Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05114291 |
| Other study ID # |
APHP210934 |
| Secondary ID |
2021-A01291-40 |
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
December 10, 2021 |
| Est. completion date |
July 7, 2023 |
Study information
| Verified date |
July 2023 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Hypertension is a public health concern and affects nearly a third of the French population.
It can be complicated by visceral impact (including brain, heart and kidney complications) as
well as on vessels especially large arteries, responsible for arterial stiffening. There are
close interactions between heart and kidneys, as well as between large arteries and
micro-vessels. These relationships also involve the water and salt balance and its regulatory
mechanisms. Urinary concentration abilities are closely linked to the renal medullary blood
flow, which in itself depends on the integrity of renal micro vessels, thus influencing the
water and salt balance. Few previous studies evaluated the interconnections between renal
urinary concentration abilities and blood pressure. A previous-one reported a positive
relation between pulse pressure and urinary concentration in men, suggesting that subjects
with higher urinary osmolarity could present a higher cardiovascular risk. Carotid-femoral
pulse wave velocity represents the gold standard for non-invasive arterial stiffness
assessment and constitutes an arteriosclerosis infra-clinical marker recommended by the
European Society of Cardiology- European Society of Hypertension. It is considered as an
independent predictor for global and cardiovascular mortality, coronary heart disease and
fatal stroke among patients with hypertension, diabetes or end stage kidney disease. The
purpose of this study is to evaluate the relations between fasting urinary osmolarity and
arterial stiffness assessed by carotid-femoral pulse wave velocity (CF-PWV) among patients
with hypertension.
Description:
1. Hypertension
1. Hypertension, kidneys et urinary sodium excretion
Kidneys are heavily involved in blood pressure regulation in particular through
water and salt balance control, and their impact on vasomotor tone through the
renin-angiotensin aldosterone system (RAAS), prostaglandins or atrial natriuretic
factor (FAN) actions. They take a central place in blood pressure regulation and
indirectly in arterial stiffening.
Daily urinary sodium excretion represents a major determinant of blood pressure. It
is defined as the product of urinary sodium concentration and urinary output. In a
steady state, it equals sodium intake. When kidneys are unable to excrete sodium,
blood volume and blood pressure increase. The result is an adaptive decrease in
sodium reabsorption (called "pressure natriuresis"), in order to restore the sodium
balance. "Salt sensitivity" has been defined as a significant increase in blood
pressure associated with the increase sodium intake. It has been associated with
age, ethnicity, obesity, metabolic syndrome, and chronic kidney disease (CKD).
Chronic kidney disease is frequently associated with salt and fluid retention,
which promote hypertension and increase cardiovascular risk.
Among dialysis patients, fluid overload has been widely described as an independent
mortality risk factor. Recently, Faucon et al. reported in the nephroTEST cohort of
CKD patients not yet on dialysis that the measured extra cellular volume (ECV) was
an independent risk factor for mortality but also for CKD progression to the end
stage of kidney disease. Reduced sodium excretion abilities associated with CKD
progression lead to fluid overload and cardiac consequences. The increase of left
ventricular preload promotes diastolic dysfunction. In parallel, the prolonged
increase of left ventricular afterload promotes left ventricular hypertrophy. Other
CKD associated factors could also contribute to left ventricular hypertrophy such
as the increased arterial stiffness, and CKD-mineral and bone disorders including
the raise of FGF-23.
2. Nephron, water and salt balance regulation, and outside of the glomerulus
The nephron represents the kidney functional unit. It plays a major role in water
and salt balance control. "Kidney function" assessment is often reduced to its
glomerular functions, including glomerular filtration rate (GFR) and albuminuria
level. The other segments of the nephron are however largely involved in this
balance control. Their function can be altered even without glomerular dysfunction
and therefore without renal insufficiency. Thus, tubular segments, peritubular
capillaries and the interstitial space can also be altered in some kidney diseases.
These structures, and more particularly the ascending limb of the loop of Henle,
the peritubular micro-vessels and the collecting duct, are involved in the
corticopapillary gradient creation and maintenance. This gradient is essential for
the urine concentrating mechanism. Tubular damages assessed on renal pathology
would also be more correlated to impaired urine concentration and acidification
than to glomeruli involvement. Fasting urinary osmolarity is a simple, non-invasive
marker for assessing urinary concentration abilities. It is yet poorly studied in
clinical research. At same level of GFR, its level would be associated with tubular
dysfunctions and peritubular vascular lesions, namely with medullary functions.
Fasting urinary osmolarity has also been associated with GFR decline and
progression of CKD to end stage kidney disease. On the other hand, some of the
tubular segments constitute direct targets of systemic hormonal regulation.
Aldosterone thus promotes sodium retention and potassium excretion through the
activation of mineralocorticoid receptors located on distal tubular cells and the
involvement of ENaC and ROMK channels.
3. Hypertension and urinary concentration
Perrucca et al. suggested that urinary concentration and its regulatory hormone,
antidiuretic hormone (ADH), may contribute to cardiovascular disease susceptibility. ADH
binding to its V2R receptor promotes distal reabsorption of free water and thus favors
urinary concentration. This hormone has thus an action through kidneys promoting urinary
concentration through free water reabsorption, but also a vascular effect leading to
vasoconstriction. Hypertension has been associated with increased plasma ADH levels.
Zhang et al. thus reported in a cohort of 534 middle-aged subjects, the significant
association between plasma ADH levels and blood pressure levels as well as with
hypertension, especially in patients with low plasma renin activity. The antidiuretic
hormone would also be at higher levels in men than in women, as well as in African
American subjects compared to Caucasians, likewise hypertension is also more frequent in
these two populations.
Furthermore, Bankir et al. described in a retrospective cohort of 141 healthy subjects
of 18 to 40 years old that black individuals presented significantly higher urine
concentration and lower urinary volume than white individuals. In addition, a
significant and positive relationship between urinary concentration levels and pulse
pressure was found among men. This association was more marked among black individuals
compared to white individuals. Since pulse pressure is currently considered as an
independent risk factor for cardiovascular disease, associated with both cardiovascular
morbidity (increased incidence of myocardial infarction or congestive heart failure) and
cardiovascular mortality from coronary artery disease, an association between urinary
concentration abilities and cardiovascular risk could be considered. In addition, urine
dilution by increasing water intake is one of the main objective in the management of
lithiasis patients. The increase of urinary concentration is indeed associated with an
increased risk of crystallization and therefore an increased risk of kidney stones
recurrence. Lithiasis patients have also been described as a population with an
increased cardiovascular risk. These additional elements support the hypothesis of a
potential association between urinary concentration and cardiovascular risk.
2. Arterial stiffness
1. Hypertension, arteriosclerosis and evaluation
Arteriosclerosis represents an arterial degeneration process associated with
physiological aging but much more marked in some pathological circumstances such as
hypertension, diabetes or chronic kidney disease. The arterial wall involvement
concerns the media of large arteries, unlike atherosclerosis in which the
involvement initially involves the intima, resulting in an accelerated stiffening
of the vascular tree. Large arteries stiffening can induce myocardial hypertrophy,
favors heart failure, arrhythmias and even myocardial ischemia. Carotid-femoral
pulse wave velocity enables non-invasive assessment of central arterial stiffness.
It currently represents the gold standard for non-invasive arterial stiffness
measurements and constitutes an arteriosclerosis infra-clinical marker recommended
by the European Society of Cardiology- European Society of Hypertension. In
practice, it corresponds to the velocity at which the pulse wave propagates over a
specific arterial segment. The pulse wave travels slowly through flexible and
elastic arteries, and rapidly through rigid arteries. CF-PWV measurement requires
an automated software. It is a simple, non-invasive, validated, robust,
reproducible and accessible procedure in clinical practice.
2. Arterial stiffness and cardiovascular risk
CF-PWV thus enables us to detect large arteries damages at an infra-clinical stage
and to identify populations at high cardiovascular risk. It has been described as
an independent predictor for global and cardiovascular mortality, coronary heart
disease and fatal stroke in many populations: in the general population, in elderly
patients, in patients with diabetes, with hypertension, in CKD-patients, patients
with end-stage kidney disease, and also in renal transplant recipients. Aortic
stiffness has been shown to be predictive of cardiovascular events, independently
and beyond traditional risk factors and the Framingham score.
3. Arterial stiffness and fluid overload
Fluid overload can also contribute to structural and functional alterations in
large arteries and therefore promote arterial stiffness. The increase in venous
pressure induced by sodium overload initiates a vicious circle. The result is an
increase in renal interstitial pressure, which disrupts renal blood flow, and
promotes further retention. Plasma volume expands, increasing venous pressure
further. The associated increase in filling pressures could thus promote structural
and functional alteration of large arteries.
Furthermore, the diastolic blood pressure decrease induce a reduction in coronary
perfusion pressure, which contributes to myocardial ischemia. In case of heart
failure, sodium retention is associated with a defective arterial filling. Urinary
sodium excretion decreases while sodium and fluid overload increases.
4. Micro- and macro-vessels relationships
Safar et al. previously reported the links between macro- and micro-vessels evidenced by
mouse models of hypertension and human studies. Indeed, pulse pressure increase
associated with arterial compliance disturbances promotes impaired microcirculation,
particularly in kidneys. An alteration of the extracellular matrix could involve both
vascular smooth muscle cells (VSMCs) and renal cells. Several underlying
physiopathological mechanisms have been suggested, involving notably the water and salt
balance and the hormonal systemic regulatory mechanisms including the
renin-angiotensin-aldosterone system. Urinary concentration abilities are closely linked
to the renal medullary blood flow which itself depends on the renal microcirculation
integrity.
3. Studied-population
This study focus on patients with severe/resistant hypertension and/or with suspicion of
secondary hypertension, who are addressed in a one-day hospitalization to benefit from
standardized examinations including hormonal analyses (renin - aldosterone ± plasma
cortisol). These hypertensive patients present an increased cardiovascular risk. The CF-PWV
measure enables aortic stiffness assessment. It constitutes an arteriosclerosis
infra-clinical marker recommended by the European Society of Cardiology- European Society of
Hypertension.
