Contribution to the phosphate-induced nephropathy in the dog. Comparative light and electron microscopic investigations on the proximal tubule after oral application of K2HPO4, Na2HPO4, KCl and NaCl

Schneider, P. M.; Ober, K.M.; Ueberberg, H

doi:10.1016/s0232-1513(81)80055-2

Cited by 6 publications

(5 citation statements)

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“…Concordance of the key events in man and animal: In several short-term and subchronic rat studies, the endpoint calcification in the kidney has been observed in a dose-dependent manner with different phosphates (Chow et al, 1980;Mars et al, 1988;Ritskes-Hoitinga et al, 1989;Seo et al, 2011). The effect has also been observed in dogs (Schneider et al, 1981). The most reliable NOAEL from the short-term and subchronic studies was 500 mg/kg bw per day, corresponding to 116 mg/kg bw per day phosphorus in a 90-day study (Seo et al, 2011).…”

Section: Mode Of Actionmentioning

confidence: 99%

“…Male Beagle dogs were given equimolar amounts of dipotassium phosphate (trihydrate) or disodium phosphate (dihydrate) daily by gavage; the control group was given the vehicle (water) (Schneider et al, 1981. In the first week, the doses were 2,080 mg/kg bw per day dipotassium phosphate and 1,625 mg/kg bw per day disodium phosphate and the animals were dosed prior to their food. Because vomiting occurred the doses were halved, and food was given prior to the test solutions.…”

Section: Dogmentioning

confidence: 99%

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Re‐evaluation of phosphoric acid–phosphates – di‐, tri‐ and polyphosphates (E 338–341, E 343, E 450–452) as food additives and the safety of proposed extension of use

Flavourings¹,

Younes²,

Aquilina³

et al. 2019

EFS2

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The Panel on Food Additives and Flavourings added to Food (FAF) provided a scientific opinion re-evaluating the safety of phosphates (E 338-341, E 343, E 450-452) as food additives. The Panel considered that adequate exposure and toxicity data were available. Phosphates are authorised food additives in the EU in accordance with Annex II and III to Regulation (EC) No 1333/2008. Exposure to phosphates from the whole diet was estimated using mainly analytical data. The values ranged from 251 mg P/person per day in infants to 1,625 mg P/person per day for adults, and the high exposure (95th percentile) from 331 mg P/person per day in infants to 2,728 mg P/person per day for adults. Phosphate is essential for all living organisms, is absorbed at 80-90% as free orthophosphate excreted via the kidney. The Panel considered phosphates to be of low acute oral toxicity and there is no concern with respect to genotoxicity and carcinogenicity. No effects were reported in developmental toxicity studies. The Panel derived a group acceptable daily intake (ADI) for phosphates expressed as phosphorus of 40 mg/kg body weight (bw) per day and concluded that this ADI is protective for the human population. The Panel noted that in the estimated exposure scenario based on analytical data exposure estimates exceeded the proposed ADI for infants, toddlers and other children at the mean level, and for infants, toddlers, children and adolescents at the 95th percentile. The Panel also noted that phosphates exposure by food supplements exceeds the proposed ADI. The Panel concluded that the available data did not give rise to safety concerns in infants below 16 weeks of age consuming formula and food for medical purposes.

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Section: Mode Of Actionmentioning

confidence: 99%

Section: Dogmentioning

confidence: 99%

Re‐evaluation of phosphoric acid–phosphates – di‐, tri‐ and polyphosphates (E 338–341, E 343, E 450–452) as food additives and the safety of proposed extension of use

Flavourings¹,

Younes²,

Aquilina³

et al. 2019

EFS2

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“…Renal calcification in the rat is also seen experimentally with vitamin D and rodenticide containing cholecalciferol (Alden and Frith, 1998), diethanolamine (Melnick et al, 1994), hydrochlorothiazide (Bucher et al, 1990) and associated with estrogen (Casey et al, 1978). Administration of a high dosage of phosphate salts in dogs and rats can lead to calcium phosphate deposition in the proximal tubules (Scheneider et al, 1981;Matsuzaki et al, 1999). Thus, calcification in the renal tubules is known to occur spontaneously or due to chemical induction; however, there have been no reports of calcium salt deposition in the glomeruli as a primary lesion in experimental studies.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is little toxicity data for dibasic sodium phosphate (Na 2 HPO 4 , CAS number: 7558-79-4), which is a commonly used form of phosphate (O'Neil et al, 2001). The LD50 for Na 2 HPO 4 is reported to be 12930 mg/kg (rat oral) (Tatken and Lewis, 1983), and, in previous studies, oral administration of Na 2 HPO 4 at high doses has been reported to cause calcium salt deposition within the renal tubular epithelium and phosphate-induced nephropathy in dogs and rats (Scheneider et al, 1981;Matsuzaki et al, 1999). No adverse effects from intravenous injection has been reported.…”

Section: Introductionmentioning

confidence: 96%

Glomerular Calcification Induced by Bolus Injection with Dibasic Sodium Phosphate Solution in Sprague—Dawley Rats

et al. 2004

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To elucidate the nephrotoxicity of phosphate, dibasic sodium phosphate solution was given to Sprague-Dawley rats by daily bolus intravenous administration at concentrations of 0, 1, 25, 250, or 360 mM (0, 1, 28, 284, or 408 mg/kg Na2HPO4) for 14 days, and the kidneys were pathologically examined. There were no remarkable changes in blood chemistry values; however, urinalysis revealed mild to moderate proteinuria in the 250 and 360 mM groups. The kidneys from the 360 mM group were macroscopically pale. Histopathology revealed panglomerular deposition of basophilic dense granules, which were positive for von Kossa's staining, accompanied by dose-dependent degeneration of the glomerular epithelium and parietal epithelium in the 250 and 360 mM groups. Electron microscopic examination showed fusion of podocytes and increased microvilli, with large amounts of debris in the Bowman's space. Low-density lamellar structures were present not only in the glomerular epithelium, basement membrane, mesangial matrix and parietal epithelium but also within the Bowman's space depending on the severity of the glomerular lesion. Phosphorus and calcium were detected by X-ray microanalysis as fine particles admixed with lamellar structures. These results suggest that high-dose phosphate used in this study transiently overloads the glomerular epithelium during filtration through glomerular capillaries and produces insoluble calcium salt and glomerular lesions, resulting in proteinuria.

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“…Electron microscopic examination of the kidney showed low-density lamellar structures in the Bowman's space, and peaks of phosphorus and calcium were detected by X-ray microanalysis in fine particles mixed with the lamellar structures 1 . Oral administration of Na 2 HPO 4 at higher doses has been reported to cause calcium salt deposition within the renal tubular epithelium, and this is known as phosphateinduced nephropathy in dogs and rats 2,3 . However, there have been no reports of calcium salt deposition in glomeruli as a primary lesion in experimental studies or human cases with bolus Na 2 HPO 4 injection.…”

Section: Introductionmentioning

confidence: 99%

Early Events Involving Glomerular Calcification Induced by Dibasic Sodium Phosphate Solution in Rats

et al. 2008

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Abstract:To investigate the early changes involved in glomerular calcification, 360 mM Na 2 HPO 4 was administered to rats at 8 mL/kg once daily via the tail vein singly or repeatedly. Urinalysis was carried out on days 1, 3, 5 and 8 of dosing, and rats were sacrificed on days 2, 4 and 9 for histopathological and electron microscopic examination of the kidneys. Following single dosing, there were no gross or histological findings, but electron microscopy revealed a number of vacuoles scattered within the Bowman's space. On day 4, minimal and focal mineralization was observed within the parietal epithelial cells. On day 9, mineralization was minimal to mild and localized within the parietal epithelial cells and glomerular basement membrane. Hypertrophy and increased mitotic figures were also frequently observed in the parietal epithelial cells. Low-density lamellar structures with effacement of podocytes, an increased number of microvilli and large amounts of debris filling the Bowman's space were the main electron microscopic changes on days 4 and 9. Increased urinary protein excretion correlated well with the glomerular changes. Immunohistochemically, increased expression of desmin and decreased expression of podoplanin were evident in glomeruli on day 9. The numbers of PCNA-positive podocytes and parietal epithelial cells showed a tendency to increase on day 9. These results suggest that the onset of glomerular calcification is preceded by primary podocyte damage. (J Toxicol Pathol 2008; 21: 229-237)

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Contribution to the phosphate-induced nephropathy in the dog. Comparative light and electron microscopic investigations on the proximal tubule after oral application of K2HPO4, Na2HPO4, KCl and NaCl

Cited by 6 publications

References 5 publications

Re‐evaluation of phosphoric acid–phosphates – di‐, tri‐ and polyphosphates (E 338–341, E 343, E 450–452) as food additives and the safety of proposed extension of use

Re‐evaluation of phosphoric acid–phosphates – di‐, tri‐ and polyphosphates (E 338–341, E 343, E 450–452) as food additives and the safety of proposed extension of use

Glomerular Calcification Induced by Bolus Injection with Dibasic Sodium Phosphate Solution in Sprague—Dawley Rats

Early Events Involving Glomerular Calcification Induced by Dibasic Sodium Phosphate Solution in Rats

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