High phosphate intake is known to aggravate renal osteodystrophy along various pathogenetic pathways. Recent studies have raised the possibility that dysregulation of the osteocyte Wnt/β-catenin signaling pathway is also involved in chronic kidney disease (CKD)-related bone disease. We investigated the role of dietary phosphate and its possible interaction with this pathway in an experimental model of adynamic bone disease (ABD) in association with CKD and hypoparathyroidism. Partial nephrectomy (Nx) and total parathyroidectomy (PTx) were performed in male Wistar rats. Control rats with normal kidney and parathyroid function underwent sham operations. Rats were divided into three groups and underwent pair-feeding for 8 weeks with diets containing either 0.6% or 1.2% phosphate: sham 0.6%, Nx+PTx 0.6%, and Nx+PTx 1.2%. In the two Nx+PTx groups, serum creatinine increased and blood ionized calcium decreased compared with sham control group. They also presented hyperphosphatemia and reduced serum parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels. Fractional urinary excretion of phosphate increased in Nx+PTx 1.2% rats despite lower PTH and FGF23 levels than in sham group. These biochemical changes were accompanied by a decrease in bone formation rates. The Nx+PTx 1.2% group had lower bone volume (BV/TV), higher osteoblast and osteocyte apoptosis, and higher SOST and Dickkopf-1 gene expression than the Nx+PTx 0.6% group. Nx+PTx 0.6% rat had very low serum sclerostin levels, and Nx+PTx 1.2% had intermediate sclerostin levels compared with sham group. Finally, there was a negative correlation between BV/TV and serum sclerostin. These results suggest that high dietary phosphate intake decreases bone volume in an experimental model of CKD-ABD, possibly via changes in SOST expression through a PTH-independent mechanism. These findings could have relevance for the clinical setting of CKD-ABD in patients who low turnover bone disease might be attenuated by optimal control of phosphate intake and/or absorption.

/pdf/effects-of-dietary-phosphate-on-adynamic-bone-disease-in-1hms9edolb.pdf

Effects of dietary phosphate on adynamic bone disease in rats with chronic kidney disease--role of sclerostin?

Hyperphosphatemia is a common condition in patients with chronic kidney disease (CKD) and can lead to bone disease, vascular calcification, and increased risks of cardiovascular disease and mortality. Inorganic phosphate (Pi) is absorbed in the intestine, an important step in the maintenance of homeostasis. In CKD, it is not clear to what extent Pi absorption is modulated by dietary Pi. Thus, we investigated 5/6 nephrectomized (Nx) Wistar rats to test whether acute variations in dietary Pi concentration over 2 days would alter hormones involved in Pi metabolism, expression of sodium-phosphate cotransporters, apoptosis, and the expression of matrix extracellular phosphoglycoprotein (MEPE) in different segments of the small intestine. The animals were divided into groups receiving different levels of dietary phosphate: low (Nx/LPi), normal (Nx/NPi), and high (Nx/HPi). Serum phosphate, fractional excretion of phosphate, intact serum fibroblast growth factor 23 (FGF-23), and parathyroid hormone (PTH) were significantly higher and ionized calcium was significantly lower in the Nx/HPi group than in the Nx/LPi group. The expression levels of NaPi-IIb and PiT-1/2 were increased in the total jejunum mucosa of the Nx/LPi group compared with the Nx/HPi group. Modification of Pi concentration in the diet affected the apoptosis of enterocytes, particularly with Pi overload. MEPE expression was higher in the Nx/HPi group than in the Nx/NPi. These data reveal the importance of early control of Pi in uremia to prevent an increase in serum PTH and FGF-23. Uremia may be a determining factor that explains the expressional modulation of the cotransporters in the small intestine segments.

Effect of variations in dietary Pi intake on intestinal Pi transporters (NaPi-IIb, PiT-1, and PiT-2) and phosphate-regulating factors (PTH, FGF-23, and MEPE)

Blood-brain barrier dysfunction characterised by brain parenchymal extravasation of plasma proteins may contribute to risk of neurodegenerative disorders, however the mechanisms for increased capillary permeability are not understood. Increasing evidence suggests vitamin D confers central nervous system benefits and there is increasing demand for vitamin D supplementation. Vitamin D may influence the CNS via modulation of capillary function, however such effects may be indirect as it has a central role in maintaining calcium homeostasis, in concert with calcium regulatory hormones. This study utilised an integrated approach and investigated the effects of vitamin D supplementation, parathyroid tissue ablation (PTX), or exogenous infusion of parathyroid hormone (PTH) on cerebral capillary integrity. Parenchymal extravasation of immunoglobulin G (IgG) was used as a marker of cerebral capillary permeability. In C57BL/6J mice and Sprague Dawley rats, dietary vitamin D was associated with exaggerated abundance of IgG within cerebral cortex (CTX) and hippocampal formation (HPF). Vitamin D was also associated with increased plasma ionised calcium (iCa) and decreased PTH. A response to dose was suggested and parenchymal effects persisted for up to 24 weeks. Ablation of parathyroid glands increased CTX- and HPF-IgG abundance concomitant with a reduction in plasma iCa. With the provision of PTH, iCa levels increased, however the PTH treated animals did not show increased cerebral permeability. Vitamin D supplemented groups and rats with PTH-tissue ablation showed modestly increased parenchymal abundance of glial-fibrillary acidic protein (GFAP), a marker of astroglial activation. PTH infusion attenuated GFAP abundance. The findings suggest that vitamin D can compromise capillary integrity via a mechanism that is independent of calcium homeostasis. The effects of exogenous vitamin D supplementation on capillary function and in the context of prevention of vascular neurodegenerative conditions should be considered in the context of synergistic effects with calcium modulating hormones.

/pdf/the-vitamin-d-ionised-calcium-and-parathyroid-hormone-axis-y0x614b4h8.pdf

The Vitamin D, Ionised Calcium and Parathyroid Hormone Axis of Cerebral Capillary Function: Therapeutic Considerations for Vascular-Based Neurodegenerative Disorders

An investigation of a vitamin D, ionised calcium and parathyroid hormone regulatory axis of cerebral capillary function: Implications for cognitive performance in ageing

Over the past decade there has been an increasing awareness of the complexity of bone and mineral complications observed in chronic kidney disease (CKD) and recognition that the consequences of these abnormalities affect not only the skeleton, but also the cardiovascular system. These scientific advances led to the naming of a systemic disorder, “Chronic Kidney Disease-Mineral Bone Disorder” (CKD-MBD) defined as abnormalities in mineral-related biochemistries, bone modeling/remodeling and strength, and extraskeletal calcification. CKD-MBD begins early in the course of progressive CKD, at estimated glomerular filtration rates of 60 ml/min or earlier, with progression such that all dialysis patients have one or more components. The older term, renal osteodystrophy is one component of CKD-MBD and should be used exclusively to define the histopathologic abnormalities of CKD-related bone remodeling. This diagnostic criteria has been further refined using a new classification system “turnover, mineralization, and volume”, that defines bone turnover, mineralization, and volume to allow for a more complete evaluation of renal osteodystrophy. The recognition of this inter-relationship between biochemical changes, bone, and extraskeletal calcification as the systemic disorder CKD-MBD allows for enhanced communication, increased awareness/diagnosis, and improved treatment approaches with the ultimate goal of improving morbidity and mortality in patients with CKD.

Chronic Kidney Disease-Mineral Bone Disorder: Definitions and Rationale for a Systemic Disorder

Bone disease is a common disorder of bone remodeling and mineral metabolism, which affects patients with chronic kidney disease. Minor changes in the serum level of a given mineral can trigger compensatory mech- anisms, making it difficult to evaluate the role of mineral disturbances in isolation. The objective of this study was to determine the isolated effects that phosphate and parathy- roid hormone (PTH) have on bone tissue in rats. Male Wistar rats were subjected to parathyroidectomy and 5/6 nephrectomy or were sham-operated. Rats were fed diets in which the phosphate content was low, normal, or high. Some rats received infusion of PTH at a physiological rate, some received infusion of PTH at a supraphysiological rate, and some received infusion of vehicle only. All nephrectomized rats developed moderate renal failure. High phosphate intake decreased bone volume, and this effect was more pronounced in animals with dietary phosphate overload that received PTH infusion at a physiological rate. Phosphate overload induced hyper- phosphatemia, hypocalcemia, and changes in bone mic- roarchitecture. PTH at a supraphysiological rate minimized the phosphate-induced osteopenia. These data indicate that the management of uremia requires proper control of die- tary phosphate, together with PTH adjustment, in order to ensure adequate bone remodeling.

The Bone Histology Spectrum in Experimental Renal Failure: Adverse Effects of Phosphate and Parathyroid Hormone

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The Bone Histology Spectrum in Experimental Renal Failure: Adverse Effects of Phosphate and Parathyroid Hormone