Iron Metabolism Disorders and

Anemia in Chronic Kidney

Diseases

Nur Samsu

Nephrology & Hypertension Division

Department of Internal Medicine FMUB
 Introduction
• Anemia is one of the laboratory and clinical findings of
CKD.
• There is an exponential relationship between decrease
GFR and anemia.
• Anemia contributes to increased COP, the development
of LVH, angina, CHF, progression of CKD.
• Iron deficiency, or its limited availability for
erythropoiesis, is an important pathogenetic mechanism
for the development of renal anemia.
• Hepcidin is currently believed to play a crucial role in the
regulation of iron metabolism.
 Systemic Iron Homeostasis

Hemodialysis International
pages S6-S20, 15 MAR 2017 DOI: 10.1111/hdi.12542
http://onlinelibrary.wiley.com/doi/10.1111/hdi.12542/full#hdi12542-fig-0001
 Intestinal Iron Absorption
Enterocyte

Fe3+ Tf Fe3+
DcytB Hephaestin

Fe2+ Fe2+ Fe2+

DMT1 Ferroportin

Heme Heme-oxygenase
Fe2+
Fe +
HCP-1
Luminal Baso-lateral
Hentze MW, et al. Cell. 2010;142:24-28
 Control of Body Iron Homeostasis by
Hepcidin
Luminal Baso-lateral
Enterocyte Macrophage
Fe3+ Tf Fe3+

DcytB
Heph HO-1

Fe2+ Fe2+ Fpn1 Fe2+ Fe2+

DMT1 -
Heme
Fe2+

Heph
+ HO-1

Fpn1
Fe
HCP-1?
-
Hepcidin
Tf-Fe+3
Fe2+ Tf Fe3+
- Hepcidin + Inflammation (IL-6, LPS)
+
Tf-Fe+3 Liver
Hentze MW, et al. Cell. 2010;142:24-28
 Regulation of Cellular Iron Homeostasis

Hemodialysis International
pages S6-S20, 15 MAR 2017 DOI: 10.1111/hdi.12542
http://onlinelibrary.wiley.com/doi/10.1111/hdi.12542/full#hdi12542-fig-0004
 Hepcidin
Master Regulator of Iron Homeostasis
• 25-AA peptide with antimicrobial potential
• Expression induced by iron in the liver
• Stimulated also by LPS and IL-6 by an iron
independent pathway
• Hepcidin over-expression leads to iron-deficient
anemia and hepcidin knock-out leads to iron overload
• Hepcidin inhibits duodenal iron absorption and
macrophage iron release
• Mechanism of action: interferes with ferroportin,
thereby leading to ferroportin degradation and
blockage of iron export
 Iron in Dialyzed Patients
• The physiological iron loss increased  iron deficiency.

• The main factor: excessive blood loss during dialysis.

• the average annual loss of iron in dialyzed patients is 1.5-2.0 g

(4.0-5.5 mg daily)

• The normal daily intake of iron is 10 to 15 mg and the maximum

absorption is about 20%.

•  the amount of iron the body can absorb from regular food is
not able to compensate for these substantial losses.

•  dialyzed patients, who receive no iron supplementation

therapy, can very easily develop a negative iron balance and
depletion of tissue iron stores.
 Is hepcidin the star player in iron
metabolism in chronic kidney disease?

Yasuhiro Hamada, Masafumi Fukagawa

Kidney International
Volume 75, Issue 9, Pages 873-874 (May 2009)
DOI: 10.1038/ki.2009.46

Copyright © 2009 International Society of Nephrology Terms and Conditions

Roles and Regulation of Hepcidin in CKD

Kidney International 2009 75, 873-874DOI: (10.1038/ki.2009.46)

Copyright © 2009 International Society of Nephrology Terms and Conditions
 Roles and Regulation of Hepcidin in CKD
• Hepcidin level was inversely correlated with eGFR in
CKD pts and was reduced by EPO therapy.
• Based on report by Ashby et al:
– Healthy subjects had a diurnal pattern of hepcidin, but not clear in
CKD pts.
– The relationship between hepcidin and ferritin was confirmed in
predialysis pts, but not in HD pts.
– There was no correlation between hepcidin and inflammation
markers (CRP; IL-6) in CKD pts (predialysis and HD).
– Plasma GDF15 (member of the BMP/TGF-β superfamily) positively
correlated with plasma hepcidin level in predialysis, but not in HD
pts.

•  iron regulation in CKD pts more complex

Ashby et al. Plasma hepcidin level are elevated but responsive to EPO therapy in renal disease.
Kidney Int 2009;75:976-981
 Factors Associated With Hepcidin Levels

Mercadel L, Metzger M, Haymann JP, Thervet E, Boffa JJ, et al. (2014) The Relation of Hepcidin to Iron Disorders, Inflammation and
Hemoglobin in Chronic Kidney Disease. PLOS ONE 9(6): e99781. https://doi.org/10.1371/journal.pone.0099781
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099781
 Factors Associated With Hepcidin Levels

Independent of mGFR, higher levels of body mass index,

albuminemia, C-reactive protein (CRP), oral iron therapy and
lower levels of proteinuria and EPO were significantly
associated with higher hepcidin concentrations

Mercadel L, Metzger M, Haymann JP, Thervet E, Boffa JJ, et al. (2014) The Relation of Hepcidin to Iron Disorders, Inflammation and
Hemoglobin in Chronic Kidney Disease. PLOS ONE 9(6): e99781. https://doi.org/10.1371/journal.pone.0099781
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099781
 Hepcidin concentration according to quintiles of ferritin (A),
transferrin saturation (B) and total iron-binding capacity (C).

Mercadel L, Metzger M, Haymann JP, Thervet E, Boffa JJ, et al. (2014) The Relation of Hepcidin to Iron Disorders, Inflammation and
Hemoglobin in Chronic Kidney Disease. PLOS ONE 9(6): e99781. https://doi.org/10.1371/journal.pone.0099781
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099781
 Pathogenesis of Anemia Associated
With CKD (renal anemia)
• EPO deficiency
• EPO resistance
• Hemodilution
• Chronic disease
• Shortened RBC lifespan from 120 to 64 days
• Iron losses (iron deficiency)
– GI bleeding
– Reduced intake
• Malnutrition
• Anemia related to ACE inhibitors/ARBs
– Increased EPO consumption
– Decreased glomerular stimulus for release
– Inhibition of hemopoetic progenitor cells

Androne AS. Circulation. 2003;107:226-229.

 Pathophysiology—Cornerstones

• Iron retention within the reticulo-

endothelial system
• Inadequate formation and function of
erythropoietin
• Impairment of erythrocyte progenitor
formation
 Pathways for Iron Retention in ACD
A collaborative work of acute phase proteins
(Hepcidin) and cytokines
Hepcidin
ACD is an immunity
Hepcidin
Fe+2 Duodenum
+ driven disease
Liver
-
Fe+2
b
+
IL-6
LPS
Monocyte IL-1 + +
Tf/TfR
TNF- Fe+2 Ferritin
α
IL-10
CD3+
IFN-γ FP-1 Macrophage
a -
-
Fe+2 +
Hepcidi
n c
Slide courtesy of Dr. G. Weiss.
Weiss G. Biochim Biophys Acta. 2009;1790:682-693.
 Cytokine Effects on Epo Production
IL-6
LPS Putative molecular mechanisms:
IL-1 • TNF-α/IL-1 induce NF-kB/GATA-2
Monocyte
TNF-α with suppression of Epo gene
promotor
IL-10
CD3+
• Cytokine mediated radical formation
IFN-γ negatively affects Epo-producing cells
in the kidney
• Interaction with Epo/EpoR signal
transduction
(JAK2/STAT5/MAPK/PKC)
- - ? • Reduction of EpoR expression on
Epo CFU-e
• Impaired Epo function because of
- reduced iron availabiltiy
Kidneys • Impaired Epo function due to
Bone marrow impaired erythroid progenitor
proliferation
Fe+2

Slide courtesy of Dr. G. Weiss.

Weiss G, Goodnough LT. N Engl J Med. 2005;352:1011-1023.
 Cytokine Effects on Erythroid Progenitor
Cell Proliferation
IL-
LPS 6 Putative molecular mechanisms:
IL-
Monocyte 1 • TNF-α -inhibitory effect via stroma
TNF-a
cells
IL-10
CD3+
• IL-1 acts primarily via IFN-g induction
IFN-abg
• IFN-γ induces apotposis of CFU-e
• IFN-γ: caspase mediated apoptosis
involving ceramide
- • IFN-γ induces NO; inhibits heme
synthesis
Epo
- • Cytokines (IFN-γ) inhibit Epo and
SCF formation and functionality
- Kidneys • Iron restriction due to
Bone marrow cytokines/hepcidin
Fe+2

Slide courtesy of Dr. G. Weiss.

Weiss G, Goodnough LT. N Engl J Med. 2005;352:1011-1023.
 ACD Diagnosis
Parameter ACD IDA
Serum iron concentration Reduced to normal Reduced
Transferrin levels Reduced to normal Increased
Transferrin saturation Reduced to normal Reduced
Ferritin Normal to increased Reduced
Serum transferrin receptor Normal Increased
sTfR/log ferritin Low (<1) High (>2)
Zinc protoporphyrin IX High High
Percentage hypochromic RBC N/A High
Cytokines (TNF, IL-1, IL-6) Increased Normal

Cytokine levels are inversely correlated with the degree of anaemia

Sole iron determination in serum is clinically not useful

Slide courtesy of Dr. G. Weiss.
Several Patients Suffer from a Combination of ACD and
Iron Deficiency (ACD/IDA) as a Consequence of
Inflammatory Anemia

Parameter ACD Both (ACD + IDA)

Serum iron Reduced Reduced

Transferrin levels Reduced to normal Reduced

TfS Reduced Reduced

Ferritin Normal to increased Reduced to normal

sTfR Normal Normal to increased

sTfR/log ferritin Low (<1) High (>2) ?

Cytokine levels Increased Increased

 Differential Diagnosis Between ACD and
ACD Plus IDA
Anaemia

Biochemical or clinical
evidence of inflammation

Transferrin saturation <16%

Rule out other causes of anaemia

Ferritin <30 mg/L Ferritin 30–100 mg/L Ferritin >100 mg/L

sTfR determination

sTfR/log ferritin >2 sTfR/log ferritin <1

ACD/IDA ACD/IDA ACD

With permission from Weiss G, Goodnough LT. N Engl J Med. 2005;352:1011-1023.
 Assessment of Iron Status in the
Setting of Inflammation and Anaemia
• Hepcidin expression is more affected by the needs of iron
for erythropoiesis than by inflammation

• Hepcidin levels closely correlate to sTfR/ log ferritin ratio

in patients with inflammation, thus both parameters can
differentiate between absolute vs functional iron
deficiency

• Haematologic indices (eg, MCH, CHr, and combinations

with sTfR) may add additional information on true iron
availability for erythropoiesis in patients with ACD and/or
sTfR/ log ferritin between 1 and 2
 Iron Therapy in Dialysis Patients

 Prospective study investigating the incidence of

infectious complications in ESRD patients
receiving IV iron therapy
― Group 1: ferritin <100 ng/mL and TfS <20%
― Group 2: ferritin >100 ng/mL and TfS >20%
― Observation period: 1 year
 Frequency of septicaemia in Group 2 was 2.5-
fold higher than in Group 1
 Too much iron may be harmful in ACD!

Plotkin SA. Clin Infect Dis. 2004;38:1030-1039.

 Iron Therapy in ACD

– May favor proliferation of pathogens

 By countering iron-withholding strategy
 By impairing immune function
– May not reach erythroid cells due to diversion into
reticulo-endothelial system
– May cause tissue damage via formation of toxic
radicals by the Fenton reaction (triggered by TNF-a).
– Iron is very poorly absorbed in ACD (down-regulation
of ferroportin in the duodenum by hepcidin)

Kaltwasser JP, et al. J Rheumatol 2001; 28:2430-2436.

Weiss G, et al. Kidney Int. 2003;64:572-578.
 Emerging therapies

– (Anti)-cytokine therapies

– Iron chelation

– Hepcidin/ferroportin agonists/antagonists

– Combination therapy

– Epo Receptor modulation