Insights in proximal and distal tubular iron reabsorption by studies on urinary iron excretion in human health and disease

The body is able to regulate iron uptake and storage, but has limited ability
to regulate iron excretion. Systemic iron bound to the iron transport protein
transferrin (ferri-transferrin) is at least partly filtered by the glomerulus
of the kidney into the renal tubular lumen and, subsequently, reabsorbed by the
proximal and distal renal tubules in the form of ferri-transferrin and/or
non-transferrin bound iron (NTBI). As a result of this, hardly any iron is
found in urine in healthy individuals. As a consequence, disturbed dietary iron
uptake, e.g. from the intestine in hereditary hemochromatosis or from multiple
blood transfusions in *-thalassemia or Diamond Blackfan anemia, can result in
systemic iron overload, which is known to affect multiple organs of the body
(e.g. liver, heart). In addition, systemic iron overload can result in
increased iron exposure to the kidney, which is associated with renal failure.
However, the physiological mechanisms of iron handling by the kidney are not
fully elucidated and have not been examined in pathological conditions of
systemic iron overload or kidney injury. In addition, renal iron reabsorption
by the renal tubules is hardly examined in vivo. A better understanding of
renal iron reabsorption will provide novel leads for treatment strategies to i)
improve the prognosis of kidney injury and ii) increase iron excretion in
patients with systemic iron overload.

We aim to gain insights in proximal and distal tubular reabsorption of iron,
transferrin, NTBI and labile plasma iron (LPI). To this purpose, we will study
urinary iron, transferrin, NTBI and LPI concentrations relative to urinary
creatinine concentration in healthy volunteers and patients with i) compromised
renal tubular function (tubulopathy); and ii) patients with increased iron
filtration (patients with systemic iron overload).
We hypothesize increased urinary iron excretion in: i) patients with
tubulopathy, since we predict that renal uptake of filtered ferri-transferrin
will be reduced in case of compromised tubular function; and ii) patients with
systemic iron overload, since the increased levels of ferri-transferrin and
NTBI in the tubular lumen are likely to exceed the reabsorption capacity of the
renal tubules.

Cross sectional study.

Participation in this study involves the collection of blood (one 3 ml tube)
and urine (one spot urine sample) at one time point. As these study procedures
are routine in diagnostic practices for these diseases and can be combined with
diagnostic practices, the risks and burden for the patients can be considered
negligible. Patients using iron chelation medication (e.g. deferasirox) will be
asked to withhold the use of this medication for at least 4 days, in order to
prevent biased urinary iron measurements by excretion of the
iron-chelator-complex.
Because we expect that urine iron levels are determined by glomerular
filtration of systemic circulating iron and by tubular reabsorption, we will
include subjects with abnormal body iron levels and tubular function, i.e.
subjects with systemic iron overload and subjects with tubular dysfunction,
respectively, next to healthy controls.