Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD)

Etiology

CKD-MBD is a multifactorial condition characterized by biochemical, morphological, skeletal, and non-skeletal abnormalities involving various body systems. The key etiological factors contributing to its development are mentioned below.

Impaired kidney function: Impaired kidney function is a critical factor in the development of CKD-MBD, which occurs in patients with CKD. The kidneys maintain mineral and electrolyte homeostasis, including calcium and phosphate levels. As kidney function declines, this delicate balance is disrupted, contributing to the development of CKD-MBD.

Dysregulated calcium, phosphate, and vitamin D homeostasis: In CKD, reduced kidney function leads to impaired phosphate excretion and decreased synthesis of active vitamin D (calcitriol or 1,25 dihydroxy vitamin D), resulting in hyperphosphatemia and hypocalcemia. These imbalances contribute to adverse effects such as vascular calcification associated with CKD-MBD.

Abnormal PTH regulation: Impaired kidney function in CKD disrupts PTH regulation, resulting in secondary hyperparathyroidism. Elevated phosphate levels, low calcium levels, and inadequate vitamin D stimulate excessive PTH secretion, leading to bone resorption and calcium release, disrupting the calcium balance in the skeletal system. Secondary hyperparathyroidism is the predominant factor contributing to renal osteodystrophy. 

Secondary Hyperparathyroidism

Secondary hyperparathyroidism is a significant manifestation of CKD-MBD, often diagnosed and monitored using PTH levels. This condition arises due to various events that initiate and maintain excess PTH secretion, resulting in the following effects:

• Phosphate retention
• Decreased free ionized calcium concentration
• Decreased calcitriol concentration
• Increased FGF23 concentration
• Reduced expression of calcium-sensing receptors (CaSRs), vitamin D receptors, and FGF receptors in the parathyroid glands [6]

Examining the alterations in their homeostasis during CKD provides insights into the importance of these factors in developing secondary hyperparathyroidism. An increase in PTH concentration typically occurs when the estimated GFR (eGFR) falls below 60 mL/min/1.73 m². At that point, serum calcium and phosphate concentrations remain within the normal range until the eGFR decreases to approximately 20 mL/min/1.73 m². However, the concentration of calcitriol begins to decline much earlier, occurring when the eGFR is less than 60 mL/min/1.73 m² due to increased FGF23 concentration rather than kidney tissue loss.[7]   Hyperphosphatemia also contributes to decreased calcitriol production by suppressing the 1-α-hydroxylase enzyme. This, in turn, leads to calcitriol deficiency and contributes to the development of hypocalcemia. These biochemical changes then stimulate the release of PTH and increase its concentration through various pathways described below:

Phosphate retention: Serum hyperphosphatemia can stimulate PTH secretion through various mechanisms. Typically, this occurs either by directly increasing PTH messenger ribonucleic acid levels or indirectly by reducing calcium and calcitriol levels, leading to an elevation in PTH levels.[8][9]

Calcium: Calcium is crucial in regulating PTH levels through the CaSR. A decrease in serum calcium levels triggers the parathyroid glands to secrete PTH, highlighting the established relationship between calcium and PTH levels.

Calcitriol: The role of calcitriol is crucial in maintaining serum calcium levels and regulating PTH secretion. Calcitriol and PTH work together to increase serum calcium levels. When calcitriol levels decrease, secondary hyperparathyroidism can develop due to reduced calcium absorption in the intestine, leading to a reflex increase in PTH secretion. Additionally, calcitriol is necessary to suppress PTH secretion by the parathyroid glands.

Fibroblast growth factor-23: FGF23 decreases phosphate levels in the body. In CKD, the first biochemical abnormality noted is decreased α-Klotho (referred to as Klotho), a transmembrane receptor primarily found in the proximal and distal renal tubules. Klotho is a cofactor for FGF23, and reduced levels lead to increased FGF23 due to the lack of negative feedback. This increase in FGF23 results in decreased urine phosphorus reabsorption through the sodium-phosphorus type II cotransporter. Additionally, FGF23 downregulates the 1-α-hydroxylase enzyme, which decreases activated vitamin D.[10][11]

Phosphate Retention

Phosphate retention in CKD involves several theoretical explanations, and a notable hypothesis being the "trade-off" hypothesis. This hypothesis posits that hyperphosphatemia contributes to secondary hyperparathyroidism by lowering ionized calcium concentration and inhibiting calcitriol synthesis.[12] The resulting excess of PTH promotes renal phosphate excretion by reducing proximal tubular phosphate reabsorption. This action increases bone resorption to elevate serum calcium levels and stimulates kidney synthesis of calcitriol, which enhances intestinal calcium absorption.[13] This hypothesis suggests that the initially adaptive increase in PTH is beneficial, resulting in increased phosphate excretion, lowered plasma phosphate concentration, and reduced phosphate reabsorption. Additionally, it tends to correct calcitriol deficiency and hypocalcemia. However, the long-term effect of excess PTH becomes maladaptive over time. Moreover, in advanced CKD stages, the compensatory rise in PTH becomes insufficient, leading to continued elevation of phosphate concentrations.[14][15] 

The pathological effects of hyperphosphatemia in patients with CKD-MBD include the following:

• FGF23 secretion, which suppresses PTH secretion [16]
• Osteoblastic transformation of smooth muscle cells in the vasculature, contributing to cardiovascular calcification and arterial stiffness [17]

Decreased Calcitriol Activity

Plasma calcitriol concentration usually decreases when the eGFR falls below 60 mL/min/1.73 m². In the earlier stages of the disease, this decrease is primarily due to the increased FGF23 concentration. However, in advanced CKD, the reduction in functioning kidney mass and hyperphosphatemia also contribute to decreased calcitriol formation. FGF23 suppresses the activity of 1-α-hydroxylase and stimulates the 24-hydroxylase enzyme, leading to decreased synthesis of calcitriol.[18] Calcitriol is an essential link among various CKD-MBD, including phosphate, calcium, PTH, FGF23, and Klotho. Decreased calcitriol activity can influence PTH in the following ways:

• Reduced intestinal absorption of calcium
• Decline in the number of vitamin D receptors in the parathyroid cells
• Removal of the inhibitory effect on the parathyroid gland [19]

Calcium Balance Disorders 

Calcium plays a pivotal role in regulating PTH secretion, with even minor fluctuations in its serum levels detected by the CaSR abundant in parathyroid glands.[20] The CaSR tightly regulates PTH secretion in response to changes in ionized calcium concentrations, with PTH secretion inversely related to serum calcium levels. Both hypocalcemia and hypercalcemia contribute to increased mortality among CKD patients.[21] Hypocalcemia is prevalent in CKD and leads to excessive PTH secretion (as sensed by the CaSR), resulting in abnormal bone remodeling; conversely, hypercalcemia is linked to extraskeletal calcification.

Fibroblast Growth Factor-23 

FGF23 plays a central role in regulating PTH levels, and its levels rise even before PTH elevation.[6] FGF23 is secreted in response to calcitriol, dietary phosphate load, calcium, and PTH.[22] Patients with CKD may also have an increased FGF23 concentration due to decreased clearance.[23] FGF23 maintains normal serum phosphate levels by decreasing renal phosphate reabsorption through the sodium/phosphorus cotransporter type II and inhibiting intestinal phosphate absorption via decreased calcitriol production. Moreover, FGF23 decreases calcitriol synthesis by inhibiting the expression of 1-α-hydroxylase in the proximal tubule.[24] These actions collectively result in increased urinary phosphate excretion and decreased intestinal phosphate absorption, leading to lower serum phosphate levels. Additionally, FGF23 suppresses PTH secretion by the parathyroid gland.[25] Klotho, a transmembrane protein expressed in proximal and distal renal tubules, is crucial in activating FGF23 receptors.[26] Klotho may also have regulatory effects on bone formation and bone mass. A feedback relationship exists between FGF23 and Klotho, where Klotho deficiency leads to increased FGF23 levels, while elevated FGF23 concentration exacerbates Klotho deficiency due to low 1,25-dihydroxy vitamin D levels.[27]

Epidemiology

CKD-MBD presents with a range of manifestations, and its prevalence varies depending on the specific aspects of the disorder. For example, vascular calcification is more common among patients on dialysis patients, with arterial morphometry revealing increased medial thickening.[28] Vascular calcification begins early and becomes more prevalent as GFR declines, with approximately 80% of dialysis patients experiencing coronary artery calcification.[29][30] Studies have reported varying prevalence rates for CKD-MBD; for instance, recent data based on the Kidney Disease Outcomes Quality Initiative (KDOQI) suggest a prevalence of 55%, while the KDIGO guidelines estimate it at 86%.[31]

In the last few decades, the trend has shifted from hyperparathyroidism-induced high bone turnover diseases to adynamic bone disease.[32] Several factors are hypothesized to contribute to this shift, such as the overuse of vitamin D analogs, which suppress PTH.[33] Similarly, calcium-containing phosphate binders exert a comparable effect on PTH levels. Patients on maintenance dialysis with diabetes also tend to have lower PTH levels than those without diabetes, resulting in a higher incidence of low bone turnover.[34] Another contributing factor to the rise in adynamic bone disease is the decline of osteomalacia, facilitated by the introduction of non-aluminum-based phosphate binders and more effective methods for treating water used in preparing the dialysate.[35][36] 

Pathophysiology

The pathophysiology of CKD-MBD can be divided into different components based on the condition's varied presentations. This disease can be categorized into skeletal and extraskeletal manifestations (see Image. Systemic Impact of Chronic Kidney Disease–Mineral Bone Disorder [CKD-MBD]).

Skeletal Abnormalities in CKD-MBD (Renal Osteodystrophy)

Renal osteodystrophy, the skeletal manifestation of CKD-MBD, is histologically classified into high or low bone turnover states. A third category is mixed uremic osteodystrophy, which exhibits high and low bone turnover and abnormal mineralization characteristics. Mixed uremic osteodystrophy encompasses features of high-turnover osteitis fibrosa cystica and low-turnover mineralization defects, as observed in osteomalacia.[9] Along with bone disorders, muscle weakness, myopathy, and calcifications are recognized components of CKD-MBD.[37]

High bone turnover: High bone turnover states are characterized by increased bone resorption and formation rates. Elevated PTH levels are significant in the pathogenesis of these states, which can manifest as primary, secondary, or tertiary hyperparathyroidism. An example of tertiary hyperparathyroidism is seen in parathyroid gland adenomas autonomously secreting PTH, leading to a state of high bone turnover.[38] End-stage high-turnover bone disease may rarely result in osteitis fibrosa cystica, a condition characterized by increased bone turnover due to secondary hyperparathyroidism. This increased turnover leads to distinctive hemosiderin deposits known as "brown tumors." Please see StatPearls' companion resource, "Osteitis Fibrosa Cystica," for further information.[39]

Low bone turnover: Low bone turnover states primarily include osteomalacia and adynamic bone disease, both seen in patients with end-stage renal disease. The critical factors that play a role in the pathogenesis are the following:

• Osteomalacia: Heavy metal intoxication, mainly aluminum, can lead to dysfunction of osteoblasts and osteoclasts. Dysfunctional osteoblasts lead to defective bone mineralization and an accumulation of excess bone matrix. Other metals, such as iron and cadmium, have also been implicated. However, this form of osteomalacia has become less prevalent in recent decades.

• Adynamic bone disease: Adynamic bone disease primarily develops due to suppressed PTH levels, resulting in low bone turnover and insufficient bone mineralization without excess osteoid accumulation seen in osteomalacia. This condition has become increasingly prevalent over time, with skeletal resistance to PTH being a key contributing factor.[40] Factors contributing to the development of adynamic bone disease include:
  • Calcium and vitamin D: Aggressive treatment with these compounds in patients with CKD causes chronic PTH suppression.[41][42]
  • Activated vitamin D (calcitriol): Supplementation with calcitriol can reduce bone turnover, as indicated by bone turnover markers; however, the mechanism by which this occurs, whether through decreased PTH levels, remains unclear.[43]
  • Continuous ambulatory peritoneal dialysis: This condition results in a significant calcium influx into the body through the dialysate. 
  • Diabetes mellitus: Evidence suggests that elevated glucose levels and reduced insulin levels are associated with suppression of PTH secretion.[43][44]
  • Other factors: Additional factors, such as interleukin-4 and deficiency of osteogenic protein-1, also have secondary roles in the pathogenesis of adynamic bone disease.[38] 

Extraskeletal Manifestations

Although skeletal manifestations (renal osteodystrophy) have received the most attention regarding the effects of CKD and CKD-MBD, evidence is growing of the systemic vast impact, especially on cardiovascular health. Other body systems affected include anemia, constipation, liver inflammation, malignancy, infection, malnutrition, and dementia. 

Vascular calcification: Vascular calcification in CKD-MBD has been extensively studied due to its association with morbidity and mortality. Previously, vascular calcification was considered a passive consequence of degenerative aging, but it is now known to be an actively regulated process similar to bone formation. The process involves complex interactions among vascular smooth muscle cells, the extracellular matrix, and calciprotein particles (CPPs). These particles, formed in high calcium and phosphate conditions, contain calcium, phosphate, fetuin-A, and other proteins. CPPs induce inflammatory responses and can cause smooth muscle cell apoptosis and extracellular matrix calcification.[11][45] In the uremic milieu, characteristic of CKD, calcification promoters such as calcium and phosphate increase, whereas calcification inhibitors such as fetuin-A and pyrophosphate decrease.[46] Additionally, decreased calcitriol levels are associated with endothelial dysfunction and increased vascular stiffness.[47]

Cardiac abnormalities: Cardiac abnormalities are prevalent in CKD-MBD and contribute significantly to morbidity and mortality. Elevated levels of PTH and FGF23 are associated with cardiovascular events. FGF23 activation of distal tubular sodium-chloride cotransporters increases the risk of volume overload and is linked to conditions such as atrial fibrillation and cardiomyocyte hypertrophy.[47] Reduced levels of Klotho, a protein decreased in CKD, are thought to have cardioprotective effects. Animal studies with Klotho knockout mice have shown left ventricular hypertrophy and cardiac fibrosis.[48] Valvular disease can be attributed to osteoblast-like cells in cardiac valves, which produce bone-related peptides, contributing to extracellular matrix calcification.[47]

Neurological events: Neurological events such as dementia, small cerebral vessel disease, and cognitive decline have been linked to elevated levels of FGF23 in data from the Framingham Heart Study.[49][37] Another large prospective study involving patients on hemodialysis revealed that hyperphosphatemia was associated with brain hemorrhage, while hypophosphatemia was linked to brain ischemic events.[50] Another large longitudinal study found that high PTH levels were associated with a higher risk of hemorrhagic stroke and myocardial infarction. This study also revealed that hyperphosphatemia and hypercalcemia were linked to an increased risk of brain hemorrhage. This is thought to be due to vascular calcification (for hypercalcemia), increased vascular smooth muscle disruption through matrix metalloproteinases II and IX, and cathepsin S in the case of hyperphosphatemia.[51]

Gastrointestinal effects: Gastrointestinal effects associated with CKD-MBD include constipation, liver inflammation, and alterations in the intestinal microbiome.[11] Hyperphosphatemia, dietary restrictions, phosphate binders, and uremic toxins can impact natural intestinal bacteria. Traditional calcium-containing phosphate binders and anion-exchange binders might influence the microbiome, with newer iron-containing binders showing potentially lesser effects, although current data are inconclusive.[52][53][54]

Infections: Infections are the second-leading cause of death in patients on hemodialysis, and evidence indicates a relationship between CKD-MBD and infection-related mortality. Elevated levels of PTH and FGF23 can hinder leukocyte recruitment and impair the host immune response. Hypercalcemia is also associated with all-cause mortality and infection-related deaths among patients on hemodialysis. This effect is particularly noticeable in younger patients and those with hypoalbuminemia, potentially due to decreased leukocyte function or elevated levels of FGF23 and CPPS.[55] This correlation is further supported by studies demonstrating a reduction in severe sepsis among patients on calcium channel blockers.[56][57]

Malnutrition: Malnutrition is prevalent in patients with end-stage renal disease due to factors such as uremic toxins, chronic inflammation, protein loss during dialysis, and dietary constraints. Studies have revealed that elevated FGF23 levels correlate with increased inflammatory markers and C-reactive protein levels. Animal models have also demonstrated that elevated PTH can convert white adipose tissue to brown, contributing to cachexia.[11] In addition, data from the Dialysis Outcomes and Practice Patterns Study have linked elevated PTH levels with greater weight loss, suggesting an independent effect beyond appetite measures.[58]

History and Physical

Patients with CKD-MBD exhibit symptoms based on prevalent metabolic abnormalities and the associated bone disease. Initially, hyperparathyroidism may be asymptomatic, but over time, patients may experience prominent symptoms such as bone pain and proximal myopathy. Due to the gradual onset of symptoms, they are often underreported until appropriate treatment is initiated, providing relief from pain. While fractures are uncommon in parathyroid disease, adolescents and children may experience rapid development of significant bone deformities due to metaphyseal erosion of long bones. Hyperparathyroidism can also diminish the efficacy of erythropoietin therapy.

The syndrome of aluminum-induced osteomalacia manifests as generalized bone pain, frequent fractures, and proximal myopathy. The involvement of proximal muscles and the axial skeleton suggests aluminum toxicity and osteomalacia.[59] Excess total body aluminum can lead to hypochromic anemia and dementia. However, this presentation is now less common due to increased awareness of aluminum toxicity. A mixed form of aluminum and parathyroid disease, as well as milder forms of aluminum-related bone disease, are also recognized. Patients with these forms of the disease tend to have fewer symptoms. Aluminum tends to accumulate more rapidly in the bones of children and younger patients compared to older patients, and it deposits more readily in patients with type 1 diabetes.

Low turnover states, which lead to defective mineralization and an inability to repair ongoing damage, are more commonly symptomatic. With increasing awareness and the development of therapies to suppress hyperparathyroidism, adynamic bone disease has emerged as a result. Bone pain is the predominant symptom in patients with adynamic bone disease.[60] These patients also have a higher risk of fractures, and growth impairment may occur in children. The increased fracture incidence in these patients can also be attributed to the poor structural integrity of bones associated with adynamic bone disease. However, maintaining higher plasma calcium concentrations to suppress the parathyroid gland increases the risk of vascular calcification.

Patients with adynamic bone disease often have an overly suppressed PTH level, coupled with an inability to buffer calcium onto the bone, which leads to hypercalcemia.[61] Vascular calcifications are a crucial complication that can result in site-specific manifestations. Calcifications in blood vessels can increase wall stiffness and pulse pressure, contributing to chronic hypertension, which can lead to a higher incidence of cardiovascular events and strokes, a significant cause of mortality in patients with CKD.[62] Moreover, hypercalcemia, hyperphosphatemia, and elevated PTH levels are also associated with calciphylaxis. Please see Statpearls' companion resource, "Calciphylaxis," for further information.[63]

In children with CKD, symptoms of renal osteodystrophy include fractures, bone pain, avascular necrosis, growth failure, and skeletal deformities.[64] Rare reports exist of patients developing intracranial hypertension due to jugular foramen stenosis caused by renal osteodystrophy.[65] Findings of renal osteodystrophy caused by secondary hyperparathyroidism in cranial bones include osteosclerosis, osteomalacia, erosion of the cortical bone, brown tumors, and resorption of the lamina dura. One of the most severe osseous complications is uremic leontiasis ossea, characterized by excessive thickening of the skull and facial bones, with only a few cases reported in the literature.[66]

Evaluation

Diagnostic Approaches for CKD-MBD

As most patients with CKD-MBD are asymptomatic at the outset of the disorder, an investigation should be performed whenever clinical suspicion is high. Although a bone biopsy is the gold standard for diagnosis, it is not always feasible due to its invasiveness. However, blood tests for markers of bone metabolism, combined with radiological imaging, can help narrow down the differential diagnosis in patients mentioned below.

• PTH plays a significant role in the pathogenesis of CKD-MBD and can differentiate between high and low bone turnover states.[38] The diagnostic cutoff level for PTH varies based on whether the patient is on dialysis.

• If PTH levels are elevated, the next reasonable step is to assess vitamin D levels in the blood.

• Serum calcium and phosphate levels are crucial in establishing the diagnosis of CKD-MBD.

• Bone-specific alkaline phosphatase (bsALP) indicates osteoblastic activity. Low levels of bsALP may suggest a low bone turnover disease, aiding in diagnosis.

• Osteocalcin and propeptide of type I collagen are bone formation markers found in the blood of patients with renal osteodystrophy. However, due to a poor association with the disease in study results, they are not commonly used in clinical practice.[8]

Radiological studies are crucial in characterizing bone disease associated with CKD-MBD. Hyperparathyroidism-related osteitis fibrosa manifests as skeletal changes indicative of underlying renal osteodystrophy. Subperiosteal resorption, endosteal resorption, and osteolysis may appear in the skull, clavicle, or distal phalanges. Dual-energy x-ray absorptiometry (DEXA) scans are utilized to measure bone mineral density, although their definitive validation remains uncertain.[67] The 2017 KDIGO guidance recommended considering bone mineral density testing to evaluate fracture risk in CKD patients with osteoporosis risk factors, suggesting therapy adjustments based on the results.

The definitive test for diagnosing CKD-MBD is a bone biopsy followed by double tetracycline labeling, which accurately identifies the patient's histological pattern of bone disease.[41] Another emerging marker, FGF23, has gained attention recently. Despite its well-established clinical effects, FGF23 is seldom used as a biomarker due to challenges such as instability (ex vivo degradation), diurnal variability, high cost, and lack of precision.[68]

Monitoring Parameters

Patients with secondary hyperparathyroidism are regularly monitored by measuring serum levels of calcium, phosphate, and PTH.[5] Some healthcare providers also include bsALP as part of their monitoring protocol to assess the need for parathyroidectomy. However, insufficient evidence prevails to fully support its utility. Although both PTH and bsALP can individually predict high-turnover bone disease, the combined use of these tests offers minimal additional predictive value.[69] Standard frequency of monitoring does not exist for CKD-MBD. Typically, measuring serum phosphate and calcium levels every 1 to 3 months and PTH every 3 to 6 months is deemed appropriate.[5] However, these intervals may be adjusted as needed based on changes in therapy that could impact these levels. Many clinicians opt to measure vitamin D concentrations on an annual basis.

Treatment / Management

The treatment for patients with CKD-MBD varies according to the prevailing metabolic abnormality, the severity of the underlying kidney impairment, and the characteristic bone disease. Management of this condition revolves around strict control of phosphate, calcium, vitamin D, and PTH levels.

Treatment for Adult Nondialysis Patients

All patients with CKD with an eGFR of less than 60 mL/min/1.73 m² are at risk of developing secondary hyperparathyroidism. Therefore, monitoring PTH, calcium, phosphate, 25-hydroxy vitamin D, and bsALP (where available) is recommended. Serial assessment of these biochemical markers guides treatment. The components of a management plan for patients who are not on dialysis include the following:

Phosphate: Maintaining serum phosphate levels below 5.5 mg/dL is crucial to reduce elevated PTH levels. Patients are strongly advised to follow a phosphorus-restricted diet, with preference given to vegetarian meals due to the lower bioavailability of phosphorus in vegetarian proteins.[70] For patients with persistently high serum phosphate levels despite dietary restrictions, phosphate binders taken with meals are recommended. Non-calcium-containing binders such as sevelamer and lanthanum are preferred as they do not affect calcium levels.[71] However, in cases of hypocalcemia requiring calcium supplementation, clinicians may prescribe calcium-containing binders such as calcium acetate and calcium carbonate. In addition, it is important to ensure that elemental calcium intake remains below 2 g/d in these situations.[72](A1)

Calcium: Patients with asymptomatic and mild hypocalcemia (above 7.5 mg/dL with normal albumin levels) typically do not require treatment with calcium or vitamin D derivatives such as synthetic vitamin D analogs or calcitriol. These treatments can potentially cause hypercalcemia or positive calcium balance. Addressing vitamin D deficiency may indirectly correct mild hypocalcemia. Another concern with the oral administration of calcium and vitamin D analogs is the heightened risk of vascular calcification. The recommended daily dietary calcium intake is approximately 1000 mg, and prescribing 1500 mg of elemental calcium daily (as calcium carbonate 1250 mg 3 times a day) significantly increases calcium intake by approximately 2.5-fold. Coupled with reduced calcium excretion in CKD, this creates a positive calcium balance, which then promotes vascular calcification and other sequelae.[73](A1)

Vitamin D: Vitamin D deficiency is prevalent among CKD patients and may present as an initial lab abnormality. This deficiency correlates with hyperparathyroidism and can exacerbate hypocalcemia. CKD patients with vitamin D deficiency are typically supplemented with cholecalciferol or ergocalciferol, except in the following cases:

• Patients with hyperphosphatemia, until phosphate levels are under control

• Patients with hypercalcemia

Activated vitamin D (calcitriol) is reserved for patients with advancing hyperparathyroidism. The effectiveness of vitamin D supplementation remains uncertain in patients with CKD.[74] A meta-analysis indicated that vitamin D supplementation can enhance vitamin D and PTH levels, potentially reducing the occurrence of hyperphosphatemia and hypercalcemia.[75](A1)

Hyperparathyroidism: Patients with CKD and persistent or progressive hyperparathyroidism should undergo treatment targeting modifiable risk factors such as vitamin D deficiency, hyperphosphatemia, and excessive phosphate intake. If these measures fail to decrease PTH levels, the use of calcitriol can be considered. Calcitriol and synthetic vitamin D analogs are known to reduce or stabilize PTH levels (sometimes with a risk of inducing hypercalcemia).[76][77] However, the decision to initiate calcitriol or synthetic vitamin D analogs varies among healthcare providers; commonly, treatment initiation occurs when PTH levels exceed 2 to 3 times the upper limit (eg, 150-200 pg/mL if the upper limit is 65 pg/mL). The recommended starting dosage is 0.25 μg administered thrice weekly, with titration to achieve a target PTH level below 150 pg/mL.(A1)

Calcitriol is contraindicated when phosphate levels exceed the normal range or if free calcium concentration is 9.5 mg/dL (2.37 mmol/L) or higher. Various oral agents such as calcitriol, alfacalcidol, paricalcitol, or doxercalciferol can be considered as comparative efficacy has not been firmly established in nondialysis patients.[78] Another class of drugs includes calcimimetics, such as cinacalcet. However, this class is not recommended for suppressing PTH among patients not on dialysis. Several adverse effects complicate its use in nondialysis patients, including hypocalcemia, increased calciuria, and hyperphosphatemia.[79] The KDIGO 2017 guidance does not offer specific recommendations regarding cinacalcet. Previous KDIGO guidelines advised against using cinacalcet due to the lack of evidence in predialysis patients with CKD.[80](A1)

Treatment for Adult Dialysis Patients

Patients on dialysis have the following recommended targets of therapy:

• Phosphate levels are typically targeted to be between 3.5 and 5.5 mg/dL (1.13-1.78 mmol/L) in patients on dialysis.

• Serum calcium levels are ideally maintained below 9.5 mg/dL (less than 2.37 mmol/L).

• PTH levels should be maintained at less than 2 to 9 times the upper limit for the assay.[81]
(A1)

Once hyperphosphatemia is under control, PTH management is based on trends rather than isolated laboratory values. Notably, it is not advisable to suppress PTH to less than 2 times the upper limit, as it may lead to adynamic bone disease.[80](A1)

Phosphate: Phosphate management is critical for patients with persistent hyperphosphatemia exceeding 5.5 mg/dL, as elevated phosphate levels can complicate treatments for high PTH due to potential serum phosphate increases. Treatment initiation should occur if serum phosphate exceeds 5.5 mg/dL (1.78 mmol/L), given its association with mortality in dialysis patients.[82] Initial strategies often include phosphate restriction and the use of phosphate binders.[83] However, it is recommended to restrict dietary phosphate intake to 900 mg/d, and this should be overseen by a dietician, especially as many dialysis patients experience overt or borderline malnutrition. Typically, patients with hyperphosphatemia require dietary adjustments and phosphate binder medications, prompting clinicians to initiate both strategies for most patients with elevated phosphate levels. (A1)

Phosphate binders are categorized into calcium-containing and non-calcium–containing types. Calcium-containing binders include calcium carbonate and calcium acetate, whereas non-calcium–containing binders encompass lanthanum and sevelamer. Additional options comprise ferric citrate and sucroferric oxyhydroxide, all demonstrating comparable efficacy in phosphate reduction.[72] Typically, non-calcium–containing binders are preferred for most patients. However, in specific scenarios where non-calcium binders are not feasible or accessible, or in the presence of hypocalcemia and hyperparathyroidism (such as with adjunct calcimimetic therapy), calcium-containing binders may be considered. Nonetheless, many experts advise against the routine use of calcium-containing binders.[5] In addition to the above, clinicians should ensure that patients are adequately dialyzed and achieving recommended Kt/V targets. However, standard 4-hour dialysis sessions 3 times per week have limitations in removing phosphate, typically eliminating around 900 mg of phosphate per session.(A1)

Calcium: Maintaining calcium levels below 9.5 mg/dL (2.37 mmol/L) is essential. Asymptomatic and mild hypocalcemia does not require treatment due to the risk of hypercalcemia. In dialysis patients, calcium levels are maintained near the upper end of the normal range by adjusting the calcium concentration in the dialysate. This is done to suppress PTH and reduce the calcium and phosphorus (Ca x P) product. Hypocalcemia is associated with increased mortality and worsening hyperparathyroidism.[84]  A different approach is adopted for patients with low bone turnover diseases. Efforts are made to prevent PTH suppression by reducing calcium and vitamin D levels. Non-calcium–containing binders are used to maintain phosphate levels without raising calcium levels, thus preventing PTH suppression. This strategy has been shown to increase bone formation rates.[85] The calcium concentration in the dialysate is also kept lower than standard dialysate levels for similar reasons. However, the advantages of stopping or restricting vitamin D intake remain uncertain.(A1)

Vitamin D: Correcting vitamin D deficiency is crucial, as low vitamin D levels have been associated with increased mortality among hemodialysis patients.[86] Both cholecalciferol and ergocalciferol are effective in correcting vitamin D levels.[87](A1)

Hyperparathyroidism: Treatment options for hyperparathyroidism include calcimimetics, calcitriol or synthetic vitamin D analogs, and a combination of both to decrease PTH levels.

In most cases, a combination is required as these agents are insufficient as monotherapy if PTH levels are very high.[88] Calcitriol or synthetic vitamin D analogs are discontinued or administered at a low dose if phosphate levels exceed 5.5 mg/dL or calcium levels above 10.2 mg/dL.[89] After hypercalcemia or hyperphosphatemia has resolved, these agents can be restarted at half the previous dose, or the patient may begin cinacalcet. Calcitriol or vitamin D analogs are typically initiated at a low dose (0.25 μg, 3 times a week). Response to treatment is usually observed within the first 3 to 6 months; dosage adjustments can be made at 4- to 8-week intervals if necessary.[90] Calcimimetics enhances the sensitivity of CaSR to calcium, leading to decreased serum PTH levels and subsequently lowering calcium and phosphate levels.[91] Cinacalcet (oral) and etelcalcetide (intravenous) are 2 widely available calcimimetics, with etelcalcetide typically reserved for refractory cases. Combining calcimimetics with ongoing calcitriol or vitamin D analogs and phosphate binders increases the likelihood of achieving target PTH levels without causing hypercalcemia or hyperphosphatemia.[92] Cinacalcet also reduces the likelihood of requiring a parathyroidectomy.[93] However, cinacalcet has not been found to improve mortality rates, and parathyroidectomy may be more effective, particularly for patients with very high PTH levels.[93] Historically, there have been 2 approaches to treating patients based on their phosphate and calcium levels, and providers typically choose a strategy based on their experience and available guidance.(A1)

The following approach is recommended in the 2017 KDIGO guidelines:

• Serum phosphate levels less than 5.5 mg/dL (1.78 mmol/L) and serum calcium levels less than 9.5 mg/dL (2.37 mmol/L): Such patients are initially treated with calcitriol monotherapy. The treatment goal is to increase the calcitriol dose to achieve target PTH levels while keeping serum phosphate below 5.5 mg/dL. If target PTH levels are not reached, cinacalcet can be initiated (assuming calcium levels are above 8.4 mg/dL). The initial cinacalcet dose is typically 30 mg/d, with gradual increments to 60, 90, and 180 mg/d as necessary.

• Serum phosphate levels greater than 5.4 mg/dL (1.78 mmol/L) or serum calcium levels greater than 9.4 mg/dL (2.37 mmol/L): In patients with these elevated levels and persistently high PTH despite maximal phosphate-reducing therapy, cinacalcet initiation takes precedence over calcitriol or other synthetic analogs. Cinacalcet usage should be avoided if calcium levels are less than 8.4 mg/dL (2.1 mmol/L) due to potential hypocalcemia risks. If target PTH levels are not achieved, the patient may be considered for calcitriol or synthetic vitamin D analogs, provided phosphate levels are below 5.5 mg/dL (1.78 mmol/L) and calcium levels are less than 9.5 mg/dL (2.37 mmol/L).

Differential Diagnosis

Patients showing signs and symptoms of bone disease or structural deformities undergo evaluation involving PTH, alkaline phosphatase, calcium, and phosphate levels. Although a history of CKD suggests CKD-MBD, ruling out other bone disorders, such as osteopenia, osteoporosis, vitamin D-resistant rickets, osteopetrosis, and Paget disease of the bone, is crucial to ensure accurate diagnosis and appropriate management.

Prognosis

Many studies have been conducted to establish a connection between deranged mineral metabolism in patients with CKD and mortality rates. Results from the Dialysis Outcomes and Practice Patterns Study (DOPPS) demonstrated a direct and independent association between abnormal mineral metabolism, including serum PTH, phosphate, calcium, vitamin D, and calcium-phosphorus product, and all-cause and cardiovascular mortality.[94]  Hyperphosphatemia has been studied as a cause of increased mortality, particularly in patients with nondialysis CKD. A notable meta-analysis involving nearly 5000 patients with CKD highlighted a 35% increase in mortality per milligram rise in serum phosphate above the normal range.[82] Achieving complete recovery from renal osteodystrophy usually requires a renal transplant. However, when assessing the overall prognosis of this condition, it is crucial to consider other factors, such as the bone-vascular axis. Vascular calcifications, arteriosclerosis of blood vessels, and subsequent cardiovascular events in patients with renal osteodystrophy are all components of this axis. Understanding and addressing these interconnected factors are essential in determining the outcome for patients with this condition.[95]

Complications

CKD-MBD is itself a complication of CKD. Once mineral bone disease develops, patients commonly experience bone pain, and skeletal deformities, while growth retardation may occur in children. Another significant complication of CKD-MBD is the gradual deterioration of cardiac parameters, including cardiac remodeling and vascular calcification. However, treatment for CKD-MBD, such as using lower calcium dialysate and calcimimetics, can lead to fatal arrhythmias due to QT prolongation. Sudden fatal cardiac events, such as sudden cardiac death or heart failure resulting from severe arrhythmias, represent a distinctive phenomenon that may be characterized as part of the CKD-MBD–specific cardiac complex syndrome.[96] Results from studies have indicated that patients with renal osteodystrophy and a history of initial fragility fracture are more likely to experience cardiovascular events and metastatic calcification.[97] Additionally, complications such as increased infections, muscle weakness, arrhythmias, and heightened risk of hemorrhagic stroke may also be associated with CKD-MBD.