Increased Phosphaturia Accelerates The Decline in Renal Function: A Search for Mechanisms

Abstract

In chronic kidney disease (CKD), high serum phosphate concentration is associated with cardiovascular disease and deterioration in renal function. In early CKD, the serum phosphate concentration is normal due to increased fractional excretion of phosphate. Our premise was that high phosphate intake even in patients with early CKD would result in an excessive load of phosphate causing tubular injury and accelerating renal function deterioration. In CKD 2–3 patients, we evaluated whether increased phosphaturia accelerates CKD progression. To have a uniform group of patients with early CKD, 95 patients with metabolic syndrome without overt proteinuria were followed for 2.7 ± 1.6 years. The median decline in eGFR was 0.50 ml/min/1.73 m2/year. Patients with a more rapid decrease in eGFR had greater phosphaturia. Moreover, the rate of decrease in eGFR inversely correlated with the degree of phosphaturia. Additionally, phosphaturia independently predicted renal function deterioration. In heminephrectomized rats, a high phosphate diet increased phosphaturia resulting in renal tubular damage associated with inflammation, oxidative stress and low klotho expression. Moreover, in rats with hyperphosphatemia and metabolic syndrome antioxidant treatment resulted in attenuation of renal lesions. In HEK-293 cells, high phosphate promoted oxidative stress while melatonin administration reduced ROS generation. Our findings suggest that phosphate loading in early CKD, results in renal damage and a more rapid decrease in renal function due to renal tubular injury.

Urinary phosphate-containing nanoparticle contributes to inflammation and kidney injury in a salt-sensitive hypertension rat model

“…These data indicate that, although phosphate metabolism is dysregulated in our model, serum phosphate levels were kept constant through increased renal phosphate excretion. Given the evidence that chronic kidney injury and phosphaturia can alter full-length, renal Klotho expression levels 29,31 , we evaluated Klotho abundance. We found that the renal Klotho levels were lower in the DSH group than in the DSN group and that these changes were alleviated by SF ( Fig.…”

Cardiac Remodeling in Chronic Kidney Disease

“…FGF23 stimulates pro-fibrotic and pro-hypertrophic factors in cardiomyocytes and induces fibrosis-related pathways in fibroblasts [55,59,60]. In addition to its direct effects on cardiac remodeling, FGF23 has also been shown to increase blood pressure [61], inflammation [62] and CKD progression itself [63], and may thus promote the development of LVH also by indirect mechanisms. FGF23 signaling in the liver causes production of inflammatory cytokines.…”

Hypocaloric Diet Prevents the Decrease in FGF21 Elicited by High Phosphorus Intake

“…Thus, adequate nutritional intake of P is essential for healthy life. However, the deleterious consequences of increased P intake are also well known, especially in patients with reduced renal function [ 11 ]. Western diets are typically rich in P and the use of P as a food additive further increases the P content of many processed foods.…”