Update on Chronic Kidney Disease Mineral and Bone Disorder in Cardiovascular Disease

2017, KDIGO 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, 7, 1, 10.1016/j.kisu.2017.04.001 Ritter, 2016, Phosphate toxicity in CKD: the killer among us, Clin J Am Soc Nephrol, 11, 1088, 10.2215/CJN.11901115 Isakova, 2011, Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease, Kidney Int, 79, 1370, 10.1038/ki.2011.47 Naveh-Many, 2017, The pas de trois of vitamin D, FGF23, and PTH, J Am Soc Nephrol, 28, 393, 10.1681/ASN.2016090944 Han, 2016, Conditional deletion of Fgfr1 in the proximal and distal tubule identifies distinct roles in phosphate and calcium transport, PLoS One, 11 Andrukhova, 2014, FGF23 promotes renal calcium reabsorption through the TRPV5 channel, EMBO J, 33, 229 Barker, 2015, The demonstration of alphaKlotho deficiency in human chronic kidney disease with a novel synthetic antibody, Nephrol Dial Transplant, 30, 223, 10.1093/ndt/gfu291 Urakawa, 2006, Klotho converts canonical FGF receptor into a specific receptor for FGF23, Nature, 444, 770, 10.1038/nature05315 Hu, 2013, Klotho and chronic kidney disease, Contrib Nephrol, 180, 47, 10.1159/000346778 Andrukhova, 2017, Klotho lacks an FGF23-independent role in mineral homeostasis, J Bone Miner Res, 32, 2049, 10.1002/jbmr.3195 Lindberg, 2014, The kidney is the principal organ mediating klotho effects, J Am Soc Nephrol, 25, 2169, 10.1681/ASN.2013111209 Hu, 2016, Renal production, uptake, and handling of circulating alphaklotho, J Am Soc Nephrol, 27, 79, 10.1681/ASN.2014101030 Scialla, 2015, Race, mineral homeostasis and mortality in patients with end-stage renal disease on dialysis, Am J Nephrol, 42, 25, 10.1159/000438999 Gutierrez, 2008, Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis, N Engl J Med, 359, 584, 10.1056/NEJMoa0706130 Block, 1998, Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study, Am J Kidney Dis, 31, 607, 10.1053/ajkd.1998.v31.pm9531176 Scialla, 2014, Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease, Nat Rev Nephrol, 10, 268, 10.1038/nrneph.2014.49 Palmer, 2011, Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis, JAMA, 305, 1119, 10.1001/jama.2011.308 Dhingra, 2010, Relations of serum phosphorus levels to echocardiographic left ventricular mass and incidence of heart failure in the community, Eur J Heart Fail, 12, 812, 10.1093/eurjhf/hfq106 Dhingra, 2007, Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community, Arch Intern Med, 167, 879, 10.1001/archinte.167.9.879 Tonelli, 2005, Relation between serum phosphate level and cardiovascular event rate in people with coronary disease, Circulation, 112, 2627, 10.1161/CIRCULATIONAHA.105.553198 Lutsey, 2014, Serum magnesium, phosphorus, and calcium are associated with risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) study, Am J Clin Nutr, 100, 756, 10.3945/ajcn.114.085167 2000, Autosomal dominant hypophosphatemic rickets is associated with mutations in FGF23, Nat Genet, 26, 345, 10.1038/81664 Saito, 2005, Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo, J Biol Chem, 280, 2543, 10.1074/jbc.M408903200 Scialla, 2014, Fibroblast growth factor 23 and cardiovascular events in chronic kidney disease, J Am Soc Nephrol, 25, 349, 10.1681/ASN.2013050465 Mehta, 2016, Association of fibroblast growth factor 23 with atrial fibrillation in chronic kidney disease, from the Chronic Renal Insufficiency Cohort study, JAMA Cardiol, 1, 548, 10.1001/jamacardio.2016.1445 Ix, 2012, Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study), J Am Coll Cardiol, 60, 200, 10.1016/j.jacc.2012.03.040 Kendrick, 2011, FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis, J Am Soc Nephrol, 22, 1913, 10.1681/ASN.2010121224 Mathew, 2014, Fibroblast growth factor-23 and incident atrial fibrillation: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS), Circulation, 130, 298, 10.1161/CIRCULATIONAHA.113.005499 Chonchol, 2016, Low vitamin D and high fibroblast growth factor 23 serum levels associate with infectious and cardiac deaths in the HEMO study, J Am Soc Nephrol, 27, 227, 10.1681/ASN.2014101009 Lutsey, 2014, Fibroblast growth factor-23 and incident coronary heart disease, heart failure, and cardiovascular mortality: the Atherosclerosis Risk in Communities study, J Am Heart Assoc, 3, 10.1161/JAHA.114.000936 Kestenbaum, 2014, Fibroblast growth factor-23 and cardiovascular disease in the general population: the Multi-Ethnic Study of Atherosclerosis, Circ Heart Fail, 7, 409, 10.1161/CIRCHEARTFAILURE.113.000952 Panwar, 2015, Fibroblast growth factor 23 and risk of incident stroke in community-living adults, Stroke, 46, 322, 10.1161/STROKEAHA.114.007489 Souma, 2016, Fibroblast growth factor 23 and cause-specific mortality in the general population: the Northern Manhattan Study, J Clin Endocrinol Metab, 101, 3779, 10.1210/jc.2016-2215 Scialla, 2015, Epidemiologic insights on the role of fibroblast growth factor 23 in cardiovascular disease, Curr Opin Nephrol Hypertens, 24, 260, 10.1097/MNH.0000000000000123 Isakova, 2011, Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease, JAMA, 305, 2432, 10.1001/jama.2011.826 Scialla, 2012, Mineral metabolites and chronic kidney disease progression in African Americans, J Am Soc Nephrol, 24, 125, 10.1681/ASN.2012070713 Nowak, 2017, Fibroblast growth factor 23 and the risk of infection-related hospitalization in older adults, J Am Soc Nephrol, 28, 1239, 10.1681/ASN.2016040401 Ishigami, 2017, Biomarkers of mineral and bone metabolism and 20-year risk of hospitalization with infection: the Atherosclerosis Risk in Communities Study, J Clin Endocrinol Metab, 102, 4648, 10.1210/jc.2017-01868 Marcais, 2017, Circulating klotho associates with cardiovascular morbidity and mortality during hemodialysis, J Clin Endocrinol Metab, 102, 3154, 10.1210/jc.2017-00104 Seiler, 2013, Plasma Klotho is not related to kidney function and does not predict adverse outcome in patients with chronic kidney disease, Kidney Int, 83, 121, 10.1038/ki.2012.288 Brandenburg, 2015, Soluble klotho and mortality: the Ludwigshafen Risk and Cardiovascular Health Study, Atherosclerosis, 242, 483, 10.1016/j.atherosclerosis.2015.08.017 Hu, 2011, Klotho deficiency causes vascular calcification in chronic kidney disease, J Am Soc Nephrol, 22, 124, 10.1681/ASN.2009121311 Seiler, 2014, Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4, Clin J Am Soc Nephrol, 9, 1049, 10.2215/CJN.07870713 Kim, 2013, Circulating alpha-klotho levels in CKD and relationship to progression, Am J Kidney Dis, 61, 899, 10.1053/j.ajkd.2013.01.024 Pavik, 2013, Secreted Klotho and FGF23 in chronic kidney disease stage 1 to 5: a sequence suggested from a cross-sectional study, Nephrol Dial Transplant, 28, 352, 10.1093/ndt/gfs460 Nowak, 2014, Prognostic value and link to atrial fibrillation of soluble Klotho and FGF23 in hemodialysis patients, PLoS One, 9, 10.1371/journal.pone.0100688 Wang, 2008, Vitamin D deficiency and risk of cardiovascular disease, Circulation, 117, 503, 10.1161/CIRCULATIONAHA.107.706127 Melamed, 2008, 25-hydroxyvitamin D levels and the risk of mortality in the general population, Arch Intern Med, 168, 1629, 10.1001/archinte.168.15.1629 Dobnig, 2008, Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality, Arch Intern Med, 168, 1340, 10.1001/archinte.168.12.1340 de Boer, 2012, Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study, Ann Intern Med, 156, 627, 10.7326/0003-4819-156-9-201205010-00004 Levin, 2012, Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes, JAMA, 308, 1898, 10.1001/jama.2012.17304 Robinson-Cohen, 2013, Racial differences in the association of serum 25-hydroxyvitamin D concentration with coronary heart disease events, JAMA, 310, 179, 10.1001/jama.2013.7228 Theodoratou, 2014, Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials, BMJ, 348, 10.1136/bmj.g2035 Al Mheid, 2017, Vitamin D and cardiovascular disease: controversy unresolved, J Am Coll Cardiol, 70, 89, 10.1016/j.jacc.2017.05.031 Teng, 2003, Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy, N Engl J Med, 349, 446, 10.1056/NEJMoa022536 Teng, 2005, Activated injectable vitamin D and hemodialysis survival: a historical cohort study, J Am Soc Nephrol, 16, 1115, 10.1681/ASN.2004070573 Thadhani, 2012, Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial, JAMA, 307, 674, 10.1001/jama.2012.120 Zoccali, 2014, Paricalcitol and endothelial function in chronic kidney disease trial, Hypertension, 64, 1005, 10.1161/HYPERTENSIONAHA.114.03748 Wang, 2014, Effect of paricalcitol on left ventricular mass and function in CKD–the OPERA trial, J Am Soc Nephrol, 25, 175, 10.1681/ASN.2013010103 Rosanoff, 2016, Essential nutrient interactions: does low or suboptimal magnesium status interact with vitamin D and/or calcium status, Adv Nutr, 7, 25, 10.3945/an.115.008631 Li, 2015, Hypomagnesemia and mortality in incident hemodialysis patients, Am J Kidney Dis, 66, 1047, 10.1053/j.ajkd.2015.05.024 Reffelmann, 2011, Low serum magnesium concentrations predict cardiovascular and all-cause mortality, Atherosclerosis, 219, 280, 10.1016/j.atherosclerosis.2011.05.038 Pun, 2017, Dialysate potassium, dialysate magnesium, and hemodialysis risk, J Am Soc Nephrol, 28, 3441, 10.1681/ASN.2017060640 Goodman, 2004, Vascular calcification in chronic kidney disease, Am J Kidney Dis, 43, 572, 10.1053/j.ajkd.2003.12.005 London, 2001, Arterial wave reflections and survival in end-stage renal failure, Hypertension, 38, 434, 10.1161/01.HYP.38.3.434 London, 2003, Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality, Nephrol Dial Transplant, 18, 1731, 10.1093/ndt/gfg414 Gungor, 2017, Role of vascular calcification inhibitors in preventing vascular dysfunction and mortality in hemodialysis patients, Semin Dial, 31, 72, 10.1111/sdi.12616 Chen, 2015, Pathophysiology of vascular calcification, Curr Osteoporos Rep, 13, 372, 10.1007/s11914-015-0293-9 El-Abbadi, 2009, Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin, Kidney Int, 75, 1297, 10.1038/ki.2009.83 Kuro-o, 1997, Mutation of the mouse klotho gene leads to a syndrome resembling ageing, Nature, 390, 45, 10.1038/36285 Scialla, 2013, Fibroblast growth factor 23 is not associated with and does not induce arterial calcification, Kidney Int, 83, 1159, 10.1038/ki.2013.3 Lau, 2012, Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet, Kidney Int, 82, 1261, 10.1038/ki.2012.322 Stubbs, 2007, Role of hyperphosphatemia and 1,25-dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice, J Am Soc Nephrol, 18, 2116, 10.1681/ASN.2006121385 Di Marco, 2013, High phosphate directly affects endothelial function by downregulating annexin II, Kidney Int, 83, 213, 10.1038/ki.2012.300 Shuto, 2009, Dietary phosphorus acutely impairs endothelial function, J Am Soc Nephrol, 20, 1504, 10.1681/ASN.2008101106 Six, 2014, Direct, acute effects of Klotho and FGF23 on vascular smooth muscle and endothelium, PLoS One, 9, e93423, 10.1371/journal.pone.0093423 Maltese, 2017, The anti-ageing hormone klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells, J Cell Mol Med, 21, 621, 10.1111/jcmm.12996 Lundwall, 2015, Paricalcitol, microvascular and endothelial function in non-diabetic chronic kidney disease: a randomized trial, Am J Nephrol, 42, 265, 10.1159/000441364 Chitalia, 2014, Impact of vitamin D supplementation on arterial vasomotion, stiffness and endothelial biomarkers in chronic kidney disease patients, PLoS One, 9, e91363, 10.1371/journal.pone.0091363 Levin, 2017, Randomized controlled trial for the effect of vitamin D supplementation on vascular stiffness in CKD, Clin J Am Soc Nephrol, 12, 1447, 10.2215/CJN.10791016 Kumar, 2017, A randomized trial of vitamin D supplementation on vascular function in CKD, J Am Soc Nephrol, 28, 3100, 10.1681/ASN.2017010003 Dai, 2012, A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model, PLoS One, 7, e44161, 10.1371/journal.pone.0044161 Singh, 2016, Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease, Kidney Int, 90, 985, 10.1016/j.kint.2016.05.019 Munoz Mendoza, 2012, Fibroblast growth factor 23 and Inflammation in CKD, Clin J Am Soc Nephrol, 7, 1155, 10.2215/CJN.13281211 Bressendorff, 2017, The effect of magnesium supplementation on vascular calcification in chronic kidney disease-a randomised clinical trial (MAGiCAL-CKD): essential study design and rationale, BMJ Open, 7, 10.1136/bmjopen-2017-016795 Bressendorff, 2017, Oral magnesium supplementation in chronic kidney disease stages 3 and 4: efficacy, safety, and effect on serum calcification propensity-a prospective randomized double-blinded placebo-controlled clinical trial, Kidney Int Rep, 2, 380, 10.1016/j.ekir.2016.12.008 Holden, 2015, Inhibiting the progression of arterial calcification with vitamin K in HemoDialysis patients (iPACK-HD) trial: rationale and study design for a randomized trial of vitamin K in patients with end stage kidney disease, Can J Kidney Health Dis, 2, 17, 10.1186/s40697-015-0053-x Sacco, 2016, The heart of 25 by 25: achieving the goal of reducing global and regional premature deaths from cardiovascular diseases and stroke: a modeling study from the American Heart Association and World Heart Federation, Circulation, 133, e674, 10.1161/CIR.0000000000000395 Forman, 2010, Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans, Hypertension, 55, 1283, 10.1161/HYPERTENSIONAHA.109.148619 Sluyter, 2017, Effect of monthly, high-dose, long-term vitamin D supplementation on central blood pressure parameters: a randomized controlled trial substudy, J Am Heart Assoc, 6, 10.1161/JAHA.117.006802 Mizuno, 2016, High dietary phosphate intake induces hypertension and augments exercise pressor reflex function in rats, Am J Physiol Regul Integr Comp Physiol, 311, R39, 10.1152/ajpregu.00124.2016 Bozic, 2014, High phosphate diet increases arterial blood pressure via a parathyroid hormone mediated increase of renin, J Hypertens, 32, 1822, 10.1097/HJH.0000000000000261 Andrukhova, 2014, FGF23 regulates renal sodium handling and blood pressure, EMBO Mol Med, 6, 744, 10.1002/emmm.201303716 Elliott, 2008, Dietary phosphorus and blood pressure: international study of macro- and micro-nutrients and blood pressure, Hypertension, 51, 669, 10.1161/HYPERTENSIONAHA.107.103747 Alonso, 2010, Dietary phosphorus, blood pressure, and incidence of hypertension in the atherosclerosis risk in communities study and the multi-ethnic study of atherosclerosis, Hypertension, 55, 776, 10.1161/HYPERTENSIONAHA.109.143461 Tzoulaki, 2012, A nutrient-wide association study on blood pressure, Circulation, 126, 2456, 10.1161/CIRCULATIONAHA.112.114058 Appel, 1997, A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group, N Engl J Med, 336, 1117, 10.1056/NEJM199704173361601 Jimenez, 2016, High dialysate calcium concentration may cause more sympathetic stimulus during hemodialysis, Kidney Blood Press Res, 41, 978, 10.1159/000452601 Sabanayagam, 2011, Serum calcium levels and hypertension among U.S. adults, J Clin Hypertens, 13, 716, 10.1111/j.1751-7176.2011.00503.x Zhang, 2016, Effects of magnesium supplementation on blood pressure: a meta-analysis of randomized double-blind placebo-controlled trials, Hypertension, 68, 324, 10.1161/HYPERTENSIONAHA.116.07664 Fyfe-Johnson, 2016, Serum fibroblast growth factor-23 and incident hypertension: the Atherosclerosis Risk in Communities (ARIC) study, J Hypertens, 34, 1266, 10.1097/HJH.0000000000000936 de Borst, 2011, Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease, J Am Soc Nephrol, 22, 1603, 10.1681/ASN.2010121251 Wohlfahrt, 2015, Association of fibroblast growth factor-23 levels and angiotensin-converting enzyme inhibition in chronic systolic heart failure, JACC Heart Fail, 3, 829, 10.1016/j.jchf.2015.05.012 de Jong, 2017, Fibroblast growth factor 23 modifies the pharmacological effects of angiotensin receptor blockade in experimental renal fibrosis, Nephrol Dial Transplant, 32, 73 Zoccali, 2011, Phosphate may promote CKD progression and attenuate renoprotective effect of ACE inhibition, J Am Soc Nephrol, 22, 1923, 10.1681/ASN.2011020175 Humalda, 2015, Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade, Am J Kidney Dis, 65, 259, 10.1053/j.ajkd.2014.07.022 Jovanovich, 2015, Mineral metabolites, angiotensin II inhibition and outcomes in advanced chronic kidney disease, Am J Nephrol, 42, 361, 10.1159/000441684 Udell, 2014, Fibroblast growth factor-23, cardiovascular prognosis, and benefit of angiotensin-converting enzyme inhibition in stable ischemic heart disease, J Am Coll Cardiol, 63, 2421, 10.1016/j.jacc.2014.03.026 Yamamoto, 2013, Dietary phosphorus is associated with greater left ventricular mass, Kidney Int, 83, 707, 10.1038/ki.2012.303 Tranaeus Lindblad, 2018, The FGF23-klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease-a prospective cohort study, Pediatr Nephrol, 33, 147, 10.1007/s00467-017-3766-5 Tanaka, 2016, Association between FGF23, alpha-klotho, and cardiac abnormalities among patients with various chronic kidney disease stages, PLoS One, 11, 10.1371/journal.pone.0156860 Faul, 2011, FGF23 induces left ventricular hypertrophy, J Clin Invest, 121, 4393, 10.1172/JCI46122 Gutierrez, 2009, Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease, Circulation, 119, 2545, 10.1161/CIRCULATIONAHA.108.844506 Saab, 2010, Association of serum phosphorus with left ventricular mass in men and women with stable cardiovascular disease: data from the heart and soul study, Am J Kidney Dis, 56, 496, 10.1053/j.ajkd.2010.03.030 Mirza, 2009, Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population, Atherosclerosis, 207, 546, 10.1016/j.atherosclerosis.2009.05.013 Seeherunvong, 2012, Fibroblast growth factor 23 and left ventricular hypertrophy in children on dialysis, Ped Nephrol, 27, 2129, 10.1007/s00467-012-2224-7 Han, 2018, Cardiovascular effects of renal distal tubule deletion of the FGF receptor 1 gene, J Am Soc Nephrol, 29, 69, 10.1681/ASN.2017040412 Touchberry, 2013, FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy, Am J Physiol Endocrinol Metab, 304, E863, 10.1152/ajpendo.00596.2012 Grabner, 2015, Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy, Cell Metab, 22, 1020, 10.1016/j.cmet.2015.09.002 Grabner, 2016, The role of fibroblast growth factor 23 and klotho in uremic cardiomyopathy, Curr Opin Nephrol Hypertens, 25, 314, 10.1097/MNH.0000000000000231 Xie, 2015, Soluble klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate, J Am Soc Nephrol, 26, 1150, 10.1681/ASN.2014040325 Hu, 2015, Klotho and phosphate are modulators of pathologic uremic cardiac remodeling, J Am Soc Nephrol, 26, 1290, 10.1681/ASN.2014050465 Yang, 2015, Klotho protects against indoxyl sulphate-induced myocardial hypertrophy, J Am Soc Nephrol, 26, 2434, 10.1681/ASN.2014060543 Isakova, 2015, Rationale and approaches to phosphate and fibroblast growth factor 23 reduction in CKD, J Am Soc Nephrol, 26, 2328, 10.1681/ASN.2015020117 Pun, 2013, Dialysate calcium concentration and the risk of sudden cardiac arrest in hemodialysis patients, Clin J Am Soc Nephrol, 8, 797, 10.2215/CJN.10000912 Zaheer, 2017, Fibroblast growth factor 23, mineral metabolism, and adiposity in normal kidney function, J Clin Endocrinol Metab, 102, 1387, 10.1210/jc.2016-3563 Zhang, 2016, Up-regulation of FGF23 release by aldosterone, Biochem Biophys Res Commun, 470, 384, 10.1016/j.bbrc.2016.01.034 Wolf, 2013, Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women, J Bone Miner Res, 28, 1793, 10.1002/jbmr.1923 Holick, 2007, Vitamin D deficiency, N Engl J Med, 357, 266, 10.1056/NEJMra070553 Slavic, 2017, Genetic ablation of Fgf23 or klotho does not modulate experimental heart hypertrophy induced by pressure overload, Sci Rep, 7, 11298, 10.1038/s41598-017-10140-4 Andrukhova, 2015, Experimental myocardial infarction upregulates circulating fibroblast growth factor-23, J Bone Miner Res, 30, 1831, 10.1002/jbmr.2527 Christov, 2013, Plasma FGF23 levels increase rapidly after acute kidney injury, Kidney Int, 84, 776, 10.1038/ki.2013.150 Leifheit-Nestler, 2016, Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease, Nephrol Dial Transplant, 31, 1088, 10.1093/ndt/gfv421 Shalhoub, 2012, FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality, J Clin Invest, 122, 2543, 10.1172/JCI61405 Block, 2012, Effects of phosphate binders in moderate CKD, J Am Soc Nephrol, 23, 1407, 10.1681/ASN.2012030223 Chertow, 2012, Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis, N Engl J Med, 367, 2482, 10.1056/NEJMoa1205624 Shieh, 2017, Assessing vitamin D status in African Americans and the influence of vitamin D on skeletal health parameters, Endocrinol Metab Clin North Am, 46, 135, 10.1016/j.ecl.2016.09.006 National Center for Biotechnology Information. Database of genotypes and phenotypes. [cited 2017 Nov 28]. Available from: https://www.ncbi.nlm.nih.gov/gap. Chang, 2015, Genome-wide association study of serum minerals levels in children of different ethnic background, PLoS One, 10 O'Seaghdha, 2013, Meta-analysis of genome-wide association studies identifies six new loci for serum calcium concentrations, PLoS Genet, 9, 10.1371/journal.pgen.1003796 Vinayagamoorthy, 2015, Association of common variants in the calcium-sensing receptor gene with serum calcium levels in East Asians, J Hum Genet, 60, 407, 10.1038/jhg.2015.46 Wang, 2010, Common genetic determinants of vitamin D insufficiency: a genome-wide association study, Lancet, 376, 180, 10.1016/S0140-6736(10)60588-0 Robinson-Cohen, 2017, Genetic variants associated with circulating parathyroid hormone, J Am Soc Nephrol, 28, 1553, 10.1681/ASN.2016010069 Ahn, 2010, Genome-wide association study of circulating vitamin D levels, Hum Mol Genet, 19, 2739, 10.1093/hmg/ddq155 Kestenbaum, 2010, Common genetic variants associate with serum phosphorus concentration, J Am Soc Nephrol, 21, 1223, 10.1681/ASN.2009111104 Moy, 2014, Genome-wide association study of circulating vitamin D-binding protein, Am J Clin Nutr, 99, 1424, 10.3945/ajcn.113.080309 Meyer, 2010, Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six loci influencing serum magnesium levels, PLoS Genet, 6, 10.1371/journal.pgen.1001045 Tin, 2015, Genetic loci for serum magnesium among African-Americans and gene-environment interaction at MUC1 and TRPM6 in European-Americans: the Atherosclerosis Risk in Communities (ARIC) study, BMC Genet, 16, 56, 10.1186/s12863-015-0219-7 Ferguson, 2013, Candidate gene association study of coronary artery calcification in chronic kidney disease: findings from the CRIC study (Chronic Renal Insufficiency Cohort), J Am Coll Cardiol, 62, 789, 10.1016/j.jacc.2013.01.103 Xie, 2015, Genome-wide association study on progression of carotid artery intima media thickness over 10 years in a Chinese cohort, Atherosclerosis, 243, 30, 10.1016/j.atherosclerosis.2015.08.034 Dehghan, 2011, Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels, Circulation, 123, 731, 10.1161/CIRCULATIONAHA.110.948570 Ellis, 2014, Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans, Hum Genet, 133, 985, 10.1007/s00439-014-1439-z Hong, 2014, Genetic risk assessment for cardiovascular disease with seven genes associated with plasma C-reactive protein concentrations in Asian populations, Hypertens Res, 37, 692, 10.1038/hr.2014.56 Ridker, 2008, Loci related to metabolic-syndrome pathways including LEPR, HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study, Am J Hum Genet, 82, 1185, 10.1016/j.ajhg.2008.03.015 Fontana, 2014, Large-scale gene-centric analysis identifies polymorphisms for resistant hypertension, J Am Heart Assoc, 3, 10.1161/JAHA.114.001398 Hong, 2010, Genetic variations in ATP2B1, CSK, ARSG and CSMD1 loci are related to blood pressure and/or hypertension in two Korean cohorts, J Hum Hypertens, 24, 367, 10.1038/jhh.2009.86 Hong, 2010, Recapitulation of two genomewide association studies on blood pressure and essential hypertension in the Korean population, J Hum Genet, 55, 336, 10.1038/jhg.2010.31 Johnson, 2011, Blood pressure loci identified with a gene-centric array, Am J Hum Genet, 89, 688, 10.1016/j.ajhg.2011.10.013 Kelly, 2013, Genome-wide association study meta-analysis reveals transethnic replication of mean arterial and pulse pressure loci, Hypertension, 62, 853, 10.1161/HYPERTENSIONAHA.113.01148 Levy, 2009, Genome-wide association study of blood pressure and hypertension, Nat Genet, 41, 677, 10.1038/ng.384 Lu, 2015, Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension, Hum Mol Genet, 24, 865, 10.1093/hmg/ddu478 Miyaki, 2012, The combined impact of 12 common variants on hypertension in Japanese men, considering GWAS results, J Hum Hypertens, 26, 430, 10.1038/jhh.2011.50 Tabara, 2010, Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project, Hypertension, 56, 973, 10.1161/HYPERTENSIONAHA.110.153429 Takeuchi, 2010, Blood pressure and hypertension are associated with 7 loci in the Japanese population, Circulation, 121, 2302, 10.1161/CIRCULATIONAHA.109.904664 Tobin, 2008, Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population, Hypertension, 51, 1658, 10.1161/HYPERTENSIONAHA.108.112664 Kutikhin, 2014, Genetic predisposition to calcific aortic stenosis and mitral annular calcification, Mol Biol Rep, 41, 5645, 10.1007/s11033-014-3434-9 Guo, 2016, Association between the DOCK7, PCSK9 and GALNT2 gene polymorphisms and serum lipid levels, Sci Rep, 6, 19079, 10.1038/srep19079 Willer, 2008, Newly identified loci that influence lipid concentrations and risk of coronary artery disease, Nat Genet, 40, 161, 10.1038/ng.76 Fox, 2013, Genome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study, Circ Cardiovasc Genet, 6, 37, 10.1161/CIRCGENETICS.111.962365 Qi, 2013, Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes, JAMA, 310, 821, 10.1001/jama.2013.276305 Smith, 2010, Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, Circ Cardiovasc Genet, 3, 256, 10.1161/CIRCGENETICS.109.895763 Swerdlow, 2015, Genetic risk factors and Mendelian randomization in cardiovascular disease, Curr Cardiol Rep, 17, 33, 10.1007/s11886-015-0584-x Wild, 2017, Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function, J Clin Invest, 127, 1798, 10.1172/JCI84840 Marz, 2007, Alanine to serine polymorphism at position 986 of the calcium-sensing receptor associated with coronary heart disease, myocardial infarction, all-cause, and cardiovascular mortality, J Clin Endocrinol Metab, 92, 2363, 10.1210/jc.2006-0071 Babinsky, 2015, Association studies of calcium-sensing receptor (CaSR) polymorphisms with serum concentrations of glucose and phosphate, and vascular calcification in renal transplant recipients, PLoS One, 10, 10.1371/journal.pone.0119459 Brondum-Jacobsen, 2015, No evidence that genetically reduced 25-hydroxyvitamin D is associated with increased risk of ischaemic heart disease or myocardial infarction: a Mendelian randomization study, Int J Epidemiol, 44, 651, 10.1093/ije/dyv078 Daffara, 2017, Impact of polymorphism rs7041 and rs4588 of vitamin D binding protein on the extent of coronary artery disease, Nutr Metab Cardiovasc Dis, 27, 775, 10.1016/j.numecd.2017.06.002 Jorde, 2012, Polymorphisms related to the serum 25-hydroxyvitamin D level and risk of myocardial infarction, diabetes, cancer and mortality. The Tromso Study, PLoS One, 7, e37295, 10.1371/journal.pone.0037295 Trummer, 2013, Vitamin D and mortality: a Mendelian randomization study, Clin Chem, 59, 793, 10.1373/clinchem.2012.193185 Wang, 2014, Common genetic variations in the vitamin D pathway in relation to blood pressure, Am J Hypertens, 27, 1387, 10.1093/ajh/hpu049 Afzal, 2014, Genetically low vitamin D concentrations and increased mortality: Mendelian randomisation analysis in three large cohorts, BMJ, 349, g6330, 10.1136/bmj.g6330 Hassanein, 2014, Triangular relationship between single nucleotide polymorphisms in the CYP2R1 gene (rs10741657 and rs12794714), 25-hydroxyvitamin d levels, and coronary artery disease incidence, Biomarkers, 19, 488, 10.3109/1354750X.2014.939226 Shen, 2010, Association of the vitamin D metabolism gene CYP24A1 with coronary artery calcification, Arterioslerol Thromb Vasc Biol, 30, 2648, 10.1161/ATVBAHA.110.211805 Vimaleswaran, 2014, Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study, Lancet Diabetes Endocrinol, 2, 719, 10.1016/S2213-8587(14)70113-5 Wilke, 2009, Genetic variation in CYP27B1 is associated with congestive heart failure in patients with hypertension, Pharmacogenomics, 10, 1789, 10.2217/pgs.09.101 Friedman, 2009, Klotho variants and chronic hemodialysis mortality, J Bone Miner Res, 24, 1847, 10.1359/jbmr.090516 Donate-Correa, 2016, Influence of Klotho gene polymorphisms on vascular gene expression and its relationship to cardiovascular disease, J Cell Mol Med, 20, 128, 10.1111/jcmm.12710 Elghoroury, 2018, Klotho G-395A gene polymorphism: impact on progression of end-stage renal disease and development of cardiovascular complications in children on dialysis, Pediatr Nephrol, 33, 1019, 10.1007/s00467-017-3877-z Tangri, 2011, Lack of association of Klotho gene variants with valvular and vascular calcification in Caucasians: a candidate gene study of the Framingham Offspring Cohort, Nephrol Dial Transplant, 26, 3998, 10.1093/ndt/gfr188 Lutsey, 2015, Race and vitamin D binding protein gene polymorphisms modify the association of 25-hydroxyvitamin D and incident heart failure: the ARIC (Atherosclerosis Risk in Communities) study, JACC Heart Fail, 3, 347, 10.1016/j.jchf.2014.11.013 Schneider, 2015, Vitamin D, vitamin D binding protein gene polymorphisms, race and risk of incident stroke: the Atherosclerosis Risk in Communities (ARIC) study, Eur J Neurol, 22, 1220, 10.1111/ene.12731 Verdoia, 2017, Vitamin D binding protein rs7041 polymorphism and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor, Vasc Pharmacol, 93-95, 42, 10.1016/j.vph.2017.04.001 Barry, 2014, Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D3 supplementation for increasing serum 25-hydroxyvitamin D levels in a randomized controlled trial, J Clin Endocrinol Metab, 99, E2133, 10.1210/jc.2014-1389 Durazo-Arvizu, 2014, 25-Hydroxyvitamin D in African-origin populations at varying latitudes challenges the construct of a physiologic norm, Am J Clin Nutr, 100, 908, 10.3945/ajcn.113.066605 Jorde, 2010, Tracking of serum 25-hydroxyvitamin D levels during 14 years in a population-based study and during 12 months in an intervention study, Am J Epidemiol, 171, 903, 10.1093/aje/kwq005 Whisner, 2017, Prebiotics, bone and mineral metabolism, Calcif Tissue Int, 102, 443, 10.1007/s00223-017-0339-3 Scholz-Ahrens, 2007, Prebiotics, probiotics, and synbiotics affect mineral absorption, bone mineral content, and bone structure, J Nutr, 137, 838S, 10.1093/jn/137.3.838S Harmon, 2016, Use of estrogen-containing contraception is associated with increased concentrations of 25-hydroxy vitamin D, J Clin Endocrinol Metab, 101, 3370, 10.1210/jc.2016-1658 Harris, 1998, The association of oral contraceptive use with plasma 25-hydroxyvitamin D levels, J Am Coll Nutr, 17, 282, 10.1080/07315724.1998.10718760 Malhotra, 2018, The effect of extended release niacin on markers of mineral metabolism in CKD, Clin J Am Soc Nephrol, 13, 36, 10.2215/CJN.05440517 Block, 2017, Effect of tenapanor on serum phosphate in patients receiving hemodialysis, J Am Soc Nephrol, 28, 1933, 10.1681/ASN.2016080855 Block, 2012, Effects of phosphate binders in moderate CKD, J Am Soc Nephrol, 23, 1407, 10.1681/ASN.2012030223 Seifert, 2013, Effects of phosphate binder therapy on vascular stiffness in early-stage chronic kidney disease, Am J Nephrol, 38, 158, 10.1159/000353569 Liabeuf, 2017, Randomized clinical trial of sevelamer carbonate on serum klotho and fibroblast growth factor 23 in CKD, Clin J Am Soc Nephrol, 12, 1930, 10.2215/CJN.03030317 Urena-Torres, 2014, Changes in fibroblast growth factor 23 levels in normophosphatemic patients with chronic kidney disease stage 3 treated with lanthanum carbonate: results of the PREFECT study, a phase 2a, double blind, randomized, placebo-controlled trial, BMC Nephrol, 15, 71, 10.1186/1471-2369-15-71 Isakova, 2009, Phosphorus binders and survival on hemodialysis, J Am Soc Nephrol, 20, 388, 10.1681/ASN.2008060609 Kovesdy, 2010, Outcomes associated with phosphorus binders in men with non-dialysis-dependent CKD, Am J Kidney Dis, 56, 842, 10.1053/j.ajkd.2010.06.011 Lopes, 2012, Phosphate binder use and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS): evaluation of possible confounding by nutritional status, Am J Kidney Dis, 60, 90, 10.1053/j.ajkd.2011.12.025 Block, 2007, Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients, Kidney Int, 71, 438, 10.1038/sj.ki.5002059 Block, 2005, Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis, Kidney Int, 68, 1815, 10.1111/j.1523-1755.2005.00600.x Chertow, 2002, Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients, Kidney Int, 62, 245, 10.1046/j.1523-1755.2002.00434.x Suki, 2007, Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients, Kidney Int, 72, 1130, 10.1038/sj.ki.5002466 Olivo, 2017, Getting out of the phosphate bind: trials to guide treatment targets, Clin J Am Soc Nephrol, 12, 868, 10.2215/CJN.04380417 Kalil, 2015, Effect of extended-release niacin on cardiovascular events and kidney function in chronic kidney disease: a post hoc analysis of the AIM-HIGH trial, Kidney Int, 87, 1250, 10.1038/ki.2014.383 Gutierrez, 2015, Impact of phosphorus-based food additives on bone and mineral metabolism, J Clin Endocrinol Metab, 100, 4264, 10.1210/jc.2015-2279 Antoniucci, 2006, Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men, J Clin Endocrinol Metab, 91, 3144, 10.1210/jc.2006-0021 Tamez, 2012, Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease, Am Heart J, 164, 10.1016/j.ahj.2012.09.018 Lu, 2017, Effects of vitamin D or its analogues on the mortality of patients with chronic kidney disease: an updated systematic review and meta-analysis, Eur J Clin Nutr, 71, 683, 10.1038/ejcn.2017.59 Westerberg, 2018, High doses of cholecalciferol alleviate the progression of hyperparathyroidism in patients with CKD stages 3-4: results of a 12-week double-blind, randomized, controlled study, Nephrol Dial Transplant, 33, 466, 10.1093/ndt/gfx059 Manson, 2012, The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease, Contemp Clin Trials, 33, 159, 10.1016/j.cct.2011.09.009 Bassuk, 2016, Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL), Contemp Clin Trials, 47, 235, 10.1016/j.cct.2015.12.022 Moe, 2015, Cinacalcet, fibroblast growth factor-23, and cardiovascular disease in hemodialysis: the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, Circulation, 132, 27, 10.1161/CIRCULATIONAHA.114.013876 Sprague, 2015, Effect of cinacalcet and vitamin D analogs on fibroblast growth factor-23 during the treatment of secondary hyperparathyroidism, Clin J Am Soc Nephrol, 10, 1021, 10.2215/CJN.03270314 Wetmore, 2010, Effects of cinacalcet and concurrent low-dose vitamin D on FGF23 levels in ESRD, Clin J Am Soc Nephrol, 5, 110, 10.2215/CJN.03630509 May, 1981, The randomized clinical trial: bias in analysis, Circulation, 64, 669, 10.1161/01.CIR.64.4.669 Fishbane, 2008, Cinacalcet HCl and concurrent low-dose vitamin D improves treatment of secondary hyperparathyroidism in dialysis patients compared with vitamin D alone: the ACHIEVE study results, Clin J Am Soc Nephrol, 3, 1718, 10.2215/CJN.01040308 Block, 2008, Combined therapy with cinacalcet and low doses of vitamin D sterols in patients with moderate to severe secondary hyperparathyroidism, Nephrol Dial Transplant, 23, 2311, 10.1093/ndt/gfn026 Moe, 2017, Calcium-sensing receptor genotype and response to cinacalcet in patients undergoing hemodialysis, Clin J Am Soc Nephrol, 12, 1128, 10.2215/CJN.11141016 Ix, 2014, Effect of dietary phosphate intake on the circadian rhythm of serum phosphate concentrations in chronic kidney disease: a crossover study, Am J Clin Nutr, 100, 1392, 10.3945/ajcn.114.085498 Jukic, 2018, Measurement of vitamin D for epidemiologic and clinical research: shining light on a complex decision, Am J Epidemiol, 187, 879, 10.1093/aje/kwx297 Smith, 2013, Method-specific differences in plasma fibroblast growth factor 23 measurement using four commercial ELISAs, Clin Chem Lab Med, 51, 1971, 10.1515/cclm-2013-0208 Cantor, 2006, Lack of comparability of intact parathyroid hormone measurements among commercial assays for end-stage renal disease patients: implication for treatment decisions, Clin Chem, 52, 1771, 10.1373/clinchem.2006.071589 Binkley, 2014, Standardizing vitamin D assays: the way forward, J Bone Miner Res, 29, 1709, 10.1002/jbmr.2252 Sturgeon, 2017, Perspective and priorities for improvement of parathyroid hormone (PTH) measurement - a view from the IFCC Working Group for PTH, Clin Chim Acta, 467, 42, 10.1016/j.cca.2016.10.016