Renal toxicity of phosphate in rats

Haut, Lewis; Alfrey, Allen C.; Guggenheim, Stephen; Buddington, Bruce; Schrier, Nancy A.

doi:10.1038/ki.1980.85

Cited by 174 publications

(128 citation statements)

References 19 publications

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“…Higher circulating levels of phosphate may promote vascular calcification and lead to kidney injury due to calcium phosphate deposition in the kidney. [20][21][22] However, our findings suggest that the association between FGF-23 and ESRD is statistically independent of serum phosphate and other markers of mineral metabolism, namely, calcium and parathyroid hormone. Another major role of FGF-23 is to inhibit 1a-hydroxylase activity in the kidney, reducing the conversion of 25-hydroxyvitamin D into the active 1,25-dihydroxyvitamin D, that may in turn contribute to kidney disease progression.…”

Section: Discussioncontrasting

confidence: 53%

Serum Fibroblast Growth Factor-23 Is Associated with Incident Kidney Disease

Rebholz

Grams

Coresh

et al. 2015

Journal of the American Society of Nephrology

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Fibroblast growth factor-23 is a bone-derived hormone that increases urinary phosphate excretion and inhibits hydroxylation of 25-hydroxyvitamin D. Recent studies suggest that fibroblast growth factor-23 may be an early biomarker of CKD progression. However, its role in kidney function decline in the general population is unknown. We assessed the relationship between baseline (1990-1992) serum levels of intact fibroblast growth factor-23 and incident ESRD in 13,448 Atherosclerosis Risk in Communities study participants (56.1% women, 74.7% white) followed until December 31, 2010. At baseline, the mean age of participants was 56.9 years and the mean eGFR was 97 ml/min per 1.73 m 2 . During a median follow-up of 19 years, 267 participants (2.0%) developed ESRD. After adjustment for demographic characteristics, baseline eGFR, traditional CKD risk factors, and markers of mineral metabolism, the highest fibroblast growth factor-23 quintile (.54.6 pg/ml) compared with the lowest quintile (,32.0 pg/ml) was associated with risk of developing ESRD (hazard ratio, 2.10; 95% confidence interval, 1.31 to 3.36; trend P,0.001). In a large, community-based study comprising a broad range of kidney function, higher baseline fibroblast growth factor-23 levels were associated with increased risk of incident ESRD independent of the baseline level of kidney function and a number of other risk factors.

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Section: Discussioncontrasting

confidence: 53%

Serum Fibroblast Growth Factor-23 Is Associated with Incident Kidney Disease

Rebholz

Grams

Coresh

et al. 2015

Journal of the American Society of Nephrology

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“…Moreover, in uremic rats fed a normal-P diet (0.5% P), renal histology presented extensive tubulointerstitial lesions and nephrocalcinosis compared with a low-P diet (0.2% P) (39). Furthermore, 5/6-nephrectomized rats placed on high-P (1.0% or 2.0%) diets developed higher renal Ca content and more histologic damage compared with animals on a normal-P (0.5%) diet (11). The demonstration in our experimental model in the rat that both P binders were equally effective in controlling serum P indicates that the lower Ca ϫ P product in the sevelamer group may be the main determinant of its advantage in a better preservation of renal function.…”

Section: Discussionmentioning

confidence: 96%

“…The role of P in the progression of renal failure (11) and the protective effects of P restriction on renal function (12) have been known for more than 20 yr. Chronic renal failure causes a reduction in nephron mass and in P excretion.…”

mentioning

confidence: 99%

The Effects of Sevelamer Hydrochloride and Calcium Carbonate on Kidney Calcification in Uremic Rats

Cozzolino

Dusso²,

Liapis

et al. 2002

Journal of the American Society of Nephrology

102

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Abstract. The control of serum phosphorus (P) and calciumphosphate (Ca ϫ P) product is critical to the prevention of ectopic calcification in chronic renal failure (CRF). Whereas calcium (Ca) salts, the most commonly used phosphate binders, markedly increase serum Ca and positive Ca balance, the new calcium-and aluminum-free phosphate binder, sevelamer hydrochloride (RenaGel), reduces serum P without altering serum Ca in hemodialysis patients. Using an experimental model of CRF, these studies compare sevelamer and calcium carbonate (CaCO 3 ) in the control of serum P, secondary hyperparathyroidism (SH), and ectopic calcifications. 5/6 nephrectomized rats underwent one of the following treatments for 3 mo: uremic ϩ high-P diet (U-HP); UHP ϩ 3% CaCO 3 (U-HPϩC); UHP ϩ 3% sevelamer (U-HPϩS). Sevelamer treatment controlled serum P independent of increases in serum Ca, thus reducing serum Ca ϫ P product and further deterioration of renal function, as indicated by the highest creatinine clearances. Sevelamer was as effective as CaCO 3 in the control of high-P-induced SH, as shown by similar serum PTH levels, parathyroid (PT) gland weight, and markers of PT hyperplasia.Also, both P binders elicited similar efficacy in reducing the myocardial and hepatic calcifications induced by uremia. However, sevelamer caused a dramatic reduction of renal Ca deposition (29.8 Ϯ 8.6 g/g wet tissue) compared with both U-HP (175.5 Ϯ 45.7 g/g wet tissue, P Ͻ 0.01) and the U-HPϩC (58.9 Ϯ 13.7 g/g wet tissue, P Ͻ 0.04). Histochemical analyses using Von Kossa and Alizarin red S staining of kidney sections confirmed these findings. The high number of foci of calcification in the kidney of uremic controls (108 Ϯ 25) was reduced to 33.0 Ϯ 11.3 by CaCO 3 and decreased even further with sevelamer (16.4 Ϯ 8.9, P Ͻ 0.02 versus CaCO 3 ). Importantly, the degree of tubulointerstitial fibrosis was also markedly lower in U-HPϩS (5%) compared with either U-HPϩC (30%) or U-HP (50%). It is concluded that in experimental CRF in rats, despite a similar control of serum P and SH, sevelamer is more effective than CaCO 3 in preventing renal Ca deposition and tubulointerstitial fibrosis, including better preservation of renal function. These findings cannot be extrapolated to human disease, and further studies in patients are necessary to determine the benefits of either P binder.In end-stage renal disease, hyperphosphatemia and elevated calcium-phosphate (Ca ϫ P) product associate with ectopic calcifications and increased risk of calciphylaxis, resulting in higher prevalence of morbidity and mortality from cardiovascular events (1-6). High serum phosphorus (P) levels worsen uremia-induced secondary hyperparathyroidism by enhancing parathyroid hyperplasia and parathyroid hormone (PTH) synthesis and secretion (7-8). Elevated PTH levels cause ectopic calcification not only by enhancing serum P and Ca ϫ P product through inducing high bone turnover, but also by increasing both serum and intracellular calcium (Ca) (9 -10). The control of serum P in patients with ch...

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“…Experimentally, high dietary phosphorus has been shown to initiate and/or worsen progression of kidney dysfunction (26), whereas dietary phosphate restriction reverses and/or restricts the dysfunction (27). Although the most common explanation has been phosphorus-induced calcification, there are other potential proposed mechanisms including phosphorus-dependent podocyte injury due to overexpression of pituitary-specific positive transcription factor 1 (Pit-1) transporter in rats (28).…”

Section: Association Between Serum Phosphorus and Progression Of Kidnmentioning

confidence: 99%

Phosphorus and the Kidney: What Is Known and What Is Needed

Nadkarni

Uribarri

2014

Advances in Nutrition

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A major role of the kidneys is to maintain phosphorus homeostasis. High serum phosphorus has been linked to all-cause and cardiovascular mortality in chronic kidney disease (CKD) both before and after initiation of renal replacement therapy. Considering the clinical implications of uncontrolled hyperphosphatemia, maintenance of phosphorus concentrations within an optimum range is standard of care in this patient population. Recently, the epidemiologic associations between serum phosphorus and worse outcome have been extended to the general population. This becomes even more important in view of the increasing dietary phosphorus intake in the American diet due in large part to the greater consumption of foods processed with phosphate additives. A greater understanding of mechanisms and epidemiology of altered phosphorus metabolism and disease in CKD may help clarify the possible role of excess dietary phosphorus as a health risk factor in the general population. Adv. Nutr. 5: 98-103, 2014.

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Renal toxicity of phosphate in rats

Cited by 174 publications

References 19 publications

Serum Fibroblast Growth Factor-23 Is Associated with Incident Kidney Disease

Serum Fibroblast Growth Factor-23 Is Associated with Incident Kidney Disease

The Effects of Sevelamer Hydrochloride and Calcium Carbonate on Kidney Calcification in Uremic Rats

Phosphorus and the Kidney: What Is Known and What Is Needed

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