Functional kidney MRI: developing new sequences

Chronic kidney disease (CKD) is characterized by an increase in systemic
sympathetic nerve activity (SNA). Inhibition of systemic activation of the
sympathetic nervous system is therefore an established therapeutic aim in these
patients. However, the aetiology of the sympathetic hyperactivity itself *
occurring in most forms of CKD* has not been fully elucidated and may yield new
therapeutic targets. Various lines of evidence suggest that a yet unidentified
process within the kidney itself drives systemic sympathetic activity. A topic
in our research is to elucidate this renal trigger that drives systemic
sympathetic hyperactivity in patients with CKD. A likely candidate is renal
hypoxia.

Assessment of renal oxygenation and other parameters such as renal blood flow
is needed in order to perform future studies in humans. Non-invasive MRI
techniques are able to assess different functional aspects of the kidneys. It
is our aim to combine three MRI techniques in a workable protocol, providing a
complete overview of kidney haemodynamics and oxygenation, consisting of A)
renal oxygenation with Blood Oxygen Level-Dependent (BOLD) MRI, B) blood in and
out-flow with phase contrast MRI and C) blood-, tissue- and urine- fractions
with diffusion-weighted imaging (DWI).

The techniques mentioned above are currently available in the AMC. However,
they have not yet been applied to the kidney in our institution. Therefore, the
aim of the present study is to develop and validate this combination of MRI
sequences for functional kidney imaging in humans in the AMC.

We propose a prospective developmental study in three phases: Phase 1, is the
development and reproducibility phase. During this phase the MRI sequences will
be developed and the scanning protocol optimized using the techniques mentioned
above. Dynamic Contrast Enhanced-MRI with gadolinium contrast medium will serve
as reference in this phase of the study. Subjects will be scanned on two
separate occasions to assess reproducibility of the measurements. Phase 2, is
the validation phase. During this phase the MRI protocol will be validated
against accurate measurements of the glomerular filtration rate and effective
renal plasma flow before and during reduced renal perfusion in healthy
volunteers. Renal perfusion will be reduced by angiotensin II infusion.
Angiotensin II induces selective kidney vasoconstriction.

To establish and validate MRI as functional imaging technique of the kidney and
determine the appropriate combination of BOLD MRI, phase contrast MRI and
diffusion weighted imaging.

This prospective developmental study will be conducted in two phases. The
complete study will be performed in the Academic Medical Center Amsterdam (AMC)
only. The next phase will only be started when the previous phase is completed.

healthy subjects will visit the AMC on four occasions, two visits during phase
1 and two during phase 2. Phase 1 comprises of a static experiment, the
subjects will undergo screening and physical assessment and a MRI scan with
gadolinium contrast medium to develop the protocol. At the second visit the
subjects will undergo a second scan with gadolinium contrast medium to assess
reproducibility. The scans will include, BOLD-, PC-MRI, DWI and DCE-MRI.

Phase 2 will comprise of dynamic measurements, the subjects will undergo ERPF
and GFR measurement and a MRI scan session during which angiotensin II is
infused. Angiotensin II induces targeted kidney vasoconstriction. This will
allow assessment of changes in renal haemodynamics and metabolism before and
during systemic sympathetic activation. No gadolinium contrast medium will be
used in this phase of the study.

The results of this study contribute to the development of novel non-invasive
MRI based kidney function analysis needed for further research purposes.
Individual subjects will gain no direct benefit from this study. The risk of
participating in this study is estimated to be low.

Incidental findings:
There is a risk of incidental findings during the MRI scans. The researcher
will consult a radiologist in case of any suspect findings. Incidental findings
will always be reported to the concerning subject.

Gadovist:
Gadovist is routinely used as a contrast agent in MR imaging. Protocols that
describe what to do in case of contrast*induced hypersensitivity reactions are
implemented at the department radiology and drugs to treat these
hypersensitivity reactions are readily available at the site of the MRI scan.
MRI is a safe imaging technique without radiation exposure.

GFR and ERPF:
GFR and ERPF measurement with 125I-iothlamate and 131I-hippuran is a clinically
applied test and the associated radiation exposure is minor (0,4 mSv, ICRP62
category IIa). During this test a total of 54 ml (9 times 6 ml) blood will be
drawn from each subject and 130 ml plus 0.375 ml/kg fluid is infused.

Angiotensin II:
The blood pressure response to Angiotensin II is dose dependent. The dose of
Angiotensin II will be titrated to a diastolic blood pressure rise of 10 mmHg.
During infusion the blood pressure will be measured every 5 minutes. Subject
may feel slight discomfort and feel warm and/or sweaty. The healthy subject
will undergo Ang II infusion twice.

Blood drawing:
Over the course of this study 66 ml of blood will be drawn from each subject.
Risks associated with intravenous canulation are formation of a local hematoma
and in rare cases inflammation.