NephrOx 2, Neural control of kidney oxygenation

Although many primary kidney diseases can be adequately managed on themselves
(i.e. diabetes, hypertension, glomerulonephritis), minor injury may often stil
lead to renal failure in the long run. To this end, there is a pressing need to
obtain a more detailed understanding of cause(s) and mechanisms underlying the
progression from minor loss of function to complete renal failure. Multiple
forms of acute and chronic kidney disease are associated with a relatively low
tissue oxygen tension (pO2) within kidney, i.e. hypoxia. This has led to the
proposition that renal parenchymal hypoxia is not just a consequence of kidney
disease, but rather a common pathogenic event in several forms of kidney
disease.

There is substancial evidence from animal models of hypertension and/or CKD
that the kidney branches of the sympathetic nervous system are a modulator of
renal blood flow and tubular sodium reabsorbtion and thus determine the
intrarenal balance between oxygen supply and demand. In humans however, the
effects of sympathetic modulation on kidney oxygenatio have not yet been
established.

Recently we developed an MRI sequence that includes assessment of renal
oxygenation with Blood Oxygen Level-Dependent (BOLD) MRI, renal blood flow and
metabolism. This enables quantification of changes in kindey flow and
oxygenation during acute and chronic modulations of renal sympathetic
activity:

To establish the role of renal sympathetic modulation on renal blood flow,
metabolism and oxygenation we propose three closely related series of
experiments.

Group 1: Sympathoactivation in healthy humans 12 healthy volunteers will
undergo a graded lower body negative pressure (LBNP) challenge (0, 10, 20, 30
mmHg for 15 minutes per step) during MRI scanning. This is a standardised
method to induce a graded induction of sympathetic activity. During each step
kidney oxygenation and flow will be assessed using MRI.

Groups 2a/2b: Chronic renal sympatho-inhibition by surgical denervation We will
measure renal blood flow and oxygenation using MRI during a graded lower body
negative pressure challenge in 12 living donor/recipient kidney transplantation
couples. Donor will undergo this testing before and after the donation
procedure and the reipients on two specified timepoints after transplantation.

Prospective etiological study

Individual subjects will gain no direct benefit from this study, there is
however direct group related benefit for kidney donors and transplantplant
recipients (groups 2a/b; identifying potential pathways underlying increased
risk for chronic kidney disease after transplantation, respectively allograft
nephropathy)

There are no risks involved in the MRI scanning (All groups)

The risk of the LBNP challenge is occurrence of a vasovagal reaction (<10%;
*matige kans*), which is a benign event (*matige schade*). This risk (*matig
risico*) is minimized by using a relatively limited LBNP challenge, monitoring
of blood pressure and heart rate and direct observation of the subject during
the LBNP challenge.