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.

A comparative analysis of serum phosphorus levels and mineral metabolic markers in non-dialysis and dialysis chronic kidney disease patient: a cross-sectional study

Background: Chronic kidney disease is a major public health problem worldwide. As kidney function declines, it leads to several metabolic abnormalities including dysregulation of mineral metabolism. It is also reported that hyperphosphatemia in patients with advanced kidney disease is associated with an increased risk of mortality and cardiovascular events, and is higher in dialysis-dependent chronic kidney disease (CKD) patients compared to non-dialysis CKD. However, data in the Indian context is limited. Objectives were to evaluate and compare serum phosphorus levels and associated factors in non-dialysis and dialysis CKD patients. Also, the impact of dietary phosphate restriction and the use of phosphate binders on serum phosphorus is analysed. Methods: A cross-sectional study was conducted at a tertiary care hospital in Kolkata, India, with 100 CKD patients: 50 non-dialysis CKD patients and 50 dialysis-dependent CKD patients. Relevant demographic, clinical and laboratory parameters including serum phosphorus, calcium, parathyroid hormone (PTH), alkaline phosphatase, albumin and estimated glomerular filtration rate (eGFR) were collected. Data was analyzed using appropriate statistical tests. Results: Mean serum phosphorus was significantly higher in the dialysis CKD group (6.12±0.34 mg/dl) compared to the non-dialysis CKD group (4.56±0.80 mg/dl). Serum calcium and PTH were also higher while eGFR and albumin were lower in the dialysis CKD group. Serum phosphorus levels increased with advancing CKD stages in the non-dialysis group. Phosphate binder helped phosphorus control in dialysis CKD patients. Conclusions: Our study is in confluence with other reports and dietary phosphate restriction and the use of phosphate binders help optimize phosphorus levels in CKD patients.

Dietary phosphate restriction prevents the appearance of sarcopenia signs in old mice.

Sarcopenia is defined by the progressive and generalized loss of muscle mass and function associated with aging. We have previously proposed that aging-related hyperphosphataemia is linked with the appearance of sarcopenia signs. Because there are not effective treatments to prevent sarcopenia, except for resistance exercise, we propose here to analyse whether the dietary restriction of phosphate could be a useful strategy to improve muscle function and structure in an animal model of aging. Five-month-old (young), 24-month-old (old) and 28-month-old (geriatric) male C57BL6 mice were used. Old and geriatric mice were divided into two groups, one fed with a standard diet (0.6% phosphate) and the other fed with a low-phosphate (low-P) diet (0.2% phosphate) for 3 or 7months, respectively. A phosphate binder, Velphoro®, was also supplemented in a group of old mice, mixed with a standard milled diet for 3months. Muscle mass was measured by the weight of gastrocnemius and tibial muscles, and quality by nuclear magnetic resonance imaging (NMRI) and histological staining assays. Muscle strength was measured by grip test and contractile properties of the tibialis muscle by electrical stimulation of the common peroneal nerve. Gait parameters were analysed during the spontaneous locomotion of the mice with footprinting. Orientation and motor coordination were evaluated using a static rod test. Old mice fed with low-P diet showed reduced serum phosphate concentration (16.46±0.77mg/dL young; 21.24±0.95mg/dL old; 17.46±0.82mg/dL low-P diet). Old mice fed with low-P diet displayed 44% more mass in gastrocnemius muscles with respect to old mice (P=0.004). NMRI revealed a significant reduction in T2 relaxation time (P=0.014) and increased magnetization transfer (P=0.045) and mean diffusivity (P=0.045) in low-P diet-treated mice compared with their coetaneous. The hypophosphataemic diet increased the fibre size and reduced the fibrotic area by 52% in gastrocnemius muscle with respect to old mice (P=0.002). Twitch force and tetanic force were significantly increased in old mice fed with the hypophosphataemic diet (P=0.004 and P=0.014, respectively). Physical performance was also improved, increasing gait speed by 30% (P=0.032) and reducing transition time in the static rod by 55% (P=0.012). Similar results were found when diet was supplemented with Velphoro®. The dietary restriction of phosphate in old mice improves muscle quantity and quality, muscle strength and physical performance. Similar results were found using the phosphate binder Velphoro®, supporting the role of phosphate in the impairment of muscle structure and function that occurs during aging.

Oxidative metabolism is impaired by phosphate deficiency during fracture healing and is mechanistically related to BMP induced chondrocyte differentiation

Prior studies of acute phosphate restriction during the endochondral phase of fracture healing showed delayed chondrocyte differentiation was mechanistically linked to decreased bone morphogenetic protein signaling. In the present study, transcriptomic analysis of fracture callus gene expression in three strains of mice was used to identify differentially expressed (FDR = q ≤ 0.05) genes in response to phosphate (Pi) restriction. Ontology and pathway analysis of these genes showed that independent of genetic background, a Pi-deficient diet downregulated (p = 3.16 × 10−23) genes associated with mitochondrial oxidative phosphorylation pathways as well as multiple other pathways of intermediate metabolism. Temporal clustering was used to identify co-regulation of these specific pathways. This analysis showed that specific Ox/Phos, tricarboxylic acid cycle, pyruvate dehydrogenase. Arginine, proline metabolism genes, and prolyl 4-hydroxylase were all co-regulated in response to dietary Pi restriction. The murine C3H10T½ mesenchymal stem cell line was used to assess the functional relationships between BMP2-induced chondrogenic differentiation, oxidative metabolism and extracellular matrix formation. BMP2-induced chondrogenic differentiation of C3H10T½ was carried out in culture media in the absence or presence of ascorbic acid, the necessary co-factor for proly hydroxylation, and in media with normal and 25 % phosphate levels. BMP2 treatment led to decreased proliferation, increased protein accumulation and increased collagen and aggrecan gene expression. Across all conditions, BMP2 increased total oxidative activity and ATP synthesis. Under all conditions, the presence of ascorbate further increased total protein accumulation, proly-hydroxylation and aggrecan gene expression, oxidative capacity and ATP production. Lower phosphate levels only diminished aggrecan gene expression with no other effects of metabolic activity being observed. These data suggest that dietary phosphate restriction controls endochondral growth in vivo indirectly through BMP signaling, which upregulates oxidative activity that is linked to overall protein production and collagen hydroxylation.

Effect of Dietary Phosphorous Restriction on Fibroblast Growth 2 Factor-23 and sKlotho Levels in Patients with Stages 1-2 Chronic Kidney Disease.

Hyperphosphatemia has emerged as an independent risk factor for cardiovascular disease (CVD) and excess mortality in chronic kidney disease (CKD). The study evaluates the effect of dietary phosphorus (Ph) restriction (DPhR) at an early stage as a therapeutic strategy for delaying CKD progression and preventing CVD. Methods: This was a one-year interventional study conducted on 79 stage 1 and 2 CKD patients. The dietary phosphorus intake (DPhI), fibroblast growth factor-23 (FGF-23), sKlotho and serum phosphorous (SP) levels were analyzed. Patients were categorized into two groups based on their DPhI, recommended DPhI (RPhI) with <1000 mg/day of dietary phosphorous (dietary counselling) and high DPhI (HPhI) with >1000 mg/day (dietary intervention). For comparisons of differences between the two groups, independent t-test; for correlation analysis, Pearson correlation; for identifying the significant associated risk factors for CKD, binary logistic regression analysis and for comparing the means across the three visits, repeated measures ANOVA were used for statistical analysis. Results: The mean age and glomerular filtration rate (GFR) of CKD patients were 38 ± 12 years and 82.95 ± 16.93 mL/min/1.73 m2. FGF-23, SP, dietary protein and DPhI were significantly higher and sKlotho was significantly lower in HPhI group than RPhI group. In HPhI group; GFR, sKlotho, SP and FGF-23 correlated significantly with DPhI. Risk factors with a statistical bearing on the progression of CKD were animal-based diet, family history of CKD and hypertension. In HPhI group; GFR, DPhI, SP and FGF-23 levels significantly improved within the intervention period whereas a significant increase in sKlotho levels was observed in both the groups. Conclusion: Restricting DPhI emerged as a favorable therapeutic strategy for CKD patients for improving renal function and controlling hyperphosphatemia. The results of the present study may serve as the basis for future interventional studies with dietary phosphate restriction in the initial stages of CKD that would preserve renal function. Highlights: Early restriction of dietary phosphorus prevents decline in eGFR, elevation in FGF23 and increases Klotho levels.

A Single-Center Study of Chronic Kidney Disease and Dietary Phosphate Restriction

Background: Phosphate Excretion Declines With Renal Failure. PTH And FGF23 Diminish Glomerular Phosphorus Filtration, Which Decreases Tubular Reabsorption. Protein And Phosphorus Are Linked. Proteinuria Who Eat A Low- Protein Diet Reduce The Progression Of Renal Disease And Improve Their Survival. Not All Animal Proteins And Plants Have The Same Phosphorus Content. Food Labels Must Indicate The Phosphorus-To-Protein Ratio For Accuracy. Low-Protein Diets May Increase Mortality And Morbidity In End-Stage CKD Patients, Sparking Debate. Using Phosphate-Binding Medications To Reduce FGF23 And Serum Phosphorus Had No Effect On Protein Intake. A Patient's Phosphate Binder Tolerance and Intestinal Dysbacteriosis May Hinder Dialysis.

MO414: Sucroferric Oxyhydroxide (Velphoro®) Treatment Mitigates the Signs of Ageing-Related Sarcopaenia in Old Mice

Abstract BACKGROUND AND AIMS Sarcopaenia, defined as the loss of muscle mass and function, is an ageing-related pathology associated with some important diseases such as chronic kidney disease (CKD). Hyperphosphatemia has been associated with both, ageing and CKD. Old mice show an increase in serum phosphate concentration and a reduction in muscle mass, forelimb strength, gait speed and transition time in the static bar, with respect to young mice. Previous results of our group showed the beneficial effects of a low phosphate diet on ageing-related sarcopaenia. Given that the implementation of dietary phosphate restriction entails difficulties in the elderly, the aim of this work was to analyse the beneficial effects of a diet supplemented with a phosphate binder on the signs of sarcopaenia. METHOD C57BL6 male mice were used for in vivo studies: 5-month-old (young) and 24-month-old (old), which were fed with a powder standard diet (containing 0.6% of phosphate). Some old mice were fed with a hypophosphatemic diet (containing 0.2% of phosphate) or with a diet supplemented with 5% sucroferric oxyhydroxide (Velphoro®) for the last 3 months before sacrifice. Serum phosphate levels were analysed with a commercial kit. Muscle mass was estimated by measuring the gastrocnemius muscle mass divided by total body mass, muscle force was measured by a grip test and physical performance was evaluated by a gait test and the static bar test. RESULTS Velphoro® treated old mice showed a significant and more effective reduction in phosphate serum levels than old mice fed with the hypophosphatemic diet. No differences were observed in the relative gastrocnemius muscle mass between the three old mice experimental groups. By contrast, old mice fed with the standard diet supplemented with Velphoro® displayed an increased muscular strength and physical performance, improving the gait speed and reducing the transition time in the static bar, compared with old mice fed with the standard diet. Results obtained with Velphoro® treatment were similar to those observed in old mice fed with the hyphophosphatemic diet, but Velphoro® treatment achieve better results in motor coordination in the static bar test. CONCLUSION Dietary restriction of phosphate is a useful approach to mitigate the signs of ageing-related sarcopaenia (muscle strength and physical performance) in old mice. The use of Velphoro®, as a phosphate binder, exhibits similar or even better results than the hypophosphatemic diet. Therefore, the administration of Velphoro® could attenuate the signs of sarcopaenia in the elderly or in ageing-related diseases in which sarcopaenia is common, like CKD.

Protective Roles of Xenotropic and Polytropic Retrovirus Receptor 1 (XPR1) in Uremic Vascular Calcification.

Cellular phosphate transporters play critical roles in the pathogenesis of vascular calcification (VC) in chronic kidney disease (CKD). However, the mechanistic link between VC and xenotropic and polytropic receptor 1 (XPR1), a newly identified phosphate exporter, remains unknown. We developed a new mouse model with rapidly progressive uremic VC in C57BL/6 mice and examined the roles of XPR1. The combination of surgical heminephrectomy and 8weeks of feeding a customized warfarin and adenine-based diet induced extensive aortic VC in almost all mice. The XPR1 mRNA level in the aorta of CKD mice was significantly lower than those in control mice as early as week 2, when there was no apparent VC, which progressively declined thereafter. Dietary phosphate restriction increased XPR1 mRNA expression in the aorta but reduced aortic VC in CKD mice. In cultured vascular smooth muscle cells (VSMCs), a calcifying medium supplemented with high phosphate and calcium did not affect XPR1 mRNA expression. The XPR1 mRNA expression in cultured VCMCs was also unaffected by administration of indoxyl sulfate or calcitriol deficiency but was decreased by 1-34 parathyroid hormone or fibroblast growth factor 23 supplementation. Furthermore, XPR1 deletion in the cultured VSMCs exacerbated calcification of the extracellular matrix as well as the osteogenic phenotypic switch under the condition of calcifying medium. Our data suggest that XPR1 plays protective roles in the pathogenesis of VC and its decrease in the aorta may contribute to the progression of VC in CKD.

Multidisciplinary Perspectives of Current Approaches and Clinical Gaps in the Management of Hyperphosphatemia.

Population-based studies have shown that most patients with advanced chronic kidney disease (CKD) do not have optimal phosphate levels. Meta-analyses suggest that there is a morbidity and mortality benefit associated with the lowering of serum phosphate levels. However, to date there is no conclusive evidence from randomized controlled trials (RCTs) that lowering serum phosphate levels reduces the risk of morbidity and mortality. However, hyperphosphatemia may pose a risk to patients and treatment should be considered. We therefore sought to conduct a multidisciplinary review to help guide clinical decision-making pending results of ongoing RCTs. Restricting dietary phosphate intake is frequently the first step in the management of hyperphosphatemia. Important considerations when proposing dietary restriction include the patient’s socioeconomic status, lifestyle, dietary preferences, comorbidities, and nutritional status. While dietary phosphate restriction may be a valid strategy in certain patients, serum phosphate reductions achieved solely by limiting dietary intake are modest and should be considered in conjunction with other interventions. Conventional dialysis is also typically insufficient; however phosphate removal may be augmented by increased frequency or duration of dialysis, or through enhanced methods such as hemodiafiltration. Phosphate binders have been shown to reduce absorption of dietary phosphate and lower serum phosphate levels. There are several phosphate binders available, and while they all lower phosphate levels to variable degrees, they differ with respect to their pill burden, potential to induce or exacerbate vascular calcification or ectopic calcification, tissue accumulation, safety, and tolerability. The widespread treatment of hyperphosphatemia requires convincing data from RCTs to ascertain whether lowering serum phosphate levels improves patient-important outcomes, as well as the optimal method and degree of phosphate control. In the interim, the decision and approach used to treat hyperphosphatemia should be based on the best available data, as well as patient needs and clinical judgment.

Enteral Ca-Intake May Be Low and Affects Serum-PTH-Levels in Pre-school Children With Chronic Kidney Disease.

Treatment of chronic kidney disease (CKD) mineral bone disorder (MBD) is challenging in growing children due to the high amount of calcium needed for normal bone mineralization and the required dietary phosphate restriction, which often includes intake of calcium-rich products such as milk. Therefore, enteral calcium-intake (Ca-I) was calculated.Patients: We looked at pediatric CKD-Patients aged 0–6 years.Design: We used a retrospective analysis of Ca-I from dietary data collections. Ca-I below 60% or above 100% of the D-A-CH and the KDOQI reference values were considered as severe Ca deficiency or Ca overload, respectively.Results: We had 41 children, median age 1.1 (range 0-5.8) years, body weight 7.3 (2.4–19.9) kg, and length 68 (48-105) cm at the time of first dietary data collection. Renal function was classified as CKD stage III in 20, IV in 28, V in 44, and VD in 142 dietary data collections. At the first dietary data collection, 5 children were in the CKD stage III, 10 in IV, 9 in V, and 17 were on dialysis. Only one child progressed to a higher CKD stage. In total, 234 dietary data collections were analyzed, and 65 follow-up collections were available from 33 children after a time interval of 26 (1–372) days. The median caloric intake was 120 (47–217)% of D-A-CH RDI. In 149 (63.6%) of the dietary data collections, enteral Ca-I was below the target (<100% of the D-A-CH and KDOQI RDI). Severe Ca-deficiency was found in 11 (26%) and 4 (12%) of the children at the first and second dietary data collection, respectively. In total, 11 children were on Ca-containing phosphate binders. In dietary data collection 1 and 2, there were seven children. From these, 4/7 and 4/7 patients had an enteral total Ca-I above the 100% D-A-CH-limit or above the KDOQI limit, respectively. Absolute dietary Ca-I and Ca-I normalized to body weight correlated negatively with PTH (r = −0.196, p < 0.005 and r = −0.13, p < 0.05).Conclusion: Enteral Ca-I should repeatedly be monitored in CKD children because many may may otherwise be underexposed to enteral calcium and overexposed when calcium-containing phosphate binders are given. Our findings suggest a major impact of dietary calcium supply on bone health in pediatric CKD.

MO588DECREASED IL-15 PRODUCTION INDUCED BY HYPERPHOSPHATEMIA AS A POSSIBLE MECHANISM OF AGED-RELATED SARCOPENIA*

Abstract Background and Aims The loss of muscle mass and function, termed sarcopenia, is an aging-related condition associated to some important diseases such as chronic kidney disease (CKD). Hyperphosphatemia has been related to both pathologies. A chronic subclinical inflammation and a dysregulated immune system function are associated to aging affecting to multiple pathways in the skeletal muscle, and this fact has been linked to the development of sarcopenia. Interleukin-15 (IL-15) is a skeletal muscle-derived cytokine which promotes muscle regeneration. The aim of this work was to analyze the role of hyperphosphatemia on the IL-15 production of the skeletal muscle and its implication in aging-related sarcopenia. Method Cultured C2C12 myoblasts were used for in vitro experiments. Cells were treated with 10 mM beta-glycerophosphate (BGP) as a phosphate donor for 2, 4, 6, 8 and 24 hours. IL-15 mRNA levels were assessed by RT-qPCR. Three groups of C57BL6 male mice were used for the in vivo studies: 5-months-old mice (young), 24-month-old mice fed with a standard diet containing 0.6 % of phosphate (old) and 24-month-old mice fed with a hypophosphatemic diet, containing a 0.2% of phosphate (old+lowPi), for the last three months before sacrifice. Muscle force was measured by a grip test. Serum phosphate levels were analyzed with a commercial kit. Quadriceps muscle samples were collected to evaluate in them the IL-15 mRNA expression by RT-qPCR. Results C2C12 cells treated with BGP show a significant decrease in the IL-15 mRNA expression. On the other hand, in vivo studies showed that old mice had an increase in serum phosphate concentration and a reduction in forelimb strength and muscle mass, compared to young mice. Old animals fed with the hypophosphatemic diet displayed lower levels of phosphate serum linked to an improvement in the muscle mass and function. IL-15 expression of quadriceps muscle was reduced in old mice compared to young mice, whereas those values were increased in old mice fed with the low phosphate diet. Furthermore, there was a negative correlation between IL-15 expression levels and serum phosphate concentrations and a positive correlation between IL-15 and forelimb strength and muscle mass, suggesting that a decreased IL-15 expression affects muscle function. Conclusion High extracellular phosphate concentrations decrease IL-15 mRNA expression in myoblasts, and it is correlated with low IL-15 mRNA expression in the quadriceps muscle isolated from old mice. This reduction was associated to a decreased muscular strength and muscle mass, whereas the dietary restriction of phosphate improved these features. These results point to a role of hyperphosphatemia in the impaired immune system function, disrupting the skeletal muscle function, and this could be involved in aging and CKD-related sarcopenia.

Low Phosphate Diet Exacerbates Hypercalciuria in the Jimbee Mouse Model of SGLT2 Loss-of Function

Selective sodium-dependent glucose co-transporter 2 inhibitors (SGLT2is) are a class of anti-hyperglycemic drugs that lower blood glucose in an insulin-independent manner by inhibiting renal glucose reabsorption and promoting glucosuria. In persons with chronic kidney disease, a potential therapeutic target group for such SGLT2i treatment, dietary phosphate restriction is a mainstay of treatment for metabolic bone disease. We investigated the impact of a low phosphate (LP) diet on the physiology of Jimbee mice which, via deletion in exon 10 of the sglt2 gene, provide a model of SGLT2 loss-of-function, albeit with otherwise normal renal function. Male (M) and female (F), 12-week (wk) old, C57BL/6J (genetic control) and Jimbee mice were randomized 1:1 to a kcal/g equivalent 0.1% phosphate (LP) or 0.4% phosphate (normal P = NP) diet and monitored for 12 wks (n=9–12 per group x 8 groups). At study end (~24 wks of age), male Jimbee vs. C57BL/6J mice had lower body mass (BM: p<0.0001), more-so on LP diet (C57BL/6J vs. Jimbee; (M) NP: 31.4 ± 2.1 vs. 28.6 ± 2.0. LP: 30.8 ± 2.0 vs. 26.0 ± 1.6 g). Female mice exhibited no differences in BM. By MRI, male mice demonstrated proportionate decrements in body composition of Jimbees, as the % fat vs. lean mass and % total body water were comparable between genotypes. HbA1c and random blood glucose were no different between groups, while glucosuria was increased in M and F Jimbee mice (p<0.0001) on either diet [C57BL/6J vs. Jimbee; (M) NP: 0.2 ± 0.2 vs. 10.2 ± 4.5. LP: 0.2 ± 0.2 vs. 7.8 ± 2.0 mg/g (body weight)/day. (F) NP: 0.5 ± 0.5 vs. 8.2 ± 2.7. LP: 0.4 ± 0.3 vs. 7.0 ± 2.9 mg/g/day]. Serum calcium and phosphorus were no different between any groups. However, Jimbee mice also exhibited hypercalciuria and hyperphosphaturia (p<0.001 for both). Hypercalciuria was amplified by LP diet in both strains, with a significant diet x strain interaction in males (p=0.01) [C57BL/6J vs. Jimbee; (M) NP: 4.7 ± 2.3 vs. 15.5 ± 8.2. LP: 27.8 ± 31.5 vs. 73.4 ± 25.8 µg/g/day of urine calcium (Ca2+). (F) NP: 4.9 ± 2.8 vs. 22.7 ± 16.9. LP: 45.8 ± 29.5 vs. 62.6 ± 39.8 µg/g/day]. In contrast, hyperphosphaturia was attenuated by LP diet [C57BL/6J vs. Jimbee; (M) NP: 8.7 ± 8.5 vs. 14.7 ± 10.4. LP: 0.9 ± 0.5 vs. 3.2 ± 2.9 µg/g/day of urine phosphate (PO4). (F) NP: 4.4 ± 6.1 vs. 16.3 ± 9.7. LP: 1.2 ± 0.8 vs. 2.9 ± 1.0 µg/g/day]. Plasma PTH levels were significantly lower (p<0.001) in male Jimbee mice on either diet (C57BL/6J vs. Jimbee; NP: 81.1 ± 31.0 vs. 41.3 ± 10.7. LP: 38.2 ± 1.9 vs. 24.1 ± 6.2 pg/mL) and negatively correlated with daily urine Ca2+ (r = -0.62; p=0.006). Consistent with PTH, renal 1-α hydroxylase gene expression was decreased by ~60% in Jimbee males, specifically on LP diet (p=0.02). Together, these data suggest that, in mice, dietary phosphate restriction might exacerbate SGLT2i-related hypercalciuria during prolonged treatment, independent of PTH, becoming potentially detrimental to bone mineralization and growth over time.

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.

The effect of attenuating dietary phosphate restriction on blood ionized calcium concentrations in cats with chronic kidney disease and ionized hypercalcemia.

BackgroundHypercalcemia is commonly observed in cats with azotemic chronic kidney disease (CKD). Dietary phosphate restriction is considered standard of care but may contribute to the development of hypercalcemia. The optimal dietary management strategy for these cats is unclear.ObjectivesTo describe the effect of feeding a moderately phosphate‐restricted diet (MP; 1.5 g/Mcal phosphorus; Ca : P ratio, 1.3) to cats with concurrent azotemic CKD and ionized hypercalcemia.AnimalsClient‐owned cats with ionized hypercalcemia (ionized calcium [iCa] concentration >1.4 mmol/L) at diagnosis of CKD (n = 11; baseline hypercalcemics) or after CKD diagnosis while eating a phosphate‐restricted clinical renal diet (0.8 g/Mcal phosphorus; Ca : P ratio, 1.9; n = 10; RD hypercalcemics).MethodsChanges in variables over time, after starting MP at visit 1, were assessed using linear mixed model analysis within each group of cats. Data are reporte as median [25th, 75th percentiles].ResultsAt visit 1, iCa was 1.47 [1.42, 1.55] mmol/L for baseline hypercalcemics and 1.53 [1.5, 1.67] mmol/L for RD hypercalcemics. Blood iCa decreased (P < .001) when RD hypercalcemics were fed MP, with iCa <1.4 mmol/L in 8/10 cats after 2.2 [1.8, 3.7] months. Plasma phosphate concentrations did not change. In contrast, the baseline hypercalcemic group overall showed no change in iCa but a decrease in plasma phosphate concentration during 8.8 [5.5, 10.6] months on the MP diet, although 4/11 individual cats achieved iCa <1.4 mmol/L by 3.4 [1.0, 6.2] months.Conclusions and Clinical ImportanceAttenuation of dietary phosphate restriction could result in normalization of iCa in cats that develop hypercalcemia while eating a clinical renal diet.

Disorders of Phosphate Metabolism: Hypophosphatemia and Hyperphosphatemia

Phosphorus in the body exists as phosphate. Phosphate is the most abundant intracellular anion and exists mostly as organic phosphate compounds critical to cellular functions such as adenosine triphosphate (ATP). The kidneys are the main regulator of phosphate homeostasis. There are three hormonal systems responsible for phosphate homeostasis, the parathyroid hormone (PTH), Fibroblast growth factor-23 (FGF-23)/klotho, and 1,25 dihydroxyvitamin D3 (1,25 (OH)2D3, calcitriol). Most cases of hypophosphatemia are acquired and are due to malnutrition as in alcoholism. The kidneys maintain phosphate level in the normal range; therefore, hyperphosphatemia is uncommon until glomerular filtration rate (GFR) falls below 30 ml/min. Hyperphosphatemia is common in patients on renal replacement therapy and is treated with dietary phosphate restriction, and phosphate binders.

Design and Rationale of HiLo: A Pragmatic, Randomized Trial of Phosphate Management for Patients Receiving Maintenance Hemodialysis

Hyperphosphatemia is a risk factor for poor clinical outcomes in patients with kidney failure receiving maintenance dialysis. Opinion-based clinical practice guidelines recommend the use of phosphate binders and dietary phosphate restriction to lower serum phosphate levels toward the normal range in patients receiving maintenance dialysis, but the benefits of these approaches and the optimal serum phosphate target have not been tested in randomized trials. It is also unknown if aggressive treatment that achieves unnecessarily low serum phosphate levels worsens outcomes. Multicenter, pragmatic, cluster-randomized clinical trial. HiLo will randomize 80-120 dialysis facilities operated by DaVita Inc and the University of Utah to enroll 4,400 patients undergoing 3-times-weekly, in-center hemodialysis. Phosphate binder prescriptions and dietary recommendations to achieve the "Hi" serum phosphate target (≥6.5 mg/dL) or the "Lo" serum phosphate target (<5.5 mg/dL). Primary outcome: Hierarchical composite outcome of all-cause mortality and all-cause hospitalization. Main secondary outcomes: Individual components of the primary outcome. The trial is currently enrolling. HiLo will not adjudicate causes of hospitalizations or mortality and does not protocolize use of specific phosphate binder classes. HiLo aims to address an important clinical question while more generally advancing methods for pragmatic clinical trials in nephrology by introducing multiple innovative features including stakeholder engagement in the study design, liberal eligibility criteria, use of electronic informed consent, engagement of dietitians to implement the interventions in real-world practice, leveraging electronic health records to eliminate dedicated study visits, remote monitoring of serum phosphate separation between trial arms, and use of a novel hierarchical composite outcome. Registered at ClinicalTrials.gov with study number NCT04095039.

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.

Urinary Phosphate Excretion and Microvascular Function in a Population-Based Cohort

Urinary Phosphate Excretion and Microvascular Function in a Population-Based Cohort

Evaluation and Treatment of Disorders of Phosphate Balance

The purpose of this article is to review (1) the molecular mechanisms and hormonal factors involved in phosphate handling and regulation, (2) how to appropriately interpret serum and urine phosphate measurements in pediatric patients, (3) the pathophysiology of hypophosphatemic and hyperphosphatemic conditions, and (4) current strategies for treatment of hypophosphatemia and hyperphosphatemia in pediatric patients. For decades, treatment of some hypophosphatemic conditions like X-linked hypophosphatemic rickets (XLH), characterized by a primary increase in fibroblast growth factor 23 (FGF23) activity, consisted of non-specific therapy with phosphate supplementation and calcitriol administration. However, in the past few years, burosumab, a targeted anti-FGF23 antibody, has been developed, representing a promising new medication for the treatment of pediatric XLH patients. The treatment of hyperphosphatemic conditions like chronic kidney disease (CKD) consists of dietary phosphate restriction and enteral phosphate binders; however, the development of new binders and inhibitors of cellular phosphate transporters may offer additional treatment options in the future. The evaluation and treatment of disorders of phosphate balance in children is complex, as numerous interrelated mechanisms and hormones are involved in phosphate handling and regulation. Knowledge of the pathophysiology of hypophosphatemic and hyperphosphatemic conditions informs optimal diagnostic and treatment strategies.

State-of-the-Art Management of Hyperphosphatemia in Patients With CKD: An NKF-KDOQI Controversies Perspective

Phosphate binders are among the most common medications prescribed to patients with kidney failure receiving dialysis and are often used in advanced chronic kidney disease (CKD). In patients with CKD glomerular filtration rate category 3a (G3a) or worse, including those with kidney failure who are receiving dialysis, clinical practice guidelines suggest "lowering elevated phosphate levels towards the normal range" with possible strategies including dietary phosphate restriction or use of binders. Additionally, guidelines suggest restricting the use of oral elemental calcium often contained in phosphate binders. Nutrition guidelines in CKD suggest<800-1,000mg of calcium daily, whereas CKD bone and mineral disorder guidelines do not provide clear targets, but<1,500mg in maintenance dialysis patients has been previously recommended. Many different classes of phosphate binders are now available and clinical trials have not definitively demonstrated the superiority of any class of phosphate binders over another with regard to clinical outcomes. Use of phosphate binders contributes substantially to patients' pill burden and out-of-pocket costs, and many have side effects. This has led to uncertainty regarding the use and best choice of phosphate binders for patients with CKD or kidney failure. In this controversies perspective, we discuss the evidence base around binder use in CKD and kidney failure with a focus on comparisons of available binders.