INTRODUCTION — Abnormalities in mineral metabolism and bone structure are an almost universal finding with progressive chronic kidney disease (CKD) . Abnormal regulation of mineral metabolism in children with CKD results in significant complications similar to those seen in adult patients (eg, fractures, bone pain, and avascular necrosis) and others that are unique to children (eg, growth failure and 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)" and "Osteoporosis in patients with chronic kidney disease: Management" and "Adynamic bone disease associated with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)
Chronic kidney disease (CKD) — In the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines, the diagnosis of CKD is based on fulfilling one of the following criteria :
●Glomerular filtration rate (GFR) of less than 60 mL/min per 1.73 m2 for greater than three months with implications for health regardless of whether other CKD markers are present.
●GFR greater than 60 mL/min per 1.73 m2 that is accompanied by evidence of structural damage or other markers of functional kidney abnormalities, including proteinuria, albuminuria, renal tubular disorders, or pathologic abnormalities detected by histology or inferred by imaging.
In addition, the KDIGO guidelines define CKD staging for children older than two years of age, which stratifies the risk for progression of CKD and its complications based on GFR. This classification is used in this topic to guide management, including what therapeutic interventions should be initiated and when (table 1):
●Stage G1 – Normal GFR (≥90 mL/min per 1.73 m2)
●Stage G2 – GFR between 60 and 89 mL/min per 1.73 m2
●Stage G3a – GFR between 45 and 59 mL/min per 1.73 m2
●Stage G3b – GFR between 30 and 44 mL/min per 1.73m2
●Stage G4 – GFR between 15 and 29 mL/min per 1.73 m2
●Stage G5 – GFR of <15 mL/min per 1.73 m2 (kidney failure) requiring kidney replacement therapy (ie, dialysis or kidney transplantation)
Children under two years of age do not fit within the above classification system because they normally have a low GFR even when corrected for body surface area. In these patients, calculated GFR based upon serum creatinine can be compared with normative age-appropriate values to detect kidney impairment. The KDIGO guideline suggests that a GFR value >1 standard deviation below the mean should raise concern and prompt more intensive monitoring (table 2). (See "Chronic kidney disease in children: Definition, epidemiology, etiology, and course", section on 'Estimated glomerular filtration rate'.)
CKD-MBD — In 2006, the Kidney Disease: Improving Global Outcomes (KDIGO) group, an international collaboration of nephrology experts who developed guidelines to improve the care of patients with CKD, recommended using the term CKD-MBD to describe the systemic bone disorder associated with CKD . In this topic, the definition of CKD-MBD in children is manifested by one or a combination of the following three components, which are similar to those used in adult patients with CKD:
●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
Overview — Clinical manifestations of CKD-MBD vary based on the severity of CKD and whether interventions to prevent MBD have been instituted. CKD-MBD, when untreated, 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 abnormal laboratory levels of serum calcium, phosphorus, parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D. Untreated patients with more severe CKD (stage G3 through G5) become increasingly symptomatic with bone pain, fractures, difficulty in walking, and/or skeletal deformities such as varus and valgus deformities of the long bones.
Complications — Children with CKD are at-risk for the following complications of CKD-MBD:
●Growth failure – MBD, along with several other factors including chronic metabolic acidosis, anorexia and inadequate caloric intake, inadequate unbound insulin-like growth factor, and/or the primary kidney disease, may contribute to poor growth in children with advanced CKD. The relative importance of these factors in growth failure is uncertain. (See "Growth failure in children with chronic kidney disease (CKD): Risk factors, evaluation, and diagnosis", section on 'Contributing factors'.)
●Rickets – Depending on the patient age and severity of disease, patients may present with rickets with its well-defined clinical (eg, parietal and frontal bossing and widening of wrists) and radiologic features (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 . 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 .
●Slipped epiphysis and genu valgum – In children with CKD, the growth plate is vulnerable to injury with disruption of the connection between the epiphyseal plate and the metaphysis . This abnormality, along with hyperparathyroid erosions of bone, puts the child at an increased risk for slipped epiphysis and genu valgum. (See "Evaluation and management of slipped capital femoral epiphysis (SCFE)".)
●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 [7-13]. Vascular calcification is accelerated in children on hemodialysis , is associated with abnormalities of circulating calcification inhibitors , and worsens with severity of mineral bone abnormalities, including elevation of fibroblast growth factor 23 (FGF23) and dialysis duration [16-18]. (See "Vascular calcification in chronic kidney disease" and "Calciphylaxis (calcific uremic arteriolopathy)".)
In an attempt to minimize the risk of soft tissue and vascular calcification, the Pediatric Renal Nutrition Taskforce recommends targeting serum calcium and phosphorus levels within the age-appropriate normal range :
Laboratory findings — Untreated or inadequately treated CKD-MBD is manifested by the following laboratory abnormalities:
●Decreased serum 1,25-dihydroxyvitamin D levels.
●Serum calcium abnormalities – Untreated CKD-MBD presents with hypocalcemia. However, hypercalcemia may be a complication of CKD-MBD therapeutic interventions or tertiary hyperparathyroidism.
●Elevated serum parathyroid hormone (PTH) levels.
●Elevated serum alkaline phosphatase (ALP) levels.
Phosphate retention and secondary hyperparathyroidism — In pediatric CKD, phosphate retention with advanced kidney disease results in 1,25-dihydroxyvitamin D deficiency, hypocalcemia, and secondary hyperparathyroidism. Phosphate retention and 1,25-dihydroxyvitamin D deficiency decrease serum calcium and contribute directly to secondary hyperparathyroidism. Secondary hyperparathyroidism results in increased bone turnover and abnormalities in bone morphology (ie, renal osteodystrophy). Hyperparathyroidism does initially increase urinary phosphate excretion in the early stages of CKD, but this adaptation becomes inadequate as CKD advances, resulting in hyperphosphatemia if not treated. (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'.)
Phosphate retention begins early in CKD as the decline in glomerular filtration rate (GFR) decreases the filtered phosphate load, resulting in a decrease in renal phosphate excretion, and leads to an increased FGF23 level. FGF23 inhibits 1-hydroxylase activity in the kidney, causing a reduction in 1,25-dihydroxyvitamin D levels from decreased 1-hydroxylation of 25-hydroxyvitamin D. The clinical implications of the pathophysiologic changes are that a child with CKD in late-stage G2 and in stage G3 disease may have normal serum calcium and phosphorus levels that are maintained in the normal range by an elevated serum PTH level. When the GFR falls below 30 mL/min per 1.73 m2 (stage G4 disease and beyond), hyperphosphatemia (levels above the normal range) and hypocalcemia will usually occur unless appropriate therapy is given.
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 [2,3]. Although bone biopsy is costly, invasive, and is rarely performed clinically, it remains the gold standard to diagnose bone disease . It represents the historical changes in MBD, which may be in a state of flux depending on of the course of CKD and treatment changes. Several biomarkers, including serum PTH, calcium, phosphorus, 25-hydroxyvitamin D, and ALP levels have been used to monitor alterations in bone turnover and mineralization; however, they have had limited success .
In children with CKD, renal osteodystrophy based on bone biopsy is classified into the following subtypes, which are also seen in adult patients with CKD [21-23] (see "Evaluation of renal osteodystrophy"). The severity of bone disease rises with the progression of CKD and children undergoing chronic dialysis have the most severe bone disease .
●Osteitis fibrosa cystica – Osteitis fibrosa cystica is characterized by high bone turnover due to secondary hyperparathyroidism (picture 1).
●Adynamic bone disease – Adynamic bone disease is characterized by low bone turnover with reductions in both osteoblast and osteoclast activity due to excessive suppression of the parathyroid glands by medication (picture 2). This represents the major bone lesion in peritoneal dialysis and hemodialysis adult patients. (See "Adynamic bone disease associated with chronic kidney disease".)
●Osteomalacia – Osteomalacia is characterized by low bone mineralization (picture 3). 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 use of efficient techniques in water treatment for preparing dialysate. However, osteomalacia can still be seen in children who have inadequate intake of substrate (calcium and phosphate) or increased renal tubular losses. (See "Aluminum toxicity in chronic kidney disease".)
●Mixed uremic osteodystrophy – Mixed uremic osteodystrophy describes bone biopsy findings of both high bone turnover and a disproportionate decrease in mineralization resulting in increased osteoid (picture 4). As in osteitis fibrosa cystica, the high bone turnover is mediated by increases in both osteoblast and osteoclast activity. In contrast to osteitis fibrosa cystica, the marked decrease in mineralization suggests a concomitant mineralization defect.
DIAGNOSIS — 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, or parathyroid hormone) is detected during ongoing screening/monitoring of children with CKD stages 2 through 4.
●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
Bone biopsy is rarely performed clinically, but can confirm the diagnosis when there are changes consistent with renal osteodystrophy (ie, abnormalities of bone turnover and mineralization) (see 'Bone pathology' above). Indications for bone biopsy are not well established for children with CKD because it is not clear when a histological diagnosis of bone disease impacts clinical treatment decision making [3,25]. At our center, we do not perform bone biopsy to make the diagnosis of renal osteodystrophy. On the rare occasion when it is decided to perform a bone biopsy, we will refer the patient to a specialized center with particular expertise in preparing the subject and handling and interpreting the biopsy tissue. 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.
Guidelines from both Kidney Disease Outcome Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) suggest that bone biopsy may be useful to guide management decisions in children with stage G5 disease who have one or more of the following findings: persistent bone pain, nontraumatic fractures, or continued abnormal laboratory findings despite adequate routine therapeutic interventions.
SCREENING/MONITORING FOR CKD-MBD — Early detection of bone metabolic abnormalities ensures that therapeutic interventions can be initiated, thereby preventing or minimizing secondary hyperparathyroidism and its consequent effect on bone disease. Screening/monitoring of serum concentrations of calcium, phosphate, alkaline phosphatase (ALP), and parathyroid hormone (PTH) in all children with CKD should begin at CKD stage G2 (figure 1) [26,27].
Our approach — At our center, we begin to monitor serum calcium, phosphorus, PTH, total ALP, and 25-hydroxyvitamin D starting at CKD stage G2 with a schedule that is consistent with the Kidney Disease Outcome Quality Initiative (KDOQI) guidelines and the European Society for Paediatric Nephrology and the CKD-MBD working group of the European Renal Association–European Dialysis and Transplant Association [1,3,28]. If therapy is initiated to correct serum abnormalities or to treat renal osteodystrophy, the guidelines recommend that laboratory evaluation should be performed more frequently to ensure a response to therapy or to identify the need to adjust therapy :
•Calcium and phosphate measurements:
-Stage G2 – Measurements at least yearly
-Stage G3 – Measurements at least every six months
-Stage G4 – Measurements at least every three months
-Stage G5 – Measurements at least monthly
•PTH and ALP measurements:
-Stage G2 – Measurements at least yearly
-Stage G3 – Measurements at least every six months
-Stages G4 and 5 – Measurements at least every three months
•Serum 25-hydroxyvitamin D concentrations are measured yearly for children with CKD stages 2 to 4 (glomerular filtration rate [GFR] of 15 to 89 mL/min per 1.73 m2) with serum PTH values above the target range for the stage of CKD [1,27,29]. In our practice, if vitamin D therapy is initiated, serum 25-hydroxyvitamin D is measured every three months until normal serum 25-hydroxyvitamin D levels are achieved and then yearly afterwards.
We do not perform radiological assessment or measure 1,25-dihyroxyvitamin D or bone turnover markers, such as bone-specific ALP, osteocalcin, or C-telopeptide, on a routine basis.
Alternative screening protocols — Other guidelines have been published regarding monitoring for pediatric CKD-MBD, including:
●Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend monitoring of serum levels of calcium, phosphate, PTH, and ALP beginning in children with stage G2 disease; however, there is no information on the type and frequency of testing for children with stage G2 disease. There is specific information for monitoring in children with more advanced disease :
•Monitoring of calcium and phosphate measurements:
-Stage G3 – Measurements at least every 6 to 12 months
-Stage G4 – Measurements at least every 3 to 6 months
-Stage G5 – Measurements at least every 1 to 3 months
•Monitoring PTH measurements:
-Stage G3 – Measurements are based on the baseline level and CKD progression
-Stage G4 – Measurements at least every 6 to 12 months
-Stage G5 – Measurements at least every 3 to 6 months
•ALP is measured for patients with CKD stage G4 and G5 every 12 months or more frequently when PTH is elevated.
The guidelines suggest it is reasonable to increase the frequency of measurements for children who are being treated for CKD-MBD to monitor for efficacy and side effects or who have identified biochemical abnormalities.
●The European Paediatric Dialysis Working Group (EPDWG) guidelines recommend obtaining calcium, phosphorus, PTH, and ALP based on GFR as follows :
•Stage 3 (GFR 30 to 59 mL/min/1.73m2) – Measurement at least every six months
•Stage 4 (GFR 15 to 29 mL/min/1.73m2) – Measurement at least every three months
•Stage 5 (GFR <15 mL/min/1.73m2, or on dialysis) – Measurement at least monthly
In addition, subsequent ESPN CKD-MBD and Dialysis WG guidelines recommend serum 25-hydroxyvitamin D levels be obtained every 6 to 12 months in children with CKD stages 2 to 5 who are not on vitamin D therapy . For those who receive vitamin D therapy, it is recommended that serum 25-hydroxyvitamin D be measured three months after initiation of vitamin D therapy. If the serum 25-hydroxyvitamin D level is normal, levels should be measured every six months. If low, replacement therapy should be provided with a repeat 25-hydroxyvitamin D level obtained in three months.
Goals and approach — 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 too aggressive therapy (see 'Bone pathology' above). Secondary hyperparathyroidism is due to hyperplasia of the parathyroid glands caused by phosphate retention, 1,25 dihydroxy-vitamin D deficiency, hypocalcemia, and skeletal resistance to parathyroid hormone (PTH) action (see 'Phosphate retention and secondary hyperparathyroidism' 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').
The management and prevention of secondary hyperparathyroidism involves:
●Correction of phosphate retention by dietary phosphate restriction, usually in combination with a calcium-containing phosphate binder. (See 'Retention of phosphate and hyperphosphatemia' below.)
●In children with stages G2 to G4 disease (table 1), assess and replenish 25-hydroxyvitamin D (if the level is low) with oral ergocalciferol or cholecalciferol and maintain adequate calcium levels. For children with normal 25-hydroxyvitamin D levels and elevated PTH, an active vitamin D analogue (eg, calcitriol) is provided in place of ergocalciferol or cholecalciferol. (See 'Vitamin D deficiency' below.)
●In children with stage G5 disease, the combination of dietary phosphate restriction, phosphate binders, and an active vitamin D analogue 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 Outcome Quality Initiative (KDOQI), Kidney Disease: Improving Global Outcomes (KDIGO), and the European Society of Paediatric Nephrology (ESPN) CKD-MBD and Dialysis Working Group (ESPN CKD-MBD and Dialysis WG) [1,3,31].
PTH target goals — The serum parathyroid hormone (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 . The optimal serum PTH values in children with CKD is uncertain as a result of the insufficient upon which to generate definitive recommendations. Most experts including the authors follow the recommendations of the European CKD-MBD and Dialysis WG that the PTH should be maintained at a near normal level in children with Stage 2 to 5 CKD and at two to three times the upper limit of normal for those on dialysis [30,32]. Additional recommendations that exist have been published by KDOQI and KDIGO.
●The KDOQI guidelines recommend targeted levels of serum intact PTH at different stages of CKD as follows :
•Stages G2 and G3 – 35 to 70 pg/mL
•Stage G4 – 70 to 110 pg/mL
•Stage G5 – 200 to 300 pg/mL
●The KDIGO guidelines suggest :
•For patients on dialysis, PTH levels are maintained in the range of approximately two to nine times the upper normal limit.
•For patients with CKD not on dialysis, if PTH is progressively rising or is persistently above the upper limit of normal, the cause for the elevated value should be evaluated for modifiable factors, including hyperphosphatemia, hypocalcemia, high phosphate intake, and vitamin D deficiency.
Retention of phosphate and hyperphosphatemia — Phosphate is a salt of oxidized phosphoric acid and is a key component of bone matrix. As noted above, 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). Management is directed at preventing hyperphosphatemia and phosphate retention because of their critical role in the development of secondary hyperparathyroidism and vascular injury. (See 'Phosphate retention and secondary hyperparathyroidism' above and "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Phosphate retention and hyperphosphatemia'.)
Normal phosphate levels — Normally, the serum phosphorus concentration is highest in infants less than three months of age. As the child ages, the normal range of phosphorus values decreases:
●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)
Goals — In our center, and in accordance with the KDOQI Pediatric Nutrition guidelines and the recommendations from the Pediatric Renal Nutrition Taskforce and the European CKD-MBD and Dialysis WG, we target age-appropriate normal serum phosphate levels. This is in contrast to the slightly elevated levels recommended for patients with Stage G5 CKD in the KDOQI Pediatric Bone guidelines .
Pediatric Renal Nutrition Taskforce and the European CKD-MBD and Dialysis WG provide guidance for the dietary intake of calcium and phosphorus in children with CKD stages 2 to 5 and on dialysis (CKD 2 to 5D). They provide information on the common calcium- and phosphorus-containing foods, the 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 the dietary management of hypo- and hypercalcemia and hyperphosphatemia .
Interventions — In children with CKD, the two therapeutic interventions used to attain and maintain the targeted serum phosphate goal are dietary phosphorus restriction followed by the use of phosphate binders.
Dietary restriction — In controlled studies of both children and adults, dietary phosphate restriction results in decreased serum PTH level and increased serum 1,25-dihydroxyvitamin D concentrations [33,34] (see "Management of hyperphosphatemia in adults with chronic kidney disease"). Conversely, an intake of phosphate that is twice the Dietary Reference Intake (DRI) in children with CKD stage G3 increases serum PTH and decreases serum 1,25-dihydroxyvitamin D .
For children with CKD stages G3 to G5 and normal phosphate levels, dietary phosphate restriction is based on age and serum PTH levels and phosphate concentrations.
●If the serum PTH is above the target range and the serum phosphate concentration is normal, dietary phosphate is restricted to 100 percent of the DRI for age :
•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
●If the serum PTH is above the target range and the serum phosphate concentration is above the age-appropriate normal range, dietary phosphate is restricted to 80 percent of the DRI for age :
•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
After the initiation of dietary restriction, serum phosphate 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 phosphate restriction with poor linear growth [35-38]. However, serum phosphate concentrations below the target range for age should be avoided because of the potential adverse effects of hypophosphatemia on linear growth and bone mineralization.
Phosphate binders — Compliance with dietary phosphate restriction in children is poor, as most of their favorite foods are rich in phosphate. Thus, despite attempts to restrict phosphate intake, phosphate binders often become necessary to prevent phosphate absorption from the gastrointestinal tract. Phosphate binders are typically prescribed if the follow-up serum phosphate is above the target goal following institution of dietary restriction.
Choice of binders — In children, several observational studies have shown that calcium-based phosphate binders are effective and safe in lowering serum phosphate and PTH levels [39-41]. These agents are recommended as the initial phosphate binder in children with CKD because other agents have significant side effects (such as aluminum ) or have shown no increased benefit regarding calcium, phosphate, or PTH levels (such as sevelamer) [1,3,43]. The choice among the many different calcium-containing phosphate binders, such as calcium carbonate, calcium acetate, calcium gluconate, and calcium ketoglutarate, is in large part dependent upon the patient's tolerance of the binder and the choice of the clinician. Several studies in adults have not shown an overall advantage of one preparation over another . 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 'Phosphate binders'.)
However, calcium-based phosphate binders should not be used as the sole agent in patients who are hypercalcemic due to concerns of soft tissue calcifications (serum calcium >10.2 mg/dL [2.55 mmol/L]). In this setting, non-calcium binders, such as sevelamer, are preferred . In children, open-label studies have shown that sevelamer carbonate lowers serum phosphate better than placebo and is as effective as calcium acetate without serious adverse effects [45,46]. Sevelamer carbonate is also associated with an improvement in serum bicarbonate levels, such that sodium bicarbonate therapy could be discontinued. (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Phosphate binders'.)
The following phosphate binders should not be used in children with CKD:
●Aluminum hydroxide because of aluminum bone toxicity . Aluminum deposition can cause low bone turnover, leading to renal osteodystrophy (eg, adynamic bone disease and osteomalacia). Aluminum usage 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. The beneficial effect is less when taken between meals, since most dietary phosphate has already been absorbed.
Phosphate binders, regardless of the agent used, have a limited phosphate-binding capacity. As examples, 1 g of calcium carbonate binds 39 mg of phosphate, 1 g of calcium acetate binds 45 mg of phosphate, and 400 mg of sevelamer HCl binds 32 mg of phosphate. Thus, phosphate-binding compounds will be effective in lowering serum phosphate levels only if dietary phosphate restriction is continued.
Vitamin D deficiency
Overview — In children with CKD, the production of 1,25-dihydroxyvitamin D is impaired due to phosphate retention, low serum 25-hydroxyvitamin D, and increased serum FGF23 [26,47]. Phosphate retention and 1,25-dihydroxyvitamin D deficiency decrease serum calcium, which contribute directly to secondary hyperparathyroidism and renal osteodystrophy. As a result, vitamin D supplementation is usually required and the choice of formulation is based on clinical settings. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)" and 'Persistent hyperparathyroidism' below.)
In our center, initial treatment is focused on replenishing inadequate stores of 25-hydroxyvitamin D with vitamin D analogues such as ergocalciferol or cholecalciferol in children with stages G2 to G4 disease as needed. Active vitamin D analogues (eg, calcitriol) are provided to children with stage G5 disease with an elevated PTH and children with stage G2 to G4 disease, normal 25-hydroxyvitamin D level, and persistent elevation of PTH.
CKD stages G2 to G4 — Management is dependent on the concentration of 25-hydroxyvitamin D.
●Elevated PTH and 25-OH vitamin D deficiency – Deficiency of 25-hydroxyvitamin D 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 . For children with 25-hydroxyvitamin D deficiency, ergocalciferol or cholecalciferol is provided when the serum 25-hydroxyvitamin D is <30 ng/mL (<75 nmol/L), which concurs with the major society guidelines [1,29,31].
Although KDOQI recommends ergocalciferol, there is no difference in efficacy between ergocalciferol and cholecalciferol. Ergocalciferol is available as an 8000 units/mL preparation, which is helpful when using high doses in small children. We follow the KDOQI guidelines for the dose of vitamin D supplementation, which depends on serum 25-hydroxyvitamin D levels as follows:
•Vitamin D insufficiency, 16 to 30 ng/mL – 2000 international units/day for three months or 50,000 international units every month for three months.
•Vitamin D deficiency, 5 to 15 ng/mL – 4000 international units/day for three months or 50,000 international units every other week for three months.
•Severe vitamin D deficiency, <5 ng/mL – 8000 international units/day for four weeks then 4000 international units/day for two months for total therapy of three months. Alternatively, 50,000 international units/week for four weeks followed by 50,000 international units two times/month for a total therapy of three months.
●Elevated PTH and normal 25-OH vitamin D – Levels of 1,25-dihydroxyvitamin D (calcitriol) usually fall below normal when the glomerular filtration is <60 mL/min/1.73 m2. In this setting, an active vitamin D analogue (eg, calcitriol) is provided. Calcitriol is our preferred initial choice of active vitamin D therapy . In children, calcitriol has been reported in observational studies to decrease serum PTH concentrations and improve the linear growth of children with CKD [54,55]. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Decreased calcitriol activity'.)
Active vitamin D analogue (eg, calcitriol) is provided if all of the following criteria are met:
•Serum 25-hydroxyvitamin D is >30 ng/mL (>75 nmol/L)
•Serum PTH is above the target range
•Serum calcium level is <10.2 mg/dL (<2.37 mmol/L) 
•Serum phosphate level is less than the age-appropriate upper limits for the stage of CKD
Once active vitamin D therapy is started, serum calcium and phosphate concentrations should be measured after one month of therapy and every three months thereafter. Serum PTH should be measured at least every three months. The dose of calcitriol should be modified or held if hypercalcemia develops or the serum PTH falls below the target range for the stage of CKD. If hyperphosphatemia develops or persists, the dose should be decreased and phosphate binder usage and dietary phosphate restriction intensified.
CKD stage 5 — In children with CKD stage G5 (GFR <15 mL/min per 1.73 m2) and serum PTH >300 pg/mL, calcitriol should be administered to reduce the serum PTH. Although the optimal PTH target remains controversial, we generally target a PTH value that is two to three times the upper limit of normal in accordance with the recommendations of the European CKD-MBD and Dialysis WG and similar to the 100 to 300 pg/mL recommendation based on data from peritoneal dialysis patients in the International Pediatric Peritoneal Dialysis Network Registry [1,56-58].
In these patients, 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 adynamic bone disease.
Calcitriol — 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.
The use of calcitriol in patients with an elevation of serum calcium or phosphate can lead to soft tissue calcification due to an increase in the calcium phosphate product. The increased gastrointestinal absorption of calcium and phosphate 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'.)
More selective vitamin D analogues, such as alfacalcidol, paricalcitol [59,60], 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 [60,61], and there is no convincing evidence supporting the use of one specific vitamin D analogue over another. These analogues 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 be titrated based on trends of serum calcium, phosphate, and PTH levels to achieve target PTH concentrations and maintain a normal serum calcium level.
Calcium — The 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) based on the laboratory that is used .
Hypocalcemia — If appropriate therapy is not provided, hypocalcemia can result due to progressive loss of kidney function resulting in phosphate retention and 1,25-dihydroxyvitamin D deficiency. Symptomatic hypocalcemia should initially be treated with parenteral calcium chloride . 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) . (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 the use of calcium supplementation stopped . 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 — In children who continue to have persistent hyperparathyroidism despite being vitamin D replete and being compliant with their dietary phosphate restriction, phosphate binders and vitamin D analogue therapy; calcimimetic therapy should be considered. On rare occasions, parathyroidectomy may be indicated if all conventional therapy fails and/or when secondary hyperparathyroidism transitions into a tertiary hyperparathyroidism.
Calcimimetics — Calcimimetics (eg, cinacalcet) are being increasingly used to suppress PTH secretion and decrease the risk of hypercalcemia associated with calcitriol. These agents, which increase the sensitivity of the calcium-sensing receptor (CaSR) in the parathyroid gland to calcium, have undergone limited study in the pediatric population. The available data suggest that the use of calcimimetics in children with severe and/or refractory hyperparathyroidism is effective in reducing PTH levels [62-67]. The European Society for Pediatric Nephrology, Chronic Kidney Disease-Mineral and Bone Disorder and Dialysis Working Groups, and the ERA-EDTA has published a position statement for the use of cinacalcet in children on dialysis in whom secondary hyperparathyroidism is not adequately controlled with standard therapy . However, additional information is needed to ensure its safety, particularly, the risk of hypocalcemia, as well as efficacy.(See "Management of secondary hyperparathyroidism in adult dialysis patients", 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 5th to 6th 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 10th to 12th 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 topics (see "Patient education: Bone problems caused by kidney disease (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Introduction and definition ‒ 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). Both in children and adults, CKD-MBD is defined as 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
●Clinical manifestations ‒ Clinical manifestations of CKD-MBD vary based on the severity of CKD (table 1) and whether interventions to prevent MBD have been instituted.
•CKD-MBD is first be detected in children with stage G2 CKD based on abnormal laboratory levels of serum calcium, phosphorus, PTH, and 1,25 dihydroxyvitamin D.
•Untreated patients with more severe CKD (stages G3 through G5) become increasingly symptomatic with bone pain, difficulty in walking, and/or skeletal deformities such as varus and valgus deformities of the long bones. (See 'Clinical manifestations' above.)
●Bone pathology ‒ Renal osteodystrophy, one of the components of CKD-MBD, is defined as alterations in bone morphology associated with CKD based upon bone biopsy. It includes several different pathologic forms (osteitis fibrosa cystica, adynamic bone disease, osteomalacia, and mixed osteodystrophy). (See 'Bone pathology' above.)
●Diagnosis ‒ 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 (eg, calcium, phosphorus, or PTH) is detected during ongoing screening/monitoring of children with CKD stages G2 through G4. Bone biopsy is rarely performed clinically, but can confirm the diagnosis when there are changes consistent with renal osteodystrophy (ie, abnormalities of bone turnover and mineralization). (See 'Diagnosis' above.)
●Screening and monitoring ‒ Screening and monitoring of serum concentrations of calcium, phosphate, PTH and total alkaline phosphatase (ALP) should occur in all children with CKD beginning at CKD stage G2. For children with elevated PTH levels, serum hydroxyvitamin D concentrations are measured yearly. (See 'Screening/monitoring for CKD-MBD' 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 too aggressive therapy. Although data are insufficient to determine with certainty optimal PTH target goals for children with CKD, we target PTH levels for near normal levels for children with stage 2 to 5 CKD and two to three times the upper limit of normal for those on dialysis as recommended by the European CKD-MBD and Dialysis working group. (See 'Goals and approach' above.)
●Management approach ‒ Prevention and treatment of secondary hyperparathyroidism include the following:
•Prevention of phosphate retention and hyperphosphatemia
-Dietary restriction is the initial intervention. The degree of daily dietary phosphate is based on the age of the child and serum PTH and phosphate concentration. (See 'Dietary restriction' above.)
For patients in whom dietary restriction is not sufficient, we suggest the administration of calcium-based phosphate binders such as calcium carbonate, calcium acetate, calcium gluconate, and calcium ketoglutarate (Grade 2C). The choice of phosphate binder is dependent upon the patient's tolerance of the binder and the preference of the clinician. For patients who are hypercalcemic, the preferred agent is sevelamer. Significant adverse effects are associated with calcium citrate, aluminum hydroxide, and magnesium-containing antacids, and these agents should not be used in children with CKD. (See 'Phosphate binders' above.)
•Provision of adequate vitamin D therapy
-In children with CKD stages G2 to G4 with an elevated PTH level and a 25-hydroxyvitamin D level is <30 ng/mL (<75 nmol/L), we suggest that ergocalciferol or cholecalciferol be given (Grade 2C). (See 'CKD stages G2 to G4' above.)
-In children with CKD stages G2 to G4 with an elevated PTH level and a 25-hydroxyvitamin D level >30 ng/mL (>75 nmol/L) and the serum calcium level is <10.2 mg/dL (2.37 mmol/L), we suggest calcitriol therapy (Grade 2C). (See 'CKD stages G2 to G4' above.)
-In children with CKD stage 5 and elevated PTH levels, we suggest that calcitriol should be administered until serum PTH is reduced to a range between two to three times the upper limit of normal (Grade 2C). However, the optimal target PTH range remains controversial. (See 'CKD stage 5' above.)
•Maintenance of normal calcium ‒ Serum calcium should be maintained within an age-appropriate normal range for the laboratory used, generally between 8.8 and 9.7 mg/dL (2.2 to 2.37 mmol/L). If the patient is hypocalcemic, calcium supplementation is provided. (See 'Hypocalcemia' above.)
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