Iron Management in CKD

Iron distribution is heterogeneous1

1 Huch R, 2006
8 Hentze WM, 2004 Transferrin : Protein that transfer iron
Ferritin : Protein that store iron
Iron metabolism: facts and figures 2
Iron Absorption Process
 Symptoms of iron deficiency with
or without anaemia

• Shortness of breath

• Fatigue

• Reduced physical performance and

endurance
• Decreased concentration span

• Reduced vitality

• Increased susceptibility for infections

• Pale skin colour, hair loss and brittle nails

1 Huch R, 2006

Iron metabolism: individuals at increased risk of iron

4
deficiency
 Measuring iron status
• The most common iron tests are serum ferritin and
TSAT (transferrin saturation)
• Results can be influenced by factors other than the amount of iron e.g.
inflammation, infection, liver disease, malignancy

Serum ferritin
Ferritin
Provides an indirect estimate of iron
stores

1 µg/l serum ferritin = 10 mg stored iron

in healthy individuals

TSAT Transferrin
Provides an estimate of how much
iron is available for erythropoeisis

Crichton RR et al. Iron therapy with special emphasis on intravenous

administration (4th edition), 2008. UNI-MED Verlag AG, Bremen.
 Absolute & functional iron deficiency

 Depleted body iron stores

Absolute iron
– Low serum ferritin (<100ng/ml) or
deficiency
– TSAT <20%

 Inadequate iron supply to meet demand despite

normal or abundant iron stores
Functional
iron  Most frequently occurs during ESA therapy
deficiency  Normal or high ferritin levels 100 – 299 ng/ml
– TSAT <20%

Wish JB. Clin J Am Soc Nephrol 2006; 1: S4-8

 Oral iron therapy

• Effective first-line strategy for treatment of iron deficiency anemia

patients

Advantages of oral iron therapy

• Only form of iron available to many patients, especially those in

resource-poor settings

• More cost effective

• Avoids the need for IV access and monitored infusion

• Eliminates the potential for infusion reactions and/or anaphylaxis

 Disadvantages of oral iron preparations

• Poor absorption

• GI side effects - dyspepsia, nausea, vomiting, abdominal pain,

constipation, or diarrhea, due to the oxidative properties of

iron on the intestinal mucosa

• Dose-dependent GI side effects affect compliance

• Pro-oxidant effect leads to staining of mucous and stools

 Ferric Pyrophosphate – Liposomal Iron
• Liposomal iron, is a preparation of ferric pyrophosphate conveyed within a

phospholipid membrane associated with ascorbic acid

 Liposomal Ferric Pyrophosphate

A new-generation oral iron with

• High gastrointestinal absorption

• High bioavailability

• Low incidence of side effects due to lack of any direct contact

with intestinal mucosa

• Does not lead to staining of mucous or stools

 Innovative Technology
• Due to the use of sophisticated technology - liposomal carrier - the
iron never comes into contact with gastrointestinal mucosa, and it is
directly absorbed in the intestine
• In the intestinal lumen, the liposome is directly absorbed by the M
cells of the small intestine, which originate from the lymphatic
system
• Subsequently, the liposome is incorporated by endocytosis, by
macrophages and through the lymphatic system it reaches intact in
the hepatocytes, where the liposome is ‘opened’ by lysosomal
enzymes, making the iron available
Liposomal Iron
 Pharmacokinetics

• Bypasses normal intestinal mechanism of absorption, thus,

achieves higher plasma concentration

• Liposomal technology is able to protect ferric iron from the

gastric pH which helps it to reach the intestine in an intact form

for absorption and to cross intestinal epithelium through a
passive route; thus minimizing the conventional oral iron side
effects and increasing hemoglobin and ferritin levels
 Bioavailability – Comparison Study

Ferritin concentration produced in proportion to the iron absorbed

• Randomized, open-label trial

• 99 patients with CKD (stage 3–5, not on dialysis) and iron deficiency
anemia
• Assigned (2:1) to receive oral liposomal iron (30 mg/day, Group OS)
or a total dose of 1000 mg of IV iron gluconate (125 mg infused
weekly) (Group IV) for 3 months
•Oral
Primary endiron
liposomal point - Evaluate
is not inferior tothe effects
IV iron of the
gluconate to two treatments
correct on Hb
anemia in ND-CKD
patients.
levels Low rate of adverse events with liposomal iron, its practicality and the
globally lower cost of oral therapy suggest that this formulation may represent the
• Iron status, compliance and adverse effects were also evaluated
first step to correct anemia in uncomplicated CKD patients
Pisani A et al. Nephrol Dial Transplant. 2015; 30(4): 645-52.
• 10 patients: 6 had a 15 months follow-up, while 4 had a 6 months
follow-up
• All patients were receiving ESAs and IV sodium ferric gluconate and
had hyperferritinemia with Hb at target
• They had serum iron in a high-normal range and elevated TSAT

• IV iron was suspended and sucrosomial iron was introduced (30

mg/day orally)
•Oral
Values of Hb, iron
sucrosomial ferritin, serum
caused iron,
a rapid andTSAT and erythropoietin
significant doseferritin,
reduction in serum were
monitored
maintaining Hb,monthly
serum iron and TSAT values within the range

Manca ML et al. Italian Society of Nephrology. 57th Congress, Rome. 2016 Oct; 33: S67.
IV Iron Therapy
Indications for IV iron treatment

Cançado RD et al. Rev Bras Hematol Hemoter. 2011; 33(6): 461-9.

 Newer IV iron formulations

• Three new IV iron compounds have been approved for clinical

use in patients with IDA - ferric carboxymaltose (FCM),
ferumoxytol and iron isomaltoside
• In their pre-registration trials, all of these three new
compounds potentially had better safety profiles than the more
traditional IV preparations
• Particularly these products can be given more rapidly and in
larger doses than their predecessors with the possibility of
complete replacement of iron in 15-60 minutes
Cançado RD et al. Rev Bras Hematol Hemoter. 2011; 33(6): 461-9.
 Newer IV iron formulations (contd.)
• Use of newer stable parenteral iron compounds carries benefits for
both the
o Patient - less disruption of life, less time away from home/work,
reduced injections, few side effects, etc.
o Hospital/health service - reduced visits, reduced physician and
nurse time, improved out-patient management, improved cost-
effectiveness, etc.
• Other benefits of high dose infusions are the significant reduction of
treatment period and the higher ferritin obtained, which may be
important to delay the recurrence of IDA

Cançado RD et al. Rev Bras Hematol Hemoter. 2011; 33(6): 461-9.

 Benefits of high-dose iron therapy

• Fewer clinic visits

• Improved patient compliance

• Preservation of venous access

• Reduction of blood transfusions

• Savings

• Total cost of disposables, total monitoring cost, true hospital

cost, total productivity loss, total travelling cost

Different IV iron formulations

Cançado RD et al. Rev Bras Hematol Hemoter. 2011; 33(6): 461-9.

 Iron Isomaltoside meets clinical needs

The challenge Iron Isomaltoside

To develop an IV iron meeting clear clinical Iron Isomaltoside (100 mg/ml)

needs:
• High single dosing
• Fast administration
• No test dose requirement
• Minimal risk of free iron toxicity
Two innovations:
• Iron matrix with tight iron binding1
• Isomaltoside with low immunogenic
potential1

Key factors for success: Iron correction in ONE visit

• A carbohydrate with low
immunological activity
• Tight iron binding

1. Monofer® SPC
 Isomaltoside
– a carbohydrate with a low immunogenic potential

• Isomaltoside consists of a short,

linear, and unbranched chain of 5

glucose units1-3

• It is prepared from carbohydrates

used for prevention of dextran

induced anaphylactic reactions1-3

• It has a low immunogenic potential1-3

1. Jahn MR et al., Eur J Pharm and Biopharm, 2011;78:480–91 3. Monofer SPC

2. Kalra PA et al., Port J Nephro Hypert, 2012;26(1):13-24
 Innovative iron Matrix structure - tight iron binding
• Iron Isomaltoside is an innovative iron carbo-hydrate complex consisting of Fe3+ and
isomaltoside1-3
• Determinants of the matrix structure with interchanging iron and isomaltoside are1-3:

• The linear structure of isomaltoside

• A unique complexing technology

• Fe3+ is positioned in the groves of the isomaltoside molecule in a ratio of 10 iron atoms per
isomaltoside molecule1-3

Schematic representation of the ironMatrix with gradual release of iron2

1. Jahn MR et al., Eur J Pharm and Biopharm, 2011;78:480–91 3. Monofer SPC
2. Kalra PA et al., Port J Nephro Hypert, 2012;26(1):13-24
 1
Easy and fast iron correction in ONE visit

Up to 20 mg/kg in just one visit

- no other dose limit

Infusion
≤ 1000 mg over > 15 minutes
> 1000 mg over ≥ 30 minutes

Injection
500 mg over 2 minutes

If iron need > 20 mg/kg, administer maximum dose at first visit - - second administration
based on clinical judgement, at least one week after first visit

IV iron should only be administered when trained staff are present and the patient should be
observed for at least 30 minutes following each injection
 Designed for safety - reducing iron toxicity

Intravenous iron preparations:

• Differ in the stability of the iron

carbohydrate complex1

• Resulting in different levels of labile

iron2,3

• It has been suggested that long-term

treatment with labile iron preparations

is associated with adverse
cardiovascular outcomes and increased
mortality4,5
Adapted from Fütterer S et al., J Pharm Biomed Anal 2013;86:151-160

1. Biggar P et al., MMW Fortschr Med, 2013; 21;155 Suppl 1:18-24

2. Fütterer S et al., J Pharm Biomed Anal, 2013;86:151-60
3. Jahn MR et al., Eur J Pharm Biopharm, 2011;78(3):480-91
4. Kalantar-Zadeh K et al., JASN, 2005;16(10):3070-80
5. Kuo KL et al., PLoS One, 2012;7(12):e50295
PROGRESS Study
A randomized trial of iron isomaltoside versus oral iron in
non-dialysis-dependent chronic kidney disease patients
with anaemia
Kalra et al. Nephrol Dial Transplant. 2015;0:1–10
Superior efficacy with Iron Isomaltoside at all time point
after 2 weeks

• Full iron correction was achieved in

one visit in 92% of the patients in
the Iron Isomaltoside infusion group

• No differences in efficacy and safety

between Iron Isomaltoside infusion
and bolus arms

Kalra et al. Nephrol Dial Transplant. 2015, doi: 10.1093/ndt/gfv293

Hb response was more pronounced with Iron
Isomaltoside doses ≥1000 mg

Kalra et al. Nephrol Dial Transplant. 2015, doi: 10.1093/ndt/gfv293

Superior ferritin and TSAT response

Kalra et al. Nephrol Dial Transplant. 2015, doi: 10.1093/ndt/gfv293

 Iron Isomaltoside had a good safety profile with
fewer withdrawals compared to oral iron

• No dose relationship was found regarding ADRs for Iron Isomaltoside

Kalra et al. Nephrol Dial Transplant. 2015, doi: 10.1093/ndt/gfv293

 Conclusions

• In ESA naïve pre-dialysis CKD patients, Iron Isomaltoside treatment

resulted in a significantly higher Hb increase than oral iron already

after 2 weeks – the difference was sustained throughout the study

• The Hb response was most pronounced with Iron Isomaltoside doses

>1000 mg

• Iron Isomaltoside demonstrated a good safety profile comparable to

oral iron. More patients stopped oral iron therapy due to side effects

• The safety profile of Iron Isomaltoside showed no dose dependency

Kalra et al. Nephrol Dial Transplant. 2015, doi: 10.1093/ndt/gfv293

PROPOSE Study
Prospective, Randomised, Comparative, Open-label, Study of
Intravenous Iron Isomaltoside compared with iron sucrose in CKD
patients on haemodialysis

Bhandari et al. Nephrol Dial Transplant 2015;0:1–13

 Comparable efficacy in maintaining
Hb levels
Hb response at Week 6
100
90 82.7 82.6
80
Hb response (%)

70
60
50
40
30
20
7.5 7.8 9.7 9.6
10
0
<9.5 9.5–12.5 >12.5
Hb concentration (g/dL)
Group A: iron isomaltoside 1000
Group B: iron sucrose split dose

Iron Isomaltoside as single high dose increased reticulocyte count significantly at week 1
compared to split low dose iron

Bhandari et al. Nephrol Dial Transplant. 2015, doi: 10.1093/ndt/gfv096

 Similar short term safety profile between treatments

Number of events Iron Isomaltoside, single Iron Isomaltoside, split Iron sucrose
dose dose

ADRs 6 6 5
SARs 1 - 2
Drug intolerance Dry mouth
Constipation
Hypersensitivitya Dyspnoeaa
Pruritus (2 events)
Malaise Chills
Description Drug intolerance
Muscle spasms Staphylococcal
Anxiety
Paraesthesia bacteraemiaa
Urticaria
Dyspepsia Limb discomfort

Iron Isomaltoside demonstrated a lower percentage of serious ADRs (<1% vs 2%),

although the trial was not powered to examine potential systematic differences

ADR=adverse drug reaction

aSAR= serious adverse drug reaction

Bhandari et al. Nephrol Dial Transplant. 2015, doi: 10.1093/ndt/gfv096

 Conclusions
• In CKD patients receiving haemodialysis, Iron Isomaltoside and iron
sucrose showed comparable efficacy and short term safety profiles
• Long term, iron complexes with more tightly bound iron such as
Iron Isomaltoside may offer a lower risk of labile iron toxicity
potentially impacting risk of infection and cardiovascular morbidity
• Possibility of larger dose administration may be an advantage since
according to the EMA there is a risk of an allergic reaction with
every dose of IV iron that is given
• More than 82% of the patients in both treatment groups were able
to maintain Hb in the desired range

Bhandari et al. Nephrol Dial Transplant. 2015, doi: 10.1093/ndt/gfv096

 Key Messages

• Liposomal iron has high absorption, high bioavailability with low

incidence of side effects

• It was found to be non-inferior to IV iron gluconate for correcting

anemia in ND-CKD patient

• It is effective in improving and/or maintaining Hb values and

normalizing ferritin values in hemodialysis patients

• In comparison to other standard oral iron preparations, sucrosomial

iron seems to be a promising new strategy of iron replacement

 Key Messages

• Iron Isomaltoside offers considerable benefits in terms of safety

and tolerability compared with other IV iron preparations

• Offers convenient administration and permits high doses of

iron to be given in a short period – Iron Correction in one visit

• Highly stable iron matrix, does not release ionic iron under

physiological conditions, and does not provoke oxidative stress

reactions – a safer parenteral iron with least labile iron

• Low immunogenic potential

Thank You!