Brenner and Rector's The Kidney, 8th ed.

CHAPTER 52. Mineral Bone Disorders in Chronic Kidney Disease

Sharon M. Moe   Stuart M. Sprague



Phosphorus, 1784



Phosphorous Measurement and Balance, 1784



Phosphorus Homeostasis, 1785



Phosphatonins, 1785



Phosphorus Abnormalities in Chronic Kidney Disease, 1786



Calcium, 1787



Calcium Measurement and Balance, 1787



Calcium Homeostasis, 1788



Calcium-Sensing Receptor, 1789



Clinical Manifestations of Disorders of Phosphorus and Calcium in Chronic Kidney Disease, 1790



Vitamin D, 1790



Synthesis and Measurement of Vitamin D, 1790



Physiologic Effects of Vitamin D, 1791



Nutritional Vitamin D Deficiency, 1793



Parathyroid Hormone, 1794



Regulation and Biologic Effects of Parathyroid Hormone, 1794



Parathyroid Hormone Receptors, 1795



Measurement of Parathyroid Hormone, 1795



Bone, 1796



Bone Biology, 1796



Bone Quality and Fracture, 1797



Bone Biopsy and Histomorphometry in Patients with Chronic Kidney Disease, 1798



The Spectrum of Bone Histomorphometry in Patients with Chronic Kidney Disease, 1800



New Classification of Bone Disease, 1801



Vascular Calcification, 1802



Pathology and Detection of Vascular Calcification, 1802



Vascular Calcification in Patients with Chronic Kidney Disease, 1803



The Pathophysiology of Vascular Calcification, 1805



Inhibitors of Vascular Calcification, 1805



The Relationship Between Bone and Vascular Calcification, 1806



Potential Mechanisms of a Bone-Vascular Calcification Link in Patients with Chronic Kidney Disease, 1807

In people with healthy kidneys, normal serum levels of phosphorus and calcium are maintained through the interaction of two hormones: parathyroid hormone (PTH) and 1,25(OH)2D (calcitriol), the main metabolite that activates the vitamin D receptor (VDR). There is also increasing evidence to support the existence of a hormone, or hormones, that directly control the renal excretion of phosphorus called phosphatonins, although the precise role in normal physiology is not yet clear. These hormones act on three primary target organs: bone, kidney, and intestine. The kidneys play a critical role in the regulation of normal serum calcium and phosphorus concentrations, thus derangements are common in patients with chronic kidney disease (CKD). Abnormalities are initially observed in patients with glomerular filtration rate (GFR) levels less than 60 mL/min and are nearly uniform at a GFR less than 30 mL/min. With the progressive development of CKD, the body attempts to maintain normal serum concentrations of calcium and phosphorus through alterations in the metabolism and regulation of vitamin D, PTH, and the phosphatonins. The progression of kidney disease is eventually associated with the inability to maintain normal mineral homeostasis, ultimately resulting in (1) altered serum levels of calcium, phosphorus, PTH, and vitamin D; (2) disturbances in bone remodeling with the development of fractures; (3) impaired linear growth in children; and (4) extraskeletal calcification in soft tissues and arteries.

Traditionally, this group of disorders has been termed renal osteodystrophy. However, strictly defined, the term renal osteodystrophy means bone abnormalities. In October 2005, a consensus conference was held under the leadership of an international organization, Kidney Disease Improving Global Outcomes (KDIGO; to define and classify renal osteodystrophy. The conclusions of this expert panel was that the manifestations of mineral and bone abnormalities were so diverse and included extraskeletal manifestations, that a new systemic disorder should be defined, called CKD-mineral bone disorder (CKD-MBD).[1] This disorder is defined in Table 52-1 .

In contrast, the term renal osteodystrophy should be reserved to define an alteration of bone morphology in patients with CKD, quantifiable by histomorphometry of bone obtained by biopsy (see Table 52-1 ). Renal osteodystrophy is one measure of the skeletal component of the systemic disorder of CKD-MBD. The rationale for the development of the new term CKD-MBD to define the systemic manifestations, and reserving the term renal osteodystrophy to define bone pathology is threefold. First, to enhance communication and raise awareness of the severity and diversity of the systemic manifestations in CKD related to disorders of mineral and bone metabolism beyond the traditional view of bone. Second, although bone biopsy remains a powerful and informative diagnostic tool for the determination of bone abnormalities, a biopsy-based definition and classification system does not provide an adequate means in clinical practice to clearly identify and classify, and ultimately treat, CKD patients with mineral and bone disorders. Third, although the mechanisms involved are still poorly understood, there is a clear association in patients with CKD between mineral and bone abnormalities and the incidence and severity of fractures, vascular calcification, and cardiovascular disease. These abnormalities that constitute CKD-MBD are interrelated. All three components of CKD-MBD are associated with increased morbidity and mortality in patients with CKD stages 4 and 5. To better understand the complex integration of these abnormalities in CKD, each component is first discussed independently.

TABLE 52-1   -- Kidney Disease Improving Global Outcomes (KDIGO) Classification of Chronic Kidney Disease (CKD)–Mineral Bone Disorder (MBD) and Renal Osteodystrophy



Definition of CKD-MBD



A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:



Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism



Abnormalities in bone turnover, mineralization, volume, linear growth, or strength



Vascular or other soft tissue calcification



Definition of Renal Osteodystrophy



Renal osteodystrophy is an alteration of bone morphology in patients with CKD.



It is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by histomorphometry of bone biopsy.

From Moe S, Drueke T, Cunningham J, et al: Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 69:1945–1953, 2006.

PTH, parathyroid hormone.






Phosphorous Measurement and Balance

Inorganic phosphorus is critical for numerous physiologic functions including skeletal development, mineral metabolism, cell membrane phospholipid content and function, cell signaling, platelet aggregation, and energy transfer through mitochon-drial metabolism. Because of its impor-tance, normal homeostasis maintains serum phosphorous concentrations between 2.5 and 4.5 mg/dL (0.81 and 1.45 mmol/L). Levels are highest in infants and decrease throughout growth, reaching adult levels in the late teens. Total adult body stores of phosphorus are approximately 700 g, of which 85% is contained in bone in the form of hydroxyapatite [(Ca)10(PO4)6(OH)2]. Of the remainder, 14% is intracellular, and only 1% is extracellular. Of this extracellular phosphorus, 70% is organic (phosphate) and contained within phospholipids, and 30% is inorganic. The inorganic fraction is 15% protein bound, and the remaining 85% is either complexed with sodium, magnesium, or calcium or circulates as the free monohydrogen or dihydrogen forms. It is this inorganic fraction that is freely circulating and measured. At a pH of 7.4, it is in a ratio of about 4 : 1 HPO4-2 to H2PO4-1. For that reason, phosphorus is usually expressed in millimoles rather than milliequivalents per liter. Thus, serum measurements reflect only a minor fraction of total body phosphorus and, therefore, do not accurately reflect total body stores in the setting of the abnormal homeostasis that occurs in CKD. The terms phosphorus and phosphate are often used interchangeably, but strictly speaking, the term phosphate means the inorganic freely available form (HPO4-2 and H2PO4-1). However, most laboratories report phosphate, the measurable inorganic component of total body phosphorus as “phosphorus.” For simplicity we will use the abbreviation Pi to represent phosphate and phosphorus.

Pi is contained in almost all foods. The average American diet contains approximately 1000 to 1400 mg Pi per day, whereas the recommended daily allowance (RDA) is 800 mg/day. Approximately two thirds of the ingested Pi is excreted in the urine, and the remaining one third in stool. Unfortunately, foods high in Pi are generally also high in protein. The National Kidney Foundation Dialysis Outcomes Quality Initiative dietary guidelines for patients on maintenance hemodialysis include a daily intake of 1.2 g of protein per kilogram body weight.[2] Protein requirements are even higher in patients receiving peritoneal dialysis than in hemodialysis patients.[3] As a result, it is challenging to balance dietary Pi restriction against the need for adequate protein intake in patients with CKD, especially with malnutrition present in up to 50% of dialysis patients.[4] Indeed, most well-nourished dialysis patients are in positive Pi balance. Roughly 60% to 70% of consumed Pi is absorbed, so about 4000 to 5000 mg of Pi per week enters the extracellular fluid. Therefore, dietary Pi restriction alone, while an important component of effective Pi management, is not sufficient to control serum Pi levels in most dialysis patients. Thus, the treatment of hyperphosphatemia in CKD patients includes optimizing dialysis and phosphate binders as discussed in Chapters 56 and 58 .

There are three organs involved in Pi homeostasis (regulation of extracellular and intracellular Pi levels): intestine, kidney, and bone. The major hormones controlling Pi levels are vitamin D and PTH. More recently, there is increasing evidence for an important role of a group of circulating factors called phosphatonins in the regulation of serum Pi.

Phosphorus Homeostasis

Between 60% and 70% of dietary Pi is absorbed by the gastrointestinal tract, in all intestinal segments. Pi absorption is dependent on both passive transport related to the concentration in the intestinal lumen (i.e., increased after a meal) and active transport stimulated by 1,25(OH)2D (calcitriol) and PTH. The absorption is dependent on luminal Pi concentration, and occurs through the epithelial brush border sodium phosphate cotransporter (Npt2b) using energy from the basolateral sodium-potassium ATPase transporter. The Npt2b sits in the terminal web, just below the brush border in ready-to-use vesicles that are then transported to the brush border in response to acute and chronic changes in Pi concentration.[5] Medications or foods that bind intestinal Pi (antacids, phosphate binders, and calcium) can decrease the net amount of Pi absorbed by decreasing the free phosphate for absorption. Calcitriol can up-regulate the sodium-phosphate cotransporter and, therefore, actively increase Pi absorption. However, in contrast to calcium, the active vitamin D-mediated absorption of Pi is a minor component of total absorption, supported by data that there is near-normal intestinal absorption of Pi in the absence of vitamin D. However, similar to calcium, the kidneys play a critical role in the maintenance of normal homeostasis.

Most inorganic Pi is freely filtered by the glomerulus. Approximately 70% to 80% of the filtered load of Pi is reabsorbed in the proximal tubule, which serves as the primary regulated site of the kidney. The remaining approximately 20% to 30% is reabsorbed in the distal tubule. Factors that increase Pi excretion are primarily increased plasma Pi concentration and PTH. Conversely, acute or chronic Pi depletion decreases excretion. Renal Pi excretion is also increased, although to a lesser extent, by volume expansion, metabolic acidosis, glucocorticoids, and calcitonin. Additional factors that may decrease Pi excretion include growth hormone and thyroid hormone. The majority of this regulation occurs in the proximal tubule through the sodium-phosphate cotransporter Npt2b.[5] Similar to the intestine, the Npt2b rests in the terminal web, and can be immediately moved to the brush border in the presence of acute or chronic phosphate depletion. Alternatively, after a phosphate load or in the presence of PTH, the exchanger is removed from the brush border and catabolized.[6]


Renal Pi excretion is exquisitely sensitive to changes in the serum Pi level. This has led to the concept that there are hormones that regulate Pi excretion, called phosphatonins. This concept is further supported by the observation that certain tumors can produce renal phosphate wasting, and that surgical removal of the tumors cures the wasting. This hypophosphatemia causes bone changes such as osteomalacia, leading to the term oncogenic osteomalacia, despite the fact that many of these tumors are not malignant. The clinical findings in oncogenic osteomalacia parallel that in X-linked hypophosphatemia rickets (XLH) and include hypophosphatemia, normocalcemia, inappropriately normal or low 1,25(OH)2D concentrations, and skeletal defects due to osteomalacia. Three phosphatonins have now been identified: secreted frizzled-related protein 4, matrix extracellular phosphoglycoprotein, and fibroblast growth factor 23 (FGF23).[7] Mutations in FGF23 have been identified in XLH rickets,[8] and elevated serum levels of FGF23 have been found in both XLH and oncogenic osteomalacia.[9] FGF23 appears to be the most relevant in the setting of CKD and thus is discussed in more detail.

FGF23 is predominately produced from bone cells (osteocytes and bone lining cells) during active bone remodeling, but mRNA is also found in heart, liver, thyroid/parathyroid, intestine and skeletal muscle.[10] FGF23 regulates Npt2a independently of PTH and affects the conversion of 25 to 1,25(OH)2D by inhibition of the 1α-hydroxylase enzyme in the renal tubules,[11] leading to hypophosphatemia and inappropriately normal or low 1,25(OH)2D levels. Mice with targeted ablation of FGF23 confirm these physiologic effects of FGF23.[12] Overexpression of FGF23 in mice also leads to the progressive development of secondary hyperparathyroidism.[13] FGF23 gene expression in bone is regulated by both Pi and 1,25(OH)2D,[14] even in uremic animals.[15] Vitamin D receptor (VDR) null mice have markedly reduced serum FGF23 levels compared with wild-type mice. When these animals are fed a rescue diet of high calcium and high phosphorus, FGF23 levels are increased, indicating that Pi-mediated changes in FGF23 are independent of the effects of vitamin D.[16] Another similar study in VDR null mice found that when given separately, only an increased calcium diet, not an increased phosphorus diet, led to changes in FGF23 levels.[17] In vitro work demonstrates that FGF23 binds to the ubiquitously expressed FGF receptors, and that this binding is enhanced by Klotho, a protein thought to be involved in aging[18] and down-regulated in CKD.[19] These data support both a pathologic and physiologic role of FGF23 in Pi homeostasis.

A summary of the physiologic response to hyperphosphatemia is depicted in Figure 52-1 . As phosphorus levels increase (or there is a chronic phosphorus load), both PTH and FGF23 are increased, the latter from bone. Both the elevated PTH and FGF23 increase urinary phosphorus excretion. The two hormones differ in respect to their effects on the vitamin D axis. PTH stimulates 1-alpha hydroxylase activity, thereby increasing the production of 1,25(OH)2D, which, in turn, negatively feeds back on the parathyroid gland to decrease PTH secretion. In contrast, FGF23 inhibits 1-alpha hydroxylase activity, thereby decreasing the production of 1,25(OH)2D feeding back to inhibit further secretion of FGF23. Because PTH is also stimulated in response to hypocalcemia, this proposed homeostatic loop implies that the effects of PTH would predominate in the setting of high phosphorus and low calcium, whereas FGF23 would predominate in the setting of high phosphorus and high calcium, because the latter would inhibit PTH secretion.[7]

FIGURE 52-1  Regulation of serum phosphorus levels. As phosphorus levels increase (or there is a chronic phosphorus load), both parathyroid hormone (PTH) and and fibroblast growth factor 23 (FGF23) are increased. Both the elevated PTH and FGF23 increase urinary phosphorus excretion. The two hormones differ in respect to their effects on the vitamin D axis. PTH stimulates 1-α hydroxylase activity, thereby increasing the production of 1,25(OH)2D, which, in turn, negatively feeds back on the parathyroid gland to decrease PTH secretion. In contrast, FGF23 inhibits 1-α hydroxylase activity, thereby decreasing the production of 1,25(OH)2D. Low calcitriol levels inhibit FGF23. (Solid line, stimulates; dashed line, inhibits.)


Phosphorus Abnormalities in Chronic Kidney Disease

The ability of the kidneys to control Pi becomes impaired at glomerular filtration rates of approximately 50 to 60 mL/min. Frank hyperphosphatemia is observed in most subjects once the GFR is less than 25 to 30 mL/min.[20] The maintenance of normal levels of Pi when the GFR is between 50 and 30 mL/min has been thought to occur at the expense of continued increase in PTH secretion. This finding was first observed by Slatopolsky and colleagues based on data in a dog model, with progressive kidney resection resembling progressive CKD. In animals treated with a normal Pi diet, fractional Pi excretion rose and PTH levels increased more than 20-fold. However, in animals fed a low-Pi diet, there was no change in fractional Pi excretion and no change in the PTH levels. This rise in serum PTH at the expense of maintaining normal serum Pi is a major mechanism by which secondary hyperparathyroidism develops and is often referred to as the “tradeoff hypothesis.”[21] Studies in humans have demonstrated that an oral load of Pi increased PTH. However it also decreased ionized calcium, and thus, both hyperphosphatemia and hypocalcemia may have caused the increase in PTH. However, subsequent human studies controlled for changes in calcium and still found that Pi loading increased PTH, and conversely, Pi restriction inhibited the rise in PTH.[22]Recent studies in humans also support the idea that hyperphosphatemia occurs earlier than had been previously appreciated. Although Pi levels are maintained in the “normal” range in patients with CKD stages 3 and 4 (GFR 60-30, and 15-30 mL/min), there is a gradual increase in the serum level, with progressive CKD indicating that a new steady state of slightly higher serum Pi and increased PTH is reached. For example, in a cross-sectional study throughout the United States, the mean serum Pi levels in patients with CKD stage 3 was 3.5 ± 0.5 mg/dL (n = 65), stage 4 was 4.1 ± 1.1 mg/dl (n = 113), and stage 5 not on dialysis 4.4 ± 1.1 (n = 22).[23]

Additional studies in isolated parathyroid glands or cells confirm a direct role of Pi on the regulation of PTH synthesis.[24] The mechanism by which Pi regulates PTH is multifactorial. First, Pi may affect the regulation of intracellular calcium in parathyroid cells, resulting in the inhibition of arachidonic acid synthesis and cytosolic phospholipase A2.[25] Second, Pi may also increase cell proliferation and growth through transforming growth factor-α (TGF-α), mediated through the epidermal growth factor receptor.[26] Third, hyperphosphatemia also reduces the expression of the calcium-sensing receptor (CaR),[27] thereby decreasing the ability of the parathyroid gland to respond to changes in ionized calcium. Fourth, studies have also revealed the presence of cytosolic proteins in the parathyroid gland that bind the 3′ untranslated region (3′UTR) of the PTH mRNA and prevent degradation, thus stabilizing the mRNA.[28] Animal studies have revealed stabilization of the mRNA transcript in glands from hypocalcemic animals but increased degradation in glands from hypophosphatemic animals[28] and decreased PTH mRNA degradation in uremic animals.[29] Additional studies have demonstrated that the cytosolic stabilizing protein is adenosine-uridine-rich-binding protein (AUF-1),[30] and that this protein is also modified by calcimimetics.[31]Lastly, hyperphosphatemia indirectly increases PTH by inhibiting the activity of 1-alpha hydroxylase, thereby reducing the conversion of 25(OH)D to 1,25(OH)2D. This reduction in 1,25(OH)2D directly leads to increased PTH secretion. These studies demonstrate the complex regulation of PTH secretion.

With new knowledge of the role of phosphatonins such as FGF23 in normal Pi homeostasis, emerging data also indicate the possible role of FGF23 in abnormal Pi homeostasis in CKD. Initial studies clearly demonstrated high levels of FGF23 in patients with CKD[32] but were questioned owing to the possibility that the assays were measuring inactive fragments. Additional analyses using a two-site immunoassay have confirmed elevated levels in CKD, with an increase as GFR declines.[33] These elevated levels of FGF23 would further decrease the circulating levels of 1,25(OH)2D, which, together with hyperphosphatemia, would exacerbate secondary hyperparathyroidism.[34] Indeed, recent studies in dialysis patients have demonstrated that serum FGF23 levels predict the development of secondary hyperparathyroidism[35] and the responsiveness to calcitriol.[36] At present, there is no evidence that parathyroid glands are a source of FGF23, even in hyperplastic glands of CKD,[35] yet levels of FGF23 decline after parathyroidectomy,[37] perhaps in response to the hypophosphatemia from the hungry bone syndrome. Therefore, the data to date suggest that an elevation in FGF23 in the setting of CKD is a factor in the development of secondary hyperparathyroidism. It is not yet known if elevations of FGF23 also contribute to abnormal bone mineralization. However, FGF23 has been shown to inhibit osteoblastic mineralization in vitro.[38] Interestingly, it appears that FGF23 may actually be protective against vascular calcification, because FGF23 null mice have vascular calcification that is mediated through the effects of vitamin D.[39] Future studies continue to lend insight into the physiologic and pathologic manifestations of the elevated FGF23 observed in CKD patients.


Calcium Measurement and Balance

Serum calcium levels are normally tightly controlled within a narrow range, usually 8.5 to 10.5 mg/dL (2.1–2.6 mmol/L). However, the serum calcium level is a poor reflection of overall total body calcium, because serum levels are only 0.1% to 0.2% of extracellular calcium, which, in turn, is only 1% of total body calcium. The remainder of total body calcium is stored in bone. Ionized calcium, generally 40% of total serum calcium levels, is physiologically active, whereas the nonionized calcium is bound to albumin or anions such as citrate, bicarbonate, and Pi. In the presence of hypoalbuminemia, there is a relative increase in the ionized calcium relative to the total calcium, thus total serum calcium may underestimate the physiologically active (ionized) serum calcium. A commonly used formula for estimating the ionized calcium from total calcium is to add 0.8 mg/dL for every 1-mg decrease in serum albumin below 4 mg/dL. However, it should be emphasized that this is indeed an estimate, and ionized calcium should be measured if more precise assessment of serum calcium levels are needed. Serum levels of ionized calcium are maintained in the normal range by inducing increases in the secretion of PTH[40] ( Fig. 52-2 ). PTH acts to increase bone resorption, increase renal calcium reabsorption, and increase the conversion of 25(OH)D to 1,25(OH)2D in the kidney, thereby increasing gastrointestinal calcium absorption. In individuals with normal homeostatic mechanisms, these interactions of PTH and vitamin D metabolites at target organs, including the kidney, maintain the serum ionized calcium level within the normal range to ensure proper cellular function.

FIGURE 52-2  Normalization of serum calcium by multiple actions of parathyroid hormone (PTH). Serum levels of ionized calcium are maintained in the normal range by inducing increases in the secretion of PTH. PTH acts to increase bone resorption, increase renal calcium reabsorption, and to increase the conversion of 25(OH)D to 1,25(OH)2D in the kidney, thereby increasing gastrointestinal calcium absorption. The green boxes are abnormal in chronic kidney disease (CKD), leading to altered calcium homeostasis.  (From Moe SM: Calcium, phosphorus, and vitamin D metabolism in renal disease and chronic renal failure. In Kopple JD, Massry SG (eds): Nutritional Management of Renal Disease. Philadelphia: Lippincott Williams & Wilkins, 2004, pp 261-285.)



In normal individuals, the net calcium balance (intake - output) varies with age. Children and young adults are usually in a slightly positive net calcium balance to enhance linear growth; beyond age 25 to 35 years, when bones stop growing, the calcium balance tends to be neutral.[41] Normal individuals have protection against calcium overload by virtue of their ability to increase renal excretion of calcium and reduce intestinal absorption of calcium by actions of PTH and 1,25(OH)2D. However, in CKD the ability to maintain normal homeostasis, including a normal serum ionized calcium level and appropriate calcium balance for age, is lost.

The K/DOQI guidelines recommend a limit on the daily ingestion of calcium in the form of calcium-containing phosphate binders to 1500 mg elemental calcium per day. This is assuming a 500-mg intake per day from diet, for a total intake of 2000 mg per day.[42] This level is slightly below the Institute of Medicine's recommended maximum intake of calcium of 2500 mg per day for healthy adults. Although early studies in patients with markedly advanced CKD not yet on dialysis revealed negative calcium balance, this was in patients not taking vitamin D or calcium binders. Now it is common for patents with CKD 5 to have a signi-ficant intake of calcium from calcium-containing phosphate binders. Unfortunately, we lack recent formal metabolic studies. However, one can extrapolate the impact of this intake from several studies.[43] In patients with CKD, approximately 18% to 20% of calcium is absorbed from the intestine. If patients are taking 2000 mg per day in total elemental calcium intake (1500 mg from binder and 500 mg from diet), and 20% is absorbed, then the net intake is 400 mg per day. On hemodialysis days, this figure is slightly greater because approximately 50 mg of calcium is infused with a 4-hour dialysis treatment using 2.5 mEq/L dialysate calcium concentration. In peritoneal dialysis patients, there is a slight efflux of calcium using a 2.5 mEq/L dialysate in four daily exchanges. Thus, the absorbed intake of elemental calcium from a 2000 mg elemental calcium diet (plus binders) and 2.5 mEq/L calcium dialysate would be 350 to 450 mg/day. In patients taking most forms of vitamin D, net intes-tinal absorption would be enhanced, thereby increasing the net intake further. The excretion of calcium in stool and sweat ranges from 150 to 250 mg per day,[42] and if patients have residual urine output, the excretion rate may increase by 50 to 100 mg per day.[44] Thus, with 400 mg net absorbed calcium, the patients will still be in positive calcium balance (350 to 450 mg in versus 220 to 350 mg out) at this K/DOQI maximum when taking 2000 mg of total elevated calcium per day.

In an anuric patient, this positive balance or calcium load has only two “compartments” to go to: bone and extraskeletal locations. If the bone is normally remodeling, the calcium should be deposited there; however, normal bone is not common in dialysis patients (see later). If no calcium-containing phosphate binder is taken, the patients should be in a neutral to slightly negative balance depending on stool and sweat output. It is important to emphasize three points: First, this 1500-mg maximum intake of elemental calcium from phosphate binders in the K/DOQI guidelines is based on opinion, because there are no recent formal metabolic balance studies. Second, in patients taking vitamin D, the intestinal absorption of calcium will be increased and thus the amount of calcium in the form of binder should probably be decreased. Third, in patients with low turnover bone disease, the bone cannot take up calcium[45]; thus, it is more likely to deposit in extraskeletal sites, and that is the rationale for the K/DQOI recommendation that calcium containing phosphate binders not be used in patients with intact PTH levels of less than 150 pg/mL.[42]

Calcium Homeostasis

Calcium absorption across the intestinal epithelium occurs through a vitamin D-dependent, saturable (transcellular through epithelial calcium transporters) and vitamin D-independent, nonsaturable (paracellular) pathway. The intracellular calcium then associates with calbindin D9K to be ferried to the basolateral membrane, where calcium is removed from the enterocytes via the calcium-ATPase. The duodenum is the major site of calcium absorption, although the other segments of the small intestine and the colon also contribute to net calcium absorption. Calbindin D9K is strongly up-regulated by 1,25(OH)2D, but additional data indicate that 1,25(OH)2D also regulates epithelial calcium transporters[46] ( Fig. 52-3 ). The epithelial uptake of calcium occurs through TRPV5 (animal homologs ECaC, CaT2) and TRPV6 (animal homologs ECaC2, CaT1) transporters located on the apical membrane. Both transporters are highly selective for calcium.[46] Activation of the channels lead to large inward fluxes of calcium, and only small outward fluxes indicate that these channels are inwardly rectifying. The channels are subject to calcium feedback inhibition and are regulated by 1,25(OH)2D, as is calbindin D28K.[47] TRPV5-/- mice were recently generated and demonstrated normal plasma calcium concentration, calciuresis, and significantly elevated 1,25(OH)2D levels. The mice had compensatory increases in TRPV6 and calbindin-D9k levels in the duodenum, leading to calcium hyperabsorption from the intestine to maintain normal serum levels in the face of increased urine excretion.[48] In contrast, TRPV6-/- mice show a significant intestinal calcium malabsorption, suggesting that TRPV6 is the main transporter responsible for intestinal 1,25(OH)2D-dependent calcium absorption.[49] In addition, TRPV6 is increased with estrogen supplementation in ovariectomized VDR-/- mice, confirming a vitamin D-independent effect of estrogen on intestinal calcium absorption.[46]

FIGURE 52-3  Epithelial calcium active transport. Calcium enters from the luminal side via the TRPV5 and TRPV6 channels, binds to calbindin (9Kd in intesting, 28Kd in kidney), and is extruded at the basolateral membrane by the Na/Ca exchanger (NCX1) or the plasma membrane Ca/ATPase (PMCA1b). 1,25(OH)2D stimulates calcium absorption by affecting all of these transport mechanisms.  (From van de Graaf SF, Hoenderop JG, Bindels RJ: Regulation of TRPV5 and TRPV6 by associated proteins. Am J Physiol Renal Physiol 290:F1295–F1302, 2006.)



In the kidney, the majority (60% to 70%) of calcium is reabsorbed passively in the proximal tubule driven by a transepithelial electrochemical gradient that is generated by sodium and water reabsorption. In the thick ascending limb, another 10% of calcium is reabsorbed through paracellular transport. This paracellular reabsorption requires the specific protein paracellin-1, and genetic defects in paracellin-1 lead to a syndrome of hypercalcuria and hypomagnesemia.[50] Although the bulk of total renal calcium reabsorption is paracellular, the regulation of reabsorption is via transcellular pathways that occur in the distal convoluted tubule (see Fig. 52-3 ), the connecting tubule, and the initial portion of the cortical collecting duct. The calcium enters these cells via TRPV5 and TRPV6 calcium channels down electrochemical gradients. In the cells, calcium binds with calbindin D28K and is transported to the basolateral membrane, where calcium is actively reabsorbed by the Na2+/Ca2+ exchanger (NCX1) and/or the Ca2+-ATPase (PMCA1b).[46] Both TRPV5 and TRPV6 are localized to these distal nephron segments, but TRPV5 is the most critical, because TRPV5-/- animals have severe hypercalcuria. PTH up-regulates TRPV5, calbindin D28K, NCX1 and PMCA1b in these distal tubule segments to facilitate calcium reabsorption.[51] Calcium supplementation (in 1-alpha hydroxylase-deficient mice to remove confounding effects of vitamin D) similarly up-regulates all four proteins.[52] Both VDR-/- and 1-alpha hydroxylase-deficient animals have down-regulation of TRPV5 and calbindin D28K, [48] [53] demonstrating a critical role of vitamin D in regulating renal calcium handling (see Fig. 52-3 ). In addition, estrogen (in VDR knockout animals) acts predominately by increasing TRPV5 expression.[52] These data support a critical role of the kidney in normal calcium homeostasis, mediated by calcium, PTH, vitamin D, and estrogen.

Calcium-Sensing Receptor

Physiologic studies in animals and humans in the 1980s demonstrated the rapid release of PTH in response to small reductions in serum ionized calcium,[54] lending support to the existence of a calcium sensor in the parathyroid glands. This CaR was cloned in 1993,[55] leading to a revolutionary understanding of the mechanisms by which cells adjust to changes in extracellular calcium. The CaR was shown to belong to the super family of G-protein-coupled receptors. The human (1078 amino acids) and bovine (1085 amino acids) CaR are glycosylated proteins with a very large extracellular domain, seven membrane-spanning segments, and a relatively large cytoplasmic domain. The CaR is localized with caveolin 1 at the cell membrane in bovine parathyroid cells.[56] Activation of the CaR stimulates ( Fig. 52-4 ) phospholipase C, leading to increased ionositol 1,4,5-triphosphate, which mobilizes intracellular calcium and decreases PTH secretion. In contrast, inactivation reduces intracellular calcium and increases PTH secretion. In addition, CaR activation also leads to intracellular accumulation of cyclic adenosine monophosphate (cAMP)[57] and activation of mitogen-activated protein kinase.[58] The primary ligand for the CaR is Ca+2, but it also senses other divalent and polyvalent cations, including Mg+2, Be+2, La+3, Gd+3, and polyarginine to name a few.[57] In addition, recent studies indicate that the CaR can also act as sensors for pH[59] and L-amino acids.[60]

FIGURE 52-4  Calcium-sensing receptor (CaR). Activation of the CaR by calcium stimulates phospholipase C, leading to increased ionositol 1,4,5-triphosphate (IP3), which mobilizes intracellular calcium and inhibits parathyroid hormone (PTH) synthesis. A decrease in serum calcium inhibits intracellular signaling leading to increased PTH synthesis and secretion.  (From Friedman PA, Goodman WG: PTH(1-84)/PTH(7-84): a balance of power. Am J Physiol Renal Physiol 290:F975–F984, 2006.)



The CaR is expressed in organs controlling calcium homeostasis such as the parathyroid gland, thyroid C cells, intestine, and kidney. In addition, CaR is also expressed in other tissues such as brain, epidermis, stomach, pancreas, liver, breast, ovary, placenta, and bone marrow cells.[61] However, its expression in bone is still controversial. [62] [63] The expression of the CaR is regulated by 1,25(OH)2D in parathyroid, thyroid and kidney cells. However, studies have failed to find evidence for calcium regulation of the gene expression of the CaR.[64] Interestingly, a recent study found that interleukin-1β up-regulated CaR mRNA.[65] CaR-/- mice die shortly after birth due to hypercalcemia, hypocalcuria, and hyperparathyroidism. If the PTH gene is also ablated, the mice survive and most organs appear histologically normal, with healing of bone mineralization defects but no change in hypocalcuria. This suggests that the renal effects of CaR are both dependent and independent of PTH.[66] In uremic animals, the expression of CaR in the parathyroid gland is down-regulated by a high Pi-diet[67] and occurs after the onset of parathyroid hyperplasia. Once down-regulated, the expression can be rescued by a low-Pi diet.[27] In uremic rats fed a high-Pi diet, activation of the CaR by calcimimetics modify PTH mRNA levels by altering AUF1 activity.[31] The use of calcimimetics to treat secondary hyperparathyroidism is discussed in Chapter 56 .

In the kidney, the CaR is expressed in mesangial cells and throughout the tubules. The highest density of protein expression is in the cortical thick ascending limb. Interestingly, the CaR is found on the apical membrane of the proximal tubule and the inner medullary collecting duct, and also on the basolateral membrane of the medullary and cortical thick ascending limb and distal convoluted tubule, suggesting that the CaR can be trafficked to either side of these polarized cells.[68] Activation of CaR on the thick ascending limb leads to increased intracellular free Ca+2, which ultimately increases several cell signaling pathways. It is hypothesized that these changes lead to decreased paracellular calcium reabsorp-tion, although the mechanism varies, depending on the methodology of the studies.[69] Interestingly, in the rat inner medullary collecting duct, the CaR is present within the same endosomes that contain the vasopressin regulated water channel aquaporin-2. This CaR responds to increases in intraluminal calcium concentration by reducing antidiuretic hormone-stimulated water absorption.[70] Teleologically, this may provide a mechanism by which the urine can stay dilute in the face of hypercalcemia/hypercalcuria to avoid dangerous calcium precipitation, and may explain the polyuria observed in patients with hypercalcemia.

Clinical Manifestations of Disorders of Phosphorus and Calcium in Chronic Kidney Disease

Epidemiologic studies have demonstrated that the serum phosphorus and the calcium × phosphorus product are associated with poor outcomes dating back to as early as the 1990s. These early studies ascribed the effect of phosphorus as the primary cause of increased mortality. However, these studies were from data sets from more than 15 years ago, during the widespread use of aluminum-containing phosphate binders, and before aggressive use of vitamin D metabolites for the treatment of secondary hyperparathyroidism. More recently, the association of elevated serum phosphorus and mortality has been confirmed in several studies. Block and colleagues used a large dialysis data base of more than 40,000 patients undergoing hemodialysis in the United States. They found an association with increased mortality for Pi levels greater than 5.0 mg/dL, with a progressive increase in mortality with increasing Pi levels.[71] In this same study, the relative risk of death correlated directly to serum calcium levels, increasing 47% as the calcium level increased from 9 to 9.5 mg/dL to more than 11 mg/dL.[71] Elevated serum Pi and calcium × phosphorus (Ca × Pi) product is also associated with poor outcomes when assessed as time-averaged values.[72] Multiple studies have confirmed this association.[73]

In a Canadian cohort, combinations of mineral metabolism parameters were modeled (overall P = 0.003). The authors found that the combinations of high serum Pi and Ca with high PTH (relative risk [RR], 3.71; 95% confidence interval [CI], 1.53 to 9.03; P = 0.004) and low PTH (RR, 4.30; 95% CI, 2.01 to 9.22; P < 0.001) had highest risks for mortality as compared with the combination of high PTH with normal serum Ca and Pi and that the risk is varied for duration of dialysis.[74] Importantly, the study by Block and colleagues in 2004 examined the mortality risk attributable to various factors, taking into account the strength of the association (i.e., relative risk) and prevalence across the population. [43] [71] The results ( Fig. 52-5 ) demonstrate that hyperpho-sphatemia conveyed a very high population attributable risk of death (even more than anemia and a low urea reduction ratio), and that the combination of hyperphosphatemia, hypercalcemia, and elevated PTH accounted for 17.5% of the observed, explainable mortality risk in hemodialysis patients. Additional epidemiologic studies have revealed the major cause of death in the presence of hyperphosphatemia and hypercalcemia to be cardiovascular events.[75] Furthermore, studies have demonstrated an association of hyperphosphatemia with increased vascular stiffening,[76] arterial calcification and calciphylaxis,[77] and valvular calcification.[78] In addition, increases in serum phosphorus have been associated with increased mortality and cardiovascular events in patients without identified CKD with docu-mented coronary artery disease.[79] The mechanism by which hyperphosphatemia leads to extraskeletal calcification is discussed in further detail in the section on vascular calcification.

FIGURE 52-5  Mortality risk of disturbances in mineral metabolism. A study of 40,538 patients identified the population attributable risk, or the percentage of risk of mortality in patients with end stage kidney disease (ESKD) attributable to various factors, and demonstrated that hyperphosphatemia conveyed the greatest risk of mortality (even more than anemia and low urea reduction ratio [URR]), and that the combination of hyperphosphatemia, hypercalcemia, and elevated parathyroid hormone (PTH) accounted for 17.5% of the observed mortality.  (From Moe SM, Chertow GM: The case against calcium-based phosphate binders. Clin J Am Soc Nephrol 1:697–703, 2006, using data from Block GA, Klassen PS, Lazarus JM, et al: Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 15:2208–2218, 2004.)




Synthesis and Measurement of Vitamin D

Cholesterol is synthesized to 7-dehydrocholesterol, which, in turn, is metabolized in the skin to vitamin D3 ( Fig. 52-6 ). This reaction is facilitated by ultraviolet light and increased temperature, and is therefore reduced in individuals with high skin melanin content, and inhibited by sunscreen of SPF 8 or greater. In addition, there are dietary sources of vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). A difference between D2 (plant source) and D3(animal source) compounds is the presence of a double bond (D2) between carbon number 22 and 23 in the side chain. Once in the blood, vitamin D2 and D3 bind with vitamin D-binding protein (DBP) and are carried to the liver, where they are hydroxylated by CYP27A1 in an essentially unregulated manner to yield 25(OH)D, often called calcidiol. Once converted to calcidiol, there appears to be no difference in their biologic activity. Of note, most assays for 25(OH)D cannot differentiate the two distinct forms, 25(OH)D2 from 25(OH)D3, so the abbreviation 25(OH)D is used. Calcidiol is then converted in the kidney to 1,25(OH)2D by the action of 1α-hydroxylase (CYP27B1). This active metabolite is also degraded by another kidney enzyme, 24,25-hydroxylase (CYP24), providing the primary metabolism of the active compound. However, this same 24,25 hydroxylase also hydroxylates 25(OH)D, yielding 24,25(OH)2D. Some controversy exists as to whether this enzyme functions as a degradation pathway or an alternative activation pathway, because 24,25(OH)2D may have an effect on bone.[80] Although there are more than 40 vitamin D metabolites identified,[81] the predominate effects of vitamin D in the body are exerted through the actions of 1,25(OH)2D (calcitriol).

FIGURE 52-6  Overview of vitamin D metabolism. Vitamin D is obtained from dietary sources, and is metabolized through ultraviolet light from 7-DHC in the skin. Both sources (diet and skin) of vitamin D2 and vitamin D3 bind to vitamin D-binding protein (VDBP) and circulate to the liver. In the liver, vitamin D is hydroxylated by CYP27A1 to 25(OH)D, commonly referred to as calcidiol. Calcidiol is then further metabolized to calcitriol by the 1-a-hydroxylase enzyme (CYP27B1) at the level of the kidney. The active metabolite 1,25(OH)2D (calcitriol) acts principally on the target organs of intestine, parathyroid (PTH) gland, bone cell precursors, and the kidney. Calcitriol is metabolized to the inert 1,24,25(OH)3D through the action of the 24,25-hydroxylase enzyme (CYP24). Calcidiol is similarly hydroxylated to 24,25(OH)2D.  (Adapted from Moe SM: Renal osteodystrophy. In Pereira BJG, Sayegh M, Blake P (eds): Chronic Kidney Disease: Dialysis and Transplantation, 2nd ed. Philadelphia, Elsevier Saunders, 2004.)

DBP is an approximately 58-kDa protein synthesized in the liver. Human serum levels are between 4 and 8 μM, and the protein has a half life of 3 days. The parent vitamin D, 25(OH)D, and 1,25(OH)2D are carried in the circulation by DBP, but the greatest affinity is for 25(OH)D.[82] Targeted gene disruption studies indicate that the primary role of DBP is to maintain stable serum stores of vitamin D metabolites and modulate the rates of bioavailability, activation, and end organ responsiveness.[83] Deficiency of DBP is known to occur in nephrotic syndrome due to urinary protein losses, leading to low 25(OH)D serum levels.[84] At the cellular level, receptor (megalin)–mediated endocytosis of both calcidiol and calcitriol occurs.[81] Inside the cell, 1,25(OH)2D can be inactivated by mitochondrial 24-hydroxylase or it can bind to the VDR in the cytoplasm. Once the VDR-ligand binding has occurred, the VDR translocates to the nucleus, where it heterodimerizes with the retinoid X receptor ( Fig. 52-7 ). This complex binds the vitamin D response element of target genes and recruits transcription factors and corepressors/activators that modulate the transcription.[81] These corepressors and coactivators appear to be specific for the ligand, and thus different forms and analogs of vitamin D may produce different effects.[85] Degradation of calcitriol is believed to occur principally in the kidney, from side cleavage and oxidation to form 24,25(OH)2D3.[81]

FIGURE 52-7  Current model for the control of vitamin D receptor (VDR)–mediated actions of 1,25(OH)2D3. The bioactivated vitamin D hormone 1,25(OH)2D3 circulates bound to the D-binding protein (DBP). 1,25(OH)2D3 is then taken up by target cells and targeted to intracellular D-binding proteins (IDBPs) to mitochondrial 24-hydroxylase or to the VDR. The 1,25(OH)2D3-VDR complex heterodimerizes with the retinoic acid receptor, and then binds to specific sequences in the promoter regions of the target gene. The DNA-bound heterodimer attracts components of the RNA polymerase II complex and nuclear transcription regulators.  (From Dusso AS, Brown AJ, Slatopolsky E: Vitamin D. Am J Physiol Renal Physiol 289:F8–F28, 2005.)



Physiologic Effects of Vitamin D

1,25(OH)2D mediates its cellular function through both nongenomic and genomic mechanisms. Calcitriol facilitates the uptake of calcium in intestinal and renal epithelium by increasing the activity of the voltage-dependent calcium channels TRPV5 and TRPV6. Calcitriol then enhances the transport of calcium through and out of the cells by up-regulating the calcium transport protein calbindin-D (9kd in intestine, and 28kd in kidney) and the basolateral calcium-ATPase,[46] as detailed earlier in this chapter. In addition, 1,25(OH)2D also directly suppresses PTH synthesis, as described above,[86] and is important for normal bone turnover. [87] [88] Elevated serum levels of PTH increases 1-a-hydroxylase activity in the kidney, thereby increasing serum 1,25(OH)2D levels. This results in a rise in serum calcium, and then 1,25(OH)2D feeds back on the parathyroid gland, decreasing PTH secretion, thus completing the typical endocrine feedback loop. PTH does not directly inhibit its own synthesis, which is one reason why PTH levels increase in the presence of renal failure, in which 1,25(OH)2D is no longer synthesized in sufficient amounts. The 1-a-hydroxylase enzyme in the kidney is also the site of regulation of 1,25(OH)2D synthesis by numerous other factors, including low calcium, low phosphorus, estrogen, prolactin, growth hormone, 1,25(OH)2D itself,[89] and FGF23.[17]

1,25(OH)2D directly inhibits PTH synthesis. In vivo in the rat, a single small dose of calcitriol decreases PTH secretion by nearly 100%. Early studies also found that radiolabeled 1,25(OH)2D localized in the parathyroid gland, the gland expressed the VDR, and 1,25(OH)2D decreased mRNA for pre-pro PTH.[90] The importance of 1,25(OH)2D in the regulation of PTH was further characterized in animal models. In these studies, hypocalcemia and hyperphosphatemia stimulated PTH, whereas 1,25(OH)2D inhibited PTH.[91] Definitive human studies demonstrated that oral 1,25(OH)2D, but not the precursor hormone vitamin D3, suppressed PTH in patients undergoing dialysis.[92] Intravenous 1,25(OH)2D also suppressed PTH with effects observed before increases in serum calcium.[93] In vitamin D knockout animal models, there is parathyroid gland hyperplasia, despite normalization of serum calcium. However, gland growth can be ameliorated by exogenous administration of calcitriol, even in the absence of VDR, demonstrating a role of 1,25(OH)2D in the regulation of parathyroid gland growth.[88] These studies have led to the widespread use of calcitriol and its analogs in the treatment of secondary hyperparathyroidism described in Chapter 56 .

The direct effects of the vitamin D system on bone have been difficult to differentiate from secondary effects of hypocalcemia and hyperparathyroidism in vitamin D-deficient models. However, over the past decade, the physiologic functions of vitamin D on bone have been better elucidated through the use of genetic knockout animals, with targeted disruption of either the 1a hydroxylase (1a(OH)ase-/-) or the VDR gene (VDR-/-), or double null mutants (1a(OH)ase-/-VDR-/-) as recently reviewed by Goltzman and associates[87] and Hendy and colleagues.[88] A summary of these changes are shown in Table 52-2 . Studies have demonstrated that both normal serum calcium levels and 1,25(OH)2D are needed for normal development of the cartilaginous growth plate, in part by VDR-independent effects. All three transgenic animals, 1a(OH)ase-/-, VDR-/- and 1a(OH)ase-/-VDR-/- have impaired bone mineralization. However, the mineralization can be corrected with normalization of serum calcium. Even exogenous calcitriol does not fully correct mineralization in the 1a(OH)ase-/- unless calcium levels are also restored. Studies evaluating bone remodeling also demonstrate an important role of the 1,25(OH)2D/VDR system. If hypocalcemia is not corrected (leading to secondary hyperparathyroidism), there is increased osteoblast activity and bone formation from the anabolic effects of PTH. The activation of osteoclasts by PTH was blunted, suggesting a synergistic effect of vitamin D and PTH. Supporting this concept is that when calcium levels are corrected by rescue diets and secondary hyperparathyroidism is prevented, osteoblast numbers, mineralization activity, and bone volume were still reduced. Comparison studies of the 1a(OH)ase-/- and PTH-/- mice demonstrate a predominant role for PTH in appositional bone growth and vitamin D in endochondral bone formation. Thus, the 1,25(OH)2D/VDR system has anabolic bone effects that are necessary for bone formation and are supplemental to that of PTH. [87] [88]

TABLE 52-2   -- Effects of 1,25(OH)2D, Calcium, and Parathyroid Hormone (PTH) on Selected Parameters of Mineral and Skeletal Metabolism Based on In Vivo Studies in Genetic Models






1,25(OH)2D + Ca


Calcium absorption





Renal calcium transporters





Parathyroid secretion





Parathyroid growth





Cartilaginous growth plate development





Endochondral bone formation





Bone mineralization





Appositional bone formation





Bone volume





Bone resorption—osteoclastic activity





Bone formation—osteoblastic activity





1α(OH)ase activity





24-(OH)ase activity





From Hendy GN, Hruska KA, Mathew S, Goltzman D: New insights into mineral and skeletal regulation by active forms of vitamin D. Kidney Int 69:218–223, 2006.

+, stimulatory effect; -, inhibitory effect; no symbol indicates no effect or effect not examined.





In addition to the effects on target organs of bone and mineral metabolism, there is increasing data supporting a more diverse role for vitamin D due to paracrine and autocrine effects[81] ( Fig. 52-8 ). The findings of vitamin D response element on multiple genes and VDR in multiple organ systems points to the wide spread systemic effects of vitamin D.[94] There is also evidence for extrarenal conversion of 25(OH)D to 1,25(OH)2D in multiple other organs, with evidence for CYP27B1 (1-alpha hydroxylase) expression and activity in both normal and abnormal cells. These include osteoblasts, breast epithelial cells (normal and cancerous), prostate gland (normal and cancerous), alveolar and circulating macrophages, pancreatic islet cells, synovial cells, and arterial endothelial cells.[95] Vitamin D is important in cell differentiation and proliferation. Additional studies have demonstrated that vitamin D and many of its analogs inhibit the secretion of inflammatory cytokines and proliferation from lymphocytes, dendritic cells, and macrophages.[96] Of importance in CKD are direct effects of calcitriol on the cardiovascular system, leading to decreased vascular tone, decreased renin-angiotensin activation, decreased cardiac contractility, and decreased myocardial fibrosis, resulting in improved blood pressure and reduction in left ventricular mass.[97]

FIGURE 52-8  Multifaceted role of 1,25(OH)2D3. Renal and extrarenal 1,25(OH)2D production serves endocrine, autocrine, and paracrine functions.  (From Dusso AS, Brown AJ, Slatopolsky E: Vitamin D. Am J Physiol Renal Physiol 289:F8–F28, 2005.)



Nutritional Vitamin D Deficiency

Although the nephrology community often thinks of the term “vitamin D” as the active metabolite 1,25(OH)2D, the correct use of the term vitamin D is for the precursor molecule. In the general population, calcidiol (25(OH)D) levels are accepted as the standard measure of nutritional uptake as they correlate best with end organ effects. The conversion of vitamin D2 and vitamin D3 to 25(OH)D by CYP27A1 is essentially unregulated, and therefore, levels of 25(OH)D (calcidiol) are a reliable indicator of the vitamin D status of a given individual. Calcidiol levels correlate well with total body stores, whereas calcitriol level may be in a normal range despite severe vitamin D deficiency.[98] This occurs, in part, because circulating 1,25(OH)2D levels are 1/1000 that of 25(OH)D. However, controversy exists as to what constitutes adequate stores. Ultraviolet B (UVB) exposure is typically the primary source of calciferol, with a full body UVB exposure equivalent to an oral dose of 10,000 IU (250 mg) cholecalciferol, and in situations of light deprivation, such as in submarine personnel, vitamin D insufficiency occurs despite a fortified vitamin D diet.[99] Although there is no absolute level of calcidiol that defines calcidiol deficiency, a level less than 10 ng/mL (25 nmol/L) is typically used, because this level is associated with rickets in children and osteomalacia in adults.[95]

More recently, the term calcidiol insufficiency has been used to describe less severe calcidiol-deficient states. Although controversial, the typical range of insufficient calcidiol levels is 10 to 30 ng/mL (25 to 75 nmol/L). In contrast to the severity of bone disease observed with deficiency, insufficiency is associated with elevated intact parathyroid hormone (iPTH) and osteoporosis.[98] For example, in a study of elderly women with calcidiol insufficiency of 16 ± 11 ng/mL (40 ± 27 nmol/L) and elevated iPTH levels of 54 ± 37 pg/mL (54 ± 37 ng/L), there was a significant reduction in iPTH levels to 30 ± 14 pg/mL (30 ± 14 ng/L) after increasing calcidiol levels to 42 ± 9 ng/mL (105 ± 22 nmol/L).[100] Another reason for controversy as to what constitutes an “insufficient” calcidiol level, is because of widespread differences in commercially available assays.[101] Unfortunately, despite supplementation of calciferol in various foods such as milk, calcidiol insufficiency is relatively common in the general population, particularly in some at risk groups such as blacks, hospitalized individuals, nursing home residents, and those living in extreme northern climates.[102] Redefinition of normal calcidiol levels are presently being debated and should be published sometime in late 2007.

The importance of vitamin D in health and disease is suggested by a number of studies. Epidemiologic and animal studies have found vitamin D deficiency and insufficiency associated with increased falls, cancer risk, hypertension, fibromyalgia-like symptoms, rheumatologic disease, diabetes, depression, and fractures. In the general population, treatment with calciferol supplementation has resulted in reduced fractures, improved mood, blood pressure reduction, and decreased risk of developing type I diabetes.[95] In many of these studies, serum levels of 1,25(OH)D2 and calcium were unchanged, suggesting that either the calciferol supplements have a direct effect on these cells, or there is extrarenal conversion leading to local effects.

Studies have also indicated that calcidiol deficiency and insufficiency are common in CKD, with only 29% and 17% of stage 3 and 4 CKD subjects, respectively, with sufficient levels[23] ( Table 52-3 ). This prevalence of deficiency and insufficiency in an ambulatory CKD population is similar to non-CKD nursing home residents, hospitalized patients, and elderly women with hip fractures. However, the prevalence of subjects with frank deficiency (<10 mg/mL), 14% and 26% in stage 3 and 4 CKD respectively,[23] was dramatically different compared with the general ambulatory population based on the NHANES III data, in which deficiency was found to be rare.[103] At greatest risk for low levels in the CKD cohort were women and blacks,[23] similar to the general population based on NHANES III data.[103] These results are also similar to a cohort of 76 Japanese subjects with CKD (mean creatinine clearance of 21 mL/min), with mean calcidiol levels of 16.9 ng/mL, despite a diet likely to contain oily fish.[104] However, recent studies are contradictory regarding the effect of CKD on calcidiol levels. [20] [23] [105]

TABLE 52-3   -- Subjects Within K/DOQI Target Ranges


CKD 3 n = 65 (%)

CKD 4 n = 113 (%)

Calcidiol sufficient (>30 ng/mL)



Calcidiol insufficient (10–30 ng/mL)



Calcidiol deficient (<10 ng/mL)



Adapted from LaClair RE, Hellman RN, Karp SL, et al: Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States. Am J Kidney Dis 45:1026–1033, 2005.




These studies support the concern raised by the K/DOQI guidelines that low calcidiol levels in patients with CKD may contribute to the etiology of secondary hyperparathyroidism.[42] In two small studies of patients on hemodialysis in which cholecalciferol was given in doses of 400 to 4000 IU (10 to 100 mg), there was no change in iPTH levels, even though in one of the studies hyperparathyroid changes in bone improved with therapy.[106]Calcidiol supplementa-tion also showed a similar effect on bone histology in peritoneal dialysis patients.[107] A study in CKD stage 3 and 4 patients who were supplemented with larger doses of ergocalciferol as recommended by K/DOQI demonstrated an approximate 20% decrease in iPTH levels in stage 3, with no change in stage 4 subjects.[108] Based on these small studies, and studies in the general population demonstrating that correction of calcidiol deficiency reduces iPTH the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines suggest obtaining calcidiol levels in those patients with stage 3 or 4 CKD and an elevated PTH.[42] A recent study also demonstrated that prodrugs of vitamin D, 1a(OH)D2 and 1a(OH)D3 suppressed PTH in cultured parathyroid cells to levels of about 10% of that induced by 1,25(OH)2D.[109] This should be interpreted with the knowledge that 25(OH)D metabolites are present in the circulation at concentrations of 1000-fold that of 1,25(OH)2D. This latter evidence provides more support for a potentially important role for nutritional vitamin D supplementation in the treatment of secondary hyperparathyroidism as recommended by K/DOQI.[42] However, more definitive prospective studies are required.


Regulation and Biologic Effects of Parathyroid Hormone

The primary function of PTH is to maintain calcium homeostasis by (1) increasing bone mineral dissolution, thus releasing calcium and phosphorus; (2) increasing renal reabsorption of calcium and excretion of phosphorus; (3) increasing the activity of the renal 1-a-hydroxylase; and (4) enhancing the gastrointestinal absorption of both calcium and phosphorus indirectly through its effects on the synthesis of 1,25(OH)2D (see Fig. 52-2 ). In healthy subjects, the increase in serum PTH concentration in response to hypocalcemia effectively restores serum calcium levels and maintains serum phosphorus levels. The kidneys are of key importance in this normal homeostatic response, and thus patients with more severe CKD may not be able to appropriately correct abnormalities in the serum ionized calcium. In addition, PTH secretion is regulated by vitamin D and phosphorus, as detailed earlier in this chapter ( Table 52-4 ).

TABLE 52-4   -- Regulators of Parathyroid Hormone (PTH)

Low calcium stimulates PTH via

 Inactivation of calcium-sensing receptor

High phosphorus stimulates PTH through

 Alteration in intracellular calcium to alter release

 Increased parathyroid cell proliferation and growth

 Reduction of expression of the calcium-sensing receptor

 Inhibition of degradation of PTH

 Indirect down-regulation of 1-α-hydroxylase to decrease 1,25(OH)2D

 Increased FGF23

Increased 1,25(OH)2D inhibits PTH through

 Direct effect on vitamin D response element on PTH gene

 Indirect effect by increasing intestinal calcium absorption




PTH is cleaved to an 84 amino acid protein in the parathyroid gland, where it is stored with fragments in secretory granules for release. Once released, the circulating 1-84 amino acid protein has a half life of 2 to 4 minutes. It is then cleaved into N-terminal, C-terminal, and midregion fragments of PTH, which are metabolized in the liver and kidney. PTH secretion occurs in response to hypocalcemia, hyperphosphatemia, and 1,25(OH)2D deficiency. The extracellular concentration of ionized calcium is the most important determinant of minute-to-minute secretion of PTH from stored secretory granules in response to hypocalcemia. The secretion of PTH in response to low levels of ionized calcium is a sigmoidal relationship, frequently referred to as the calcium-PTH curve ( Fig. 52-9 ). The rapid response, within seconds, of changes in ionized calcium concentration has long been hypothesized to be due to a CaR. As detailed earlier in this chapter, this CaR was identified in the early 1990s, has been sequenced and cloned, and has been found to be a member of the G- protein receptor superfamily, with a 7 membrane-spanning domain.[55]Inactivating mutations have been associated with neonatal severe hyperparathyroidism and benign familial hypocalcuric hypercalcemia.[110] These patients have asymptomatic elevations of serum calcium in the presence of nonsuppressed PTH, representing a true shift to the right of this curve. Activating mutations have been found in patients with autosomal-dominant hypocalcemia shifting the curve to the left.[111]

FIGURE 52-9  The ionized calcium-parthyroid hormone (PTH) curve. The ionized calcium-PTH curve as calculated from data obtained from an actual hemodialysis patient. Data are obtained during successive dialysis sessions against a low calcium dialysate (hypocalcemic) curve and high calcium dialysate (hypercalcemic) curve, and fitted mathematically using the four-parameter model (solid line). The maximal (max) PTH and minimal (min) PTH are indicated. The four-parameter set point (solid square) is the ionized calcium corresponding to a PTH midway between max and min PTH. The 75% to 25% non-normalized slope (dashed line) also is shown.  (From Ouseph R, Leiser JD, Moe SM: Calcitriol and the parathyroid hormone-ionized calcium curve: a comparison of methodologic approaches. J Am Soc Nephrol 7:497–505, 1996.)



Early studies indicated that the calcium-PTH curve was shifted to the right in CKD, creating an altered set point, defined as the calcium concentration that results in 50% maximal PTH secretion[93] (see Fig. 52-9 ). The extrapolation of this data to clinical practice was that patients with renal failure required supraphysiologic serum levels of calcium to suppress PTH. However, several studies failed to confirm these findings.[112] In parathyroid glands removed from patients with severe secondary hyperparathyroidism, there was altered sensitivity to calcium (a shift to the right of the curve), when glands were incubated in the presence of phosphorus.[24] Confirming this was an in vivo study in dialysis patients demonstrating that an infusion of phosphorus shifts the calcium-PTH curve to the right.[113] Thus, it is possible that some of the earlier discrepancy in the literature regarding possible alterations of the set point in CKD may have been due to differences in serum phosphorus levels in the various studies,[114] although methodologic differences can also explain some of this discrepancy.[112]

This interrelationship of calcium, phosphorus, and calcitriol in the development of secondary hyperparathyroidism in CKD is complex, and nearly impossible to fully evaluate in humans, because changes in one level lead to rapid changes in the other parameters. However, based on available literature, it appears that calcium is more important in stimulat-ing PTH release, whereas calcitriol is more important in inhibiting PTH release. The presence of hyperphosphatemia impairs both of these homeostatic mechanisms. Thus, the combination of loss of renal mass, low 1,25(OH)2D, hyperphosphatemia, hypocalcemia, and elevated FGF23 contribute to increased PTH secretion in secondary hyperparathyroidism. However, other factors are also involved includ-ing down-regulation of the VDR, acidosis, resistance to PTH at the skeletal level, and other yet identified uremic toxins.[115]

Parathyroid Hormone Receptors

PTH binds to the PTH1 receptor, which is a member of the G-protein linked 7-membrane spanning receptor family. PTHrp shares homology with the first few amino acids of PTH and also binds the PTH1 receptor. This receptor is found in many tissues including osteoblasts and vascular smooth muscle cells. Thus, depending on the tissue concentration of receptor and ligand, both hormones can affect both vasculature and bone, as well as other tissues. There is also evidence that secondary binding to midregions of each protein confers binding stability.[116] Activation of the PTH1R is known to induce changes in cAMP and PKA, PKC, and transient changes in intracellular calcium.[117]Thus, the result of PTH1R activation may vary in response to time exposure, secondary conformational changes after binding, and which cell-signaling mechanism is preferentially activated. In general, the effects of PTH are systemic, and the effect of PTHrp is the same as an autocrine factor.

In the kidney, PTHR1 is widely expressed. As detailed earlier, PTH up-regulates TRPV5, TRPV6, calbindin D28K, NCX1, and PMCA1b in these distal tubule segments to facilitate calcium reabsorption.[46] PTH also facilitates Pi wasting by inducing the catabolism of the brush border sodium-phosphate cotransporter Npt2b.[5] In bone, PTH receptors are located on osteoblasts, with a time-dependent effect. PTH administered chronically inhibits osteoblast differentiation and nodule formation[118] In contrast, Ishizuya demonstrated that the administration of PTH to osteoblasts in a pulse rather than a continuous manner stimulated osteoblast proliferation through cAMP/PKA, and PKC.[119] PTH-induced signaling predominately affects mineral metabolism; however, there are many extraskeletal manifestations of PTH excess in CKD. These include encephalopathy, anemia, extraskeletal calcification, peripheral neuropathy, cardiac dysfunction, hyperlipidemia, and impotence.[120]

The apparent tissue-specific differences of PTH and PTHrp have led to a search for midregion and C-terminal receptors. C-terminal PTH fragments are cosecreted with N-terminal fragments in response to changes in serum calcium.[116] In addition, the intact PTH is degraded into C-terminal fragments in the liver and kidney, leading to abnormal elevation in renal failure.[121] There is now clear evidence for a C-terminal (type II) PTH receptor.[122] C-PTH has the opposite effect on calcium release from bone in animals[121] and cultured calvariae[122] than PTH with an intact N-terminus. In addition, the C-terminal PTH inhibits apoptosis in osteoblasts, whereas the N-PTH induces apoptosis.[122] Thus, C-terminal PTH fragments are antagonistic to the effects of full-length PTH. In dialysis patients, the circulating levels of C-terminal PTH fragments are markedly elevated and may lead to impaired bone formation in dialysis patients.[123]

Measurement of PTH

Reliable measurements of the concentration of PTH in serum or plasma are essential for the clinical management of patients with CKD. Plasma PTH concentrations generally serve not only as a noninvasive biochemical method for the initial diagnosis of renal bone disease but also as a useful index for monitoring evolution of the disorder[124] and as a surrogate measure of bone turnover in patients with CKD. However, the definitive method for establishing the specific type of renal bone disease in individual patients requires bone biopsy, an invasive diagnostic procedure, and access to specialized laboratory personnel and equipment capable of providing assessments of bone histology. Unfortunately, such resources are not widely available; thus, clinicians rely almost exclusively on plasma PTH determinations to identify patients with either high turnover skeletal lesions, due predominantly to secondary hyperparathyroidism, or low turnover lesions that are often associated with normal or reduced plasma PTH levels.

The measurement of PTH in blood has evolved considerably in recent years[124] ( Fig. 52-10 ). In the early 1960s, radioimmunoassays were developed for measurement of PTH. However, these assays proved not to be reliable owing to different characteristics of the antisera used and the realization that PTH circulates not only in the form of the intact 84 amino acid peptide but also as multiple fragments of the hormone, particularly from the middle and carboxy (C)-terminal regions of the PTH molecule. These PTH fragments arise from direct secretion from the parathyroid gland as well as from metabolism of PTH (1-84) by peripheral organs, especially liver and kidney. For these reasons, assays for PTH that were directed toward different parts of the PTH molecule yielded different results. Furthermore, because the kidney is the major route of elimination of the PTH fragments, values were markedly elevated in patients with advanced CKD and those requiring dialysis when compared with those determined in subjects with normal renal and parathyroid gland function. Thus in patients with CKD, the results were not highly reproducible and they were poor predictors of the underlying type of renal bone disease, as assessed independently by quantitative bone histology.[125]

FIGURE 52-10  Parathyroid hormone (PTH) assays. In the 1980s, only the N-terminal and mid/C-terminal PTH (first-generation) assays were available, both of which detected multiple PTH fragments in the circulation. First- and second-generation immunometric (IRMA) PTH assays differ with respect to the location of the epitope targeted by the labeling antibody in these assay systems. For second-generation assays, the epitope is located within the most amino-terminal portion of the molecule. Peptides missing one or more amino acid residues from the amino terminus of PTH will not be detected by second-generation immunometric PTH assays.  (Adapted from Goodman WG, Juppner H, Salusky IB, Sherrard DJ: Parathyroid hormone [PTH], PTH-derived peptides, and new PTH assays in renal osteodystrophy. Kidney Int 63:1–11, 2003.)



As assay techniques became more refined, a new era of PTH measurement began with the use of two-site immunoradiometric assays (commonly called INTACT assay) (see Fig. 52-10 ).[124] Such assays capture PTH peptides from plasma with a solid phase-coupled antibody, usually directed toward the COOH-terminal region of the PTH molecule, and the captured PTH peptides are detected with a second antibody directed toward a different region of the molecule, usually the NH2 terminus. This intact assay is more discriminatory than N- or C-terminal assays in patients with renal failure[126]; however, its ability to discriminate between low and high bone turnover in dialysis patients as compared with bone histology is limited to very low levels (<100–150 pg/mL) and very high levels (>500 pg/mL). [127] [128] Furthermore, racial differences exist. In one series, the mean intact PTH level was 460 ± 110 pg/mL in blacks, with bone biopsy-proven low-turnover bone disease compared with 144 ± 43 pg/mL in whites with the same degree of bone turnover.[129]

Further refinements have been instituted since the demonstration that such intact PTH assays detect more than a single species of PTH when serum is fractionated by high-performance liquid chromatography. [130] [131] New assays have been developed in which the detection antibody recognizes the precise NH2 terminus of the PTH molecule, so that only intact PTH (1-84) is measured. [124] [131] Assays that truly detect only the 1-84 amino acid full-length molecule are now commercially available. The development of these assays has refined our understanding of the measurement of PTH in serum and has initiated new interest in the nature and actions of other PTH peptides that are truncated at the NH2 terminus, such as PTH (7-84).

Large NH2-terminally truncated PTH fragments can be found within the parathyroid gland, because PTH undergoes degradation after synthesis. This degradation of PTH within the parathyroid gland has been known for some time to be influenced by the levels of extracellular calcium. This regulated intracellular degradation of PTH makes it possible for the parathyroid gland to respond quickly when varying amounts of active hormone are required for tightly maintaining serum ionized calcium concentrations. After secretion from the parathyroid gland, intact PTH is rapidly metabolized in peripheral tissues.[132] Intact PTH cleared from the blood is cleaved by endoproteases to a number of large fragments, which reenter the circulation, most of which appear to begin with residues between 34 and 43 of the PTH peptide.[132] Additional fragments from the NH2-terminal region of PTH or middle-molecule fragments may also circulate and have the potential to accumulate when GFR is reduced. Recent studies have suggested that NH2-terminally truncated PTH fragments may have biologic actions, [121] [122] perhaps through the COOH-terminal regions of PTH, as detailed above. In vivo studies have demonstrated that PTH (7-84) can blunt the calcemic response to PTH (1-84).[121] Studies in vitro have shown that PTH (7-84) can decrease bone resorption stimulated by a variety of agonists, such as 1,25-dihydroxyvitamin D, interleukin-11, and prostaglandin E2.[122] These data imply that circulation of these carboxy-terminal PTH fragments in significant concentrations may modulate the effects of PTH in bone.

In dialysis patients, initial studies demonstrated that the measurement of the intact PTH led to results that were always greater (approximately twofold) than the whole (1-84 amino acid only) assay, regardless of whether the patients had low or high PTH levels. [121] [133] Although this new assay offers hope of better reproducibility across laboratories, its role in the diagnosis of underlying bone histology is controversial. An initial study demonstrated that the whole PTH was superior to the former intact assay, and that a ratio of the 1-84 amino acid to 7-84 amino acid (active/antagonist) PTH levels less than one was predictive of underlying low turnover bone disease, and more accurate than either assay alone.[123] However, subsequent studies failed to confirm these findings, and found no difference in the area under a receiver operating curve (ROC) with the traditional intact and 1-84 assays. [123] [134] [135] The patient characteristics, especially serum calcium levels, and vitamin D use were different in these studies. This is important, as a recent study demonstrated that although both 1-84 and non 1-84 fragments are secreted from the PTH gland in response to serum calcium levels, the secretory responses are not proportional.[136] Unfortunately, variability in assay methodologies and performance of PTH assays further limit the clinical utility of PTH to predict underlying bone disease.[137]


Bone Biology

The majority of the total body stores of calcium and phosphorus are located in bone. Trabecular (cancellous) bone is located predominately in the epiphyses of the long bones, which is 15% to 25% calcified, and serves a metabolic function with a relatively short turnover rate of 45Ca. In contrast, cortical (compact) bone is in the shafts of long bones, and is 80% to 90% calcified. This bone serves primarily a protective and mechanical function, and has a calcium turnover rate of months. Bone consists principally (90%) of highly organized cross-linked fibers of type I collagen; the remainder consists of proteoglycans, and “non-collagen” proteins such as osteopontin, osteocalcin, osteonectin, and alkaline phosphatase. Hydroxyapatite (Ca10(PO4)6(OH)2) is the major bone salt.

The cellular components of bone consist of cartilage cells, which are key to bone development; osteoblasts, which are the bone-forming cells; and osteoclasts, which are the bone-resorbing cells. Osteoblasts are derived from progenitor mesenchymal cells located in the bone marrow. They are then induced to become osteoprogenitor cells, then endosteol or periosteol progenitor cells, then mature osteoblasts. The control of this differentiation pathway is due to bone morphogenic proteins and the transcription factor core-binding factor a 1 (Cbfa1 or Runx2) early, and other hormones and cytokines later. Once bone formation is complete, osteoblasts may undergo apoptosis, or become quiescent cells trapped within the mineralized bone in the form of osteocytes.[138] The osteocytes are interconnected through a series of canaliculi. Although these cells were previously thought to be of little importance, it is now clear that they transmit the signaling involved with mechanical loading and mineralization cues. [7] [139]

Osteoclasts are derived from hematopoietic precursor cells that differentiate and are somehow “signaled” to arrive at a certain place in the bone. Once there, they fuse to form the multinucleated cells known as osteoclasts, which become highly polarized, reabsorbing bone through the release of degradative enzymes. They move along a resorption surface through changes in the cytoskeleton. PTH, cytokines, and 1,25(OH)2D are all important in inducing the fusion of the committed osteoclast precursors. Once resorption is complete, estrogens and cytokines can induce, and PTH can inhibit, apoptosis.[138] Numerous hormones and cytokines have been evaluated, mostly in vitro, for their role in controlling osteoclast function.

The control of bone remodeling is highly complex but appears to occur in very distinct phases ( Fig. 52-11 ): (1) osteoblast activation, (2) osteoclast recruitment resorption, (3) preosteoblast migration and differentiation, (4) osteoblast deposition of matrix (osteoid or unmineralized bone), (5) mineralization, and (6) quiescent stage. At any one time, less than 15% to 20% of the bone surface is undergoing remodeling, and this process in a single bone remodeling unit can take 3 to 6 months.[140] How a certain piece of bone is chosen to undergo a remodeling cycle is not completely clear.

FIGURE 52-11  Bone remodeling cycle. For a complete description, see text. CFU, colony-forming unit; PTH, parathyroid hormone.  (From González E, Martin K: Bone cell response in uremia. Semin Dial 9:339–346, 1996, with permission.)



The discovery of the osteoprotegerin (OPG) and receptor activator of nuclear-factor kB (RANK) system has shed new light on the control of osteoclast function, and the long observed coupling of osteoblasts and osteoclasts. RANK is located on osteoclasts, and the RANK-ligand (RANK-L) on osteoblasts. Osteoblasts also synthesize the protein OPG, which can bind to OPG ligand on osteoblasts and inhibit the subsequent binding of OPG-L to RANK on osteoclasts, thus inhibiting bone resorption. Alternatively, if OPG production is decreased, the RANK-L can bind with RANK on osteoclasts and induce osteoclastic bone resorption. This control system is regulated by nearly every cytokine and hormone thought important in bone remodeling, including PTH, 1,25(OH)2D, estrogen, glucocorticoids, interleukins, prostaglandins, and members of the TGF-β superfamily of cytokines.[141] OPG has been successful in preventing bone resorption in animal models of osteoporosis and tumor-induced bone resorption. [142] [143] Interestingly, abnormalities in the OPG/RANK have been found in renal failure, [144] [145] and early animal models suggest that treatment with OPG may have a protective role in hyperparathyroid bone disease.[146] Clearly, more information is required to understand how this system regulates bone remodeling in the context of CKD.

Bone Quality and Fracture

The gold standard test for bone quality is its ability to resist fracture under strain. In animal models, this can be directly tested with three-point bending engineering tests. Bone quality is impaired in CKD because there is an increased prevalence of hip fracture in dialysis patients compared with the general population in all age groups. [147] [148] [149] Dialysis patients in their 40s have a relative risk of hip fracture 80-fold that of age- and sex-matched controls.[148]Furthermore, a hip fracture in a dialysis patient was associated with a doubling of the mortality rate observed in hip fractures in nondialysis patients. [149] [150] In a multivariate analysis, the risk factors for hip fracture include age, gender, duration of dialysis, and presence of peripheral vascular disease.[151] Other analyses found race, gender, duration of dialysis. and low or very high PTH levels as risk factors. [149] [150] Importantly, a secondary analysis of the Study for Osteoporotic Fracture, a cohort study of 9704 women, found CKD was an independent risk factor for hip fracture.[152]

In the past, most of the emphasis was on bone mass, generally assessed by dual x-ray absorptiometry (DEXA). However, there was recognition of an apparent discrepancy between the small increase in bone mineral density by DEXA and the disproportionate decrease in fracture risk in various therapeutic trials.[153] These data, and advances in other imaging modalities, led to a National Institutes of Health consensus conference to redefine osteoporosis as “a skeletal disorder characterized by compromised bone strength that results in an increased risk of fracture. Bone strength reflects the integration of two main features: bone density and bone quality” ( These “quality” factors include abnormal bone turnover or remodeling and other indices of bone architecture such as geometry, connectivity, mineralization, and collagen cross-linking. These factors appear additive to bone mineral density as determinants of bone strength.

Most studies have observed a high prevalence of osteopenia and osteoporosis in ESKD by DEXA. [147] [154] However, DEXA can detect only the overall density of bone but not the quality of the bone. To date, two studies have demonstrated a relationship between DEXA-measured bone mineral density and fractures in cross-sectional analysis, [152] [155] but there are no longitudinal studies. In addition, blacks have less osteopenia and osteoporosis than do white patients, and the lumbar spine appears less affected than the hip. [147] [154] The differences in DEXA findings at the lumbar spine versus the hip may also be due to artifact from vascular calcification of the aorta. Thus, there are limitations to the use of DEXA in ESKD patients. Quantitative CT (qCT) scan may offer an alternative to DEXA because it can differentiate cortical and trabecular bone and local patterns of mineral content.[156] This may be particularly important in ESKD subjects, [157] [158] in whom different patterns have been identified in cortical and trabecular bone. In some studies in nondialysis patients, computed tomography (CT) is more predictive of fracture than DEXA[159]; however, the studies evaluating this technique in dialysis patients are limited.

Abnormal bone quality may be especially prominent in dialysis patients owing to the coexistence of disordered bone turnover and may be a critical factor in the increased fractures observed in ESKD. Because of the potential effects of extremes of bone turnover and remodeling (see later), the sensitivity and specificity of DEXA for predicting fracture in CKD is unknown. This was the conclusion reached by an expert panel at a special symposium sponsored by the National Kidney Foundation.[160] Thus, at the present time, bone biopsy remains the gold standard for the diagnosis of renal osteodystrophy and assessment of bone architecture.

Bone Biopsy and Histomorphometry in Patients with Chronic Kidney Disease

The clinical assessment of bone remodeling is best done with a bone biopsy of the trabecular bone, usually at the iliac crest. The patient is given a tetracycline derivative approximately 3 to 4 weeks before the bone biopsy and a different tetracycline derivative 3 to 5 days before the biopsy. Tetracycline binds to hydroxyapatite and emits fluorescence, thereby serving as a label of the bone. A core of predominately trabecular bone is taken, embedded in a plastic material, and sectioned. The use of this plastic material is why only some laboratories are equipped to process bone biopsies. Typical pathology laboratories normally decalcify tissue and paraffin embed, which destroys the very architecture that is necessary to differentiate metabolic bone disorders. The sections can then be visualized with special stains under fluorescent microscopy to determine the amount of bone between the two tetracycline labels, or that formed in the time interval between the two labels. This dynamic parameter assessed on bone biopsy is the basis for assessing bone turnover, which is key in discerning types of renal osteodystrophy. In addition to dynamic indices, bone biopsies can be analyzed by histomorphometry for many static parameters as well. The nomenclature for these assessments has been standardized.[161]

Clinically, bone biopsies are most useful for differentiating bone turnover, as well as other undiagnosed metabolic disorders. However, with the advent of several new markers of bone turnover, the use of bone biopsy has recently been reserved primarily for the diagnosis of renal osteodystrophy and for research purposes.[162] Sherrard and others[162] proposed a classification system for renal osteodystrophy, which used the parameters of osteoid (unmineralized bone) area as a percent of total bone area, and fibrosis. These two static parameters, together with the dynamic bone turnover assessed by bone formation rate or activation frequency, have been used to distinguish the various forms of renal osteodystrophy over the past 20 years ( Table 52-5 ).

TABLE 52-5   -- 1993 Histologic Classification of Renal Osteodystrophy


Area of Fibrosis (% of Tissue Area)

Area of Osteoid (% of Total Bone Area)

Bone Formation Rate (μm2/mm2 Tissue Area/Day)





Osteitis fibrosa
















Normal range




Adapted from Sherrard DJ, Hercz G, Pei Y, et al: The spectrum of bone disease in end-stage renal failure—an evolving disorder. Kidney Int 43:436–442, 1993.

X is not a diagnostic criterion.





Figure 52-12 illustrates bone histology using this classification scheme. Normal bone is illustrated in Figure 52-12A . The histologic features of high turnover disease (predominant hyperparathyroidism or osteitis fibrosa) are characterized ( Fig. 52-12B ) by an increased rate of bone formation, increased bone resorption, extensive osteoclastic and osteoblastic activity, and a progressive increase in endosteal peritrabecular fibrosis. High osteoblast activity is manifested by an increase in unmineralized bone matrix. The number of osteoclasts is also increased in osteitis fibrosa, as is the total resorption surface. There may be numerous dissecting cavities through which the osteoclasts tunnel into individual trabeculae. In osteitis fibrosa, the alignment of strands of collagen in the bone matrix has an irregular woven pattern that contrasts with the normal lamellar (parallel) alignment of strands of collagen in normal bone. Although woven bone may appear to be thicker, the disorganized collagen structure may render the bone physically more vulnerable in response to stress.

FIGURE 52-12  Bone histology. (A) Normal bone. (B) Hyperparathyroid bone. (C) Adynamic bone. (D) Aluminim bone disease. (E) Osteomalacia. (F) Mixed uremic osteodystrophy.  (A, B, D (part 2) and E, courtesy of S.L. Teitelbaum, MD. D (part 1), courtesy of D. J. Sherrard, MD.)

The histologic features of low turnover (adynamic) bone disease ( Fig. 52-12C ) is characterized histologically by absence of cellular (osteoblast and osteoclast) activity, osteoid formation, and endosteal fibrosis. It appears that this is essentially a disorder of decreased bone formation, accompanied by a secondary decrease in bone mineralization. Although, low turnover disease is common in the absence of aluminum, it was initially described as a result of aluminum toxicity. Aluminum bone disease is diagnosed by special staining, which demonstrates the presence of aluminum deposits at the mineralization front ( Fig. 52-12D ). Frequently, aluminum disease is associated with osteomalacia. Osteomalacia is characterized by an excess of unmineralized osteoid, manifested as wide osteoid seams and a markedly decreased mineralization rate ( Fig. 52-12E ). The presence of increased unmineralized osteoid per se does not necessarily indicate a mineralizing defect, because increased quantities of osteoid appear in conditions associated with high rates of bone formation when mineralization lags behind the increased synthesis of matrix. Other features of osteomalacia include the absence of cell activity and the absence of endosteal fibrosis.

Mixed uremic osteodystrophy is the term that has been used to describe bone biopsies that have features of second-ary hyperparathyroidism together with evidence of a mineralization defect ( Fig. 52-12F ). There is extensive osteoclastic and osteoblastic activity and increased endosteal peritrabecular fibrosis coupled with more osteoid than expected, and tetracycline labeling uncovers a concomitant mineralization defect. Unfortunately, mixed uremic osteodystrophy, in particular, as well as high and low turnover bone disease have been inconsistent and poorly defined.

The Spectrum of Bone Histomorphometry in Patients with Chronic Kidney Disease

Using this classification system, the prevalence of different forms of renal osteodystrophy has changed over the past decade ( Fig. 52-13 ). Whereas osteitis fibrosa cystica due to severe hyperparathyroidism had previously been the predominant lesion, the prevalence of mixed uremic osteodystrophy and adynamic bone disease has recently increased. However, the overall percentage of patients with high bone formation compared with low bone formation has not changed dramatically over the past 20 to 30 years, but osteomalacia has been essentially replaced with adynamic bone disease. Because of differences in mixed uremic osteodystrophy in patients not yet on dialysis, the series of bone biopsies yield widely different results depending on the level of GFR and the country in which the study was performed. [40] [163] However, it is clear from these data that histologic abnormalities of bone begin very early in the course of chronic kidney disease. Also of importance is that histologic changes due to secondary hyperparathyroidism remain common.

FIGURE 52-13  The spectrum of histologic types of renal osteodystrophy in patients with chronic kidney stages 3 to 5. This graph represents the distribution of various pathologic forms of renal osteodystrophy in three recent studies with a total number of 319 subjects. [127] [134] [280]Adynamic, adynamic bone disease; HPT, hyperparathyroidism; MUO, mixed uremic osteodystrophy OF, osteitis fibrosa or severe HPT; OM, osteomalacia.


In contrast, low turnover bone disease has diverse pathophysiology. In the 1980s, aluminum-induced osteomalacia was common. The potential toxicity of aluminum was initially recognized by Alfrey and colleagues,[164] who identified a fatal neurologic syndrome in dialysis patients consisting of dyspraxia, seizures, and electroencephalographic abnormalities in association with high brain aluminum levels on autopsy. The source of aluminum in these severe cases was believed to be elevated concentrations in dialysate water. Subsequently, aluminum-containing phosphate binders were also identified as a source. The additional symptoms of fractures, myopathy, and microcytic anemia were described several years after the initial reports of the neurologic syndrome. [42] [164] In the more recent (late 1980s), the Toronto bone biopsy study, in which unselected patients at three dialysis units underwent bone biopsies and noninvasive tests (n = 259), 69 patients had aluminum bone disease defined as greater than 25% surface aluminum staining. In this series, aluminum bone disease was the most common bone histologic disorder associated with proximal myopathy, pathologic fractures, unexplained bone pain, microcytic anemia, and hypercalcemia.[165] The ingestion of aluminum-containing phosphate binders, sucralfate, and some over-the-counter antacids can also lead to aluminum accumulation and children, diabetics, and individuals taking citrate are at increased risk of developing the disease.[164] The diagnosis of aluminum-induced bone disease can be difficult, because aluminum toxicity is due to tissue burden, not serum levels. Alternative assessments include the deferoxamine stimulation test and random serum aluminum levels. However, bone biopsy remains the gold standard.[42] Fortunately, this disease is now uncommon, at least in the United States, where aluminum-containing phosphate binders are rarely used.

In the past 10 to 15 years, as aluminum has been removed as a cause of low turnover, an entity called adynamic bone disease has been described.[166] In adynamic bone disease (see Fig. 52-12C ), there is a paucity of cells with resultant low bone turnover. In contrast to osteomalacia, in adynamic bone, there is no increase in osteoid or unmineralized bone. The lack of bone cell activity led to the initial description of the disease as “aplastic” bone disease. Early studies indicated that the disease was still due to aluminum, but it was later identified in the absence of positive staining for aluminum. The etiology of adynamic bone disease is unknown but risk factors ( Fig. 52-14 ) include age, diabetes, oversuppression of PTH with vitamin D and calcium-containing phosphate binders, diabetes, peritoneal dialysis, and possibly calcium overload.[167] In addition, there is evidence for altered osteoblast response to PTH owing to down-regulation of the PTH receptor in renal failure,[168] which further contributes to the paucity of cells observed in adynamic bone disease. Circulating fragments of PTH (so called 7-84 amino acid fragments) may also be antagonists to PTH, [121] [169] resulting in an effective resistance to 1-84 amino acid at the level of bone. There is also abnormal regulation of cell differentiation in the presence of renal failure, which may explain, in part, the relative paucity of cells in adynamic bone, although this remains to be proven. In rats, the administration of bone morphogenic-7 can restore normal cell function, supporting the fact that a failure of normal cell differentiation, likely due to a number of causes, may be critical.[170] The pathophysiology of altered bone cell respon-siveness is clearly mutlifactorial, as shown in Figure 52-14 . Although most patients with low bone turnover disease are asymptomatic, they are at increased risk of fracture due to impaired remodeling[149] and are at risk of vascular calcification due to the inability of bone to buffer an acute calcium load.[45]

FIGURE 52-14  The pathogenesis of low bone turnover in chronic kidney disease. One set of factors serves to decrease secretion of parathyroid hormone, whereas several other factors act to decrease the bone formation rate (BFR). OPG, osteoprotegerin; VDR, vitamin D receptor.  (Adapted from Couttenye MM, D'Haese PC, Verschoren WJ, et al: Low bone turnover in patients with renal failure. Kidney Int 73(suppl):S70–S76, 1999.)



Clinically, serum PTH is used as a surrogate biomarker to predict bone turnover. However, as detailed earlier, studies evaluating the ability of the serum concentration of intact PTH to predict both low and high turnover bone disease have been disappointing. In general, the risk of high-turnover bone disease increases with the concentration of intact PTH. [127] [128] However, the ability to reliably predict the presence of high-turnover bone disease is poor until intact PTH levels of 450 to 500 pg/mL are reached. Levels of intact PTH less than 100 pg/mL are fairly reliable for the prediction of low-turnover bone disease,[127] but again, not perfect. Based primarily on these studies, the K/DOQI guidelines recommend a target intact PTH level of 150 to 300 pg/mL.[42] Unfortunately, these studies that correlate intact PTH with bone histology were done before the widespread use of vitamin D derivatives, calcimimetics, and the noncalcium-containing phosphate binders and may not be applicable in the current treatment environment.

As described earlier, the new whole or bioactive 1-84 amino acid PTH assays are claimed to offer improved diagnostic capabilities, but this remains to be proved. Initially, there was great hope for the new bone markers such as osteocalcin and bone-specific alkaline phosphatase to be predictive of underlying bone histology. Unfortunately, these specialized tests offer little additive value to our usual measurement of calcium, phosphorus, PTH, and total alkaline phosphatase.[171] This is also true for patients not yet on dialysis, in whom a study in 84 subjects determined that measurement of intact PTH, bone alkaline phosphatase, total alkaline phosphatase, or osteocalcin had sensitivities of 72% to 83% but specificity of 53% to 67% to discriminate adynamic bone from other types of renal osteodystrophy.[172] A new assay that measures circulating tartrate-resistant acid phosphatase 5b as a marker of osteoclast activity may be promising,[173] but more evaluation is necessary. Thus, to date biomarkers for the prediction of underlying bone histology are disappointing. In the absence of bone biopsy, we must use clinical judgment, trends in PTH hormone levels, and various other bone markers to guide therapy. The disconnect between serum markers and bone histomorphometry is one rationale for the new classification system of CKD-MBD. However future studies are required to determine if this classification system allows better prediction (and treatment of) fractures and cardiovascular disease.

New Classification of Bone Disease

As previously mentioned, the recent recommendations of KDIGO are that the definition of renal osteodystrophy be limited to describing the alterations of bone morphology in patients with CKD. It is one measure of the skeletal component of the systemic disorder of CKD-MBD that can be quantifiable by histomorphometry.[1] Historically, renal osteodystrophy has been defined as detailed earlier, as a spectrum of disorders ranging from low-turnover (adynamic) to high-turnover disease (osteitis fibrosa) with a poorly defined entity termed mixed uremic osteodystrophy, which represented various degrees of bone turnover with a defect in mineralization.[162] Unfortunately, mixed uremic osteodystrophy is defined differently by different investigators. As our understanding of bone biology progresses, there is increased appreciation of diverse physiologic processes leading to similar bone biopsy findings. In addition, there has been new information on bone volume as an independent parameter.[174] Thus, the previous classification system needs to be updated.

In order to clarify the interpretation of bone biopsy results in the evaluation of renal osteodystrophy, it was agreed by KDIGO to use three key histologic descriptors—bone turnover, mineralization, and volume (TMV system), with any combination of each of the descriptors possible in a given specimen ( Table 52-6 ).[1] The TMV classification scheme provides a clinically relevant description of the underlying bone pathology as assessed by histomorphometry, which, in turn, helps define the pathophysiology and thereby guide therapy.

TABLE 52-6   -- Bone Turnover, Mineralization, and Volume (TMV) Classification System for Renal Osteodystrophy













From Moe S, Drueke T, Cunningham J, et al: Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 69:1945–1953, 2006.




Turnover reflects the rate of skeletal remodeling that is normally the coupled process of bone resorption and bone formation. It is assessed with histomorphometry by dynamic measurements of osteoblast function using double-tetracycline labeling. Bone formation rates and activation frequency represent acceptable parameters for assessing bone turnover. Bone turnover is affected mainly by hormones, cytokines, mechanical stimuli, and growth factors that influence the recruitment, differentiation, and activity of osteoclasts and osteoblasts. It is important to clarify that although bone formation rate is frequently similar to the bone resorption rate, which cannot be measured directly, this is not always true. An imbalance in these processes can affect bone volume. For example, excess resorption over formation will lead to negative bone balance and decreased bone volume.

Mineralization reflects how well bone collagen becomes calcified during the formation phase of skeletal remodeling. It is assessed with histomorphometry by static measurements of osteoid volume and osteoid thickness and by dynamic, tetracycline-based measurements of mineralization lag time and osteoid maturation time. Causes of impaired mineralization include inadequate vitamin D nutrition, mineral (calcium or phosphorus) deficiency, acidosis, or bone aluminum toxicity.

Volume indicates the amount of bone per unit volume of tissue. It is assessed with histomorphometry by static measurements of bone volume in cancellous bone. Determinants of bone volume include age, gender, race, genetic factors, nutrition, endocrine disorders, mechanical stimuli, toxicities, neurological function, vascular supply, growth factors, and cytokines. This new classification is consistent with the current commonly used classification system[162] but provides more information on parameters other than turnover. A comparison of the new system with the old system is shown in Figure 52-15 .

FIGURE 52-15  Bone turnover, mineralization, and volume (TMV) classification system for bone histomorphometry. The figure is a graphic example of how the TMV system provides more information than the present, commonly used classification scheme. Each axis represents one of the descriptors in the TMV classification: turnover (from low to high), mineralization (from normal to abnormal), and bone volume (from low to high). Individual patient parameters could be plotted on the graph, or means and ranges of grouped data could be shown. For example, many patients with renal osteodystrophy cluster in areas shown by the bars. The red bar (osteomalacia [OM]) is currently described as low-turnover bone with abnormal mineralization. The bone volume may be low to medium, depending on the severity and duration of the process and other factors that affect bone. The green bar (adynamic bone disease [AD]) is currently described as low-turnover bone with normal mineralization, and the bone volume in this example is at the lower end of the spectrum, but other patients with normal mineralization and low turnover will have normal bone volume. The yellow bar (mild hyperparathyroid (HTP)–related bone disease) and purple bar (osteitis fibrosa [OF] or advanced HTP-related bone disease) are currently used distinct categories but in actuality represent a range of abnormalities along a continuum of medium to high turnover, and any bone volume depending on the duration of the disease process. Finally, the blue bar (mixed uremic osteodystrophy [MUO]) is variably defined internationally. In the present graph, it is depicted as high-turnover, normal bone volume, with abnormal mineralization. In summary, the TMV classification system more precisely describes the range of pathologic abnormalities that can occur in patients with chronic kidney disease.  (From Moe S, Drueke T, Cunningham J, et al: Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes [KDIGO]. Kidney Int 69:1945–1953, 2006.)




In patients with CKD, cardiovascular disease remains the leading cause of morbidity and mortality (see Chapter 48 ). As described earlier, disorders of bone and mineral metabolism have been shown to be associated with cardiovascular mortality. One potential mechanism by which this may occur is through arterial or vascular calcification.

Pathology and Detection of Vascular Calcification

In the general population, vascular disease may be due to a variety of different pathologic processes, all of which can also be associated with calcification. Atherosclerotic disease is characterized by fibrofatty plaque formation, and based on autopsy data and animal models, calcification had been thought to occur late in the disease course.[175] These plaques can protrude into the arterial lumen, leading to a filling defect on angiography ( Fig. 52-16A ). However, recent advances in imaging and intravascular ultrasound have demonstrated that atherosclerosis can also be a circumferential lesion (without an obstructed lumen) with calcification earlier in the course of the disease.[176]The medial layer may also be affected in arteriosclerosis, which leads to thickening of the medial layer of elastic arteries ( Fig. 52-16B ). This clinically manifests as increased pulse wave velocity and elevated pulse pressure, and is commonly associated with systolic hypertension in the elderly, a known risk factor for cardiovascular disease in the general population.[177] In addition to the larger elastic arteries, the smaller elastic arteries may also be affected by medial thickening and calcification, classically described as Mönckeberg calcification, or medial calcinosis.[178] This disease is more common in patients with diabetes, kidney disease, and advanced aging. Although previously thought to be a pathologic observation of little clinical significance, recent studies have clearly demonstrated that this form of medial calcification in distal vessels is associated with increased all-cause and cardiovascular mortality in diabetic patients without CKD[179] and in patients with CKD.[76]

FIGURE 52-16  Arterial calcification. Histologic differences between atherosclerotic, or intimal calcification (A) and medial calcification (B).  (A, from Stary HC: Atlas of Atherosclerosis. New York, Parthenon, 1999. B, from Moe SM, O'Neill KD, Duan D, et al: Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins. Kidney Int 61:638–647, 2002.)



The mechanism by which arterial calcification leads to clinical sequelae is also multifactorial. Intimal calcification (in association with atherosclerotic disease) can lead to myocardial infarction from stenosis and acute occlusions in the coronary arteries, or ischemic rest pain and gangrene in the peripheral arteries. However, medial calcification (or circumferential calcification) can lead to arterial stiffening, with reduced compliance of the artery and an inability to appropriately vasodilate in the setting of increased stress. In the coronary arteries, similar symptoms of ischemia can develop and, in theory, could lead to arrhythmias and sudden death. If the large central/peripheral arteries are calcified (such as the aorta), there is increased systolic blood pressure, and increased pulse wave velocity. The prema-ture return of wave reflections during systole (instead of diastole) can lead to altered coronary perfusion and eventually left ventricular hypertrophy. Lastly, calcification of the arterioles of the skin and other organs can lead to localized infarction and ischemia including ischemic bowel and calciphylaxis.

Clinically, arterial calcification can be detected through a number of techniques including plain radiographs, tomography, scintigraphy, and CT scan. More recent technologic advances have led to ultrafast CT scans (electron beam CT [EBCT] and newer multislice CT [MSCT]) that use electrocardiographic gating to allow imaging only in diastole, thus avoiding motion artifact.[180] These techniques have allowed reproducible quantitation of coronary artery and aorta calcification, and therefore serve as excellent research end points. Unfortunately, these techniques do not allow differentiation of medial from intimal calcification. In addition to these rather expensive techniques, plain radiographs can be used to assess the prevalence of vascular calcification, although they lack the sensitivity to allow quantitation of calcium during longitudinal follow-up. There is some distinct appearance to medial compared with intimal calcification on plain radiographs.[76] Furthermore, calcification on plain radiographs are predictive of coronary artery calcification by CT.[180] Ultrasound can also assess the magnitude of vascular calcification but, similar to plain radiographs, only allow semiquantitative assessments. Although there are several techniques that can detect vascular calcification, a universally accepted, standardized system has yet to be developed.

Vascular Calcification in Patients with Chronic Kidney Disease

The high prevalence of vascular calcification in patients with CKD is not a new observation. Ibels and associates[181] in 1979 demonstrated that both renal and internal iliac arteries of patients undergoing a renal transplant had increased atherogenic and intimal disease and increased calcification (detected by chemical methods) compared with transplant donors. In addition, the medial layer was thicker and more calcified in the uremic patients compared with that of the donors.[181] A more recent study compared histologic changes in coronary arteries from dialysis patients with age-matched, nondialysis patients who had died from a cardiac event.[182] This study found a similar magnitude of atherosclerotic plaque burden and intimal thickness in the dialysis patients compared with that of controls, but with more calcification. In addition, morphometry of the arteries demonstrated increased medial thickening.[182] Thus, there is histologic evidence for increased arterial calcification in coronary, renal, and iliac arteries from patients on dialysis compared with nondialysis patients.

Braun and associates[183] demonstrated that coronary artery calcification by EBCT increased with advancing age in patients on dialysis and that the calcification scores were two- to fivefold greater in dialysis patients than age-matched individuals with normal kidney function and angiographically proven coronary artery disease ( Fig. 52-17 ). Guerin and co-workers[184] found that the magnitude of large artery calcification by ultrasound was associated with increased intake of calcium binders. Goodman and associates[185] subsequently demonstrated by EBCT that advanced calcification can also occur in the coronary arteries of children and young adults and also found a relationship between calcification score and increasing doses of calcium-containing phosphate binders, and increased calcium × phosphorus product (Ca × P). Multislice (spiral) CT can also detect coronary artery calcification in patients with CKD.[186] Several authors have reported vascular calcification using these and other techniques, and have determined the risk factors associated with the presence or absence of coronary artery calcification or the degree of calcification. More recent data in patients not yet on dialysis also demonstrates an increased risk of coronary artery calcification, especially in diabetic patients.[187] Nearly 50% to 60% of patients starting hemodialysis have evidence of coronary artery calcification,[188] and most series describing prevalent hemodialysis patients find 70% to 80% of all patients with evidence of coronary artery calcification.[189] The only risk factors for coronary artery calcification that are uniform across studies are advancing age and duration of dialysis. Mineral metabolism abnormalities in the form of elevated phosphorus, elevated Ca × P, or calcium load in the form of phosphate binders have been identified as risk factors in several, but not all, studies.[190]

FIGURE 52-17  Relationship of coronary artery calcification to angiographic disease. Patients underwent assessment of coronary artery calcification by electron beam computed tomography. Hemodialysis patients (red bars), at any age group, had two- to fivefold more coronary artery calcification than patients with angiographically proven coronary artery disease (blue bars) or no coronary artery disease (green bars).  (Adapted from Braun J, Oldendorf M, Moshage W, et al: Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 27:394–401, 1996.)



In the general population, coronary artery calcification is predictive of future cardiac events in both asymptomatic and symptomatic individuals. [191] [192] Less robust data exist for patients with CKD. Two small studies have demonstrated an increase in mortality with increased coronary artery calcification. [193] [194] A recent study of 114 patients were followed prospectively after baseline EBCT and determined that a calcification score greater than 400 was associated with a 16-fold increase in mortality.[195] In addition, coronary artery calcification in patients with CKD is associated with increased LVH.[196] Finally, increased valvular calcification in patients with CKD is also associated with increased mortality.[197] Interestingly, both nocturnal dialysis[198] and transplantation[193] appear to stabilize progression of coronary artery calcification, suggesting that the uremic milieu contributes to calcification.

Peripheral artery calcification is even more common in patients with CKD. [76] [189] In dialysis patients, intimal calcification of the femoral artery by plain radiograph had increased all-cause and cardiovascular mortality compared with those with medial calcification, which was, in turn, statistically greater than those with no calcification[76] ( Fig. 52-18B ). These data have been duplicated by Adragao and colleagues[199] using hand and pelvic radiographs. In addition, calcification of the larger arteries is associated with reduced baroreflex sensitivity[200] and increased pulse wave velocity and pulse pressure. [184] [199] Furthermore, increased pulse wave velocity[201] and pulse pressure[202] are associated with increased mortality rates. Alterations in mineral metabolism appears to be associated with increased calcification in peripheral arteries in the majority of studies. The National Kidney Foundation convened an international consensus panel that reviewed the various risk factors for both coronary and peripheral artery calcification ( Table 52-7 ).

FIGURE 52-18  Peripheral artery calcification. Plain radiographs of the thigh demonstrate calcification of the femoral artery in a plaque-like arrangement (A) or a medial (circumferential) arrangement (B). Using these radiographs, patients were classified into medial or intimal (including mixed medial and intimal lesions) or no calcification, and followed prospectively. There was lowest survival for patients with intimal calcification, followed by medial calcification, followed by no calcification (C)..  (From London GM, Guerin AP, Marchais SJ, et al: Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 18:1731–1740, 2003.)



TABLE 52-7   -- Risk Factors for Medial and Intimal Calcification

Risk Factor

Intimal/Atherosclerotic Calcification

Medial/Mönkeberg's Calcification




Advanced age



Elevated blood pressure


Reciprocal (medial lesions worsen blood pressure)








Yes (local)

Yes (systemic mediators)

Diabetes/glucose intolerance



Kidney disease



Reduced GFR









Positive balance






PTH abnormalities



Duration of treatment with dialysis



Adapted from Goodman WG, London G, Amann K, et al: Vascular calcification in chronic kidney disease. Am J Kidney Dis 43:572–579, 2004.

GFR, glomerular filtration rate; PTH, parathyroid hormone.




The Pathophysiology of Vascular Calcification

Although initially believed to be an “innocent bystander,” recent evidence suggests that vascular calcification is a tightly regulated process that resembles mineralization in bone.[77] Work in the past decade has demonstrated that vascular smooth muscle cells and vascular pericytes are also capable of producing bone-like proteins in cell culture, and are capable of forming mineralized nodules in vitro in the presence of a phosphorus donor, beta-glycerophosphate, identical to the requirements for bone nodule formation from osteoblasts in vitro. [203] [204] Evidence for similar osteogenesis in vascular calcification in dialysis patients were found in small skin arterioles from dialysis patients with calcific uremic arteriolopathy (calciphylaxis) that expressed osteopontin and bone sialoprotein, whereas noncalcified vessels did not.[205] Similarly, both intimal and medial vascular calcification in arteries from ESKD patients is associated with expression of bone matrix proteins and the osteoblast differentiation factor core binding factor alpha-1 (Cbfa1) [206] [207] now called RUNX-2. Runx-2 is thought to be the transcription factor that switches a pluripotent mesenchymal stem cell to the chondrocyte-osteoblast lineage, because animals deficient in RUNX-2 fail to mineralize bone.[208] In vitro, vascular smooth muscle cells up-regulate RUNX-2 in response to phosphorus, mediated by the type III sodium-dependent phosphate cotransporter Pit 1.[209] In addition, vascular smooth muscle cells incubated with uremic serum (pooled from anuric dialysis patients) compared with normal serum express RUNX-2 and its downstream protein osteopontin in a non-phosphorus-mediated mechanism. [206] [207] Non RUNX-2 pathways such as MSX may also be stimulated by bone morphogenic proteins (BMPs).[210] Uremic rats with hyperparathyroidism have up-regulation of both Runx-2 and Pit-1 in calcified arteries,[211] supporting these pathways. Using an in vitro calcification model of vascular smooth muscle cells, several nontraditional CKD cardiovascular risk factors can accelerate vascular calcification, including PTH and PTH-related peptide, calcitriol, advanced glycation end products, alterations of lipoproteins, and homocysteine.[77] Lastly, excess calcium can also induce mineralization in vitro and the effects of calcium are additive to that of increased phosphorus. [212] [213] Thus, patients with CKD have increased arterial calcification associated with morbidity and mortality, and numerous cardiovascular risk factors in CKD can induce vascular calcification in vitro. Given this data, it is not surprising that arterial calcification is so prevalent in patients with CKD.

Inhibitors of Vascular Calcification

Vascular calcification, although very prevalent in dialysis patients, is not uniform. Depending on the series, an average of 17% of dialysis patients have no vascular calcification, and continue to not have calcification on follow up.[189] [195] Although younger age is partially responsible for the protection against calcification, the data also support the presence of naturally occurring inhibitors of calcification. Animal knockout models have demonstrated that selective deletion of many genes, including matrix gla protein,[214] osteoprotegerin,[215] and others[216] leads to vascular calcification. These studies imply that mineralization (or calcification) of arteries will occur unless inhibited. This concept that the regulation of calcification is by inhibitors as opposed to promoters may also be true in bone, as has been recently hypothesized by Murshed and colleagues.[217] Many inhibitors found in bone also appear to have a role in the prevention of vascular calcification.

Matrix gla protein (MGP) is a vitamin K-dependent protein expressed in a number of tissues but highly expressed in arteries and bone, where it acts predominantly as a local regulator of vascular calcification. MGP knockout mice have excessive cartilage and growth plate mineralization and excessive arterial medial calcification.[214] The mechanism by which MGP inhibits extraskeletal calcification appears to be through binding to BMP-2 or modulation of BMP-2 activity, because BMP-2 is known to induce vascular calcification.[218] In vitro studies have demonstrated that MGP expression was minimal in BVSMC that were not mineralizing, but is up-regulated during mineralization.[219] Supporting a role for inhibition of mineralization is the finding of increased immunostaining for MGP and areas of vascular calcification in arteries from patients with[220] and without[221] CKD. MGP activity is inhibited by warfarin and in dialysis patients, warfarin is associated with calciphylaxis.[205] Unfortunately, studies evaluating circulating levels of MGP have found disparate results, perhaps in part because of difficulty in differentiating active versus inactive forms of MGP by currently available methodologies.

OPG knockout mice also develop osteopenia and arterial calcification, suggesting that OPG is an important direct inhibitor of vascular calcification. An alternative explanation is that the impaired bone remodeling induced by targeted disruption of OPG-/- impairs the ability of bone to mineralize to the extent that it may lead to arterial calcification. Data supporting this view include that OPG administration to OPG-/- mice reverses the bone phenotype but can only prevent, not reverse, vascular calcification.[222] Interestingly, in several studies, increased OPG serum levels were associated with increased calcification of the coronary artery and aorta in the general population,[223] and in hemodialysis patients. [220] [224] In the study by Nitta, OPG levels were independent predictors of vascular calcification.[224] In postmenopausal women with osteoporosis and in rats, the administration of OPG reduces bone resorption and, therefore, bone turnover.[225] London and colleagues[226] recently demonstrated by biopsy in CKD-5 patients that low bone turnover was associated with increased vascular calcification, and in a study of CKD-5 patients by Coen and colleagues,[227] elevations in serum OPG were associated with low turnover bone disease. Thus, the patients with the higher OPG levels may have had lower bone turnover, which does not allow bone to take up a mineral load,[45] thereby leading to extraskeletal calcification. However, others have found that elevated OPG in CKD-5 patients was associated with high turnover bone disease.[228] This conflicting data is likely due to the complex interaction of PTH and OPG, and more research is required to fully understand the physiologic function of OPG in vascular calcification.

Another potential inhibitor of extraskeletal calcification is fetuin-A (α2-HS glycoprotein), a circulating inhibitor. Fetuin-A is abundant in the plasma and is mainly produced by the liver in adults.[229] Fetuin-A inhibits the de novo formation and precipitation of the apatite precursor mineral basic calcium phosphate but does not dissolve it once the basic calcium phosphate is formed.[230] Therefore, fetuin-A can prevent undesirable calcification in the circulation without causing bone demineralization. In bone marrow stromal cells, fetuin-A binds to BMP-2 and transforming growth factor-β, inhibiting mineralization, and suppressing the expression of bone matrix proteins.[231]Fetuin-A knockout mice have extraskeletal calcification in the presence of hypercalcemia or when cross-bred on a mouse strain with a predisposition to calcification.[232] Fetuin-A is inversely correlated with the acute phase response. Serum from dialysis patients with calciphylaxis had impaired ex-vivo capacity to inhibit hydroxyapatite precipitation, which could be normalized by the addition of purified fetuin-A.[232] In vitro, fetuin-A inhibits mineralization in osteoblasts[230] and VSMC. [220] [233] Fetuin-A has been found in matrix vesicles from VSMC, and its presence renders the vesicles incapable of mineralization.[233]

Clinical interest in fetuin-A as an important inhibitor of vascular calcification in CKD was stimulated by a study by Ketteler et al has demonstrated that low fetuin-A levels were associated with increased cardiovascular mortality in dialysis patients.[234] These findings have been confirmed by others. [235] [236] Serum levels of fetuin-A in individual CKD patients were inversely correlated to coronary artery calcification by spiral CT scan,[220] carotid artery plaques,[236] and valvular calcification.[237] It should be clarified that serum fetuin-A levels are not uniformly low in dialysis patients.[234] Thus, fetuin-A deficiency may be a factor only in some patients, or there may be a relative deficiency of fetuin-A in the setting of elevated calcium and phosphorus. Alternatively, altered function due to gene polymorphisms may be important.[236]

Another naturally occurring inhibitor of mineralization is pyrophosphate. Bisphosphonates have pyrophosphate as a backbone structure, perhaps accounting for the effectiveness of bisphosphonates in the inhibition of calcification in bone[238] and in arteries.[239] Defects in pyrophosphate metabolism are involved in craniometaphyseal dysplasia and familial calcium pyrophosphate dihydrate deposition disease.[240] In vitro, calcification of cultured aortic rings can be inhibited by pyrophosphate.[241] Furthermore, circulating levels of pyrophosphate are decreased in dialysis patients and are partially cleared with dialysis.[242]

The precise role of these and other inhibitors in the vascular calcification in patients with CKD remains to be determined, but clearly, there are multiple mechanisms to regulate extraskeletal calcification. We are only beginning to understand this complex process ( Fig. 52-19 ).

FIGURE 52-19  Hypothetical pathophysiology of vascular calcification. Vascular calcification is common in patients with chronic kidney disease as well as the general aging population, and is an active process. An initial step in the process of calcification of arteries may be dedifferentiation of VSMCs to osteoblast-like cells through up-regulation or down-regulation of transcription factors such as RunX, bone morphogenic proteins (BMPs), and MSX. These osteoblast-like cells are capable of producing bone matrix proteins, which may subsequently regulate mineralization. Once mineralization is initiated, increased calcium × phosphorus product from abnormal bone, secondary hyperparathyroidism, or excessive calcium intake may accelerate the process. In contrast, serum fetuin-A and other inhibitors such as matrix gla protein (MGP) or pyrophosphate may be protective. Thus, similar to findings in bone, mineralization proceeds when the balance of promoting factors outweighs inhibitory proteins.  (Adapted from Moe SM, Chen NX: Pathophysiology of vascular calcification in chronic kidney disease. Circ Res 95:560–567, 2004.)



The Relationship Between Bone and Vascular Calcification

Epidemiologic studies in postmenopausal women and the aging general population have demonstrated that patients with osteoporosis have increased atherosclerosis and, more recently, increased coronary artery calcification. [243] [244] The ability of bone to mineralize appears to peak at age 25 to 35 years old. Thereafter, bone mineral content decreases gradually, with a 5-year acceleration at the time of menopause in women. Interestingly, coronary artery calcification progresses from the age of 25 to 35 until death.[245] This same inverse relationship has been found in dialysis patients, because Braun and co-workers also found a significant inverse correlation between coronary artery calcification by EBCT and bone mineral density by CT in a cross-sectional analysis.[183] Two other recent studies have demonstrated a similar relationship [226] [246] and are discussed in detail later.

Additional evidence of the relationship of vascular calcification and osteoporosis has been gained from knockout mice models, as detailed earlier. Animals deficient in matrix gla protein (MGP) and OPG have osteopenia and severe medial vascular calcification, leading to ruptured aneurysms as a cause of death. [214] [215] Additional evidence is provided by a series of experiments by Price and colleagues.[247] They have taken rats and induced vascular calcification by excessive vitamin D administration with or without warfarin (which inhibits MGP). They were then able to inhibit the vascular calcification with therapies that inhibit bone turnover, including several different bisphosphonates, OPG, and a vacuolar ATPase osteoclast inhibitor. These data provide strong evidence that impaired bone remodeling can lead to vascular calcification.

Potential Mechanisms of a Bone-Vascular Calcification Link in Chronic Kidney Disease

There are several different, but not mutually exclusive, mechanisms by which disturbances in mineral and bone metabolism (CKD-MBD) may lead to or accelerate vascular calcification.

Abnormal Bone Remodeling

A cross-sectional study by Braun and colleagues[183] also found a significant correlation between increased coronary artery calcification by EBCT and decreased bone mineral density by CT. Interestingly, it appears to be low-turnover bone disease that leads to greatest risk of vascular calcification. In 1993, Hutchinson and associates[248] found that 90% of peritoneal dialysis patients with biopsy-proven adynamic bone disease had evidence of vascular calcification on plain radiography compared with only 35% of those without adynamic bone disease. More recently, London and colleagues[226] evaluated hemodialysis patients. In this study, patients underwent assessment of vascular calcification by ultrasound with semi-quantitative scoring, and bone biopsy with histomorphometry. Those patients with lowest bone formation rates and decreased osteoblast surfaces had the greatest degree of peripheral artery calcification, and this relationship held true in patients with and without previous parathyroidectomy. The likely mechanism for these findings is that adynamic bone cannot incorporate an acute calcium load, whereas actively remodeling bone can, as demonstrated by elegant studies using radiolabeled calcium by Kurz and co-workers.[45]

Another study prospectively compared calcium-containing phosphate binders with the non-calcium phosphate binder sevelamer. The results showed that sevelamer attenuated aorta and coronary artery calcification, and improved trabecular bone calcium content, whereas calcium-based phosphate binders increased aorta and coronary artery calcification and decreased trabecular calcium content. Interestingly, patients without pre-existing calcification did not develop calcification in both treatment arms. [246] [249] Although excess calcium load from the calcium-based phosphate binder may contribute, another, likely additive, explanation is the oversuppression of PTH from high (and continuous) calcium intake. PTH secretion is normally oscillatory, and this PTH pattern can be anabolic, increasing osteoblast activity. This phenomenon is the rationale behind administrating PTH intermittently to increase bone-mineral content in postmenopausal and glucocorticoid-induced osteoporosis. In CKD, both calcitriol, and hypercalcemia (and likely calcium load) can blunt this oscillatory pattern, [250] [251] thus leading to impaired bone formation. Further evidence for this factor is that the exogenous administration of intermittent PTH to CKD rats improved bone-mineral density, bone calcium content, and linear bone growth, whereas continuous administration had no effect.[252] While these data may support avoiding excessive administration of calcium and calcitriol in patients with CKD, definitive harm has yet to be proven.

In contrast to low-turnover bone disease, the data are less robust on the effects of high-turnover bone disease on vascular calcification in CKD patients, perhaps because the treatments for high-turnover disease confound the effects of the disease itself. One small study found subtotal parathyroidectomy resulted in a significant decrease in vascular calcification in two of 10 dialysis patients with high coronary artery calcium scores and stabilization in seven of 10 patients with low baseline scores.[253] In animal models of excessive bone resorption, treatments aimed at decreasing bone remodeling by inhibition of osteoclast activity (i.e., bisphosphonates) have been found helpful in preventing vascular calcification,[247] suggesting that severe high-turnover bone disease may also predispose to vascular calcification. A small study in dialysis patients also showed that bisphosphonates slowed down the normal progression of coronary artery calcification.[239] The potential for abnormal remodeling at both extremes is also supported by work of Hruska and colleagues. [254] [255] They have demonstrated that bone morphogenic protein-7 can improve both a high-turnover and low-turnover bone model of vascular calcification in animals with CKD. In other animal models of CKD, secondary hyperparathyroidism develops spontaneously with loss of kidney function and can be associated with vascular calcification. [256] [257] Thus, it appears that both extremes of bone remodeling may enhance vascular calcification.

Abnormal Serum Mineral Levels

In the past, a calcium × phosphorus product of 70 mg2/dL2 was considered the threshold above which calcitriol should not be given. This was believed to be the level above which metastatic calcification occurred. Unfortunately, this level of 70 was based on theoretical, in vitro data and extrapolations from case reports. In addition, this number originated when the process of extraskeletal calcification was believed to be purely due to physicochemical deposition from supersaturation of sera with calcium and phosphorus. As detailed earlier, in vitro work has demonstrated that vascular smooth muscle cells can mineralize in the presence of elevated phosphorus concentrations similar to levels observed with increased mortality in CKD.[209] The addition of excess calcium to the media of vascular smooth muscle cells, again at concentrations similar to that observed clinically in dialysis patients, can also induce vascular calcification and, importantly, potentiates the effects of hyperphosphatemia. [212] [213] Thus, there is now a clear explanation by which elevations in calcium, phosphorus, and the calcium × phosphorus product can increase extraskeletal calcification by both passive precipitation and what appears to be a direct effect on vascular smooth muscle cells. These data may explain the clinical findings that elevations in serum phosphorus, calcium, and calcium × phosphorus product are associated with all-cause and cardiovascular mortality, as detailed previously in this chapter. In vascular calcification of the small arterioles of the skin (calciphylaxis or calcific uremic arteriolopathy), elevated phosphorus and calcium × phosphorus product were found to be a risk factor in a case-control study.[205] This was confirmed by Mazhar et al,[258] who found that the risk of calcific uremic arteriolopathy increased 3.5 fold for each milligram-per-deciliter increase in serum phosphorus levels. Lastly, elevated serum phosphorus, calcium, calcium × phosphorus product, and PTH were all greater in peritoneal dialysis patients with valvular calcification, [197] [259]and the presence of valvular calcification was predictive of all cause and cardiovascular mortality.[197] These data are supported by those of Rubel and co-workers[260] demonstrating that a serum phosphorus level of 5.0 mg/dL (1.62 mmol/L) or more was independently associated with having undergone a cardiac valve replacement procedure. Thus, there is mounting evidence that disturbances of mineral metabolism in renal failure contributes to the excessive cardiovascular calcification observed in dialysis patients.

Therapies for Chronic Kidney Disease and Mineral Bone Disease

Studies described earlier implicate calcium-based phos-phate binders in the pathogenesis of vascular calcification. The treat-to-goal study[249] was a prospective study of hemodialysis patients randomized to either calcium-containing phosphate binder or sevelamer, a noncalcium binder. One end point was the change in the magnitude of coronary artery and aorta calcification by EBCT at 26 and 52 weeks. Both forms of calcification increased in the calcium-binder treatment arm, whereas there was no increase in the sevelamer arm. Patients had similar, good control of serum phosphorus in both arms (mean 5.1 mg/dl). However, there was more hypercalcemia and oversuppression of PTH in the calcium-binder arm, and a lowering of the low-density lipoprotein (LDL) cholesterol in the sevelamer arm. These results demonstrate a difference in the effect of arterial calcification between the two treatments, but whether the mechanism of this difference was excess calcium intake, the impaired bone remodeling as a result of low PTH level, or the LDL cholesterol lowering is not known. A study in patients new to dialysis confirmed these results.[188] Of importance, CKD animal data have confirmed these results demonstrating increased calcification in calcium-treated animals compared with those treated with sevelamer. [256] [257]

Another therapy that may increase vascular calcification is vitamin D therapy.[261] The VDR is found in vascular smooth muscle cells.[262] In vitro, calcitriol at very supraphysiologic doses induces mineralization in vascular smooth muscle cells in some studies, but not all. [261] [263] Calcitriol, in toxic doses, is frequently used to induce vascular calcification in animal models without CKD. [264] [265] However, in these models, there is a deliberate attempt to induce hypercalcemia. In a study of dialysis patients, serum levels of calcidiol and calcitriol were not related to arterial calcification or distensibility.[266]

Even in animal models with CKD, it is difficult to separate a direct effect of vitamin D from an indirect effect of either hypercalcemia/hyperphosphatemia or oversuppression of bone remodeling.[261] However, Hirata and colleagues[267] demonstrated that the analog 22-oxacalcitriol suppressed PTH with decreased calcium content of the heart and aorta measured chemically compared with animals treated with 1,25(OH)2D3 at similar doses (1.25 and 6.25 mg given intravenously twice weekly for 2 weeks). This difference was observed despite similar increases in Ca × P over control animals in both groups indicating differences due to the type of D analog.[267] Similarly, Rodriquez and co-workers[268] using a 5/6th nephrectomy rat model found that calcitriol at 5 ng/kg given every 48 hours for 15 days had significant increased calcium and phosphate content in the aorta, whereas calcimimetic treated animals did not. However, the calcimimetic administration prevented the calcitriol-induced increase in calcium and phosphorus content of the aorta. The coadministration of these two agents led to additive suppression of PTH, but calcimimetic therapy failed to lower the hypercalcemia and hyperphosphatemia induced by calcitriol. Thus, in CKD animal models, there is evidence that calcitriol in doses somewhat comparable to those given to dialysis patients can cause vascular calcification but usually in association with elevations in the Ca × P product.

In clinical studies, the administration of vitamin D in any form has not been clearly linked to vascular calcification in patients with ESKD. In fact, the use of intravenous vitamin D had been associated with improved overall survival in dialysis patients, independent of the underlying PTH concentration or the degree of hyperphosphatemia or hypercalcemia. [269] [270] In particular, patients with the lowest PTH as well as those with the highest serum phosphorus had a significant survival advantage when administered intravenous vitamin D. Theoretically, the treatment of secondary hyperparathyroidism with calcitriol could result in vascular calcification by a number of mechanisms including alterations in bone remodeling, increased calcium and phosphorus levels in the blood, or a direct effect. More data are needed at the present time, but judicious use of vitamin D in patients with CKD without adverse effects on Ca × P or oversuppression of PTH is likely safe.

Post-Renal Transplant Bone Disease

CKD-MBD is a universal complication in patients with CKD before transplantation. Ideally, CKD-MBD would be improved with successful kidney transplantation. Unfortunately, in many cases, kidney transplantation returns individuals to CKD (as opposed to normal kidney function), and thus patients who undergo transplant surgery still suffer from disorders associated with CKD-MBD. In addition, disorders of mineral metabolism occur following successful transplant surgery and include the effects of medications (steroids and calcineurin inhibitors), persistence of underlying disorders (hyperparathyroidism and vitamin D deficiency), development of hyperphosphaturia with hypophosphatemia, and the recurrence of varying degrees of renal insufficiency ( Table 52-8 ). These disorders of mineral metabolism and the associated bone disease lead to the development of fractures following transplantation, which occur in up to 44% of successful transplant recipients.[271] This fracture risk appears to be less than that observed with other solid organ transplants.[271] The combination of a kidney-pancreas transplant increases fracture risk above that associated with renal transplant alone. [272] [273]

TABLE 52-8   -- Spectrum of Post Transplant Bone Disease

Preexisting Bone Disease




 Mixed Uremic


 β2-microglobulin amyloidosis





 Vitamin D

 Non-vitamin D


  Metabolic acidosis





Metabolic abnormalities

Adapted from Sprague SM, Josephson MA: Bone disease after kidney transplantation. Semin Nephrol 24:82–90, 2004.




There are limited studies evaluating bone histology in recipients of renal transplants. There appears to be a persistent mineralization defect.[274] In some studies, bone turnover normalized,[274] but in others, there is low turnover with histology consistent with adynamic bone disease.[275] Aluminum staining resolves in the majority of patients. However, longitudinal studies are lacking. There does appear to be a consistent decrease in bone mineral content by densitometry, although more recent studies, [271] [276] have not found the dramatic decrease initially described,[274] perhaps due to the current practice of reducing steroid dose more rapidly.

The use of corticosteroids is the major determinant of low bone mineral content, because these agents impair calcium absorption from the gastrointestinal tract, and inhibit bone cell recruitment and function.[271] The diagnosis of corticosteroid induced osteoporosis is best done with DEXA of the hips and spine for assessment of changes in trabecular bone. However, as indicated earlier in this chapter, abnormal bone turnover may alter the predictive value of DEXA in patients with CKD, and thus preexisting bone turnover likely affects the assessment and outcomes of bone disease in transplant recipients. There are no studies in kidney transplant recipients that demonstrate the ability of bone mineral density to predict fractures.

There are a limited number of therapeutic studies in patients undergoing kidney transplantation, whereas the majority of the therapeutic trials are in patients undergoing other solid organ transplantation. These studies have focused on the use of vitamin D metabolites and antiresorptive drugs, particularly the bisphosphonates.

Vitamin D metabolites may reduce post-transplantation bone loss by reversing glucocorticoid-induced decreases in intestinal calcium absorption and by mitigating secondary hyperparathyroidism. There have been no studies evaluating the use of the parent form of vitamin D and only one prospective study using calcidiol (25-hydroxyvitamin D3) in the prevention or treatment of post-kidney transplant bone disease. The use of 500 mg calcium and 50 mg calcidiol did not increase either proximal femur or lumbar BMD in six patients treated for 1 year after transplantation. However, calcidiol has been shown to both prevent bone loss and increase lumbar spine BMD following cardiac transplantation. There are also very few studies with calcitriol for the prevention or treatment of bone disease post kidney transplantation. The results of these studies are not conclusive.[271] However, in a preliminary report, Josephson and co-workers were able to demonstrate an increase in BMD of the femoral neck, lumbar spine, and radius following 12 months of calcitriol and calcium treatment compared with double placebo, when used to prevent early post-transplantation bone loss.[276]

Several studies suggest that bisphosphonates may be useful in either preventing or treating bone loss following renal transplantation.[271] Administration of intravenous pamidronate at time of transplantation and repeated 1 month later was shown to prevent lumbar spine and proximal femoral bone loss at 1 year. However, bone biopsy revealed that most patients developed a low turnover lesion.[277] Haas and associates[278] evaluated bone biopsies in six patients given placebo and seven patients who received zoledronic acid, and found similar resolution of the high-turnover lesions in both groups; however, those receiving zoledronic acid had significant improvement in trabecular calcification. Of concern is the high degree of low turnover observed in those receiv-ing bisphosphonate therapy. Furthermore, in a long-term (4 years) follow-up study of 17 male renal transplant recipients, two doses of intravenous pamidronate, given at the time of transplant and 1 month later, continued to show protective effects of bone mineral density 4 years later.[279] This conservative approach of short-term, limited administration of bisphosphonates may be prudent given the current practice to quickly decrease steroid dose, and limited data on potential long-term adverse effects of bisphosphonates on bone histology.

Thus, bisphosphonates may be promising for the management of post-transplant bone loss. This may be especially true immediately following transplantation and in those patients with high-turnover bone lesions. However, controversies remain regarding the optimal administration of bisphosphonates, whether continuous or intermittent therapy should be used, the duration of therapy, the level of kidney function at which bisphosphonates should be avoided, whether they are safe in kidney transplant recipients with low-turnover bone disease, and their utility following pediatric transplantation. Finally, one must be cautious in the use of bisphosphonates because there are reports of the development of sclerosing focal segmental glomerulonephritis following the use of pamidronate.

There is essentially no data on the use of calcitonin or hormone replacement therapy following transplantation. Hypogonadism is a common sequela in patients with chronic kidney disease and may persist following transplantation, thus an evaluation of gonadal status would be appropriate. The potential benefits of either estrogen replacement or testosterone therapy have to be weighed against the potential risks in the individual patient.


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