Treatment of vascular stiffness in patients with autosomal dominant polycystic kidney disease

Autosomal dominant polcystic kidney disease (ADPKD) is the most common
inherited kidney disease characterized by cystic kidneys and caused by
mutations in the polycystin genes. It is associated with salt-sensitive
hypertension, which accounts for the majority of morbidity and mortality. About
70% of patients with ADPKD develop hypertension, prior to the onset of kidney
function decline.

Early onset hypertension, despite its treatment, is independently associated
with rapid kidney function decline, and is therefore used as a marker for those
with rapid disease progression. Knowledge of its etiology is therefore crucial
for its targeted therapy.

Although incompletely understood, arterial stiffness and sodium-retention are
thought to precede hypertension in ADPKD. Recent insights show that the
endothelial glycocalyx (a protein layer) localized on arteries plays a
significant role in development of vascular stiffness. In normal situation,
glycocalyx buffers sodium and prevents hypernatremia. A high-salt diet disrupts
the glycocalyx, which leads to sodium influx into endothelial cells through the
so-called epithelial sodium channel (ENaC). This results in interstitial sodium
accumulation in the skin and vascular stiffness.

We hypothesize that a high-sodium diet in patients with ADPKD is required for
the development of hypertension and inhibition of the ENaC reverses this
phenomenon.

This study has been transitioned to CTIS with ID 2024-512544-27-00 check the CTIS register for the current data.

We aim to investigate if arterial stiffness is exacerbated due to a high-salt
diet in patients with ADPKD. We also intend to explore whether treatment with
amiloride prevents the effect of high salt on arterial stiffness.

Randomized, double blinded and placebo-controlled clinical trial with
open-label treatment with amiloride

After obtaining informed consent, patients will be subjected to a low-salt diet
(3,5 grams/day) for 6 weeks, and randomized into two treatment groups for 4
weeks:

Group 1: Sodium chloride capsules (6 grams/day) + additional amiloride (20
mg/day) in last two weeks
Group 2: Placebo capsules + additional amiloride (20 mg/day) in last two weeks

Furthermore, the following measurements will be performed during the trial:
- 3x non-invasieve measurements of vascular stiffness, using pulse wave velocity
- 4x office bloodpressure measurements
- 3x 24-hours ambulatory blood pressure measurements
- 4x blood withdrawals
- 4x spot urine measurements
- 3x 24-hours urine collections
- 4x Salt tasting test
- For a subgroup patients (n=8): 3x MRI scans in AMC, Amsterdam

The burden of participation includes:
- A dietary salt restriction of 3,5 grams/day for a total period of 6 weeks
- Salt supplement intervention as mentioned above for a total period of 4 weeks
- Additional drug intervention with amiloride during the last 2 weeks
- Five visits to the hospital and one phone call
- The following measurements:

Screening visit (week 0):
Office blood pressure measurement
Blood samples
Spot urine samples

Duration: 45 minutes

Dietician visit (week 0):
Salt tasting test

Duration: 45 minutes

Baseline visit (week 3) :
Pulse wave velocity measurement
Office blood pressure measurement
Blood samples
Spot urine samples
24-hours blood pressure measurement
24-hours urine collection
Salt tasting test
23Na-MRI (Amsterdam UMC) (n=8 per group)

Duration: 90 minutes for patients without MRI;
120 minutes for patients with MRI

Mid-term visit (week 5):
Pulse wave velocity measurement
Office blood pressure measurement
Blood samples
Spot urine samples
24-hours blood pressure measurement
24-hours urine collection
Salt tasting test
23Na-MRI (Amsterdam UMC) (n=4 per group)

Duration: 90 minutes for patients without MRI;
120 minutes for patients with MRI

Final visit (week 7):
Pulse wave velocity measurement
Office blood pressure measurement
Blood samples
Spot urine samples
24-hours blood pressure measurement
24-hours urine collection
Salt tasting test
23Na-MRI (Amsterdam UMC) (n=4 per group)

Duration: 90 minutes for patients without MRI;
120 minutes for patients with MRI

Total study duration: 360 minutes for patients without MRI;
450 minutes for patients with MRI

Risks:
Although expected risks are limited, side effects of treatment may include
exacerbated hypertension and hyperkalemia:
1. Hypertension: an increase in mean arterial blood pressure (MAP) of 7 mmHg
was observed after an exceptionally high-salt diet of 18 grams/day in patients
with ADPKD (Doulton et al., J Hypertens, 2006). Several studies have shown an
average blood pressure increase of 8/4 mmHg in hypertensive patients after
discontinuation of their hypertension treatments. Together with cessation of
antihypertensive drugs, the expected maximum rise of MAP is ±15 mmHg for those
receiving salt capsules (group 1). Considering the short duration of the trial,
this will unlikely be harmful. Blood pressure will be monitored during the
trial (visit 3 = safety visit) and study will be terminated prematurely if an
office blood pressure of >=190/>=100 mmHg is reached.

2. Hyperkalemia: using a daily dose of 20 mg amiloride increased serum
potassium levels by 0.52 mmol/L in hypertensive patients, without serious
adverse events (Williams et al., Lancet 2018). A mild hyperkalemia occurred in
7% of hypertensive patients when treated with amiloride 20 mg per day, with
highest potassium concentration of 5.8 mmol/L (Brown et al., Lancet 2016). Only
those with renal function decline and concomitant ACE-inhibitor use are at a
mild risk of hyperkalemia ((Oxlund et al., J Am Soc Hypertens, 2014). We
therefore do not expect any severe events of hyperkalemia.

Possible benefits:
1. Regular blood pressure and arterial stiffness measurements/monitoring. After
finishing/deblinding of the study, participants and their physicians will
receive reports on outcomes, which may facilitate better treatment.

2. Insight into the compliance of a low-salt diet, which may be beneficial for
blood pressure measurements.