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Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)

Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)
Author:
Wajeh Y Qunibi, MD
Section Editor:
Jeffrey S Berns, MD
Deputy Editor:
Albert Q Lam, MD
Literature review current through: Jun 2022. | This topic last updated: Jun 22, 2022.

INTRODUCTION AND DEFINITIONS — Chronic kidney disease (CKD) is commonly associated with disorders of mineral and bone metabolism, manifested by either one or a combination of the following three components:

Abnormalities of calcium, phosphorus, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and vitamin D metabolism

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

Extraskeletal calcification

The work group of the Kidney Disease: Improving Global Outcomes (KDIGO) recommended in 2006 the use of the term chronic kidney disease-mineral and bone disorder (CKD-MBD) to describe a systemic disorder that incorporates these abnormalities [1]. Each of these abnormalities is associated with high mortality rates, primarily from cardiovascular complications. Following the introduction of the term CKD-MBD, various clinical practice guidelines have recommended laboratory targets and therapeutic approaches aimed at ameliorating the consequences of this systemic disorder.

The term "renal osteodystrophy" is now exclusively used to define alterations in bone morphology associated with CKD based upon bone biopsy, and it is only one component of the bone abnormalities of CKD-MBD [1-3]. Based upon bone biopsy, bone formation is classified into high-turnover, low-turnover, and mixed bone disease. Patients with CKD can develop bone formation rates ranging from abnormally low to very high.

This topic reviews the pathogenesis of CKD-MBD. The treatment of hyperphosphatemia and of secondary hyperparathyroidism in nondialysis CKD patients and in end-stage kidney disease (ESKD) patients is discussed elsewhere:

(See "Management of hyperphosphatemia in adults with chronic kidney disease".)

(See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

(See "Management of secondary hyperparathyroidism in adult dialysis patients".)

(See "Refractory hyperparathyroidism and indications for parathyroidectomy in adult dialysis patients".)

Low-turnover (or adynamic) bone disease and the use of bone biopsy to establish a specific diagnosis are discussed elsewhere:

(See "Adynamic bone disease associated with chronic kidney disease".)

(See "Bone biopsy and the diagnosis of renal osteodystrophy".)

The pathophysiology of CKD-MBD is complex and involves feedback loops between the kidney, the parathyroid glands, bone, intestine, and the vasculature. The main goal of this system is maintenance of calcium and phosphorus balance, often at the expense of abnormalities in other components of the system.

While most elements of CKD–MBD are usually present when the glomerular filtration rate (GFR) falls below 40 mL/min, some components may be observed earlier in the course of CKD and precede the onset of clinically detectable abnormalities in serum phosphorus, calcium, PTH, and vitamin D [4-9]. These include loss of klotho, increased FGF23 secretion, decreased bone formation rates, and vascular calcification.

With progressive loss of functioning nephrons, phosphate excretion is maintained by reducing the proximal tubular reabsorption of filtered phosphate in the remaining functioning nephrons, an effect mediated by both FGF23 and PTH. Bone disease develops as early as CKD stage 2 (ie, estimated GFR [eGFR] 60 to 89 mL/min/1.73 m2) and becomes almost universal in patients with CKD stage 5 (eGFR <15 mL/min/1.73 m2) [4,9-11]. Vascular calcifications also develop early, and their prevalence increases as the GFR declines such that approximately 80 percent of incident dialysis patients have evidence of coronary artery calcification [12,13].

ABNORMALITIES OF PARATHYROID HORMONE, CALCIUM, PHOSPHORUS, FIBROBLAST GROWTH FACTOR 23, AND VITAMIN D METABOLISM

Overview — Diagnosis of CKD-MBD entails serial evaluation of parameters of mineral metabolism, bone histomorphometry, and radiologic evaluation of vascular calcification. Bone biopsy is not routinely performed; instead, we use biomarkers of mineral metabolism such as serum phosphate, calcium, parathyroid hormone (PTH), total or bone-specific alkaline phosphatase (BSAP), vitamin D, and FGF23.

PTH level was the first biomarker used for the diagnosis and monitoring of CKD-MBD and bone turnover. Secondary hyperparathyroidism, a major feature of CKD-MBD, begins early in the course of CKD, and its prevalence increases as kidney function declines. Only 12 percent of patients with glomerular filtration rate (GFR) >80 mL/min/1.73 m2 had a high PTH level (defined as >65 pg/mL, the upper limit of normal of the assay used), but almost 60 percent of patients with GFR <60 mL/min/1.73 m2 had elevated PTH levels [14].

Secondary hyperparathyroidism occurs in response to a series of mineral abnormalities that initiate and maintain increased PTH secretion [15]:

Phosphate retention

Decreased free ionized calcium concentration

Decreased 1,25-dihydroxyvitamin D (calcitriol) concentration

Increased fibroblast growth factor 23 (FGF23) concentration

The reduced expression of vitamin D receptors (VDRs), calcium-sensing receptors (CaSRs), fibroblast growth factor receptors, and klotho in the parathyroid glands

The relative importance of these abnormalities in triggering PTH production can be understood by examining the changes in their respective concentrations in relation to the increase in PTH during the course of CKD. Increased PTH concentrations first become evident when the eGFR drops below 60 mL/min/1.73 m2. At that time, serum calcium and phosphate concentrations are normal and remain within normal ranges until the eGFR decreases to approximately 20 mL/min/1.73 m2 [14]. However, circulating calcitriol concentrations begin to fall much earlier, when the GFR is <60 mL/min/1.73 m2 (occasionally even at higher eGFRs [14]), and are typically markedly reduced in subjects with end-stage kidney disease (ESKD) [16]. The primary reason for the decline in calcitriol concentration is the increase in FGF23 concentration, rather than the loss of functioning kidney tissue [17]. Hyperphosphatemia (a relatively late phenomenon in CKD) may also contribute to the decline in calcitriol synthesis by suppression of 1-alpha-hydroxylase enzyme. In turn, calcitriol deficiency and hyperphosphatemia contribute to the development of hypocalcemia. These abnormalities stimulate the synthesis and secretion of PTH and increase its concentration via different mechanisms.

Phosphate retention and hyperphosphatemia — Before the discovery of FGF23, phosphate retention was thought to be the initial trigger for many of the components of CKD-MBD. A tendency to phosphate retention, beginning early in CKD as the decline in GFR decreases the filtered phosphate load, was thought to play a central role in the development of secondary hyperparathyroidism [18-20]. Three major but not mutually exclusive theories have been proposed to explain how phosphate retention initially promotes PTH release [21-23]:

The induction of hypocalcemia

Decreased formation or activity of calcitriol (1,25-dihydroxyvitamin D, the active form of vitamin D that is produced by the kidney)

Increased PTH gene expression

According to the "trade-off" hypothesis, phosphate retention contributes to secondary hyperparathyroidism in early CKD, at least in part by decreasing serum free calcium concentration and calcitriol synthesis [21-24]. The increase in PTH level increases kidney phosphate excretion by decreasing proximal tubular resorption of phosphate, mobilizing calcium from bone, and stimulating the production of calcitriol by the kidney, which in turn increases intestinal absorption of calcium [23-26]. If phosphate retention is prevented by restricting phosphate intake in proportion to the reduction in GFR, the rise in plasma PTH concentration can be prevented [23,25,26]. Even in patients who have moderate kidney function impairment and already established secondary hyperparathyroidism, lowering the plasma phosphate concentration with oral phosphate binders can partially reverse the hypocalcemia, hyperparathyroidism, and calcitriol deficiency [27,28]. (See "Management of hyperphosphatemia in adults with chronic kidney disease".)

However, serum phosphate levels are not elevated in the majority of patients in the early stages of CKD, probably due to a reduction in renal proximal tubular phosphate resorption mediated by increased levels of PTH and FGF23 [17]. The effects of FGF23 on phosphate excretion may be blunted by klotho deficiency, which occurs early in CKD. At this point, PTH may become the primary factor in maintaining serum phosphate level.

From the viewpoint of phosphate homeostasis, the initial elevation in PTH secretion is appropriate since the ensuing increase in phosphate excretion lowers the plasma phosphate concentration toward normal. Among patients with severely reduced GFR, PTH inhibits proximal tubule phosphate reabsorption from the normal 80 to 95 percent to as low as 15 percent of the filtered phosphate [15,29]. Hyperparathyroidism also tends to correct both the hypocalcemia (by increasing bone resorption) and the calcitriol deficiency (by stimulating the 1-alpha-hydroxylation of calcidiol [25-hydroxyvitamin D] in the proximal tubule). (See "Overview of vitamin D", section on 'Metabolism'.)

Despite this seemingly beneficial adaptive increase in PTH secretion, hyperparathyroidism becomes maladaptive over the long term [23]. Furthermore, the effect of PTH on phosphate balance changes as GFR declines. In advanced stages of CKD, when the GFR drops below 30 mL/min, the compensatory increase in the levels of PTH and FGF23 becomes inadequate, and hyperphosphatemia develops [8,30]. Moreover, since phosphate reabsorption by the renal tubules cannot be lowered below a minimum threshold, other factors exacerbate the hyperphosphatemia including continued phosphate reabsorption by the renal tubules, decreased phosphate deposition into bone, and continued PTH-induced release of phosphate from bone.

Hyperphosphatemia may also have a direct effect on PTH synthesis and secretion that is independent of the plasma concentrations of calcium and calcitriol in advanced CKD [31-34]. A study in experimental animals with ESKD demonstrated that dietary phosphate restriction to normalize the plasma phosphate concentration lowered plasma PTH concentrations from 130 to 35 pg/mL [32]. This occurred without changes in the plasma calcium or calcitriol concentrations. Parathyroid gland size also decreased in these animals, suggesting that hyperphosphatemia stimulates parathyroid growth in kidney failure. This effect is mediated by the reduction of PTH messenger RNA (mRNA) concentrations via increasing posttranscriptional PTH mRNA message stability [34].

These observations are applicable to humans, as illustrated by the following findings:

One report evaluated the effect of adding phosphate to the dialysate of patients on maintenance hemodialysis [33]. Phosphate was added to the dialysate to raise the plasma phosphate concentration by 2.4 mg/dL (0.75 mmol/L) above the baseline of 4.7 to 5.9 mg/dL (1.5 to 1.9 mmol/L). At 12 weeks, 7 of 15 patients showed significant elevations in plasma PTH concentrations without changes in the plasma concentrations of ionized calcium or calcitriol (the latter was low initially and remained low throughout the study).

Another study showed that in vitro exposure of hyperplastic parathyroid tissue obtained from patients with kidney failure to high phosphate concentrations increased preproPTH mRNA and enhanced PTH secretion [35].

However, the phosphate-sensing mechanism remains unknown. One study found that raising phosphate concentration within the pathophysiologic range for CKD significantly inhibits activity of the calcium-sensing receptor (CaSR), the main controller of PTH secretion, via noncompetitive antagonism [36]. High phosphate concentrations elicited rapid and reversible increases in PTH secretion from freshly isolated human parathyroid cells consistent with a receptor-mediated action. The same effect was seen in wild-type murine parathyroid glands but not in CaSR knockout glands. By sensing moderate changes in extracellular phosphate concentration, the CaSR represents a phosphate sensor in the parathyroid gland, and, therefore, advances an explanation for the stimulatory effect of phosphate on PTH secretion.

Hyperphosphatemia also stimulates the secretion of FGF23, which acts to suppress PTH secretion [37,38]. (See 'Fibroblast growth factor 23' below.)

Perhaps the most important consequence of hyperphosphatemia is on the cardiovascular system since hyperphosphatemia stimulates osteoblastic transformation of the vascular smooth muscle cell in the vasculature and directly contributes to cardiovascular calcification and arterial stiffness [39,40].

The pathophysiology of secondary hyperparathyroidism has evolved with the discovery of FGF23 and the understanding of its function. This has led to a rethinking of the "trade-off" hypothesis. In this updated scenario, circulating FGF23 levels progressively increase with decline in kidney function before the observed changes in the serum phosphate and PTH level. (See 'Fibroblast growth factor 23' below.)

Decreased calcitriol activity — Plasma calcitriol concentrations generally fall below normal when the GFR is <60 mL/min/1.73 m2, although low concentrations have also been found in some patients with higher eGFR (ie, <80 mL/min/1.73 m2) [14,23,41-43].

Initially, the decline in calcitriol concentration is likely to be due to the increase in FGF23 concentration rather than the loss of functioning kidney mass [17]. The FGF23-induced decrease in calcitriol begins early, when the GFR drops to <80 mL/min/1.73 m2 [13,23,41-43]. However, in advanced CKD, hyperphosphatemia and loss of kidney mass in addition to increased FGF23 levels contribute to the decline in calcitriol synthesis.

FGF23 decreases the synthesis of calcitriol by suppressing the activity of 1-alpha-hydroxylase, which converts 25-hydroxyvitamin D to calcitriol, and by stimulating the 24-hydroxylase enzyme, which converts calcitriol (1,25-dihydroxyvitamin D3) to inactive metabolites in the proximal tubule [17,44,45]. Increased dietary phosphate load and increased calcitriol stimulate the secretion of FGF23, predominantly by bone osteocytes, which act on target tissues by binding to and activating the FGF23 receptor in the presence of its co-receptor, klotho [46]. Concentrations of FGF23 increase soon after renal injury and progressively increase as kidney function worsens, possibly as a physiologic adaptation to maintain normal serum phosphate by enhancing its excretion in the urine. Thus, the increase of FGF23, while important for maintaining phosphate balance in early CKD, results in a "trade-off" of reduced calcitriol concentrations, which may act as the initial trigger for increased PTH production. (See 'Fibroblast growth factor 23' below.)

Phosphate retention (or perhaps increased phosphate concentrations in the proximal tubule) also can directly suppress the renal synthesis of calcitriol by inhibiting 1-alpha-hydroxylase activity [23].

Calcitriol is a major link among various components of CKD-MBD including phosphorus, calcium, PTH, FGF23, and klotho. Low calcitriol concentrations increase PTH secretion by indirect and direct mechanisms [47-49]. Indirect effects on PTH are achieved through decreased intestinal absorption of calcium and calcium release from bone, both of which promote the development of hypocalcemia, which stimulates PTH secretion.

Calcitriol normally acts on the VDR in the parathyroid gland to suppress PTH transcription but not PTH secretion [50]. A decrease in calcitriol concentrations also lowers the number of VDRs in the parathyroid cells [51]. The lack of calcitriol and the decreased number of receptors may both promote parathyroid chief cell hyperplasia and nodule formation through potential nongenomic effects.

Even normal plasma calcitriol concentrations do not necessarily preclude a role for initial calcitriol deficiency, since the ensuing secondary hyperparathyroidism will increase calcitriol synthesis. However, not all PTH fragments stimulate the 1-alpha-hydroxylase and increase calcitriol synthesis. In an animal model, the PTH fragment (1-34) increased calcitriol concentrations, whereas PTH (1-84) did not. Moreover, infusion of carboxyl (C)-terminal PTH fragments actually reduced the synthesis of calcitriol by a posttranscriptional mechanism [52].

More importantly, low calcitriol concentration can increase PTH secretion by removing the inhibitory effect of calcitriol on the parathyroid gland [23,53]. The administration of calcitriol, on the other hand, can partially reverse the hyperparathyroidism both in early [42] and advanced disease [53]. Calcitriol and other vitamin D analogs can reduce parathyroid cell proliferation in vitro, in part by blocking the increase in the growth-promoting factor transforming growth factor-alpha (TGF-alpha) [54,55].

There is also evidence that decreased responsiveness to calcitriol contributes to the development of hyperparathyroidism. In particular, physiologic concentrations of calcitriol may be unable to normally suppress PTH secretion, perhaps due to a reduction in the number of VDRs in the parathyroid gland [51,56]. In experimental models, this change can be demonstrated relatively early in the course of kidney failure (ie, when the plasma creatinine concentration has only doubled) [47]. Low calcitriol concentrations appear to play an important role in the decline in VDRs since the defect can be largely corrected by calcitriol supplementation [51]. At a later stage, retained uremic toxins may also contribute by decreasing both receptor synthesis and the ability of the active hormone-receptor complex to bind to vitamin D response elements in the nucleus [47,57].

Studies in patients on maintenance dialysis reveal that the decrease in receptor density is most prominent in areas of nodular, rather than diffuse, hyperplasia [56]. Thus, a reduced number of VDRs may contribute both to the progression of hyperparathyroidism and to the proliferation of parathyroid cells, leading to nodule formation. (See 'Tertiary hyperparathyroidism' below.)

Disorders of calcium balance — Studies have suggested that disorders of calcium balance due to CKD-MBD may play a role in the high cardiovascular mortality in patients with CKD.

Both hypocalcemia and hypercalcemia are associated with increased mortality in patients with CKD [58,59].

Total serum calcium concentration decreases during the course of CKD due to phosphate retention, decreased calcitriol concentration, and resistance to the calcemic actions of PTH on bone. Hypocalcemia is common among CKD patients and contributes to increased PTH secretion and abnormal bone remodeling.

On the other hand, hypercalcemia has been implicated in the pathogenesis of extraskeletal calcification. In CKD, positive calcium balance may be an important factor in progression of calcification. An animal model of CKD showed that calcium added to the drinking water led to increased thoracic aorta, heart, and aortic valve calcification regardless of the serum calcium level [60].

Calcium is a major regulator of PTH secretion. Minute changes in the serum ionized calcium are sensed by a specific membrane calcium-sensing receptor (CaSR), which is highly expressed on the surface of the chief cells of the parathyroid glands [61]. Changes in PTH secretion in response to serum calcium are tightly regulated by the CaSR.

The fall in serum calcium concentration in CKD, as sensed by the CaSR, is a potent stimulus for the release of PTH [62,63]. This is best shown in mouse and human genetic studies, in which extracellular calcium, acting through the CaSR, was the major regulator of PTH transcription, secretion, and parathyroid gland hyperplasia [62,63]. A review of the function of the CaSR can be found elsewhere. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)

PTH secretion varies inversely with serum calcium concentration [31]. Persistently low serum calcium concentrations also appear to directly increase PTH mRNA concentrations via posttranscriptional actions and stimulate the proliferation of parathyroid cells over days or weeks [31,42]. (See "Parathyroid hormone secretion and action" and "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)

In CKD, the number of CaSRs may be reduced in hypertrophied parathyroid glands, particularly in areas of nodular hypertrophy [64-66]. Decreased expression of the CaSR appears to be related to the proliferation of parathyroid tissue, and both may be related to increased phosphorus [65,67]. The change in receptor number can lead to inadequate suppression of PTH secretion by calcium, resulting in inappropriately high PTH concentrations in the setting of normal or even high calcium concentrations. (See "Parathyroid hormone secretion and action".)

The role of the CaSR in regulating parathyroid gland function has direct therapeutic implications. The administration of a calcimimetic agent increases the sensitivity of the receptor to extracellular calcium and can lower PTH secretion from the parathyroid gland [61,68]. Calcimimetic agents also mediate reductions in serum PTH concentrations by directly decreasing PTH gene expression [69] and by increasing the VDR expression in the parathyroid glands [70]. The administration of calcimimetic agents reduces plasma PTH concentrations by >50 percent in both humans and animal models of kidney failure and can suppress parathyroid cell hyperplasia in animals. The use of calcimimetic agents in patients with ESKD is discussed elsewhere. (See "Management of secondary hyperparathyroidism in adult dialysis patients", section on 'Calcimimetics'.)

Fibroblast growth factor 23 — FGF23 is a circulating peptide that plays a key role in the control of serum phosphate concentrations. [15,71,72]. FGF23 is secreted by bone osteocytes and osteoblasts in response to calcitriol, increased dietary phosphate load, PTH, and calcium [72-77]. Among patients with CKD, increased FGF23 concentrations may also be due to decreased clearance [17,76,77]. An animal model suggested that the kidney itself plays a key role in FGF23 metabolism [78]. In this study, the half-life of exogenous recombinant human FGF23 was significantly prolonged in anephric rats. Moreover, measurements of plasma FGF23 in the renal artery and renal vein of rats demonstrated a significant renal extraction of FGF23.

FGF23's primary function is to maintain normal serum phosphate concentration by reducing renal phosphate reabsorption and by reducing intestinal phosphate absorption through decreased calcitriol production. In renal proximal tubular cells, FGF23 binds to the FGF receptor (FGFR) and its coreceptor, klotho, causing downregulation of the luminal membrane sodium phosphate cotransporter Na/Pi IIa (and possibly also the Na/Pi IIc transporter) [79]. Decreased cotransporters in the proximal tubule lead to reduced phosphate reabsorption and increased urinary phosphate excretion. FGF23 also inhibits the proximal tubular expression of 1-alpha-hydroxylase enzyme, leading to decreased calcitriol synthesis by the kidney [44]. Thus, FGF23 directly increases urinary excretion of phosphate and indirectly decreases intestinal phosphate absorption by downregulating the production of calcitriol. The net effect of both hormonal actions is to lower serum phosphate concentration.

Increased FGF23 levels may be one of the earliest detectable biomarkers of CKD-MBD [8,9]. In patients with CKD, FGF23 levels increase prior to changes in the serum calcium, phosphorus, or PTH levels. Also, different experimental models of CKD have demonstrated increases in FGF23 before PTH. However, one study of over 1000 adults with generally normal kidney function found that PTH levels began to increase when eGFR decreased below 126 mL/min/1.73 m2, whereas FGF23 levels only began to increase when eGFR decreased below 102 mL/min/1.73 m2 [80].

Moreover, the study found that plasma FGF23 is associated with reduced plasma 1,25-dihydroxyvitamin D3 and reduced renal calcium excretion but not with increased renal phosphate excretion [80]. These data suggest that the role of FGF23 as a 1,25-dihydroxyvitamin D3 counterregulatory hormone may be more important than its role as a phosphaturic hormone, at least when the kidney function is normal.

Another study found that, in patients with CKD and vitamin D deficiency, PTH levels were markedly elevated relative to those of FGF23, suggesting that FGF23 may have a lower phosphaturic role when PTH secretion is stimulated in response to vitamin D deficiency [81].

FGF23 also suppresses PTH secretion by the parathyroid gland [82]. However, among patients with CKD, the presence of high PTH concentrations, despite high FGF23 concentrations, suggests that the parathyroid gland becomes relatively resistant to the elevated concentrations of FGF23. This may be related to the markedly decreased expression of FGFR 1 and klotho protein in the hyperplastic parathyroid gland [83,84].

Klotho, a single-pass transmembrane protein, is mainly expressed in the cell surface membrane of proximal and distal renal tubules and is required for FGF23 receptor activation [46]. The protein consists of a large N-terminal extracellular domain, a transmembrane domain, and a small intracellular C-terminal domain. The extracellular domain is cleaved by the metalloproteinases ADAM-10 and ADAM-17 and released into the circulation as soluble klotho; the main functional form of klotho is in the circulation but is also detected in the urine and cerebrospinal fluid. Osteocytes also express klotho, which may play a role as a potent regulator of bone formation and bone mass [85].

The klotho extracellular domain does not directly bind to FGF23 but enhances FGF23 binding to its receptor complex with a much higher affinity than to the FGFR alone [86]. FGF23 has a feedback relationship with its coreceptor klotho. Thus, klotho deficiency can increase FGF23 levels, whereas high FGF23 levels can exacerbate klotho deficiency via low 1,25-dihydroxyvitamin D [87].

Klotho expression declines early in the course of CKD and then progressively with decreasing GFR [88]. The reduction in klotho temporally coincides with the rise in FGF23, suggesting that this decline may be partially responsible for the progressive rise in FGF23 concentration. Moreover, the decrease in klotho expression on hyperplastic parathyroid glands may contribute to the resistance and impaired parathyroid suppression by FGF23 [4,89]. One study showed that proteinuria induced elevation of both plasma phosphate and FGF23 concentrations and impaired urinary phosphate excretion [90]. The decreased phosphaturic effect of FGF23 in this study was related to decreased renal klotho expression and increased proximal tubule Na/Pi IIa cotransporter expression [90].

Elevated FGF23 levels have been associated with an increased risk of ESKD in patients with CKD and relatively preserved kidney function [91].

FGF23 levels are also associated with increased risk of cardiovascular disease [92,93] and mortality [91,94] in patients with CKD. Clinical and experimental studies have shown that FGF23 has a direct pathogenic effect causing left ventricular hypertrophy [95]. FGF23 also augments sodium and calcium reabsorption in the distal tubule by increasing the apical membrane expression of the sodium-chloride cotransporter and the epithelial calcium channel, through a klotho-dependent activation of The serine/threonine-protein kinase, WNK4 [96,97]. These effects could conceivably lead to renal sodium retention, volume overload, hypertension, heart failure, and cardiac hypertrophy. However, FGF23 does not seem to promote cardiovascular calcification [98].

Skeletal resistance to PTH — Skeletal resistance to the calcemic action of parathyroid hormone (PTH) appears to contribute to the genesis of secondary hyperparathyroidism in CKD [34]. The underlying mechanisms of the skeletal resistance to PTH are likely multifactorial, including hyperphosphatemia, decreased calcitriol action, and downregulation of PTH receptors [99]. Other factors include oxidative modification of PTH [100] and an increase in circulating osteoprotegerin and sclerostin levels [101,102]. Finally, the potential antagonistic actions of PTH fragment PTH-(7-84) to those of PTH-(1-84) may contribute to the higher PTH concentrations in patients with CKD [103].

Tertiary hyperparathyroidism — Some patients with ESKD develop markedly elevated PTH concentrations, often associated with hypercalcemia that cannot be explained by the administration of calcium carbonate or calcitriol supplements. Such patients often fail medical therapy and ultimately require parathyroidectomy. This unremitting hyperparathyroidism, called tertiary hyperparathyroidism, in part reflects severe parathyroid hyperplasia, with autonomous secretion of PTH that is no longer adequately responsive to the plasma calcium concentration. Autonomous function of parathyroid tissue results from the increase in parathyroid gland mass rather than an alteration in the set point of PTH release [104]. Set-point abnormalities are present in familial hypocalciuric hypercalcemia (in which it is the primary defect) and primary hyperparathyroidism (in which there is both a set-point error and increased gland mass) [104]. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)

In patients with tertiary hyperparathyroidism, decreased expression of CaSR and VDRs results in a lack of suppression of PTH by increasing calcium or vitamin D analogs [105]. The state of prolonged stimulation of parathyroid cell growth in CKD patients due to high phosphate, low calcitriol, and hypocalcemia results in nodular hyperplasia. Nodular parathyroid glands do not undergo involution, despite resolution of some of the triggering mechanisms. This is best illustrated by the high PTH concentrations and hypercalcemia that may persist in CKD patients after receiving kidney transplant.

Another important pathogenetic factor in many cases of tertiary hyperparathyroidism is neoplastic transformation, leading to overgrowth by a monoclonal parathyroid adenoma [106,107]. The mechanisms responsible for the switch to monoclonal proliferation are not well understood [107]. One factor may be VDR density, which appears to be markedly reduced in areas of nodular transformation [56]. This change would further reduce the normal inhibitory effect of calcitriol on PTH secretion and, perhaps, parathyroid growth [107].

ABNORMALITIES IN BONE TURNOVER, MINERALIZATION, VOLUME LINEAR GROWTH, OR STRENGTH — As noted above, renal osteodystrophy refers to bone pathology, as assessed by bone biopsy [108] (see 'Introduction and definitions' above). The gold standard for the diagnosis and classification of bone disease in CKD is bone biopsy. However, because bone biopsy is invasive and costly, several bone biomarkers have been used for the diagnosis and monitoring of bone turnover. Unfortunately, all have limitations in the assessment of renal bone disease.

Bone turnover can be viewed as the ratio between bone formation and bone resorption and thus is a function of the degree of hyperparathyroidism. Although parathyroid hormone (PTH) may be a better indicator of parathyroid gland activity rather than of bone turnover, PTH level has traditionally been used as a marker of bone turnover.

Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend the use of serum PTH in conjunction with total or bone-specific alkaline phosphatase (BSAP) since high or low levels of these markers correlate with underlying bone turnover. However, PTH levels within the Kidney Disease Outcomes Quality Initiative (KDOQI)- or KDIGO-recommended therapeutic targets are not consistently helpful in predicting the nature of the underlying bone turnover. One study suggested that the combination of BSAP with PTH may improve the diagnostic ability of either marker alone in predicting the type of bone disease in CKD [109]. However, a subsequent study showed that this combination only marginally improved the ability to discriminate high from low bone turnover, suggesting that, despite its limitations, PTH level remains a reasonable marker of bone turnover [110].

KDIGO recommends that three parameters be used to assess bone pathology [2]. These parameters include bone turnover, mineralization, and volume (TMV system). Any combination of parameters may be used to describe a given sample. The TMV system of classification of renal osteodystrophy serves to emphasize the contributions of mineralization and volume, as well as turnover, to bone quality [111].

TMV characteristics of the major CKD-related bone diseases are as follows:

Osteitis fibrosa cystica – Osteitis fibrosa cystica is characterized by high bone turnover due to secondary hyperparathyroidism.

Adynamic bone disease – Adynamic bone disease is characterized by low bone turnover. Although aluminum deposition may cause this disorder, most current cases result from excessive suppression of the parathyroid glands. This represents the major bone lesion in peritoneal dialysis and hemodialysis patients. (See "Adynamic bone disease associated with chronic kidney disease".)

Osteomalacia – Osteomalacia is characterized by low bone turnover in combination with abnormal mineralization [21,22]. In osteomalacia, the mineralization lag time is prolonged to >100 days in comparison with <35 days in normal subjects and those with pure osteitis fibrosa. Osteomalacia, which is now uncommon, was due primarily to aluminum deposition in bone at a time when aluminum-containing antacids were used as phosphate binders. The incidence of osteomalacia has decreased with the abandonment of aluminum-based phosphate binders and the introduction of more efficient techniques for treatment of water used in preparing the dialysate [112-115]. (See "Aluminum toxicity in chronic kidney disease".)

Mixed uremic osteodystrophy – Mixed uremic osteodystrophy is characterized by either high or low bone turnover and by abnormal mineralization.

A fifth, but different, type of uremic bone disease, with a unique pathogenesis, occurs in patients on long-term dialysis and presents as bone cysts, which result from beta2-microglobulin-associated amyloid deposits. (See "Dialysis-related amyloidosis".)

Despite progressive lesions, symptoms and/or signs due to the various bone disorders, such as fractures and bone pain, generally do not occur until the patient is already on maintenance dialysis [21]. However, subclinical changes in bone remodeling begin early in the course of CKD. Alterations in bone quality in both high-turnover and low-turnover bone diseases may contribute to the diminished mechanical competence of bone in CKD. Bone quality refers to the structural and material parameters that enable bone to bear load and resist fracture [116]. One study reported that low turnover is manifested by changes in microstructural parameters, while bone with high turnover is manifested by changes in material composition and nanomechanical properties [117].

The prevalence of high-turnover bone disease (osteitis fibrosa cystica) among dialysis patients has markedly decreased, while non-aluminum-induced low-turnover bone disease (adynamic bone disease) has increased, with variations based in part upon geographic region evaluated [113,114,118,119]. As examples:

In a study of 56 dialysis patients from Thailand followed between 1996 and 1998, bone biopsy in combination with other analyses revealed that low-turnover (adynamic) bone disease was present in 41 percent, and high-turnover (osteitis fibrosa cystica) disease was present in 29 percent of patients [114].

In a 2003 trial of 98 dialysis patients in Europe, bone biopsy showed low-turnover disease (defined as bone formation rate <5 percent and osteoclast surface <20 percent) and high-turnover disease in approximately 20 percent of patients each [113].

In a 2008 study, bone biopsies revealed low-turnover disease in 59 percent of 119 hemodialysis patients [120]. This high prevalence was observed despite treating most patients in accordance with KDOQI guidelines and having serum mineral parameters within recommended ranges.

In a study of 97 bone biopsies from dialysis patients with intact PTH levels of 150 to 300 pg/mL, two thirds had low-turnover bone disease, and one quarter had high-turnover bone disease [121].

In a study of 630 bone biopsies from adult patients on dialysis, white individuals exhibited predominantly low turnover (62 percent), whereas black individuals showed mostly normal or high-turnover bone disease (68 percent). Moreover, PTH levels were a predictor of high and low turnover only in white individuals [122].

In another study of 492 dialysis patients from Brazil, Portugal, Turkey, and Venezuela, PTH concentrations differentiated high bone turnover from non-high turnover, but not low turnover from non-low turnover, using the intact PTH thresholds suggested by KDIGO [110].

Even among CKD patients not yet on dialysis, the prevalence of low-turnover disease has increased. In a bone biopsy study in 84 unselected patients with stage 5 CKD, adynamic bone disease was the most prevalent type of renal osteodystrophy, particularly in diabetic patients [123].

This increased prevalence of low-turnover bone disease may reflect multiple factors, including changes in patients' demographics (older and increased number of diabetic patients) and changes in therapeutic strategies, such as the increased and earlier use of vitamin D analogs and calcium-containing phosphate binders, and differences in dialysis techniques [115]. This issue is discussed elsewhere. (See "Adynamic bone disease associated with chronic kidney disease".)

Patients on maintenance dialysis with diabetes have lower PTH levels compared with those without diabetes. These patients have a high incidence of low bone turnover [124], which has been attributed to an inhibition of PTH secretion or a modification of the PTH peptide by the accumulation of advanced glycation end-products [125] or oxidation of PTH [126]. However, low bone turnover with decreased osteoblast surface and bone formation rate was shown to develop in five-sixths of nephrectomized diabetic rats due to the poor control of diabetes, independent of PTH [127].

Given the recommendation by KDIGO to target PTH concentrations two to nine times the upper limit of normal, the prevalence of adynamic bone disease is likely to decrease, while that of osteitis fibrosa may increase [128].

EXTRASKELETAL CALCIFICATION — Extraskeletal calcification is common in patients with CKD, particularly those on dialysis [129-131]. Vascular calcification contributes to mortality. The pathogenesis and clinical implications of vascular and other soft-tissue calcification is discussed elsewhere. (See "Vascular calcification in chronic kidney disease".)

CLINICAL PRESENTATION — The clinical presentation of patients with CKD-MBD varies depending upon the prevailing metabolic abnormality and the characteristic bone disease.

TREATMENT — The treatment of patients with CKD-MBD varies depending upon the prevailing metabolic abnormality, the characteristic bone disease, and the severity of underlying kidney dysfunction.

(See "Management of secondary hyperparathyroidism in adult dialysis patients", section on 'Treatment'.)

(See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Treatment approach'.)

(See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease", section on 'Initial treatment'.)

SUMMARY AND RECOMMENDATIONS

Disorders of mineral and bone metabolism are common sequelae of chronic kidney disease (CKD). Such disorders are collectively termed chronic kidney disease-mineral and bone disorder (CKD-MBD). The term "renal osteodystrophy" is exclusively used to define bone pathology observed on biopsy. CKD-MBD is characterized by the following (see 'Introduction and definitions' above):

Abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism and/or

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

Extraskeletal calcification

Secondary hyperparathyroidism encompasses most of the biochemical abnormalities that characterize CKD-MBD. Causes of secondary hyperparathyroidism include phosphate retention; decreased free calcium concentration; decreased 1,25-dihydroxyvitamin D (calcitriol) concentration; and the reduced expression of vitamin D receptors (VDRs), calcium-sensing receptors (CaSR), fibroblast growth factor receptors (FGFRs), and klotho in the parathyroid glands. (See 'Abnormalities of parathyroid hormone, calcium, phosphorus, fibroblast growth factor 23, and vitamin D metabolism' above.)

Three parameters are used to assess bone pathology (ie, renal osteodystrophy): bone turnover, mineralization, and volume (TMV system). Any combination of parameters may be used to describe a given sample. The TMV system of classification of renal osteodystrophy emphasizes the contribution of mineralization and volume, as well as turnover rate, to bone quality. TMV characteristics of the major CKD-related bone diseases are as follows (see 'Abnormalities in bone turnover, mineralization, volume linear growth, or strength' above):

Osteitis fibrosa cystica is characterized predominantly by high turnover due to secondary hyperparathyroidism.

Adynamic bone disease is characterized predominantly by low turnover. Most cases result from excessive suppression of the parathyroid glands. This is the most common CKD-related bone lesion among dialysis patients.

Osteomalacia is characterized by low bone turnover in combination with abnormal mineralization. Osteomalacia is uncommon since the decline in use of aluminum-containing phosphate binders.

Mixed uremic osteodystrophy is characterized by either high- or low-bone turnover and by abnormal mineralization.

Patients with any of the lesions defined above are at greater risk of bone fractures than the general population because of changes in bone quality. However, despite progressive lesions, symptoms and/or signs due to the various bone disorders, such as fractures and bone pain, generally do not occur until the patient is already on maintenance dialysis. (See 'Abnormalities in bone turnover, mineralization, volume linear growth, or strength' above.)

Vascular or other soft-tissue calcification is caused by multiple factors that facilitate calcium phosphate precipitation. It is associated with increased mortality. (See 'Extraskeletal calcification' above and "Vascular calcification in chronic kidney disease".)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge William L Henrich, MD, MACP, who contributed to an earlier version of this topic review.

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