Acute Tissue Mineral Deposition in Response to a Phosphate Pulse in Experimental CKD

Abstract

Pathogenic accumulation of calcium (Ca) and phosphate (PO ) in vasculature is a sentinel of advancing cardiovascular disease in chronic kidney disease (CKD). This study sought to characterize acute distribution patterns of radiolabeled PO and Ca in cardiovascular tissues of rats with CKD (0.25% dietary adenine). The disposition of PO and Ca was assessed in blood and 36 tissues after a 10-minute intravenous infusion of one of the following: (i) PO pulse + tracer PO ; (ii) PO pulse + tracer Ca; or (iii) saline + tracer Ca in CKD and non-CKD animals. After the infusion, PO in blood was elevated (2.3× at 10 minutes, 3.5× at 30 minutes, p < 0.05) in CKD compared with non-CKD. In contrast, there was no difference in clearance of Ca from the blood. Compared with controls, CKD rats had a markedly increased PO incorporation in several tissues (skeletal muscle, 7.8×; heart, 5.5×), but accrual was most pronounced in the vasculature (24.8×). There was a significant, but smaller, increase in Ca accrual in the vasculature of CKD rats (1.25×), particularly in the calcified rat, in response to the acute phosphate load. Based on the pattern of tissue uptake of PO and Ca, this study revealed that an increase in circulating PO is an important stimulus for the accumulation of these minerals in vascular tissue in CKD. This response is further enhanced when vascular calcification is also present. The finding of enhanced vascular mineral deposition in response to an acute PO pulse provides evidence of significant tissue-specific susceptibility to calcification. © 2018 American Society for Bone and Mineral Research.

Development of experimental chronic kidney disease and vascular calcification alters diurnal variation of phosphate and its hormonal regulators

“…The major findings were that (i) renal impairment did not markedly alter normal daily variations in circulating minerals or hormonal regulators in low-normal dietary phosphate conditions, (ii) that the generation of severe hyperphosphatemia in CKD was associated with an attenuated diurnal variation in phosphate and PTH, (iii) the development of VC in CKD was predicted by an early increase in the circulating level of FGF-23, but not PTH or hyperphosphatemia, and (iv) the presence of VC associated with an altered diurnal variation in circulating phosphate. Consistent with previous studies the use of the dietary adenine-induction model of CKD resulted in the progressive development of renal dysfunction with corresponding elevations to circulating creatinine, phosphate, calcium, and FGF-23 (McCabe et al, 2013Shobeiri et al, 2010b;Zelt et al, 2015Zelt et al, , 2019. A high phosphate diet was required to induce severe hyperphosphatemia as well as marked elevation of PTH and FGF-23 in the CKD rats.…”

“…Data are represented as Mean ± SD. Diurnal variation was assessed by Cosinor analysis for the clearance of phosphate from the circulation (Zelt et al, 2019). Tissue analysis revealed that in CKD animals with VC a preferential deposition for phosphate into the arteries occurs, contrasting the preference for bone in non-calcified animals, and the kidneys and bone for Controls.…”

“…were demineralized in hydrochloric acid (50 µl/mg tissue 1.0 N, room temperature) for 1 week. The resultant homogenate was assessed for calcium and phosphate content using the same colorimetric assays used for the analysis of serum calcium and phosphate (McCabe et al, 2013(McCabe et al, , 2018Zelt et al, 2015Zelt et al, , 2019).…”

Kidney Disease Progression Does Not Decrease Intestinal Phosphorus Absorption in a Rat Model of Chronic Kidney Disease–Mineral Bone Disorder

“…Furthermore, we have extensively characterized the Cy/+ rat as a model of progressive CKD‐MBD, observing biochemical and tissue changes similar to the human disease . Second, the interpretation of absorption using the ligated loop assumes that differences in renal filtration and tissue distribution within the 30 minute timeframe of the test will not significantly affect plasma 33 P. Recently, Zelt and colleagues performed experiments in nephrectomized rats that address these questions. Although kidney filtration was only different between pre‐nephrectomy and post‐nephrectomy beyond a 30‐min period, suggesting that this does not affect our interpretation, the nephrectomized group experienced differences in tissue distribution 30 min post‐i.v.…”

PTH suppression by calcitriol does not predict off‐target actions in experimental CKD

“…As expected, this modified adenine‐based dietary protocol caused a slight reduction in bodyweight during the induction of CKD (Table 1). 15,16,26,32 After 4 weeks on the adenine diet, CKD rats were stratified, based on circulating creatinine, into the five calcitriol treatment groups with similar overall severity of CKD: (a) No treatment (0 ng/kg), (b) 5 ng/kg 4 times/day (5D QID, n = 9), (c) 20 ng/kg/ once/day (20D SD, n = 8), (d) 20 ng/kg 4 times/day (20D QID, n = 9), and (d) 80 ng/kg once/day (80D SD, n = 8). Following the sorting of groups according to creatinine, there were no between‐group differences regarding bodyweight, PTH, or FGF‐23.…”