Effects of Phosphate Binder Therapy on Vascular Stiffness in Early-Stage Chronic Kidney Disease

Background/Aims: Cardiovascular disease (CVD) is increased in chronic kidney disease (CKD), and contributed to by the CKD-mineral bone disorder (CKD-MBD). CKD-MBD begins in early CKD and its vascular manifestations begin with vascular stiffness proceeding to increased carotid artery intima-media thickness (cIMT) and vascular calcification (VC). Phosphorus is associated with this progression and is considered a CVD risk factor in CKD. We hypothesized that modifying phosphorus balance with lanthanum carbonate (LaCO3) in early CKD would not produce hypophosphatemia and may affect vascular manifestations of CKD-MBD. Methods: We randomized 38 subjects with normophosphatemic stage 3 CKD to a fixed dose of LaCO3 or matching placebo without adjusting dietary phosphorus in a 12-month randomized, double-blind, pilot and feasibility study. The primary outcome was the change in serum phosphorus. Secondary outcomes were changes in measures of phosphate homeostasis and vascular stiffness assessed by carotid-femoral pulse wave velocity (PWV), cIMT and VC over 12 months. Results: There were no statistically significant differences between LaCO3 and placebo with respect to the change in serum phosphorus, urinary phosphorus, tubular reabsorption of phosphorus, PWV, cIMT, or VC. Biomarkers of the early CKD-MBD such as plasma fibroblast growth factor-23, Dickkopf-related protein 1 (DKK1), and sclerostin were increased 2- to 3-fold at baseline, but were not affected by LaCO3. Conclusion: Twelve months of LaCO3 had no effect on serum phosphorus and did not alter phosphate homeostasis, PWV, cIMT, VC, or biomarkers of CKD-MBD.

[1]  K. Hruska,et al.  Early chronic kidney disease-mineral bone disorder stimulates vascular calcification , 2013, Kidney international.

[2]  G. McCabe,et al.  Oral calcium carbonate affects calcium but not phosphorus balance in stage 3–4 chronic kidney disease , 2012, Kidney international.

[3]  P. Dechow,et al.  Repression of osteocyte Wnt/β‐catenin signaling is an early event in the progression of renal osteodystrophy , 2012, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[4]  B. Kestenbaum,et al.  Effects of phosphate binders in moderate CKD. , 2012, Journal of the American Society of Nephrology : JASN.

[5]  H. Brenner,et al.  Calcium, phosphate and the risk of cardiovascular events and all-cause mortality in a population with stable coronary heart disease , 2012, Heart.

[6]  C. Zoccali,et al.  Comparison of calcium acetate and sevelamer on vascular function and fibroblast growth factor 23 in CKD patients: a randomized clinical trial. , 2012, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[7]  A. Go,et al.  FGF23 induces left ventricular hypertrophy. , 2011, The Journal of clinical investigation.

[8]  C. Shanahan,et al.  Arterial Calcification in Chronic Kidney Disease: Key Roles for Calcium and Phosphate , 2011, Circulation research.

[9]  S. Sardiwal Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease – a systemic review and meta-analysis , 2011 .

[10]  A. Ortiz,et al.  Lanthanum carbonate reduces FGF23 in chronic kidney disease Stage 3 patients. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[11]  Huiliang Xie,et al.  Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. , 2011, Kidney international.

[12]  M. Wolf,et al.  Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. , 2011, Journal of the American Society of Nephrology : JASN.

[13]  A. Branscum,et al.  Sclerostin and Dickkopf-1 in renal osteodystrophy. , 2011, Clinical journal of the American Society of Nephrology : CJASN.

[14]  A. Hayen,et al.  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. , 2011, JAMA.

[15]  M. Wolf,et al.  Pilot study of dietary phosphorus restriction and phosphorus binders to target fibroblast growth factor 23 in patients with chronic kidney disease. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[16]  A. Bierhals,et al.  Effects of Sodium Thiosulfate on Vascular Calcification in End-Stage Renal Disease: A Pilot Study of Feasibility, Safety and Efficacy , 2011, American Journal of Nephrology.

[17]  Yasmin,et al.  Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’ , 2010, European heart journal.

[18]  S. Cummings,et al.  Serum phosphorus levels and the spectrum of ankle-brachial index in older men: the Osteoporotic Fractures in Men (MrOS) study. , 2010, American journal of epidemiology.

[19]  M. Shlipak,et al.  Fibroblast growth factor-23 and early decrements in kidney function: the Heart and Soul Study. , 2010, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[20]  V. Jorgetti,et al.  Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[21]  R. Pereira,et al.  Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease. , 2009, Bone.

[22]  B. Kestenbaum,et al.  A randomized double‐blind pilot study of serum phosphorus normalization in chronic kidney disease: A new paradigm for clinical outcomes studies in nephrology , 2009, Hemodialysis international. International Symposium on Home Hemodialysis.

[23]  K. K. Quan,et al.  Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin. , 2009, Kidney international.

[24]  B. Kestenbaum,et al.  Serum phosphorus concentrations and arterial stiffness among individuals with normal kidney function to moderate kidney disease in MESA. , 2009, Clinical journal of the American Society of Nephrology : CJASN.

[25]  B. Kestenbaum,et al.  Association of serum phosphate with vascular and valvular calcification in moderate CKD. , 2009, Journal of the American Society of Nephrology : JASN.

[26]  R. Foley,et al.  Serum phosphorus levels associate with coronary atherosclerosis in young adults. , 2009, Journal of the American Society of Nephrology : JASN.

[27]  F. Flachskampf,et al.  Recommendations for the evaluation of left ventricular diastolic function by echocardiography. , 2008, European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology.

[28]  J. Mourad Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. , 2008 .

[29]  Christopher B. Kendall,et al.  Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. , 2008, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[30]  Sharon M Moe,et al.  Mechanisms of vascular calcification in chronic kidney disease. , 2008, Journal of the American Society of Nephrology : JASN.

[31]  J. Coresh,et al.  Prevalence of chronic kidney disease in the United States. , 2007, JAMA.

[32]  R. D'Agostino,et al.  Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. , 2007, Archives of internal medicine.

[33]  G. Eknoyan,et al.  Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). , 2006, Kidney international.

[34]  M. Pfeffer,et al.  Relation Between Serum Phosphate Level and Cardiovascular Event Rate in People With Coronary Disease , 2005, Circulation.

[35]  Michael F O'Rourke,et al.  An updated clinical primer on large artery mechanics: implications of pulse waveform analysis and arterial tonometry , 2005, Current opinion in cardiology.

[36]  B. Kestenbaum,et al.  Serum phosphate levels and mortality risk among people with chronic kidney disease. , 2005, Journal of the American Society of Nephrology : JASN.

[37]  A. Murray,et al.  Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. , 2005, Journal of the American Society of Nephrology : JASN.

[38]  Charles E McCulloch,et al.  Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. , 2004, The New England journal of medicine.

[39]  A. Levin,et al.  Vascular calcification in chronic kidney disease. , 2004, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[40]  G. London,et al.  Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. , 2003, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[41]  M. O'Rourke,et al.  Prospective Evaluation of a Method for Estimating Ascending Aortic Pressure From the Radial Artery Pressure Waveform , 2001, Hypertension.

[42]  K. Hruska,et al.  Pathophysiological mechanisms of vascular calcification in end-stage renal disease. , 2001, Kidney international.

[43]  J. Staessen,et al.  Non-invasive assessment of local arterial pulse pressure: comparison of applanation tonometry and echo-tracking , 2001, Journal of hypertension.

[44]  D. Levy,et al.  Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. , 1999, Kidney international.

[45]  J. Blacher,et al.  Impact of aortic stiffness on survival in end-stage renal disease. , 1999, Circulation.

[46]  A. Levey,et al.  A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation , 1999, Annals of Internal Medicine.

[47]  D. Webb,et al.  Reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysis , 1998, Journal of hypertension.

[48]  R. Foley,et al.  Clinical epidemiology of cardiovascular disease in chronic renal disease. , 1998, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[49]  F. Port,et al.  Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. , 1998, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[50]  M. O'Rourke,et al.  Pulse wave analysis. , 1996, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[51]  S. Daniels,et al.  Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. , 1992, Journal of the American College of Cardiology.

[52]  R. Detrano,et al.  Quantification of coronary artery calcium using ultrafast computed tomography. , 1990, Journal of the American College of Cardiology.

[53]  O. Djurdjev,et al.  Responsiveness of FGF-23 and mineral metabolism to altered dietary phosphate intake in chronic kidney disease (CKD): results of a randomized trial. , 2013, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[54]  K. Hruska,et al.  Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy. , 2007, Journal of the American Society of Nephrology : JASN.