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American Journal of Nephrology 2021Chronic kidney disease (CKD) affects approximately 15% of adults in the USA. As CKD progresses, urinary phosphate excretion decreases and results in phosphate retention... (Review)
Review
BACKGROUND
Chronic kidney disease (CKD) affects approximately 15% of adults in the USA. As CKD progresses, urinary phosphate excretion decreases and results in phosphate retention and, eventually, hyperphosphatemia. As hyperphosphatemia is associated with numerous adverse outcomes, including increased cardiovascular mortality, reduction in phosphorus concentrations is a guideline-recommended, established clinical practice. Dietary phosphate restriction, dialysis, and phosphate binders are currently the only options for phosphate management. However, many patients with hyperphosphatemia have phosphorus concentrations >5.5 mg/dL, despite treatment.
SUMMARY
This review pre-sents recent advances in the understanding of intestinal phosphate absorption and therapeutic implications. Dietary phosphate is absorbed in the intestine through two distinct pathways, paracellular absorption and transcellular transport. Recent evidence indicates that the paracellular route accounts for 65-80% of total phosphate absorbed. Thus, the paracellular pathway is the dominant mechanism of phosphate absorption. Tenapanor is a first-in-class, non-phosphate binder that inhibits the sodium-hydrogen exchanger 3 or solute carrier family 9 member 3 (SLC9A3) encoded by the SLC9A3 gene, and blocks paracellular phosphate absorption. Key Messages: Targeted inhibition of sodium-hydrogen exchanger 3 effectively reduces paracellular permeability of phosphate. Novel therapies that target the paracellular pathway may improve phosphate control in chronic kidney disease.
Topics: Animals; Biological Transport; Humans; Hyperphosphatemia; Intestinal Absorption; Intestine, Small; Isoquinolines; Phosphates; Renal Insufficiency, Chronic; Sodium-Hydrogen Exchanger 3; Sulfonamides
PubMed: 34515051
DOI: 10.1159/000518110 -
Deutsches Arzteblatt International Apr 2018
Topics: Aged; Calciphylaxis; Humans; Hyperphosphatemia; Kidney Failure, Chronic; Male; Phosphates; Treatment Outcome
PubMed: 29735007
DOI: 10.3238/arztebl.2018.0265 -
Kidney International Oct 2016Maintenance of phosphate balance is essential for life, and mammals have developed a sophisticated system to regulate phosphate homeostasis over the course of evolution.... (Review)
Review
Maintenance of phosphate balance is essential for life, and mammals have developed a sophisticated system to regulate phosphate homeostasis over the course of evolution. However, due to the dependence of phosphate elimination on the kidney, humans with decreased kidney function are likely to be in a positive phosphate balance. Phosphate excess has been well recognized as a critical factor in the pathogenesis of mineral and bone disorders associated with chronic kidney disease, but recent investigations have also uncovered toxic effects of phosphate on the cardiovascular system and the aging process. Compelling evidence also suggests that increased fibroblastic growth factor 23 and parathyroid hormone levels in response to a positive phosphate balance contribute to adverse clinical outcomes. These insights support the current practice of managing serum phosphate in patients with advanced chronic kidney disease, although definitive evidence of these effects is lacking. Given the potential toxicity of excess phosphate, the general population may also be viewed as a target for phosphate management. However, the widespread implementation of dietary phosphate intervention in the general population may not be warranted due to the limited impact of increased phosphate intake on mineral metabolism and clinical outcomes. Nonetheless, the increasing incidence of kidney disease or injury in our aging society emphasizes the potential importance of this issue. Further work is needed to more completely characterize phosphate toxicity and to establish the optimal therapeutic strategy for managing phosphate in patients with chronic kidney disease and in the general population.
Topics: Animals; Bone Diseases; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Homeostasis; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Kidney; Minerals; Parathyroid Hormone; Phosphates; Phosphorus, Dietary; Renal Dialysis; Renal Elimination; Renal Insufficiency, Chronic; Vitamin D
PubMed: 27282935
DOI: 10.1016/j.kint.2016.03.039 -
Journal of Cachexia, Sarcopenia and... Oct 2021Hyperphosphatemia has been related to the development of sarcopenia in aging mice. We describe the intracellular mechanisms involved in the impairment of the myogenic...
BACKGROUND
Hyperphosphatemia has been related to the development of sarcopenia in aging mice. We describe the intracellular mechanisms involved in the impairment of the myogenic differentiation promoted by hyperphosphatemia and analyse these mechanisms in the muscle from older mice.
METHODS
C C cells were grown in 2% horse serum in order to promote myogenic differentiation, in the presence or absence of 10 mM beta-glycerophosphate (BGP) for 7 days. Troponin T, paired box 7 (Pax-7), myogenic factor 5 (Myf5), myogenic differentiation 1 (MyoD), myogenin (MyoG), myocyte enhancer factor 2 (MEF2C), P300/CBP-associated factor (PCAF), histone deacetylase 1 (HDAC1), fibronectin, vimentin, and collagen I were analysed at 48, 72, and 168 h, by western blotting or by immunofluorescence staining visualized by confocal microscopy. Studies in mice were performed in 5- and 24-month-old C57BL6 mice. Three months before sacrifice, 21-month-old mice were fed with a standard diet or a low phosphate diet, containing 0.6% or 0.2% phosphate, respectively. Serum phosphate concentration was assessed by a colorimetric method and forelimb strength by a grip test. Fibrosis was observed in the tibialis anterior muscle by Sirius Red staining. In gastrocnemius muscle, MyoG, MEF2C, and fibronectin expressions were analysed by western blotting.
RESULTS
Cells differentiated in the presence of BGP showed near five times less expression of troponin T and kept higher levels of Pax-7 than control cells indicating a reduced myogenic differentiation. BGP reduced Myf5 about 50% and diminished MyoD transcriptional activity by increasing the expression of HDAC1 and reducing the expression of PCAF. Consequently, BGP reduced to 50% the expression of MyoG and MEF2C. A significant increase in the expression of fibrosis markers as collagen I, vimentin, and fibronectin was found in cells treated with BGP. In mice, serum phosphate (17.24 ± 0.77 mg/dL young; 23.23 ± 0.81 mg/dL old; 19.09 ± 0.75 mg/dL old with low phosphate diet) correlates negatively (r = -0.515, P = 0.001) with the muscular strength (3.13 ± 0.07 gf/g young; 1.70 ± 0.12 gf/g old; 2.10 ± 0.09 gf/g old with low phosphate diet) and with the expression of MyoG (r = -0.535, P = 0.007) and positively with the expression of fibronectin (r = 0.503, P = 0.001) in gastrocnemius muscle. The tibialis anterior muscle from old mice showed muscular fibrosis. Older mice fed with a low phosphate diet showed improved muscular parameters relative to control mice of similar age.
CONCLUSIONS
Hyperphosphatemia impairs myogenic differentiation, by inhibiting the transcriptional activity of MyoD, and enhances the expression of fibrotic genes in cultured myoblasts. Experiments carried out in older mice demonstrate a close relationship between age-related hyperphosphatemia and the decrease in the expression of myogenic factors and the increase in factors related to muscle fibrosis.
Topics: Aging; Animals; Cell Differentiation; Fibrosis; Hyperphosphatemia; Mice; Mice, Inbred C57BL; Muscle, Skeletal
PubMed: 34337906
DOI: 10.1002/jcsm.12750 -
Kidney360 Aug 2022Persistent hyperkalemia (hyperK) and hyperphosphatemia (hyperP) despite renal replacement therapy (RRT) was anecdotally reported in COVID-19 and acute kidney injury...
BACKGROUND
Persistent hyperkalemia (hyperK) and hyperphosphatemia (hyperP) despite renal replacement therapy (RRT) was anecdotally reported in COVID-19 and acute kidney injury (AKI) requiring RRT (CoV-AKI-RRT). However, observation bias could have accounted for the reports. Thus, we systematically examined the rate and severity of hyperK and hyperP in patients with CoV-AKI-RRT in comparison with the pre-COVID-19 era.
METHODS
We identified patients with CoV-AKI-RRT treated with sustained low-efficiency dialysis (SLED) for ≥2 days in March-April 2020. As pre-COVID-19 control, we included patients with AKI treated with SLED in December 2019. We examined the rates of hyperK (serum potassium [sK] ≥5.5 mEq/L), severe hyperK (sK ≥6.5 mEq/L), hyperP (serum phosphate [sP] ≥4.5 mg/dl), and moderate or severe hyperP (sP ≥7-10 and >10 mg/dl, respectively) as %SLED-days with an event.
RESULTS
Along the duration of SLED, the incidence of hyperK was greater in CoV-AKI-RRT (=64; mean 19%±2% versus 14%±3% SLED-days, =0.002) compared with control (=60). The proportion of patients with one or more event of severe hyperK was greater in CoV-AKI (33% versus 7%, <0.001). The incidence of hyperP was similar between groups (mean 56%±4% versus 53%±5% SLED-days, =0.49). However, the proportion of patients with one or more event of moderate and severe hyperP was greater in CoV-AKI-RRT (86% versus 60%, =0.001, and 50% versus 18%, <0.001, respectively). Among those with CoV-AKI-RRT, sK and sP correlated with lactate dehydrogenase (LDH; =0.31, =0.04, and =0.31, =0.04, respectively), whereas hyperP also correlated with shorter SLED runs (hours/run; =-0.27, =0.05).
CONCLUSIONS
Refractory hyperK and hyperP were more frequent in CoV-AKI-RRT compared with the pre-COVID-19 era. Because of the correlation of sK and sP with higher LDH and sP with shorter SLED runs, intracellular ion release from cell injury due to cytokine storm and RRT interruptions may account for the findings.
Topics: Acute Kidney Injury; COVID-19; Humans; Hyperkalemia; Hyperphosphatemia; Lactate Dehydrogenases; Phosphates; Potassium; Renal Dialysis
PubMed: 36176653
DOI: 10.34067/KID.0001632022 -
BMC Nephrology Sep 2019Hyperphosphatemia is associated with vascular calcification and bone mineral disorders and is a major concern among patients with chronic kidney disease (CKD). However,...
BACKGROUND
Hyperphosphatemia is associated with vascular calcification and bone mineral disorders and is a major concern among patients with chronic kidney disease (CKD). However, the relationship between hyperphosphatemia and renal outcome in non-CKD patients has not been studied. Furthermore, the clinical implications of hyperphosphatemia in relation to the risks of acute kidney injury (AKI), end-stage renal disease (ESRD), and mortality after hospitalization remain unresolved.
METHODS
A total of 20,686 patients (aged ≥18 years) admitted to Seoul National University Bundang Hospital from January 2013 to December 2013 were retrospectively reviewed. Patients were divided into quartiles according to serum phosphorus level at the time of admission. The odds ratios (ORs) for AKI and hazard ratios (HRs) for ESRD and all-cause mortality were calculated after adjustment of multiple covariates.
RESULTS
AKI developed in 2319 patients (11.2%), with higher ORs for patients in the third and fourth quartiles (1.4 [1.24-1.68] and 2.8 [2.44-3.22], respectively) compared with the first quartile group. During a median follow-up period of 4.0 years, 183 patients (0.88%) developed ESRD and 3675 patients (17.8%) died. Patients in the fourth quartile had higher risks of ESRD and mortality than patients in the first quartile (HRs, 2.3 [1.46-3.75] and 1.4 [1.22-1.49], respectively). These trends remained consistent in patients with an estimated glomerular filtration rate > 60 ml/min/1.73 m.
CONCLUSIONS
Hyperphosphatemia is related to the risks of AKI, ESRD, and mortality, and it may therefore be necessary to monitor serum phosphorus level in hospitalized patients, irrespective of kidney function.
Topics: Acute Kidney Injury; Adult; Aged; Female; Hospitalization; Humans; Hyperphosphatemia; Kidney Failure, Chronic; Male; Middle Aged; Mortality; Phosphorus; Retrospective Studies; Risk Factors
PubMed: 31533650
DOI: 10.1186/s12882-019-1556-y -
Journal of Renal Nutrition : the... Jan 2020Phosphate binders are commonly prescribed in patients with end-stage kidney disease to prevent and treat hyperphosphatemia. These binders are usually associated with... (Review)
Review
Phosphate binders are commonly prescribed in patients with end-stage kidney disease to prevent and treat hyperphosphatemia. These binders are usually associated with gastrointestinal distress, may bind molecules other than phosphate, and may alter the gut microbiota, altogether having systemic effects unrelated to phosphate control. Sevelamer is the most studied of the available binders for nonphosphate-related effects including binding to bile acids, endotoxins, gut microbiota-derived metabolites, and advanced glycation end products. Other binders (calcium- and noncalcium-based binders) may bind vitamins, such as vitamin K and folic acid. Moreover, the relatively new iron-based phosphate binders may alter the gut microbiota, as some of the iron or organic ligands may be used by the gastrointestinal bacteria. The objective of this narrative review is to provide the current evidence for the nonphosphate effects of phosphate binders on gastrointestinal function, nutrient and molecule binding, and the gut microbiome.
Topics: Calcium; Chelating Agents; Gastrointestinal Tract; Humans; Hyperphosphatemia; Kidney Failure, Chronic; Phosphates; Sevelamer
PubMed: 30846238
DOI: 10.1053/j.jrn.2019.01.004 -
Pediatric Nephrology (Berlin, Germany) Sep 2012Regulation of phosphate homeostasis is critical for many biological processes, and both hypophosphatemia and hyperphosphatemia can have adverse clinical consequences.... (Review)
Review
Regulation of phosphate homeostasis is critical for many biological processes, and both hypophosphatemia and hyperphosphatemia can have adverse clinical consequences. Only a very small percentage (1%) of total body phosphate is present in the extracellular fluid, which is measured by routine laboratory assays and does not reflect total body phosphate stores. Phosphate is absorbed from the gastrointestinal tract via the transcellular route [sodium phosphate cotransporter 2b (NaPi2b)] and across the paracellular pathway. Approximately 85% of the filtered phosphate is reabsorbed from the kidney, predominantly in the proximal tubule, by NaPi2a and NaPi2c, which are present on the brush border membrane. Renal phosphate transport is tightly regulated. Dietary phosphate intake, parathyroid hormone (PTH), 1,25 (OH)2 vitamin D3, and fibroblast growth factor 23 (FGF23) are the principal regulators of phosphate reabsorption from the kidney. Recent advances in genetic techniques and animal models have identified many genetic disorders of phosphate homeostasis. Mutations in NaPi2a and NaPi2c; and hormonal dysregulation of PTH, FGF23, and Klotho, are primarily responsible for most genetic disorders of phosphate transport. The main focus of this educational review article is to discuss the genetic and clinical features of phosphate regulation disorders and provide understanding and treatment options.
Topics: Animals; Fibroblast Growth Factor-23; Homeostasis; Humans; Hyperphosphatemia; Hypophosphatemia, Familial; Metabolism, Inborn Errors; Phosphates; Sodium-Phosphate Cotransporter Proteins, Type II
PubMed: 22350303
DOI: 10.1007/s00467-012-2103-2 -
Hyperphosphatemia-induced degradation of transcription factor EB exacerbates vascular calcification.Biochimica Et Biophysica Acta.... Mar 2022Chronic kidney disease (CKD) and subsequent hyperphosphatemia causes vascular calcification (VC), a strong predictor of mortality. Dysregulation of the...
AIMS
Chronic kidney disease (CKD) and subsequent hyperphosphatemia causes vascular calcification (VC), a strong predictor of mortality. Dysregulation of the autophagy-lysosomal pathway in vascular smooth muscle cells (VSMCs) mediates hyperphosphatemia-dependent VC. However, the process through which lysosomes become dysfunctional remains unknown. Transcription factor EB (TFEB) is a master regulator of lysosome biogenesis. The present study examined the hypothesis that TFEB dysfunction causes VC progression.
METHODS AND RESULTS
Inorganic phosphate (Pi) dose-dependently promoted VC in mouse aorta ex vivo, in rat VSMCs in vitro, and in human aortic smooth muscle cells in vitro, all accompanied by a decrease in TFEB protein. Lysosomal inhibitors or TFEB knockdown using small interfering RNA exacerbated Pi-induced VC in VSMCs. Conversely, TFEB downregulation was not observed in the hypercalcemia-sensitive VC model induced by excessive vitamin D dosages. Feeding rats an adenine-containing diet caused CKD and hyperphosphatemia. VC occurred in the adenine-fed rat aorta and regressed after adenine cessation. In this CKD model, aortic TFEB expression decreased at VC onset but recovered to average levels during recovery from VC after adenine cessation. The calcified area of the CKD rat aorta exhibited lysosomal damage and enhanced TFEB ubiquitination. Hyperphosphatemia in vitro increased insoluble TFEB and decreased soluble TFEB in VSMCs, both of which were abrogated by the proteasome inhibitor, MG-132.
CONCLUSION
Hyperphosphatemia caused VC via TFEB downregulation in VSMCs. Under hyperphosphatemia, TFEB was insolubilized and degraded via the ubiquitin-proteasome system. Our results suggest a new mechanism for the pathogenesis of VC under CKD and hyperphosphatemia.
Topics: Animals; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Hyperphosphatemia; Male; Mice; Mice, Inbred C57BL; Proteolysis; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Vascular Calcification
PubMed: 34921974
DOI: 10.1016/j.bbadis.2021.166323 -
Renal Failure Dec 2022Hyperphosphatemia and anemia, which are common complications of chronic kidney disease (CKD), can independently contribute to cardiovascular events. Several previous... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hyperphosphatemia and anemia, which are common complications of chronic kidney disease (CKD), can independently contribute to cardiovascular events. Several previous studies have found that the iron-based phosphate binder, ferric citrate (FC), could be beneficial to both hyperphosphatemia and anemia.
METHODS
Relevant literature from PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials (CCRCT) and MEDLINE databases were searched up to 21 February 2022, in order to conduct a meta-analysis to investigate the efficacy, safety and economic benefits of ferric citrate treatment in CKD patients with hyperphosphatemia and anemia. The meta-analysis was conducted independently by two reviewers using the RevMan software (version 5.3).
RESULTS
In total, this study included 16 randomized clinical trials (RCT) involving 1754 participants. The meta-analysis showed that ferric citrate could significantly reduce the serum phosphorus in CKD patients compared to the placebo control groups (MD -1.76 mg/dL, 95% CI (-2.78, -0.75); = 0.0007). In contrast, the difference between ferric citrate treatment and active controls, such as non-iron-based phosphate binders, sevelamer, calcium carbonate, lanthanum carbonate and sodium ferrous citrate, was not statistically significant (MD - 0.09 mg/dL, 95% CI (-0.35, 0.17); = 0.51). However, ferric citrate could effectively improve hemoglobin levels when compared to the active drug (MD 0.43 g/dL, 95% CI (0.04, 0.82); = 0.03) and placebo groups (MD 0.39 g/dL, 95% CI (0.04, 0.73); = 0.03). According to eight studies, ferric citrate was found to be cost-effective treatment in comparison to control drugs. Most of the adverse events (AE) following ferric citrate treatment were mild at most.
CONCLUSION
Collectively, our review suggests that iron-based phosphate binder, ferric citrate is an effective and safe treatment option for CKD patients with hyperphosphatemia and anemia. More importantly, this alternative treatment may also less expensive. Nevertheless, more scientific studies are warranted to validate our findings.
Topics: Anemia; Ferric Compounds; Humans; Hyperphosphatemia; Phosphates; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic
PubMed: 35912897
DOI: 10.1080/0886022X.2022.2094273