Effects of oral iron supplementation on the gut microbiome and plasma uremic toxin levels in patients with chronic kidney disease

There is a high prevalence of anemia in patients with chronic kidney disease
(CKD), as a result of chronic inflammation. To correct anemia, patients are
often treated with iron, given orally or parenterally. Our previous experiments
in a kinetic model of the human large intestine have shown that the provision
of iron to a human gut microbiota changed its composition and increased protein
fermentation, which resulted in a more toxic microbial metabolome. Furthermore,
we recently investigated the influence of protein intake on plasma uremic toxin
levels in healthy volunteers who were randomized to either a high protein diet
or a low protein diet for 2 weeks. In the high protein diet, we observed a
significant increase in plasma levels of indoxyl sulfate as well as significant
increases in the urinary excretion of indoxyl sulfate, indoxyl glucuronide,
kynurenic acid, quinolinic acid and p-cresyl sulfate. Comparable results were
obtained in a rodent study. Together, this raises the question whether the
administration of iron to patients with CKD contributes to gut microbial
protein fermentation and increased production of uremic toxins. Although it is
not yet fully clear whether uremic toxins are involved in the pathways leading
to progression of CKD, p-cresol and indole derivates (the most studied uremic
toxins) have been associated with mortality, cardiovascular disease and
progression of CKD.
We hypothesize that oral iron supplementation in iron deficient predialysis CKD
patients changes gut microbiome composition, and causes an increase in faecal
and plasma uremic toxin levels, due to stimulation of the proteolytic activity
of the gut microbiota.

This study assesses the effect of oral iron supplementation on gut-derived
plasma uremic toxin levels in patients with chronic kidney disease (CKD) and
with iron deficiency. The main research questions to be answered are:

1. Does oral iron supplementation cause an increase of uremic toxin levels in
the faeces and plasma of predialysis CKD patients?
2. Does oral iron supplementation stimulate gut microbial protein fermentation
in predialysis CKD patients?
3. What is the effect of oral iron supplementation on the composition of the
gut microbiome of predialysis CKD patients?
4. Does the gut microbiome recover from the iron intervention and does it
change back to the situation before intervention?

Longitudinal study

With regarding to treatment with ferrous fumarate there are no extra risks
associated with participation in this study, as this a therapy is a standard
regimen for iron deficient predialysis CKD patients. To be complete we here
mention the adverse effects related to this therapy: mild constipation (1-10%),
diarrhoea (0.1-1%) and allergic skin responses (rash, urticaria, itch,
erythema, photosensibilisation) (0.01-0.1%). Other events that have been
recorded are nausea, aching stomach, vomiting, anorexia, black colouring of the
stools (Farmacotherapeutisch kompas; accessed online on 6-11-2014).

Participation in this study involves the withdrawal of 8 extra blood samples
(3-6 mL) over the course of 4 months. It also involves in-home collection (and
short-term storage) of faeces at 9 time points, and the completion of a simple
food questionnaire at the same time points. Patients from the region of the
city of Nijmegen will be included, it is therefore possible to visit the
patient at home to collect blood samples and the faecal samples. This reduces
the number of site visits by the patient. The risks and burden for the patients
can therefore be considered as minimal. To answer our research questions
predialysis CKD patients is the most related group, as this group is most
vulnerable for an increase in circulating uremic toxins that will not be
efficiently cleared by the kidneys.