This document discusses anemia in chronic kidney disease (CKD). It notes that anemia is a clinical hallmark of advanced CKD, characterized by decreased hemoglobin and hematocrit levels. Around 90% of patients with a GFR below 25-30 mL/min develop anemia, many with hemoglobin levels below 10 g/dL. The main causes of renal anemia are erythropoietin deficiency and reduced red blood cell lifespan and production. Inflammation and uremic toxins also contribute by suppressing erythropoiesis and erythropoietin production. Treatment involves iron supplementation and administration of erythropoiesis-stimulating agents to compensate for reduced endogenous erythropoietin levels

1. Anemia in CKD
Arun Sedhain
DM Resident, Nephrology
NAMS
September, 2015

2. • Clinical hallmark of advanced kidney disease
• Characterized by
• decreased levels of hemoglobin and hematocrit
• content of Hb in reticulocytes (CHr)
• KDIGO/WHO:
• Hb: <13.0 g/dL for adult males and postmenopausal women and Hgb <12.0 g/dL for
premenopausal women.
• 90 % of patients with a GFR <25 to 30 mL/min have anemia (many have Hgb <10 g/dL)
• Some of the symptoms that were previously attributed to reduced renal
function are, in fact, a consequence of anemia
• Anemia also contributes to the progression of CKD

3. Prevalence
NHANES
• Diabetic patients develop anemia more frequently, at earlier stages of CKD and
more severely at a given level of renal impairment.
• In patients with PKD, Hb is on average higher than in other patients with similar
degrees of renal impairment

4. Relationship Between Hb & eGFR

5. Regulation of erythropoiesis
• Erythroid differentiation
• Erythropoiesis occurs mainly in the bone marrow, and involves the
differentiation of erythroid progenitor cells from hematopoietic stem cells
(HSCs).
• Hemoglobin synthesis
• begins in late basophilic erythroblasts and continues through to reticulocyte
maturation
• During hemoglobin production, large quantities of iron are imported into
erythroblasts, but this iron is directed towards heme synthesis

7. Pathophysiology
• Renal anemia
• Normochromic, normocytic anemia with no leukopenia or thrombocytopenia
• Reduction in both:
• RBC life span and
• Rate of RBC production
• Renal anemia is caused by underproduction of erythrocytes due to multiple
factors
• erythropoietin deficiency is most prominent and specific
• Erythropoietin (EPO)–induced compensatory increase in RBC production is
impaired in CKD.

8. Mechanism of renal anemia
• In renal anemia, the ability of the kidney to produce EPO is impaired.
• Inflammatory cytokines suppress erythropoiesis in the bone marrow,
EPO production in the kidney, and stimulate hepcidin production in
the liver, which negatively affects iron absorption and mobilization.
• Uremic toxins have been shown to suppress erythroid colony
formation in vitro as well as EPO transcription in hepatoma cells

9. Mechanism of renal anemia

10. The role of inflammation
• Systemic inflammation in renal failure is caused by
• autoimmune diseases
• infections related to diabetes mellitus and/or
• use of intravascular devices
• CKD-MBD: Bone marrow inflammatory cytokines are increased
• IL-1β acted indirectly through TNF, to suppress renal erythropoietin
production
• Inflammatory cytokines, (IL-6, TNF and IFN-γ)) inhibit differentiation of
erythropoietic progenitors.
• During erythropoiesis when iron is required for hemoglobin production,
inflammation and/or infection restricts iron supply to the bone marrow

11. Erythropoietin & kidney
• The kidney is ideally placed to regulate RBC production, as it is uniquely able to
sense and control both O2 tension and circulating volume
• Control of red cell mass is mediated by EPO
• Circulating volume is regulated by renal salt and water excretion
• Is a glycoprotein hormone consisting of a 165–amino acid protein backbone and
four complex, heavily sialylated carbohydrate chains.
• Carbohydrate chain is essential for the biologic activity of EPO in vivo
• because partially or completely deglycosylated EPO is rapidly cleared from the circulation
• This is also why rHuEPO has to be manufactured in mammalian cell lines; bacteria
lack the capacity to glycosylate recombinant proteins.

12. Erythropoietin
• Normally produced by peritubular interstitial fibroblasts in the renal cortex,
• Hepatocytes and peri-sinusoidal Ito cells in the liver can produce EPO
• 10-15%
• If GFR is normal, plasma EPO levels are inversely proportional to Hb
concentration.
• This relationship breaks down in CKD

13. • Anemia or ↓environmental O2
 ↓blood O2 content  O2 -
dependent gene expression 
↑EPO secretion.
• Factors stimulating EPO
secretion are changes in blood
oxygen content induced by
• anemia,
• reduced environmental oxygen
concentrations, and
• high altitude

14. Erythropoietin deficiency in CKD
• In the normal kidney, EPCs are recruited from peritubular interstitial
fibroblast & pericytes. Tubular epithelial cells do not produce EPO.
• Under conditions of injury, EPCs or interstitial cells with EPC potential
transd-ifferentiate into myofibroblasts, which synthesize collagen and
lose their ability to produce EPO.
• In CKD, EPC recruitment is impaired, resulting in reduced renal EPO
output and the development of anemia.
• Under conditions of severe hypoxia or in patients with advanced CKD,
the liver contributes to plasma EPO levels. Abbreviations:

15. Cellular basis of erythropoietin deficiency CKD

16. • Three HIF α-subunits have been
identified—HIF-1α, HIF-2α and HIF-3α—
however, investigations have largely
focused on HIF-1α and HIF-2α, as these
subunits have the most critical roles in
the regulation of cellular hypoxia
responses.
• In states of normal O2 tension,
intracellular HIF-1 & 2 are continuously
inactivated by (iron-dependent) proline
hydroxylation (by PHD) of their α-subunit
Role of HIF

17. • In hypoxic conditions, α subunit
hydroxylation and degradation do not
occur, and HIF α remains free to enter
the nucleus and form a heterodimer
with HIF B.
• The HIF α + HIF B heterodimer binds the
hypoxia response element (HRE) and
initiates EPO transcription.

18. • Together, HIF-1 and HIF-2 facilitate oxygen delivery and cellular
adaptation to hypoxia by controlling biological processes-
• regulation of erythropoiesis,
• anerobic metabolism,
• angiogenesis,
• mitochondrial metabolism,
• cellular growth and differentiation pathways

19. HIF coordinates erythropoietin production with iron metabolism
Koury, M. J. & Haase, V. H. Nat. Rev. Nephrol. 11, 394–410 (2015)

20. Stabilizing HIF to treat renal anemia
• Pharmacologic activation of HIF responses offers great therapeutic potential
• more physiologic approach to treating renal anemia
• Less CV risks associated with ESA
• enhanced iron absorption and mobilization
• minimize the risk of over-reaching hematologic targets
• PHD inhibitors (PHIs)-
• stimulate endogenous erythropoietin synthesis and other cellular HIF responses,
• 6 PHIs are registered in clinical trials
• AKB-6548
• BAY85-3934/Molidustat
• DS-1093
• FG-4592/ASP1517/Roxadustat
• GSK1278863
• JTZ-951

21. Other control mechanisms
• Several mechanisms exist to regulate EPO production & are potential
therapeutic targets
• GATA family of transcription factors
• Hepatocyte nuclear factor 4 (HNF-4) and
• hematopoietic cell phosphatase (HCP-1).

22. EPO beyond anemia
• Anti-apoptotic and cytoprotective effect
• EPO-R is widely distributed (e.g. neurons, cardiac myocytes, endothelial cells,
hepatocytes, and mesangial cells)
• expression is increased in response to hypoxic injury
• exogenous ESA administration might offer protection from injury in various clinical
scenarios
• On going trials:
• traumatic brain injury,
• SAH,
• MI
• cardiopulmonary bypass,
• Renal transplantation,
• Sepsis
• Short-acting ESAs with retained cytoprotective, but reduced erythropoietic, effects
are under development

23. Role of Hepcidin
• 25 amino acid peptide with anti-microbial potential
• produced and secreted by hepatocytes and expression is induced by iron
in the liver.
• Plays role in iron metabolism-
• Hepcidin knocked out mice models produce hereditary hemochromatosis with
severe multi-organ iron overload.
• In humans, most forms of hereditary hemochromatosis result from a deficiency of
hepcidin.
• Hepcidin’s biologic actions are mediated by its binding to ferroportin, the
principal cellular iron efflux channel.
• Ferroportin functions as a major exporter of iron- transports iron from mother to
fetus, transfer absorbed iron from enterocytes into the circulation, and allow
macrophages to recycle iron from damaged red cells back into the circulation
• Once hepcidin is bound, it causes the rapid internalization and degradation of
ferroportin

24. Ferroportin

25. Hepcidin contd…
• High level of hepcidin leads to anemia by preventing movement of
• Dietary iron through ferroportin into circulation
• Stored iron from liver and RE cells into the circulation
• Conversely, the absence of hepcidin leads to unregulated duodenal iron
absorption and subsequent iron overload.
• Hepcidin levels have been described in association with
• markers of inflammation (CRP, IL-6),
• anemia and
• iron status (e.g. ferritin)

26. Hepcidin as regulator of iron homeostasis

27. Regulation of
hepcidin in CKD
Nephrol Dial Transplant (2008) 23: 2450–2453

28. Initial evaluation
• In patients with CKD and anemia (regardless of age and CKD stage), include the following
tests in initial evaluation of the anemia (Not Graded):
• CBC
• Hb concentration, RBC, TLC, DLC, platelet count
• Absolute reticulocyte count
• 40,000 - 50,000 cells/μl of blood,
• Useful marker of erythropoietic activity
• Serum ferritin level
• 40 to 200 ng/ml
• < 30 ng/ml- severe iron deficiency
• Serum transferrin saturation (TSAT)
• Se. iron/TIBC x 100
• Serum vitamin B12 and folate levels

30. Frequency of testing anemia
• For CKD patients without anemia, measure Hb concentration
• when clinically indicated and
• at least annually in patients with CKD 3
• at least twice per year in patients with CKD 4–5ND
• at least every 3 months in patients with CKD 5HD and CKD 5PD
• For CKD patients with anemia not being treated with an ESA, measure
Hb concentration
• when clinically indicated and
• at least every 3 months in patients with CKD 3–5ND and CKD 5PD
• at least monthly in patients with CKD 5HD

31. Treatment

33. Use of iron to treat anemia in CKD
• Iron is an essential ingredient for heme synthesis, and adequate amounts
are required for the manufacture of new RBC.
• Iron content of a normal person : 4-5 grams (30% remains as stored iron)
• Iron loss in adult males : 0.5 to 1.5 mg daily
• Iron loss in females : 2-2.5 mg/day
• Iron loss in CKD HD : 1.5-2.0 g/ year
Examination of stainable iron in the bone marrow is the "gold standard" for
determining the iron store levels in the body
• CKD 5HD patients have reported to lose between 1–2 gm of iron/year

34. • Iron supplementation is widely used in CKD patients to
• Treat iron deficiency,
• Prevent IDA in ESA treated patients,
• Raise Hb levels in the presence or absence of ESA treatment,
• Reduce ESA doses in patients receiving ESA treatment
• IV iron can enhance erythropoiesis and raise Hb levels in CKD patients
with anemia even when
• TSAT and ferritin levels are not indicative of absolute iron deficiency, and
• Bone marrow studies reveal adequate iron stores

35. • When prescribing iron therapy, balance the potential benefits of avoiding or
minimizing blood transfusions, ESA therapy, and anemia related symptoms
against the risks of harm in individual patients
• For adult CKD patients with anemia not on iron with or without ESA therapy, a
trial of IV iron (or in CKD ND patients alternatively a 1–3 month trial of oral
iron therapy) is suggested if (2C):
• an increase in Hb concentration without starting ESA treatment is desired &
• TSAT is <30% and ferritin is <500 ng/ml
• Do not recommend routine use of iron supplementation in patients with TSAT
>30% or serum ferritin >500 ng/ml

36. Route of iron supplementation
Oral iron
• inexpensive,
• readily available, and
• Does not require IV access,
• a particular concern in CKD patients not on HD.
• Free of severe adverse effects
• GI side effects are common
• may limit adherence.
• Preparations:
• Ferrous fumarate – 106 mg elemental iron/tablet
• Ferrous sulfate – 65 mg elemental iron/tablet
• Ferrous gluconate – 28 to 36 mg iron/tablet
• Dose:
• Prescribed to provide approx. 200 mg of elemental iron daily (i.e. ferrous sulfate 325 mg three times daily;
each pill provides 65 mg elemental iron).
No evidence to suggest that other oral iron formulations are more effective or have less A/E ferrous sulfate

37. IV iron
• Avoids concerns about medication adherence and efficacy in treating iron
deficiency,
• Requires IV access and
• Associated with infrequent but severe A/Es
• Evidence support the IV route of iron administration in CKD 5HD patients
over oral iron.
• In most of these studies, IV iron administration led to a greater increase in Hb, a
lower ESA dose, or both
• Limited studies of iron administration in CKD 5PD patients indicate that
oral iron is of limited efficacy and that IV iron is superior to oral iron.

38. • IV iron may be provided as a single large dose or as repeated smaller doses
depending on the specific IV iron preparation used.
• Common practice is to provide an initial course of IV iron approx. 1000 mg,
which may be repeated if, initial dose fails to
• increase Hb level and/or
• allow a decrease in ESA dose
• Evaluate iron status (TSAT and ferritin) at least every 3 months
• during ESA therapy,
• To decide start or continue iron therapy

39. Parenteral iron preparations
• Iron dextran
• A/w acute reactions, including abdominal pain, nausea, chest pain, shortness of breath,
flushing, pruritus, rash, hypotension, and anaphylactic-like reactions.
• Initial test dose is recommended
• Sodium ferric gluconate
• Iron sucrose
• Safe
• Ferumoxytol
• Safe and effective when given as a rapid infusion of up to 510 mg in CKD-HD patients (up to
30 mg/second)
Avoid administering IV iron to patients with active systemic infections. (Not Graded)

40. Recommended Dosing regimen
• If iron therapy is indicated, :
• 125 mg of sodium ferric gluconate complex in sucrose can be given at each consecutive
hemodialysis treatment for a total of eight doses (1000 mg in total).
OR
• 100 mg iron sucrose can be given at each consecutive hemodialysis treatment for a total of 10
doses (1000 mg in total).
OR
• Ferumoxytol 510 mg, given one to four weeks apart.
• Repeat the initial loading regimen if TSAT remains <30 % and the Hb is below target.

41. • Included 13 RCTs performed between 1990 and 2008.
• Outcome measurement:
• Primary outcome: absolute Hb level or change in Hb level from baseline after 2 to 3 months of
treatment
• Secondary outcome: all-cause mortality at the end of the trial, CV morbidity and mortality,
bacterial infections, A/E
• Conclusion:
• In HD patients,
• Hb level was greater with IV iron compared with oral iron
• ESA dose was significantly decreased by the use of IV compared with oral iron
• In patients with CKD,
• In terms of Hb level, more benefit with IV iron compared with oral iron
• A/E:
• All-cause mortality, severe A/E, did not differ between groups
American Journal of Kidney Diseases, Vol 52, No 5 (November), 2008: pp 897-906

42. • Randomly allocated 136 CKD 3 & 4 patients with IDA between 2008 to 2014
• Oral iron group:
• 69 patients
• Ferrous sulfate: 325 mg TDS for 8weeks
• IV iron group:
• 67 patients
• Iron sucrose: 200 mg every 2 weeks, (total 1 g)
REVOKE

43. • Primary outcome
• between-group difference in slope of measured GFR change over two years
• GFR declined similarly in both treatment groups (oral iron –3.6 ml/min/1.73
m2/year vs IV iron –4.0 ml/min/1.73 m2/year)
• There were 36 serious CV events among 19 participants assigned to the oral iron
treatment group and 55 events among 17 participants of the i.v. iron group.
• Infections resulting in hospitalizations: 2.12 times more on i.v. iron group.
• The trial was terminated early based on little chance of finding differences in
mGFR slopes, but a higher risk of serious A/Es in the i.v. iron treatment group

44. Use of ESA
Erythropoietin
• rHuEPO was discovered in late 1980s.
• Can be given S/C or IV
• Bioavailability of S/C EPO is 20% to 30%
• Prolonged half-life of s/C than IV  allows less frequent injections.
• Little difference between the thigh, arm or abdomen as injection sites
Darbepoietin-α
• second-generation ESA that is a supersialylated analogue of EPO
• Confers greater metabolic stability and a lower clearance rate in vivo,
and the elimination T1/2 after a single i.v. use is 3 times more than
epoetin alfa (25.3 hrs vs. 8.5 hrs)
• In contrast to the EPO, same dose for i.v or S/C injection.
• Conversion factor between EPO and Darbepoietin-α
• 200:1

45. C.E.R.A. (Methoxy Polyethylene Glycol–Epoetin Beta)
• pegylated derivative of epoetin beta
• Long T1/2 life:
• 130 hrs both IV & S/C
• once-monthly administration is sufficient
• PATRONUS trial-
• Compared CERA with darbepoetin alfa (both monthly dose)
• CERA more efficient than darbepoetin alfa.

46. A/E of ESA
• Moderate increase in BP
• Increased rate of thromboembolic events
• Increased risk of malignancy
• In TREAT study- patients with a h/o malignancy were found to have an
increased rate of cancer-related deaths when treated with darbepoetin.

47. Other ESA
• Peginesatide
• EPO-mimetic peptide & has same functional and biologic properties as EPO.
• Effective treatment for anti-EPO antibody–mediated pure red cell aplasia.
• Can increase CVD risks in CKD-ND.
• Higher risks of severe anaphylactic reactions.
• HIF stabilizers
• competitive inhibitors of HIF prolyl hydroxylases & asparagyl hydroxylase, which are
involved in the metabolism of HIF.
• Being tested in Phase II and III clinical trials

48. Initiation and maintenance of ESA
• Address all correctable causes of anemia (including iron deficiency
and inflammatory states) prior to initiation of ESA therapy.
• In initiating and maintaining ESA therapy, we recommend balancing
the potential benefits of reducing blood transfusions and anemia-
related symptoms against the risks of harm in individual patients (e.g.,
stroke, vascular access loss, hypertension).

49. RCT by Canadian Erythropoietin Study Group
• 118 CKD- 5HD in 1990
• Baseline Hb- 7 gm/dL
• 3 groups:
• Placebo
• Target Hb: 9.5-11 gm/dL
• Target Hb: >11 gm/dL
• After 8 weeks of F/U transfusion was required in
• 58% in the placebo group
• 2.5% in the group with target Hb of 9.5–11g/dl
• 2.6% in the group with target Hb >11g/dl.
• After 6 months,
• significant improvements in fatigue and physical function in low Hb group compared to
placebo,
• but no improvement was observed comparing low vs high Hb group

50. CREATE study
• Open label study of 603 CKD 3–5 patients were used epoetin-beta
• 2 groups:
• Hb target of 13.0–15.0 g/dl or
• Hb target of 10.5–11.5 g/dl
• Dialysis was required in significantly
• More patients in the high Hb group than in the low Hb group.
• However the rate of fall of GFR in the two groups during the 3 year study was
similar

51. US CHOIR study
• Open label study among 1432 CKD 3–4 patients were randomized
using epoetin alfa to Hb targets of
• 13.5 g/dl and
• 11.3 g/dl
• study was prematurely stopped after an interim analysis with a
median study duration of 16 months
• 125 patients in the complete anemia correction group & 97 patients
in the standard correction group had reached the primary combined
Cardiovascular endpoint (P=0.03)

52. TREAT
• Double blinded placebo controlled largest RCT
• Tested darbepoetin-alfa in 4038 pts with DM-2 and CKD 3-4.
• 2 groups:
• Treatment group: Hb target of 13.0 g/dl
• placebo with rescue darbepoetin-alfa when the Hb concentration was <9.0 g/dl
• Median F/U duration was 29 months
• No differences in outcome
• First primary endpoints: death or a cardiovascular event
• Second primary end points: death or ESRD
• increased risk of
• Stroke in high Hb group than placebo (5% vs 2.6%)
• VTE in high hb group (2.0% vs 1.1%)

53. • For adult CKD ND patients with Hb ≥10.0 g/dl, we suggest that ESA
therapy not be initiated. (2D)
• For adult CKD ND patients with Hb ≤10.0 g/dl we suggest that the decision whether
to initiate ESA therapy be individualized (2C)
• For adult CKD 5D patients, we suggest that ESA therapy be used to avoid having the
Hb fall below 9.0 g/dl.
• In general, we suggest that ESAs not be used to maintain Hb >11.5 g/dl in adult
patients with CKD. (2C)
• In all adult patients, we recommend that ESAs not be used to intentionally increase
the Hb >13 g/dl. (1A)

54. Dose of ESA
• objective of initial ESA therapy is
• rate of increase in Hb concentrations of 1.0 to 2.0 g/dl /month.
• Epoetin-α or β
• 20 to 50 IU/kg body weight three times a week.
• Darbepoetin-α
• 0.45 mg/kg once weekly by S/C or IV
• CERA
• 0.6 mg/kg once every 2 weeks
• If the Hb increases by >1.0 g/dl in any 2-week period, the dose should be
decreased by approximately 25%

55. Monitoring of ESA
• During the initiation phase of ESA therapy,
• measure Hb at least monthly. (Not Graded)
• During maintenance
• For CKD ND patients, measure Hb at least every 3 months. (Not Graded)
• For CKD 5D patients, measure Hb at least monthly. (Not Graded)

56. ESA hyporesponsiveness
Major Minor
Poor compliance/Adherence Poor compliance, to ESA therapy
Infection Infection
Underdialysis Blood loss
Hyperparathyroidism
Aluminum toxicity (now rare)
Vitamin B12 or folate deficiency
Hemolysis
Primary bone marrow disorders (e.g., myelodysplastic syndrome)
Hemoglobinopathies (e.g., sickle cell disease)
ACE inhibitors, angiotensin receptor blockers
Carnitine deficiency
Anti-EPO antibodies causing PRCA

57. Management of Anemia in CKD

58. Blood transfusion to treat anemia of CKD
• We recommend avoiding, when possible, red cell transfusions to
minimize the general risks related to their use. (1B)
• In patients eligible for organ transplantation, we specifically
recommend avoiding, when possible, red cell transfusions to
minimize the risk of allo-sensitization.(1C)

59. Indications of Blood transfusions
• When rapid correction of anemia is required to stabilize the patient’s
condition (e.g., acute hemorrhage, unstable MI)
• Rapid pre-operative Hb correction is required
• When symptoms and signs related to anemia are present in patients
in whom ESA therapy is ineffective
• e.g., bone marrow failure, hemoglobinopathies, ESA resistance)

62. Risk of allosensitization

63. Functional iron deficiency
• Condition characterized by insufficient iron supply to RBC precursors with
apparently adequate body iron stores, as defined by
• Normal stainable iron in the bone marrow and
• Normal serum ferritin value
• Functional iron deficiency is usually diagnosed when there is a
• normal or increased ferritin level
• reduced transferrin saturation (<20%) or
• Increased hypochromic red cells (>10%).

64. • NICE recommendation
• MCV & MCH values are useful at diagnosis and in assessing trends over
periods of weeks or months
• Most reliable parameters of FID are
• Percentage hypochromic red cells (%HRC)
• Reticulocyte hemoglobin content (CHr)- CHr value <29 pg predicts FID in patients
receiving ESA therapy
• RBC zinc protoporphyrin concentration- alternative to %HRC & CHr
• Hepcidin measurement as a diagnostic tool is currently uncertain

66. Thank you