Calibration of extracellulair fluid volume measurement by 125I-iothalamate in subjects with a low GFR using Bromide distribution volume.

Extra celullar fluid volume (ECFV) is an important parameter of renal function.
ECFV not only has an important role in normalisation of glomerular filtration
rate (GFR) (1), but is also an important marker of renal function itself,
because of the central role of the kidney in regulation of fluid balance. In
previous research the feasibility of measuring ECFV during regular renal
function tests using 125I-iothalamate and 131-Hippuran by distribution volume
of iothalamate (VdIOT) has been tested. (2,3) The required steady state of
iothalamate was reached, and a change in fluid balance induced by high sodium
intake was adequately detected by a corresponding rise in the distribution
volume of iothalamate (VdIOT). Therefore, VdIOT appears to be a feasible
measure of the ECFV. Two factors that influence the measurement of ECFV by
VdIOT are voiding errors and the extrarenal clearance of iothalamate. The
latter seems to be dependent of GFR, with a higher percentage of extrarenal
clearance in subjects with a lower GFR. (4) Correction for these factors can be
made by collecting a recovery urine of 24 hours after iothalamate infusion.
This method includes the assumption that al infused 125I-iothalamate is cleared
and excreted in the urine within these 24 hours. In subjects with a low GFR
this might not be true. In the aforementioned study the mean GFR was 79 ml/min
and only a few subjects with a GFR <30 ml/min were included. Therefore, the
validation of VdIOT as an indicator of ECFV cannot be generalised to the
population with diminished renal function. Especially in this population the
possibility of calculating ECFV and normalising GFR to ECFV is very useful, as
it provides insights in fluid balance and pathophysiology in patients with
chronic renal disease. We therefore want to calibrate VdIOT as a measure of
ECFV in this population, using an accepted measurement of ECFV: distribution
volume of Bromide.

Primary Objective:

To calibrate the measurement of ECFV by 125I-iothalamate in subjects with a GFR
<60 ml/min and GFR <30 ml/min, using an accepted measurement of ECFV:
distribution volume of Bromide.

Secondary Objective(s):

To determine if urinary clearance of 125I-iothalamate is complete within 48
hours in subjects with a GFR < 60 ml/min.
To determine the percentage of extrarenal clearance in subjects of
125I-iothalamate with a GFR < 60 ml/min and < 30 ml/min.

To be able to draw an accurate conclusion to answer our research question, the
study population of this observational study will consist of 25 renal
transplant recipients with a GFR of 30-60 ml/min and of 25 renal transplant
recipients with a GFR <30 ml/min. This sample size is comparable to the largest
validation study on this subject in the current literature. 50 adult renal
transplant recipients undergoing GFR-measurement by 125I-iothalamate and
131I-Hippuran during regular post-transplant follow-up will receive an oral
dose of sodium bromide in a dosage of 50 mg Br/kg. Standard blood drawings will
be performed (t=0, t=90 min, 150 min, 210 min, 270 min and 330 min) and at each
time point an extra 3cc of blood will be drawn for measurement of serum
bromide. This serum will be centrifuged and frozen until measurement of
bromide concentration at the end of the study period. At the standard time
points serum concentration of 125I-iothalamate will also be measured. Subjects
will be asked to collect urine from the end of the GFR-measurements up to 48
hours (2 x 24 hour samples) afterwards. This will be used for optimal
calculation of the distribution volume of 125I-iothalamate.

Calculation of the extracellular volume will be done using the following
equations:

For the distribution volume of Bromide (VdBromide):


Br dose
VdBromide = ---------------------------- x 0.90 x 0.95 x 0.94
[Br]before - [Br]after

In this equation 0.90 is the correction factor for distribution of Bromide in
non extracellular space (mainly erythrocytes), 0.95 represents the correction
factor for the Gibbs-Donnan equilibrium (the high plasma content of negatively
charged proteins leads to a lower concentration of negatively charged Bromide
in plasma relative to the rest of the ECFV) and 0.94 the correction factor for
the water concentration in serum.

For the distribution volume of 125I-iothalamate:



[IOT] bolus * Volume + [IOT] infusion fluid * Volume - SUM ([IOT] urine
* Volume)
VdIOT=
--------------------------------------------------------------------------------
-----------------------------
[IOT] serum in steady state

This study involves administration of a single, low dose of Bromide. No
(serious) side effects are expected. The burden for subjects participating in
this study consists of taking a single oral dose of sodium bromide (50mg/kg
body weight), collection of a 48-hour urine sample and drawing and extra 18cc
of blood (6x3cc). During renal function measurement, a bio-impedance
measurement will be performed. This measurement takes fifteen minutes, is
painless and without any risks.