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

INTRODUCTION — 

Abnormalities in mineral metabolism and bone structure are an almost universal finding with progressive chronic kidney disease (CKD) [1]. Abnormal regulation of mineral metabolism in children with CKD results in significant complications similar to those seen in adult patients (eg, fractures, bone pain, avascular necrosis) and others that are unique to children (eg, growth failure, skeletal deformities).

The diagnosis, prevention, and management of pediatric CKD-mineral and bone disorder (CKD-MBD) will be reviewed here. CKD-MBD in adults is discussed elsewhere. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

DEFINITIONS

Chronic kidney disease — Chronic kidney disease (CKD) is defined as the presence of structural or functional kidney damage that persists over a minimum period of three months [2]. CKD is categorized by stages based on the estimated glomerular filtration rate (GFR); stages for children ≥2 years are outlined in the table (table 1). Methods for estimating GFR and staging for children <2 years are discussed separately. (See "Chronic kidney disease in children: Clinical manifestations, evaluation, and diagnosis", section on 'Staging' and "Chronic kidney disease in children: Clinical manifestations, evaluation, and diagnosis", section on 'Estimation of glomerular filtration rate'.)

CKD-MBD — CKD-mineral and bone disorder (CKD-MBD) is defined as CKD with one or more of the following features [3]:

●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 pediatric criteria for CKD-MBD are similar to those used for adults, although the clinical manifestations vary by age and severity of CKD. These features were described by the Kidney Disease: Improving Global Outcomes group, an international collaboration of nephrology experts who developed guidelines to improve the care of patients with CKD [3]. The previously used term "renal osteodystrophy" exclusively defines alterations in bone morphology associated with CKD based on bone biopsy (see 'Pathophysiology' below), rather than the broader clinical features of CKD-MBD listed above [4].

PATHOPHYSIOLOGY

●Phosphate retention and secondary hyperparathyroidism – Phosphate retention begins early in the course of CKD due to a decline in glomerular filtration rate (GFR), which decreases the filtered phosphate load, resulting in a decrease in renal phosphate excretion. This has several downstream effects:

•Decreased renal phosphate excretion leads to an increase in fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) levels (secondary hyperparathyroidism).

•FGF23 inhibits 1-hydroxylase activity in the kidney, resulting in reduced conversion of 25-hydroxyvitamin D (25-OHD) to the active form, 1,25-hydroxyvitamin D (figure 1).

•Phosphate retention and 1,25-dihydroxyvitamin D deficiency decrease serum calcium and further contribute to secondary hyperparathyroidism.

•Secondary hyperparathyroidism results in increased bone turnover and abnormalities in bone morphology (ie, renal osteodystrophy). (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Abnormalities of parathyroid hormone, calcium, phosphorus, fibroblast growth factor 23, and vitamin D metabolism'.)

●Bone pathology – Renal osteodystrophy is defined as alterations in bone morphology due to abnormalities of bone turnover and mineralization and is one of the components of CKD-MBD (figure 2) [2,3,5]. Renal osteodystrophy can be categorized into subtypes based on the histologic appearance: Undertreated CKD-MBD results in osteitis fibrosa cystica, which is characterized by high bone turnover and reflects secondary hyperparathyroidism. Mixed uremic osteodystrophy is the combination of high bone turnover and defective mineralization. Conversely, overtreatment can lead to adynamic bone disease or osteomalacia, which are characterized by low bone turnover, with the latter including a defect in mineralization. The details of these subtypes are discussed separately. (See "Evaluation of renal osteodystrophy".)

Bone biopsy is the gold standard method for characterizing renal osteodystrophy but is rarely performed clinically in children with CKD because it is invasive [6]. (See 'Diagnosis' below.)

CLINICAL MANIFESTATIONS

Overview — Clinical manifestations of CKD-MBD vary and are based on the severity of CKD:

●Early CKD – When untreated, CKD-MBD can first be detected in children with stage G2 CKD. Although these patients typically have no signs or symptoms related to bone disease, they often have elevated serum parathyroid hormone (PTH) levels, which tend to maintain serum calcium and phosphorus concentrations at normal levels. Other laboratory abnormalities may include decreased 25-hydroxyvitamin D (25-OHD) levels and increased fibroblast growth factor 23 (FGF23) levels (figure 3) [7,8]. FGF23 is an early mediator of secondary hyperparathyroidism and PTH elevations. (See 'Pathophysiology' above.)

●Advanced CKD – When the glomerular filtration rate (GFR) falls below 30 mL/min per 1.73 m² (stage G4 disease and beyond), the compensatory hyperparathyroidism becomes inadequate and patients will develop hyperphosphatemia and hypocalcemia unless appropriate therapy is given. Untreated patients with advanced CKD (stage G4 through G5) become increasingly symptomatic with bone pain, fractures, difficulty walking, and/or skeletal deformities such as varus and valgus deformities of the long bones.

Laboratory findings — Untreated or inadequately treated CKD-MBD is manifested by the following laboratory abnormalities:

●Hyperphosphatemia

●Hypocalcemia

●Vitamin D deficiency, with low serum 25-OHD and 1,25-dihydroxyvitamin D

●Elevated serum PTH, alkaline phosphatase, and FGF23

Conversely, hypercalcemia can occur as a complication of aggressive intervention or as a result of tertiary hyperparathyroidism in advanced CKD. Although hyperphosphatemia is commonly seen in CKD, hypophosphatemia can occur with aggressive management, especially in infants and young children.

Complications — Complications of CKD-MBD in children include:

●Growth failure – In children with advanced CKD, growth impairment is common. Contributing factors include:

•CKD-MBD

•Chronic metabolic acidosis

•Anorexia and inadequate caloric intake

•Low level of bioavailable insulin-like growth factor

•The primary kidney disease

The relative importance of these contributory factors in growth failure is uncertain. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Contributing factors'.)

●Rickets – Depending on the child's age and severity of disease, CKD-MBD may cause rickets. The clinical features are similar to other causes of rickets and include characteristic clinical findings (eg, parietal and frontal bossing and widening of wrists) and radiologic abnormalities (eg, osteopenia; widening of the epiphyseal plate; and cupping, splaying, and fraying of metaphysis). (See "Overview of rickets in children".)

●Fractures – The risk for fracture is increased two- to threefold in children with CKD compared with the general pediatric population [9]. In a retrospective cohort study of 537 children with CKD, advanced pubertal stage, greater height Z-score, difficulty walking, and higher average log-transformed PTH level were independently associated with greater fracture risk, while calcium-based phosphate binder treatment was associated with lower fracture risk [9].

●Slipped capital femoral epiphysis and knee deformities – In children with CKD, the growth plate is vulnerable to injury, with disruption of the connection between the epiphyseal plate and the metaphysis [10]. This abnormality, along with erosions of bone due to hyperparathyroidism, puts the child at an increased risk for slipped capital femoral epiphysis and knee deformities (genu valgum and varus). (See "Evaluation and management of slipped capital femoral epiphysis (SCFE)" and "Approach to the child with knock-knees" and "Approach to the child with bow-legs".)

●Extraskeletal calcification – Extraskeletal soft tissue calcifications (also called calcinosis) include vascular, ocular, periarticular, and visceral calcifications. Limited data in children have reported soft tissue calcification within the coronary arteries [11-17]. Vascular calcification is accelerated in children on hemodialysis [18], is associated with abnormalities of circulating calcification inhibitors [19], and worsens with severity of mineral bone abnormalities including elevation of FGF23 and dialysis duration [20-22]. (See "Vascular calcification in chronic kidney disease" and "Calciphylaxis (calcific uremic arteriolopathy)".)

To minimize risks for the above complications, prevention and management of CKD-MBD includes maintaining serum calcium, phosphorus, 25-OHD, and PTH within target ranges, as outlined below. (See 'Management' below.)

SURVEILLANCE AND MONITORING FOR CKD-MBD — 

Early detection of bone metabolic abnormalities facilitates the prompt initiation of therapeutic interventions, thereby preventing or minimizing secondary hyperparathyroidism and its consequent effect on bone disease. Surveillance and monitoring of children should begin at CKD stage G2 and include measurements of serum calcium, phosphorus, parathyroid hormone (PTH), alkaline phosphatase, and 25-hydroxyvitamin D (25-OHD). Protocols for monitoring from key society guidelines are summarized in the table (table 2) [1,3,23,24]. If therapy is initiated to correct serum abnormalities and/or treat renal osteodystrophy, laboratory evaluation should be performed more frequently to ensure a response to therapy or to inform dose adjustments.

DIAGNOSIS

●Laboratory tests – The diagnosis of pediatric CKD-MBD is made upon fulfilling one of the criteria for the definition of CKD-MBD. This typically occurs when a laboratory abnormality of bone mineralization (eg, calcium, phosphorus, parathyroid hormone [PTH], or 25-hydroxyvitamin D [25-OHD]) is detected during routine surveillance and monitoring of children with CKD stages 2 through 4. Increased concentrations of fibroblast growth factor 23 (FGF23), abnormalities in markers of bone turnover or strength, or extraskeletal calcifications also fulfill the definition of CKD-MBD but are rarely necessary to make the diagnosis. (See 'CKD-MBD' above.)

●Bone biopsy – Bone biopsy is rarely performed clinically because it is invasive and also not widely available and most clinical decision-making can be guided by monitoring serum PTH, calcium, phosphorus, and alkaline phosphatase. However, these biomarkers are not always able to clearly distinguish between high versus low bone turnover and different degrees of bone mineralization [6].

Indications for bone biopsy are not well established for children with CKD, because it is not clear when a histologic diagnosis of bone disease impacts clinical treatment decision-making [3,25]. European guidelines suggest that bone biopsy may be useful to guide management decisions in children with CKD-MBD when the clinical and biochemical findings do not explain the underlying bone disease (eg, severe bone deformities or pain) despite optimizing treatment [23]. Thus, bone biopsy is not routinely required for management but may be useful in selected cases in which the histologic findings are deemed necessary to optimize therapy.

On the rare occasion when it is decided to perform a bone biopsy, we refer the patient to a specialized center with particular expertise in evaluating for renal osteodystrophy. The site of biopsy is typically the iliac crest, and the specimen is obtained after the administration of tetracycline markers, which are used to determine the rate of new bone formation. The findings can help determine if the CKD-MBD is undertreated (osteitis fibrosa cystica, characterized by high bone turnover due to secondary hyperparathyroidism) versus overtreated (adynamic bone disease, which is characterized by low bone turnover). (See 'Pathophysiology' above.)

MANAGEMENT

Overview

●Goals – Management goals are to:

•Prevent and treat secondary hyperparathyroidism, which results in bone disease (osteitis fibrosa cystica and mixed osteodystrophy). Secondary hyperparathyroidism is due to hyperplasia of the parathyroid glands caused by phosphate retention, 1,25-dihydroxyvitamin D deficiency, hypocalcemia, and skeletal resistance to parathyroid hormone (PTH) action. (See 'Pathophysiology' above and "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Abnormalities of parathyroid hormone, calcium, phosphorus, fibroblast growth factor 23, and vitamin D metabolism'.)

and

•Avoid overtreatment, which can cause adynamic bone disease or osteomalacia. (See 'Pathophysiology' above.)

●Interventions – Management and prevention of secondary hyperparathyroidism involves:

•Correction of phosphate retention by dietary phosphate restriction, usually in combination with a phosphate binder for those children with more advanced CKD. (See 'Hyperphosphatemia' below.)

•In children with CKD stages G2 to G4 (table 1), assess and replenish 25-hydroxyvitamin D (25-OHD) as needed with oral ergocalciferol or cholecalciferol and maintain adequate calcium levels. For children with normal 25-OHD concentrations and elevated PTH, an active vitamin D analog (eg, calcitriol) is provided in place of ergocalciferol or cholecalciferol. (See 'Vitamin D deficiency' below.)

•In children with CKD stage G5, the combination of dietary phosphate restriction, phosphate binders, and an active vitamin D analog is generally required to maintain a normal age-appropriate serum phosphate value and a serum PTH concentration that is no more than two to three times normal.

The following discussion regarding the specific interventions involved in the management of bone metabolism in children with CKD is consistent with guidelines from the Kidney Disease Outcomes Quality Initiative (KDOQI), Kidney Disease: Improving Global Outcomes, and European Society of Paediatric Nephrology (ESPN) CKD-MBD and Dialysis Working Group [1,3,26].

●Serum PTH targets – Serum PTH is the primary clinical laboratory marker of secondary hyperparathyroidism and, in conjunction with serum calcium, phosphorus, and alkaline phosphatase, helps guide the intensity of therapy for CKD-MBD. Target PTH concentrations and protocols for monitoring from key society guidelines are summarized in the table (table 2) [1,3,23,24].

Serum PTH concentration is inversely correlated with kidney function and is almost always elevated when the glomerular filtration rate (GFR) falls below 60 mL/min per 1.73 m² (ie, stage G3) [27]. The optimal target serum PTH values in children with CKD is uncertain. As outlined in the above table, most experts, including the authors, aim to maintain PTH at a near-normal level in children with stage G2 to G3 CKD, slightly above the normal range for stage G4, and at two to three times the upper limit of normal for those on dialysis [23,28].

Hyperphosphatemia — Management is directed at preventing hyperphosphatemia and phosphate retention because of their critical role in promoting secondary hyperparathyroidism and vascular injury. Phosphate retention begins with the decline in GFR resulting in hyperphosphatemia when GFR falls below 30 mL/min per 1.73 m² (CKD G4 to G5 disease). Phosphate is a salt of oxidized phosphoric acid and is a key component of bone matrix. (See 'Pathophysiology' above and "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Phosphate retention and hyperphosphatemia'.)

Serum phosphorus targets — We target normal age-appropriate serum phosphorus concentrations, consistent with guidance from the KDOQI, Pediatric Renal Nutrition Taskforce, and ESPN CKD-MBD and Dialysis Working Group [1,23,29,30]. The normal range for serum phosphorus is highest in young infants, then decreases with increasing age:

●0 to 3 months of age – 4.8 to 7.4 mg/dL (1.55 to 2.39 mmol/L)

●1 to 5 years of age – 4.5 to 6.5 mg/dL (1.45 to 2.1 mmol/L)

●6 to 12 years of age – 3.6 to 5.8 mg/dL (1.16 to 1.87 mmol/L)

●13 to 20 years of age – 2.3 to 4.5 mg/dL (0.74 to 1.45 mmol/L)

For children with stage G5 CKD, we suggest targeting phosphorus concentrations slightly above the normal range, consistent with the KDOQI Pediatric Bone guidelines [1].

Management — We use a stepwise approach to maintain the targeted serum phosphate goal, beginning with dietary phosphorus restriction, followed by the addition of phosphate binders as needed.

Dietary phosphorus restriction — For children with CKD stages G3 to G5, dietary phosphate restriction is based on age, serum PTH levels, and serum phosphorus concentrations:

●Elevated serum PTH with normal serum phosphorus – Restrict dietary phosphorus intake to 100 percent of the dietary reference intake (DRI) for age, as follows [30]:

•0 to 0.5 years – 100 mg/day

•0.5 to 1 year – 275 mg/day

•1 to 3 years – 460 mg/day

•4 to 8 years – 500 mg/day

•9 to 19 years – 1250 mg/day

●Elevated serum PTH with elevated serum phosphorus – Restrict dietary phosphorus intake to 80 percent of the DRI for age, as follows [1]:

•0 to 0.5 years – 80 mg/day

•0.5 to 1 year – 220 mg/day

•1 to 3 years – 368 mg/day

•4 to 8 years – 400 mg/day

•9 to 19 years – 1000 mg/day

The Pediatric Renal Nutrition Taskforce guideline provides information on common calcium- and phosphorus-containing foods, assessment of dietary calcium and phosphorus intake, requirements for calcium and phosphorus in healthy children and necessary modifications for children with CKD 2 to 5D, and dietary management of hypo- and hypercalcemia and hyperphosphatemia [29].

After the initiation of dietary restriction, serum phosphorus should be monitored at least every three months in children with CKD stages G3 and G4 and monthly in those with CKD stage G5. Studies in children with CKD report no association of dietary phosphorus restriction with poor linear growth [31-34]. However, serum phosphorus concentrations below the target range for age should be avoided because of the potential adverse effects of hypophosphatemia on linear growth and bone mineralization.

In controlled studies of both children and adults, dietary phosphorus restriction results in decreased serum PTH level and increased serum 1,25-dihydroxyvitamin D concentrations [35,36] (see "Management of hyperphosphatemia in adults with chronic kidney disease"). Conversely, an intake of phosphorus that is twice the DRI in children with CKD stage G3 increases serum PTH and decreases serum 1,25-dihydroxyvitamin D [35].

Phosphate binders — Phosphate binders are typically prescribed if the serum phosphorus concentration remains above the target goal after initiating dietary restriction. Compliance with dietary phosphorus restriction in children is poor as many preferred foods are rich in phosphorus. Thus, phosphate binders often become necessary to prevent phosphorus absorption from the gastrointestinal tract.

●Choice of binders

•Children without hypercalcemia – For children without hypercalcemia, a calcium-based phosphate binder can be used for initial therapy. Several observational studies have shown that calcium-based phosphate binders are effective and safe in lowering serum phosphorus and PTH levels in children [37-39]. A non-calcium-based phosphate binder (such as sevelamer) is a reasonable alternative but is more expensive and is not more effective. Calcium citrate, aluminum hydroxide, and magnesium-containing antacids should be avoided in children with CKD because of potential adverse effects [1,3,40,41].

The choice among the many different calcium-containing phosphate binders (calcium carbonate, calcium acetate, calcium gluconate, and calcium ketoglutarate) depends primarily on the patient's tolerance of the binder and availability. Several studies in adults have not shown an overall advantage of one preparation over another [1]. The total dose of elemental calcium should not exceed twice the DRI for calcium based on age, with a maximum of 2500 mg/day, including the dietary calcium intake. (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Dose and specific agents'.)

•For children with hypercalcemia – For children with hypercalcemia (serum calcium >10.2 mg/dL [2.55 mmol/L]), non-calcium binders, such as sevelamer, are preferred rather than calcium-based phosphate binders [42] because calcium-based phosphate binders may promote soft tissue calcifications in patients with hypercalcemia. Open-label studies in children have shown that sevelamer carbonate lowers serum phosphorus better than placebo and is as effective as calcium acetate without serious adverse effects [43,44]. Sevelamer carbonate was also associated with an improvement in serum bicarbonate levels, such that sodium bicarbonate therapy could be discontinued. For children nine years and older, an alternative non-calcium phosphate binder is sucroferric oxyhydroxide, which may have a lower pill burden than sevelamer [45,46]. (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Dose and specific agents'.)

•Binders that should be avoided – The following phosphate binders should not be used in children with CKD unless they are the only available or affordable medications, as may be the case in some countries:

-Aluminum hydroxide, because of aluminum bone toxicity [40]. Aluminum deposition can cause low bone turnover, leading to renal osteodystrophy (eg, adynamic bone disease and osteomalacia). Aluminum use can also be associated with neurocognitive and hematologic complications. (See "Aluminum toxicity in chronic kidney disease".)

-Magnesium-containing antacids (such as magnesium hydroxide), because of the risk of hypermagnesemia and the frequent development of diarrhea.

-Calcium citrate, because it markedly increases the absorption of dietary aluminum.

●Administration – Phosphate binders should be taken 10 to 15 minutes before or during the meal. They are much less effective when taken between meals, when most dietary phosphorus has already been absorbed.

Phosphate binders must be used in conjunction with dietary phosphorus restriction because all phosphate binders have limited phosphate-binding capacity. As examples, 1 g of calcium carbonate binds 39 mg of dietary phosphorus, 1 g of calcium acetate binds 45 mg of phosphorus, and 400 mg of sevelamer HCl binds 32 mg of phosphorus.

Vitamin D deficiency — In children with CKD, production of 1,25-dihydroxyvitamin D is impaired due to retention of phosphorus, low serum 25-OHD, and increased serum fibroblast growth factor 23 (FGF23) [7,47]. Retention of phosphorus and 1,25-dihydroxyvitamin D deficiency decrease serum calcium, which contributes directly to secondary hyperparathyroidism (elevated PTH) and renal osteodystrophy.

As a result, vitamin D supplementation is usually required. The choice of formulation depends on the stage of CKD and serum concentrations of 25-OHD and PTH. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)" and 'Persistent hyperparathyroidism' below.)

Chronic kidney disease stages G2 to G4 — Vitamin D deficiency is common in children with CKD [48-51]. Additional risk factors for vitamin D deficiency include older age, darker skin pigmentation, higher body mass index, lower daily milk intake, more advanced CKD, and no vitamin D supplementation [52]. Management of vitamin D deficiency depends on the concentration of 25-OHD.

●Patients with low 25-OHD concentrations – For children with CKD, we recommend vitamin D supplementation to maintain serum 25-OHD concentration >30 to 48 ng/mL (>75 to 120 nmol/L), consistent with the major society guidelines [1,26,30].

•Children – For children >1 year, recommended doses for vitamin D replacement depend on serum 25-OHD concentrations [26]:

-Vitamin D in target range (25-OHD >30 to 48 ng/mL [75 to 120 nmol/L]) – Give maintenance doses of oral vitamin D 1000 to 2000 international units (25 to 50 micrograms) daily.

-25-OHD 20 to 30 ng/mL (50 to 75 nmol/L) – Give oral vitamin D 2000 international units (50 micrograms) daily for three months.

-25-OHD 5 to 20 ng/mL (12 to 49 nmol/L) – Give oral vitamin D 4000 international units (100 micrograms) daily for three months.

-25-OHD <5 ng/mL (12 nmol/L) – Give oral vitamin D 8000 international units (200 micrograms) daily for four weeks, then 4000 international units (100 micrograms) daily for two months, for total therapy of three months. Alternatively, 50,000 international units/week for four weeks (1250 micrograms) followed by 50,000 international units two times/month for a total therapy of three months.

Either ergocalciferol or cholecalciferol can be used for vitamin D replacement [26]. Ergocalciferol is available as an 8000-units/mL preparation, which is helpful when using high doses in small children.

Serum 25-OHD concentrations should be measured after three months of replacement therapy. If serum 25-OHD is in the target range, continue a maintenance dose of 1000 to 2000 international units (25 to 50 micrograms) daily. If serum 25-OHD is below the target range, repeat the three-month replacement regimen [26].

Other protocols have also been successfully used for vitamin D replacement in children with CKD. In randomized trials, doses ranging from 3000 international units (75 micrograms) daily to 100,000 international units (2500 micrograms) monthly were equally effective in normalizing serum 25-OHD concentrations, with no toxicity or hypercalcemia [53,54]. However, guidelines recommend against this type of high-dose intermittent therapy (including mega-dose or "stoss therapy") due to possible adverse effects on kidney function or cardiovascular disease and limited data on potential adverse effects in children with CKD [26].

•Infants – For infants <1 year with CKD, give a replacement dose of 600 international units (15 micrograms) daily for at least three months (regardless of serum 25-OHD concentrations). Then, if serum 25-OHD is >30 ng/mL (75 nmol/L), switch to a maintenance dose of 400 international units (10 micrograms) daily [26].

●Patients with elevated PTH and normal 25-OHD – Levels of 1,25-dihydroxyvitamin D (calcitriol) usually fall below normal when the GFR is <60 mL/min per 1.73 m² (stage G3b and higher). For these children, calcitriol is our preferred initial choice of active vitamin D therapy [55]. Observational studies in children with CKD suggest that treatment with calcitriol may decrease serum PTH concentrations and improve linear growth [56,57]. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Decreased calcitriol activity'.)

Thus, we provide an active vitamin D analog (eg, calcitriol) if all of the following criteria are met:

•Serum 25-OHD >30 ng/mL (>75 nmol/L)

•Serum PTH above the target range

•Serum calcium level <10.2 mg/dL (<2.37 mmol/L) [52]

•Serum phosphorus level less than the age-appropriate upper limits for the stage of CKD (see 'Serum phosphorus targets' above)

Once active vitamin D therapy is started, serum calcium and phosphorus concentrations should be measured after one month of therapy and every three months thereafter. Serum PTH should be measured at least every three months, with a goal of maintaining PTH approximately in the target range for those children with CKD stages G2 to G4. The dose of calcitriol should be modified or held if hypercalcemia develops or the serum PTH falls below the target range. If hyperphosphatemia develops or persists, the dose should be decreased and phosphate binder use and dietary phosphorus restriction intensified.

Chronic kidney disease stage G5 — Children with CKD stage G5 (GFR <15 mL/min per 1.73 m²) usually have an elevated serum PTH as a result of phosphorus retention and impaired conversion of 25-OHD to 1,25-dihydroxyvitamin D.

●Indications for calcitriol – If serum PTH is elevated (eg, >300 pg/mL), calcitriol should be administered to reduce the serum PTH. This includes patients on dialysis.

The optimal PTH target for this group of patients is controversial and varies between guidelines (table 2). We generally target a PTH value that is two to three times the upper limit of normal in children on dialysis, in accordance with the recommendations of the ESPN CKD-MBD and Dialysis Working Group [28]. This is similar to the 100 to 300 pg/mL target based on data from peritoneal dialysis patients in the International Pediatric Peritoneal Dialysis Network Registry [1,58-60].

●Calcitriol dose – The recommended starting dose for calcitriol is based on the body weight of the child:

•Weight <10 kg – 0.05 mcg every other day

•Weight between 10 kg and 20 kg – 0.1 mcg to 0.15 mcg per day

•Weight >20 kg – 0.25 mcg per day

Dosing of calcitriol should be adjusted based on subsequent laboratory results. Serum PTH should be measured monthly for three months and then at least every three months. Serum PTH concentrations <100 ng/L should be avoided to prevent overtreatment (potentially causing adynamic bone disease).

●Adverse effects – In patients with elevated serum calcium or phosphorus concentrations, calcitriol can lead to soft tissue calcification due to an increase in the calcium phosphorus product. The increased gastrointestinal absorption of calcium and phosphorus that occurs with calcitriol usage can also contribute to soft tissue calcification. (See 'Complications' above and "Vascular calcification in chronic kidney disease", section on 'Risk factors'.)

●Alternatives – More selective vitamin D analogs, such as alfacalcidol, paricalcitol [61,62], or doxercalciferol, have been developed to reduce the risk of hypercalcemia and hyperphosphatemia. Limited pediatric data have shown that these agents are effective in lowering PTH levels [62,63], and there is no convincing evidence supporting the use of one specific vitamin D analog over another. These analogs are most often used in children who have developed elevated serum calcium levels associated with calcitriol therapy. These agents should be started at the lowest possible dose and titrated based on trends of serum calcium, phosphorus, and PTH levels to achieve target PTH concentrations and maintain a normal serum calcium level.

Calcium homeostasis — Total serum calcium should be maintained within the age-appropriate normal range, generally between 8.8 and 9.7 mg/dL (2.2 to 2.37 mmol/L) depending on the laboratory used [3,29].

Hypocalcemia — If appropriate therapy is not provided to patients with CKD, they can develop hypocalcemia due to progressive loss of kidney function, resulting in phosphorus retention and 1,25-dihydroxyvitamin D deficiency. Symptomatic hypocalcemia should initially be treated with parenteral calcium chloride [1]. Long-term therapy requires appropriate management of hyperphosphatemia and vitamin D deficiency, as described above, and sufficient dietary calcium.

For children with CKD stages G2 to G5, the 2008 KDOQI pediatric nutrition guidelines suggest that the total calcium intake (nutritional sources and phosphate binders) be in the range of 100 to 200 percent of the DRI for age (table 3) [30]. These recommendations are similar to those of the Pediatric Renal Nutrition Taskforce for children with CKD and on dialysis [29]. (See "Treatment of hypocalcemia".)

Hypercalcemia — Children with CKD who are treated with vitamin D therapy and calcium-containing phosphate binders may develop hypercalcemia. If the total serum calcium value exceeds 10.2 mg/dL (2.55 mmol/L), the dose of calcium-based phosphate binders should be reduced and/or therapy changed to sevelamer and calcium supplementation stopped [29]. Vitamin D therapy should also be discontinued until the serum calcium returns to the target range and then restarted with an appropriate dose adjustment.

Persistent hyperparathyroidism — Calcimimetic therapy should be considered for children who continue to have persistent hyperparathyroidism despite being vitamin D replete with optimal dietary phosphorus restriction, accompanied by phosphate binder and vitamin D analog therapy. On rare occasions, parathyroidectomy may be indicated if all conventional therapy fails and/or when secondary hyperparathyroidism transitions into tertiary hyperparathyroidism.

Calcimimetics (eg, cinacalcet) suppress PTH secretion and decrease the risk of hypercalcemia associated with calcitriol. These agents, which increase the sensitivity of the calcium-sensing receptor in the parathyroid gland to calcium, have undergone limited study in the pediatric population. The available data suggest that calcimimetics are effective in reducing PTH levels in children with severe and/or refractory hyperparathyroidism [64-69]. However, calcimimetics are also associated with frequent adverse effects. In a meta-analysis of studies of cinacalcet for CKD-MBD in children and adolescents, 10.7 percent developed hypocalcemia, 16 percent of participants had a serious adverse event (including hypertension, diarrhea, ileus, and dialysis catheter-related events), and 0.2 percent died [70]. While this report highlights the importance of closely monitoring patients who receive cinacalcet, additional information is needed to ensure its safety, particularly the risk of hypocalcemia, as well as efficacy.

For children on dialysis in whom secondary hyperparathyroidism is not adequately controlled with standard therapy, guidance on the use of cinacalcet is available in a position statement from expert groups in Europe [71]. (See "Management of secondary hyperparathyroidism in adult patients on dialysis", section on 'Calcimimetics'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in children" and "Society guideline links: Chronic kidney disease-mineral and bone disorder".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Bone problems caused by kidney disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical and laboratory manifestations ‒ In children with chronic kidney disease (CKD), abnormalities in mineral bone metabolism occur early and are universal. If untreated, these patients will develop CKD-mineral and bone disorder (CKD-MBD). Clinical and laboratory manifestations of CKD-MBD vary with the severity of CKD (table 1) and treatment interventions (see 'Clinical manifestations' above and 'Pathophysiology' above):

•Early CKD – In early (stage G2) CKD, the first sign of CKD-MBD is elevated serum parathyroid hormone (PTH), indicating secondary hyperparathyroidism, which tends to maintain serum calcium and phosphorus concentrations at normal levels.

•Advanced CKD – In advanced CKD (stage G4 disease and beyond), the compensatory hyperparathyroidism becomes inadequate and patients develop hyperphosphatemia and hypocalcemia unless appropriate therapy is given. Untreated patients become increasingly symptomatic with bone pain, fractures, difficulty walking, and/or skeletal deformities such as varus and valgus deformities of the long bones.

●Surveillance and monitoring ‒ Surveillance and monitoring of serum concentrations of PTH, calcium, phosphorus, and total alkaline phosphatase should be performed in all children with CKD, beginning at CKD stage G2 (table 2). (See 'Surveillance and monitoring for CKD-MBD' above.)

●Diagnosis ‒ The diagnosis of CKD-MBD is made upon fulfilling one of the criteria for the disorder. This typically occurs when a laboratory abnormality (often, elevated PTH) is detected during surveillance and monitoring of children with CKD stages G2 through G4. Increased concentrations of fibroblast growth factor 23 (FGF23), abnormalities in markers of bone turnover or strength, or extraskeletal calcifications also fulfill the definition of CKD-MBD but are rarely necessary to make the diagnosis. Bone biopsy is rarely performed clinically. (See 'Definitions' above and 'Diagnosis' above.)

●Management goals ‒ The goals of therapy are to prevent and treat secondary hyperparathyroidism, which results in bone disease (osteitis fibrosa cystica and mixed osteodystrophy), while avoiding the development of adynamic bone disease or osteomalacia from overtreatment. We aim to maintain PTH at a near-normal level for children with stage G2 to G3 CKD, slightly above the upper limit of normal for stage G4 CKD, and two to three times the upper limit of normal for those on dialysis. (See 'Overview' above.)

●Management approach ‒ Prevention and treatment of secondary hyperparathyroidism include:

•Phosphorus homeostasis – To prevent phosphorus retention and hyperphosphatemia:

-Dietary phosphorus restriction is the initial intervention. The target for maximum daily dietary phosphorus intake is based on the child's age and serum PTH and phosphorus concentrations. (See 'Dietary phosphorus restriction' above.)

-For patients with serum phosphorus concentrations above the target goal despite dietary phosphate restriction, we suggest adding a phosphate binder rather than dietary restriction alone (Grade 2C). Phosphate binders effectively reduce the serum phosphorus concentration, which is a key mediator of CKD-MBD.

The choice of phosphate binder depends on availability and the patient's tolerance of the binder and serum calcium concentrations. For patients without hypercalcemia, either a calcium-based phosphate binder or sevelamer can be used. Calcium-based phosphate binders should not be used for patients with hypercalcemia, because of the risk for soft tissue calcifications. Calcium citrate, aluminum hydroxide, and magnesium-containing antacids should not be used in children with CKD, because of potential adverse effects. (See 'Phosphate binders' above.)

•Vitamin D therapy – Children with CKD may have low serum 25-hydroxyvitamin D (25-OHD) levels. As a result, supplementation with vitamin D is usually required. The goal is to maintain serum 25-OHD concentrations in the normal range (>30 to 48 ng/mL [>75 to 120 nmol/L]) and PTH in the target range (table 2). For most children with CKD stages G2 to G4, a 25-hydroxyvitamin D analog (ergocalciferol or cholecalciferol) is appropriate. Those with elevated PTH and hypocalcemia but serum 25-OHD and phosphorus in the target range require calcitriol. In addition, we suggest calcitriol for patients with CKD stage G5 (or on dialysis), elevated PTH, and normal 25-OHD concentrations, even in the absence of hypocalcemia (Grade 2C). For the latter group, the goal is to maintain serum PTH between two to three times the upper limit of normal. (See 'Vitamin D deficiency' above.)

•Calcium homeostasis ‒ Children with CKD are at risk for hypocalcemia due to progressive loss of kidney function, resulting in phosphorus retention and 1,25-dihydroxyvitamin D deficiency. They usually require increased calcium intake to maintain serum calcium in the age-appropriate normal range, generally between 8.8 and 9.7 mg/dL (2.2 to 2.37 mmol/L). Sources of calcium include dietary intake and calcium supplements given away from meals. (See 'Hypocalcemia' above.)