Phosphate Is a Uremic Toxin

Phosphate Is a Uremic Toxin

Phosphate Is a Uremic Toxin Steven K. Burke, MD Hyperphosphatemia is one of the more prevalent metabolic disturbances in kidney failure. Phosphate can...

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Phosphate Is a Uremic Toxin Steven K. Burke, MD Hyperphosphatemia is one of the more prevalent metabolic disturbances in kidney failure. Phosphate can be considered a uremic toxin based on the accumulation of phosphate during chronic kidney disease, the effects of phosphate on biological systems, and the adverse effects of hyperphosphatemia. The renal clearance of phosphate is maintained until later stages of chronic kidney disease, when the remaining nephrons are no longer able to excrete sufficient phosphate to offset dietary phosphate absorption. Clearance of phosphate by conventional forms of dialysis is insufficient to prevent hyperphosphatemia in most endstage kidney-disease patients. Phosphate contributes to metabolic disturbances such as hyperparathyroidism, vitamin D resistance, and hypocalemia. In combination with these and other factors, hyperphosphatemia damages many organs, including the parathyroid glands, bones, and most importantly the cardiovascular system. Elevated phosphorus is associated with arterial and valvular calcification, arteriosclerosis, and an increased risk of cardiovascular death. Importantly, the adverse effects of hyperphosphatemia are partially preventable with the effective treatments available today. Ó 2008 by the National Kidney Foundation, Inc.

Phosphate Metabolism in Health

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NORGANIC PHOSPHORUS EXISTS in food, blood, and living tissues as phosphate compounds.1 However, most analytic techniques measure inorganic phosphorus as opposed to phosphate. Phosphate is abundant in dairy and highprotein foods. In regard to ingested phosphate, about 70% is absorbed through the gastrointestinal tract by passive and active mechanisms, partly under the control of calcitriol (1,25-dihydroxyvitamin D).1,2 Absorbed phosphate is excreted by the kidneys. The rate of phosphate excretion is controlled by variations in the tubular reabsorption of filtered phosphate, partly under the control of parathyroid hormone (PTH) and fibroblast growth factor (FGF)-23.2,3 Total body phosphate is approximately 700 g in a 70-kg human. Of this 700 g, approximately 85% is in bone, 14% is in soft tissue, and the remaining 1% is in extracellular fluids.1,2 Bone phosphate exists as insoluble calcium precipitates of hydroxyapatite, formed around a collagen matrix, that give bone its hardness. Bone calcium and phosphate serve as a reserve that can be mobilized through resorption of bone when dietary calcium or phosphate is deficient. Bone resorption by osteoclasts is stimulated by PTH.2,3 Proteon Therapeutics, Waltham, Massachusetts. Address reprint requests to Steven K. Burke, MD, Proteon Therapeutics, 200 West St., Waltham, MA 02451. E-mail: sburke@

proteontherapeutics.com 2008 by the National Kidney Foundation, Inc. 1051-2276/08/1801-0006$34.00/0 doi:10.1053/j.jrn.2007.10.007

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Journal of Renal Nutrition, Vol 18, No 1 (January), 2008: pp 27–32

In addition to a structural role in bone, phosphate is essential in a wide range of biological processes, including membrane fluidity, energy production and storage, chemical synthesis, cellsignaling, protein function, and neucleic acid synthesis. As a result of these diverse roles, there exist in the body a large number of phosphatases, kinases, and cyclases that act upon phosphate. Acute phosphate deficiency leads to anorexia, dizziness, bone pain, proximal muscle weakness, myopathy, and hemolytic anemia.4–6 Chronic hypophosphatemia may cause reduced cardiac function, insulin resistance and other features of metabolic syndrome, short stature, decreased bone mineralization and fractures, and an increased risk of mortality in kidney disease.5 Acute phosphate excess, although rare, can result in renal failure, hypocalcemia, and hypotension.5 Chronic phosphate excess is associated with a number of metabolic disturbances that will be discussed in the present review. Hyperphosphatemia, the elevation of serum phosphorus (phosphate), is most commonly caused by a decrease in kidney function. Phosphate accumulation in chronic kidney disease (CKD) has a number of effects on biological systems that result in adverse effects such as hyperparathyroidism and arterial calcification.

Serum Phosphate Concentration Increases in Kidney Disease Hyperphosphatemia as a consequence of CKD has been recognized for many years, and can be reproduced in CKD models in which the diet is 27

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supplemented with phosphate.7,8 In these models, animals develop hyperphosphatemia, hyperparathyroidism, accelerated bone turnover, and arterial calcification, which can be prevented or reversed by low-phosphate diets or phosphate binders.7–11 Disturbance in phosphate metabolism starts early in kidney disease, but overt hyperphosphatemia does not develop until the later stages of CKD. As the glomerular filtration rate (GFR) falls, there is a kidney adaptation characterized by a decline in the tubular reabsorption of phosphate, which increases the rate of phosphaturia in residual nephrons. This adaptation is mediated in part by an increase in PTH and FGF-23 that maintains normal or low serum phosphate in the earlier stages of CKD.2,3,12 Parathyroid hormone also stimulates osteoclasts to reabsorb bone, including hydroxyapatite, thereby liberating calcium, phosphate, magnesium, and bicarbonate in the process. Thus PTH corrects hypocalcemia while promoting the excretion of phosphate. After GFR falls to ,25% of normal, the residual nephrons are no longer able to increase phosphaturia, and hyperphosphatemia ensues. At this stage, elevated PTH exacerbates hyperphosphatemia by moving bone phosphate into the blood.

Phosphate Contributes to Hyperparathyroidism Experiments using partial nephrectomy in dogs demonstrated an inverse relationship between GFR and serum PTH and parathyroid-gland size. This hyperparathyroidism was preventable with a proportional decrease in dietary phosphate intake. However, once hyperparathyroidism was established, switching to a low-phosphate diet only partially normalized gland size, indicative of permanent hypertrophy or hyperplasia.7,8,13 The last 35 years of research have elucidated many of the cellular and molecular mechanisms involved in this process, and clarified the critical role of phosphate. In vitro studies of intact parathyroid glands demonstrated a direct effect of phosphate concentration on parathyroid hormone secretion, independent of calcium and vitamin D.14 This was subsequently determined to be mediated through the stabilization of PTH messenger RNA and increased PTH gene transcription.15 In addition, phosphate induces parathyroid-cell proliferation in part through its suppression of p21, an inhibitor

of cell-cycle progression, and through induction of transforming growth factor alpha (TGFa) and its ligand epidermal growth factor receptor (EGFR), a cell-cycle promoter. High phosphate promotes parathyroid cell proliferation and gland hyperplasia, whereas low phosphate suppresses them.16 In patients with CKD, there is an increasing prevalence of hyperparathyroidism through the stages of GFR loss.16–18 Consistent with animal studies, the elevation of serum phosphate concentration in patients is associated with hyperparathyroidism and hyperplasia.2 Lowering intestinal phosphate absorption via a dietary restriction of phosphate intake can prevent or treat the development of hyperparathyroidism in CKD patients.12,19–23 Several interrelated mechanisms are responsible. Lowering phosphate absorption has a direct inhibitory effect on PTH secretion, independent of changes in calcium or calcitriol, and normalizes the calcemic response of bones to PTH.13,24 Lowering phosphate absorption also produces a rise in serum calcitriol in mild or moderate renal-failure patients.12,25 Calcitriol enhances the gastrointestinal absorption of calcium, raises the level of serum calcium toward normal,25,26 increases the parathyroid glands’ sensitivity to inhibition by serum calcium,27 corrects the blunted calcemic response of bones to PTH in renal failure,25,28 and decreases PTH synthesis by a direct effect on PTH gene transcription.15

Bone Disease Persistent hyperparathyroidism causes the bone disease osteitis fibrosa, also referred to as ‘‘highturnover bone disease.’’ Parathyroid hormone normally stimulates bone resorption by osteoclasts with the release of calcium and phosphate into the blood, and increases calcitriol synthesis by the kidneys. These actions, coupled with the ability of PTH to induce phosphaturia, allow the parathyroid glands to regulate serum phosphate and calcium concentrations within a narrow range. However, an excessive elevation of PTH, as seen in secondary hyperparathyroidism, can cause an abnormal increase in osteoclast function, with deleterious consequences for bones.29 Evidence of bone disease appears relatively early in renal failure, with histological changes occurring at GFRs of ,50 mL/min 3 1.73 m2.30 Elevated

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PTH increases osteoclast activity, and induces cell proliferation and hypertrophy. Resorption lacunae increase in size, and bone resorption is accelerated.30 This expansion of osteoclasts induces a parallel increase in osteoblasts that produces new osteoid. Woven osteoid is increased. Woven osteoid, unlike normal lamellar osteoid, is a haphazard arrangement of collagen fibers that promotes the formation of amorphous calcium-phosphate mineralization rather than normal hydroxyapatite crystals. The resulting bone is mechanically poor and more susceptible to fracture. Fortunately, a reduction in dietary phosphate absorption, phosphate binders, vitamin D, and calcimimetics can prevent or treat secondary hyperparathyroidism and osteitis fibrosa. Treatment has been so effective that parathyroidectomies and fractures have become less common,31 and abnormally low bone turnover is now as common as high-turnover bone disease.32

Hyperphosphatemia Promotes Vascular Calcification Hyperphosphatemia also increases the risk of developing metastatic calcification, i.e., the deposition of calcium-phosphate precipitates in soft tissues such as arteries.33 Arterial calcification occurs in nondialyzed, hemodialyzed, and peritoneal dialyzed kidney-disease patients.34–37 The risk of metastatic calcification increases with increasing age, number of years on dialysis, serum phosphorus, serum calcium, and calcium-phosphorus product,35,37,38 and with the use of calcium-based phosphate binders.37–40 Calcification, once present, appears to increase at a rapid rate, and is not reversible in a meaningful way.34,37,41,42 Microscopic examination of calcified blood vessels reveals structures resembling bone. Experimental data, using cultured vascular smooth muscle cells, support the concept that hyperphosphatemia promotes calcification of the arteries.43,44 The effect of phosphate is mediated in part by a sodium-dependent phosphate cotransporter, Pit-1, that transports phosphate into the cell.43 This transporter is increased in the setting of high serum calcium.45 The smooth muscle cell uptake of phosphate changes the cell’s phenotype to an osteoblasticlike cell capable of secreting calcifiable extracellular matrix, matrix vesicles, and apoptotic bodies that comprise the nidus for calcification.44,46 Deficiencies of circulating inhibitors of calcification,

such as fetuin A (alpha2-Heremans Schmid glycoprotein) and matrix Gla protein, also appear to modulate vascular calcification.47,48

Arterial Disease The majority of published data suggest that arterial calcification has a negative prognostic significance for CKD patients. Arterial calcification is thought to cause arterial disease by stiffening the arterial wall, leading to arterial dilation and hypertrophy, increasing systolic pressure, reducing diastolic pressure, and increasing pulse pressure. These changes increase the left-ventricular afterload and reduce coronary perfusion.49 Much of this work behind these findings was conducted by Blacher et al.50 and Guerin et al.,51 using ultrasound-based methods. They demonstrated that the severity of calcification, as determined by the presence or absence of calcification at four sites (the carotid artery, abdominal aorta, ileofemoral axis, and legs), was associated with an arterial stiffening that alters left-ventricular cardiovascular function and increases the risk of death.50,51 Calcification can occur in either the intima in association with atherosclerotic plaque, or in the media in association with the elastic lamina. On plain-film radiographs, intimal calcification is seen as discrete, irregular, and patchy arterial calcifications, and medial calcification is seen as uniform, linear, railroad track-type calcifications. Both forms of calcification were associated with low diastolic pressure, increased pulse pressure, arterial dilation, arterial stiffening, and an increased relative risk of mortality.39 Quantitative measurement of arterial calcification, using fast computed-tomography (CT) scans, confirmed that the presence of arterial calcification is a predictor of mortality in dialysis patients.52 Simpler semiquantitative radiographic scores correlate well with results obtained with CT scans, and could replace the more expensive detection method.53,54

Mortality Multiple investigators established a strong association between hyperphosphatemia and an increased risk of all-cause and of cardiovascular mortality.31,55–58 In one analysis, the risk of death increased with serum phosphorus above the referent range of 4 to 5 mg/dL. Serum phosphorus below the reference range was associated with

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a reduced risk of death. The risk of death also increased with increasing serum calcium.31 Similar results were obtained in other analyses. The current consensus is that phosphate is associated with increased mortality primarily because of arterial calcification (discussed in Arterial Disease, above), which causes damage foremost by stiffening large arteries, leading to arterial dilation and hypertrophy, increasing systolic pressure and pulse pressure, and reducing diastolic pressure. These changes increase the left-ventricular afterload and reduce coronary perfusion.50,59 However, other mechanisms may be operative.

Treatment of Elevated Serum Phosphate Concentration Diet, dialysis, and phosphate binders are crucial in the prevention and treatment of hyperphosphatemia. Lowering dietary phosphate intake is typically achieved by the avoidance of dairy products and by limiting protein intake. Malnutrition frequently occurs in dialysis patients, and is associated with greater mortality.60 Therefore, the benefits of the dietary restriction of phosphate must be weighed against the adverse consequences of malnutrition. Dialysis clears phosphate that has been absorbed from the diet. The slow movement of phosphate from the tissues limits phosphate clearance with conventional forms of dialysis.61 As a result of these limitations, almost all dialysis patients require some form of phosphate-binder therapy. However, nocturnal dialysis (every night) is very effective in lowering serum phosphate levels. Lowering serum phosphorus should decrease the toxicity associated with hyperphosphatemia. Changes in diet or the prescription of binders can decrease PTH.12 Maintaining serum phosphorus in dialysis patients below the KDOQI target of 5.5 mg/dL may lessen the progression of arterial calcification.38 Because there is limited evidence that calcification is reversible, prevention should be the goal. Even with current therapies, a substantial percentage of patients undergoing hemodialysis have serum phosphorus concentrations greater than the recommended 5.5 mg/dL, and these higher levels are associated with increased mortality.31,38,57 No placebo-controlled outcomes studies will ever be conducted in stage 5 CKD patients. We can only assume that untreated patients would

develop severe hyperparathyroidism, bone disease, arterial calcification, cardiovascular events, and mortality. The best data concerning the effects of treatment on clinical outcomes are from comparative studies of different phosphate binders. The Treat-to-Goal Study40 in prevalent hemodialysis patients and the Renagel in New Dialysis Patients (RIND) Study62 in incident hemodialysis dialysis showed less arterial calcification progression in sevelamer versus the calciumbased treatment of patients. In the RIND Study, this reduction in calcification was associated with better survival.52 The Dialysis Clinical Outcomes Revisited (DCOR) Trial, which compared clinical outcomes in calcium-treated and sevelamer-treated prevalent dialysis patients, did not show an overall survival benefit, but did show better survival in older dialysis patients, especially with prolonged adherence to the assigned therapy.63 These differences between calcium and sevelamer were evident despite very similar phosphorus control, suggesting that other factors, such as serum calcium, calcium load, PTH level, or bone turnover, are important.

Conclusion Hyperphosphatemia is a very common metabolic complication of CKD. Elevated phosphate is active in such biological systems as cultured parathyroid glands and vascular smooth muscle cells. High phosphate concentrations lead to clearly defined changes in these cells that are becoming better understood at the molecular level. High phosphate stimulates PTH secretion, cellular hypertrophy, and hyperplasia of the parathyroid glands. Persistent hyperparathyroidism causes bone disease that increases the risk of fractures. High phosphate stimulates phenotypic change in vascular smooth muscle cells, promoting arterial calcification. Arterial calcification alters arterial and cardiac function, and increases the risk of cardiovascular events and death. These effects of phosphate qualify it as a uremic toxin that calls for aggressive treatment.

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52. Block GA, Raggi P, Bellasi A, et al: Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 71:438-441, 2007 53. Raggi P, Bellasi A, Ferramosca E, et al: Association of pulse wave velocity with vascular and valvular calcification in hemodialysis patients. Kidney Int 71:802-807, 2007 54. Adragao T, Pires A, Lucas C, et al: A simple vascular calcification score predicts cardiovascular risk in haemodialysis patients. Nephrol Dial Transplant 19:1480-1488, 2004 55. Young EW, Akiba T, Albert JM, et al: Magnitude and impact of abnormal mineral metabolism in hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 44:34-38, 2004 56. Teng M, Wolf M, Lowrie E, et al: Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 349:446-456, 2003 57. Melamed ML, Eustace JA, Plantinga L, et al: Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: a longitudinal study. Kidney Int 70: 351-357, 2006 58. Block GA, Hulbert-Shearon TE, Levin NW, et al: Association of serum phosphorus and calcium 3 phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31:607-617, 1998 59. Blacher J, Guerin AP, Pannier B, et al: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 99: 2434-2439, 1999 60. Kaysen GA, Muller HG, Young BS, et al: The influence of patient- and facility-specific factors on nutritional status and survival in hemodialysis. J Ren Nutr 14:72-81, 2004 61. Leypoldt JK: Kinetics of beta2-microglobulin and phosphate during hemodialysis: effects of treatment frequency and duration. Semin Dial 18:401-408, 2005 62. Chertow GM, Burke SK, Raggi P: Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 62:245-252, 2002 63. Suki WN, Zabaneh R, Cangiano JL, et al: Effects of sevelamer and calcium-based phosphate binder on mortality in hemodialysis patients. Kidney Int 72:1130-1137, 2007