Hyperphosphatemia of chronic kidney disease.

Observational studies have determined hyperphosphatemia to be a cardiovascular risk factor in chronic kidney disease. Mechanistic studies have elucidated that hyperphosphatemia is a direct stimulus to vascular calcification, which is one cause of morbid cardiovascular events contributing to the excess mortality of chronic kidney disease. This review describes the pathobiology of hyperphosphatemia that develops as a consequence of positive phosphate balance in chronic kidney disease and the mechanisms by which hyperphosphatemia acts on neointimal vascular cells that are stimulated to mineralize in chronic kidney disease. The characterization of hyperphosphatemia of chronic kidney disease as a distinct syndrome in clinical medicine with unique disordered skeletal remodeling, heterotopic mineralization and cardiovascular morbidity is presented.

[1]  M. Rué,et al.  Mineral metabolism parameters throughout chronic kidney disease stages 1-5--achievement of K/DOQI target ranges. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[2]  R. Foley,et al.  Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. , 2005, Journal of the American Society of Nephrology : JASN.

[3]  K. Watson,et al.  Bone morphogenetic protein expression in human atherosclerotic lesions. , 1993, The Journal of clinical investigation.

[4]  C. Stehman-Breen.  Bone Mineral Density Measurements in Dialysis Patients , 2001, Seminars in dialysis.

[5]  Michael Pignone,et al.  Using the coronary artery calcium score to predict coronary heart disease events: a systematic review and meta-analysis. , 2004, Archives of internal medicine.

[6]  R. Virmani,et al.  Decorin Promotes Aortic Smooth Muscle Cell Calcification and Colocalizes to Calcified Regions in Human Atherosclerotic Lesions , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[7]  L. Calvi,et al.  The interplay of osteogenesis and hematopoiesis , 2004, The Journal of cell biology.

[8]  Y. Fukui,et al.  Effects of dietary Pi on the renal Na+-dependent Pi transporter NaPi-2 in thyroparathyroidectomized rats. , 1998, The Biochemical journal.

[9]  P. Geusens,et al.  Differential Expression of Bone Matrix Regulatory Proteins in Human Atherosclerotic Plaques , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[10]  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.

[11]  J. Silver,et al.  Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D. , 1995, The Journal of clinical investigation.

[12]  Jason R. Stubbs,et al.  Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. , 2006, Journal of the American Society of Nephrology : JASN.

[13]  S. Ott,et al.  Osteoporosis in chronic kidney disease. , 2004, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[14]  E. Slatopolsky,et al.  Phosphorus accelerates the development of parathyroid hyperplasia and secondary hyperparathyroidism in rats with renal failure. , 1996, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[15]  L. Chaudhary,et al.  Differential growth factor control of bone formation through osteoprogenitor differentiation. , 2004, Bone.

[16]  D. Sherrard,et al.  Aplastic osteodystrophy without aluminum: the role of "suppressed" parathyroid function. , 1993, Kidney international.

[17]  K. Hruska,et al.  Low turnover osteodystrophy and vascular calcification are amenable to skeletal anabolism in an animal model of chronic kidney disease and the metabolic syndrome. , 2005, Journal of the American Society of Nephrology : JASN.

[18]  M. Razzaque,et al.  Premature aging‐like phenotype in fibroblast growth factor 23 null mice is a vitamin D‐mediated process , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  Alex J. Brown,et al.  FGF-23 and sFRP-4 in Chronic Kidney Disease and Post-Renal Transplantation , 2006, Nephron Physiology.

[20]  L. Demer.  A skeleton in the atherosclerosis closet. , 1995, Circulation.

[21]  D. Miao,et al.  Inactivation of the 25-Hydroxyvitamin D 1α-Hydroxylase and Vitamin D Receptor Demonstrates Independent and Interdependent Effects of Calcium and Vitamin D on Skeletal and Mineral Homeostasis* , 2004, Journal of Biological Chemistry.

[22]  A. Dusso,et al.  A novel mechanism for skeletal resistance in uremia. , 2000, Kidney international.

[23]  L. Chaudhary,et al.  The mechanism of phosphorus as a cardiovascular risk factor in CKD. , 2008, Journal of the American Society of Nephrology : JASN.

[24]  G. London,et al.  Association of hyperphosphataemia with haemodynamic disturbances in end-stage renal disease. , 1999, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[25]  K. White,et al.  A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. , 2007, The Journal of clinical investigation.

[26]  G. Beck.  Inorganic phosphate as a signaling molecule in osteoblast differentiation , 2003, Journal of cellular biochemistry.

[27]  Y. Bogaert,et al.  Characterization of Phosphate Transport in Rat Vascular Smooth Muscle Cells: Implications for Vascular Calcification , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[28]  G. Segre,et al.  Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy. , 1994, Kidney international.

[29]  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.

[30]  M. Traebert,et al.  Regulation of small intestinal Na-Pi type IIb cotransporter by dietary phosphate intake. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[31]  G. Segre,et al.  Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD. , 1994, Kidney international.

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

[33]  H. Mayan,et al.  Pseudohypoaldosteronism type II: marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density. , 2002, The Journal of clinical endocrinology and metabolism.

[34]  H. Takagi,et al.  Clonal Analysis of Nodular Parathyroid Hyperplasia in Renal Hyperparathyroidism , 1996, World Journal of Surgery.

[35]  J. Silver,et al.  The Effects of Calcium, Phosphate, and Vitamin D , 1995 .

[36]  P. Weissberg,et al.  High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. , 1994, The Journal of clinical investigation.

[37]  H. Murer,et al.  Phosphate transporters: a tale of two solute carrier families. , 2007, American journal of physiology. Renal physiology.

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

[39]  D. Arking,et al.  KLOTHO allele status and the risk of early-onset occult coronary artery disease. , 2003, American journal of human genetics.

[40]  P. Eskildsen,et al.  Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. , 1999, Kidney international.

[41]  I. Mian,et al.  Association of human aging with a functional variant of klotho , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[42]  K. Kurokawa,et al.  Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. , 1993, The Journal of clinical investigation.

[43]  M. Mohammadi,et al.  The parathyroid is a target organ for FGF23 in rats. , 2007, The Journal of clinical investigation.

[44]  M. Coco,et al.  Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone. , 2000, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[45]  M. McKee,et al.  Phosphate regulation of vascular smooth muscle cell calcification. , 2000, Circulation research.

[46]  K. Miyamoto,et al.  Physiological regulation of renal sodium-dependent phosphate cotransporters. , 2004, The Japanese journal of physiology.

[47]  D. Scadden,et al.  Osteoblastic cells regulate the haematopoietic stem cell niche , 2003, Nature.

[48]  C. Stehman-Breen.  Osteoporosis and chronic kidney disease. , 2004, Seminars in nephrology.

[49]  Haiyang Huang,et al.  Identification of the haematopoietic stem cell niche and control of the niche size , 2003, Nature.

[50]  P. Raggi,et al.  Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease? , 2002, Journal of the American College of Cardiology.

[51]  M. Levi,et al.  Molecular Regulation of Renal Phosphate Transport , 1996, The Journal of Membrane Biology.

[52]  W. Goodman,et al.  Implications of intermittent calcitriol therapy on growth and secondary hyperparathyroidism , 2000, Pediatric Nephrology.

[53]  Xianwu Li,et al.  Role of the Sodium-Dependent Phosphate Cotransporter, Pit-1, in Vascular Smooth Muscle Cell Calcification , 2006, Circulation research.

[54]  P. Raggi,et al.  Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. , 2007, Kidney international.

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

[56]  M. Razzaque,et al.  Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. , 2004, Matrix biology : journal of the International Society for Matrix Biology.

[57]  A. Robson,et al.  Control of phosphate excretion in uremic man. , 1968, The Journal of clinical investigation.

[58]  E. Moran,et al.  Phosphate is a specific signal for induction of osteopontin gene expression. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[59]  H. Murer,et al.  Regulation of Na/Pi transporter in the proximal tubule. , 2003, Annual review of physiology.

[60]  R. Detrano,et al.  Coronary artery calcification and myocardial perfusion in asymptomatic adults: the MESA (Multi-Ethnic Study of Atherosclerosis). , 2006, Journal of the American College of Cardiology.

[61]  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.

[62]  N. Bricker,et al.  The control of phosphate excretion in uremia. , 1966, The Journal of clinical investigation.

[63]  N. Chen,et al.  Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels. , 2003, Kidney international.

[64]  Craig S. Wong,et al.  Increased risk of hip fracture among patients with end-stage renal disease. , 2000, Kidney international.

[65]  K. Hruska,et al.  BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure. , 2003, Journal of the American Society of Nephrology : JASN.

[66]  Bertram L Kasiske,et al.  Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. , 2003, Hypertension.

[67]  Jason R. Stubbs,et al.  Role of hyperphosphatemia and 1,25-dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. , 2007, Journal of the American Society of Nephrology : JASN.

[68]  K. Hruska,et al.  New insights into mineral and skeletal regulation by active forms of vitamin D. , 2006, Kidney international.

[69]  J. Aubin,et al.  Mesenchymal progenitor self-renewal deficiency leads to age-dependent osteoporosis in Sca-1/Ly-6A null mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[70]  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.

[71]  T. Latifi,et al.  Diet-induced Diabetes Activates an Osteogenic Gene Regulatory Program in the Aortas of Low Density Lipoprotein Receptor-deficient Mice* , 1998, The Journal of Biological Chemistry.

[72]  H. DeLuca,et al.  Metabolism and excretion of 3H-1,25-(OH)2-vitamin D3 in healthy adults. , 1978, The Journal of clinical endocrinology and metabolism.

[73]  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.

[74]  Mei Wang,et al.  Relationship between intact 1-84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity. , 1995, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[75]  Xianwu Li,et al.  BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells. , 2008, Atherosclerosis.

[76]  K. Rosenblatt,et al.  Regulation of Fibroblast Growth Factor-23 Signaling by Klotho* , 2006, Journal of Biological Chemistry.

[77]  C. Stehman-Breen,et al.  Racial differences in bone mineral density and bone loss among end-stage renal disease patients. , 1999, American journal of kidney diseases : the official journal of the National Kidney Foundation.