Dietary Phosphorus Intake and the Kidney

Abstract

Although phosphorus is an essential nutrient required for multiple physiological functions, recent research raises concerns that high phosphorus intake could have detrimental effects on health. Phosphorus is abundant in the food supply of developed countries, occurring naturally in protein-rich foods and as an additive in processed foods. High phosphorus intake can cause vascular and renal calcification, renal tubular injury, and premature death in multiple animal models. Small studies in human suggest that high phosphorus intake may result in positive phosphorus balance and correlate with renal calcification and albuminuria. Although serum phosphorus is strongly associated with cardiovascular disease, progression of kidney disease, and death, limited data exist linking high phosphorus intake directly to adverse clinical outcomes. Further prospective studies are needed to determine whether phosphorus intake is a modifiable risk factor for kidney disease.

Keywords: GFR; chronic kidney disease; glomerular filtration rate; kidney function; phosphate; phosphorus.

Figure 1

Phosphorus metabolism in health. Average phosphorus intake is approximately 1,000–1,500 mg/d. Approximately 65% of phosphorus is absorbed in the gastrointestinal tract, although the exact amount is dependent on the vitamin D status, source, and bioavailability of the dietary phosphorus, and on the ratio of calcium to phosphorus intake. Nearly 100% of phosphorus is filtered in the glomeruli and ~80–90% is reabsorbed, depending on the activity of PTH and FGF23 in the kidneys. Assuming a steady state with neutral bone balance in a healthy adult, 24-h urinary phosphorus should approximate daily phosphorus intake. Abbreviations: FGF23, fibroblast growth factor 23; PTH, parathyroid hormone.

Figure 2

Dysregulation of phosphorus homeostasis. High phosphorus intake leads to increased time-averaged 24-h serum phosphorus, particularly resulting in exaggerated peaks in the afternoon and early morning. In the setting of CKD, nephron mass is decreased, leading to compensatory mechanisms, including elevations in PTH and FGF23 to maintain phosphate homeostasis. Klotho, a cofactor found in the kidney, is required by FGF23 to exert its phosphaturic effects, and appears to decrease before PTH and FGF23 in CKD (95, 148). Renal acid excretory capacity is diminished in CKD, resulting in decreased lumenal citrate, an important inhibitor of calcium phosphate precipitation, whereas PTH levels can stimulate cytosolic free calcium concentrations; both of these factors increase the chances of intratubular calcium phosphate precipitation (99). Elevated levels of PTH and phosphorus intake can impair bone metabolism, increasing available calcium and phosphorus (65, 115). All these factors in combination with inflammation and decreased levels of calcification inhibitors may result in a perfect storm for ectopic calcification in blood vessels and the renal parenchyma. Another potential mechanism leading to kidney injury and albuminuria is endothelial dysfunction, which occurs with phosphorus loading through the nitric oxide pathway (41, 145, 150, 155). Abbreviations: 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D₃; CKD, chronic kidney disease; FGF23, fibroblast growth factor 23; PTH, parathyroid hormone.

Figure 3

Distribution and risk of ESRD by serum phosphorus levels. We modeled serum phosphorus using linear splines (knot at 3.5 mg/dL), adjusted Cox regression models for demographics, time of day, fasting status, menopause, renal risk factors (e.g., smoking, body mass index, systolic blood pressure, diabetes, cholesterol, eGFR, urine albumin/creatinine ratio, cardiovascular disease), and medications affecting serum phosphorus levels (e.g., estrogens, testosterone, vitamin D, calcium, and phosphorus binders). Above 3.5 mg/dL, higher serum phosphorus was associated with an increased risk of kidney failure (per 1 mg/dL increase: aHR 1.40; 95% CI, 1.32–1.47; P < 0.001). Below 3.5 mg/dL, there was no relationship between phosphorus and kidney failure (per 1 mg/dL increase: aHR 0.99; 95% CI, 0.90–1.09; P = 0.8). Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease.

Figure 4

Serum phosphate concentration and urine phosphate-to-creatinine ratio in healthy controls (n = 4) and CKD patients (n = 11) throughout the day and across high-, normal-, and low-phosphate diets. Point estimates reflect mean concentrations, and error bars reflect standard errors. The top panels show serum phosphate concentrations in healthy control and CKD participants. P values for diet × time interactions were 0.02 in the healthy control group and 0.02 in CKD participants. The bottom panels show urine phosphate-to-creatinine ratios in healthy control and CKD participants. P values for the diet × time interactions were 0.11 and 0.48 in the healthy control group and in CKD participants, respectively. Abbreviations: CKD, chronic kidney disease. Image reproduced with permission from AJCN [Ix JH, Anderson CA, Smits G, Persky MS, Block GA. Effect of dietary phosphate intake on the circadian rhythm of serum phosphate concentrations in chronic kidney disease: a crossover study. Am J Clin Nutr. 2014 Nov;100(5):1392–7.].

Figure 5

Distribution and adjusted hazard ratio of death by absolute phosphorus intake in a healthy U.S. adult population: NHANES III. Cox proportional hazards regression was used to estimate hazard ratios of mortality by absolute phosphorus intake using linear splines with a knot at 1,400 mg/d adjusted for age, gender, race, ethnicity, poverty/income ratio, total energy intake, BMI, systolic blood pressure, current and former smoking, physical activity, non-HDL cholesterol, log ACR, eGFR, and low vitamin D level. The values were centered at 700 mg/d, and the graph is truncated at 200 and 4,000 mg/d for ease of presentation. ^*The Recommended Daily Allowance (700 mg/d) represents the daily dietary intake of phosphorus considered sufficient by the Food and Nutrition Board to meet the requirements of nearly all (97.5%) of healthy adults. ^**The tolerable upper intake level (4,000 mg/d) is the highest average phosphorus intake that is likely to pose no adverse health effects to almost all individuals in a general population. Abbreviations: ACR, albumin-creatinine ratio; BMI, body mass index; eGFR, estimated glomerular filtration rate; HDL, high density lipoprotein; NHANES III, Third National Health and Nutrition Examination Survey. Image reproduced with permission from AJCN [Chang AR, Lazo M, Appel LJ, Gutiérrez OM, Grams ME. High dietary phosphorus intake is associated with all-cause mortality: results from NHANES III. Am J Clin. Nutr. 2014 Feb;99(2):320–7.].