Mineral metabolism is modulated by

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1 REGULATION OF PHOSPHATE IN HEALTH AND DISEASE * William F. Finn, MD, and Hartmut H. Malluche, MD, FACP ABSTRACT As is true of many physiologically critical systems, metabolism is a highly regulated process. The traditional view of hormonal control of the physicochemical relationship between minerals and tissues has given way to an expanding view of elaborate, active processes that bridge multiple organ systems. The impact of early changes in mineral metabolism that accompany loss of renal function in chronic kidney disease (CKD) may be more important to cardiovascular complications of CKD than previously thought. An understanding of these metabolic processes is critical to treating hypermia and to preventing the serious consequences of this common complication of CKD. (Adv Stud Med. 2007;7(5): ) *This article is based on content from a presentation developed as part of a continuing medical education lecture series, which comprised presentations held in various US cities throughout Professor of Medicine, Division of Nephrology, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Robert G. Luke Chair in Nephrology, Professor of Medicine, Chief, Division of Nephrology, Bone and Mineral Metabolism, Director, General Clinical Research Center, University of Kentucky, Lexington, Kentucky. Address correspondence to: William F. Finn, MD, University of North Carolina at Chapel Hill, 349 McNider, CG #7155, Division of Nephrology and Hypertension, Chapel Hill, NC wffinn@med.unc.edu. Mineral metabolism is modulated by complex neuroendocrine interactions involving multiple organ systems. Calcium and phosphorus homeostasis is maintained through a combination of effects on kidney and bone orchestrated by parathyroid hormone (PTH). 1 In the kidney, PTH modulates calcium and phosphorus reabsorption and excretion. In bone, PTH regulates turnover of these minerals. Serum mineral concentrations reflect dietary intake as well as the actions of PTH, vitamin D, and other hormones. 1,2 In patients with chronic kidney disease (CKD), the progressive loss of renal function is uniformly accompanied by altered mineral metabolism. PTH levels begin to rise as glomerular filtration rate (GFR) decreases to 60 ml/min/1.73 m2. 3 As GFR declines and the intake of dietary phosphorus does not change, the filtered load of phosphorus ultimately also decreases. Increasing secretion of PTH appears to be an adaptive response to the need for increased fractional phosphorous excretion in order to maintain phosphorus balance. Eventually, even a state of hyperparathyroidism and other adaptive mechanisms cannot compensate for loss of kidney function, and serum levels rise beyond the physiologic range. 4 Apart from the effects on PTH secretion and serum calcium levels, the resulting state of hypermia is an independent risk factor for mortality in patients with stage 5 CKD. With less severe forms of renal dysfunction, incremental increases in serum levels even within the generally accepted reference range are associated with cardiovascular events that are, in turn, a major cause of morbidity and mortality in these patients. 5,6 This article will describe the regulation of homeostasis in individuals with normal renal function and the progressive changes in Johns Hopkins Advanced Studies in Medicine 133

2 metabolism that occur in CKD. The correlations between disordered mineral metabolism and cardiovascular risk will also be explained. PHOSPHATE METABOLISM Phosphorus is a multivalent nonmetal of the nitrogen group, with atomic number 15. The alchemist Hennig Brand first identified phosphorus in urine in 1669, a discovery that was immortalized in a painting by Joseph Wright in 1771 entitled, The Alchymist in Search of the Philosophers Stone Discovers Phosphorus. The story of phosphorus is compelling and is well chronicled in John Emsley s book, The Shocking History of Phosphorus: A Biography of the Devil s Element (UK title) or The 13th Element: The Sordid Tale of Murder, Fire, and Phosphorus (US title). 7,8 Phosphorus is one of most abundant elements in the body, accounting for approximately 1% of total body weight. 1 Eighty-five percent of phosphorus is found in bones and teeth, 14% is intracellular, and the remaining 1% is extracellular. 2 Phosphate is continuously in flux between bone and extracellular fluid. 9 Phosphate is a component of an array of biologically active molecules, such as nucleic acids, signaling proteins, phosphorylated enzymes, and cell membranes. All tissues can absorb and secrete to meet tissue demand. 9 Therefore, it is not surprising that maintenance of homeostasis is a complex, highly regulated process (Figure 1). necessarily be considered the normal range. Because individuals with CKD of varying degrees may have been included in the reference population, it is possible that the upper limit for the true normal range (ie, for those without CKD) is below 4.5 mg/dl (<1.45 mmol/l). In addition, the time of measurement is important. In healthy subjects eating 3 meals per day, serum phosphorus levels have been found to decrease in the early morning, reaching a nadir of 3.3 ± 0.3 mg/dl at 11:00 AM, followed by an increase to a plateau at 4:00 PM, and a further increase to a peak of 4.6 ± 0.2 mg/dl between 1:00 AM and 3:00 AM. 12 PHOSPHORUS ABSORPTION The percentage of dietary phosphorus that is absorbed varies with intake. At high levels of intake (>10 mg/kg/d), approximately 70% of the ingested phosphorus is absorbed, whereas at lower levels of intake, as much as 80% to 90% may be absorbed. Net intestinal phosphorus absorption may be somewhat lower in patients with end-stage renal disease (ESRD). 13,14 Phosphorus is absorbed throughout the entire small intestine. 15 In the highly acidic environment of the stomach (ph of 1 3.5), phosphorus exists as the Figure 1. Phosphate Homeostasis PHOSPHORUS INTAKE Dietary phosphorus intake plays an important regulatory role in mineral homeostasis. The recommended daily allowance for phosphorus is 800 mg and is similar to that of calcium. 10 However, the current average daily dietary intake is approaching 1500 mg, in large part because of the use of s as food preservatives. 1,11 Consequently, the desired balanced ratio of dietary calcium to phosphorus is difficult to achieve. In individuals with normal dietary phosphorus intake and renal function, serum levels vary from a peak of approximately 4.6 ± 0.2 mg/dl (1.5 ± 0.1 mmol/l) to a nadir of 3.3 ± 0.3 mg/dl (1.1 ± 0.1 mmol/l), with a fairly predictable circadian rhythm. 2 The generally accepted reference range for adult serum phosphorus levels is 2.5 to 4.6 mg/dl ( mmol/l). However, the reference range should not S Ca S PTH excretion S Ca S PTH Normal serum S Pi excretion S Pi Normal serum 1,25(OH) 2 D 3 synthesis Intestinal phosphorous absorption 1,25(OH) 2 D 3 synthesis Intestinal phosphorous absorption Ca = calcium; Pi = ; PTH = parathyroid hormone; S = serum. Reprinted with permission from Berndt et al. Am J Physiol Physiol. 2005;289:F1170-F Vol. 7, No. 5 May 2007

3 weak acid H 3 PO 4 and the monobasic ion H 2 PO 4 - (ph = 2.1). As the gut becomes progressively less acidic duodenum (ph = 2-6.4), jejunum (ph = 6), and ileum (ph = 7) phosphorus exists in varying proportions as the monobasic ion H 2 PO 4 - and the dibasic ion HPO 4 2- (ph = 6.8). PHOSPHORUS TRANSPORT Intestinal inorganic (Pi) absorption involves 2 separate processes. 16 The first is a paracellular pathway that is a sodium-independent process and operates by passive diffusion down an electrochemical potential gradient. 17 This pathway is most important when the intraluminal concentration of phosphorus is high, as occurs following a meal. The second is a trans-cellular, sodium-dependent, carrier-mediated pathway that involves the type IIb sodium-dependent cotransporter (NaPi-IIb) located on enterocytes. This pathway falls under the control of 1,25-dihydroxyvitamin D 3, dietary phosphorus, and other regulatory signals. 2,18,19 NAPI COTRANSPORTERS In addition to enterocytes lining the intestine, NaPi cotransporters are found in many epithelial cells throughout the body. 11 Three types of NaPi cotransporters have been described based on structural similarities deduced from their amino acid sequence. They differ by their affinity for, distribution in the body, and mechanisms that control their action. 11 The type I NaPi cotransporters (NPT1, NPT3, NPT4) are expressed at the plasma or at the microsomal membranes of the cells in the kidney, the intestine, and the liver. 20 Although they display uptake capacity, they may also transport other anions, and their physiologic role and contribution to renal phosphorus reabsorption remains to be established. 21,22 Members of the type III NaPi cotransporter family (PiT1, PiT2) transport into cells and have high affinity for. 11 Both transporters are widely expressed in tissues. Functional differences exist between PiT1 and PiT2. These cotransporters appear to be important in controlling intracellular content and bone mineralization, and they may be involved in the pathologic calcification of soft tissue. 11 Phosphate uptake through PiT1 appears to be essential for smooth muscle cell calcification, phenotypic modulation, and the induction of osteogenic markers in response to elevated phosphorus levels. 23 The type II NaPi cotransporters (NPT2a, NPT2b, NPT2c) are expressed on different cell types and are differentially regulated. 11 NPT2a cotransporters are the most abundant of the renal NaPi cotransporters. 24 They are expressed on apical domains of renal proximal tubular cells and are responsible for the major portion of renal reabsorption. 11 The NPT2c cotransporters are similar to NPT2a and colocalize with NPT2a in the brush border membrane of renal proximal tubular cells, and may play an important role in the maintenance of phosphorus homeostasis. 25 The NPT2b cotransporters are expressed on the apical domain of enterocytes in the small intestine, lungs, testis, and mammary glands; intestinal expression can be upregulated by calcitriol. 11,26 PHOSPHORUS EXCRETION excretion is dependent on the filtered load of phosphorus and the amount of phosphorus reabsorbed by the renal tubules. 1 The majority of the phosphorus is reabsorbed in the proximal convoluted tubule, with evidence of additional phosphorus reabsorption in the proximal straight tubule and possibly the distal tubule. PTH decreases phosphorus reabsorption at all 3 sites. Ultimately, a steady state is achieved so that the daily excretion usually balances the amount absorbed. 1 As GFR declines, there is a tendency for serum phosphorus concentration to rise, although serum phosphorus levels are generally maintained at less than 4.6 mg/dl until GFR falls below 25 ml/min/1.73 m2. 1 The fact that a persistent increase in serum phosphorus concentration is not observable until late stage 4 or early stage 5 CKD is associated with several interrelated adjustments in PTH secretion and 1,25-dihydroxyvitamin D 3 formation, and in some cases with dietary intake. Further studies are needed to address the role of phosphatonins. The majority of patients with ESRD will eventually develop overt hypermia (ie, serum phosphorus concentration >4.6 mg/dl). 27 Phosphorus homeostasis is maintained through a combination of effects on kidney and bone orchestrated by PTH. 2 The decrease in the filtered load of phosphorus that accompanies decline in GFR is exquisitely balanced by an increase in the fractional excretion of phosphorus by the kidney. This is due to an increase in PTH secretion and its effect on decreasing proximal tubule phospho- Johns Hopkins Advanced Studies in Medicine 135

4 rus reabsorption through its inhibitory action on type IIa NaPi cotransporters. The increase in PTH secretion is influenced both indirectly and directly by serum phosphorus concentration. The indirect effect is a consequence of the reciprocal relationship between serum concentrations of calcium and phosphorus, and the effect of reduced calcium level on the calcium-sensing receptors of the parathyroid gland, facilitating PTH secretion. The direct effect of hypermia on PTH secretion is independent of changes in serum calcium or 1,25- dihydroxyvitamin D 3 levels and is mediated, at least in part, by direct effects on the parathyroid gland itself. 28 EFFECTS OF RENAL DYSFUNCTION ON MINERAL METABOLISM PARATHYROID HORMONE In healthy individuals, when circulating levels of calcium are low, PTH is secreted by the parathyroid gland. It acts on the kidney to increase reabsorption of calcium and to decrease reabsorption of phosphorus. In addition, PTH stimulates renal 1α-hydroxylase, the enzyme that converts vitamin D to its active form, calcitriol. As circulating levels of calcium rise, PTH secretion is inhibited. In this way, PTH contributes to calcium and phosphorus homeostasis. 29 However, a similar compensatory mechanism is activated by loss of renal function. Once renal excretory function declines to a GFR of 60 ml/min/1.73 m2 or below, PTH levels begin to rise. 4 The threshold GFR for compensatory PTH increases may vary from less than 70 ml/min/1.73 m2 to less than 40 ml/min/1.73 m2. In dogs, increases in PTH concentrations appear to be an adaptive response, allowing increased phosphorous excretion by the remaining nephrons. 4 The compensatory rise in PTH results in phosphorus and calcitriol levels returning to the reference range until GFR declines to approximately 25 to 30 ml/min/1.73 m2. Eventually, hypertrophy of parathyroid gland may occur, leading to secondary parathyroidism. The altered mineral metabolism that occurs elicits profound changes in bone turnover that begin long before patients reach stage 5 disease. 4 As CKD progresses, abnormalities in the endocrine function of the kidney appear, including a decline in the level of 1,25-dihydroxyvitamin D 3, which is apparent as early as stage In addition to renal parenchymal injury, elevation of the serum phosphorus concentration directly inhibits 1α-hydroxylase production. The net result is a decrease in intestinal calcium absorption and a further increase in PTH production. Moreover, 25-hydroxyvitamin D deficiency and insufficiency are common in patients with CKD and may influence the coexisting abnormalities in 1,25-dihydroxyvitamin D 3 and PTH (measured as intact PTH) metabolism. 31,32 HYPERPHOSPHATEMIA IN CHRONIC KIDNEY DISEASE In patients with ESRD, elevations in serum phosphorus are associated with increased mortality, 5 even among patients undergoing dialysis 3 times weekly. 33 In patients with CKD but not undergoing dialysis, average serum levels increase slowly with declining renal function until GFR (estimated from deduced urinary clearance of creatinine) falls below 30 ml/min/1.73 m2. 5 At estimated GFR below 30 ml/min/1.73 m2, serum levels increase progressively. Serum levels above 3.5 mg/dl were independently associated with a significantly increased risk of death. 5 Risk of hypermia was also observed in patients with near-normal kidney function. In a posthoc analysis of the Cholesterol and Recurrent Events trial, postmyocardial infarction patients with relatively preserved kidney function were studied. 6 A significant and graded association between baseline serum concentration (ranges of mg/dl) and risk of mortality and cardiovascular events over 5 years were examined. 6 These findings demonstrate that even small increases in serum phosphorus concentrations that fall within or near the normal range in the early stages of kidney disease contribute to cardiovascular risk. Elevated serum is also predictive of poor renal outcomes. In the African American Study of Hypertension and Kidney Disease, 1094 black patients with hypertensive nephrosclerosis (GFR, ml/min/1.73 m2) were studied. 34 At baseline, mean GFR was 46.4 ± 13.6 ml/min/1.73 m2 and serum phosphorus was 3.52 ± 0.56 mg/dl. In this population, the risk of reaching the renal composite outcome of 50% reduction in GFR or a 25- ml/min/1.73 m2 decline in GFR, or the occurrence of ESRD, was significantly associated with elevated levels of serum creatinine, urea nitrogen, and phosphorus. The hazard ratio was 1.09 (95% confidence interval, ) for each 0.3-mg/dL increase in phosphorus Vol. 7, No. 5 May 2007

5 PHOSPHATONINS There are several factors in addition to PTH and vitamin D that are known to influence phosphorus balance. The so-called phosphatonins include fibroblast growth factor (), secreted frizzled-related protein-4, and matrix extracellular phosphoglycoprotein. Of these, is the best characterized, originally identified in a patient with tumor-induced osteomalacia and renal phosphorus wasting. 35 is emerging as a key regulatory factor in homeostasis (Figure 2). 36 This 251-amino acid circulating protein is synthesized in bone by osteoblasts, suppresses reabsorption in renal proximal tubular cells, 37 and decreases 1α,25-dihydroxyvitamin D 3 production in the kidney. 36 Reduced serum concentrations of 25-hydroxyvitamin D 1αhydroxylase are found in transgenic mice with overexpressing, 38 with the opposite being the case in mice with ablation of the gene. 39 In turn, 1α,25-dihydroxyvitamin D 3 stimulates. 36 When is overexpressed, urinary excretion increases and serum levels decrease. These effects are accompanied by a decrease in NPT2a expression. 11,37 levels increase with dietary content. 40,41 Calcitriol causes suppression of PTH as a result of increases in gastrointestinal calcium absorption and directly suppresses PTH production by the parathyroid glands. is hypothesized to be a counterregulatory phosphaturia factor that prevents hypermia in response to calcitriol-mediated increases in gastrointestinal absorption consequent to the loss of PTH-mediated phosphaturia (Figure 3). 36,42 is thought to be a substrate for a membrane-bound metallopeptidase, -regulating gene with homology to endopeptidases on the X chromosome (PHEX), found in bone and teeth but not kidney. PHEX and klotho protein are newly identified regulators of metabolism. 11 KLOTHO GENE The klotho gene was first described in 1997 and named after the mythical Greek Fate, who controlled the length of normal life. Klotho is a membrane protein that is abundantly expressed in the kidney. A unique short-lifespan mouse strain with a single gene mutation was developed that caused multiple agerelated disorders, including arterial calcification. 43 Figure 2. Phosphate Homeostasis Regulated by Kidney FGF = fibroblast growth factor; PHEX = -regulating gene with homology to endopeptidases on the X chromosome; Pi =. Reprinted with permission from Takeda et al. J Cell Mol Med. 2004; 8: Figure 3. Model Depicting the Potential Role of in Mineral Homeostasis A B 5 5 Pi Pi Brush Border Membrane CaP0 4 CaP0 4 Ca +2 1 P0 4 PTH Proxymal Tubule Endocytosis NPT2a,c Protein Transcription NPT2a,c, 1αOHase mrna Ca +2 CaP0 4 CaP0 4 Ca +2 6 P0 4 PTH P0 4 7 Basolateral Membrane P ,25-(OH) 2 D 3 25-OH D PTH actions initiate control of and calcium balance (A). The proposed function of to counterbalance PTH regulation of vitamin D (B). FGF = fibroblast growth factor; PTH = parathyroid hormone. Reprinted with permission from Schiavi. Kidney Int. 2006;69: FGFR1 8 High Pi Inactive Serum levels 1α25(OH) 2 D Pi 1,25-(OH) 2 D 3 Bone PHEX 25-OH D Johns Hopkins Advanced Studies in Medicine 137

6 Klotho null mutant mice (kl-/-) display abnormal calcium and phosphorus homeostasis. 44 As early as 3 weeks of age, elevated levels of serum calcium, phosphorus, and 1,25-dihydroxyvitamin D 3 are observed with ensuing vascular and soft-tissue calcification. Notably, the vascular lesions follow a pattern that resembles Monckeberg s medial calcification. A reduction in 1,25-dihydroxyvitamin D 3 by dietary means results in the alleviation of most phenotypes, including hypermia. 44 The klotho gene appears to be negatively controlled by dietary phosphorus. A lowphosphorus diet promotes growth and prolongs life. 45 CONCLUSIONS Phosphorus homeostasis is regulated by a complex combination of dietary, endocrine, and paracrine factors. New regulatory factors are now being investigated that may improve our understanding and lead to specific therapies for the disordered mineral metabolism of CKD. At the present time, the complexity of this critical physiological system makes targeted intervention difficult. REFERENCES 1. Albaaj F, Hutchinson AJ. Hypermia in renal failure: causes, consequences, and current management. Drugs. 2003;63: Amanzadeh J, Reilly RF Jr. Hypomia: an evidencebased approach to its clinical consequences and management. Nat Clin Pract Nephrol. 2006;2: Malluche HH, Ritz E, Lange HP, et al. Bone histology in incipient and advanced renal failure. Kidney Int. 1976; 9: Malluche HH, Mawad H, Monier-Faugere MC. The importance of bone health in end-stage renal disease: out of the frying pan into the fire? Nephrol Dial Transplant. 2004; 199(suppl 10):i9-i Kestenbaum B, Sampson JN, Rudser KD, et al. Serum levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005;16: Tonelli M, Sacks F, Pfeffer M, et al. Relation between serum level and cardiovascular event rate in people with coronary disease. For the Cholesterol And Recurrent Events (CARE) Trial Investigators. Circulation. 2005; 112: Emsley J. The Shocking History of Phosphorus: A Biography of the Devil s Element. London, United Kingdom: Macmillan; Emsley J. The 13th Element: The Sordid Tale of Murder, Fire, and Phosphorus. New York, NY: Johns Wiley & Sons; Berndt TJ, Schiavi S, Kumar R. Phosphotonins and the regulation of phosphorus homeostasis. Am J Physiol Physiol. 2005;289:F1170-F Subcommittee on the Tenth Edition of the RDAs, Food and Nutrition Board, Commission on Life Sciences, National Research Council. Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press; 1989: Takeda E, Yamamoto H, Nashiki K, et al. Inorganic homeostasis and the role of dietary phosphorus. J Cell Mol Med. 2004;8: Portale AA, Halloran BP, Morris RC Jr. Dietary intake of phosphorus modulates the circadian rhythm in serum concentration of phosphorus. J Clin Invest. 1987;80: Kaye M, Turner M, Ardila M, et al. Aluminum and. Kidney Int Suppl. 1988;24:S172-S Ramirez JA, Emmett M, White MG, et al. The absorption of dietary phosphorus and calcium in hemodialysis patients. Kidney Int. 1986;30: Wilkinson R. Absorption of calcium, phosphorus, and magnesium. In: Nordin BEC, ed. Calcium, Phosphate, and Magnesium Metabolism. New York, NY: Churchill Livingstone; 1976: Eto N, Tomita M, Hayashi M. NaPi-mediated transcellular permeation is the dominant route in intestinal inorganic absorption in rats. Drug Metab Pharmacokinet. 2006;21: Cross HS, Debiec H, Peterlik M. Mechanism and regulation of intestinal absorption. Miner Electrolyte Metab. 1990;16: Segawa H, Kaneko I, Yamanaka S, et al. Intestinal Na-P(i) cotransporter adaptation to dietary P(i) content in vitamin D receptor null mice. Am J Physiol Physiol. 2004;287:F39-F Capuano P, Radanovic T, Wagner CA, et al. Intestinal and renal adaptation to a low-pi diet of type II NaPi cotransporters in vitamin D receptor- and 1alphaOHase-deficient mice. Am J Physiol Cell Physiol. 2005;288:C429-C Ishibashi K, Matsuzaki T, Takata K, Imai M. Identification of a new member of type I Na/ co-transporter in the rat kidney. Nephron Physiol. 2003;94: Murer H, Hernando N, Forster I, Biber J. Proximal tubular reabsorption: molecular mechanisms. Physiol Rev. 2000;80: Soumounou Y, Gauthier C, Tenenhouse HS. Murine and human type I Na- cotransporter genes: structure and promoter activity. Am J Physiol Physiol. 2001;281:F1082-F Li X, Yang HY, Giachelli CM. Role of the sodium-dependent cotransporter, Pit-1, in vascular smooth muscle cell calcification. Circ Res. 2006;98: Tenenhouse HS, Roy S, Martel J, Gauthier C. Differential expression, and regulation of Na+- cotransporter genes in murine kidney. Am J Physiol. 1998;275:F527-F Tenenhouse HS, Martel J, Gauthier C, et al. Differential effects of Npt2a gene ablation and X-linked Hyp mutation on renal expression of Npt2c. Am J Physiol Physiol. 2003;285:F1271-F Hilfiker H, Hattenhauer O, Traebert M, et al. Characterization of a murine type II sodium- cotransporter expressed in mammalian small intestine. Proc 138 Vol. 7, No. 5 May 2007

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