Impact of Lowering Phosphate Additive Intake on Metabolism and Cardiovascular Health in Community-Living Adults

Disturbances in phosphate homeostasis are strongly associated with cardiovascular morbidity
and mortality. High dietary phosphate intake plays a central role in the development of
disturbed phosphate metabolism and is common in persons consuming typical American diets rich
in processed and fast foods. An important reason for the high phosphate content of these
foods is the widespread use of phosphate-based food additives in the food supply. Phosphate
additives are heavily utilized by the food manufacturing industry to enhance the appearance,
taste and shelf-life of processed foods, accounting for as much as 50% of total phosphate
intake per day. Prior work from our group suggest that high phosphate additive intake has
serious cardiovascular consequences. We showed that phosphate excess induces heart disease
and inflammation in experimental studies, and associates with heart disease and death
independently of classic risk factors in epidemiology studies. Further, we showed that high
phosphate additive intake stimulates the secretion of fibroblast growth factor 23 (FGF23), a
phosphate-regulatory hormone directly implicated in the pathogenesis of cardiovascular
disease. Together, these data strongly suggest that high phosphate additive intake promotes
cardiovascular disease, with important potential implications for efforts to reduce
disparities in cardiovascular disease. This is because individuals with low socioeconomic
status have limited means to purchase healthy foods, resulting in excessive consumption of
processed foods rich in phosphate additives. Moreover, low income neighborhoods have a
disproportionately high prevalence of individuals with chronic kidney disease and black
individuals, both groups that have impaired ability to excrete excess phosphate. Together,
these data support our overriding hypothesis that high phosphate additive intake is a novel
target for reducing socioeconomic and racial disparities in cardiovascular. We will test this
hypothesis in detailed feeding studies of 80 individuals fed standardized meals with low
phosphate additive content for 6 weeks. We will investigate the impact of reducing phosphate
additive intake on changes in FGF23 levels, inflammatory markers and vascular function, and
test for effect modification by race and chronic kidney disease (CKD). The results of these
studies will help determine whether high phosphate additive intake is a modifiable risk
factor for disparities in cardiovascular disease.

Inclusion Criteria:

- (i.) Inclusion criteria for healthy volunteers: ≥18 years of age, normal kidney
function (eGFR > 60 and normal urinalysis).

Exclusion Criteria:

- Exclusion criteria for healthy volunteers will include:

- current smoking

- extreme obesity (BMI ≥ 35 kg/m2)

- pregnancy or breastfeeding

- conditions affecting phosphate metabolism (e.g., hyper- or hypothyroidism;
irregular menses for menstruating women)

- current intake of medications that impact phosphate metabolism (high-dose vitamin
D, chronic antacid use)

- current use of blood pressure medications

- abnormal serum phosphate (≥ 4.6 or < 2.5 mg/dl) or calcium levels (≥ 10.6 or <
8.5 mg/dl)

- severe anemia (hemoglobin < 8 g/dl for women and < 9 g/dl for men).

- Inability to receive weekly shipments of food at home.

- Requirement for any special diet other than a regular diet.

- Allergies to any foods in the standardized diets (ii.) Inclusion criteria for CKD
patients: ≥18 years of age, eGFR 20-50 ml/min

Exclusion criteria for CKD patients will include:

- clinical need for a low potassium, low sodium or low protein diet

- new or recent change (<3 months) in dosage of medications known to impact vascular
reactivity

- current smoking

- poorly controlled hypertension (≥160/100 mmHg)

- extreme obesity (BMI ≥ 35 kg/m2)

- pregnancy or breastfeeding

- conditions affecting phosphate metabolism (e.g., hyper- or hypothyroidism)

- current intake of medications that impact phosphate metabolism (e.g., high-dose
vitamin D)

- abnormal serum phosphate (≥ 4.6 or < 2.5 mg/dl) or calcium levels (≥ 10.6 or < 8.5
mg/dl)

- severe anemia (hemoglobin < 8 g/dl for women and < 9 g/dl for men).

- Inability to receive weekly shipments of food at home.

- Allergies to any foods in the standardized diets