The Effects of Dietary Nitrate in Patients With Hypertensive Kidney Injury

Overview

The study aims to study the effects of diatery nitrate in patients with hypertension and hypertensive kidney injury. The study is a randomized, placebo-controlled, double-blinded crossover trial. 14-20 patients with hypertension and CKD I-III will be randomized to receive either nitrate or placebo delivered in the form of beetroot juice. Effect variables will be measured before and after a 2 week treatment. After a washout period of 14 days, the subjects are crossed over to the opposite treatment. The study is terminated by measuring effect variables after the second treatment period.

Detailed description

AIM: We aim to investigate the mechanisms behind the cardiovascular and renal effect of nitrates in patients with hypertension and hypertensive kidney injury.

HYPOTHESIS: Dietary nitrate decreases BP and increases renal blood flow. This is independent of renal function or enhanced during low eGFR due to reduced renal clearance of nitrate.

METHODS: The study is a randomized, placebo-controlled, double-blinded crossover trial. 14-20 patients with hypertension and CKD I-III will be randomized to receive either nitrate or placebo delivered in the form of beetroot juice.

Effect variables will be measured before and after a 2 week treatment. After each treatment period effect variables will be measured, including include 24 hour bloodpressure measurment. Technetium(Tc)99m - Diethylenetriamine pentaacetate (DTPA) clearance and water based positron emission tomography computed tomography (PET/CT) is performed only after the intervention periods.

After a washout period of 14 days, the subjects are crossed over to the opposite treatment. The study is terminated by measuring effect variables after the second treatment period.

PERSPECTIVE: The knowledge gained from these studies can lead to improved dietary counselling, which is a promising approach in the treatment of hypertension.

Interventions

• Dietary supplement Beetroot Juice - Active
  Intervention is beetroot juice ("Beet It concentrated beetroot juice shots", James White Drinks Ltd, Ipswich, England) The nitrate content of the juice is standardized. The dose of nitrate will be 70 ml/day corresponding to intake of 6.5 mmol/400 mg of nitrate.
• Dietary supplement Beetroot juice placebo
  The placebo beetroot juice is a corresponding nitrate free beetroot juice, obtained from the manufacturer ("Beet It nitrate depleted shots", James White Drinks Ltd, Ipswich, England.). The placebo juice appears identical to the nitrate containing juice regarding color and taste.

Primary outcome measures

• Changes in 24 h systolic blood pressure [Time frame: Measured on day 1 and day 15 of the intervention period (This represents baseline and after conclusion of each intervention period)]

Secondary outcome measures (12)

• Diastolic blood pressure [Time frame: Measured on day 1 and day 15 of the intervention period (This represents baseline and after conclusion of each intervention period)]
• Heart rate [Time frame: Measured on 1 and day 15 of the intervention period (This represents baseline and after conclusion of each intervention period)]
• Pulsewave velocity [Time frame: Measured on day 1 and day 15 of the intervention period (This represents baseline and after conclusion of each intervention period)]
• Augmentation index [Time frame: Measured on day 1 and day 15 of the intervention period (This represents baseline and after conclusion of each intervention period)]
• Vascular resistance [Time frame: Measured on day 1 and day 15 of the intervention period (This represents baseline and after conclusion of each intervention period)]
• Reflection index [Time frame: Measured on day 1 and day 15 of the intervention period (This represents baseline and after conclusion of each intervention period)]
• Dipping status [Time frame: Measured on day 1 and day 15 of the intervention period (This represents baseline and after conclusion of each intervention period)]
• Blood pressure variability [Time frame: Measured on day 1 and day 15 of the intervention period (This represents baseline and after conclusion of each intervention period)]
• Unattended office blood pressure [Time frame: Measured on day 1 and day 15 of the intervention period (This represents baseline and after conclusion of each intervention period)]
• Renal Blood Flow (RBF) [Time frame: Measured on Day 15 of each intervention period]
• GFR [Time frame: Measured on Day 15 of each intervention period]
• Urine concentration of renal tubular transport proteins [Time frame: Measured on day 1 and day 15 of the intervention period (This represents baseline and after conclusion of each intervention period)]

Eligibility criteria

Inclusion criteria

• Hypertension, treated with a maximum of 2 antihypertensive drugs and unattended office BP < 150/95 mmHg at the screening visit, or newly diagnosed without antihypertensive treatment by 24-hour BP or home BP measurement (above 130/80 or 135/85 respectively), and unattended office BP < 160/100 mmHg.

• CKD I-III based on hypertensive kidney injury. Patients, who previously met the criteria for CKD I within the last 5 years, but no longer has proteinuria after relevant treatment, can also be included. Diagnosis of CKD I can be based on eGFR and either urine albumin/creatine ration or urine-dipstick test with presence of protein.
• Albumin/creatinine ratio < 500 mg/g
• eGFR > 30 ml/min/1,73m2
• Body Mass Index (BMI) ≤ 35 kg/m2
• Able to adhere to dietary regimen
• Fertile women must use safe contraception (oral contraceptive pill, hormonal or copper intrauterine device, vaginal ring, contraceptive implant, transdermal contraceptive patch or contraceptive injections) or abstinence. Excluded from this are postmenopausal woman without menstrual bleeding for at least 12 months before inclusion, surgically sterilized women and women with surgically sterilized partner.

Exclusion criteria

• • Diagnosis of heart failure, NYHA II-IV

• Diagnosis of liver failure
• Diabetes mellitus (all types)
• Current malignant disease (other than non-melanoma skin cancer)
• Indicators of other aetiologies of CKD than hypertensive kidney injury, e.g. through kidney biopsy or biochemistry.
• Previous kidney transplant recipient
• History of stroke or transient cerebral ischemic attack
• Current indication of untreated cardiovascular disease, e.g. planned work-up for ischemia.
• History of myocardial infarction, apart from non-STEMI more than 1 year prior to the study, if the subject is currently revascularized and relevantly medicated.

Organic nitrate treatment Diagnosed secondary hypertension other than renal parenchymal hypertension (i.e. renal artery stenosis, primary hyperaldosteronism, low renin hypertension etc.)

• Pregnancy or lactation
• Alcohol abuse (intake above the recommended guidelines from Danish Health Authorities)
• Conditions treated with medication that investigator finds may interfere with the effect parameters, and cannot be discontinued during the trial (e.g. atrial fibrillation treated with betablockers)
• If, according to the investigator's assessment, the participant is considered unsuitable to participate.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Denmark · 1 center

• University Clinic in Nephrology and Hypertension, Gødstrup Regional Hospital and Aarhus Un — Herning

Identifiers

NCT: NCT07290842 · KTM-1-2025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗