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 mitochondrial metabolism. Because of the importance of phosphorus in these functions, normal homeostasis maintains serum phosphorus concentrations between 2.5 and 4.5 mg/dL (0.81 and 1.45 mmol/L). Serum concentrations 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 [PO ₄ ] 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 form. It is this inorganic fraction that is freely circulating and measured. At a pH of 7.4, inorganic phosphates are in a ratio of about 4:1 HPO ₄ ^–2 to H ₂ PO ^–1 . For that reason, the serum phosphorus concentration is usually expressed in mmol/L rather than mEq/L. 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. Furthermore, there is considerable diurnal variation in serum phosphorus concentrations in healthy persons, as well as in patients with advanced CKD. The terms “phosphorus” and “phosphate” are often used interchangeably, but strictly speaking, phosphate means the inorganic freely available form (HPO ₄ ^–2 and H ₂ PO ^–1 ). However, most laboratories report phosphate, the measurable inorganic component of total body phosphorus, as phosphorus. For simplicity, we use the abbreviation Pi to represent phosphate and/or phosphorus throughout this chapter.

Pi is contained in almost all foods and is generally associated with a food’s protein content or phosphate-containing additives. In most commonly ingested foods without additives, the mean Pi content ranges from 9.0 to 14.6 mg per gram of protein, with many foods having up to a 28% higher Pi content because of additives, which are used as preservatives, acidifying agents, acidity buffers, and emulsifying agents. Although the recommended daily allowance for Pi is 800 mg/day, the average American diet contains approximately 1000 to 1400 mg Pi and that amount does not necessarily include inorganic Pi added as a preservative, a common practice. The source of Pi has a significant impact on bioavailability. Pi in the form of preservatives or additives is nearly 100% bioavailable, whereas Pi bound to phytate, as in legumes, is less bioavailable owing to the lack of the enzyme phytase in humans. In studies, the source of Pi directly affects Pi homeostasis. 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 patients undergoing dialysis. Pi balance in earlier stages of CKD (stage G3a, G3b, and in most cases G4) is generally neutral because of the phosphaturic effects of PTH and FGF-23 ⁷ ; as these compensatory mechanisms begin to fail and particularly when patients have little to no residual kidney function, however, positive Pi balance likely ensues.

Approximately 60% to 70% of dietary Pi is absorbed by the gastrointestinal tract, predominantly in the small intestine, although transport can occur in all intestinal segments. Pi absorption occurs via passive sodium-independent transport and active sodium-dependent transport. Although it can vary depending on the study and experimental design, active transport is approximately 50% of total transport ( Fig. 52.1 ). Passive transport occurs down electrochemical gradient through paracellular tight junctions; claudins and occludins appear to be involved and control transport rates and ion specificity. Active absorption occurs via the epithelial brush border type II (solute carrier A34) transporters, specifically the sodium-Pi cotransporter (NaPi-IIb) using energy from the basolateral sodium-potassium ATPase transporter. Complete ablation of the NaPi-IIb gene in mice demonstrates that this transporter is responsible for 90% of sodium-dependent transport but only 50% of total intestinal Pi transport. In animals with CKD induced by adenine, ablation of the NaPi-IIb gene lowers serum Pi, with additional lowering by the Pi binder sevelamer, suggesting that both active transport and passive transport are important in CKD. The NaPi-IIb transporter is predominantly stimulated by high dietary Pi and calcitriol. In addition, studies suggest that the phosphatonins, matrix extracellular phosphoglycoprotein, and FGF-23 may play a role in intestinal transport. Tenapanor, an inhibitor of the gut sodium/hydrogen exchanger, also affects Pi transport in the intestine. Tenapanor decreases paracellular absorption by increasing resistance to Pi transport at tight junctions and decreasing NaPi-IIb expression, thereby decreasing active Pi transport. However, dietary Pi appears the most important regulator of intestinal absorption.

Intestinal phosphate transport.

Approximately 50% of phosphate (Pi) transport is sodium (Na ⁺ ) dependent, due to active transport, and regulated by a number of factors. The remaining phosphate transport is sodium independent and due to paracellular or transcellular transport. FGF-23, Fibroblast growth factor 23; MEPE, matrix extracellular phosphoglycoprotein; Na ⁺ /K ⁺ ATPase, sodium-potassium adenosine triphosphatase; NaPi-IIb, the sodium-Pi cotransporter.

From Lee GJ, Marks J. Intestinal phosphate transport: a therapeutic target in chronic kidney disease and beyond? Pediatr Nephrol. 2015;30:363–371. With permission.

The kidneys are responsible for maintaining Pi balance by excreting the net amount of Pi absorbed (see Chapter 7 ). Most inorganic Pi is freely filtered by the glomerulus with approximately 70% to 80% reabsorbed in the proximal tubule, which serves as the primary regulated site of the kidney. The remaining 20% to 30% is reabsorbed in the distal tubule. Pi transport across the apical lumen occurs via an active transport process that is driven by active sodium transport on the basolateral side by the sodium-potassium adenosine triphosphatase (Na ⁺ -K ⁺ -ATPase). The primary transporters on the luminal surface are NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3), with a minor component via the type III sodium-dependent Pi cotransporter Pit-2 (SLC20A2). PTH and FGF-23 both downregulate these NaPi transporters but through different signaling mechanisms. FGF-23 stimulates endocytosis of the transporters after signaling through the FGF receptor (FGFR)–klotho complex, described later. PTH, after binding to PTHR1 receptor, leads to increased cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling with the scaffolding protein Na ⁺ -H ⁺ exchanger regulatory factors 1 and 3 (NHERF1 and NHERF3) playing an important role. Pi has been shown to stimulate FGF23 release from osteocytes via induction of kidney-specific glycolysis and synthesis of glycerol-3-phosphate (G-3-P) by the proximal tubule. The enzyme required for glycosis, G-3-P dehydrogenase, is Pi dependent and reabsorption of Pi via NaPi-IIa is critical for the G-3-P production. FGF-23 also decreases calcitriol production by reducing the conversion of 25(OH)D to calcitriol and increasing its catabolism. The reduction in calcitriol results in further reduction of intestinal Pi absorption.

Serum calcium concentrations are tightly controlled within a relatively narrow range, usually 8.5 to 10.5 mg/dL (2.1 to 2.6 mmol/L). However, the serum calcium concentration is a poor reflection of overall total body calcium because serum concentrations account for <1% of total body calcium; the remainder of total body calcium is stored in bone. Ionized calcium, generally 40% of total serum calcium, is physiologically active, whereas 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 measurement may underestimate the physiologically active (ionized) serum calcium. A commonly used formula for estimating the ionized calcium from the total calcium value is to add 0.8 mg/dL for every 1-mg decrease in serum albumin below 4 mg/dL. However, in a study in patients with CKD stages 3 to 5 not undergoing dialysis, total calcium concentration and albumin-corrected total calcium values failed to correctly classify 20% of patients as either hypocalcemic or hypercalcemic whose state was documented by ionized calcium measurement. The sensitivity to detect true hypocalcemia or hypercalcemia was only 40% and 21% for total serum calcium and 36% and 21% for albumin-corrected serum calcium, respectively. The primary causes of this discordance are thought to be albumin, PTH, and pH, although the latter has been questioned. Thus whenever possible, ionized calcium measurement should be used. Serum concentrations of ionized calcium are maintained within the normal range by the secretion of PTH, as discussed later.

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 ages 25 to 35 years, when bones stop growing, calcium balance tends to be neutral. Individuals with normal kidney function have protection against calcium overload by virtue of their ability to increase renal excretion of calcium and reduce intestinal absorption of calcium through the actions of PTH and calcitriol. However, in CKD the ability to maintain normal homeostasis, including a normal serum ionized calcium level and appropriate calcium balance for age, is diminished, and lost completely when kidney function is absent. Two studies in patients with CKD stages G3b to G4 demonstrate that 1000 mg per day of dietary or calcium supplement/binder leads to near-neutral calcium balance (reviewed in Chapter 17 ). ^, Concerns about inadequate calcium intake in the CKD population contributing to worsening bone health have led to updated guidelines, emphasizing the need for 800 to 1000 mg per day of calcium in adults and age-appropriate normal calcium intake in children.

Calcium absorption across the intestinal epithelium occurs via a vitamin D–dependent, saturable (transcellular) pathway and a vitamin D–independent, nonsaturable (paracellular) pathway. In states of adequate dietary calcium, the paracellular mechanism prevails, but the vitamin D–dependent pathways are critical in calcium-deficient states. The transcellular absorption occurs via three steps: 1. calcium enters from the lumen into the cells via transient receptor potential vanilloid (TRPV) channels, of which TRPV6 is most important in the intestine ; 2. the intracellular calcium associates with calbindin-D9K to be “ferried” to the basolateral membrane; and 3. calcium is removed from the enterocytes predominantly via the calcium-ATPase, with the Na ⁺ -Ca ²⁺ exchanger playing a minor role. 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. All of the key regulatory components of active calcium transport—TRPV, calbindin, the Ca ²⁺ -ATPase (PMCA1b), and the Na ⁺ -Ca ²⁺ exchanger (NCX1)—are upregulated by calcitriol. Mice with intestinal knockdown of the vitamin D receptor (VDR) are still able to maintain normal calcium levels because of PTH-induced increased bone resorption; by contrast, global knockdown of VDR leads to hypocalcemia. Hypocalcemia with VDR knockdown can be corrected with either a high-calcium diet (and presumed intestinal paracellular calcium transport) or the administration of calcitriol. Thus bone and kidney can compensate for impaired responsiveness of the intestinal VDR, and diet alone can compensate for a total lack of vitamin D. The 1α-hydroxylase enzyme (CYP27B1) is also located throughout the intestine; to date, however, conversion of 25(OH)D to calcitriol has been identified only in the colonic epithelial cells in inflammation.

The renal transport of calcium is further detailed in Chapter 7 . In the kidney, the majority (60%–70%) of calcium is reabsorbed passively in the proximal tubule, a process driven by a transepithelial electrochemical gradient that is generated by sodium and water reabsorption. Paracellular movement of calcium occurs via pore-forming claudins 5, 10a, and 17. In the thick ascending limb, another 10% of calcium is reabsorbed via paracellular transport. Calcium-sensing receptor (CaSR) activation in this segment inhibits calcium absorption. This paracellular reabsorption occurs via claudins 14, 16 (paracellin), and 19, with genetic defects in claudins resulting in syndromes of hypercalciuria and hypomagnesemia. However, the more regulated aspect of calcium reabsorption occurs via transcellular pathways in the distal convoluted tubule and connecting tubule ( Fig. 52.2 ). The mechanism is similar to intestinal transport: Calcium enters these cells via TRPV5 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 Na ⁺ /Ca ²⁺ exchanger (NCX1), and the plasma membrane adenosine triphosphatase (ATPase; PMCA1b). As in the intestinal epithelial cell, calcitriol upregulates all of these transport proteins. PTH has an indirect effect on renal calcium handling via stimulating the synthesis of calcitriol and increases TRPV5 activity. The enzymatic activity of circulating klotho has been shown to cleave the extracellular domain of TRPV5 channels, keeping these channels at the cell membrane and thereby facilitating calcium reabsorption.

Epithelial calcium active transport.

The late part of the distal convoluted tubule (DCT) and connecting tubule (CNT) play an important role in fine-tuning renal excretion of Ca ²⁺ . The epithelial Ca ²⁺ channel (TRPV5) is primarily expressed apically in these segments and colocalizes with calbindin-D _28K (28K), Na ⁺ /Ca ²⁺ exchanger (NCX1), and the plasma membrane adenosine triphosphatase (ATPase; PMCA1b). Upon entry via TRPV5, Ca ²⁺ is buffered by 28K and diffuses to the basolateral membrane, where it is released and extruded by a concerted action of NCX1 and PMCA1b. In addition, the basolateral membrane exposes a parathyroid hormone (PTH) receptor (PTHR) and the Na ⁺ /K ⁺ -ATPase consisting of the α, β, and γ subunits. PTHR activation by PTH stimulates TRPV5 activity and entered Ca ²⁺ can subsequently control the expression level of the Ca ²⁺ transporters. At the apical membrane, there is a bradykinin receptor (BK2) that is activated by urinary tissue kallikrein (TK) to activate TRPV5-mediated Ca ²⁺ influx. In the cell, entered Ca ²⁺ acts as negative feedback on channel activity, and 28K plays a regulatory role by association with TRPV5 under low intracellular Ca ²⁺ concentrations. Extracellular urinary klotho directly stimulates TRPV5 at the apical membrane by modification of the N-glycan, whereas intracellular klotho enhances Na ⁺ /K ⁺ -ATPase surface expression, which in turn activates NCX1-mediated Ca ²⁺ efflux. ADP, Adenosine diphosphate; DCT1, early part of distal convoluted tubule; PT, proximal tubule; TAL, thick ascending limb of Henle.

From Boros S, Bindels RJM, Hoenderop JGJ. Active Ca ²⁺ reabsorption in the connecting tubule. Pflügers Arch Eur J Physiol. 2009;458:99–109.

Physiologic studies in animals and humans in the 1980s demonstrated the rapid release of PTH in response to small reductions in blood-ionized calcium, lending support to the existence of a CaSR in the parathyroid gland that was subsequently cloned in 1993. The CaSR was shown to belong to the superfamily of G protein–coupled receptors and is a glycosylated protein with a large extracellular domain, seven membrane–spanning segments, and a relatively large cytoplasmic domain. The primary ligand for the CaSR is Ca ²⁺ , but it also senses other divalent and polyvalent cations including Mg ²⁺ , Be ²⁺ , La ³⁺ , Gd ³⁺ , and polyarginine. Extracellular calcium binds to multiple sites, leading to conformational changes that result in activation of phospholipases C, A ₂ , and D, as well as inhibition of cAMP production. Activation of the CaSR stimulates phospholipase C, leading to an increase in inositol 1,4,5-triphosphate (IP ₃ ), which mobilizes intracellular calcium and decreases PTH secretion ( Fig. 52.3 ). By contrast, inactivation of the CaSR reduces intracellular calcium and increases PTH secretion. CaSR messenger RNA (mRNA) is widely expressed in multiple tissues including organs responsible for CKD-MBD (parathyroid, kidney, thyroid, bone, intestine, vasculature). Studies have demonstrated a diverse role for the CaSR in disease including in the gastrointestinal tract, where it regulates gastrin, glucagon-like peptide-1, acid, and hormone secretion and is involved in taste, gastrointestinal fluid transport, and cell turnover.

Calcium-sensing receptor (CaR).

Activation of the CaR by calcium stimulates phospholipase C, leading to increased inositol 1,4,5-triphosphate (IP ₃ ), which mobilizes intracellular calcium and inhibits parathyroid hormone (PTH) synthesis. A decrease in serum calcium (Ca ²⁺ ) inhibits intracellular signaling, leading to increased PTH synthesis and secretion. ER, Endoplasmic reticulum.

From Friedman PA, Goodman WG. PTH(1-84)/PTH(7-84): a balance of power . Am J Physiol Renal Physiol. 2006;290:F975–F984.

CaSR ^–/– mice die shortly after birth owing to hypercalcemia, hypocalciuria, 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 hypocalciuria. However, these CaSR ^–/– /PTH ^–/– mice demonstrate hypercalcemia in response to oral calcium, infusion of PTH, or administration of calcitriol, whereas the CaSR ^+/+ /PTH ^–/– mice are able to decrease gastrointestinal calcium absorption and increase renal calcium excretion to maintain normal levels of serum calcium. ^, These data indicate that CaSR activation corrects hypocalcemia by increasing PTH, whereas in hypercalcemia, the CaSR acts independent of PTH by increasing renal calcium excretion. In uremic animals, the expression of CaSR in the parathyroid gland is downregulated by a high-Pi diet and upregulated by magnesium and calcimimetics. In parathyroid glands from patients with secondary hyperparathyroidism, the expression of the CaSR is downregulated in comparison with expression in nonuremic patients but can be upregulated with the administration of calcimimetics.

The CaSR is expressed throughout the kidney, where it is found in diverse locations and performs multiple physiologic functions: podocyte (cytoskeleton changes); proximal tubule (phosphate reabsorption, calcitriol synthesis, acidification/fluid reabsorption); macula densa (renin secretion); thick ascending loop of Henle (calcium, sodium, potassium, and chloride handling); distal convoluted tubule/connecting tubule (calcium transport); and collecting duct (acid/base, water handling). Diverse functions in the kidney signify how important calcium homeostasis is to normal kidney function and vice versa. Furthermore, many of these functions avoid renal calcium precipitation. Most notably, activation of the luminal CaSR in the collecting duct by elevated urine calcium values leads to urinary acidification and polyuria, ⁴¹⁹ a common clinical symptom in hypercalcemia, and prevents calcium-Pi precipitation.

There is some disagreement as to the role of the CaSR in bone and whether this role depends on PTH. Clearly bone cells respond to calcium. The CaSR is important in fetal bone development; conditional deletion of the CaSR in early osteoblasts leads to altered bone phenotype, although the results vary depending on the construct used. Studies suggest that the CaSR modulates both bone resorption and formation induced by PTH. In vitro, mesenchymal stem cells appear to require CaSR for differentiation, but in more differentiated cells, calcium channels appear more involved in calcium transport. An initial report found that calcium also regulates FGF-23 synthesis in bone, although this effect does not appear to be mediated via the CaSR. Calcimimetics, allosteric activators of the CaSR, are used to treat secondary hyperparathyroidism as discussed in Chapter 62 .

Data also suggest a role for the CaSR in vascular calcification. Immunohistochemical staining demonstrates expression of CaSR on normal human arteries with downregulation in areas of calcification. The CaSR is expressed on cultured vascular smooth muscle cells (VSMCs), and calcimimetics inhibit in vitro calcification. ^, The calcimimetic R-568 reverses calcitriol-induced arterial calcification and inhibits proliferation of VSMCs and endothelial cells in the 5/6 nephrectomy rat model. Calcimimetics also retard uremia-enhanced vascular calcification and atherosclerosis in the ApoE ^–/– mouse and prevent arterial and myocardial calcification in the Cy/+ model of slowly progressive CKD-MBD. Calcimimetics also upregulate a potential local inhibitor of arterial calcification, matrix gla protein. A trial of cinacalcet in patients with end-stage kidney disease (ESKD) treated with calcium-based phosphate binders showed amelioration in calcification relative to placebo (and active vitamin D analogs). These data support a role for the CaSR in all three components of CKD-MBD.

The primary function of PTH is to maintain calcium homeostasis ( Fig. 52.4 ) by 1. increasing bone mineral dissolution, thus releasing calcium and Pi; 2. increasing renal reabsorption of calcium and excretion of Pi; 3. increasing the activity of the renal CYP27B1 enzyme to convert 25(OH)D to calcitriol; and 4. enhancing the gastrointestinal absorption of both calcium and Pi indirectly through its effects on the synthesis of calcitriol. In healthy persons, the increase in serum PTH concentration in response to hypocalcemia effectively restores serum calcium and maintains serum Pi concentrations. The kidneys are critical to this normal homeostatic response; thus patients with more severe CKD may lose the capacity to maintain calcium homeostasis.

Normalization of serum calcium by multiple actions of parathyroid hormone (PTH).

Serum levels of ionized calcium (Ca) are maintained in the normal range by induction of increases in the secretion of PTH. PTH acts to increase bone resorption, renal calcium reabsorption, and the conversion of 25(OH)D to calcitriol in the kidney, thereby increasing gastrointestinal calcium absorption. The blue boxes indicate processes that are abnormal in chronic kidney disease, leading to altered calcium homeostasis. PO ₄ , Phosphate.

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; 2004:261–285.

PTH is cleaved to an 84–amino acid protein in the parathyroid gland, where it is stored as fragments in secretory granules for release. Once released, the circulating 1–84–amino acid protein has a half-life of 2 to 4 minutes and is further metabolized in the liver and kidney. PTH secretion occurs in response to hypocalcemia, hyperphosphatemia, and calcitriol deficiency. The extracellular concentration of ionized calcium is the most important determinant of minute-to-minute secretion of PTH from stored secretory granules. The CaSR mediates the rapid response in PTH secretion, which occurs within seconds of changes in ionized calcium concentration. Inactivating mutations of the CaSR have been associated with neonatal severe hyperparathyroidism and benign familial hypocalciuric hypercalcemia. Affected patients have asymptomatic elevations of serum calcium in the presence of nonsuppressed PTH. Activating mutations have been found in patients with autosomal dominant hypocalcemia resulting in inhibition of PTH secretion at relatively lower serum calcium concentrations. PTH is released as both an intact (1–84) protein and carboxy (C)-terminal fragments (often called PTH [7–84]; see Fig. 52.3 ). C-terminal PTH has the opposite effect on calcium release from bone in animals and cultured calvariae from that of PTH with an intact N terminus. In addition, the C-terminal PTH inhibits apoptosis in osteoblasts, whereas the N-terminal PTH induces apoptosis. Regulators of PTH secretion act by changing the proportion of intact 1–84 and C-terminal fragments.

PTH binds to the PTH1 receptor (PTH1R), which is a member of the G protein–linked seven membrane–spanning receptor family and is widely expressed. PTH-related peptide (PTHrp) shares homology with the first few amino acids of PTH and also binds the PTH1R. Activation of the PTH1R stimulates heterodimeric G proteins G _s (leading to stimulation of cAMP and PKA signaling) and G _αq (leading to activation of IP ₃ and protein kinase C), ultimately resulting in changes in intracellular calcium. 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 those of PTHrp are autocrine.

The relations among calcium, Pi, FGF-23, and calcitriol in the development of secondary hyperparathyroidism in CKD are complex and nearly impossible to fully evaluate in humans because changes in one lead to rapid changes in the others. The response to a decrease in ionized calcium mediated by the CaSR is likely the most potent stimulus for PTH release. Pi increases PTH production by enhancing the stability of PTH mRNA. FGF-23 directly stimulates PTH release in a klotho-independent manner. Calcitriol suppresses PTH release via the VDR to lead to direct suppression of the gene. Other vitamin D compounds that bind to the VDR with lower affinity still reduce PTH release if given in high enough quantities. Although PTH-induced signaling predominantly affects mineral metabolism, there are also many extraskeletal manifestations of PTH excess in CKD. These include encephalopathy, anemia, extraskeletal calcification, peripheral neuropathy, cardiac dysfunction, hyperlipidemia, bone and muscle pain, pruritus, and impotence.

In the kidney, PTH facilitates calcium reabsorption and Pi excretion, as noted earlier. In bone, PTH receptors are located on osteoblasts, with a time-dependent effect. PTH administered long term inhibits osteoblast differentiation and mineralization. By contrast, the administration of PTH to osteoblasts in a pulse rather than a continuous manner stimulates osteoblast proliferation, forming the basis for the administration of PTH as an anabolic therapy for osteoporosis. PTH also interacts with wnt/β-catenin signaling, as discussed in the bone section.

Cholesterol is synthesized to 7-dehydrocholesterol, which in turn is metabolized in the skin to vitamin D ₃ ( Fig. 52.5 ). This reaction is facilitated by ultraviolet light (ultraviolet B) and higher temperature and is therefore reduced in individuals with high skin melanin content and inhibited by sunscreen containing sun protection factor 8 or higher. In addition, there are dietary sources of vitamin D ₂ (ergocalciferol) and vitamin D ₃ (cholecalciferol). The difference between D ₂ (plant source) and D ₃ (animal source) compounds is the presence of a double bound (D ₂ ) between carbon numbers 22 and 23 in the side chain. Once in the blood, both D ₂ and D ₃ bind with vitamin D–binding protein (DBP) and are carried to the liver, where they are hydroxylated by CYP27A1 (25-hydroxylase) in an essentially unregulated manner to yield 25(OH)D, often called calcidiol. Once they are converted to calcidiol, there appears to be no difference between the biologic activities of D ₂ and D ₃ . Calcidiol is then converted in the kidney (or other cells) to calcitriol by the action of CYP27B1. This active metabolite is also degraded by other kidney enzymes, 24,25-hydroxylase (CYP24A1), and CYP3A4, providing the primary metabolism of the active compound.

Overview of vitamin D metabolism.

Vitamin D is obtained from dietary sources and is metabolized via ultraviolet light (ultraviolet B [UVB] ) from 7-dehydrocholesterol in the skin. Both sources (diet and skin) of vitamin D ₂ and vitamin D ₃ bind to vitamin D–binding protein (DBP) and circulate to the liver. In the liver, vitamin D is hydroxylated by CYP27A1 (25-hydroxylase) to 25(OH)D, commonly referred to as calcidiol. Calcidiol is then further metabolized to calcitriol by the 1α-hydroxylase enzyme (CYP27B1) at the level of the kidney. The active metabolite 1,25(OH) ₂ D (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) ₃ D through the action of the 24,25-hydroxylase enzyme (CYP24) . Calcidiol is similarly hydroxylated to 24,25(OH) ₂ D.

Modified 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.

Vitamin D–binding protein is a 58-kDa protein synthesized in the liver. Its serum levels in humans are between 4 and 8 mM, and the protein has a half-life of 3 days. Both the parent vitamin D, 25(OH)D, and calcitriol are carried in the circulation by DBP, but its greater affinity is for 25(OH)D. Targeted gene disruption studies show that DBP-null mice have a marked reduction in both circulating and tissue distributions of calcitriol and yet are normocalcemic, indicating that the primary role of DBP is to maintain stable serum stores of vitamin D metabolites. At the cellular level, both 25(OH)D and calcitriol are endocytosed. Inside the cell, calcitriol can be inactivated by mitochondrial 24-hydroxylase (CYP24A1) or 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. This complex binds the vitamin D response element of target genes and recruits transcription factors and corepressors/coactivators that modulate the transcription. These corepressors and coactivators appear to be specific for the ligand, and thus different forms and analogs of vitamin D may produce different effects at each tissue, forming the basis for the pharmacologic development of analogs. Degradation of calcidiol is believed to occur principally in the kidney, from side cleavage and oxidation, to form 24,25(OH) ₂ D.

It is generally accepted that the major source of the circulating levels of calcitriol in the kidney. There is evidence that both 25(OH)D and calcitriol have local tissue effects because the VDR, CYP27B1, and CYP24A1 are found in many cells throughout the body. While the kidneys are the predominant site of conversion of 25(OH)D to calcitriol, there is evidence of conversion in other organs, associated with CYP27B1 expression and/or activity in normal and abnormal cells. Other cell types active in conversion of 25(OH)D to calcitriol 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. Some of these cells may directly take up calcitriol, and others may endocytose the DBP–25(OH)D complex in a megalin-mediated manner ( Fig. 52.6 ), after which the 25(OH)D is hydroxylated by CYP27B1 to act on that specific cell. The presence of CYP24A1 in cells also indicates that the metabolism of calcitriol may be regulated at a cellular level. Circulating concentrations of 25(OH)D are 1000 times higher than those of calcitriol, and thus 25(OH)D exhibits a local, or autocrine/paracrine, effect on many cell types.

Concept of the role of the extrarenal 1α-hydroxylase.

The metabolism of vitamin D in the context of the cells involved is shown. Upper right, Proximal tubular cell showing the key elements in the uptake of 25(OH)D ₃ and its conversion to 1α,25(OH) ₂ D ₃ . Megalin/cubilin are cell surface receptors that execute endocytosis of the vitamin D–binding protein (DBP)–25(OH)D ₃ complex, and CYP27B1 is the main component of the 1α-hydroxylase, responsible for making 1α,25(OH) ₂ D ₃ . Middle left, Simple target cell that takes up 1α,25(OH, the vitamin D response element [VDRE]) ₂ D ₃ as the free ligand originally ferried to the target cell bound to DBP. The picture shows the key elements of the transcriptional machinery, as well as some representative gene products, including the cell division protein p21, the bone matrix protein osteopontin, the calcium transport protein calbindin, and the autoregulatory protein CYP24A1. Lower right, Target cell expressing extrarenal 1α-hydroxylase, which possesses megalin/cubilin machinery to take up the DBP–25(OH)D ₃ complex and also expresses CYP27B1, enabling it to make 1α,25(OH) ₂ D ₃ intracellularly and also to respond in a likewise manner to the simple target cell because it also possesses the vitamin D receptor (VDR) and other transcriptional machinery. The expectation is that cells involved in cell differentiation or in control of cell division require higher concentrations of 1α,25(OH) ₂ D ₃ in order to modulate a different set of genes and that the CYP27B1 boosts local production to augment “circulating” 1α,25(OH) ₂ D ₃ arriving from the kidney in the bloodstream. With normal physiologic processes, locally produced 1α,25(OH) ₂ D ₃ would not enter the general circulation, although in pathologic conditions (e.g., sarcoidosis) it might. At this time, it is not clear how many cell types can be considered simple target cells and how many possess the CYP27B1 and megalin/cubilin to allow for local production of hormones. mRNA, Messenger RNA; RXR, retinoid X receptor.

From Jones G. Expanding role for vitamin D in chronic kidney disease: importance of blood 25-OH-D levels and extra-renal 1α-hydroxylase in the classical and nonclassical actions of 1α,25-dihydroxyvitamin D _3. Semin Dial. 2007;20:316–324. With permission.

Circulating calcitriol mediates its cellular function via 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 cells, by upregulating the calcium transport protein calbindin (calbindin-D9k in intestine, and calbindin-D28k in kidney) and the basolateral calcium-ATPase as detailed earlier. The CYP27B1 in the kidney is the site of regulation of calcitriol synthesis by numerous other factors including serum calcium, serum Pi, estrogen, prolactin, growth hormone, FGF-23, and calcitriol itself. Studies show that FGF-23 and inflammatory mediators such as interferon regulate CYP27B1 at nonrenal sites. In vitamin D knockout animals, parathyroid gland hyperplasia is consistently observed despite normalization of serum calcium. However, gland growth can be blunted by exogenous administration of calcitriol even in the absence of VDR, demonstrating a role for calcitriol in regulation of parathyroid gland growth. In the rat, a single small dose of calcitriol decreases PTH secretion by nearly 100%. Studies in the 1970s demonstrated that oral calcitriol, but not the precursor hormone vitamin D ₃ , suppressed PTH in patients undergoing dialysis, leading to widespread use of calcitriol or its analogs in the management of secondary hyperparathyroidism. However, later studies in animals have demonstrated efficacy of 25(OH)D in suppression of PTH, but the doses required are much greater than for calcitriol. Studies in humans have shown efficacy of 25(OH)D in suppressing PTH in patients with advanced CKD, but direct comparison studies are lacking.

Calcitriol has multiple effects on many cells that are important in bone remodeling; therefore it is not surprising that bone defects are well described in vitamin D–deficient states. However, the direct effects of the vitamin D system on bone have been difficult to differentiate from the secondary effects of hypocalcemia and hyperparathyroidism in vitamin D–deficient models. Transgenic animals including 1α-hydroxylase ^–/– /VDR ^–/– and 1α-hydroxylase ^–/– /VDR ^–/– , have impaired bone mineralization. In these animals, mineralization can be corrected with normalization of serum calcium; even exogenous calcitriol does not fully correct mineralization in the 1α-hydroxylase ^–/– animals unless serum calcium concentrations are also restored. Studies evaluating bone remodeling also demonstrate an important role for the calcitriol/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 is blunted, suggesting a synergistic effect of vitamin D and PTH. Supporting this suggestion is the finding that when serum calcium concentrations are corrected by “rescue” diets and secondary hyperparathyroidism is prevented, osteoblast numbers, mineralization activity, and bone volume are still reduced. Comparison studies of 1α-hydroxylase ^–/– and PTH ^–/– mice demonstrate a predominant role for PTH in appositional bone growth and for vitamin D in endochondral bone formation. Thus the calcitriol/VDR system has anabolic bone effects that are necessary for bone formation and are supplemental to the effect of PTH.

“Phosphatonins” are circulating factors that regulate urinary Pi excretion. Two main phosphatonins have been described: FGF-23 and matrix extracellular phosphoglycoprotein. Various forms of rickets have now been found to be due to abnormalities in FGF-23. Autosomal dominant hypophosphatemic rickets is rare and is associated with a mutation that limits normal degradation of FGF-23. Autosomal recessive hypophosphatemic rickets is also rare and is due to a mutation in dentin matrix protein (DMP), a locally produced inhibitor of FGF-23. X-linked hypophosphatemic rickets is the most common form of rickets due to a mutation in PHEX (phosphate-regulating gene with homologies to endopeptidases located on the X chromosome). Mutations in PHEX have been found to have deficient degradation of FGF-23 in the osteocyte, leading to inappropriately high serum concentrations of FGF-23. Thus what previously was thought to be disorders of different etiologies are now all linked to FGF-23.

FGF-23 is a 251–amino acid hormone predominantly produced from bone cells (osteocytes and osteoblasts) during active bone remodeling, but its mRNA is also found in the heart, liver, thyroid/parathyroid, intestine, and skeletal muscle. FGF-23 production in the osteocyte is stimulated by PTH and calcitriol. Elevated Pi or Pi load and hypercalcemia may also stimulate FGF-23, but this stimulation appears to be indirect. In the osteocyte, both DMP1 and PHEX proteins degrade FGF-23 such that mutations in their corresponding genes lead to excess FGF-23. In turn, calcitriol increases PHEX and FGF-23 inhibits calcitriol, completing a feedback loop. Regulation of NaPi-IIa by FGF-23 is independent of PTH; FGF-23 also inhibits the conversion of 25(OH)D to calcitriol by inhibition of CYP27B1 in the renal tubules and at extrarenal sites, and it increases catabolism of calcitriol by activation of CYP24, ⁷³ leading to hypophosphatemia and inappropriately normal or low serum calcitriol concentrations. An overview of the FGF-23–klotho axis is shown in Fig. 52.7 .

The bone–kidney–parathyroid endocrine axes mediated by fibroblast growth factor 23 (FGF-23) and klotho.

Active form of vitamin D (calcitriol) binds to vitamin D receptor (VDR) in the bone (osteocytes). The ligand-bound VDR forms a heterodimer with a nuclear receptor (RXR) and transactivates expression of the FGF-23 gene. FGF-23 secreted from bone acts on the klotho–FGF receptor (FGFR) complex expressed in the kidney (the bone–kidney axis) and parathyroid gland (the bone-parathyroid axis). In the kidney, FGF-23 suppresses synthesis of active vitamin D by downregulating expression of the Cyp27b1 gene and promotes its inactivation by upregulating expression of the Cyp24 gene, thereby closing a negative feedback loop for vitamin D homeostasis. In the parathyroid gland, FGF-23 suppresses production and secretion of parathyroid hormone (PTH) . PTH binds to the PTH receptor (PTHR) expressed on renal tubular cells, leading to upregulation of Cyp27b1 gene expression. Thus suppression of PTH by FGF-23 reduces expression of the Cyp27b1 gene and serum levels of calcitriol. This step closes another long negative feedback loop for vitamin D homeostasis.

From Kuro-o M. Overview of the FGF23-Klotho axis. Pediatr Nephrol. 2010;25:583–590. With permission.

FGF-23 is a member of a diverse family of 18 FGFs that bind to one of four receptors (FGFRs) via a heparan sulfate cofactor– or klotho coreceptor–dependent manner, leading to diverse biologic effects. ⁷⁴² Identification of klotho as a coreceptor for FGF-23 was due to nearly identical phenotypes of the knockout mice including hyperphosphatemia, hypercalcemia, and excess calcitriol levels associated with early mortality, growth retardation, vascular calcification, cardiac hypertrophy, and osteopenia. Klotho was originally identified as an aging suppressor gene. α-Klotho is expressed in the kidney, skin, choroid plexus, pancreas, and parathyroid gland and forms complexes with FGFR1 and FGFR4 to enhance FGF-23 signaling. β-Klotho is expressed in the liver and fat, forms complexes with FGFR1 and FGFR4, and supports FGF-15/19 and FGF-21 signaling. γ-Klotho increases FGF-19 activity and is expressed in the eye, fat, and kidney. All three klothos are transmembrane proteins, with short intracellular domains and large extracellular domains that have β-glucosidase cleavage sites. In animals, α-klotho expressed in the distal tubule can be cleaved to release the extracellular domain into the circulation. Further, alternative splicing of the α-klotho gene produces only the extracellular domain that is released from cells and is called circulating or soluble klotho. The soluble α-klotho acts as a coreceptor at nonrenal sites and prevents FGF-23–induced cardiac hypertrophy. The kidney regulates both renal production of soluble klotho and renal excretion.

In the kidney, tissue klotho is downregulated and FGF-23 is upregulated early in the course of CKD. Klotho is shed from the distal convoluted tubule to serve as a coreceptor with FGF-23 on the proximal tubule, where it inhibits reabsorption of Pi that is regulated by NaPi-IIa, NaPi-IIc, and Pit-1 (similar to PTH but via different signaling mechanisms) and suppresses CYP27B1 to inhibit calcitriol production (opposite of PTH). α-Klotho also increases calcium reabsorption by stimulating TRPV5, decreases potassium excretion through effects on the ROMK1 (renal outer medullary potassium 1) channel, protects against kidney injury and fibrosis, and decreases insulin resistance. Table 52.2 demonstrates the parallel changes in klotho deficiency and CKD.

In recent years a two-way relationship between iron deficiency and FGF23 has been described. Initially identified in patients with autosomal dominant hypophosphatemic rickets in whom iron deficiency exacerbated hypophosphatemia, iron deficiency has now been confirmed to increase FGF23 production. Because this rise is typically balanced by increased cleavage of FGF23, perturbations in serum Pi are not classically noted. Severe hypophosphatemia can result when the balance of production and cleavage is disturbed, such as with administration of specific IV iron formulations (ferric caboxymaltose) that may impair FGF23 cleavage by mechanisms that are not yet clear. Inflammation and erythropoietin administration are also potent drivers of FGF23 production, but these factors are classically coupled with increased cleavage. In CKD, the balance of production and cleavage is disturbed, with a concomitant decrease in the ability of the kidney to excrete Pi. Notably, FGF23 itself can promote inflammation, iron deficiency, and anemia via secretion of inflammatory cytokines through FGFR4 activation. In a mouse model of CKD, inhibition of FGF23 signaling reverses iron deficiency, anemia, and markers of inflammation.

In addition to klotho’s role in mineral metabolism, klotho and FGF-23 are implicated in cardiovascular disease. FGF-23 can induce cardiac hypertrophy and increases intracellular calcium in a klotho-independent manner. ^{, ,} In humans, diminished kidney function and the associated inflammation may be required to manifest the negative cardiac effects of FGF23. Klotho is localized in the heart at the sinoatrial node, and klotho deficiency may lead to arrhythmias. Klotho suppresses cardiomyocyte apoptosis ⁹³⁰ and downregulates TRPC6 (transient receptor potential cation 6) calcium channel in the cardiomyocyte. Both klotho and FGFR1 and FGFR3, but not FGF-23 and FGFR4, are expressed in human arteries. ^, In human arteries from patients with CKD, klotho, FGFR1, and FGFR3 are downregulated in the presence of calcification. VDR activators upregulate klotho, leading to an anticalcific effect on FGF-23-induced calcification. Decreased klotho impairs endothelial function. Activation of the renin–angiotensin–aldosterone system reduces renal klotho expression. In summary, discovery of the many systemic effects of FGF-23 and klotho has revolutionized our understanding of CKD-MBD.

The identification of the OPG and RANK system in the 1980s sheds new light on the control of osteoclast function and the long-observed coupling of osteoblasts and osteoclasts. RANK is located on osteoclasts, and RANK ligand (RANKL) is secreted by osteoblasts. Osteoblasts also synthesize the decoy protein OPG, which can bind to RANK ligand and inhibit the subsequent binding of RANKL to RANK on osteoclasts, thus inhibiting bone resorption ( Fig. 52.8 ). Alternatively, if OPG production is decreased, RANKL 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, calcitriol, estrogen, glucocorticoids, interleukins, prostaglandins, and members of the transforming growth factor-β superfamily of cytokines. OPG has been successful in preventing bone resorption in models of osteoporosis, as well as hormone- and cytokine-induced bone resorption, and denosumab, an anti-RANKL antibody, is an approved anabolic drug for the treatment of osteoporosis. Interestingly, abnormalities in the OPG/RANKL system have been found in kidney disease, and early animal models suggest that treatment with OPG may have a protective role in hyperparathyroid bone disease. Initial studies in patients receiving dialysis have demonstrated hypocalcemia as a severe adverse effect of denosumab as an inhibitor of osteoclastic resorption. More information is required to understand how this system regulates bone remodeling in the context of CKD.

Role of osteoprotegerin (OPG)/ receptor activator of nuclear factor κB ligand (RANKL) in bone remodeling.

Mechanisms of action for OPG, RANKL, and RANK (receptor activator of nuclear factor κB) are depicted in this diagram. RANKL is produced by osteoblasts, bone marrow stromal cells, and other cells under the control of various proresorptive growth factors, hormones, and cytokines. Osteoblasts and stromal cells produce OPG, which binds to and thereby inactivates RANKL. The major binding complex is likely to be a single OPG homodimer interacting with high affinity with a single RANKL homotrimer. In the absence of OPG, RANKL activates its receptor, RANK, found on osteoclasts and preosteoclast precursors. RANK–RANKL interactions lead to preosteoclast recruitment, fusion into multinucleated osteoclasts, osteoclast activation, and osteoclast survival. Each of these RANK-mediated responses can be fully inhibited by OPG. CFU-M, Macrophage colony-forming unit.

From Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor κB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29:155–192.

Genetic defects in the gene SOST have been identified in rare bone disorders. Sclerostin, the protein product of this gene, binds to low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/LRP6) on the osteocyte to competitively inhibit the binding of the protein Wnt ( Fig. 52.9 ). Normally, Wnt binding to LRP5/LRP6 leads to stabilization of β-catenin (canonical pathway) and regulation of normal bone accrual via osteoblast differentiation. In the presence of sclerostin, the β-catenin is degraded, and mesenchymal stem cell differentiation to mature bone cells is inhibited. In animal models, sclerostin deletion enhances bone accrual, and in early human trials, treatment with an antibody to sclerostin was found to be anabolic. ^, Sclerostin concentrations are elevated in the blood and bone of patients with CKD and bone in animals with CKD and are associated with decreased BMD and increased fracture risk. Increased cardiovascular disease risk and mortality have been correlated with sclerostin levels in some studies, ^, though not confirmed by others. The anabolic agent, romosozumab, an antisclerostin antibody, may be efficacious in the treatment of renal osteodystrophy. However, initial studies in animals found that romosozumab was not efficacious in the setting of elevated PTH, although it did improve bone volume when PTH was suppressed. Dickkopf-related protein 1 (dkk-1) also inhibits Wnt binding to LRP5/LRP6, and an antibody to this circulating inhibitor of Wnt signaling improved bone remodeling in a model of early CKD. In osteocytes, PTH directly suppresses sclerostin and dkk-1 secretion ^, and thus inhibits the production of circulating inhibitors of Wnt signaling.

Parathyroid hormone (PTH) and β-catenin signaling in bone remodeling.

Osteocytes control bone formation through the secretion of the WNT antagonists sclerostin (SOST) and Dickkopf Wnt signaling pathway inhibitor 1 (dkk-1), the expression of which is regulated by mechanosignals and by signaling of PTH and bone morphogenetic protein (BMP) . PTH represses expression of these antagonists, whereas BMP signaling, which is mediated by BMP receptor 1A (BMPR1A), induces their expression. Moreover, Wnt signaling in osteocytes controls the production of osteoprotegerin (OPG), which is the decoy receptor for the key osteoclast differentiation factor RANKL (receptor activator of nuclear factor κB ligand). Osteoblast-expressed WNT5a stimulates differentiation of osteoclast precursors as a result of binding to the FZD–ROR2 (frizzled and receptor tyrosine kinase–like orphan receptor 2) receptor complex. In a feedback loop for bone remodeling, osteoclasts stimulate the local differentiation of osteoblasts at the end of the resorption phase by secreting Wnt ligands. In addition, activation of parathyroid hormone 1 receptor (PTH1R) –mediated signaling in osteoblasts and osteocytes leads to stabilization of β-catenin and thus activation of Wnt signaling. LRP5/6, Low-density lipoprotein (LDL) receptor–related proteins 5 and 6; PKA, protein kinase signaling.

From Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013;19:179–192. With permission.

VSMCs, osteoblasts, chondrocytes, and adipocytes differentiate from mesenchymal precursors with normal differentiation and transformation (dedifferentiation), which are controlled by various transcription factors ( Fig. 52.12 ). Expression of the osteoblast differentiation factor core-binding factor α-1 (Cbfα1), now called Runx-2, has been identified in the inferior epigastric artery of adults undergoing kidney transplantation and in sections from the brachial arteries of children undergoing dialysis. Runx-2 is essential for normal bone development, in that Runx-2 knockout mice fail to form a skeleton. Genetic techniques have confirmed that VSMCs give rise to osteochondrogenic-like cells in calcified blood vessels (as opposed to circulating cells). Osteoclast-like cells can also be seen, more commonly in intimal lesions, and as in bone, they appear to arise from circulating precursors.

Factors that regulate pathways involved in the pathogenesis of vascular calcification.

Multiple factors regulate each step of extraskeletal calcification. ACE, Angiotensin-converting enzyme; AII, angiotensin II; Ca, calcium; LRP5, low-density lipoprotein (LDL) receptor–related protein 5; MGP, matrix gamma-carboxyglutamate (Gla) protein; miRNA, microRNA; OPG, osteoprotegerin; Pi, phosphate; pOPN, osteopontin; PPi, pyrophosphate; RAGE, advanced glycosylation end product receptor; RANKL, receptor activator of nuclear factor κB ligand; ROS, reactive oxygen species; Runx2, runt-related transcription factor 2; TGF-β, transforming growth factor β; VSMCs, vascular smooth muscle cells; Wnt, wingless-type MMTV integration site family member.

From Wu M, Rementer C, Giachelli CM. Vascular calcification: an update on mechanisms and challenges in treatment. Calcif Tissue Int. 2013;93:365–373. With permission.

In vitro, VSMCs upregulate Runx-2 in response to elevated Pi mediated by the type III sodium-dependent Pi cotransporters Pit-1 and Pit-2. In addition, VSMCs incubated with uremic serum (pooled from anuric patients undergoing dialysis), in comparison with normal serum, express Runx-2 and its downstream protein osteopontin via a non–Pi-mediated mechanism. Excess calcium can also induce mineralization in vitro, and the effects of calcium are additive to those of increased Pi. FGF-23 enhances Pi-induced vascular calcification in rat aortic rings and rat aorta VSMCs by promoting osteoblastic differentiation. Most recently, calprotectin has been identified as a critical contributor to calcification in human VSMC and mouse aortic rings and was separately associated with cardiovascular outcomes and mortality in a diverse international cohort. Numerous traditional and nontraditional cardiovascular risk factors in CKD can induce the transformation of VSMCs into osteoblast-like cells, with subsequent calcification in vitro (see Fig. 52.12 ). Given these data, it is not surprising that arterial calcification is so common in patients with CKD.

In animal models of CKD, secondary hyperparathyroidism develops spontaneously with loss of kidney function and can be associated with vascular calcification. ^{, ,} Unfortunately, it is difficult to distinguish between the effects of Pi and PTH. However, one study found that vascular calcification developed in nephrectomized animals achieving supraphysiologic PTH levels by infusion, regardless of the Pi intake. In a similar study, Runx-2 was upregulated in animals in three of the four Pi/PTH intake groups—those fed normal PTH + high Pi, high PTH + high Pi, and high PTH + low Pi—indicating that both Pi and PTH may lead to Runx-2 upregulation in arteries. However, the animals given high PTH + low Pi did not demonstrate arterial calcification, suggesting that Pi is needed to provide the substrate for calcification to progress.

Arterial calcification and mineralization of bone are inversely related. In animal models of excessive bone resorption, treatments aimed at decreasing bone remodeling by inhibition of osteoclast activity (i.e., bisphosphonates and calcimimetics) have been found helpful in preventing vascular calcification in some but not all studies. Correction of low-turnover bone disease also appears to improve arterial calcification in animals. ^, The role of vitamin D has been controversial, but more recent data suggest that it is only when the circulating levels of calcitriol are increased (and thus induce hypercalcemia or hyperphosphatemia) that calcification is observed.

In chondrocytes and osteoblasts, normal mineralization is initiated when matrix vesicles are released into the extracellular space from the cell surface via polarized budding with subsequent attachment to extracellular matrix proteins. Matrix vesicles are characterized by both their appearance as small (50–200 nm), electron-dense spherical particles on electron microscopy and the biochemical presence of calcium and Pi, alkaline phosphatase, and the membrane protein annexins. Matrix vesicles have been identified in nearly all forms of mineralization/calcification in human tissues including bone, cartilage, tendon, calciphylaxis, and atherosclerosis. Cultured VSMCs incubated with elevated concentrations of calcium and Pi release matrix vesicles into the media, and the presence of fetuin-A (AHSG or α-2-Heremans-Schmid glycoprotein), the circulating inhibitor of mineralization (see later), decreases calcium uptake of the matrix vesicles. Collagenase digestion of VSMCs has been found to lead to two populations of matrix vesicles, a secreted form in the media that had high fetuin-A and low annexin II content and could not mineralize type I collagen, and cellular matrix vesicles that had low fetuin-A and high annexin II content and could mineralize. Matrix vesicles are similar to exosomes, which are known to transfer microRNAs from cell to cell and thus may play a role in calcification. MicroRNAs have been found to regulate the phenotypic switch from contractile to synthetic VSMCs and are involved in the regulation of arterial calcification in vitro in animal models. ^, These results suggest that the cellular regulation of the content of matrix vesicles may regulate the type and mineralizing capacity of the vesicle.

In addition to matrix vesicles, apoptotic bodies can induce calcification in vitro in VSMCs. Apoptotic bodies stimulated by calcium-Pi crystals of approximately 1 μm or less in diameter cause a rapid rise in intracellular calcium concentration and apoptosis, an effect triggered by lysosomal degradation. Apoptosis has been identified in arterial segments with calcification obtained from children with ESKD. Activation of the DNA damage response by prelamin A accelerates arterial calcification. Autophagy, a regulated process of cell survival, counteracts Pi-induced calcification by reducing matrix vesicle release. By contrast, atorvastatin protects against calcification by inducing autophagy via suppression of the β-catenin pathway. Thus cells appear to guard against calcification when able via a number of pathways.

Vascular calcification, although prevalent in patients with CKD and particularly in patients receiving dialysis, is not uniform. Approximately 20% (depending on the published series) of patients undergoing dialysis have no vascular calcification and continue to have no calcification on follow-up despite risk factors similar to those in patients who do have calcification. These data support the concept of calcification inhibitors. Knockout animal models have demonstrated that selective deletion of many genes leads to vascular calcification. These studies imply that mineralization (or calcification) of arteries will occur, at least in some species or individuals, unless inhibited. This concept, that the regulation of calcification in blood vessels occurs principally via inhibition rather than promotion, may also be true in bone. Inhibitors can be circulating or locally produced and site specific. Three inhibitors that have been well characterized in the arterial calcification of CKD are fetuin-A, matrix γ-carboxyglutamate (Gla) protein (MGP), and OPG.

Many other inhibitors of calcification exist. In aggregate, the data discussed in this section support the diversity and abundance of naturally occurring inhibitors of calcification. Thus vascular calcification in CKD represents a state of increased calcification promoters and decreased calcification inhibitors.

Matrix Gla protein (MGP) is a vitamin K–dependent protein expressed in many 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 arterial medial calcification, resulting in early mortality. In MGP-deficient mice, calcification depends on elastin fragmentation due to increased elastase production. Warfarin use and/or nutritional vitamin K deficiency result in undercarboxylation of MGP and impaired function. Warfarin use is also a known risk factor for calcific uremic arteriolopathy (also referred to as calciphylaxis) and can induce calcification in an animal model of CKD. Serum concentrations of carboxylated MGP were found to be nearly undetectable in patients undergoing dialysis and in patients with atherosclerotic disease. Furthermore, lower levels of carboxylated MGP were associated with coronary artery calcification, arterial stiffness, and higher serum Pi in patients undergoing dialysis. Lower serum concentrations of relative carboxylated MGP, as well as vitamin K deficiency, were also found in 20 patients with calcific uremic arteriolopathy compared with matched controls. Progression of coronary calcification was more pronounced in patients taking warfarin. Supplementation of vitamin K in patients undergoing dialysis can restore carboxylated MGP and perhaps prevent progression of calcification, but studies to determine whether such supplementation reduces calcification and cardiovascular events remain small and inconclusive.

The four hormones PTH, FGF-23, calcitriol, and klotho work together to maintain normal Pi and calcium homeostasis to achieve appropriate balance in the blood and urine of these ions to avoid extraskeletal calcification and ensure adequate availability of these ions for bone that is growing (modeling) or remodeling. A summary of the integrated physiologic response to hyperphosphatemia is depicted in Fig. 52.13 . This response is a complex system of multiple integrated feedback loops and is easier to understand if broken into loops that regulate calcitriol, Pi, and calcium.

Regulation of serum phosphorus levels.

As phosphorus levels increase (or there is a long-term phosphorus load), levels of both parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) are increased. Both of these elevations in turn increase urinary phosphate (Pi) excretion. The two hormones differ in respect to their effects on the vitamin D axis. PTH stimulates 1α-hydroxylase activity, thereby increasing the production of calcitriol, which in turn negatively feeds back on the parathyroid gland to decrease PTH secretion. By contrast, FGF-23 inhibits 1α-hydroxylase activity, thereby decreasing the production of calcitriol, thus feeding back to stimulate further secretion of FGF-23. FGF-23 and PTH also regulate each other. Finally, low calcium levels stimulate PTH, whereas high calcium levels stimulate FGF-23. Lastly, there is some evidence that FGF-23 also inhibits PTH secretion.

PTH concentration in plasma or serum serves as not only an indicator of abnormal mineral metabolism in CKD-MBD but also a noninvasive biochemical sign for the initial diagnosis of osteitis fibrosa cystica, the most common form of renal osteodystrophy in CKD-MBD. PTH measurement also can be a useful index for monitoring the evolution of renal osteodystrophy and can serve as a surrogate measure of bone turnover in patients with CKD. Although the sensitivity and specificity of PTH as a marker of bone remodeling are not ideal, it is the best single marker available at the current time. The combination of PTH, bone-specific alkaline phosphatase, and amino-terminal propeptide of type 1 collagen discriminates high versus low bone turnover in patients receiving dialysis. However, the definitive method for establishing the specific type of renal osteodystrophy 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.

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 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. The biologically active hormone produced (PTH[1–84]) exerts its effects through the interaction of its first 34 amino acids with PTHR1. PTH(1–84) has a plasma half-life of 2 to 4 minutes. In comparison, the half-life of C-terminal fragments, which are cleared principally by the kidney, is 5 to 10 times longer with normal kidney function and even longer in the presence of CKD. There is also a diurnal variation in the secretion of PTH and the release is oscillatory, further complicating measurement.

Assays for PTH have undergone many improvements over the years ( Fig. 52.14 ). In the early 1960s, radioimmunoassays were developed for measurement of PTH. However, these assays proved to be unreliable owing to different characteristics of the antisera used and are referred to as “first-generation” assays; consequently, two-site immunometric assays (IMAs) are referred to as “second- and third-generation” assays. The typical second-generation IMAs (known as intact PTH assays) measure PTH(1–84) and other large C-terminal PTH fragments because the antibodies do not bind to amino acid 1. These assays are commonly used in clinical practice. By contrast, third-generation assays (bioactive, whole, or bio-intact PTH assays) use capture antibodies similar to that of the intact PTH assays but also use detection antibodies directed against epitopes at the extreme N-terminal end (epitopes 1–4) of the molecule, and therefore they are believed to detect exclusively the biologically active PTH(1–84) ( Fig. 52.14 ). This difference may be important because C-terminal fragments (lacking small or large portions of the N terminus) are most abundant, representing approximately 80% of circulating PTH in healthy persons and 95% in patients with CKD. This finding may in part explain why elevated PTH concentrations are “normal” in CKD yet are increased relative to values observed in patients without CKD. The second-generation intact assays are commonly used on automated platforms. Although each assay has a reasonable coefficient of variation, the standards for the commercially available assays are not uniform and the detection antibodies do not all bind at the same sites. Thus the assay kit-to-kit variability can be high, with as much as a fivefold difference depending on the kit used. This is the reason the Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommended using the same assay every time and evaluating trends rather than targeting precise PTH values.

Parathyroid hormone (PTH) assays.

Schematic presentation of PTH(1–84) and the relationship between PTH assays, PTH assay epitopes, and PTH molecular forms detected in the circulation. The upper panel depicts the structure of human PTH and the epitopes detected by various PTH assays. First-generation PTH assays detect full-length PTH (1–84) in addition to PTH fragments. These assays include radioimmunoassays (RIAs) that use antisera specific to the amino-terminal (N-RIA), middle (MID-RIA), or carboxyl-terminal (C-RIA) regions of PTH. Second-generation “intact PTH” assays detect full-length PTH (1–84) and non(1–84)–PTH fragments. Third-generation PTH assays (biointact PTH) detect only full-length PTH (1–84). The bottom panel depicts PTH molecular forms present in the circulation. IMA, Immunometric assay; N-PTH, amino-terminal PTH; term., terminal.

From Henrich LM, Rogol AD, D’Amour P, et al. Persistent hypercalcemia after parathyroidectomy in an adolescent and effect of treatment with cinacalcet HCl. Clin Chem. 2006;52:2286–2293.

Serum calcidiol concentrations are generally measured by immunoassay, although the gold standard for calcidiol measurement is high-performance liquid chromatography, which is not widely available clinically. Unlike in PTH assays, sample handling in calcidiol immunoassays has little effect on results. However, vitamin D circulates as both D ₂ and D ₃ , and some laboratory kits measure only D ₂ , others measure only D ₃ , and still others measure both (expressed as 25-hydroxyvitamin D). The rationale for distinguishing D ₂ from D ₃ is controversial because it is unclear how differentiating the forms of vitamin D affects management- or patient-level outcomes. As with PTH, there is some assay-to-assay variability, which could affect the classification of insufficiency/deficiency or sufficient levels of calcidiol. Fortunately, current initiatives are under way to standardize these assays. The half-life of calcidiol is long and thus represents total body stores.

By contrast, calcitriol levels are generally measured only in the setting of hypercalcemia. The half-life is comparatively short, and the assay more expensive and difficult. Interpretation also requires consideration of clinical context. In other words, a patient with stage G4 or G5 CKD and hypercalcemia may have high normal serum calcitriol, which may be distinctly abnormal given the CKD stage and serum calcium concentration and should prompt consideration of an extrarenal source of calcitriol.

FGF-23 is currently measured primarily with two different assays ( Fig. 52.15 ). The first uses two antibodies directed against the C-terminal end and thus measures the intact, as well as C-terminal, fragments (results are reported in relative unit/mL). The second assay uses one antibody directed against an epitope within the N-terminal region and a second antibody directed against an epitope within the C-terminal region of the molecule, and thus it detects intact molecules (results are reported in picograms per milliliter). Although these two assays appear comparable in the association with clinical events, they have poor agreement because of differences in FGF-23 fragment detection, antibody specificity, and calibration. Such analytic variability does not permit direct comparison of FGF-23 measurements made with different assays, a fact that probably, at least in part, accounts for some of the inconsistencies noted among observational studies. FGF-23 can be detected in the urine, although at this time it is unclear how much, if any, of the hormone is cleared by the kidneys. ^, From a clinical perspective, more data are required before the use of FGF-23 measurements for routine clinical management.

Fibroblast growth factor 23 (FGF-23) assays.

(A) FGF-23 O-glycosylation site and epitopes recognized by antibodies used in current assays. (B) Spectrum of serum FGF-23 levels in early chronic kidney disease and end-stage kidney disease (ESKD) compared with the normal reference range and levels associated with different disorders affecting FGF-23. ADHR, Autosomal dominant hypophosphatemic rickets; ARHP, autosomal recessive hypophosphatemia; TIO, tumor-induced osteomalacia; XLH, X-linked hypophosphatemia.

From Block GA, Ix JH, Ketteler M, et al. Phosphate homeostasis in CKD: report of a scientific symposium sponsored by the National Kidney Foundation. Am J Kidney Dis. 2013;62:457–473. With permission.

It is unclear whether the circulating or soluble α-klotho levels reflect tissue-level expression of klotho. Some studies have found that low circulating levels were associated with progression of CKD, but other studies have failed to confirm this finding. A decrease in soluble klotho is detectable before aberrations in FGF23, PTH, or Pi, which may herald onset of CKD-MBD. Klotho can be detected in urine, suggesting its levels may be altered by residual renal function. Different assay kits give variable results. ^,

Circulating sclerostin concentrations are elevated in CKD and rise with progressive disease. However, sclerostin does not appear to be renally excreted, suggesting that the rising levels reflect underlying biology. The role of sclerostin in clinical diagnosis of CKD remains exploratory, although elevated sclerostin values are associated with arterial calcification and increased osteoblast number in human bone biopsy specimens.

Bone-specific alkaline phosphatase (BALP) is not cleared renally. BALP concentration has relatively good correlation with bone formation in CKD and may be additive to the interpretation of PTH measurements. However, its concentration has limited ability as an independent measurement. ^,

Osteoblasts secrete C- and N-terminal cleavage products of type I procollagen called secreted procollagen type IN propeptide (s-PINP) and secreted procollagen type IC propeptide (s-PICP), which are markers for bone formation. By contrast, serum C-terminal cross-linking telopeptide of type 1 collagen (s-CTX) and serum N-terminal cross-linking telopeptide of type I collagen (s-NTX) are measured as fragments of cross-links that are released when bone is resorbed. With the exception of the s-PICP, all of these markers are renally excreted, making interpretation of their measurements difficult. In cross-sectional analyses, higher serum concentrations are associated with higher odds of fracture.

Tartrate-resistant acid phosphatase 5b is released by osteoclasts during bone resorption and thus may be a good marker of bone resorption. Use of this biomarker is growing because, in concert with others, it may be useful to discriminate low versus high bone turnover in CKD-MBD.

Clinical assessment of bone remodeling is best performed 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 prior. Tetracycline binds to hydroxyapatite and emits fluorescence, thereby serving as a label for the bone. A core of predominantly trabecular bone is collected and embedded in plastic material and then sectioned. The sections can be visualized with special stains under fluorescent microscopy to determine the amount of bone between administrations of the two tetracycline labels or that formed in the interval. This dynamic parameter assessed with bone biopsy is the basis for evaluating bone turnover, which is key in discerning types of renal osteodystrophy. In addition to dynamic indices, bone biopsies can be analyzed by quantitative histomorphometry for static parameters as well. The nomenclature for these assessments has been standardized.

Clinically, bone biopsies are most useful for differentiating bone turnover, as well as bone volume and mineralization. However, with the advent of several new markers of bone turnover, the use of bone biopsy has been reserved primarily for the diagnosis of renal osteodystrophy and for research purposes. Sherrard and colleagues proposed a classification system for renal osteodystrophy that used the parameters of osteoid (unmineralized bone) area as a percentage 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 30 years ; however, this evaluation has been replaced by the KDIGO TMV (turnover, mineralization, volume) system (discussed later).

Fig. 52.17 illustrates bone histology using the original classification scheme. Normal bone is illustrated in Fig. 52.17A . Histologic features of high-turnover disease (predominant hyperparathyroidism or osteitis fibrosa cystica) are characterized by an increased rate of bone formation, increased bone resorption, extensive osteoclastic and osteoblastic activity, and progressive increase in endosteal peritrabecular fibrosis ( Fig. 52.17B ). High osteoblast activity is manifested by an increase in unmineralized bone matrix. The number of osteoclasts is also increased, as well as total resorption surface. There may be numerous dissecting cavities through which the osteoclasts tunnel into individual trabeculae. In osteitis fibrosa cystica, the alignment of strands of collagen in the bone matrix has an irregular woven pattern, unlike 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 to stress.

Bone histology.

(A) Normal bone. (B) Hyperparathyroid bone (increased osteoclast and osteoblasts and fibrosis). (C) Adynamic bone (no cellular activity and no osteoid). (D) Aluminum bone disease (left aluminum staining at mineralization front) and right two panels show accumulation of osteoid (orange-red stain). (E) Osteomalacia (increased unmineralized osteoid in pink/red ). (F) Mixed uremic osteodystrophy presence of increased osteoid (orange red) indicating mineralization defect and increased osteoclast activity.

A, B, D [right] , and E, courtesy S. L. Teitelbaum, M.D.; D [left] , courtesy D. J. Sherrard, M.D.

Low-turnover (adynamic) bone disease ( Fig. 52.17C ) is characterized histologically by absence of cellular (osteoblast and osteoclast) activity, osteoid formation, and endosteal fibrosis. It appears to be 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 with special staining that demonstrates the presence of aluminum deposits at the mineralization front ( Fig. 52.17D ). Frequently, aluminum disease is associated with osteomalacia. Osteomalacia is characterized by an excess of unmineralized osteoid, which manifests as wide osteoid seams and a markedly decreased mineralization rate ( Fig. 52.17E ). The presence of increased unmineralized osteoid per se does not necessarily indicate a mineralizing defect because larger 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 cellular activity and absence of endosteal fibrosis.

“Mixed uremic osteodystrophy” is the term used to describe bone biopsies that have features of secondary hyperparathyroidism together with evidence of a mineralization defect ( Fig. 52.17F ). 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, and high- and low-turnover bone diseases have been inconsistent and poorly defined.

The prevalence of different forms of renal osteodystrophy has changed over the past decade. 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 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, although osteomalacia has been essentially “replaced” by adynamic bone disease. There are differences in prevalence of mixed uremic osteodystrophy in patients not yet undergoing dialysis, which appears to depend on the level of GFR and the country in which the study was performed. Two large analyses of patients undergoing long-term dialysis revealed a relatively high incidence of low bone turnover; one study of 489 biopsy specimens in predominantly white patients revealed low turnover in 59%, whereas in another study of 630 patients, low-turnover disease was noted in 62% of White but only 32% of Black patients. The prevalence of mineralization defect or osteomalacia was relatively low at only 3%. Thus these data demonstrate that histologic abnormalities of bone begin early in the course of CKD and that differences in bone turnover may differ on the basis of race or country/region of origin.

By 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, who identified a fatal neurologic syndrome in patients receiving dialysis 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 aluminum 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. Fortunately, exposure to aluminum is limited in the modern era, and the incidence of aluminum bone disease is relatively rare. However, the diagnosis of aluminum-induced bone disease can be difficult because aluminum toxicity is due to tissue burden, not serum concentrations. Thus if aluminum bone disease is suspected, bone biopsy remains the gold standard for making the diagnosis. ^,

In adynamic bone disease, there is a paucity of cells with resultant low bone turnover ( Fig. 52.17C ). Unlike in 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 investigators believed that the disease was due to aluminum, but it was later identified in the absence of aluminum. The etiology of adynamic bone disease is likely multifactorial, and major contributory factors include diabetes mellitus, aging, and malnutrition.

Proposed pathophysiologic mechanisms of low bone turnover are listed in Table 52.4 . Increases in both sclerostin and dkk-1, which are soluble inhibitors of Wnt signaling that inhibit osteoblastic bone formation, likely play a role in development of adynamic bone disease. ^{, ,} Circulating fragments of PTH (7–84–amino acid fragments) may also be antagonists to PTH, resulting in an effective resistance to 1–84 amino acid at the level of bone. There is evidence that markedly elevated concentrations of FGF-23 may be associated with decreased osteoblastic activity. Furthermore, abnormal regulation of cell differentiation in the presence of kidney failure may explain, in part, the relative paucity of cells in adynamic bone, although this possibility remains to be proven. In rats, the administration of bone morphogenetic protein-7 can restore normal cell function, supporting that a failure of normal cell differentiation, likely due to a number of causes, may be critical. Although most patients with low-turnover bone disease are asymptomatic, they are at increased risk of fracture owing to impaired remodeling ^{, ,} and at risk of vascular calcification because of the inability of bone to buffer both acute and chronic calcium loads. ^{, ,}

Table 52.4

Causes and Proposed Mechanisms of Decreased Bone Formation in Patients With Chronic Kidney Disease

	Mechanism of Decreased Osteoblast Activity
Low serum calcitriol	↓︎ Osteoblast differentiation
	↓︎ Osteoblast life span
Metabolic acidosis	↓︎ Calcitriol production
	↓︎ Collagen synthesis
High serum phosphate	↓︎ Calcitriol production
Calcium loading/hypercalcemia	↓︎ Calcitriol production and ↑︎calcitriol degradation (mediated by calcium-sensing receptor)
High serum interleukins 1 and 6, tumor necrosis factor	↓︎ Osteoblast life span
Low serum insulinlike growth factor-I (IGF-I) activity	↓︎ IGF-I and IGF binding protein 5 (IGFBP5) levels
	↑︎ Inhibitory IGFBP (2, 4, 6) levels
	↓︎ Osteoblast life span
Sclerostin	↓︎ Wnt/β-catenin signaling
	↓︎ Osteoblastic activity
Dickkopf-1 (dkk-1)	↓︎ Wnt/β-catenin signaling
	↓︎ Osteoblastic activity
Malnutrition, proteinuria	↓︎ IGF-I; 25-hydroxyvitamin D levels
Diabetes	↓︎ 25-Hydroxyvitamin D and calcitriol levels
	↑︎ Advanced glycation end products (AGEs)
	↓︎ Osteoblast life span
Age-related	↑︎ AGEs
	↓︎ Osteoblast life span
Hypogonadal
Women (↓︎ estrogen and ↑︎ sex hormone–binding globulin [SHBG])	↓︎ Osteoblast life span
Men (↓︎ testosterone and ↑︎SHBG)	↓︎ Osteoblast life span
Uremic toxins (uric acid)	↓︎ Calcitriol production
	↓︎ Vitamin D receptor activity
	↓︎ Osteoblast proliferation
Aluminum toxicity	↓︎ Osteoblast activity

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