Chronic kidney disease mineral and bone disorder in children

Traditionally, renal osteodystrophy has been classified primarily on alterations in bone turnover. The primary lesion of renal osteodystrophy in children is one of high bone turnover, also termed “secondary hyperparathyroidism”. Long-term exposure to high serum PTH levels often leads to fibrous changes in bones; this lesion is termed “osteitis fibrosa cystica”. Since PTH activates the PTH/parathyroid hormone-related protein (PTHrP) receptor on osteocytes and osteoblasts, increasing cellular activity of both osteoblasts and osteoclasts [21, 22], excessive levels of circulating PTH result in increased bone turnover [23]. Increased bone turnover (secondary hyperparathyroidism) is evident in patients with early and advanced stages of CKD and is nearly universal in untreated children at the initiation of dialysis [24]. This condition is marked by increased numbers of osteoblasts and osteoclasts. Due to excess osteoclastic activity, increased resorption of mineral and matrix along trabecular surfaces and haversian canals is evident. Osteitis fibrosa cystica, the advanced lesion of secondary hyperparathyroidism, is also associated with peritrabecular fibrosis [25].

A state of low-turnover bone disease (adynamic renal osteodystrophy) also occurs in children treated with maintenance dialysis, although it has not been demonstrated in adults or children with earlier stages of CKD [26]. Adynamic bone results from over-suppression of serum PTH, due to excess treatment with vitamin D and calcium salts and is characterized by normal osteoid volume, an absence of fibrosis, and a reduced bone formation rate, as indicated by reduced or absent double tetracycline label on bone histology [27, 28]. A paucity of osteoblasts and osteoclasts is present [23]. Adynamic bone has also been associated with low alkaline phosphatase levels, high serum calcium levels, and a propensity for increased vascular calcification [29, 30]. In addition to the increased risk of fractures that is observed in adults with adyamic bone, adynamic bone in children treated with dialysis is associated with an increased severity of growth retardation [31, 32].

Alterations in skeletal mineralization are also prevalent in children with CKD [33]. Increases in unmineralized bone (osteoid), in conjunction with delayed rates of mineral deposition, are common [25, 33]. Defective mineralization that is associated with high-turnover bone disease is termed “mixed lesion”; when associated with low-to-normal bone turnover, it is referred to as “osteomalacia” [1]. While the implications of defective mineralization remain to be established, increased fracture rates, bone deformities, and growth retardation are prevalent in patients with CKD and may be due, in part, to altered mineralization.

Since PTH is an anabolic steroid at the level of trabecular bone, high levels of serum PTH are typically associated with increases in bone volume, trabecular volume, and trabecular width [20, 33‐35]. Thus, children with CKD typically have normal or high bone volume as assessed by bone histomorphometry. Those treated with corticosteroids, however, may display loss of bone volume, termed “osteoporosis”. The impact of osteoporosis in childhood may not always be immediately apparent; however, sub-optimal peak bone mass accretion in adolescence is associated with an increased risk of osteoporosis, hip fractures, and mortality in adulthood [36].

Growth retardation is the hallmark of CKD in children. Protein and calorie malnutrition, metabolic acidosis, end-organ growth hormone resistance, and renal bone disease are the factors most commonly implicated in growth failure [37]. Despite correction of acidosis and anemia, normalization of serum calcium and phosphorus levels, and vitamin D sterol therapy replacement, the majority of children with CKD continue to grow poorly. Growth failure worsens as renal function declines; the average height of children with even mild CKD [glomerular filtration rate (GFR) 50–70 ml/min per 1.73 m² body surface area] is 1 standard deviation score (SDS) below the average for healthy children. Moderate CKD (GFR 25–49 ml/min per 1.73 m²) is associated with a height SDS of −1.5, and, at the time of initiation of dialysis, the mean height SDS is −1.8 [38].

Secondary hyperparathyroidism contributes to growth retardation, although optimal target values for PTH in children in all stages of CKD remain controversial. In children with moderate CKD, some data indicate that normal growth velocity is achieved when PTH levels are maintained within the normal range [39], while others have demonstrated a linear correlation between growth and PTH levels in the same patient population, those with the highest PTH values maintaining the highest rates of growth [40]. In children treated with maintenance dialysis, adynamic bone disease and growth failure have been associated with PTH levels around 100 pg/ml (1st generation assay), causing many experts to recommend target PTH levels 3–5 times the normal range in advanced CKD [32]. Data from the European community, however, have demonstrated that optimal growth velocity in this population may be associated with PTH levels of 2–3 times the normal range [41]. As a result, optimal PTH targets remain controversial, and recommendations vary between experts (Table 1).

Alterations in the growth hormone/insulin-like growth factor (IGF) pathway axis and their receptors also contribute to growth retardation. Despite normal or elevated circulating levels of growth hormone, decreased growth hormone receptor expression results in end-organ resistance. Furthermore, increased levels of IGF binding proteins, in the presence of normal IGF1 levels, result in decreased bioactivity of IGF1 [42‐44].

Bone deformities are also common in uremic children, due to altered skeletal remodeling. Epiphyseal widening, particularly around wrists, ankles, and the costochondral junctions (rachitic rosary), is common in infants. Slipped epiphyses, genu valgum, and femoral and wrist deformities are most common in pre-adolescent children with long-standing CKD [24, 45]. Avascular necrosis of the femoral head and pathologic fractures of the extremities and chest wall due to osteoporosis and bone deformities may occur with minimal trauma. In addition, vertebral crush fractures contribute to significant morbidity in this population. The initial management of skeletal deformities requires the normalization of serum calcium, phosphorus, and PTH levels. Surgical correction is often also necessary but should be performed only after correction of biochemical abnormalities [18].

Serum calcium and phosphorus levels remain stable in mild-to-moderate stages of CKD. As renal failure advances, however, serum calcium levels drop in response to decreased intestinal calcium absorption resulting from low circulating levels of 1,25(OH)₂D₃ [2]. Treatment with active vitamin D sterols and phosphate binders corrects hypocalcemia, and, in stage 5 CKD, hypercalcemia may develop in response to aggressive treatment with high doses of vitamin D sterols and calcium-based phosphate binders. In this context, increased serum calcium, in conjunction with low levels of PTH and alkaline phosphatase, may signal the development of adynamic bone [32]. Adjustment of vitamin D dosage and the use of non-calcium-containing phosphate binders can prevent the development of this complication as well as its associated growth failure [32]. Avoidance of increased serum calcium levels, which are associated with an increased risk of mortality in large populations of adult dialysis patients, also may prevent the progression of cardiovascular calcification (vide infra) [46, 47].

Similar to those of serum calcium, serum phosphorus levels remain within the normal range until CKD stages 4 to 5 are reached, when decreased GFR limits urinary phosphate excretion. Serum PTH levels rise but fail to compensate for phosphorus retention [2]. In stage 5 CKD, traditional hemodialysis or peritoneal dialysis typically removes less than half of ingested phosphate, necessitating the use of phosphate binders to control serum phosphorus and PTH levels. Since elevated values for the serum calcium × phosphorus product have been associated with vascular calcification and increased rates of mortality [48‐50], maintaining serum calcium and phosphorus levels within the normal range is important for optimizing cardiovascular health in all stages of CKD (vide infra) [18].

Serum alkaline phosphatase values are fair markers of osteoblastic activity in children with CKD. Osteoblasts normally express large amounts of the bone isoenzyme of alkaline phosphatase, and elevated serum levels correlate with increased bone formation, high levels of serum PTH, and growth hormone therapy [51]. Since alkaline phosphatase is also present in the liver, elevated serum levels of total alkaline phosphatase may not always indicate increased bone turnover. Measurement of the heat-stabile and heat-labile fractions may help to separate skeletal from hepatic causes of elevated levels. Alkaline phosphatase measurements are useful in monitoring the skeletal response to treatment with vitamin D sterols in patients with osteitis fibrosa; values that decrease over several months usually indicate histologic improvement [52]. However, consistently low serum alkaline phosphatase values, particularly in children with stage 5 CKD receiving large doses of vitamin D sterols and calcium-containing phosphate binders, are consistent with adynamic bone [32].

Serum PTH levels are widely used as non-invasive markers in distinguishing low-turnover lesions from osteitis fibrosa [33, 53]. Current recommendations for target PTH levels are based on measurements obtained by the 1st generation PTH assay in cross-sectional bone biopsy data from children treated with maintenance dialysis and receiving either low-dose oral calcitriol or no vitamin D sterol therapy. Since the 1st generation assays measure both full-length molecule and amino-terminally truncated fragments, 2nd generation PTH assays have been developed which measure, exclusively, the full-length molecule (“PTH(1–84)”). Although some data suggest improved ability of the newer 2nd generation assays to predict low-turnover bone disease [54], this finding has not been substantiated by others [34, 55].

Increasing skeletal resistance to the actions of PTH requires that PTH be maintained at higher levels in advanced stages of CKD [56‐58] (Table 1). Downregulation of the PTH receptor, decreased expression of osteoblast differentiation factor, and increased levels of osteoclastogenesis inhibitory factor occur with decreased renal function, contributing to the skeletal resistance to PTH [57, 59]. In patients with mild to moderate CKD, PTH levels that are within the normal range generally correspond to normal rates of bone formation, while mildly increased levels suggest the presence of secondary hyperparathyroidism [26]. In patients undergoing maintenance dialysis who are either untreated or are receiving small daily oral doses of calcitriol, PTH(7–84) levels of approximately two to five times the upper limit of normal generally correspond to normal bone formation rates [26, 33, 41, 53, 60]. Over-suppression of PTH in patients on dialysis has also been shown to result in growth failure, hypercalcemia, and adynamic bone [32]. In summary, PTH levels should be maintained in the range appropriate to the stage of CKD; levels appropriate for early stages of CKD would indicate low-turnover disease in patients treated with dialysis, while appropriate levels for stage 4 CKD represent osteitis fibrosa in mild CKD.

Careful attention to 25(OH) vitamin D (native vitamin D) nutrition is also fundamental to the optimal management of renal osteodystrophy [18]. Native vitamin D deficiency is prevalent in all children, including those with normal renal function [61], and the presence of renal insufficiency exacerbates this deficiency. Currently, therapeutic native vitamin D is available in two forms: vitamin D₂ (ergocalciferol) is obtained from plants and vitamin D₃ (cholecalciferol) is obtained from animal sources. Repletion of vitamin D stores has been shown to increase calcitriol production, ameliorate secondary hyperparathyroidism [62, 63], and heal lesions of poor mineralization in patients with CKD stages 2 through 4 [64]. Thus, assessment and repletion of native vitamin D stores are recommended in this population [18]. Of note, current dosage recommendations for native vitamin D repletion are similar to doses recommended for the treatment of nutritional rickets and far exceed recommendations for routine daily intake (Table 2).

FGF-23 is a newly described phosphaturic hormone associated with renal phosphate wasting [65], low serum 1,25(OH)₂D₃ levels, and osteomalacia in animals and humans with normal kidney function [66‐68]. Levels increase as kidney disease progresses and are markedly elevated in patients treated with maintenance dialysis [16]. Current data indicate that increased levels correlate with calcitriol deficiency in adults with CKD stages 2 to 4 [17], that dietary phosphorus regulates serum levels of FGF-23 [69, 70], and that the administration of vitamin D sterols increases levels [71]. Furthermore, elevated pre-treatment values of serum FGF-23 may predict resistance of the parathyroid glands to therapy with vitamin D sterols [72, 73]. These findings implicate a role for FGF-23 in the control of serum phosphorus and vitamin D metabolism, as well as in the pathogenesis of secondary hyperparathyroidism.

A schematic representation of the interplay between PTH, FGF-23, and calcitriol is depicted in Fig. 1.

As a result of phosphorus retention in CKD stages 4 and 5 [91], patients with advanced CKD and those undergoing treatment with traditional maintenance dialysis regimens—thrice-weekly hemodialysis or nightly peritoneal dialysis—often require dietary phosphate restriction as well as treatment with phosphate-binding agents. Serum phosphorus levels should be maintained within the appropriate range for age and, due to increased rates of growth, infants and young children must maintain higher levels of serum phosphorus than older children. Calcium-containing salts have been recommended as the mainstay in phosphorus binding therapy in CKD stages 3 through 5. While several calcium salts are widely used, including calcium carbonate, calcium acetate, and calcium citrate, calcium carbonate is currently the most commonly used compound [27, 92, 93]. In recent years, however, increasing concern about the progressive vascular calcifications associated with a positive calcium balance and hypercalcemia has led to the development of non-calcium-containing phosphate binders. Current recommendations suggest that total calcium intake from calcium-based phosphate binders should not exceed twice the recommended daily recommended intake (DRI) for dietary calcium. Elevated serum calcium levels (greater than 10.2 mg/dl) should be treated by the withdrawal of calcium-based phosphate binder therapy and, if persistent, by the discontinuation of active vitamin D sterols [18].

To avoid excess calcium intake, a metal-free calcium-free phosphate binder, sevelamer hydrochloride (sevelamer HCl, RenaGel) was developed. Although sevelamer is not yet approved for use in children, it has been shown in prospective trials to lower serum phosphorus levels effectively and control the skeletal lesions of secondary hyperparathyroidism without increasing serum calcium levels in children treated with dialysis [35, 46, 47, 94‐96]. Use of sevelamer HCl has also been shown to halt the progression of vascular calcification in patients on dialysis, in contrast to the worsening cardiovascular disease associated with long-term calcium-based binder therapy [47, 94]. Lower mortality rates have also been associated with the use of sevelamer over calcium [97].

Lanthanum carbonate is a non-calcium-containing, but metal-containing (lanthanum), phosphorus binding agent. Several studies have demonstrated that lanthanum carbonate effectively reduces serum phosphorous levels, and there are fewer hypercalcemic episodes than with calcium carbonate [98‐100]. However, plasma lanthanum levels increase over time. Although levels return to baseline after withdrawal of the drug, bone lanthanum content increases during therapy and remains elevated at least a year after discontinuation of treatment [101]. Further evidence from experiments on rodents indicates progressive liver, bone, and growth plate accumulation [102]. Thus, although lanthanum carbonate is an effective phosphate binder, long-term therapy results in its accumulation in a number of tissues, the long term consequences of which have yet to be defined [103].

In select patient populations and dialysis centers which are able to perform daily hemodialysis, the use of phosphate binding medications may be decreased or entirely avoided. Daily hemodialysis has been demonstrated to normalize serum phosphate levels in these patients, leading to improved nutrition, improved growth, and decreased phosphate binder usage [104, 105].

25(OH) vitamin D deficiency is common in children with CKD, and assessment and repletion is recommended for all children in stages 2 to 4 CKD with secondary hyperparathyroidism. After repletion of native vitamin D stores, therapy with active vitamin D sterols is effective in suppressing PTH levels to the target range for the stage of CKD. Vitamin D sterols suppress PTH levels by two mechanisms: indirectly, through increased intestinal calcium absorption, and directly, via suppression of PTH gene transcription. Calcitriol and alfacalcidol are widely used in children, have been shown to be effective in suppressing PTH when given in daily or intermittent doses, and improve growth in children with CKD [39, 40]. However, hypercalcemia has been linked to their administration, particularly when given with calcium-containing phosphate binders. Thus, newer vitamin D analogues have been developed to maximize affinity for parathyroid tissue, while minimizing effects on intestinal calcium and phosphorus absorption. Three new vitamin D analogues are available for use in patients with CKD: 22-oxacalcitriol (OCT) in Japan, as well as 19-nor-1,25-dihydroxyvitamin D₂ (paricalcitol) and 1α-hydroxyvitamin D₂ (doxercalciferol) in the USA. Oral forms of paricalcitol and doxercalciferol have been approved for CKD 3 through 5 in adults, though not yet in children. Doxercalciferol and paricalcitol are effective in lowering PTH levels and may have a lower calcemic potential than calcitriol in both adults and children with CKD [35, 106].

Calcimimetic agents, which act as allosteric activators of the calcium sensing receptor (CaSR), are also available for the treatment of secondary hyperparathyroidism in the adult dialysis population. By increasing the sensitivity of the CaSR, these small organic molecules are able to reduce PTH levels, decrease the calcium–phosphorus product, and may provide a medical means of halting the progression of parathyroid gland hyperplasia [107]. Cinacalcet has been shown to be effective in the control of secondary hyperparathyroidism in adults with CKD [108], in those treated with maintenance dialysis [109‐112], and in those with functioning renal allografts [113]. These agents have not been approved for use in children, and, due to the presence of the CaSR on the growth plate [114], studies are required to confirm their safety and efficacy in young patients.

Despite correction of acidosis and optimization of nutrition, many children with CKD continue to grow poorly. Recombinant growth hormone therapy may be indicated in those whose height is below the 5th percentile for age and who have open epiphyseal plates. Skeletal X-rays to evaluate bone age are indicated prior to initiation of hormone therapy. Skeletal deformities, such as active rickets or slipped capital femoral epiphyses, should be allowed to heal prior to initiation of therapy. Furthermore, since growth hormone therapy may worsen secondary hyperparathyroidism, serum PTH levels must be well controlled prior to start of therapy and should be routinely monitored during treatment. Of note, the clinical response to recombinant growth hormone differs according to stage of CKD, children with stage 5 CKD displaying a less robust growth response than those with less severe kidney disease [115, 116]. Thus, many factors, including growth potential, degree of kidney failure, optimal dialysis prescription [105], concomitant morbidities, and control of renal osteodystrophy, should be considered prior to the initiation of growth hormone therapy.

Since cardiovascular disease is the leading cause of death in both adults and children with CKD, the prevention of cardiovascular disease progression is crucial in the management of the CKD-MBD. The etiology of vascular disease in CKD is multifactorial and includes traditional risk factors, such as hyperlipidemia, hypertension, and inflammation, as well as alterations in mineral metabolism specific to CKD; thus, treatment is also multifaceted. Lipid lowering agents are effective in reducing cardiac mortality in adults with CKD [117] and in those with stable renal allografts [118], although no benefit from their use has been established in patients treated with maintenance dialysis [119]. Normalization of mineral metabolism, by the avoidance of PTH over-suppression, avoidance of hypercalcemia, and the maintenance of normal serum phosphorus and the overall calcium × phosphorus product, is essential in all patients with CKD [18]. The limiting of total calcium intake to less than twice the DRI for age, in conjunction with the routine monitoring of biochemical parameters and adjustment of both phosphate binder and vitamin D sterol therapy, is recommended to prevent progressive vascular disease. Evaluation of vascular calcifications in children may be performed by ultrasound of carotid intimal–medial wall thickness [120]. The methodology for coronary electron beam computed tomography (EBCT) and the value of echocardiogram or abdominal X-rays [121], useful in the adult population, have not been well established in children.