Clinical trial NCT03234361: Preventing Hypertension and Sympathetic Overactivation by Targeting Phosphate
Official title: Preventing Hypertension and Sympathetic Overactivation by Targeting Phosphate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypertension
Keywords: Hypertension
High phosphorus diet
FGF 23
24 hour ambulatory blood pressure
Muscle sympathetic nerve
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
First posted: 2017-07-31
Enrollment: 94
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: An increasing number of studies have indicated that most fast food and common grocery items, contain large amount of inorganic phosphate-based food additives , which are highly absorbable. The long-term cardiovascular consequences of a high phosphate diet are unknown but the existing database implicates phosphate excess as an independent risk factor for cardiovascular events in individuals with and without chronic kidney diseases (CKD). High phosphate consumption clearly induces BP elevation in rats with normal kidneys. However, the mechanisms underlying phosphate-induced hypertension and the relevance of these rodent studies to human hypertension have not been determined. We seek to investigate the role of high phosphate diet in human hypertension and assess the effect of high phosphate diet on muscle sympathetic nerve activity and the exercise pressor reflex.

Detailed description: Animal studies suggest that high phosphate diet raises blood pressure but the mechanism underlying this phenomenon is not known. To study the effect of high phosphorus diet on blood pressure in humans, we will perform randomized crossover studies in stage 1 prehypertensive subjects. To ensure stable Pi intake prior to randomization, Pi consumption will be estimated by food recall during a run-in and washout phase for 2 consecutive days, using the Automated Self-Administered 24-Hour (ASA24®) Dietary Assessment Tool (https://epi.grants.cancer.gov/asa24/). After the run-in period, all subjects will be maintained on a low Pi diet (700 mg/d) and a low Na diet of approximately 1,930 mg/d throughout the study for 8 weeks. Subjects will also be randomized to receive Sodium Phosphate 2 capsules daily (containing a total of 500 mg of Pi, 372mg of sodium) for 4 weeks during the high Pi phase (total Pi intake 1,200 mg/d) vs 2 capsules of Sodium Chloride (NaCl, containing a total of 372mg of sodium) to match Na content to Sodium Phosphate without extra Pi daily for 4 weeks during the low Pi phase (total Pi intake = 700 mg/d).

The total Na intake during the entire study will be at recommended level of 2,300 mg/d. Investigational drug service at UT Southwestern will dispense Sodium Phosphate vs. NaCl tablets tablets and the study subjects will be blinded to the type of supplement they receive.

During the periods of high and low Pi phases, we will monitor 24-hr UPiV to ensure adherence. Since approximately 70% of ingested Pi is absorbed and excreted in the urine, we expect 24-hr UPiV excretion to be approximately 840 mg during the high Pi phase and 490 mg during the low Pi phase. If 24-hr UPiV is \< 800 mg during the high Pi diet or \> 500 mg during the low Pi diet, the research dietitian will provide additional counseling to improve adherence to the menu plan. If needed, the research diet will be altered to be more compatible with subject preference. 24-hr UPiV will be reassessed within 1 week in these individuals. If the levels remain below goal, subjects will be excluded from the study.

24-hr urinary Pi, Na, K, Cr, and Ca excretion will be assessed after weeks 2 and 4 of the low and high Pi phases. Serum electrolytes and Pi will be monitored every 2 weeks. Serum FGF23, PTH, and soluble Klotho levels and 24-h ambulatory BP will be obtained after 4 weeks on the study diet. Then, on a separate day, we will assess muscle SNA and BP at rest and during rhythmic handgrip of 30% and 45% each for 3 minutes. Additionally, we will test the role of dietary Pi on the response to isometric exercise by assessing SNA and BP during static handgrip at 30% MVC for 2 minutes followed by post exercise circulatory arrest (PECA). The latter maneuver will maximally activate the metaboreflex. Each exercise intervention will be separated by at least 30 minutes. The order of exercise intervention will be randomized. Subsequently, subjects will stop the first study supplement and undergo washout for 2 weeks. After 2 weeks of washout, they will receive the 2nd study supplement. Measurement of 24-h ambulatory BP, SNA at rest and during handgrip exercise will be repeated in the same fashion.

Eligibility criteria: Inclusion Criteria: (answer must be yes to all to enter trial; check yes or no)

º ≥ 18 years of age

º Stage 1 Prehypertension (office BP 120-129/80-84 mmHg and normal ABPM \<130/80)

Exclusion Criteria: (answer must be no to all to enter trial)

º Diabetes mellitus or other systemic disease

º Cardiopulmonary disease

º Treatment with antihypertensive medications

º eGFR\< 60 ml/min/1.73m2

º Pregnancy

º Hypersensitivity to nitroprusside or phenylephrine

º Psychiatric illness

º H/o substance abuse or current smoker

º H/o malignancy

º Serum Phos \<2.4 mg/dL or \>4.5 mg/dL

Primary outcomes:
measure: 24-hour Blood Pressure measured by Ambulatory Blood Pressure Monitor.
timeFrame: 4 weeks
Secondary outcomes:
measure: Muscle Sympathetic Nerve Activity (MSNA)
timeFrame: 4 weeks after high phosphorus and 4 weeks after low phosphorus diet
Other outcomes:
Locations:
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
Study officials:
affiliation: UT southwestern
name: Wapen Vongpatanasin, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sullivan CM, Leon JB, Sehgal AR. Phosphorus-containing food additives and the accuracy of nutrient databases: implications for renal patients. J Ren Nutr. 2007 Sep;17(5):350-4. doi: 10.1053/j.jrn.2007.05.008.
citation: Benini O, D'Alessandro C, Gianfaldoni D, Cupisti A. Extra-phosphate load from food additives in commonly eaten foods: a real and insidious danger for renal patients. J Ren Nutr. 2011 Jul;21(4):303-8. doi: 10.1053/j.jrn.2010.06.021. Epub 2010 Nov 5.
citation: Ketteler M, Wolf M, Hahn K, Ritz E. Phosphate: a novel cardiovascular risk factor. Eur Heart J. 2013 Apr;34(15):1099-101. doi: 10.1093/eurheartj/ehs247. Epub 2012 Oct 7. No abstract available.
citation: Karp H, Ekholm P, Kemi V, Itkonen S, Hirvonen T, Narkki S, Lamberg-Allardt C. Differences among total and in vitro digestible phosphorus content of plant foods and beverages. J Ren Nutr. 2012 Jul;22(4):416-22. doi: 10.1053/j.jrn.2011.04.004. Epub 2011 Jul 13.
citation: Suzuki Y, Mitsushima S, Kato A, Yamaguchi T, Ichihara S. High-phosphorus/zinc-free diet aggravates hypertension and cardiac dysfunction in a rat model of the metabolic syndrome. Cardiovasc Pathol. 2014 Jan-Feb;23(1):43-9. doi: 10.1016/j.carpath.2013.06.004. Epub 2013 Aug 8.
citation: Scanni R, vonRotz M, Jehle S, Hulter HN, Krapf R. The human response to acute enteral and parenteral phosphate loads. J Am Soc Nephrol. 2014 Dec;25(12):2730-9. doi: 10.1681/ASN.2013101076. Epub 2014 May 22.
citation: Hu MC, Shi M, Cho HJ, Adams-Huet B, Paek J, Hill K, Shelton J, Amaral AP, Faul C, Taniguchi M, Wolf M, Brand M, Takahashi M, Kuro-O M, Hill JA, Moe OW. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol. 2015 Jun;26(6):1290-302. doi: 10.1681/ASN.2014050465. Epub 2014 Oct 17.