CHALLENGES IN MANAGEMENT OF

CKD ASSOCIATED ANAEMIA

Kamal Mohamed Okasha

MD Internal Medicine &Nephrology
Vice president of Tanta University
Tanta School of Medicine, Egypt
Okash70@yahoo.com
 Agenda

 What we think we know about CKD associated anemia

 Iron therapy

 ESAs therapy

 HIF – PHIs

 Take home message

 Erythropoiesis and iron metabolism

Anemia may:
• Result from inadequate erythropoietin synthesis.
• Develop early and worsen as CKD progresses.
• Occur earlier in people with diabetes.
• Involve inadequate iron intake, impaired iron absorption and chronic
inflammation.
prevalence
 Laboratory and clinical assessment of
anemia in (CKD)
• Diagnosis of anemia
 Hemoglobin
 Males: Hb <13 g/dL
 Females: Hb <12 g/dL

 Additional workup
 CBC
 RBC indices
 Ferritin
 Transferrin saturation (TSAT)
 Stool screen for occult blood
 Serum folate
 Vitamin B12
 Assessing iron status

• Serum iron
 Measures ferric iron (Fe3+), subject diurnal variation
• Total iron-binding capacity (TIBC)
 TIBC measures the amount of iron binding sites available on serum
transferrin.
• Transferrin saturation (TSAT)
 Generally reflects iron available for transport to the bone marrow
 Calculated as serum iron/TIBC x 100 = TSAT
• Serum ferritin
 Ferritin in the liver reflects stored iron, however, serum ferritin may
not be as robust in reflecting stored iron
 Acute phase reactant and will be elevated in acute & chronic
inflammation

http://www.cdc.gov/nutritionreport/report.html
 Suggested laboratory targets
to initiate iron supplementation in CKD patients

KDIGO (2012)
Parameter
ND-CKD HD-CKD

TSAT 30%< 30%<

Serum ferritin ng/mL 500≤ ng/mL 500≤

 Agenda

 What we think we know about CKD associated anemia

 Iron therapy

 ESAs therapy

 HIF – PHIs

 Take home message

 Iron Therapy (KDIGO recommendations)

• Goal: TSAT<30% and ferritin <500 ng/mL.

• CKD patients with anemia not on iron
 Increase in hemoglobin without starting ESA desired.

• CKD non-dialysis patients (ND)

 1-3 months of oral iron.
 Choice of route should be chosen based on severity of iron
deficiency, ongoing blood losses, iron status tests, Hb concentration,
ESA responsiveness, ESA dose and clinical status.
• Hemodialysis patients (HD)
• Trial of IV iron.
 Oral versus IV iron

 The KDIGO guideline does not recommend the use of oral iron in CKD-5D
patients, but suggests that either oral or IV iron may be considered in
CKD-ND patients.
 The route of administration is selected based upon the severity of anemia
and iron deficiency, the patient’s ability to tolerate oral iron, the response
to prior oral iron therapy, history of adverse reactions to intravenous iron,
and the availability of venous access.

Horl WH. Clinical aspects of iron use in the anemia of kidneydisease. J Am Soc Nephrol 2007; 18: 382–393
 Oral versus IV iron
Advantages of oral iron

 Oral iron does not require administration in the health care setting may
make it a convenient option for patients with CKD-ND.
 The preservation of the vasculature to allow for the creation of
anarteriovenous fistula may be a priority and oral administration may
therefore be favored over IV.
 Oral iron is widely available and inexpensive.

Horl WH. Clinical aspects of iron use in the anemia of kidney disease. J Am Soc Nephrol 2007; 18: 382–393
 Oral versus IV iron
Disadvantages of oral iron

 Oral iron therapy imposes a high pill burden on patients, with a typical
regimen of 200mg elemental iron per day as ferrous sulphate requiring
the patient to take multiple tablets three times per day.
 Both the high pill burden and unpleasant side effects associated with oral
iron therapy can lead to adherence issues that may ultimately limit
efficacy as well as patient quality of life.
 It should also be considered that uremia is associated with reduced
gastrointestinal absorption of iron, while chronic inflammation and
medication interactions can also impair gastrointestinal iron uptake.

Horl WH. Clinical aspects of iron use in the anemia of kidneydisease. J Am Soc Nephrol 2007; 18: 382–393
 Oral versus IV iron
Advantages of IV iron

 IV administration of iron has been demonstrated to be more effective

than oral administration with respect to the elevation of Hb, ferritin and
TSAT levels in patients with CKD-ND.
 Patients receiving IV iron have also been shown to achieve target Hb
levels more quickly.
 ESA dose requirements are lower in patients treated with IV iron
compared with those receiving oral iron.
 The ability to give large dosages of IV iron (up to 1000 mg) at one
administration, the number of required IV cannulations can be limited.

Charytan C, Qunibi W, Bailie GR. Comparison of intravenous iron sucrose to oral iron in the treatment of anemic
patients with chronic kidney disease not on dialysis. Nephron Clin Pract 2005; 100: c55–c62
 Oral versus IV iron
Disadvantages of IV iron

 Hypersensitivity reactions particularly high molecular weight iron

dextran (no longer available in most countries).
 Potential for increased oxidative stress and risk for infection .
 Because IV administration of iron bypasses physiological controls over
absorption from the gut, it has been suggested that the long-term use of
IV iron could result in the deposition of iron in the liver, pancreas and
heart, ultimately resulting in organ damage

Charytan C, Qunibi W, Bailie GR. Comparison of intravenous iron sucrose to oral iron in the treatment of anemic
patients with chronic kidney disease not on dialysis. Nephron Clin Pract 2005; 100: c55–c62
 Oral versus IV iron

Fishbane S, Block GA, Loram L et al. Effects of ferric citrate in patients with nondialysis-dependent CKD and iron
deficiency anemia. J Am Soc Nephrol 2017; 28: 1851–1858
 Oral versus IV iron

Fishbane S, Block GA, Loram L et al. Effects of ferric citrate in patients with nondialysis-dependent CKD and iron
deficiency anemia. J Am Soc Nephrol 2017; 28: 1851–1858
 IV iron dosing regimen and Formulation

Simon D. Practical considerations for iron therapy in the management of anaemia in patients with chronic
kidney disease. Clinical Kidney Journal, 2017, vol. 10, Suppl 1, i9–i15
 Agenda

 What we think we know about CKD associated anemia

 Iron therapy

 ESAs therapy

 HIF – PHIs

 Take home message

 ESAs therapy

Brand Route Half-Life

Drug Starting Dose in Adults
Name s (h)
Epoetin alfa Epogen
units/kg once weekly or 50-100
Procri
every 2 weeks (ND-CKD) IV or /)IV( 8.5
t
units/kg one to three times per 50-100 SQ )SQ( 24
week (HD)

Darbepoetin Aranesp
alfa mcg/kg once every 4 weeks (ND- 0.45
CKD) IV or
/)IV( 25
mcg/kg once per week 0.45 SQ
)SQ( 48
or
mcg/kg every 2 weeks (HD) 0.75

Methoxy Mircera
polyethylene mcg/kg SQ or 0.6 IV or
/)IV( 134
Glycol-epoetin IV once every 2 weeks SQ
)SQ( 139
beta )ND-CKD or HD(
 ESAs dose conversion

Darbepoetin alfa
Epoetin alfa dose Methoxy Polyethylene
dose
)units/week( Glycol-Epoetin Beta
)mcg/week(

mcg IV/SQ once a month or 120

8,000 < 40<
mcg IV/SQ every 2 weeks 60

mcg IV/SQ once a month or 200

to 16,000 8,000 40-80
mcg IV/SQ every 2 weeks 100

mcg IV/SQ once a month or 360

16,000> 80>
mcg IV/SQ every 2 weeks 180
 ESAs adverse events

• Common adverse events (≥20%)

 Hypertension (most common)
 Infection
 Hypotension
 Myalgia
 Nausea
 Diarrhea
• Monitoring Parameters
 Hemoglobin once weekly upon initiation of an ESA and until stable;
then once monthly.
 Evaluate transferrin saturation and serum ferritin.
ESAs RESISTANCE
ESAs RESISTANCE
 Hemoglobin target is controversial:
Boxed Warning for ESAs

• In controlled trials, patients experienced greater risks for death, serious

adverse cardiovascular reactions, and stroke when administered
erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of
greater than 11 g/dL .
• No trial has identified a hemoglobin target level, ESA dose, or dosing
strategy that does not increase these risks.
• Use the lowest ESA dose sufficient to reduce the need for red blood cell
(RBC) transfusions.
ESAs: what is the optimal treatment target
 Hemoglobin in CKD: Guidelines
Suggestions

KDIGO (2012)
ND-CKD HD-CKD

If Hb ≥ 10 g/dL do not initiate an ESA Use ESAs to avoid drop in Hb to

<9 g/dL by starting ESA when
If Hb < 10 g/dL, consider rate of fall of Hb, prior response to Hb is between
iron, risk of needing a transfusion, risk of ESA therapy, and 9 and 10 g/dL
presence of anemia symptoms before initiating an ESA
Do not use ESAs to maintain Hb
Do not use ESAs to maintain Hb above 11.5 g/dL above 11.5 g/dL

Note: Most institutions utilize their own

ESA dosing protocol with more detailed
dosing changes recommended based on Hb
response. Some protocols have lower and
upper limits of Hb that differ from
guideline suggestions.
 Agenda

 What we think we know about CKD associated anemia

 Iron therapy

 ESAs therapy

 HIF – PHIs

 Take home message

 HIF- PHIs

 Hypoxia-inducible factor prolyl hydroxylase inhibitors, belong to a new

class of oral medicine indicated for the treatment of anaemia in CKD
patients not on dialysis and on dialysis.
 Inhibition of oxygen-sensing prolyl hydroxylase enzymes stabilises
hypoxia-inducible factors, which can lead to transcription of erythropoietin
and other genes involved in the production of red blood cells and iron
metabolism.
 HIF-PHIs have been developed to provide an orally-convenient treatment
option which avoids the administration challenges and cold storage
requirements of injectable ESAs/recombinant human erythropoietin.

P Patrick. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors for Anemia in CKD. N Engl J Med 2021; 385:2390-2391
 HIF- PHIs

P Patrick. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors for Anemia in CKD. N Engl J Med 2021; 385:2390-2391
 Erythropoietic effects of hypoxia-inducible factor (HIF)

(1) HIF upregulates

divalent metal transporter
1 (DMT1) and
duodenal cytochrome B
(DcytB) to increase
(5) HIF upregulates
intestinal iron (Fe)
absorption. transferrin receptor,
increasing iron uptake
by proerythrocytes.
(2) Transferrin transports
Fe to transferrin receptors
in
the bone marrow; (3) Fe is
released from transferrin
into the developing
erythrocyte. (6) HIF promotes the
formation of fully
functional mature
(4) HIF upregulates the erythrocytes replete
erythropoietin (EPO)
with hemoglobin.
receptor
(EPO-R) and endogenous
EPO production.

P Patrick. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors for Anemia in CKD. N Engl J Med 2021; 385:2390-2391
Summary
 Agenda

 What we think we know about CKD associated anemia

 Iron therapy

 ESAs therapy

 HIF – PHIs

 Take home message

 Take home message

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

 ESAs hyporesponsivness requires rechecking of iron store status, infection and other
associated causes that may lead to ESAs resistance.
 It is better to avoid blood transfusion, but there are some situations that it may be
mandatory. RISK vs BENEFIT.
 HIF-PHIs is a new class provide an orally-convenient treatment option with
comparable efficacy to ESAs but long term safety trials are still needed.
Thank You