PErirenal Adipose tissue and RenaL hemodynamics in patients with Heart Failure with Preserved Ejection Fraction

In patients with obesity the thickness of perirenal adipose tissue (PRAT) has
been associated with chronic kidney disease, hypertension and onset of
diabetes1. This correlation is likely the result of compression of the kidney
and the renal vasculature2. Compression on the renal artery leads to increases
in renin release and activation of the renin-angiotensin-aldosterone (RAAS)
cascade, an important pathophysiological mechanism in onset and progression of
heart failure. Moreover, adipose tissue has been consistently shown to have
inflammatory properties and increased levels of TNF-α lead to renal arterial
vasculopathy, further increasing pathological RAAS-activation2. Lastly, one
study in rats showed that congestion induced by clipping of the inferior caval
vein (ICV) leads to increased intrarenal pressures3. Renal compression caused
by interstitial renal congestion was associated with increased concentrations
of tubular damage/dysfunction markers, such as kidney injury marker-1 (KIM-1)
and osteopontin (OPN). These increases were attenuated by decapsulation of the
kidney, allowing for additional space for renal expansion3. One hypothesis is
that renal compression by interstitial congestion and perirenal adiposity
causes impaired function of both glomeruli and tubules.
Dynamic contrast-enhanced computed tomography (DCE-CT) is a technique which
acquires CT images serially after the administration of an intravenous contrast
agent. In-flow and wash-out of contrast material (CM) can be seen on CT and
plotted against time. Kidney DCE-CT perfusion has shown to be an accurate and
feasible technique to assess both renal function and renal perfusion4,5.
Moreover, this technique provides the possibility to differentiate between
cortical and medullar perfusion.
Several small studies have shown that renal venous flow patterns, assessed with
ultrasound, are consistently correlated with renal congestion6,7. As the kidney
is an encapsulated organ, increased intrarenal pressures will lead to collapse
of both renal tubules and renal veins. The collapsing of renal veins gives a
discontinuous flow pattern recognizable as a congestive flow pattern. Depending
on the degree of intrarenal pressure venous flow can be either monophasic or
biphasic, indicating different degrees of collapsibility of intrarenal veins.
These venous flow patterns are correlated to increased intravenous pressures.
Hypothetically, increases in PRAT will compress the renal vein in a similar
matter, leading to congestive flow patterns.
The factors described here, i.e. obesity, chronic kidney disease and
hypertension, are all important comorbidities found in HFpEF. A recent study
indicated that in women with obesity visceral adipose tissue (all the fat
around the organs, including PRAT) was associated with presence of HFpEF and
with hemodynamic deterioration during exercise8. These associations could not
be found for men. The relationship between PRAT and renal hemodynamics,
assessed with DCE-CT and renal venous ultrasound, RAAS-activation and markers
of glomerular and tubular damage have not been investigated in HFpEF.

2.1 Primary objective
The primary objective is to determine whether perirenal adipose tissue
thickness is increased in patients with HFpEF compared with age, sex and
BMI-matched healthy controls

2.2 Secondary objectives
The secondary objectives are to
• Determine whether a greater PRAT volume correlates to impaired kidney
perfusion on DCE- CT in patients with HFpEF
• Determine whether a greater PRAT volume correlates to renal venous flow
patterns assessed with ultrasound in patients with HFpEF.
• Determine whether a greater PRAT volume correlates to glomerular filtration
rate assessed with CDE- CT.
• Determine whether a greater PRAT volume correlates to markers of glomerular
and tubular damage and dysfunction (urinary KIM-1, urinary OPN, serum
creatinine, plasma Cystatin C) in patients with HFpEF.
• Determine whether a greater PRAT volume correlates to plasma NT pro-BNP,
renin and aldosterone concentrations in patients with HFpEF as well as to
pulmonary arterial pressure as assessed with cardiac ultrasound.
• Determine whether correlations between renal hemodynamics and PRAT volumes
are different between men and women with HFpEF.
2.3 Exploratory objectives
Exploratory objectives include
• Whether clinical signs and symptoms of congestion correlate to renal
ultrasound flow patterns and to degree of renal damage as assessed with tubular
markers
• Whether size and shape of other abdominal organs (e.g. pancreas and liver)
differ in patients with HFpEF.

The current study is a single-center, cross-sectional, case-control
observational study. Patients with chronic HFpEF will be asked to participate,
as will their partners, if considered healthy by the study physician.
During the first visit written informed consent will be obtained from both
patients and healthy controls. After ICF procedure, patients and healthy
controls will be screened for eligibility. The obtaining of ICF and assessment
of eligibility does not necessarily have to happen on the same day. If more
convenient, an extra visit can be planned.
Since obesity is strongly related to increased PRAT thickness, but can also be
increased in lean patients we aim to include both patients with obesity (BMI
>30 kg/m2) and lean patients (BMI <25 kg/m2). The same BMI -categories will be
maintained for the healthy controls. Moreover, this allows us to distinguish
whether our finding are more strongly related to obesity or to HFpEF.
During screening height, weight and abdominal girth will be measured. Vital
signs will be obtained. If no echocardiography has been performed in the past
12 months, a new echocardiography will be performed during the screening
period. An NT pro BNP concentration will be measured if this has not been done
in the last 12 months. Moreover, an eGFR will be determined to assess whether
pre-hydration is required to prevent contrast nephropathy during CT imaging.
For healthy controls an echocardiography will be performed to exclude any
concurrent structural heart disease, such as hypertrophy. An ECG will be
conducted at both visits to differentiate between sinus rhythm and atrial
fibrillation.
When patients are eligible for participation, the testing visit will be planned
within 28 days of screening visit.
During the testing visit outpatient HFpEF patients and healthy age, sex and BMI
matched controls will undergo renal perfusion DCE-CT and renal ultrasound on
the same day. During 24 hours prior to the testing visit urine will be
collected to evaluate natriuresis, which typically has a circadian rhythm and
can therefore not be evaluated from a spot urine sample. Moreover, a 24 hour
urine sample will allow for calculation of creatinine clearance, as estimation
of glomerular filtration rate using solely serum creatinine typically
underestimates GFR in obese subjects9. On the day of DCE-CT and ultrasound,
blood and spot urine samples will be collected as well from both the HFpEF
patients and the healthy controls. These sampes will be collected prior to
prehydration, to avoid interference of infusion with blood and urine results. A
clinical congestion score, comprised of jugular venous distention, presence of
rales, peripheral edema and orthopnea.*

Additional risk for participants is low and include risks associated with
venapunction (discomfort, redness, bleeding and infection), and risks
associated with CT, which are mostly related to hypersensitivity reactions to
intravenous contrast media. Mild reactions to intravenous media occur in
approximately 3% of patients and include nausea, flushing, urticaria and
headache. More severe reactions include bronchospasm, facial edema and
laryngeal edema. Life threatening reactions are very rare with an estimated
incidence of 0.04 - 0.0004%. In the case of a severe reaction epinephrine,
prednisolone and antihistamines will be available to treat hypersensitivity.
Patients with a known hypersensitivity to contrast agents will be excluded from
participation. To minimize the burden related to venapunction, drawing of blood
will occur during placement of intravenous access required for CT contrast
infusion. Allergic dermatitis caused by ultrasound gel has been reported in
case reports but is very rare, no other risks are associated with the
ultrasound procedure.
Subjects are burdened with a visit to the UMCG, during which they will undergo
CT with infusion of intravenous contrast, blood drawing and renal ultrasound.
The CT procedure is relatively short (± 5-10 minutes) and does not come with
increased burden. Subjects with a contra-indication for CT diagnostics will be
excluded from participation. Subjects with an eGFR <30 ml/min will be
prehydrated with 250mL sodium bicarbonate 1.4% during the hour prior to contast
admission, per local and national guidelines.
The renal venous ultrasound is performed in supine or lateral position.
Ultrasound gel will be warmed prior to application.