IRON MANAGEMENT IN

CHRONIC KIDNEY
DISEASE
SPEAKER’S
Based GUIDE
on the 2014 KDIGO Controversies Conference
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EDUCATIONAL GRANT FROM

Kidney Disease: Improving Global Outcomes

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Kidney Disease: Improving Global Outcomes

PART 1:
IRON DEFICIENCY VS.
OVERLOAD

Kidney Disease: Improving Global Outcomes

 CAUSES OF ABSOLUTE IRON
• DEFICIENCY
Blood losses associated with: 1–3

– Laboratory tests and hospitalization

– HD (from dialyzer and access)

Healthy Patient Non-dialysis CKD Hemodialysis

Patient Patient
Daily Blood Loss 0.83 ml/d 3.2 ml/d 5.0 ml/d
Annual Blood Loss 0.3 L/yr 1.2 L/yr 2–5 L/yr
Annual Iron Loss 0.1 g/yr 0.4 g/yr 1–2 g/yr to
4–5 g/yr

1. Sargent JA et al. Blood Purif 2004;22:112-113.

2. Rosenblatt SG et al. Am J Kidney Dis 1982;1:232-236.
3. Wizemann V et al. Kidney Int Suppl 1983;16:S218-S220.

Kidney Disease: Improving Global Outcomes

 CAUSES OF ABSOLUTE IRON
DEFICIENCY
• GI losses due to anticoagulant or antiplatelet drugs.
• Reduced iron absorption due to medications (e.g., proton
pump inhibitors and phosphate binders).
• Reduced iron absorption due to increased hepcidin levels.
• Reduced iron intake due to poor appetite, diet, and
malnutrition.

Kidney Disease: Improving Global Outcomes

 CAUSES OF FUNCTIONAL IRON
DEFICIENCY
• Inflammation results in:
– Sequestration of iron within reticuloendothelial system (RES).
– Reduced total iron binding capacity.
– Lowered absolute amount iron available for erythropoiesis.

ESAs can create increased demand for iron and worsen iron availability in
chronically inflamed patients.

Kidney Disease: Improving Global Outcomes

 MEASURING IRON DEFICIENCY
• Both ferritin and TSAT have shortcomings when used to assess
iron status.
• Ferritin 200 µg/l is frequently used as a cutoff value in dialysis
patients.
• Although evidence is limited, TSAT <20% generally indicates
absolute iron defiency.1 However, TSAT >20% does not exclude
this condition.
• In CKD patients, ferritin and TSAT should be used together. 1,2
• Percentage of hypochromic red cells and reticulocyte Hb content
can indicate inadequate iron supply, but the method is not
practical for wide adoption.
1. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl. 2012;2:279–335.
2. NICE Guideline No. 8, 2015.

Kidney Disease: Improving Global Outcomes

 IRON DOSING
• Precise dosing to correct iron deficiency is uncertain, since the
true amount of iron loss is unknown.
• In general, IV iron doses >3 g/yr are likely to be associated
with an increased risk of exceeding the ongoing iron loss and
inducing positive iron balance.
• The consequences of applying IV iron in excess of ongoing
losses remain unknown.
• Higher IV iron requirements should prompt investigation of
increased losses (especially GI).

Kidney Disease: Improving Global Outcomes

 IRON DEPOSITION IN THE LIVER

Intravenous iron is
deposited and stored
in Kupffer cells of the
reticuloendothelial
system (RES) which is
the iron storage
system of the liver

Iron can also be

deposited in
hepatocytes of the
liver parenchyma

Liver: structure of human liver. Art. Encyclopædia Britannica Online. Web. 07 Dec. 2015. http://www.britannica.com/science/liver/images-videos/Microscopic-structure-of-the-liver-
Liver-cells-or-hepatocytes-have/60419 >

Kidney Disease: Improving Global Outcomes

 IRON COMPARTMENTALIZATION IN
It has been hypothesizedTHE BODY iron excess and labile
that parenchymal
iron can be harmful while iron sequestered within cells of the
reticuloendothelial system may be of less concern

Size of the circles

denotes the relative
proportion of iron in
various compartments

Source: Hoffmann Hematology Basic Principles and Practice, 2012

Kidney Disease: Improving Global Outcomes

 DEFINING IRON OVERLOAD
• No feasible method exists to determine total body iron
content.
• Iron overload is a condition of increased body iron content.
– Possibly associated with risk of organ dysfunction
• Pathologic iron overload is a condition of increased total body
iron content with signs of organ dysfunction.
– Described for hematological diseases (e.g., hemochromatosis)

Kidney Disease: Improving Global Outcomes

 ASSESSING IRON OVERLOAD
• Elevated serum ferritin does not always correlate with
elevated liver iron content.
• High ferritin + high TSAT can be of particular concern based on
observations in hereditary hemochromatosis and transfusion-
induced iron overload.

Kidney Disease: Improving Global Outcomes

FERRITIN: ASSESSING IRON OVERLOAD
• Hyperferritinemia is not synonymous with iron overload.
• Serum ferritin does not differentiate iron stored in
parenchymal cells or RES.
– Serum ferritin does not always correlate with liver iron content
• Experience from patients with hemochromatosis suggest that
combination of high TSAT and ferritin may be better indices as
markers of parenchymal iron excess.

Kidney Disease: Improving Global Outcomes

 MRI: ASSESSING IRON OVERLOAD
• MRI has been shown to be reliable for detecting tissue iron
content in the non-CKD population.
• However, there is limited experience in HD patients.
• The relevance of increased liver iron content in the absence of
elevated liver enzymes is unclear.
• There is insufficient evidence to use MRI to guide IV iron
therapy.

Kidney Disease: Improving Global Outcomes

 IRON OVERLOAD: HEMATOLOGICAL
DISORDERS
• Organ toxicity associated with iron overload depends upon
the magnitude and speed of iron accumulation.
• The main target organs are liver, myocardium, endocrine
glands, and joints.

Kidney Disease: Improving Global Outcomes

 ORGAN TOXICITY INDUCED BY IRON
OVERLOAD
• The magnitude, distribution, and duration of iron overload in
CKD may be insufficient to produce similar toxicity as
observed for hematological disorders.
• Given that IV iron use has increased markedly in HD over the
last few years, the exposure may not have been long enough
to detect toxicity.
• End-organ damage has not been established unequivocally;
therefore, the toxicity of repeated high-dose IV iron cannot be
excluded.

Kidney Disease: Improving Global Outcomes

 CASE STUDY: “BARRY”
• 58-y.o.male on HD for 3 yrs
• End-stage kidney failure due to hypertensive nephropathy
• Known chronic liver disease due to hepatitis C
• On EPO alfa 4000 units x3 per week + IV iron 200 mg monthly
• Lab results
o Hb 9.4 g/dL
o Ferritin 1145 µg/L
o TSAT 18%
o CRP 2 mg/L

Kidney Disease: Improving Global Outcomes

 CASE STUDY: “BARRY”
What would you do next?
A. Continue present dose of EPO and IV iron
B. Increase his dose of EPO and continue IV iron
C. Increase his monthly prescription of IV iron and continue
same dose of EPO
D. Increase both his dose of EPO and his monthly dose of IV iron
E. Continue EPO and reduce monthly iron dose

Kidney Disease: Improving Global Outcomes

PART 2:
OXIDATIVE STRESS

Kidney Disease: Improving Global Outcomes

 OXIDATIVE STRESS IN CKD
• Oxidative stress early in CKD and is thought to herald poor
prognosis.
• It results from an overproduction of reactive oxygen/nitrogen
species or impairment in the cellular antioxidant enzymatic
activities, leading to oxidation of macromolecules.
• Markers (NO2, HOCl, and OH) are present in uremic plasma
and are thought to be the fingerprints of increased oxidative
stress.
• However, diagnostic tools and the relevance of these markers
to guide therapy in CKD are not established.

Kidney Disease: Improving Global Outcomes

 IV IRON, OXIDATIVE STRESS, AND CV
RISK
• IV iron promotes oxidative damage of peripheral lymphocyte
DNA1 and endothelial dysfunction.2,3
• However, the question of how IV iron accelerates
atherosclerosis remains unresolved.
• Accumulation of iron in plaques has not been proven to
promote CV disease.
• Limitations of observational studies do not allow any firm
conclusions to be made on IV iron dose and CV risk.

1. Kuo KL et al. J Am Soc Nephrol. 2008;19:1817-1826.

2. Kamanna VS et al. Am J Nephrol. 2012;35:114-119.
3. Rooyakkers TM et al. Eur J Clin Invest. 2002;32 (Suppl 1): 9-16.

Kidney Disease: Improving Global Outcomes

 HEPCIDIN AND CV RISK
• Some studies suggest that hepcidin upregulation may increase
CV risk in the general population. However, there is limited
evidence in CKD patients.

Potential mechanism of
hepcidin-mediated plaque
instability

Source: Li JJ, et al. Arterioscler Thromb Vasc Biol. 2012;32:1158–1166.

Kidney Disease: Improving Global Outcomes

 FERRITIN AS A RISK FACTOR
• Like hepcidin, ferritin is just as likely to reflect an
inflammatory response as an iron-replete state.
• In the general population, elevated serum ferritin is
associated with increased risk for MI and carotid plaques.
• In CKD patients, the association between ferritin levels and
outcomes is not clear.
• Prospective controlled studies are needed to assess whether
elevated ferritin merely represents a risk marker or is an
actual risk factor.

Kidney Disease: Improving Global Outcomes

 ANTIOXIDANTS AND IRON
SUPPLEMENTATION
• Some studies have shown benefits of limited antioxidant
treatments on lipid peroxidation.
• However, a recent RCT in HD patients did not show beneficial
effects of antioxidative therapy.1
• No definitive conclusion can be drawn as to whether iron-
related oxidative stress responds to antioxidant therapy.

1. Himmelfarb J, et al. J Am Soc Nephrol. 2014;25:623–633.

Kidney Disease: Improving Global Outcomes

 CASE STUDY: “JOHN”
• 68-y.o. male on HD for 6 yrs
• On EPO and IV iron to maintain ferritin levels above KDIGO
minimum
• Wants to stop IV iron because of his concerns about “oxidative
stress”

Kidney Disease: Improving Global Outcomes

 CASE STUDY: “JOHN”
What would you do next?
A. Agree to John’s request and stop IV iron without further
discussion
B. Tell John you will run some tests to assess oxidative stress
level
C. Continue with IV iron after explaining the reasons for
confusion in the medical literature
D. Do options B and C

Kidney Disease: Improving Global Outcomes

PART 3:
RISK OF INFECTIONS

Kidney Disease: Improving Global Outcomes

 IV IRON: INFECTION RISK IN HD
PATIENTS
• Critical review1 of studies (largely observational) evaluating
infection risk association with a) ferritin, and b) iron usage:
– Ferritin: 9 showed association (1.5- to to 3.1-fold higher incidence of
infection or infection-related mortality), 4 did not.
– Iron usage: 12 showed association (14%–45% higher risk of infection-
related mortality), 10 did not.
• Bolus dosing was reported to show higher risk than
maintenance dosing for patients with a catheter and history
of infection.2
– In contrast, maintenance dosing or low dosing was not associated with
increased risk.

1. Ishida JH, Johansen KL. Semin Dial. 2014;27:26–36.

2. Brookhart MA, et al. J Am Soc Nephrol. 2013;24:1151–1158.

Kidney Disease: Improving Global Outcomes

IV IRON IN HD: INFECTION-RELATED
Association ofOUTCOMES
IV iron dose and cause-specific mortality in HD. 1

IV iron dose is the total 4-month dose, expressed as average mg/month.

1. Bailie G, et al. Kidney Int. 2015;87:162–168.

Kidney Disease: Improving Global Outcomes

IV IRON IN HD: INFECTION-RELATED
Relationship between IV iron dose and infection-related hospitalization. 1

Duration of Iron
Exposure
OUTCOMES Doses (mg) N (Hosp.) Infectious Hosp:
HR (95% CI)
None 2187 0.92 (0.76, 1.11)
>0 to 150 1200 1 (ref)
1 month
>150 to 350 1648 0.94 (0.77, 1.15)
>350 1825 0.91 (0.77, 1.09)
None 1047 1.03 (0.81, 1.33)
>0 to 450 1381 1 (ref)
3 months 2151 1.01 (0.81, 1.25)
>450 to 1050
>1050 1513 1.08 (0.86, 1.36)
None 399 1.15 (0.79, 1.68)
>0 to 900 1383 1 (ref)
6 months
>900 to 2100 2589 0.94 (0.75, 1.19)
>2100 845 1.26 (0.94, 1.69)

1. Tangri N, et al. Nephrol Dial Transplant. 2015;30:667–675.

Kidney Disease: Improving Global Outcomes

IV IRON IN HD: INFECTION-RELATED
OUTCOMES
Association between IV iron and CV or sepsis-related mortality.
1

1. Zitt E, et al. PLoS ONE. 2014;9:e114144.

Kidney Disease: Improving Global Outcomes

 STUDIES IN PD AND NONDIALYSIS
PATIENTS
• One study showed more peritonitis episodes in PD patients
after IV iron infusion.1
• A recent single-center RCT (REVOKE) also showed IV iron was
associated with higher rate of adverse events; however, the
findings are controversial.2
• The FIND-CKD global multicenter study (non-dialysis CKD
patients) found that the incidence of infections and CV events
was identical for high-ferritin, low-ferritin, and oral iron
groups.3

1. Prakash S, et al. Perit Dial Int. 2001;21:290–295.

2. Agarwal R, et al. Kidney Int. 2015;88:905–914.
3. Macdougall IC, et al. Nephrol Dial Transplant. 2014;29:2075–2084.

Kidney Disease: Improving Global Outcomes

 REVOKE STUDY

REVOKE1
Oral ferrous sulfate IV iron sucrose
Patients 69 67
Study Period 104 weeks
SAE (%) 40 (58) 37 (55)
SAE infections (%) 11 (16) 19 (28)

1. Agarwal R, et al. Kidney Int. 2015;88:905–914.

Kidney Disease: Improving Global Outcomes

 FIND-CKD STUDY

FIND-CKD1
Oral ferrous sulfate IV ferric
carboxymaltose
Patients 312 304
Study Period 56 weeks
SAE (%) 59 (19) 75 (25)
SAE infections (%) 12 (3.8) 11 (3.6)

1. Macdougall IC, et al. Nephrol Dial Transplant. 2014;29:2075–2084.

Kidney Disease: Improving Global Outcomes

 EXISTING EVIDENCE: INCONCLUSIVE
• Studies in HD, PD, and non-dialysis CKD patients provide
conflicting evidence for the association between IV iron and
infection risk.
– Most data are derived from observational studies in HD (subject to
confounding) and the few RCTs conducted to date were of short
duration or underpowered to assess the risk of infection
• Current KDIGO recommendations are still prudent which calls
for:
– balancing potential benefits vs. risks of IV iron
– avoiding IV iron use in patients with active systemic infections

Kidney Disease: Improving Global Outcomes

 CASE STUDY: “TAMMY”
• 67-y.o. female on HD
• Admitted with ruptured diverticular abscess and cutaneous
fistula
• On weekly protocol: iron sucrose 100 mg/wk (KDOQI
Guidelines) and epoetin alfa 6000 units/wk, target Hb 10.0–
11.5 g/dL
• Lab results
o Hb 9.2 g/dL
o Ferritin 335 µg/L
o TSAT 10%

Kidney Disease: Improving Global Outcomes

 CASE STUDY: “TAMMY”
What would you do next?
A. Increase the EPO dose
B. Continue to administer IV iron due to low TSAT
C. Withhold IV iron and increase EPO dose
D. Withhold IV iron and maintain EPO dose
E. Continue with the same dose of EPO and frequency of IV iron

Kidney Disease: Improving Global Outcomes

PART 4:
HYPERSENSITIVITY TO IRON

Kidney Disease: Improving Global Outcomes

 HYPERSENSITIVITY REACTIONS TO IV
IRON
• Concerns regarding IV iron safety largely originate from older
formulations containing dextran.
– Higher-molecular weight (HMW) iron dextran should not be used,
since alternative formulations are available.
– Alternatives include LMW iron dextran, iron sucrose, ferric sodium
gluconate, ferric carboxymaltose, iron isomaltoside 1000, ferumoxytol.
• These formulations may be viable alternatives to oral iron and
may be cost-effective in certain settings, despite higher cost.

Kidney Disease: Improving Global Outcomes

CLASSIFICATION OF HYPERSENSITIVITY REACTIONS

KDIGO suggests classifying the severity of reactions and

then determining subsequent approaches to therapy.
Anaphylactic reactions
• Characterized by 2 or more organ systems involved (skin, gut, respiratory, CV)
• Objective evidence of bronchoconstriction, stridor, hypotension, severe
generalized urticaria, nausea, abdominal pain
Minor infusion reaction
• Often described as pressure in the chest or lumbar region, associated with
flushing, with or without minor urticaria, but no hypotension or other organ
involvement
Flare in pre-existing immune and/or inflammatory conditions, particularly
rheumatoid arthritis
• Manifesting as arthralgia

Kidney Disease: Improving Global Outcomes

SEVERE HYPERSENSITIVITY REACTIONS
• Excluding HMW iron dextran, anaphylactic reactions to IV iron
are extremely rare, with an incidence of <1:200,000.
• No anaphylactic reactions have been demonstrated with
intradialytic iron or newer oral iron formulations, but risks
cannot be ruled out.
• No established and validated tests exist to predict or confirm
iron hypersensitivity.

Kidney Disease: Improving Global Outcomes

 POSSIBLE RISK FACTORS FOR
•
HYPERSENSITIVITY
No established and validated tests exist to predict or confirm
iron hypersensitivity.
• The following patient characteristics may indicate a higher risk
for hypersensitivity reactions.
• Prior reaction to any IV iron formulation
• Moderate to severe asthma
• Multiple pre-existing drug hypersensitivities or allergies
• Pre-existing immune-mediated disease (e.g., autoimmune disorders)
• Mast cell–associated disorders
• High TSAT or low plasma transferrin levels, which may increase the likelihood of circulating labile
iron during infusion

Local skin reactions to extravasated iron can occur. Infusion-specific risk factors such as use of higher
doses and rapid rate of infusion should also be considered when evaluating for any potential
reactions. Whether generic formulations have a greater propensity for increased labile iron reactions
is as yet unclear.

Kidney Disease: Improving Global Outcomes

 MINOR REACTIONS
• Minor reactions to IV iron include flushing, mild chest
discomfort, dizziness, light-headedness, nausea, or itching.
• These reactions resolve when the infusion is stopped or
slowed and should generally not preclude ongoing IV iron
therapy.

Kidney Disease: Improving Global Outcomes

 MANAGEMENT OF HYPERSENSITIVITY
• First dose should be administered in a clinical facility.
• IV doses of iron gluconate or iron sucrose should not exceed
125 mg or 200 mg per dialysis, respectively.
• No recommendation to observe patient for 30 min, as delayed
reaction is unlikely.
• Prior desensitization is not recommended.
• Follow local jurisdictional requirements regarding IV iron
administration.

Kidney Disease: Improving Global Outcomes

SUGGESTED MANAGEMENT OF REACTIONS TO IV IRON

Kidney Disease: Improving Global Outcomes

 CASE STUDY: “JUDY”
• 38-y.o. female with CKD (IgA glomerulonephritis) and asthma
• Lab results:
o eGFR 22 ml/min/1.73 m2
o Hb 9.5 g/dL
o Ferritin 101 µg/L
o TSAT 14%

• Given IV ferumoxytol 510 mg over 20 min

• Judy reports breathing problems, light-headedness, swelling,
new erythematous rash. Nurses report slowly falling BP.

Kidney Disease: Improving Global Outcomes

 CASE STUDY: “JUDY”
What do you think is happening, and what should you do next?
A. She may be getting the flu
B. She is having an anaphylactic reaction
C. She is having an anaphylactoid reaction
D. She is having a minor reaction to IV iron

Kidney Disease: Improving Global Outcomes

 RESEARCH RECOMMENDATIONS:
• SUMMARY
Development of a methodology to objectively determine
body iron stores and tissue distribution in CKD patients.
• Do thresholds for increased risk of organ damage in patients
with HFE hereditary hemochromatosis apply to CKD patients?
• Further clarification of the predictive value of hepcidin.
• Further studies to assess the safety and efficacy of IV iron
using hard clinical endpoints.
• Observational studies of risks/benefits of IV iron in predialysis,
PD, and transplant patients.
• Development of a standardized questionnaire to report any
adverse reaction associated with IV iron.

Kidney Disease: Improving Global Outcomes

 CONCLUSIONS
• Available data do not allow any firm statement to be made on the
potential dangers of high-dose iron use and high ferritin levels.
• RCTs are needed to assess the safety and efficacy of IV iron therapy
using hard clinical endpoints.
– The ongoing, event-driven trial, PIVOTAL, recruiting > 2000 HD patients
across 50 sites in UK, randomized to a high and low IV iron regimen (planned
follow-up of 2-4 years) will help to fill this gap of evidence.
• There is consensus that further studies are needed to determine
the clinical relevance of iron therapy beyond stimulation of
erythropoiesis in CKD such as in patients with congestive heart
failure, pulmonary arterial hypertension, restless leg syndrome and
premenopausal women with low ferritin.
• Meanwhile, nephrologists would do well to recognize the benefits
and limitations of IV iron therapy.
Kidney Disease: Improving Global Outcomes
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EDUCATIONAL GRANT FROM

Kidney Disease: Improving Global Outcomes