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• W3161530003 abstract "Chronic kidney disease–mineral bone disorder (CKD-MBD) is a common comorbidity in patients with CKD. Characterized by laboratory abnormalities, bone abnormality, and vascular calcification, CKD-MBD encompasses a group of mineral and hormone disturbances that are strongly associated with increased cardiovascular (CV) morbidity and mortality. Abnormal serum phosphate concentrations are an independent risk factor for CV morbidity and mortality, and overall mortality. Phosphate retention plays a central role in initiating and driving many other disturbances in CKD-MBD (e.g., increased parathyroid hormone and fibroblast growth factor 23 concentrations, hypocalcemia, low vitamin D) that are also linked to increased CV risk. Thus, effective phosphate control is a logical therapeutic target for CKD-MBD treatment. Current phosphate management strategies (dietary restrictions, dialysis, phosphate binders) are insufficient to consistently achieve and maintain target phosphate concentrations in patients on dialysis. Phosphate binders reduce available phosphate for intestinal absorption but do not impair the dominant phosphate absorption pathway. Novel therapies that consider new mechanistic understandings of intestinal phosphate absorption are needed. One such therapy is tenapanor, a targeted sodium-hydrogen exchanger isoform 3 inhibitor that has been shown to reduce serum phosphate concentrations in multiple clinical trials. Tenapanor has a novel mechanism of action that reduces intestinal phosphate absorption in the primary paracellular phosphate absorption pathway. Chronic kidney disease–mineral bone disorder (CKD-MBD) is a common comorbidity in patients with CKD. Characterized by laboratory abnormalities, bone abnormality, and vascular calcification, CKD-MBD encompasses a group of mineral and hormone disturbances that are strongly associated with increased cardiovascular (CV) morbidity and mortality. Abnormal serum phosphate concentrations are an independent risk factor for CV morbidity and mortality, and overall mortality. Phosphate retention plays a central role in initiating and driving many other disturbances in CKD-MBD (e.g., increased parathyroid hormone and fibroblast growth factor 23 concentrations, hypocalcemia, low vitamin D) that are also linked to increased CV risk. Thus, effective phosphate control is a logical therapeutic target for CKD-MBD treatment. Current phosphate management strategies (dietary restrictions, dialysis, phosphate binders) are insufficient to consistently achieve and maintain target phosphate concentrations in patients on dialysis. Phosphate binders reduce available phosphate for intestinal absorption but do not impair the dominant phosphate absorption pathway. Novel therapies that consider new mechanistic understandings of intestinal phosphate absorption are needed. One such therapy is tenapanor, a targeted sodium-hydrogen exchanger isoform 3 inhibitor that has been shown to reduce serum phosphate concentrations in multiple clinical trials. Tenapanor has a novel mechanism of action that reduces intestinal phosphate absorption in the primary paracellular phosphate absorption pathway. Patients with CKD are often affected by CKD-MBD.1Chuang S.H. Wong H.C. Vathsala A. et al.Prevalence of chronic kidney disease-mineral and bone disorder in incident peritoneal dialysis patients and its association with short-term outcomes.Singapore Med J. 2016; 57: 603-609Crossref PubMed Scopus (2) Google Scholar Characterized by hormone and bone abnormalities,2KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD).Kidney Int Suppl. 2017; 7: 1-59Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar CKD-MBD is known to be associated with increased CV mortality,3Block G.A. Kilpatrick R.D. Lowe K.A. et al.CKD–mineral and bone disorder and risk of death and cardiovascular hospitalization in patients on hemodialysis.Clin J. Am. Soc. Nephrol. 2013; 8: 2132-2140Crossref PubMed Scopus (0) Google Scholar a significant cause of death in patients on dialysis.4U.S. Renal Data System2019 Annual Data Report: Epidemiology of kidney disease in the United States. National Institute of Diabetes and Digestive and Kidney Diseases, 2019Google Scholar Phosphate control is a logical and attractive approach for treatment of CKD-MBD due to both the centrality of phosphate homeostasis in the development and progression of CKD-MBD and the independent association between hyperphosphatemia and CV disease (CVD).5Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2066) Google Scholar,6Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (857) Google Scholar Well-managed phosphate would likely decrease the risk of vascular calcification,7Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Crossref PubMed Scopus (939) Google Scholar hyperparathyroidism,8de Francisco A.L.M. Cobo M.A. Setien M.A. et al.Effect of serum phosphate on parathyroid hormone secretion during hemodialysis.Kidney Int. 1998; 54: 2140-2145Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar and hypocalcemia9Goyal R. Jialal I. Hyperphosphatemia.StatPearls. StatPearls Publishing, 2020Google Scholar and decrease fibroblast growth factor 23 (FGF23) production,10Rodelo-Haad C. Rodríguez-Ortiz M.E. Martin-Malo A. et al.Phosphate control in reducing FGF23 levels in hemodialysis patients.PLoS One. 2018; 13e0201537Crossref PubMed Scopus (17) Google Scholar thus attenuating the progression of CKD-MBD and reducing CV mortality risk. The implementation of effective phosphate control for the treatment of CKD-MBD is stalled by the lack of phosphate management strategies that can achieve and maintain normal phosphate concentrations in patients on dialysis as most patients with CKD on dialysis do not reach phosphate levels <5.5 mg/dl, let alone more normal levels of <4.5 mg.11Serum phosphorus (most recent), categories.DOPPS Practice Monitor. 2020; Google Scholar Currently, phosphate binders are the pharmacological treatment for hyperphosphatemia.12PhosLo gelcaps (calcium acetate): 667 mg [prescribing information]. Fresenius Medical Care North America, 2011.Google Scholar, 13VELPHORO (sucroferric oxyhydroxide) [prescribing information]. Fresenius Medical Care North America, 2013.Google Scholar, 14FOSRENAL (lanthanum carbonate) [prescribing information]. Shire US Inc., 2016.Google Scholar, 15AURYXIA (ferric citrate) tablets [prescribing information]. Keryx Biopharmaceuticals Inc., 2017.Google Scholar, 16RENVELA (sevelamer carbonate) [prescribing information]. Genzyme Corp., 2020.Google Scholar However, phosphate binders only bind a portion of dietary phosphate and, in general, require patients to take many pills with meals.12PhosLo gelcaps (calcium acetate): 667 mg [prescribing information]. Fresenius Medical Care North America, 2011.Google Scholar, 13VELPHORO (sucroferric oxyhydroxide) [prescribing information]. Fresenius Medical Care North America, 2013.Google Scholar, 14FOSRENAL (lanthanum carbonate) [prescribing information]. Shire US Inc., 2016.Google Scholar, 15AURYXIA (ferric citrate) tablets [prescribing information]. Keryx Biopharmaceuticals Inc., 2017.Google Scholar, 16RENVELA (sevelamer carbonate) [prescribing information]. Genzyme Corp., 2020.Google Scholar, 17Daugirdas J.T. Finn W.F. Emmett M. et al.The phosphate binder equivalent dose.Semin Dial. 2011; 24: 41-49Crossref PubMed Scopus (0) Google Scholar, 18Martin P. Wang P. Robinson A. et al.Comparison of dietary phosphate absorption after single doses of lanthanum carbonate and sevelamer carbonate in healthy volunteers: a balance study.Am J Kidney Dis. 2011; 57: 700-706Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Moreover, proper adherence to phosphate binders is a challenge.19Chiu Y.-W. Teitelbaum I. Misra M. et al.Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.Clin J Am Soc Nephrol. 2009; 4: 1089-1096Crossref PubMed Scopus (333) Google Scholar The effectiveness of phosphate binders and dietary phosphate restriction are further limited by a maladaptive upregulation of phosphate absorption.20Hattenhauer O. Traebert M. Murer H. et al.Regulation of small intestinal Na-P(i) type IIb cotransporter by dietary phosphate intake.Am J Physiol. 1999; 277: G756-G762Crossref PubMed Google Scholar, 21Giral H. Caldas Y. Sutherland E. et al.Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate.Am J Physiol Renal Physiol. 2009; 297: F1466-F1475Crossref PubMed Scopus (108) Google Scholar, 22Schiavi S.C. Tang W. Bracken C. et al.Npt2b deletion attenuates hyperphosphatemia associated with CKD.J Am Soc Nephrol. 2012; 23: 1691-1700Crossref PubMed Scopus (70) Google Scholar New phosphate management strategies should incorporate the latest understandings of phosphate absorption—namely, that the paracellular phosphate absorption pathway is the dominant route of intestinal phosphate absorption.23Davis G.R. Zerwekh J.E. Parker T.F. et al.Absorption of phosphate in the jejunum of patients with chronic renal failure before and after correction of vitamin D deficiency.Gastroenterology. 1983; 85: 908-916Abstract Full Text PDF PubMed Google Scholar A novel phosphate absorption inhibitor, tenapanor, has been recently developed. It directly targets the intestinal sodium/hydrogen exchanger isoform 3 (NHE3), leading to reduced sodium absorption.24King A.J. Siegel M. He Y. et al.Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability.Sci Transl Med. 2018; 10Crossref Scopus (35) Google Scholar In clinical trials, tenapanor has also been shown to reduce serum phosphate concentrations and was generally well tolerated.25Block G.A. Rosenbaum D.P. Yan A. et al.Efficacy and safety of tenapanor in patients with hyperphosphatemia receiving maintenance hemodialysis: a randomized phase 3 trial.J Am Soc Nephrol. 2019; 30: 641-652Crossref PubMed Scopus (25) Google Scholar, 26Rosenbaum DP, Yang Y. Efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis: novel mechanism of action allows for both monotherapy and dual mechanism approaches. Paper presented at the American Society of Nephrology (ASN) Kidney Week [Virtual meetihng], October 20–25, 2020.Google Scholar, 27Chertow GM, Yang Y, Rosenbaum DP. Paper presented at the Long-term safety and efficacy of tenapanor for the control of serum phosphorus in patients with chronic kidney disease on dialysis. Presented at the American Society of Nephrology (ASN) Kidney Week 2020 [Virtual meeting], October 20–25, 2020.Google Scholar It may offer a novel treatment approach for CKD-MBD. A major cause of CV mortality in patients with CKD on dialysis is CKD-MBD,3Block G.A. Kilpatrick R.D. Lowe K.A. et al.CKD–mineral and bone disorder and risk of death and cardiovascular hospitalization in patients on hemodialysis.Clin J. Am. Soc. Nephrol. 2013; 8: 2132-2140Crossref PubMed Scopus (0) Google Scholar a common comorbidity in patients with CKD that is characterized by laboratory abnormalities, bone abnormality, and extraskeletal calcification.1Chuang S.H. Wong H.C. Vathsala A. et al.Prevalence of chronic kidney disease-mineral and bone disorder in incident peritoneal dialysis patients and its association with short-term outcomes.Singapore Med J. 2016; 57: 603-609Crossref PubMed Scopus (2) Google Scholar,28Moe S. Drüeke T. Cunningham J. et al.Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2006; 69: 1945-1953Abstract Full Text Full Text PDF PubMed Scopus (1289) Google Scholar As kidney function declines, progressive disruptions in mineral homeostasis (e.g., calcium and phosphate) are associated with abnormalities in circulating hormone concentrations such as increases in parathyroid hormone (PTH) and FGF23 and decreases in calcitriol.29Isakova T. Wahl P. Vargas G.S. et al.Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.Kidney Int. 2011; 79: 1370-1378Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar These mineral and endocrine changes lead to abnormalities in bone turnover and extraskeletal calcification.30Torres A. Lorenzo V. Hernández D. et al.Bone disease in predialysis, hemodialysis, and CAPD patients: evidence of a better bone response to PTH.Kidney Int. 1995; 47: 1434-1442Abstract Full Text PDF PubMed Google Scholar, 31Zhang D. Bi X. Liu Y. et al.High phosphate-induced calcification of vascular smooth muscle cells is associated with the TLR4/NF-κb signaling pathway.Kidney Blood Pressure Res. 2017; 42: 1205-1215Crossref PubMed Scopus (0) Google Scholar, 32Barreto F.C. Barreto D.V. Moysés R.M. et al.K/DOQI-recommended intact PTH levels do not prevent low-turnover bone disease in hemodialysis patients.Kidney Int. 2008; 73: 771-777Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 33Wang H. Yoshiko Y. Yamamoto R. et al.Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro.J Bone Miner Res. 2008; 23: 939-948Crossref PubMed Scopus (194) Google Scholar Multiple components of CKD-MBD such as hyperphosphatemia,3Block G.A. Kilpatrick R.D. Lowe K.A. et al.CKD–mineral and bone disorder and risk of death and cardiovascular hospitalization in patients on hemodialysis.Clin J. Am. Soc. Nephrol. 2013; 8: 2132-2140Crossref PubMed Scopus (0) Google Scholar vascular calcification,34London G.M. Guérin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease:impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (0) Google Scholar and elevated FGF23 concentrations35Kendrick J. Cheung A.K. Kaufman J.S. et al.FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis.J Am Soc Nephrol. 2011; 22: 1913-1922Crossref PubMed Scopus (341) Google Scholar are known to be significantly associated with increased CV morbidity and mortality.36KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral and bone disorder (CKD-MBD).Kidney Int Suppl. 2009; : S1-S130Google Scholar CVD accounted for ~62% of deaths among patients with CKD on dialysis in 2017.4U.S. Renal Data System2019 Annual Data Report: Epidemiology of kidney disease in the United States. National Institute of Diabetes and Digestive and Kidney Diseases, 2019Google Scholar Mortality due to CVD in this population is approximately 20 times higher than in a general population.37Foley R.N. Parfrey P.S. Sarnak M.J. Epidemiology of cardiovascular disease in chronic renal disease.J Am Soc Nephrol. 1998; 9: S16-S23Crossref PubMed Scopus (30) Google Scholar Traditional risk factors for CV mortality (e.g., hypertension, diabetes, diet, and lifestyle) alone do not explain the high CV morbidity and mortality in patients with CKD,38Cheung A.K. Sarnak M.J. Yan G. et al.Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients.Kidney Int. 2000; 58: 353-362Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar and the established treatment strategies for these risk factors have not seen significant recent advancements. Better control of phosphorus may be necessary to improve clinical outcomes and quality of life in patients on dialysis and reduce unacceptably high mortality risk.6Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (857) Google Scholar Therapeutic approaches for CKD-MBD that may decrease CV mortality include improving dialysis modalities,39Maduell F. Moreso F. Pons M. et al.High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients.J Am Soc Nephrol. 2013; 24: 487-497Crossref PubMed Scopus (415) Google Scholar decreasing inflammation,40Panichi V. Rizza G.M. Paoletti S. et al.Chronic inflammation and mortality in haemodialysis: effect of different renal replacement therapies. results from the RISCAVID study.Nephrol Dial Transplant. 2008; 23: 2337-2343Crossref PubMed Scopus (0) Google Scholar and better management of serum phosphorus concentrations.41Lopes M.B. Karaboyas A. Bieber B. et al.Impact of longer term phosphorus control on cardiovascular mortality in hemodialysis patients using an area under the curve approach: results from the DOPPS.Nephrol Dial Transplant. 2020; 35: 1794-1801Crossref PubMed Scopus (0) Google Scholar Hyperphosphatemia, in particular, is a major remaining modifiable target.42Major R.W. Cheng M.R.I. Grant R.A. et al.Cardiovascular disease risk factors in chronic kidney disease: a systematic review and meta-analysis.PLoS One. 2018; 13e0192895Crossref PubMed Scopus (27) Google Scholar Among the disturbances in mineral metabolism that fall under CKD-MBD, phosphate retention is by far the greatest risk factor for increased mortality, 2- to 6-fold higher than other top risk factors such as hypercalcemia, hyperparathyroidism, low urea reduction ratio, and anemia (12% vs. 4%, 2%, 5%, and 6%, respectively).43Moe S.M. Chertow G.M. The case against calcium-based phosphate binders.Clin J Am Soc Nephrol. 2006; 1: 697-703Crossref PubMed Scopus (82) Google Scholar Abnormal phosphate concentrations have been shown to be an independent risk factor for CV morbidity and mortality in patients with CKD,44McGovern A.P. de Lusignan S. van Vlymen J. et al.Serum phosphate as a risk factor for cardiovascular events in people with and without chronic kidney disease: a large community based cohort study.PLoS One. 2013; 8e74996Crossref PubMed Scopus (68) Google Scholar and there is a linear relationship between risk of CVD calcification progression and increasing serum phosphorus concentrations.45Shang D. Xie Q. Ge X. et al.Hyperphosphatemia as an independent risk factor for coronary artery calcification progression in peritoneal dialysis patients.BMC Nephrol. 2015; 16: 107Crossref PubMed Scopus (25) Google Scholar Additionally, the interplay between increasing phosphate retention, increased PTH, and decreased calcium concentrations create a worsening cycle that causes CKD-MBD to progress as CKD progresses.29Isakova T. Wahl P. Vargas G.S. et al.Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.Kidney Int. 2011; 79: 1370-1378Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar,46Slatopolsky E. Caglar S. Gradowska L. et al.On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using “proportional reduction” of dietary phosphorus intake.Kidney Int. 1972; 2: 147-151Abstract Full Text PDF PubMed Google Scholar, 47Khan M. Jose A. Sharma S. Physiology, parathyroid hormone.StatPearls. StatPearls Publishing, 2021Google Scholar, 48Massry S.G. Coburn J.W. Lee D.B. et al.Skeletal resistance to parathyroid hormone in renal failure. Studies in 105 human subjects.Ann Intern Med. 1973; 78: 357-364Crossref PubMed Google Scholar Phosphate retention is a known risk factor for decreased vascular health,49Shuto E. Taketani Y. Tanaka R. et al.Dietary phosphorus acutely impairs endothelial function.J Am Soc Nephrol. 2009; 20: 1504-1512Crossref PubMed Scopus (253) Google Scholar increased vascular calcification,50Adeney K.L. Siscovick D.S. Ix J.H. et al.Association of serum phosphate with vascular and valvular calcification in moderate CKD.J Am Soc Nephrol. 2009; 20: 381-387Crossref PubMed Scopus (293) Google Scholar and increased CV morbidity and mortality.3Block G.A. Kilpatrick R.D. Lowe K.A. et al.CKD–mineral and bone disorder and risk of death and cardiovascular hospitalization in patients on hemodialysis.Clin J. Am. Soc. Nephrol. 2013; 8: 2132-2140Crossref PubMed Scopus (0) Google Scholar One mechanism by which hyperphosphatemia directly affects vascular health is through increasing the production of reactive oxygen species, thereby causing oxidative damage and endothelial dysfunction.49Shuto E. Taketani Y. Tanaka R. et al.Dietary phosphorus acutely impairs endothelial function.J Am Soc Nephrol. 2009; 20: 1504-1512Crossref PubMed Scopus (253) Google Scholar,51Di Marco G.S. Hausberg M. Hillebrand U. et al.Increased inorganic phosphate induces human endothelial cell apoptosis in vitro.Am J Physiol Renal Physiol. 2008; 294: F1381-F1387Crossref PubMed Scopus (0) Google Scholar Even short-term phosphate elevations (2 h) can have a negative effect on endothelium-dependent vasodilation in both healthy individuals and patients with CKD.49Shuto E. Taketani Y. Tanaka R. et al.Dietary phosphorus acutely impairs endothelial function.J Am Soc Nephrol. 2009; 20: 1504-1512Crossref PubMed Scopus (253) Google Scholar Another primary mechanism by which phosphate retention increases mortality risk is the induction of vascular calcification. High phosphate conditions create a disturbance in the actively regulated vascular calcification process,52Jono S. McKee M.D. Murry C.E. et al.Phosphate regulation of vascular smooth muscle cell calcification.Circ Res. 2000; 87: E10-E17Crossref PubMed Google Scholar leading to extraskeletal mineralization. Calcium-phosphate deposition in the media of the arterial wall eventually results in increased media thickness and vascular stiffening.34London G.M. Guérin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal disease:impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (0) Google Scholar,53Schwarz U. Buzello M. Ritz E. et al.Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure.Nephrol Dial Transplant. 2000; 15: 218-223Crossref PubMed Google Scholar Growing evidence indicates that phosphate retention also induces changes in vascular smooth muscle cells.31Zhang D. Bi X. Liu Y. et al.High phosphate-induced calcification of vascular smooth muscle cells is associated with the TLR4/NF-κb signaling pathway.Kidney Blood Pressure Res. 2017; 42: 1205-1215Crossref PubMed Scopus (0) Google Scholar,54Walton J. Gray T.K. Absorption of inorganic phosphate in the human small intestine.Clin Sci (London). 1979; 56: 407-412Crossref PubMed Scopus (0) Google Scholar Phosphate directly targets the PiT1 receptor on vascular smooth muscle cells, causing them to permanently transform into osteoblast-like cells.52Jono S. McKee M.D. Murry C.E. et al.Phosphate regulation of vascular smooth muscle cell calcification.Circ Res. 2000; 87: E10-E17Crossref PubMed Google Scholar This transformation is driven by the deposition of hydroxyapatite crystals, which are normally found in the bone.55Lei Y. Sinha A. Nosoudi N. et al.Hydroxyapatite and calcified elastin induce osteoblast-like differentiation in rat aortic smooth muscle cells.Exp Cell Res. 2014; 323: 198-208Crossref PubMed Scopus (27) Google Scholar Phosphate-induced CV of vascular smooth muscle cells increases the risk of coronary artery events, CV morbidity and mortality, and hypertension.56Detrano R. Guerci A.D. Carr J.J. et al.Coronary calcium as a predictor of coronary events in four racial or ethnic groups.N Engl J Med. 2008; 358: 1336-1345Crossref PubMed Scopus (1878) Google Scholar, 57Blacher J. Guerin A.P. 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Vargas G.S. et al.Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.Kidney Int. 2011; 79: 1370-1378Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar Abnormalities in mineral metabolism (e.g., secondary hyperparathyroidism, decreased vitamin D) are seen in patients before increases in phosphate, indicating that these compensatory mechanisms are at work before hyperphosphatemia develops.29Isakova T. Wahl P. Vargas G.S. et al.Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.Kidney Int. 2011; 79: 1370-1378Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar,60Levin A. Bakris G.L. 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Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells.J Endocrinol. 2009; 200: 207-221Crossref PubMed Scopus (106) Google Scholar and proinflammatory effect.71Olszowiec-Chlebna M. Koniarek-Maniecka A. Brzozowska A. et al.Vitamin D inhibits pro-inflammatory cytokines in the airways of cystic fibrosis patients infected by Pseudomonas aeruginosa—pilot study.Ital J Pediatr. 2019; 45: 41Crossref PubMed Scopus (0) Google Scholar PTH increases the production of calcitriol (1,25-dihydroxyvitamin D), as well as increases bone resorption, which leads to increasing both serum calcium and phosphate concentrations.72Nussey S. Whitehead S. The parathyroid glands and vitamin D.Endocrinology: An Integrated Approach. BIOS Scientific Publishers, 2001Crossref Google Scholar Thus, by the time hyperphosphatemia develops (>4.5 mg/dl), patients have already experienced the deleterious effects of elevated PTH, elevated FGF23, hypocalcemia, and low vitamin D (Figure 1). In CKD stages 4 and 5, phosphate concentrations begin to increase despite elevations in FGF23 and PTH, indicating that compensatory mechanisms are no longer sufficient to maintain phosphate balance and prevent hyperphosphatemia.29Isakova T. Wahl P. Vargas G.S. et al.Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.Kidney Int. 2011; 79: 1370-1378Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar Numerous studies have documented the link between hyperphosphatemia and increased all-cause mortality and CVD in both healthy individuals and patients with CKD.5Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metab" @default.
• W3161530003 created "2021-05-24" @default.
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• W3161530003 date "2021-08-01" @default.
• W3161530003 modified "2023-10-14" @default.
• W3161530003 title "Phosphate Balance and CKD–Mineral Bone Disease" @default.
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