Phosphate restriction significantly reduces mortality in uremic rats with established vascular calcification

Abstract

The role of hyperphosphatemia in the pathogenesis of secondary hyperparathyroidism, cardiovascular disease, and progression of renal failure is widely known. Here we studied effects of dietary phosphate restriction on mortality and vascular calcification in uremic rats. Control and uremic rats were fed a high-phosphate diet and at 3 months a portion of rats of each group were killed. Serum phosphate and the calcium phosphate product increased in uremic rats, as did aortic calcium. Of the rats, 56% had positive aortic staining for calcium (von Kossa), RUNX2, and osteopontin. The remaining uremic rats were continued on diets containing high phosphate without and with sevelamer, or low phosphate, and after 3 more months they were killed. Serum phosphate was highest in uremic rats on high phosphate. Serum PTH and FGF-23 were markedly lower in rats on low phosphate. Mortality on high phosphate was 71.4%, with sevelamer reducing this to 37.5% and phosphate restriction to 5.9%. Positive aortic staining for von Kossa, RUNX2, and osteopontin was increased, but phosphate restriction inhibited this. Kidneys from low-phosphate and sevelamer-treated uremic rats had less interstitial fibrosis, glomerulosclerosis, and inflammation than those of uremic rats on high phosphate. Importantly, kidneys from rats on low phosphate showed improvement over kidneys from high-phosphate rats at 3 months. Left ventricles from rats on low phosphate had less perivascular fibrosis and smaller cardiomyocyte size compared to rats on high phosphate. Thus, intensive phosphate restriction significantly reduces mortality in uremic rats with severe vascular calcification.

Phosphate Toxicity in CKD: The Killer among Us

“…Phosphate levels were positively associated with protein intake and peritoneal dialysis adequacy, suggesting that restriction of phosphate intake may be useful in slowing the progression of vascular calcification. Our laboratory recently reported a significant reduction in aortic calcification and decreased mortality as well as preserved renal function using phosphate binders and dietary phosphate restriction in uremic rats; the Kaplan-Meier analysis of the mortality and survival rates in this study is shown in Figure 3 (89).…”

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

“…64 Vascular calcification in rats reversed when they were switched to a low-phosphate diet, which the researchers suggested was associated with calcification inhibition by osteopontin. 65 One type of soft tissue that is susceptible to ectopic calcification from the deposition of CaxPi product is the endothelium of the arterial system. Arterial calcification increases mortality risk by threefold to fourfold.…”

Inactivation of AMPK Mediates High Phosphate-Induced Extracellular Matrix Accumulation via NOX4/TGFß-1 Signaling in Human Mesangial Cells

“…Maneuvers aimed at reduction in plasma Pi levels are associated with reduction of glomerulosclerosis and interstitial fibrosis in uremic rats [4]. In the current study, the medium concentrations used in mesangial cells are comparable to a 2- to 4-fold increase of serum Pi concentrations, which indicate that even mild increases in serum Pi concentrations in vivo may have a critical stimulatory role on fibrogenesis in the kidney.…”

“…Clinical and experimental data indicate that elevated plasma phosphate (Pi) may contribute to progression of chronic kidney disease (CKD) [1,2,3,4,5] by a not fully elucidated mechanism. In spite of that, the effect of high Pi levels per se on kidney cells may play a role, since it has been shown that addition of higher Pi concentrations to the culture medium of kidney fibroblasts elicits increased extracellular matrix (ECM) production [6].…”