This document discusses the management of anemia in chronic kidney disease (CKD). It defines CKD and stages of CKD based on glomerular filtration rate. It then discusses the definition of anemia, prevalence of anemia in CKD patients, and the effects of anemia. The causes of anemia in CKD are listed, including erythropoietin deficiency and iron deficiency. Guidelines for hemoglobin targets and frequency of testing are provided. The document discusses iron therapy options including oral and intravenous preparations and guidelines for use. Erythropoiesis-stimulating agent (ESA) therapy is also summarized including starting doses and monitoring.

1. Management of Anaemia in CKD-
An Update
Dr. S. M. Shamsuzzaman
MD (Nephrology)
Medical Officer
Department of Nephrology
Shaheed Suhrawady Medical College Hospital

2. Definition of CKD
CKD is defined as abnormalities of kidney structure or function,
present for >3 months, with implications for health.
Criteria for CKD (either of the following present for >3 months):
1. Markers of kidney damage-
1. Albuminuria (ACR>30mg/g, AER>30mg/24hrs)
2. Urine sediment abnormalities
3. Electrolyte and other abnormalities due to tubular
disorders
4. Abnormalities detected by histology
5. Structural abnormalities detected by imaging
6. History of kidney transplantation
2. Decreased GFR<60ml/min/1.73m2

3. Staging of CKD
GFR category GFR(ml/min/1.73
m2 )
Terms
G1 ≥90 Normal or high
G2 60-89 Mildly decreased
G3a 45-59 Mildly to moderately decreased
G3b 30-44 Moderately to severely decreased
G4 15-29 Severely decreased
G5 <15 Kidney failure

4. Defining anaemia in general population
Age or gender group Hb below (g/dl)
Children
6 months to 5 years 11.0
5 to 11 years 11.5
12 to 14 years 12.0
Women > 15 years(non-pregnant) 12.0
Men > 15 years 13.0
When estimated glomerular filtration rate ( eGFR ) of less than 60
ml/min/1.73m2 should trigger investigation into whether anaemia is due to
CKD (Source: WHO global database on anaemia)

5. Anaemia Prevalence in CKD

6. Hemoglobin Levels in Patients Undergoing
Dialysis

7. Normal erythropoiesis

8. Effects of anaemia in CKD
Quality of life: anaemia results poorer quality of life
Cardiovascular: 50% of deaths in CKD are due to CV disease
Mortality : Increase of 1g/dl of Hb results in 4% decline in
mortality

9. Causes of anaemia in CKD patients
• Erythropoietin deficiency
• Iron deficiency
– Absolute iron deficiency
– Functional iron deficiency
– Reticuloendothelial block
• Decreased red cell survival
– Chronic uraemic haemolysis
– GI blood loss (often occult)
– Haemodialysis (red cell trapping)

10. Causes of anaemia in CKD patients
• Decreased bone marrow response
– ‘Uraemic inhibitors’
– Suppression of erythropoiesis by pro- inflammatory
cytokines
– Hyperparathyroidism
• Haematinic deficiencies
– Vitamin B12 deficiency
– Folate deficiency
• Relating to underlying disease
– Myeloma
– SLE
– Amyloid

11. Causes of anaemia in CKD patients
• Relating to treatment
– Immunosuppressant therapy, azathioprine, mycophenolate,
sirolimus
– Idiosyncratic reactions
• Concurrent unrelated disease
– Pernicious anaemia
– Haemoglobinopathies
– Celiac disease
– Hypothyroidism

12. Management of anaemia in CKD
• Identification of cause
• Investigations
• Therapeutic options:
– Iron administration
– ESA therapy
– Blood transfusion
• Monitoring

13. Haemoglobin Low or High?
Death and CV Complications
Hypertension
Increased Risk of Stroke
Vascular access thrombosis
Tiredness
Exhaustion
Fatigue
Shortness of Breath
Poor quality of life
High transfusion rate
Higher rate of death and
CV complications
Low Hb
High Hb

14. Challenges in anaemia management
• Common challenges faced are –
– Maintenance of stable hemoglobin levels in the patients
– Avoid overshooting Hb targets
– Balance intravenous iron & EPO
– Improve EPO response to use the lowest effective EPO
dose
• A major concern is EPO hyporesponsiveness & insufficient
iron replacement
• IV iron is important in managing these challenges to a large
extent
Kapoian T. Challenge of effectively using erythropoiesis-stimulating agents and
intravenous iron. Am J Kidney Dis. 2008 Dec;52(6 Suppl):S21-8.

15. Investigations

16. Recommended tests for evaluation of anaemia
in CKD population
Recommended initial investigations
• FBC with red cell indices
• Determine iron status:
– Serum ferritin
– TSAT
– %HRBC (percentage hypochromic red cells)
• Absolute Reticulocyte count
• CRP

17. Recommended tests for evaluation of anaemia
in CKD population
Further investigation in selected patients
• Serum vitamin B12 and folate concentration
• Parathyroid hormone concentration
• Haptoglobin levels, lactate dehydrogenase, bilirubin
• Direct Coombs test
• Serum and urine protein electrophoresis, serum
• Free light chains
• Haemoglobin electrophoresis

18. Frequency of testing for anaemia (KDIGO)
Without anaemia
• measure Hb concentration when clinically indicated
• CKD 3 - yearly
• Twice per year with CKD 4–5ND
• At least every 3 months with CKD 5HD and CKD 5PD
With anaemia not being treated with an ESA
• Measure Hb concentration when clinically indicated
• At least every 3 months in patients with CKD 3–5ND and
CKD 5PD
• At least monthly in patients with CKD 5HD
Treated with ESA
• Initial phase monthly
• CKD ND -3 monthly
• CKD 5D- monthly

19. Frequency of Iron Status Tests
According to NKF KDOQI-
• Every month during initial ESA treatment
• At least every 3 months during stable ESA treatment or in
patients with HD-CKD not treated with an ESA

20. Guidelines for target indices in CKD associated
anaemia
Hb
target(gm/dl)
Iron indices
KDOQI 11.0-12.0
(avoid >13)
Ferritin
>200 micrograms/L (HD)
>100 micrograms/L (non-HD )
UK Renal
Association
11.0-12.0 Ferritin
200 -500 micrograms/L (HD)
>100 - 500micrograms/L ( non-HD )
or
TSAT > 20%
or
%HRBC < 6%

21. Iron therapy

22. Iron metabolism
•Daily diet contain 15-20 mg of iron and only 10% is absorbed
•Haem iron is better absorbed than non-haem iron
•Ferrous iron absorbed better than ferric iron
•Gastric acidity helps to keep iron in ferrous state
•Absorption is favored by acidity of stomach

23. Iron requirements
• For adult men and menopausal women:8mg/day
• For menstruating women:18 mg/day
• Pregnancy :27 mg/day
• Lactating women : 9-10 mg/day
• Dietary requirement of iron is about 10 times of the actual
requirements because only 10% of dietary iron is absorbed

24. Iron stores
• 65% as Hb
• 29% as ferritin
• 4% as myoglobin
• 2% as enzyme

25. Iron deficiency in CKD
• Occult blood loss
• Infection
• Systemic inflammatory conditions
• Surgical procedures
• Venipuncture
• Impaired absorption secondary to elevated hepcidin
concentrations
• In dialysis, retention of blood by the dialysis apparatus.(≥2,000
mg of iron per year)

26. Iron deficiency in CKD patient
Types of iron deficiency anaemia in CKD-
• Absolute iron deficiency
• Functional iron deficiency
• Reticuloendothelial Block

27. Role of Hepcidin in iron absorption
• Hepcidin, an acute phase
reactant may play a role by
preventing the release of
iron from macrophages to
circulating transferrin

28. When to Treat With Iron in CKD (KDIGO)
• For adult CKD patients with anaemia not on iron or ESA
therapy we suggest a trial of IV iron (or in CKD ND patients
alternatively a 1–3 month trial of oral iron therapy) if :
• an increase in Hb concentration without starting ESA
treatment is desired and
• TSAT is ≤30% and ferritin is ≤500 ng/ml (500 μg/l)
• For adult CKD patients on ESA therapy who are not
receiving iron supplementation, we suggest a trial of IV iron
(or in CKD ND patients alternatively a 1–3 month trial of
oral iron therapy) if :
• an increase in Hb concentration or a decrease in ESA dose
is desired and
• TSAT is ≤30% and ferritin is ≤500 ng/ml (500 μg/l)

29. Route of Iron therapy
• CKD on dialysis patient is preferred parenteral Iron
• For CKD ND patients who require iron supplementation,
select the route of iron administration based on the
• severity of iron deficiency
• availability of venous access
• response to prior oral iron therapy
• side effects with prior oral or IV iron therapy
• patient compliance and cost.
• .

30. Iron therapy
• Iron preparation:
- Oral
- Intravenous

31. Dose and duration of oral therapy
•Typically for iron replacement, upto 200mg of elemental iron
per day is given usually as three or four iron tablets(each
containing 50-65 mg elemental iron) given over the course of the
day
•Ideally, oral iron should be taken on an empty stomach, since
food may inhibit iron absorption
•The goal of therapy with IDA, is not only to repair anaemia but
also to provide stores of at least 0.5-1 gm of iron
•Sustained treatment for a period of 6-12 months after correction
of anaemia will be necessary to achieve this

32. Response of oral therapy
•Reticulocyte count should begin to increase within 4th -7th days
after initiation of therapy and peak at 1-11/2 weeks
•Hb increase on 7th day
•Tongue papillae regenerate
•Fissuring of mouth angle disappear
•Brittle flattened nails are replaced

33. Failure to response oral therapy
•Incorrect diagnosis
•Noncompliance (which is common)
•Difficulty with absorptionIron tolerance test
•Iron loss > amount ingested

34. Parenteral iron preparation
•Iron dextran
•Ferric gluconate
•Iron sucrose
•Ferric carboxymaltose
•Ferumoxytol

35. Parenteral iron preparation
Indications
• When oral form is
intolerable
• If iron loss exceeds oral iron
• Inflammatory bowel disease
• Dialysis patients
• Anaemic cancer patients
Contraindications
•History of allergy
•H/O previous serious reaction

36. Use of Intravenous Iron
Iron dextran
Complex
Iron Sucrose
complex
Ferric
carboxymaltose
Dose of
elemental iron
50mg/ml 20mg/ml 50mg/ml
Test dose
required
Yes before
every iv dose
First dose
new patients
only
No
Able to
administer
total dose
Yes
up to 20mg/kg over
4-6 hours
No Yes
up to 20mg/kg
maximum of
1000mg/week
over 15 mins

37. ESA therapy

38. EPO and the kidney
• Erythropoietin regulates erythropoiesis
• Glycosylated polypeptide(165 AA)
• Mostly produced in the peritubular interstitial fibroblasts in
deep cortex and outer medulla of kideny ; liver is an important
source in fetal life
• No preformed stores
• Produced in response to low oxygen tension in the tissues of
kidneys
• Normal erythropoietin conc in man 10-30mu/ml
• Half life 5-9 hrs
• Endogenous production 2-4unit/kg/24 hr

39. Starting ESA
• Various types of ESA, but efficacy almost same
• Route of administration: SC or IV
• Hb and BP should be measured 2-4 weekly at first and after a
dose change
• Aim for increased Hb of 1-2gm/dl/month until target achieved
• 25% increments of dose monthly if slow Hb rise
• 25-50% reduction of dose if Hb rises >2gm/dl in a month
• An intercurrent illness may reduce Hb; temporary increase of
dose can be consider

40. According to KDIGO
• Address all correctable causes of anaemia prior to initiation of
ESA therapy
• For adult CKD ND pt with Hb ≥10gm/dl, ESA therapy not to
be initiated
• For adult CKD ND pt with Hb <10gm/dl,decision to initiate
ESA therapy be individualized
• For adult CKD 5D ESA therapy needed to start when Hb is
between 9-10gm/dl, to avoid fall of Hb <9gm/dl

41. According to KDIGO
• In general, ESA not be used to maintain Hb >11.5gm/dl
• ESA not be used to intentionally increase Hb >13gm/dl
• When Hb approaches 11.5gm/dl, ESA dose should be reduced
by 25%. If Hb continues to increase, dose should be
temporarily withheld until Hb begins to decrease, at which
point therapy should be reinitiated at a dose approximately
25% below the initial dose

42. ESA Dosing
Generic name Half life Initial dosing
Epoetin α 4-8h 80-120IU/Kg /wk
Epoetin ß 4-12h 80-120IU/Kg /wk
Darbepoetin α 21-25h 0.45 micrograms/Kg /wk
Methoxy polyethelene
glycol epoetin ß (CERA)
130h 0.6 micrograms/Kg
fortnightly, then monthly

43. Side effects of ESA therapy
• Worsening of hypertension
• Seizures
• Graft clotting
• Stroke
• PRCA
• Anaphylactoid reaction

44. ESA hyporesponiveness
• Initial ESA hyporesponiveness:
- If no increase in Hb concentration from baseline after the
1st month of ESA treatment on appropriate weight-based
dosing
• Subsequent ESA hyporesponsiveness:
- If after treatment with stable doses of ESA, require 2
increases in ESA doses upto 50% beyond the dose at which
they had been stable in an effort to maintain a stable Hb
concentration

45. ESA hyporesponiveness
Major causes
• Iron deficiency
• Infection
• Inflammation
• Underdialysis
Minor causes
• Poor compliance
• Blood loss
• Hemolysis
• vitamin deficiency
• Hemoglobinopathies
• ACEi, ARB
• Primary bone marrow
disease
• Anti EPO antibody

46. Practical approach in presence of ESA
hyporesponsiveness

47. ESA hyporesponiveness
• Management:
- Correction of underlying cause, if possible
- Maximize ESA doses no greater than 4 times the initial
weight based appropriate doses
- Blood transfusion

48. Blood transfusion

49. Indication of blood transfusion
Acute clinical situation
•Acute severe hemorrhage
•Unstable coronary artery disease
•When rapid preoperative Hb
correction is required
Chronic clinical situations
• Chronic anaemia and ESAs are ineffective
• Hemoglobinopathies
• bone marrow failure
• ESA resistance
Special chronic clinical situations
Chronic severe symptomatic anaemia and
a relative contraindication to an ESA
(e.g., current or previous malignancy, previous stroke

50. Risk of Transfusion Therapy
• Immediate
– Fluid overload
– Bacterial infection
– Graft Vs host disease
– Allergic reaction to patient
• Long Term
– Red blood cell sensitization
– Anti HLA allo immunization
– Iron overload
– Transmission of viral disease

51. Emerging treatment in CKD Anaemia

52. Hypoxia Sensing: The HIF System
• The body’s sensing of tissue hypoxia, and thereby
recognition of anaemia, occurs by the HIF system.
• Central to this function are 2 proteins, HIF-α and HIF-β.
HIF-α is continually produced, but when sufficient oxygen is
present, it is rapidly “marked” (hydroxylated) for degradation
by enzymes, the HIF-prolyl hydroxylases. The prolyl
hydroxylases work as oxygen sensors because they require
oxygen as a co-substrate. After hydroxylation, HIF-α is
recognized by the von Hippel-Lindau protein,
polyubiquitinated, and destroyed.
• When tissue hypoxia occurs, HIF-α accumulates, translocates
to the nucleus, forms a heterodimer with HIF-β, and binds to
hypoxia response elements of a large number of oxygen-
sensitive genes.

53. Hypoxia Sensing: The HIF System
• One of these is the erythropoietin gene, leading to increased
erythropoietin production. Numerous other genes, including
those coding for enzymes and transporters involved with iron
metabolism, angiogenesis, and mitochondrial genesis, are
also stimulated.
• HIF-2 appears to play a greater role in the regulation of
erythropoietin production and activation of iron metabolism
genes.
• Small-molecule inhibitors of prolyl hydroxylases, which in
effect stabilize HIF-α, are currently being studied for the
potential treatment of anaemia in patients with CKD. By
stimulating the production of erythropoietin and iron-
regulatory proteins, a concerted approach to anaemia
treatment may be achievable.

54. Hypoxia Sensing: The HIF System

55. Hypoxia-Inducible Factor Prolyl Hydroxylase
Inhibitors
• Roxadustat
• Vadadustat
• Daprodustat
• Molidustat

56. Roxadustat
• This novel agent treat anaemia of CKD
"through multiple pathways, beyond increasing
erythropoietin levels, by means of effects on
inflammation and iron handling, and
particularly by decreasing the hepcidin level.
• Adverse effects were not properly evaluated.
• Multiple trials of ESAs have shown, at best, no
improvement in outcome, and at worst,

57. Roxadustat
• Mechanism of action Roxadustat is a hypoxia-inducible factor,
prolyl hydroxylase inhibitor (HIF-PHI).
• Through the reversible inhibition of HIF-PH, roxadustat
stimulates a coordinated erythropoietic response that includes
the
– increase of plasma endogenous erythropoietin (EPO)
levels, regulation of iron transporter proteins
– reduction of hepcidin (an iron regulator protein that is
increased during inflammation in CKD). This results in
improved iron bioavailability, increased Hb production and
increased red cell mass.

58. Roxadustat
• The appropriate dose of roxadustat must be taken orally tab
70-100 mg three times per week and not on consecutive days.
The dose should be individualised to achieve and maintain
target Hb levels of 10 to 12 g/dL as

59. Hepcidin antagonist-
• PRS-080#22, a novel, rationally engineered
PEGylated (polyethylene glycol bound)
Anticalin protein that antagonizes hepcidin
with picomolar affinity.
• Anticalin proteins are a novel class of small,
highly stable proteins with designed ligand-
binding properties derived from the natural
human lipocalin scaffold.
• Lipocalins are a widespread family of low
molecular weight binding proteins that

60. Take home message
• Avoid injudicious Blood transfusion
• Adequate iron supply is necessary for optimum ESA response
• When Hb is >10gm/dl, ESA therapy not to be initiated
• Aim for increased Hb of 1-2gm/dl/month until target achieved,
beyond that 25-50% dose should be adjusted
• Hb should be monitored 1-3 monthly
• Side effects should take in corncern
• Novel therapies may be a hope in future

61. QUESTION 1
A 54-year-old man with diabetes mellitus, hypertension, and
coronary artery disease is being treated for chronic kidney disease
(CKD). His estimated glomerular filtration rate has declined over
the past 2 years from 40 to 14 mL/min/1.73 m2. The patient
reports increased fatigue and asks about the causes of his
anaemia. Red blood cell indexes are normal, and iron test results
and serum folate and vitamin B12 concentrations are found to be
normal.
Question 1: What is the most likely cause or causes of the
patient’s anaemia?
a) Diabetes mellitus
b) Relative erythropoietin deficiency
c) Iron deficiency
d) Multiple myeloma
Answer to Question 1: (b) In stage
5 CKD, anaemia is common,
especially among patients with
diabetes. Diabetes is not the cause
of the anaemia. Rather, relative
erythropoietin deficiency is the
primary causal factor

62. Question 2
Question 2: Which factor is most responsible for sensing
cellular hypoxia?
a) Erythropoietin
b) Hepcidin
c) Hypoxia-inducible factor (HIF)-prolyl hydroxylase
d) Fibroblast growth factor 23
e) Ferroportin
Answer to Question 2: (c) Hypoxia-inducible factor (HIF)-
prolyl hydroxylase plays the central role in oxygen sensing.
In the presence of sufficient oxygen, prolyl hydroxylases
(PHDs) “tag” HIF with ubiquitin, triggering degradation.
When hypoxia is present, HIF is stabilized and interacts with
and promotes transcription of many genes responsible for
cellular protection against hypoxia, including erythropoietin.

63. Question 3
A 76-year-old woman with diabetes mellitus and stage 4 CKD is evaluated for
progressive anaemia. Blood test results are notable for the following values:
serum potassium, 5.5 mEq/L; serum creatinine, 3.2 mg/dL; and serum calcium,
12.6 mg/dL. Hb concentration is 7.5 g/dL with normal erythrocyte indexes.
Serum ferritin concentration is 358 ng/mL and TSAT is 20.2%.
Question 3: In addition to erythropoietin deficiency, what other cause of
anaemia is important to exclude in this case?
a) Iron deficiency
b) Hyperparathyroidism
c) Malignancy
d) Hypothyroidism
e) Endocarditis
Answer to Question 3: (c) The patient’s level of kidney
function is sufficiently diminished to indicate that relative
erythropoietin deficiency is probably present. However,
as part of a complete evaluation of anaemia,
hypercalcemia was identified. When present in CKD,
hypercalcemia should always suggest the possibility of a
malignancy (in CKD, patients generally have a normal or
low serum calcium concentration). The triad of anaemia,
reduced kidney function, and hypercalcemia might place
special emphasis on the possibility of multiple myeloma.

64. Question 4
Case: A 28-year-old woman with systemic lupus initiates hemodialysis
treatment after a long course of various immunoregulatory treatments. As she
begins dialysis therapy, epoetin alfa treatment is started as well, with an Hb
concentration of 7.1 g/dL. The Hb concentration increases over 2 months to
9.8 g/dL but fails to increase further despite subsequent increases in her
epoetin dose. She reports continued fatigue. Her lupus is inactive by symptoms
and serologic test results. Erythrocyte indexes are normal, serum ferritin
concentration is 26 ng/mL, and TSAT is 13.7%.
Question 4: What would be the next step in anaemia treatment?
a) Increase lupus treatment drugs
b) Increase dialysis time
c) Increase the epoetin dose further
d) Change to peritoneal dialysis
e) Treat with IV iron
Answer to Question 4: (e) During the fairly large
increase in hemoglobin concentration from 7.1 to
9.8 g/dL, large quantities of iron were transferred
from the body’s storage pools to the developing
erythron. Iron deficiency frequently develops
during the first months of recombinant human
erythropoietin therapy for this reason. The best
answer is to add treatment with intravenous iron.

65. References
• Update on anaemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018
• Comprehensive clinical nephrology (6th edition)
• Oxford handbook of nephrology and hypertension (2nd edition)
• KDIGO clinical practice guideline for anaemia in CKD-2012
• Handbook of dialysis- 5th edition
• Renders L, Budde K, Rosenberger C, van Swelm R, Swinkels D, Dellanna F, et al.
(2019) First-in-human Phase I studies of PRS-080#22, a hepcidin antagonist, in
healthy volunteers and patients with chronic kidney disease undergoing
hemodialysis. PLoS ONE 14(3): e0212023.
https://doi.org/10.1371/journal.pone.0212023
• Pablo E, Pergola, Steven Fishbane, and Tomas Ganz (2019) Novel Oral Iron
Therapies for Iron Deficiency anaemia in Chronic Kidney Disease. Adv Chronic
Kidney Dis. 26(4):272-291
• New Oral Agent for anaemia in CKD Encouraging but Questions Remain Pam
Harrison. News > Medscape Medical News July 25, 2019