from the beginning or after the treatment is established
• Characterized excessive doses during initiation of therapy or by the
inability to maintain target hemoglobin levels despite maximum
dosage in the iron replate patients
• Commonly 75-90% of patients in a given dialysis facility
• Erythropoietin Resistance Index (ERI) is defined as the weekly ESA dose
per kg of body weight divided by hemoglobin level
Santos EJF, Dias RSC, Lima JFB, et al. Int J Nephrol and Renovasc Dis. 2020;13:231-237
KDIGO. Anemia work group. Kidney Int. 2012;2(4)(Suppl):279-335
Rosati A, Ravaglia F, Panichi V. Blood Purif. 2018;45:139-146
The causes of apparent resistance to
ESA therapy
• Chronic blood loss
• Hyperparathyroidism/ osteitis fibrosa
• Aluminium toxicity
• Haemoglobinopathies (e.g. α and β-thalassaemia, sickle cell anaemia)
• Vitamin deficiencies (e.g folate or vitamin B12 deficiency)
• Multiple myeloma, myelofibrosis
• Other malignancies
• Malnutrition
• Haemolysis
• Inadequate dialysis
• Adverse effects of certain drugs [e.g. cytotoxic and immunosuppressive agents, angiotensin-
converting enzyme (ACE) inhibitors]
Locatelli F, Aljama P, Barany P, et al. Nephrol Dial Transplant 2004;19(Suppl 2:ii1
Alves MT, Vilaca SS, Carvalho MDG, et al. Rev Bras Hematol Hemoter 2015;37(3):190-197
Suttorp MM, Hoekstra T, Rotmans JI. BMC Nephrology 2013;14:200
Iron deficiency
• Blood loss should always be suspect in patients
- need a higher dose of ESA to maintain a stable Hb concentration
- Hb concentration is declining
- fail to increase iron stores, even after i.v. iron administration
• Iron deficiency significantly increases the risk of anemia in CKD and is considered a causative
factor of the resistance to EPO across CKD stages
• Several factors contribute to absolute and functional iron deficiency in CKD; blood losses,
impaired iron absorption, and chronic inflammation
• Clinical practice guidelines recommend that oral iron will, in general, be sufficient to maintain and
may be sufficient to attain the Hb within targets in ESA treated CKD patients not yet requiring
dialysis and in those on peritoneal dialysis

1. Fishbane S, Spinowitz B. AJKD 2018;71(3):423-435 4. Santos EJF, Dias RSC, Lima JFB, et al. Int J Nephrol and Renov. 2020;13:231-237
2. KDIGO Anemia work group. Kidney Int. 2012;2(4)(Suppl):279-335 5. Drozdz M, Weigert A, Silva F, et al. BMC Nephrology 2019;20:5
3. Alves MT, Vilaca SS, Carvalho MG, et al. Rev Bras Hematol Hemoter. 2015;37(3):190-197
Iron deficiency
• There is a wide choice of both oral and IV iron agents available for treatment
• Oral agents are generally ineffective for hemodialysis patients and only modestly effective in non-dialysis-
dependent CKD
• In dialysis patients, a phosphate binder, significantly increases iron parameters and potentially improves
ESA response
• IV iron is generally highly efficacious
• The most commonly used agent in the USA is iron sucrose, usually administered 5-100 mg/week
• A typical course would be 1,000 mg of iron sucrose or ferric gluconate over 10 to 12 dialysis treatments
• In patients with non-dialysis-dependent CKD or those treated with peritoneal dialysis may be initiated on
oral iron agents instead of or before treatment with IV iron

1. Fishbane S, Spinowitz B. AJKD 2018;71(3):423-435 4. Santos EJF, Dias RSC, Lima JFB, et al. Int J Nephrol and Renov. 2020;13:231-237
2. KDIGO Anemia work group. Kidney Int. 2012;2(4)(Suppl):279-335 5. Drozdz M, Weigert A, Silva F, et al. BMC Nephrology 2019;20:5
3. Alves MT, Vilaca SS, Carvalho MG, et al. Rev Bras Hematol Hemoter. 2015;37(3):190-197
Chronic inflammation and infection
• The release of cytokines such as interferon-gamma (IFN-ɤ), tumor necrosis factor alpha (TNF-α), interleukin 1
(IL-1), interleukine 6 (IL-6) and interleukin 10 (IL-10) can induce rHuEPO erythroid progenitor cell resistance or
impair the release of stored iron in the RES for production of hemoglobin
• Infectious disease may also be related to anemia resulting in chronic inflammation (released of IFN-ɣ and TNF-
α as proinflammatory cytokines in CMV infection, related with lack of response to rHuEPO)
• Its showed low hemoglobin levels in patients with CKD undergoing hemodialysis and high doses of rHuEPO
• Human Parvovirus B19 can also cause anemia due to infection and lysis of erythroid precursors in the bone
marrow
• Generally Viral infection (CMV, Parvovirus B19, HIV) has been associated with transient aplastic crisis and
unresponsiveness to treatment with rHuEPO
• Acquired pure red cell aplasia (PRCA) and severe transfusion-dependent anemia in kidney transplant patients
infected by B19 also be reported in several studies

1. Betjes MG, Weimar W, Litjens NHR. J am Soc Nephrol. 2009;20(12):2661-6 4. Chisaka H, Morita E, Yaegashi N, et al. Rev. Med Virol. 2003;13(6):347-59
2. Alvess MT, Vilaca SS, Carvalho MG, et al. Rev Bras Hematol Hhemoter. 2015;37(3):190-7 5. Egbuna O, Zand MS, Arbini A, et al. Am J Transplant. 2006;6(1):225-31
3. Junior WVO, Sabino AP, Figueiredo RC, Rios DRA. J Bras Nephrol2015;37(2):255-263
Gangguan pembentukan Eritrosit
Malnutrition and Cofactor deficiency
• The inflammatory process is also a major cause of protein energy malnutrition, occur
in 13-51% of patients under hemodialysis
• Malnutrition has been associated with resistance to treatment with rHuEPO in patients
under dialysis
• Laboratory tests show low percentages of transferrin saturation index, low serum
albumin concentrations and body mass index (BMI), with high levels of C-reactive
protein (PCR), and a marker of iron stores, ferritin may also be increased in
malnutrition
• Deficiencies of folic acid and vitamin B12 may be associated with anemia and
resistance to treatment with rHuEPO
• Folic acid and vitamin B12 deficiencies can lead to increases in homocysteine levels,
associated with increased risk of cardiovascular complications in renal patients
Locatelli F, Andrulli S, Memoli B, et al. Nephrol Dial Transplant. 2006;21:991-8
Kalantar –Zadeh K, Lee GH, Miller JE, et al. Am J Kidney dis. 2009;53(5):823-34
Qureshi AR, Alvestrand A, Danielsson A, et al. Kidney Int 1998;53(3):773-82
Gaweda AE, Goldsmith IJ, Brier ME, et al. Clin J Am Soc Nephrol. 2010;5(4):576-81
Shaefer R, Teschner M, Kosch M. Nephrol Dial Transplant. 202;17(S5):24-7
Malnutrition in chronic kidney disease

Systemic inflammation
IL-6 IL-10 Dialysis technique
Uremic toxins IL-8 IL-18 and underdialysis

Decreased Nutrient intake

Protein Energy Wasting Increased catabolism
In chronic Kidney Disease

Metabolic dysfunction

Increase in appetite supressing

hormones
insulin
leptin
pre-inflammatory cytokines

Lorember FM. Front. Pediater. 2018

Inadequate dialysis

• In patients with CKD, damage to erythrocytes can occurs; 1, in the presence of

uremic toxins and 2, the dialysis procedure and leads to blood loss
• Uremic toxins also inhibit the production of EPO and erythropoiesis
• According to the NKF/KDOQI guidelines for patients under hemodialysis, the Kt/V
target is ≥ 1.3, and in patients under peritoneal dialysis the target is ≥ 1.7/ week
• The pathophysiological mechanism that links inadequate dialysis to the lack
response rHuEPO is still not completely understood
• Other factors such as inflammation and vascular access complications may be
associated with poorer response to treatment
National Kidney Foundation. K/DOQI Clinical practice Guideline for Nutrition in CKD:
2020 Update. Am J Kidney Dis 2020;76(3)(Suppl 1):S1-S107
Alves MT, Vilaca SS, Carvalho MG, et al. Rev Bas Hematol Hemoter. 2015;37(3):190-7
Gaweda AE, Goldsmith IJ, Brier ME, et al. Clin J Am Soc Nephrol. 2010;5(4):576-81
Increased iron losses in
hemodialysis patients
• Estimated 1-3 g per year in hemodialysis patients
• Chronic bleeding from uremic associated platelet dysfunction
• Frequent phlebotomy
• Blood trapping in the dialysis apparatus
• Impaired dietary iron absorption
• Intravenous iron preferred for hemodialysis patients because
impaired dietary iron absorption

Babitt JL, Lin HY. J Am Soc Nephrol. 2012;23:1631-1634

Drozdz M, Weigert A, Silva F, et al. BMC Nephrology 2019;20:5
 Hyperparathyroidism
• Increased parathyroid hormone (PTH) as a uremic toxin is associated with lack of response to treatment
rHuEPO due to; endogenous EPO inhibition, reduction of erythroid precursors in the bone marrow, and
erythrocyte survival
• The target range of plasma level of intact PTH in the various stage of CKD; CKD stage 4  70-110 pmol/L, stage
5 or in dialysis  150-300 pmol/L (evidence)
• PTH is also associated to the induction of bone marrow fibrosis in patients with established hemodialysis
• How far the threshold of the PTH levels could affect the response to rHuEPO remains unclear
• Several studies showed that increased of iPTH levels were associated with decreased of response to rHuEPO
treatment (compared 266±322pg/L and 800±248pg/L) and iPTH levels of 300, 600, 900 pg/L were associated
with approx. 90, 79 and 67% of the maximum response to treatment with rHuEPO
• Treatment of secondary hyperparathyroidism in chronic uremia focuses on avoiding hyperphosphatemia by the
use oral phosphate binder and concomitant substitution by a 1 alpha-hydroxy cholecalciferol / 1α(OH)D3 as an
active vitamin D analog
1. Druek TB, Eckard K. Nephrol Dial Transplant. 2002.17(S5):28-31 4. Brancaccio D, Cozzolino M, Gallieni M. J Am Soc Nephrol. 2004;15 Suppl.1:S21-24
2. Rhao DS, Shih M, Mohini R. N Engl J Med. 1993;328(3):171-5 5. Santos EJF, Dias RSC, Lima JFB, etal. Int J Nephrol and Renovasc Dis. 2020;13:231-37

3. Gaweda AE, Goldsmith IJ, Brier ME, et al. Clin J Am Soc Nephrol. 2010;5(4):576-81
Anti-erythropoietin antibodies
•Several studies have reported the occurrance of acquired pure red cell aplasia (PRCA) in patients with CKD who
take rHuEPO
•Treatment with rHuEPO is well tolerated by most patients, a small number produce antibodies that can neutralize
either endogenous EPO and recombinant protein
•The anti-erythropoietin (anti-EPO) antibody production can lead to development of serious PRCA and transfusion
dependent anemia
•Pure red cell aplasia (PRCA) is a disorder characterized by anemia that leads to the almost complete absence of
erythroid cells from precursors in the bone marrow but with normal production of granulocytes and
megakaryocytes
•Treatment recommendations for patients with PRCA induced by erythropoiesis stimulating agents (ESA) are: (1)
Discontinuation of ESA; (2) correction of anemia with blood transfusion, if necessary; (3) kidney transplant and (4)
introduction of immunosuppressive therapy starting with cyclosporine A alone or in combination with
corticosteroids or corticosteroids with cyclophosphamide

1. MacDougall IC, Roger SD, Francisco A, et al. Kidney Int. 2012;81(8):727-32 3. Casadevall N. Nephrol Dial Transplant 2002;17(S5):42-47
2. Kharagjitsingh AV, Korevaar JC, Vandenbroucke JP, et al. Kidney Int. 2005;68(3):1215-22 4. Santos EJF, Dias RSC, Lima JFB, et al. Int J Nephrol and Renov Dis. 2020;13:231-37
Pure red cell aplasia
• PRCA should be strongly suspected: treated with ESA for ≥ 4 weeks has:
- a sudden, rapid decline in Hb concentration of ~ 0.5-1 g/dl/week
despite ongoing ESA therapy, or requires transfusion of 1-2 units or
red blood cells per week to maintain Hb level AND
- normal platelet and white cell counts AND
- a reticulocyte count < 10 x 109/l
• Serum ferritin and and serum transferrin concentrations rise markedly , reflecting a decrease use of
iron as red blood cell production
• A small decline in platelet count has been observed at the onset of PRCA which may reflect a
stimulatory role of erythropoietin on megakaryocytes or more complex interactions between
different precursor cell lines
1. MacDougall IC, Roger SD, Francisco A, et al. Kidney Int. 2012;81(8):727-32 3. Casadevall N. Nephrol Dial Transplant 2002;17(S5):42-47
2. Kharagjitsingh AV, Korevaar JC, Vandenbroucke JP, et al. Kidney Int. 2005;68(3):1215-22 4. Santos EJF, Dias RSC, Lima JFB, et al. Int J Nephrol and Renov Dis. 2020;13:231-37
5. KDIGO Clinical practice Guideline for anemia in CKD. Kidney Int. 2012;2 (Suppl):279-335
Angiotensin-converting enzyme inhibitors and
angiotensin II type 1 receptor blocker
• The renin-angiotensin system plays in important role in hematopoiesis, can reduce hematocrit levels or anemia
as side effect of treatment using ACEIs and ARBs
• The ACE is responsible for the hydrolysis of acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), a tetrapeptide which
naturally occurs in many body tissues
• AcSDKP is a negative regulator of erythropoiesis, inhibits the entry of hematopoietic stem cells in the S phase
of the cell cycle, keeping them in phase G0
• Several studies have shown that the use of ACEIs increased plasma tetrapeptide concentration, can cause
resistant to treatment with rHuEPO
• Ang II acts as growth factor and directly stimulates proliferation of erythroid progenitors in the bone marrow
and enhances EPO secretion, results in increased red blood cell mass
• These drugs have been associated with a dose dependent, effect can be reversible, considering to decrease
the dose or discontinue as alternative therapy
1. Lenfant M, Wdzieczak-bakala J, Guittet E, et al. Proc Natl Acad Sci USA. 1989;86(3):779-82 4. Azizi M, Rousseau A, Ezan E, et al. J Clin Invest. 1991;97(3):839-44
2. Vlahakos DV, Marathias KP, Madias NE. Am J Kidney Dis. 2010;56(3):558-65 5. Rodgers KE, diZerega JS. Front Endocrinol (Lausanne). 201323(4):157
3. Meur YL, Lorgeot V, Comte L, et al. Am J Kiney Dis. 2001;38(3):510-17 6. Cole J, Ertoy D, Lin H, et al. J Clin Invest. 2000;106(11):1391-8
 Algorithm for assessment of poor response
Assess compliance
to erythropoiesis stimulating agent
Screen for iron deficiency
(serum ferritin < 150 µg/l Give trial of IV iron as per protocol
Or TSAT < 20%
( > 70 x 109 /L)
Investigate / treat for blood
Reticulocyte count loss / test for haemolysis

CRP Treat appropriately

Infection / inflammation

Adequacy of dialysis
Kt/V < 1.2 HD Increase dialysis
Kt/V < 1.7 PD

PTH Try high dose ESA

B12 and Folate Epoetin alpha 30,000 units total
Serum aluminium weekly dose
PSA
Hb electrophoresis
On ACEI ? Rever to haemotologist / Bone marrow
Iron supplementation in patients with CKD
(pre dialysis and conservative management)
Oral iron
Should not be considered in patients on ESA therapy or those with Hb < 120 g/l (unless intolerant to IV iron). Petients on
EPO therapy and hemodialysis will require a higher degree of iron replacement than can be delivered by oral supplementation
in order to maintain recommended Hb levels

NOT ON EPO If no improvement in iron

Start ORAL IRON
Hb 120-140 g/l Status or Hb after 6 weeks
200 mg ferrous sulphate
Ferritin < 150 µg/l or not tolerated,
Up to TDS
And / or TSAT < 20% discontinue and consider IV therapy

NHS Trust
 Iron supplementation in patients with CKD
(pre dialysis and conservative management)
IV iron
Oral iron should be discontinued when the patient is receiving IV iron

Ferritin

Ferritin < 150 µg/l Ferritin 150-500 µg/l Ferritin < 150 µg/l Ferritin >500 µg/l Ferritin150-500µg/l Ferritin > 150 µg/l
TSAT < 20% TSAT < 20% TSAT > 20% TSAT < 20% TSAT > 20% TSAT > 20%

Give IV iron as protocol Discuss with Nephrologist Do Not give IV iron

Consider ESA if Hb < target
Repeat Hb, Ferritin, iron, and TIBC 2-4 weeks post IV iron infusion NHS Trust
Summary
• Anemia is common complication in chronic kidney disease, and has been
associated with increased mortality in end stage renal disease, especially in
dialysis patients
• Relative erythropoietin deficiency is the main cause of anemia
• The treatment of anemia in CKD patients usually involves the use of recombinant
human erythropoietin (rHuEPO)
• Clinical practice guidelines on the use of erythropoietin stimulating agents (ESAs)
were developed and improved with focus on evidence-based medicine
• Although ESAs are known to be effective for reversing the anemic state, the
response capacity of patients with CKD vary widely, due to the etiology of
enemia is multifactorial
Summary
• The definition of resistance to ESAs is continued need for > 20 000
IU/week (300 IU/kg/week) or 1.5 µg/kg of darbepoietin alfa (µ 100
mg/week), or has a continued need for such high dosages to maintain
the target
• Many conditions may cause apparent resistance to EASs therapy, but
the most common causes are iron deficiency, either absolute or
functional, and inflammatory disorders
• Causes of EASs resistance should be investigated, such as; chronic
inflammation, infection, malnutrition, secondary hyperparathyroidism,
inadequate dialysis, used of ACEIs or ARBs, and treated appropriately
 Key Points:
Anemia of Chronic Kidney Disease
Causes and Effects Treatments and Modulators
•  EPO production • Exogenous EPO/Erythropoesis Stimulating Agents
•  hepcidin (ESAs)
• Due to  renal clearance and  IL-6 • Causes pulsatile erythropoiesis and transient high
• Leads to:
demand for iron.
• Iron sequestration in macrophages • High doses  hepcidin but at the cost of side effects.
• Iron-restricted erythropoiesis, resistance to EPO • Iron
• True iron deficiency • Overcomes hepcidin-induced blockade of iron release
• Due to increased blood loss and hepcidin-mediated decrease from macrophages
in intestinal iron absorption. • Decrease resistance to EPO
• Supression of erythropoiesis by inflammatory cytokines • HIF-PHD inhibitors
(important in acute inflammation) • Increase uptake of iron
• Shortened erythrocyte lifespan • Increases endogenous EPO release, leads to:
• Inhibiton of downstream effects of hepcidin
• Due to inflammation and uremia
Batchelor EK, Kapitsinou P, Pergola PE, Kovesdy CP, Jalal DI. Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment. J Am Soc Nephrol. 2020;31(3):456-468. doi:10.1681/ASN.2019020213
Thank you