Effect Of Dietary Phosphate Restriction Research Articles

Blood fibroblast growth factor 23 concentration in cats with and without chronic kidney disease: a scoping review.

This study undertook a scoping review of research on blood fibroblast growth factor 23 (FGF-23) concentrations in healthy non-azotemic cats and cats with chronic kidney disease (CKD) to describe the volume and nature of existing literature, to determine whether published studies provide adequate evidence to support the use of FGF-23 as a biomarker in clinical practice and to identify any existing gaps in knowledge. PRISMA Extension for Scoping Reviews guidelines were used to design and perform the scoping review. Online databases were used to identify observational and clinical studies of blood FGF-23 concentrations in healthy cats and cats with CKD published before December 2022. Study and population characteristics and descriptive data on FGF-23 concentrations were extracted. A total of 205 publications were reviewed; 17 were retained for inclusion. Most studies were retrospective. Most studies included cats with International Renal Interest Society stage 2-4 CKD, with some variation. Key concepts explored in the literature include FGF-23 concentrations by CKD stage, effect of dietary phosphate restriction on FGF-23 concentrations, relationship between FGF-23 concentrations and blood phosphorus, calcium and magnesium concentrations, and FGF-23 concentrations in cats with progressive CKD. FGF-23 concentrations tended to be higher in cats with CKD compared with healthy cats, with an overlap between healthy and CKD populations, and there was significant variation within stages of CKD. FGF-23 is a biomarker of interest for the management and monitoring of phosphate overload in cats. Studies support several potential clinical applications for measuring FGF-23 concentration in practice; however, evidence is limited. Research on FGF-23 in cats with CKD would benefit from longitudinal, prospective studies that standardize CKD diagnosis and categorize cats by stage using current guidelines. Studies should include cats with early-stage, non-azotemic CKD and use commercially available assays so such results are comparable across studies.

Effectiveness of fibroblast growth factor 23 lowering modalities in chronic kidney disease: a systematic review and meta-analysis.

The heightened fibroblast growth factor 23 (FGF23) level in patients with chronic kidney disease (CKD) is associated with increased cardiovascular disease and mortality. We performed a systematic review and meta-analysis to synthesize the available strategies to reduce FGF23 in CKD patients. We conducted a meta-analysis by searching the databases of MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) and single-arm studies that examined the effects of dietary phosphate restriction, phosphate binders, iron supplements, calcimimetics, parathyroidectomy, dialysis techniques, and the outcome of preservation of residual renal function (RRF) on FGF23 levels in CKD patients. Random-effects model meta-analyses were used to compute changes in the outcome of interests. A total of 41 articles (7590 patients), comprising 36 RCTs, 5 prospective studies were included in this meta-analysis. Dietary phosphate restriction less than 800mg per day yielded insignificant effect on FGF23 reduction. Interestingly sevelamer, lanthanum, iron-based phosphate binders, and iron supplement significantly lowered FGF23 levels. In CKD patients with secondary hyperparathyroidism, calcimimetics prescription could significantly reduce FGF23 levels, while surgical parathyroidectomy had no significant effect. In dialysis patients, preservation of RRF and hemoperfusion as well as hemodiafiltration provided a significant decrease in FGF23 levels. The present meta-analysis demonstrated that non-calcium-based phosphate binders including sevelamer, lanthanum, and iron-based phosphate binders, iron supplements, calcimimetics, hemoperfusion, and preservation of RRF could effectively reduce FGF23 in CKD patients.

Investigation of the transforming growth factor-beta 1 signalling pathway as a possible link between hyperphosphataemia and renal fibrosis in feline chronic kidney disease

Chronic kidney disease (CKD) is common in geriatric cats, and is characterised in the majority of cases by tubulointerstitial inflammation and fibrosis. Hyperphosphataemia is a frequent complication of CKD and is independently associated with severity of renal fibrosis and disease progression. Transforming growth factor-beta 1 (TGF-β1) signalling is thought to be a convergent pathway which mediates the progression of renal fibrosis in CKD. The aims of this study were to explore the interaction between increased extracellular phosphate and the TGF-β1 signalling pathway by investigating: (a) the effect of a commercially available, phosphate-restricted, diet on urinary TGF-β1 excretion in cats with CKD; and (b) the role of increased extracellular phosphate in regulating proliferation, apoptosis, and expression of genes related to TGF-β1 signalling and extracellular matrix (ECM) production in feline proximal tubular epithelial cells (FPTEC) and cortical fibroblasts from cats with azotaemic CKD (CKD-FCF).The dietary intervention study revealed no effect of dietary phosphate restriction on urinary active TGF-β1 excretion after 4–8 weeks (P=0.98), despite significantly decreasing serum phosphate (P<0.001). There was no effect of increased growth media phosphate concentration (from 0.95mM to 2mM and 3.5mM) on proliferation (P=0.99) and apoptotic activity in FPTEC (P=0.22), or expression of genes related to ECM production and the TGF-β1 signalling pathway in FPTEC and CKD-FCF (P>0.05). These findings suggest the beneficial effects of dietary phosphate restriction on progression of feline CKD may not occur through modulation of renal TGF-β1 production, and do not support a direct pro-fibrotic effect of increased extracellular phosphate on feline renal cells.

Acute Phosphate Restriction Impairs Bone Formation and Increases Marrow Adipose Tissue in Growing Mice.

Phosphate plays a critical role in chondrocyte maturation and skeletal mineralization. Studies examining the consequences of dietary phosphate restriction in growing mice demonstrated not only the development of rickets, but also a dramatic decrease in bone accompanied by increased marrow adipose tissue (MAT). Thus studies were undertaken to determine the effects of dietary phosphate restriction on bone formation and bone marrow stromal cell (BMSC) differentiation. Acute phosphate restriction of 28-day-old mice profoundly inhibited bone formation within 48 hours. It also resulted in increased mRNA expression of the early osteolineage markers Sox9 and Runt-related transcription factor 2 (Runx2), accompanied by decreased expression of the late osteolineage markers Osterix and Osteocalcin in BMSCs and osteoblasts, suggesting that phosphate restriction arrests osteoblast differentiation between Runx2 and Osterix. Increased expression of PPARγ and CEBPα, key regulators of adipogenic differentiation, was observed within 1 week of dietary phosphate restriction and was followed by a 13-fold increase in MAT at 3 weeks of phosphate restriction. In vitro phosphate restriction did not alter BMSC osteogenic or adipogenic colony formation, implicating aberrant paracrine or endocrine signaling in the in vivo phenotype. Because BMP signaling regulates the transition between Runx2 and Osterix, this pathway was interrogated. A dramatic decrease in pSmad1/5/9 immunoreactivity was observed in the osteoblasts of phosphate-restricted mice on day 31 (d31) and d35. This was accompanied by attenuated expression of the BMP target genes Id1, KLF10, and Foxc2, the latter of which promotes osteogenic and angiogenic differentiation while impairing adipogenesis. A decrease in expression of the Notch target gene Hey1, a BMP-regulated gene that governs angiogenesis, was also observed in phosphate-restricted mice, in association with decreased metaphyseal marrow vasculature. Whereas circulating phosphate levels are known to control growth plate maturation and skeletal mineralization, these studies reveal novel consequences of phosphate restriction in the regulation of bone formation and osteoblast differentiation. © 2016 American Society for Bone and Mineral Research.

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

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.

Effects of Dietary Phosphate Restriction and Phosphate Binders on FGF23 Levels in CKD

Elevated levels of fibroblast growth factor 23 (FGF23) are associated with increased risk of adverse outcomes in patients with CKD. Reducing dietary phosphate intake or absorption may decrease FGF23 levels, but data on the combined effects of dietary phosphate restriction and phosphate binders in CKD are limited. In this 2×2 factorial, single-blinded, placebo-controlled, 3-month study, conducted between July 2009 and March 2012, 39 patients with CKD stages 3 or 4 and normal serum phosphate levels were randomly assigned to one of four groups: ad libitum diet plus lanthanum carbonate (LC) placebo (n=10), 900-mg phosphate diet plus LC placebo (n=10), ad libitum diet plus LC (n=11), or 900-mg phosphate diet plus LC (n=8). The dose of LC was 1000 mg three times daily with meals. Dietary restriction was accomplished with outpatient counseling. The primary end point was change in FGF23 levels from baseline. Compared with ad libitum diet, the 900-mg phosphate diet did not significantly reduce FGF23 levels (diet × time interaction, P=0.05). Compared with placebo, LC alone also did not significantly reduce FGF23 levels (LC × time interaction, P=0.21). However, the dual intervention significantly decreased FGF23 levels throughout the study period (diet × LC × time interaction, P=0.02), resulting in a 35% (95% confidence interval, 8%-62%) reduction by study end. The combination of LC plus counseling for a phosphate-restricted diet decreased FGF23 levels in patients with CKD stages 3-4 and normal serum phosphate levels.

Abstract

Effect of dietary phosphate restriction on renal secondary hyperparathyroidism in the cat, Ber, P. J., Rawlings, J. M., Markwell, P. J. & Elliott, J. (1999) Journal of Small Animal Practice...

Effect of dietary phosphate restriction on renal secondary hyperparathyroidism in the cat.

Twenty-three cats with stable chronic renal failure (CRF) were examined in a prospective study of the effects of feeding a veterinary diet restricted in phosphorus and protein with or without an intestinal phosphate binding agent (aluminium hydroxide) on plasma phosphate and parathyroid hormone (PTH) concentrations. Fifteen cats accepted the veterinary diet; compliance was not achieved in the remaining eight (due to limited intake by the cats or owner resistance to diet change). Feeding the veterinary diet was associated with a significant fall in plasma phosphate and PTH concentrations by five months, with only two cats requiring aluminium hydroxide therapy. The maximum decrease in plasma PTH concentration was not associated with a significant change in plasma 1,25 dihydroxycholecalciferol concentration. Euparathyroidism was achieved in eight cats. Conversely, in cats with CRF fed proprietary diets over the same time period, mean plasma PTH concentrations did not change significantly; indeed, in seven of the eight cats, PTH concentrations increased. Dietary therapy alone or in combination with intestinal phosphate binders does reduce PTH concentrations in cats with CRF and, when effective control of phosphate intake is achieved, plasma PTH can be normalised.

Role of 1,25(OH) 2D in the genesis of secondary hyperparathyroidism of early renal failure and its use in the prevention of this abnormality

To clarify the mechanisms of hypocalcemia with renal insufficiency and to gain more insight into the mechanisms of secondary hyperparathyroidism in these patients, an 85-day study was conducted to examine the effect of dietary phosphate restriction on divalent ion metabolism in patients with early renal insufficiency. The study was conducted on four male patients with stable mild renal insufficiency who had creatinine clearances of 55 to 60 mL/min. Our results correspond with those of other studies that indicate that phosphate restriction is adequate to reverse and correct secondary hyperparathyroidism as well as other abnormalities in divalent ion metabolism. Because dietary phosphate restriction appears to exert its effect through the increased production of 1,25(OH) 2D, an alternative therapeutic approach would be supplementation of 1,25(OH) 2D 3 (calcitriol). To test this, another study was conducted evaluating the effect of 1-year therapy with 1,25(OH) 2D 3 on blood levels of parathyroid hormone (PTH) and on various parameters of bone pathology in patients with creatinine clearances of 15 to 55 mL/min. Our results showed that the use of calcitriol is safe and effective in the management of secondary hyperparathyroidism and bone disease in patients with moderate renal failure.

Attenuation of hypermetabolism in the remnant kidney by dietary phosphate restriction in the rat

In vivo energy metabolism in remnant and normal kidney nephrons and the effect of dietary phosphate restriction on energy metabolism were studied. Tissue concentrations of ATP did not differ between remnant and normal kidneys; however, the tissue concentration of inorganic phosphate (Pi) was higher in remnant kidneys (1.17 +/- 0.10 vs. 0.82 +/- 0.09 mumol/g, P less than 0.05) as assessed by 31P-nuclear magnetic resonance (NMR). Intracellular pH was also higher in remnant kidneys (7.48 +/- 0.04 vs. 7.20 +/- 0.05, P less than 0.01), as was oxygen consumption (QO2) when normalized for rate of net tubular sodium reabsorption (Tna; 0.032 +/- 0.005 vs. 0.018 +/- 0.002 mumol.min-1.g-1, P less than 0.01). Compared with glycine supplemented controls, dietary phosphate restriction induced by the phosphate binder diaminodihydroacetoacetate, a maneuver which independently of protein restriction has been shown to ameliorate the progression of chronic renal failure, resulted in no major change in tissue levels of ATP, intracellular pH, or TNa+ but decreased Pi (0.62 +/- 0.07 vs. 1.40 +/- 0.11 mumol/g, P less than 0.01) and QO2 (4.0 +/- 0.4 vs. 7.7 +/- 1.0 mumol.min-1.g-1, P less than 0.01) in remnant kidneys. For the amount of sodium reabsorption performed, remnant kidneys are hypermetabolic, and this hypermetabolism is attenuated by dietary phosphate restriction. These data suggest that hypermetabolism may be involved in the tubulointerstitial mechanisms operant in the progression of chronic renal failure that occurs in the rat remnant kidney, and that attenuation of this abnormality may be the mechanism by which dietary phosphate restriction ameliorates this process.

Bone turnover and 1,25-dihydroxycholecalciferol during treatment with phosphate binders

The effect of dietary phosphate restriction with high-dose aluminum hydroxide or calcium carbonate on bone disease assessed by histomorphometry and on the plasma levels of 1,25-dihydroxycholecalciferol was investigated in 12 children with chronic renal failure (GFR 8 to 45 ml/min/1.73 m2, age 5 to 15 years) over a one year period. Prior to treatment patients had biochemical and histological hyperparathyroidism with greatly increased bone formation rates. During treatment, plasma phosphate levels decreased from the upper to the lower limit of normal for age (pre, 1.69 +/- 0.06 mmol/liter; 6 months, 1.28 +/- 0.06 mmol/liter; 1 year, 1.34 +/- 0.06 mmol/liter; P less than 0.01). Circulating 1,25-dihydroxycholecalciferol rose to supranormal levels within three months and remained high throughout the period of study (pre, 96 +/- 32 pmol/liter; 6 months, 144 +/- 46 pmol/liter; 1 year, 169 +/- 53 pmol/liter; P less than 0.001). Significant falls in bone formation rate at tissue and cellular levels (P less than 0.005) and in total resorption surface (P less than 0.005) were observed. A mild mineralization defect present before treatment worsened, with a decrease in mineral appositional rate (P less than 0.01) and increase in mineralization lag time (P less than 0.01). Staining for aluminum in post-treatment biopsies was positive in 9 of 11 cases. Phosphate restriction produced suppression of biochemical and histological hyperparathyroidism and sustained elevation of circulating 1,25-dihydroxycholecalciferol. The adverse changes in bone mineralization may be related to aluminum hydroxide therapy; calcium carbonate is therefore recommended.

Effects of dietary phosphate restriction in children with chronic renal failure

Effects of dietary phosphate restriction in children with chronic renal failure