- Email: [email protected]
Bone and Mineral Metabolism: The Imperfect Storm
Chronic Kidney Disease/Bone and Mineral Metabolism: The Imperfect Storm Mark E. Williams, MD Summary: As kidney function declines, chronic kidney disease (CKD) becomes an increasingly systemic disorder. Most patients with CKD eventually develop subclinical or clinical abnormalities in bone and mineral metabolism. Recent observational and basic scientific studies have led to a new emphasis on the changes in phosphorus and calcium metabolism, parathyroid hormone, and vitamin D that lead to this complex systemic bone/mineral disorder (CKD/BMD). At the center of the disorder are relationships among all 4 factors that conspire to create a perfect storm, leading to secondary hyperparathyroidism (SHPT). Some key current issues that are reviewed here are as follows: (1) factors promoting SHPT, (2) the role of fibroblast growth factor-23 in CKD/BMD, (3) molecular mechanisms of SHPT, (4) mechanisms of vascular calcification, and (5) medical management of the disorder, including calcimimetics. Current therapies directed at correcting the primary abnormalities (ie, improve conditions to an imperfect storm) and minimizing the consequences of CKD/BMD are discussed. Semin Nephrol 29:97-104 © 2009 Published by Elsevier Inc. Keywords: Kidney, mineral, hyperparathyroidism, vitamin D
ith progressive decline in kidney function, most patients with chronic kidney disease (CKD) ultimately develop subclinical or clinical abnormalities in bone and mineral metabolism (CKD/BMD) (Fig. 1). Derangements in phosphorus, calcium, vitamin D, and parathyroid hormone (PTH) interact to create a complex systemic disorder, a so-called perfect storm. At the center is secondary hyperparathyroidism (SHPT) (Fig. 2), a condition in which oversecretion of PTH is associated with increased parathyroid gland growth. In the normal feedback loop, PTH, secreted in response to hypocalcemiaandmediatedthroughthecalciumsensing receptor, leads to increasing bone resorption of calcium and renal calcium reabsorption and promotion of 1,25(OH)2 vitamin D synthesis, which enhances intestinal calcium uptake. In advancing CKD, phosphate retention further stimulates PTH secretion directly1 and
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Beth Israel Deaconess Medical Center, Boston, MA. Address reprint requests to Mark E. Williams, MD, FACP, FASN, Associate Professor of Medicine, Harvard Medical School, Co-Director of Dialysis, Beth Israel Deaconess Medical Center, 1 Joslin Pl, Boston, MA 02215. E-mail: [email protected] 0270-9295/09/$ - see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.semnephrol.2009.01.002
indirectly by leading to a reciprocal decrease in serum calcium levels. Reduced calcitriol activity (secondary to reduced renal 1-hydroxylation of 25(OH)-vitamin D in kidney impairment, hyperphosphatemia, low vitamin D stores, and the phosphaturic hormone fibroblast growth factor-23 (FGF-23), stimulated by hyperphosphatemia), enhanced degradation of the active hormone, and loss of vitamin D–receptor expression further contribute to SHPT (Fig. 2). The prevalence of hyperphosphatemia and hypocalcemia become significant in CKD stage 4, and the increase in PTH levels commonly is preceded by declining active vitamin D concentrations.2 SHPT has been linked increasingly to higher morbidity and mortality rates in hemodialysis patients, although the risk may relate in part to hyperphosphatemia and vitamin D use.3 A recent report indicated that SHPT is associated independently with higher mortality in CKD patients4 with supranormal PTH levels. In addition to vascular calcification (discussed later), SHPT also is associated with renal osteodystrophy, which refers to several subtypes of abnormal bone morphology secondary to CKD based
Seminars in Nephrology, Vol 29, No 2, March 2009, pp 97-104
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Figure 1. CKD progression and its complications. Stages 1 through 5 of CKD are as designated by the National Kidney Foundation Kidney Disease Quality Outcome Initiative guidelines. Risk of complications and death increase in general as kidney disease worsens. Among the complications of CKD/BMD are cardiovascular disease, vascular and soft-tissue calcification, and fractures.
on bone mineralization and turnover. Histologic evidence of high bone turnover (osteitis fibrosa cystica), mixed bone disorder, or low bone turnover (adynamic bone disease) is found in the majority of patients with end-stage renal disease (ESRD). Osteitis fibrosa cystica is caused primarily by SHPT. High PTH levels are associated with loss of bone mass because the osteoclastic response of bone to increase resorption overbalances the formation of new bone by activated osteoblasts. Bone fracture risk is increased in patients with moderate or severe CKD, according to data from the National Health and Nutrition Examination Survey III and the Cardiovascular Health Study.5 Although bone pain and fractures are infrequent in earlier stages, morphologic bone abnormalities do occur early: in one bone biopsy study, three quarters of CKD stage 3 and 4 patients had histologic evidence of bone disease, mostly high turnover forms resulting from poorly controlled SHPT, including osteitis fibrosa cystica and mixed osteodystrophy.6 The risk of high-turnover bone disease increases with higher PTH levels. Decreased bone mineral density values are associated commonly with low 25(OH)D levels,7 but decreased bone density on dual-energy x-ray absorptiometry scanning of the spine, hips, and arms also has been related to low PTH levels. However, bone histology does not correlate
well with bone mineral density in CKD patients, but is instead influenced by multiple factors, including biochemical parameters and vitamin D treatment. Low-turnover forms, including adynamic bone disease and osteomalacia, were once uncommon but may be increasing in the ESRD population, possibly related to excessive vitamin D use, calcium-containing phosphate binders, and oversuppression of PTH. Pasch8 recently suggested that continued vitamin D therapy could preserve bone mass in adynamic bone disease patients, despite its inhibition of PTH synthesis through effects on bone remodeling. Adynamic bone is characterized by low or absent bone formation (detected by tetracycline labeling) and reduced numbers of osteoblasts and osteoclasts.9 Adynamic bone, present in up to 40% of patients with CKD, increases the risks of fracture and cardiovascular disease.10 The risk of fractures in CKD increases with worsening kidney function, is associated weakly with PTH levels, and is associated with excessive morbidity and mortality. Advances in medical management of renal osteodystrophy with new vitamin D analogues, non– calcium-based phosphate binders, and calcimimetic therapy can improve the bone/mineral disorder,11 making it an “imperfect storm” (Fig. 2). Phosphate control with diet and binder therapy ameliorates 1,25(OH)2 vitamin D deficiency.
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Figure 2. CKD effects on vitamin D, hyperparathyroidism, and mineral metabolism combine in CKD/BMD. Specific examples conspiring to create the so-called perfect storm include the role of vitamin D deficiency in SHPT, the effect of hyperphosphatemia and FGF-23 to produce vitamin D deficiency, and the contribution of phosphorus released from bone during SHPT to hyperphosphatemia. GFR, glomerular filtration rate.
Vitamin D analogues, proven to inhibit PTH hormone release before changes in serum calcium occur when given intravenously, can correct SHPT and prevent bone disease when given orally in CKD stages 3 and 4. The Kidney Disease Quality Outcome Initiative patient target levels are above the normal range to maintain bone remodeling and avoid iatrogenic adynamic bone, which presents as fractures and hypercalcemia. The standard vitamin D therapy for vitamin D deficiency in CKD stages 3 and 4 is ergocalciferol, which also may elicit modest PTH suppression. Cinacalcet (discussed later) is a recently approved calcimimetic agent that suppresses PTH production independent of vitamin D. HYPERPHOSPHATEMIA Recent research has established that hyperphosphatemia is central to the high mortality
rate among CKD patients.12 Because phosphorus plays an important role in membrane transport, production of metabolic energy, and cell signal transduction, its levels normally are regulated within a fairly narrow range. The kidneys play an important role through regulation of phosphorus excretion; in CKD the kidneys adapt to increase fractional phosphorus excretion by residual nephrons in response to increased levels of PTH and FGF-23. Nonetheless, failure to excrete phosphorus eventually results in hyperphosphatemia, which is compounded by the development of excess bone resorption relative to formation, and loss of the bone reservoir function.13 The resulting hyperphosphatemia is associated with SHPT, renal osteodystrophy, and vascular calcification. Emerging evidence indicates that mortality from cardiovascular disease (CVD) increases
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with higher levels of serum phosphorus as well as the calcium/phosphorus product in hemodialysis14 and among predialysis15 patients, although it was less closely evaluated in the latter group. Observational data in CKD indicate that increased phosphorus levels are associated with increased mortality.16 Recent data also suggest a similar relationship between phosphorus and CVD risk. Increased phosphorus levels are associated closely with coronary atherosclerosis and coronary calcification in ESRD.17 A 2007 study suggested that higher serum levels within the reference range (⬍4.5 mg/dL) are associated with increased CVD risk in community individuals free of baseline kidney disease (MDRD eGFR ⬎ 60 mL/min/1.73 m2).18 The analysis was restricted to individuals with eGFR greater than 90 mL/min/1.73 m2 and without proteinuria, and adjusted for established CVD risk factors in a model incorporating time-varying covariates. Over a mean duration of 16 years, individuals in the highest serum phosphorus quartile had a 1.5-fold increased CVD risk compared with the lowest quartile. A recent study of 985 male US veterans reported that progression of kidney disease was associated with higher baseline levels of serum phosphorus,19 after adjustment for multiple potential confounders. Current guidelines advise phosphate-binder therapy to achieve target levels in predialysis and dialysis patients. However, there are few studies on phosphate binders in CKD patients not on dialysis.20 Approved phosphate binders do not have an Food and Drug Administration indication specific to predialysis patients. Growing evidence has raised concern that the use of calcium-containing binders may produce calcium overload, with clinical consequences. The use of current phosphate binders (aluminum hydroxide, calcium carbonate, calcium acetate, sevelamer, and lanthanum) are reviewed elsewhere.21 FGF-23 The complex interrelationship of bone and mineral metabolism in CKD also is reflected by FGF-23, a recently characterized circulating peptide that originates in bone osteocytes.22 FGF-23 is a key factor in the control of phosphate homeostasis that, unlike vitamin D and
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parathyroid hormone, has no direct involvement in calcium balance. A member of the fibroblast growth factor family, the gene encoding FGF-23 originally was found to be mutated in autosomal-dominant hypophosphatemic rickets, an inherited renal phosphate-wasting condition associated with increased circulating FGF-23 levels. FGF-23 is secreted as a 30-kd protein that is modified by a proconvertase-type enzyme into several 18-kd amino and 12-kd carboxypeptide cleavage products.23 FGF-23 is one of the phosphate-regulating products known as phosphatonins, and a number of FGF-23 receptors have been identified. Injection of recombinant FGF-23 induces phosphaturia and hypophosphatemia in animals through inhibition of the renal proximal tubular Na-coupled phosphate cotransporter.24 A normal transmembrane Klotho protein is required for FGF-23 receptor activation.25 In normal subjects, some (but not all) studies have suggested that FGF-23 levels increase with dietary phosphate loading.26,27 CKD is now known to be associated with a progressive increase in FGF-23 levels, secreted from bone cells as kidney function worsens. Both phosphate ingestion (causing the release of FGF-23 from skeletal osteoclasts and osteoblasts) and reduced renal catabolic clearance have been implicated. Circulating FGF-23 levels increase as kidney function decreases,28 resulting in a correlation between FGF-23 and serum creatinine levels.29 With impaired kidney function, FGF-23 can be modulated by high dietary phosphate intake, although a recent study indicated that FGF-23 levels in CKD patients, although increased compared with normal controls, did not increase further in association with postprandial phosphaturia.30 Although it has been suggested that FGF levels increase early in CKD, before significant abnormalities in mineral metabolism are identified, a recent study linked FGF-23 increases in CKD stages 4 and 5 to hyperphosphatemia, with increased levels independently predicting progression of CKD.31 It is increasingly clear that any compensatory role of FGF-23 in phosphate balance in CKD may be offset by an exacerbation of calcitriol deficiency.32 In animal models, administration of FGF-23 is followed by severe bone demineralization. FGF-23 appears to inhibit 1-␣ D3 hydroxy-
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lase, reducing synthesis of 1,25(OH)2-vitamin D3, as well as stimulating the 24,25-hydroxylase, which leads to its degradation. The presence of an FGF receptor in bone cells might account for the direct decrease in bone mineralization.24 In turn, FGF-23 appears to be regulated by 1,25-D levels and increases in response to high-dose calcitriol.33 Binding of 1,25(OH)2-D3 to the promoter region of the FGF-23 gene has been reported. Although FGF-23 could reduce bone mineralization by direct effects or through phosphate lowering in CKD, there was no significant correlation between serum FGF-23 levels and bone mineral density in a recent report on hemodialysis patients.34 MOLECULAR MECHANISMS OF SHPT Increased synthesis and secretion of PTH in SHPT results from enlargement of the parathyroid glands.35 Parathyroid gland growth in experimental animal models of renal failure is caused primarily by cell proliferation, not hypertrophy. The molecular mechanisms underlying parathyroid cell proliferation in conditions of CKD and uremia are incompletely understood.36 In early uremia, parathyroid hyperplasia induced by high phosphate intake is associated with increased expression of the growth-promoting factor transforming growth factor-␣ (TGF-␣). High immunoreactivity for TGF-␣ is noted in parathyroid glands when uremic rats are fed a high-phosphate diet and is associated with markers of mitotic activity.37 Vitamin D analogues can reduce parathyroid cell proliferation in vitro, and vitamin D compounds are clinically effective in controlling parathyroid levels and gland enlargement. In rats with early uremia, vitamin D analogues arrest parathyroid growth in part by preventing increases in TGF-␣.38 Furthermore, parathyroid hyperplasia correlates with enhanced co-expression of TGF-␣ and its receptor, the epidermal growth factor receptor.39 Recent studies have indicated that activation of the epidermal growth factor receptor is required for the development of parathyroid hyperplasia,40 and that increased activator protein 2(␣) may mediate the effect.41 VASCULAR CALCIFICATION MECHANISMS Once considered an indolent process of passive deposition of calcium and phosphate as insolu-
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ble precipitates, vascular calcification is now thought to be a highly regulated activity, both locally and systemically. Phenotypic changes in vascular cells and loss of inhibitory defense proteins within the circulation contribute to this process. Abnormalities in calcium/phosphorus/parathyroid hormone/vitamin D may provide a link to this aspect of the perfect storm of CKD/BMD. Vascular calcification may begin with bone-like phenotypic differentiation of multilineage vascular smooth muscle cells into osteochondrocytic cells in the arterial wall. Multiple components are actively involved in triggering the conversion and matrix release, including tumor necrosis factor-␣, reactive oxygen species, advanced glycation end-products, and inflammatory proteins.42 Release of matrix vesicles able to nucleate calcium/phosphorus, production of collagenous extracellular matrix, and secretion of calcium-binding proteins by transformed vascular smooth muscle cells create a synergistic environment for calcification. Growing evidence suggests that in CKD, natural local or systemic calcification inhibitors may be overwhelmed or just deficient.43 Matrix GLA protein, for example, is a potent local inhibitor at high concentrations in vascular smooth muscle cells and is present in matrix vesicles.44 Deficiency of this protein in knockout mice is associated with spontaneous calcification of arterial tissue.45 Matrix GLA protein may exert its anticalcification effect through chelation or by inactivating the promineralization factor bone morphogenic protein-2, which appears to be up-regulated in conditions such as diabetes. Separate evidence suggests that a known systemic inhibitor of vascular calcification, fetuin A, is deficient in CKD and may protect against mineralization by inhibiting calcium/phosphate precipitation. CKD 5 patients may have reduced systemic levels of fetuin A compared with those without renal disease, possibly because it is regulated as a negative acute phase reactant. The processes responsible for osteogenic differentiation and imbalance in inhibitors of calcification likely are influenced by CKD/BMD. Increased phosphate levels themselves appear to trigger both phenotypic changes and calcification of the matrix secreted by the transformed cells.46 PIT 1, the sodium-dependent
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phosphate transporter required for both processes, actively mediates the uptake of extracellular phosphate by vascular smooth muscle cells. The increase in intracellular phosphate levels then may tip the balance away from smooth muscle features and toward osteoblast/ chondrocyte differentiation of the cells. Increased calcium levels synergistically promote vascular calcification, promoting osteogenic differentiation by up-regulating the expression of Pit 1 and by increasing matrix vesicle production. The direct role of vitamin D and PTH in inducing vascular calcification is less clear.47 Vitamin D is known to increase calcium uptake of vascular smooth muscle cells.48 Recent data indicate that another metabolic abnormality prevalent in CKD patients, metabolic acidosis, may prevent soft-tissue calcification despite the associated loss of calcium from bone, possibly supporting the similarities in its effect on bone and vascular smooth cells in uremia.49,50 CINACALCET Calcimimetics are noncalcium agents that activate the calcium-sensing receptor (CSR), a Gprotein– coupled receptor expressed on parathyroid chief cells that plays a central role in parathyroid/calcium homeostasis.51 Cinacalcet, currently in use as an approved calcimimetic agent in dialysis-dependent patients with SHPT,52 binds to the CSR, increases cell sensitivity to extracellular calcium, and suppresses PTH production independent of vitamin D. Despite allosteric interaction between cinacalcet and the CSR, extracellular calcium still is required to activate the CSR and maintain control of PTH secretion.53 In hemodialysis patients with SHPT, the result is to reduce the set-point (ie, the midrange of the PTH/calcium curve).54 Notwithstanding the extensive published data on cinacalcet in ESRD, and despite its growing use in CKD patients not on dialysis, limited data are available on this population. The presence of reduced renal function has raised concerns regarding the potential for symptomatic hypocalcemia, increased urinary calcium excretion owing to the decrease in anticalciuric actions of PTH, and reductions in urinary phosphorus excretion with increases in serum phosphorus levels owing
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to loss of the phosphaturic effects of the hormone. The limited available clinical trial data recently were reviewed from opposing viewpoints in articles by Coyne55 and deFrancisco et al.56 In a phase II, placebo-controlled trial involving 54 patients with CKD not on dialysis treated for 18 weeks, cinacalcet-induced hypocalcemia (⬍8.4 mg/dL) occurred in more than three quarters of treated patients, with almost half of those reaching a nadir calcium of 6.5 to 7.6 mg/dL.57 Treatment of hypocalcemia required calcium supplementation in almost half and vitamin D initiation in a quarter of cinacalcettreated patients. Compared with those given placebo, more treated patients had adverse events potentially attributable to hypocalcemia (41% vs 31%), although patients generally were asymptomatic, and only 2% of enrolled patients withdrew from the trial owing to low serum calcium levels. Parathyroid levels decreased by a third overall with cinacalcet, with 3 times as many treated patients reaching 30% PTH reductions versus placebo (56% vs 19%). How much of the PTH reduction was owing to initiation of vitamin D analogues, and whether the PTH response is superior to reductions achieved with vitamin D analogues in earlier trials have been raised as concerns. Of note, approval of cinacalcet for CKD patients recently was withdrawn in Canada after a larger trial than the one cited earlier indicated similar levels of hypocalcemia.58 Additional potential concerns are mild increases in serum phosphorus levels, whether CKD cinacalcet use might worsen calcitriol deficiency through direct and indirect effects on 1-␣-hydroxylase activity in the renal proximal tubule, and the lack of clinical data on outcomes such as bone loss.59 Growing clinical experience with the calcimimetic will help determine how these safety and efficacy issues are to be managed, in particular the requirement for supplemental calcium and vitamin D to treat hypocalcemia. CONCLUSIONS New emphasis on interrelated changes in phosphorus and calcium metabolism, vitamin D, and PTH has led to a deeper understanding of the complexities of CKD/BMD. Key observations
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reviewed here have created an awareness of the systemic nature of this complication of CKD, the molecular events involving SHPT, the nature of vascular calcification, and the role of calcimimetics. Therapies are aimed at minimizing the consequences of CKD/BMD, thus reducing the severity to that of an imperfect storm. REFERENCES 1. Almaden Y, Hernandez A, Torregrosa V, Canckejo A, Sabate L, Fernandez Cruz L, et al. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol. 1998;9:1845-52. 2. Levin A, Bakris GL, Molitch M, Sulders M, Tian J, Williams LA, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 2007;71:31-8. 3. Block GA, Klasssen PS, Lazarus JM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15:2208-18. 4. Kovesdy CP, Ahmadzadeh S, Anderson JE, KalantarZadeh K. Secondary hyperparathyroidism is associated with higher mortality in men with moderate to severe chronic kidney disease. Kidney Int. 2008;73: 1296-302. 5. Nickolas TL, Leonard MB, Shane E. Chronic kidney disease and bone fracture: a growing concern. Kidney Int. 2008;74:721-31. 6. Hamdy NA, Kanis JA, Benetn MN. Effect of alfacalcidiol on natural course of renal bone disease in mild to moderate renal failure. BMJ. 1995;310:358-63. 7. Bouillon R, Bischoff-Ferrari H, Willett W. Vitamin D and health: from mice and man. J Bone Miner Res. 2008;23:974-9. 8. Pasch A. Bone mass gain after parathyroidectomy. Kidney Int. 2008;74:697-702. 9. Andress DL. Adynamic bone in patients with chronic kidney disease. Kidney Int. 2008;73:1345-54. 10. Brandenburg VM, Floege J. Adynamic bone disease— bone and beyond. Nephrol Dial Transplant Plus. 2008;3:135-147. 11. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42:S1-201. 12. Go AS, Chertow GM, Fan D, McCulloch DE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-1302. 13. Hruska KA, Mathew S, Lund R, Qiu P, Pratt R. Hyperphosphatemia of chronic kidney disease. Kidney Int. 2008;74:148-57. 14. Block GA, Temple E, Hulbert-Shearon TE. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis. 1998;31: 607-14.
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15. Kestenbaum B, Sampson JN, Rudser KD. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005;16:52-8. 16. Voormolen N. High plasma phosphate as a risk factor for decline in renal function and mortality in predialysis patients. Nephrol Dial Transplant. 2007;27: 2909-16. 17. Goodman WG, Goldin J, Juison BD. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478-83. 18. Dhingra R, Sullivan LM, Fox CS, Wang TJ, D’Agostino RB, Gaziano M, et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med. 2007; 167:879-85. 19. Schwarz S, Rivedi BK, Kalantar-Zadeh K, Kovesdy CP. Association of disorders of mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol. 2006;1:825-31. 20. Ketteler M, Rix M, Fan S, Pritchard N, Oestergard O, Chasan-Taber S, et al. Efficacy and tolerability of sevelamer carbonate in hyperphosphatemic patients who have chronic kidney disease and are not on dialysis. Clin J Am Soc Nephrol. 2008;3:1125-50. 21. Salusky IB. A new era in phosphate binder therapy: what are the options? Kidney Int. 2006;70:S10-6. 22. Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol. 2007;18:1637-41. 23. Razzaque MS, Lanske B. The emerging role of the fibroblast growth factor -23-Klotho axis in renal regulation of phosphate homeostasis. J Endocrinol. 2007;194:1-10. 24. Emmett M. What does serum fibroblast growth factor 23 do in hemodialysis patients? Kidney Int. 2008;73:3-8. 25. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444:770. 26. Ferrari SL, Bonjour JP, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab. 2005;90:1519-24. 27. Burnett SM, Gunawardene SC, Bringhurst FR, Juppner H, Lee H, Finkelstein JS. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res. 2006;21:1187. 28. Shigematsu T, Kazama JJ, Yamashita T, Fukumoto S, Hosoya T, Gejyo F, et al. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis. 2004;44:250-6. 29. Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int. 2003;64:2272-9. 30. Isakova T, Gutierrez O, Shah A, Castaldo L, Holmes J,
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31.
32.
33.
34.
35. 36.
37.
38.
39.
40.
41.
42.
43.
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Lee H, et al. Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol. 2008;19:615-23. Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel A, et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) study. J Am Soc Nephrol. 2007;18:2600-7. Guetierez O, Isakova T, Rhee E, Shah A, Holmes J. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol. 2005;16: 2205-15. Collins MT, Lindsay JR, Jain A, Kelly MH, Cutler CM, Weinstein LS, et al. Fibroblast growth factor-23 is regulated by 1alpha, 25-dihrydoxyvitamin D. J Bone Miner Res. 2005;20:1944-50. Urena-Torres P, Friedlander G, deVernejoul MC. Bone mass does not correlate with the serum fibroblast growth factor 23 in hemodialysis patients. Kidney Int. 2008;73:102-9. Parfitt AM. The hyperparathyroidism of chronic renal failure: a disorder of growth. Kidney Int. 1997;52:3-6. Felsenfeld AJ, Rodriguez M, Aguilera-Tejero A. Dynamics of parathyroid hormone secretion in health and secondary hyperparathyroidism. Clin J Am Soc Nephrol. 2007;2:1283-7. Dusso AS, Pavlopoulos T, Naumovich L, Lu Y, Finch J, Brown AJ, et al. p21 (WAF1) and transforming growth factor-alpha mediate dietary phosphate regulation of parathyroid cell growth. Kidney Int. 2001;59:855-61. Cozzolino M, Lu Y, Finch J, Slatopolsky E, Dusso AS. p21WAF1 and TGF-alpha mediate parathyroid growth arrest by vitamin D and high calcium. Kidney Int. 2001;60:2109-17. Arcidiacono MV, Sato T, Alvarez-Hernandez D, Yang J, Tokumoto M, Gonzalez-Suarez I, et al. EGFR activation increases parathyroid hyperplasia and calcitriol resistance in kidney disease. J Am Soc Nephrol. 2008; 19:310-20. Dusso AS, Sato T, Arcidiacono MV, Alvarez-Hernandez D, Yang J, Gonzalez-Suarez I, et al. Pathogenic mechanisms for parathyroid hyperplasia. Kidney Int Suppl. 2006;102:S8-11. Arcidiacono MV, Cozzolino M, Spiegel N, Tokumoto M, Yang J, Lu Y, et al. Activator protein 2(alpha) mediates parathyroid TGF-{alpha} self-induction in secondary hyperparathyroidism. J Am Soc Nephrol. 2008 [accessed 2008 October 15]. Epub PMID 18579641. Schoppet M, Shroff RC, Hofbauer LC, Shanahan CM. Exploring the biology of vascular calcification in chronic kidney disease: what’s circulating? Kidney Int. 2008;73:384-90. Ix JH, Katz R, Kestenbaum B, Fried LF, Kramer H, Stehman-Breen C. Association of mild to moderate kidney dysfunction and coronary calcification. J Am Soc Nephrol. 2008;19:579-85.
44. El-Abbadi M, Giachelli CM. Mechanisms of vascular calcification. Adv Chronic Kidney Dis. 2007;14:54-66. 45. Luo G, Ducy P, McKee MD. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386:78-81. 46. Ketteler M, Giachelli C. Novel insights into vascular calcification. Kidney Int. 2006;70:S5. 47. Andress DL. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int. 2006;69:33. 48. Mizobuchi M, Finch JL, Martin D, Slatopolsky E. Differential effects of vitamin D receptor activators in vascular calcification in uremic rats. Kidney Int. 2007; 72:9-16. 49. Al-Aly Z. Metabolic acidosis and vascular calcification: using blueprints from bone to map a new venue for vascular research. Kidney Int. 2008;73:37-44. 50. Mendoza FJ, Lopez L, Montes de Oca P. Metabolic acidosis inhibits soft tissue calcification in uremic rats. Kidney Int. 2008;3:407-14. 51. Harrington PE, Fotsch C. Calcium sensing receptor activators: calcimimetics. Curr Med Chem. 2007;14: 3027-34. 52. Moe SM. Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl. Kidney Int. 2005;67:760-71. 53. deFrancisco AL, Izquierdo M, Cunningham J, Pinera C, Palomar R, Fresnedo GF, et al. Calcium-mediated parathyroid hormone release changes in patients treated with the calcimimetic agent cinacalcet. Nephrol Dial Transplant. 2008;23:2895-901. 54. Valle C, Rodriquez M, Santamaria R, Almaden Y, Rodriguez ME, Canadillas S, et al. Cinacalcet reduces the set point of the PTH-calcium curve. J Am Soc Nephrol. 2008 [accessed 2008 October 17]. Epub PMID 18632847. 55. Coyne DW. Cinacalcet should not be used to treat secondary hyperparathyroidism in stage 3-4 chronic kidney disease. Nat Clin Pract. 2008;4:364-7. 56. deFrancisco ALM, Pinera C, Palomar R. Cinacalcet should be used to treat secondary hyperparathyroidism in stage 3-4 chronic kidney disease. Nat Clin Pract. 2008;4:366-9. 57. Charytan C. Cinacalcet hydrochloride is an effective treatment for secondary hyperparathyroidism in patients with CKD not receiving dialysis. Am J Kidney Dis. 2005;46:58-66. 58. Health Canada online. Sensipar R no longer indicated for chronic kidney disease patients (stages 3 and 4) not receiving dialysis. [accessed 2008 September 9]. Available from: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/sensipar_hpc-cps_e.html. 59. Chonchoi M, Locatelli F, Abboud HE, Charytan C, de Francicso AL, Jolly S, et al. A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet HCl in participants with CKD not receiving dialysis. Am J Kidney Dis. 2009;53:197-207.
ith progressive decline in kidney function, most patients with chronic kidney disease (CKD) ultimately develop subclinical or clinical abnormalities in bone and mineral metabolism (CKD/BMD) (Fig. 1). Derangements in phosphorus, calcium, vitamin D, and parathyroid hormone (PTH) interact to create a complex systemic disorder, a so-called perfect storm. At the center is secondary hyperparathyroidism (SHPT) (Fig. 2), a condition in which oversecretion of PTH is associated with increased parathyroid gland growth. In the normal feedback loop, PTH, secreted in response to hypocalcemiaandmediatedthroughthecalciumsensing receptor, leads to increasing bone resorption of calcium and renal calcium reabsorption and promotion of 1,25(OH)2 vitamin D synthesis, which enhances intestinal calcium uptake. In advancing CKD, phosphate retention further stimulates PTH secretion directly1 and
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Beth Israel Deaconess Medical Center, Boston, MA. Address reprint requests to Mark E. Williams, MD, FACP, FASN, Associate Professor of Medicine, Harvard Medical School, Co-Director of Dialysis, Beth Israel Deaconess Medical Center, 1 Joslin Pl, Boston, MA 02215. E-mail: [email protected] 0270-9295/09/$ - see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.semnephrol.2009.01.002
indirectly by leading to a reciprocal decrease in serum calcium levels. Reduced calcitriol activity (secondary to reduced renal 1-hydroxylation of 25(OH)-vitamin D in kidney impairment, hyperphosphatemia, low vitamin D stores, and the phosphaturic hormone fibroblast growth factor-23 (FGF-23), stimulated by hyperphosphatemia), enhanced degradation of the active hormone, and loss of vitamin D–receptor expression further contribute to SHPT (Fig. 2). The prevalence of hyperphosphatemia and hypocalcemia become significant in CKD stage 4, and the increase in PTH levels commonly is preceded by declining active vitamin D concentrations.2 SHPT has been linked increasingly to higher morbidity and mortality rates in hemodialysis patients, although the risk may relate in part to hyperphosphatemia and vitamin D use.3 A recent report indicated that SHPT is associated independently with higher mortality in CKD patients4 with supranormal PTH levels. In addition to vascular calcification (discussed later), SHPT also is associated with renal osteodystrophy, which refers to several subtypes of abnormal bone morphology secondary to CKD based
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Figure 1. CKD progression and its complications. Stages 1 through 5 of CKD are as designated by the National Kidney Foundation Kidney Disease Quality Outcome Initiative guidelines. Risk of complications and death increase in general as kidney disease worsens. Among the complications of CKD/BMD are cardiovascular disease, vascular and soft-tissue calcification, and fractures.
on bone mineralization and turnover. Histologic evidence of high bone turnover (osteitis fibrosa cystica), mixed bone disorder, or low bone turnover (adynamic bone disease) is found in the majority of patients with end-stage renal disease (ESRD). Osteitis fibrosa cystica is caused primarily by SHPT. High PTH levels are associated with loss of bone mass because the osteoclastic response of bone to increase resorption overbalances the formation of new bone by activated osteoblasts. Bone fracture risk is increased in patients with moderate or severe CKD, according to data from the National Health and Nutrition Examination Survey III and the Cardiovascular Health Study.5 Although bone pain and fractures are infrequent in earlier stages, morphologic bone abnormalities do occur early: in one bone biopsy study, three quarters of CKD stage 3 and 4 patients had histologic evidence of bone disease, mostly high turnover forms resulting from poorly controlled SHPT, including osteitis fibrosa cystica and mixed osteodystrophy.6 The risk of high-turnover bone disease increases with higher PTH levels. Decreased bone mineral density values are associated commonly with low 25(OH)D levels,7 but decreased bone density on dual-energy x-ray absorptiometry scanning of the spine, hips, and arms also has been related to low PTH levels. However, bone histology does not correlate
well with bone mineral density in CKD patients, but is instead influenced by multiple factors, including biochemical parameters and vitamin D treatment. Low-turnover forms, including adynamic bone disease and osteomalacia, were once uncommon but may be increasing in the ESRD population, possibly related to excessive vitamin D use, calcium-containing phosphate binders, and oversuppression of PTH. Pasch8 recently suggested that continued vitamin D therapy could preserve bone mass in adynamic bone disease patients, despite its inhibition of PTH synthesis through effects on bone remodeling. Adynamic bone is characterized by low or absent bone formation (detected by tetracycline labeling) and reduced numbers of osteoblasts and osteoclasts.9 Adynamic bone, present in up to 40% of patients with CKD, increases the risks of fracture and cardiovascular disease.10 The risk of fractures in CKD increases with worsening kidney function, is associated weakly with PTH levels, and is associated with excessive morbidity and mortality. Advances in medical management of renal osteodystrophy with new vitamin D analogues, non– calcium-based phosphate binders, and calcimimetic therapy can improve the bone/mineral disorder,11 making it an “imperfect storm” (Fig. 2). Phosphate control with diet and binder therapy ameliorates 1,25(OH)2 vitamin D deficiency.
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Figure 2. CKD effects on vitamin D, hyperparathyroidism, and mineral metabolism combine in CKD/BMD. Specific examples conspiring to create the so-called perfect storm include the role of vitamin D deficiency in SHPT, the effect of hyperphosphatemia and FGF-23 to produce vitamin D deficiency, and the contribution of phosphorus released from bone during SHPT to hyperphosphatemia. GFR, glomerular filtration rate.
Vitamin D analogues, proven to inhibit PTH hormone release before changes in serum calcium occur when given intravenously, can correct SHPT and prevent bone disease when given orally in CKD stages 3 and 4. The Kidney Disease Quality Outcome Initiative patient target levels are above the normal range to maintain bone remodeling and avoid iatrogenic adynamic bone, which presents as fractures and hypercalcemia. The standard vitamin D therapy for vitamin D deficiency in CKD stages 3 and 4 is ergocalciferol, which also may elicit modest PTH suppression. Cinacalcet (discussed later) is a recently approved calcimimetic agent that suppresses PTH production independent of vitamin D. HYPERPHOSPHATEMIA Recent research has established that hyperphosphatemia is central to the high mortality
rate among CKD patients.12 Because phosphorus plays an important role in membrane transport, production of metabolic energy, and cell signal transduction, its levels normally are regulated within a fairly narrow range. The kidneys play an important role through regulation of phosphorus excretion; in CKD the kidneys adapt to increase fractional phosphorus excretion by residual nephrons in response to increased levels of PTH and FGF-23. Nonetheless, failure to excrete phosphorus eventually results in hyperphosphatemia, which is compounded by the development of excess bone resorption relative to formation, and loss of the bone reservoir function.13 The resulting hyperphosphatemia is associated with SHPT, renal osteodystrophy, and vascular calcification. Emerging evidence indicates that mortality from cardiovascular disease (CVD) increases
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with higher levels of serum phosphorus as well as the calcium/phosphorus product in hemodialysis14 and among predialysis15 patients, although it was less closely evaluated in the latter group. Observational data in CKD indicate that increased phosphorus levels are associated with increased mortality.16 Recent data also suggest a similar relationship between phosphorus and CVD risk. Increased phosphorus levels are associated closely with coronary atherosclerosis and coronary calcification in ESRD.17 A 2007 study suggested that higher serum levels within the reference range (⬍4.5 mg/dL) are associated with increased CVD risk in community individuals free of baseline kidney disease (MDRD eGFR ⬎ 60 mL/min/1.73 m2).18 The analysis was restricted to individuals with eGFR greater than 90 mL/min/1.73 m2 and without proteinuria, and adjusted for established CVD risk factors in a model incorporating time-varying covariates. Over a mean duration of 16 years, individuals in the highest serum phosphorus quartile had a 1.5-fold increased CVD risk compared with the lowest quartile. A recent study of 985 male US veterans reported that progression of kidney disease was associated with higher baseline levels of serum phosphorus,19 after adjustment for multiple potential confounders. Current guidelines advise phosphate-binder therapy to achieve target levels in predialysis and dialysis patients. However, there are few studies on phosphate binders in CKD patients not on dialysis.20 Approved phosphate binders do not have an Food and Drug Administration indication specific to predialysis patients. Growing evidence has raised concern that the use of calcium-containing binders may produce calcium overload, with clinical consequences. The use of current phosphate binders (aluminum hydroxide, calcium carbonate, calcium acetate, sevelamer, and lanthanum) are reviewed elsewhere.21 FGF-23 The complex interrelationship of bone and mineral metabolism in CKD also is reflected by FGF-23, a recently characterized circulating peptide that originates in bone osteocytes.22 FGF-23 is a key factor in the control of phosphate homeostasis that, unlike vitamin D and
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parathyroid hormone, has no direct involvement in calcium balance. A member of the fibroblast growth factor family, the gene encoding FGF-23 originally was found to be mutated in autosomal-dominant hypophosphatemic rickets, an inherited renal phosphate-wasting condition associated with increased circulating FGF-23 levels. FGF-23 is secreted as a 30-kd protein that is modified by a proconvertase-type enzyme into several 18-kd amino and 12-kd carboxypeptide cleavage products.23 FGF-23 is one of the phosphate-regulating products known as phosphatonins, and a number of FGF-23 receptors have been identified. Injection of recombinant FGF-23 induces phosphaturia and hypophosphatemia in animals through inhibition of the renal proximal tubular Na-coupled phosphate cotransporter.24 A normal transmembrane Klotho protein is required for FGF-23 receptor activation.25 In normal subjects, some (but not all) studies have suggested that FGF-23 levels increase with dietary phosphate loading.26,27 CKD is now known to be associated with a progressive increase in FGF-23 levels, secreted from bone cells as kidney function worsens. Both phosphate ingestion (causing the release of FGF-23 from skeletal osteoclasts and osteoblasts) and reduced renal catabolic clearance have been implicated. Circulating FGF-23 levels increase as kidney function decreases,28 resulting in a correlation between FGF-23 and serum creatinine levels.29 With impaired kidney function, FGF-23 can be modulated by high dietary phosphate intake, although a recent study indicated that FGF-23 levels in CKD patients, although increased compared with normal controls, did not increase further in association with postprandial phosphaturia.30 Although it has been suggested that FGF levels increase early in CKD, before significant abnormalities in mineral metabolism are identified, a recent study linked FGF-23 increases in CKD stages 4 and 5 to hyperphosphatemia, with increased levels independently predicting progression of CKD.31 It is increasingly clear that any compensatory role of FGF-23 in phosphate balance in CKD may be offset by an exacerbation of calcitriol deficiency.32 In animal models, administration of FGF-23 is followed by severe bone demineralization. FGF-23 appears to inhibit 1-␣ D3 hydroxy-
The imperfect storm
lase, reducing synthesis of 1,25(OH)2-vitamin D3, as well as stimulating the 24,25-hydroxylase, which leads to its degradation. The presence of an FGF receptor in bone cells might account for the direct decrease in bone mineralization.24 In turn, FGF-23 appears to be regulated by 1,25-D levels and increases in response to high-dose calcitriol.33 Binding of 1,25(OH)2-D3 to the promoter region of the FGF-23 gene has been reported. Although FGF-23 could reduce bone mineralization by direct effects or through phosphate lowering in CKD, there was no significant correlation between serum FGF-23 levels and bone mineral density in a recent report on hemodialysis patients.34 MOLECULAR MECHANISMS OF SHPT Increased synthesis and secretion of PTH in SHPT results from enlargement of the parathyroid glands.35 Parathyroid gland growth in experimental animal models of renal failure is caused primarily by cell proliferation, not hypertrophy. The molecular mechanisms underlying parathyroid cell proliferation in conditions of CKD and uremia are incompletely understood.36 In early uremia, parathyroid hyperplasia induced by high phosphate intake is associated with increased expression of the growth-promoting factor transforming growth factor-␣ (TGF-␣). High immunoreactivity for TGF-␣ is noted in parathyroid glands when uremic rats are fed a high-phosphate diet and is associated with markers of mitotic activity.37 Vitamin D analogues can reduce parathyroid cell proliferation in vitro, and vitamin D compounds are clinically effective in controlling parathyroid levels and gland enlargement. In rats with early uremia, vitamin D analogues arrest parathyroid growth in part by preventing increases in TGF-␣.38 Furthermore, parathyroid hyperplasia correlates with enhanced co-expression of TGF-␣ and its receptor, the epidermal growth factor receptor.39 Recent studies have indicated that activation of the epidermal growth factor receptor is required for the development of parathyroid hyperplasia,40 and that increased activator protein 2(␣) may mediate the effect.41 VASCULAR CALCIFICATION MECHANISMS Once considered an indolent process of passive deposition of calcium and phosphate as insolu-
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ble precipitates, vascular calcification is now thought to be a highly regulated activity, both locally and systemically. Phenotypic changes in vascular cells and loss of inhibitory defense proteins within the circulation contribute to this process. Abnormalities in calcium/phosphorus/parathyroid hormone/vitamin D may provide a link to this aspect of the perfect storm of CKD/BMD. Vascular calcification may begin with bone-like phenotypic differentiation of multilineage vascular smooth muscle cells into osteochondrocytic cells in the arterial wall. Multiple components are actively involved in triggering the conversion and matrix release, including tumor necrosis factor-␣, reactive oxygen species, advanced glycation end-products, and inflammatory proteins.42 Release of matrix vesicles able to nucleate calcium/phosphorus, production of collagenous extracellular matrix, and secretion of calcium-binding proteins by transformed vascular smooth muscle cells create a synergistic environment for calcification. Growing evidence suggests that in CKD, natural local or systemic calcification inhibitors may be overwhelmed or just deficient.43 Matrix GLA protein, for example, is a potent local inhibitor at high concentrations in vascular smooth muscle cells and is present in matrix vesicles.44 Deficiency of this protein in knockout mice is associated with spontaneous calcification of arterial tissue.45 Matrix GLA protein may exert its anticalcification effect through chelation or by inactivating the promineralization factor bone morphogenic protein-2, which appears to be up-regulated in conditions such as diabetes. Separate evidence suggests that a known systemic inhibitor of vascular calcification, fetuin A, is deficient in CKD and may protect against mineralization by inhibiting calcium/phosphate precipitation. CKD 5 patients may have reduced systemic levels of fetuin A compared with those without renal disease, possibly because it is regulated as a negative acute phase reactant. The processes responsible for osteogenic differentiation and imbalance in inhibitors of calcification likely are influenced by CKD/BMD. Increased phosphate levels themselves appear to trigger both phenotypic changes and calcification of the matrix secreted by the transformed cells.46 PIT 1, the sodium-dependent
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phosphate transporter required for both processes, actively mediates the uptake of extracellular phosphate by vascular smooth muscle cells. The increase in intracellular phosphate levels then may tip the balance away from smooth muscle features and toward osteoblast/ chondrocyte differentiation of the cells. Increased calcium levels synergistically promote vascular calcification, promoting osteogenic differentiation by up-regulating the expression of Pit 1 and by increasing matrix vesicle production. The direct role of vitamin D and PTH in inducing vascular calcification is less clear.47 Vitamin D is known to increase calcium uptake of vascular smooth muscle cells.48 Recent data indicate that another metabolic abnormality prevalent in CKD patients, metabolic acidosis, may prevent soft-tissue calcification despite the associated loss of calcium from bone, possibly supporting the similarities in its effect on bone and vascular smooth cells in uremia.49,50 CINACALCET Calcimimetics are noncalcium agents that activate the calcium-sensing receptor (CSR), a Gprotein– coupled receptor expressed on parathyroid chief cells that plays a central role in parathyroid/calcium homeostasis.51 Cinacalcet, currently in use as an approved calcimimetic agent in dialysis-dependent patients with SHPT,52 binds to the CSR, increases cell sensitivity to extracellular calcium, and suppresses PTH production independent of vitamin D. Despite allosteric interaction between cinacalcet and the CSR, extracellular calcium still is required to activate the CSR and maintain control of PTH secretion.53 In hemodialysis patients with SHPT, the result is to reduce the set-point (ie, the midrange of the PTH/calcium curve).54 Notwithstanding the extensive published data on cinacalcet in ESRD, and despite its growing use in CKD patients not on dialysis, limited data are available on this population. The presence of reduced renal function has raised concerns regarding the potential for symptomatic hypocalcemia, increased urinary calcium excretion owing to the decrease in anticalciuric actions of PTH, and reductions in urinary phosphorus excretion with increases in serum phosphorus levels owing
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to loss of the phosphaturic effects of the hormone. The limited available clinical trial data recently were reviewed from opposing viewpoints in articles by Coyne55 and deFrancisco et al.56 In a phase II, placebo-controlled trial involving 54 patients with CKD not on dialysis treated for 18 weeks, cinacalcet-induced hypocalcemia (⬍8.4 mg/dL) occurred in more than three quarters of treated patients, with almost half of those reaching a nadir calcium of 6.5 to 7.6 mg/dL.57 Treatment of hypocalcemia required calcium supplementation in almost half and vitamin D initiation in a quarter of cinacalcettreated patients. Compared with those given placebo, more treated patients had adverse events potentially attributable to hypocalcemia (41% vs 31%), although patients generally were asymptomatic, and only 2% of enrolled patients withdrew from the trial owing to low serum calcium levels. Parathyroid levels decreased by a third overall with cinacalcet, with 3 times as many treated patients reaching 30% PTH reductions versus placebo (56% vs 19%). How much of the PTH reduction was owing to initiation of vitamin D analogues, and whether the PTH response is superior to reductions achieved with vitamin D analogues in earlier trials have been raised as concerns. Of note, approval of cinacalcet for CKD patients recently was withdrawn in Canada after a larger trial than the one cited earlier indicated similar levels of hypocalcemia.58 Additional potential concerns are mild increases in serum phosphorus levels, whether CKD cinacalcet use might worsen calcitriol deficiency through direct and indirect effects on 1-␣-hydroxylase activity in the renal proximal tubule, and the lack of clinical data on outcomes such as bone loss.59 Growing clinical experience with the calcimimetic will help determine how these safety and efficacy issues are to be managed, in particular the requirement for supplemental calcium and vitamin D to treat hypocalcemia. CONCLUSIONS New emphasis on interrelated changes in phosphorus and calcium metabolism, vitamin D, and PTH has led to a deeper understanding of the complexities of CKD/BMD. Key observations
The imperfect storm
reviewed here have created an awareness of the systemic nature of this complication of CKD, the molecular events involving SHPT, the nature of vascular calcification, and the role of calcimimetics. Therapies are aimed at minimizing the consequences of CKD/BMD, thus reducing the severity to that of an imperfect storm. REFERENCES 1. Almaden Y, Hernandez A, Torregrosa V, Canckejo A, Sabate L, Fernandez Cruz L, et al. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol. 1998;9:1845-52. 2. Levin A, Bakris GL, Molitch M, Sulders M, Tian J, Williams LA, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 2007;71:31-8. 3. Block GA, Klasssen PS, Lazarus JM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15:2208-18. 4. Kovesdy CP, Ahmadzadeh S, Anderson JE, KalantarZadeh K. Secondary hyperparathyroidism is associated with higher mortality in men with moderate to severe chronic kidney disease. Kidney Int. 2008;73: 1296-302. 5. Nickolas TL, Leonard MB, Shane E. Chronic kidney disease and bone fracture: a growing concern. Kidney Int. 2008;74:721-31. 6. Hamdy NA, Kanis JA, Benetn MN. Effect of alfacalcidiol on natural course of renal bone disease in mild to moderate renal failure. BMJ. 1995;310:358-63. 7. Bouillon R, Bischoff-Ferrari H, Willett W. Vitamin D and health: from mice and man. J Bone Miner Res. 2008;23:974-9. 8. Pasch A. Bone mass gain after parathyroidectomy. Kidney Int. 2008;74:697-702. 9. Andress DL. Adynamic bone in patients with chronic kidney disease. Kidney Int. 2008;73:1345-54. 10. Brandenburg VM, Floege J. Adynamic bone disease— bone and beyond. Nephrol Dial Transplant Plus. 2008;3:135-147. 11. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42:S1-201. 12. Go AS, Chertow GM, Fan D, McCulloch DE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-1302. 13. Hruska KA, Mathew S, Lund R, Qiu P, Pratt R. Hyperphosphatemia of chronic kidney disease. Kidney Int. 2008;74:148-57. 14. Block GA, Temple E, Hulbert-Shearon TE. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis. 1998;31: 607-14.
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15. Kestenbaum B, Sampson JN, Rudser KD. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005;16:52-8. 16. Voormolen N. High plasma phosphate as a risk factor for decline in renal function and mortality in predialysis patients. Nephrol Dial Transplant. 2007;27: 2909-16. 17. Goodman WG, Goldin J, Juison BD. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478-83. 18. Dhingra R, Sullivan LM, Fox CS, Wang TJ, D’Agostino RB, Gaziano M, et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med. 2007; 167:879-85. 19. Schwarz S, Rivedi BK, Kalantar-Zadeh K, Kovesdy CP. Association of disorders of mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol. 2006;1:825-31. 20. Ketteler M, Rix M, Fan S, Pritchard N, Oestergard O, Chasan-Taber S, et al. Efficacy and tolerability of sevelamer carbonate in hyperphosphatemic patients who have chronic kidney disease and are not on dialysis. Clin J Am Soc Nephrol. 2008;3:1125-50. 21. Salusky IB. A new era in phosphate binder therapy: what are the options? Kidney Int. 2006;70:S10-6. 22. Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol. 2007;18:1637-41. 23. Razzaque MS, Lanske B. The emerging role of the fibroblast growth factor -23-Klotho axis in renal regulation of phosphate homeostasis. J Endocrinol. 2007;194:1-10. 24. Emmett M. What does serum fibroblast growth factor 23 do in hemodialysis patients? Kidney Int. 2008;73:3-8. 25. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444:770. 26. Ferrari SL, Bonjour JP, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab. 2005;90:1519-24. 27. Burnett SM, Gunawardene SC, Bringhurst FR, Juppner H, Lee H, Finkelstein JS. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res. 2006;21:1187. 28. Shigematsu T, Kazama JJ, Yamashita T, Fukumoto S, Hosoya T, Gejyo F, et al. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis. 2004;44:250-6. 29. Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int. 2003;64:2272-9. 30. Isakova T, Gutierrez O, Shah A, Castaldo L, Holmes J,
104
31.
32.
33.
34.
35. 36.
37.
38.
39.
40.
41.
42.
43.
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Lee H, et al. Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol. 2008;19:615-23. Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel A, et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) study. J Am Soc Nephrol. 2007;18:2600-7. Guetierez O, Isakova T, Rhee E, Shah A, Holmes J. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol. 2005;16: 2205-15. Collins MT, Lindsay JR, Jain A, Kelly MH, Cutler CM, Weinstein LS, et al. Fibroblast growth factor-23 is regulated by 1alpha, 25-dihrydoxyvitamin D. J Bone Miner Res. 2005;20:1944-50. Urena-Torres P, Friedlander G, deVernejoul MC. Bone mass does not correlate with the serum fibroblast growth factor 23 in hemodialysis patients. Kidney Int. 2008;73:102-9. Parfitt AM. The hyperparathyroidism of chronic renal failure: a disorder of growth. Kidney Int. 1997;52:3-6. Felsenfeld AJ, Rodriguez M, Aguilera-Tejero A. Dynamics of parathyroid hormone secretion in health and secondary hyperparathyroidism. Clin J Am Soc Nephrol. 2007;2:1283-7. Dusso AS, Pavlopoulos T, Naumovich L, Lu Y, Finch J, Brown AJ, et al. p21 (WAF1) and transforming growth factor-alpha mediate dietary phosphate regulation of parathyroid cell growth. Kidney Int. 2001;59:855-61. Cozzolino M, Lu Y, Finch J, Slatopolsky E, Dusso AS. p21WAF1 and TGF-alpha mediate parathyroid growth arrest by vitamin D and high calcium. Kidney Int. 2001;60:2109-17. Arcidiacono MV, Sato T, Alvarez-Hernandez D, Yang J, Tokumoto M, Gonzalez-Suarez I, et al. EGFR activation increases parathyroid hyperplasia and calcitriol resistance in kidney disease. J Am Soc Nephrol. 2008; 19:310-20. Dusso AS, Sato T, Arcidiacono MV, Alvarez-Hernandez D, Yang J, Gonzalez-Suarez I, et al. Pathogenic mechanisms for parathyroid hyperplasia. Kidney Int Suppl. 2006;102:S8-11. Arcidiacono MV, Cozzolino M, Spiegel N, Tokumoto M, Yang J, Lu Y, et al. Activator protein 2(alpha) mediates parathyroid TGF-{alpha} self-induction in secondary hyperparathyroidism. J Am Soc Nephrol. 2008 [accessed 2008 October 15]. Epub PMID 18579641. Schoppet M, Shroff RC, Hofbauer LC, Shanahan CM. Exploring the biology of vascular calcification in chronic kidney disease: what’s circulating? Kidney Int. 2008;73:384-90. Ix JH, Katz R, Kestenbaum B, Fried LF, Kramer H, Stehman-Breen C. Association of mild to moderate kidney dysfunction and coronary calcification. J Am Soc Nephrol. 2008;19:579-85.
44. El-Abbadi M, Giachelli CM. Mechanisms of vascular calcification. Adv Chronic Kidney Dis. 2007;14:54-66. 45. Luo G, Ducy P, McKee MD. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386:78-81. 46. Ketteler M, Giachelli C. Novel insights into vascular calcification. Kidney Int. 2006;70:S5. 47. Andress DL. Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int. 2006;69:33. 48. Mizobuchi M, Finch JL, Martin D, Slatopolsky E. Differential effects of vitamin D receptor activators in vascular calcification in uremic rats. Kidney Int. 2007; 72:9-16. 49. Al-Aly Z. Metabolic acidosis and vascular calcification: using blueprints from bone to map a new venue for vascular research. Kidney Int. 2008;73:37-44. 50. Mendoza FJ, Lopez L, Montes de Oca P. Metabolic acidosis inhibits soft tissue calcification in uremic rats. Kidney Int. 2008;3:407-14. 51. Harrington PE, Fotsch C. Calcium sensing receptor activators: calcimimetics. Curr Med Chem. 2007;14: 3027-34. 52. Moe SM. Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl. Kidney Int. 2005;67:760-71. 53. deFrancisco AL, Izquierdo M, Cunningham J, Pinera C, Palomar R, Fresnedo GF, et al. Calcium-mediated parathyroid hormone release changes in patients treated with the calcimimetic agent cinacalcet. Nephrol Dial Transplant. 2008;23:2895-901. 54. Valle C, Rodriquez M, Santamaria R, Almaden Y, Rodriguez ME, Canadillas S, et al. Cinacalcet reduces the set point of the PTH-calcium curve. J Am Soc Nephrol. 2008 [accessed 2008 October 17]. Epub PMID 18632847. 55. Coyne DW. Cinacalcet should not be used to treat secondary hyperparathyroidism in stage 3-4 chronic kidney disease. Nat Clin Pract. 2008;4:364-7. 56. deFrancisco ALM, Pinera C, Palomar R. Cinacalcet should be used to treat secondary hyperparathyroidism in stage 3-4 chronic kidney disease. Nat Clin Pract. 2008;4:366-9. 57. Charytan C. Cinacalcet hydrochloride is an effective treatment for secondary hyperparathyroidism in patients with CKD not receiving dialysis. Am J Kidney Dis. 2005;46:58-66. 58. Health Canada online. Sensipar R no longer indicated for chronic kidney disease patients (stages 3 and 4) not receiving dialysis. [accessed 2008 September 9]. Available from: http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/2007/sensipar_hpc-cps_e.html. 59. Chonchoi M, Locatelli F, Abboud HE, Charytan C, de Francicso AL, Jolly S, et al. A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet HCl in participants with CKD not receiving dialysis. Am J Kidney Dis. 2009;53:197-207.