Pediatr Nephrol (2018) 33:1475–1488
DOI 10.1007/s00467-017-3788-z
EDUCATIONAL REVIEW
Hypercalcemia: a consultant’s approach
Ari Auron 1 & Uri S. Alon 1
Received: 14 February 2017 / Revised: 24 July 2017 / Accepted: 11 August 2017 / Published online: 6 September 2017
# IPNA 2017
Abstract Due to their daily involvement in mineral metabo-
lism, nephrologists are often asked to consult on children with
hypercalcemia. This might become even more pertinent when
the hypercalcemia is associated with acute kidney injury and/
or hypercalciuria and renal calcifications. The best way to
assess the severity of hypercalcemia is by measurement of
plasma ionized calcium, and if not available by adjusting se-
rum total calcium to albumin concentration. The differential
diagnosis of the possible etiologies of the disturbance in the
mineral homeostasis starts with the assessment of serum para-
thyroid hormone concentration, followed by that of vitamin D
metabolites in search of both genetic and acquired etiologies.
Several tools are available to acutely treat hypercalcemia with
the current main components being fluids, loop diuretics, and
antiresorptive agents. This review will address the pathophys-
iologic mechanisms, clinical manifestations, and treatment
modalities involved in hypercalcemia.
Keywords Acute kidney injury . Parathyroid hormone .
PTH-related peptide . Vitamin D . Calcitriol .
Bisphosphonates
Introduction
Of total body calcium, 98–99% resides in the skeleton and the
other 1–2% is present in the extracellular and intracellular
* Uri S. Alon
ualon@cmh.edu
1
Bone and Mineral Disorders Clinic, Division of Pediatric
Nephrology, Children’s Mercy Hospital, University of Missouri at
Kansas City School of Medicine, 2401 Gillham Road, Kansas
City, MO 64108, USA
compartments. Of circulating calcium, 45% is bound to pro-
tein (mainly albumin) and the other 55% is regarded as
Bultrafiltrable^ [1]. The latter is obtained by applying pressure
on serum against a semipermeable membrane, and is further
divided between 10% complex calcium (bound to anions like
phosphate, bicarbonate, and citrate) and 45% free (ionized)
calcium, which is the fraction of this mineral participating in
various crucial physiologic processes.
Serum calcium concentration is usually reported as total
calcium. This fact requires further attention, as total calcium
is never a reflection of ionized calcium concentration. The
major factor affecting total calcium concentration is serum
albumin. A change in serum albumin concentration by 1 g/dl
will change total serum calcium by 0.8 mg/dl. A typical ex-
ample is the child with early nephrotic syndrome with low
serum albumin and low serum total calcium, at a time when
serum ionized calcium concentration is normal. On the other
hand, Bpseudo-hypercalcemia^ is seen in the face of high se-
rum albumin concentration.
Assuming average serum albumin concentration of 4.0 g/
dl, the equation to calculate Bcorrected^ serum calcium is:
Corrected calcium (mg/dl) = measured total calcium (mg/
dl) + [4.0 – serum albumin (g/dl)] × 0.8.
A factor that will shift calcium from being protein-bound to
a free one is blood pH. Increase or decrease by 0.1 pH in-
creases or decreases protein-bound calcium by 0.12 mg/dl,
respectively. Thus in an individual with normal total serum
calcium concentration, metabolic acidosis may lead to ionized
hypercalcemia, whereas metabolic alkalosis to ionized hypo-
calcemia. An example of the latter is the patient with anxiety-
induced hyperventilation, respiratory alkalosis, and conse-
quently tetany, namely at the time total serum calcium is nor-
mal, ionized calcium concentration is low. Another reason for
low serum ionized calcium is when concentrations of com-
plexed calcium are high as it happens when high doses of
1476
phosphate or citrate are introduced. The former can be seen in
patients with hypophosphatemia treated with intermittent high
oral doses of phosphate and the latter is typically seen in
patients receiving large quantities of blood transfusions anti-
coagulated with citrate, as happens during liver transplant op-
erations. It is thus evident that the best way to assess physio-
logically relevant serum calcium concentration is by directly
measuring the ionized fraction. As this is not always available,
one can still use total calcium for clinical purposes taking into
account the above considerations.
Hypercalcemia is defined as serum ionized calcium con-
centration above 1.4 mmol/l (5.6 mg/dl) or total calcium con-
centration higher than 10.6 mg/dl, with possible variations
among laboratories. Hypercalcemia is usually mild and
asymptomatic, but at times can be severe with potential seri-
ous manifestations, as detailed below.
Physiology of calcium homeostasis
and pathophysiology of hypercalcemia
Calcium homeostasis is tightly regulated by the interplay of
three processes: absorption from the small intestine and renal
tubular reabsorption, bone remodeling, and disposal through
the gut and the kidney [2–4]. These processes are regulated by
local and circulating factors. The two main hormones
influencing the homeostasis of calcium are PTH and calcitriol.
Additional factors include phosphate, 25(OH)-vitamin D, cal-
citonin, calcium sensing receptor (CaSR), fibroblast growth
factor 23 (FGF-23); PTH related peptide (PTHrP), and weight
bearing [2].
Parathyroid hormone
Serum-ionized calcium concentration is tightly maintained
within a very narrow range and its regulation is conducted
by PTH [5]. This is governed by a sigmoid curve in which a
small change in serum-ionized calcium concentration instant-
ly results in a change in serum PTH. This is executed through
binding of serum-ionized calcium to the calcium-sensing re-
ceptor (CaSR, vide infra), which regulates the release of PTH;
high serum calcium will suppress its secretion and vice versa.
PTH actions are mediated by binding to the PTH receptor in
bone and kidney. When activated in bone, PTH receptor indi-
rectly increases osteoclast activity, which causes bone resorp-
tion and release of calcium to the circulation. In the kidney,
PTH increases reabsorption of calcium in the distal tubules
and stimulates 1-alpha hydroxylation of 25(OH)-vitamin D
to 1,25(OH)2-vitamin D in the proximal renal tubules, which
in turn increases calcium absorption from the gut (vide infra).
Overall, the role of PTH is to Brecruit calcium^ from all pos-
sible sources. In addition, in order to prevent the creation of
too high serum Ca X P product, due to phosphate released
Pediatr Nephrol (2018) 33:1475–1488
from bone together with calcium, PTH activity decreases
proximal tubular phosphate reabsorption by reducing NPT2a
and NPT2c expression. Thus, over-activity of the gland in the
patient with normal kidney function results in high serum
calcium and low phosphate, but in the face of renal failure,
serum phosphate is high due to the inability of the kidneys to
eliminate it. Besides the effect of calcium, PTH secretion is
affected by serum magnesium, calcitriol, FGF-23, and possi-
bly serum phosphate, although the search for a Bphosphate-
sensing-receptor^ is still elusive.
Calcitriol
Vitamin D undergoes hydroxylation by a 25 hydroxylase in
the liver, which leads to formation of 25(OH)-vitamin D
(Fig. 1). The activity of the liver enzyme is poorly regulated
and serum 25(OH)-vitamin D level indicates the status of
body stores of the vitamin. A second hydroxylation by 1-
alpha hydroxylase in the kidney (CYP27B1) converts it to
1,25(OH)2 -vitamin D (calcitriol), which is the active hor-
mone. Although the kidney is the major source of circulating
1,25(OH)2-vitamin D, it can be produced by extra-renal cells
like monocytes/macrophages, skin cells, and placenta cells
[5]. The renal production of 1,25(OH)2-vitamin D is stimulat-
ed by low serum calcium and phosphate, and high PTH, and
suppressed by FGF-23 and by 1,25(OH)2-vitamin D itself.
The latter two, as well as serum calcium, stimulate 24-
hydroxylase enzyme (CYP24A1). Its activity catabolizes
25(OH)D to 24,25 (OH)2D and 1,25(OH)2D to
1,24,25(OH)3D [6, 7]. Both 24 metabolites are regarded as
inert.
Calcitriol promotes calcium and phosphate absorption
from the intestine, and possibly increases calcium reabsorp-
tion in the distal renal tubule, both actions contributing to bone
mineralization by maintaining serum minerals at their optimal
levels. However, when dietary calcium intake or serum calci-
um is low, the calcitriol interacts with the vitamin D receptor
in osteoblasts to induce the expression of the plasma mem-
brane protein receptor activator of factor k beta ligand
(RANKL), which binds to RANK on osteoclast precursors,
causing their differentiation to mature osteoclasts, which in
turn cause bone resorption and release of calcium into the
circulation. Thus, in cases of hypocalcemia, calcitriol acts on
bone like PTH, namely increasing bone resorption to maintain
serum calcium. Calcitriol suppresses PTH secretion and stim-
ulates FGF-23 production. Calcitriol levels are low during
hyperphosphatemia because of reduced activity of 1-alpha
hydroxylase, which is mediated by phosphate-induced in-
crease in circulating FGF-23. On the other hand,
hypophosphatemia leads to increased calcitriol production
[2, 5]. In cases of excessive calcitriol production or decreased
degradation, resulting in elevated blood calcitriol levels, hy-
percalcemia will develop.
Pediatr Nephrol (2018) 33:1475–1488
Fig. 1 Principles of vitamin D
metabolism
Calcium sensing receptor
The CaSR, a G protein coupled receptor is expressed in the
cells of organs that participate in calcium homeostasis such as
parathyroid, kidney, osteoblasts, and intestinal cells. The
CaSR is the main regulator of PTH secretion. When calcium
binds to the extracellular domain, it induces a conformational
change in the intracellular domain, resulting in second mes-
senger signaling, which reduces PTH production and secre-
tion. Thus, the receptor serves to apply negative feedback in
which hypercalcemia suppresses PTH release, and vice versa.
Serum magnesium has a similar effect but its potency is about
one-third that of calcium. Interestingly though, profound hy-
pomagnesemia can be associated with hypoparathyroidism
and hypocalcemia due to a yet unknown mechanism. In the
thick ascending limb of the loop of Henle (TAL), the CaSR is
present in the basolateral side and its activation leads to sup-
pression of the Na-K-2Cl symporter (SLC12A1). Its activa-
tion results in decreased sodium reabsorption, and coupled
with that decreased calcium reabsorption, leading to hypercal-
ciuria. A genetic mutation leading to loss of function of the
CaSR (discussed later) will result in hypercalcemia and
hypocalciuria [2, 8, 9].
PTH-related peptide (PTHrP)
The PTHrP is produced by a variety of tissues and acts in
paracrine and autocrine manners to control local tissue calci-
um concentration. PTHrP has a role in calcium homeostasis
during fetal life and is involved in placental calcium transport
and fetal chondrocyte maturation. PTHrP may also have some
role in mobilizing calcium from maternal bone during lacta-
tion. The PTHrP is homologous in configuration to the PTH
and acts on the same type I PTH/PTHrP receptor. Having a
PTH-like effect induces osteoclastic activity and increases
bone resorption, production of calcitriol, and renal
1477
reabsorption of calcium. Its main clinical significance is as a
mediator of humoral hypercalcemia of malignancy as
discussed below [10–12].
Calcitonin
This is an endogenous polypeptide secreted by the
parafollicular C cells of the thyroid gland. Its secretion is stim-
ulated by hypercalcemia and it opposes many of the effects of
PTH. By inhibiting osteoclastic activity its final effect is of
deposition of calcium in bone [1, 13].
Serum phosphate and fibroblast growth factor 23
(FGF-23)
Hypophosphatemia, indirectly can cause hypercalcemia, by
stimulating 1,25(OH)2-vitamin D production either directly
or via a decrease in FGF-23 production. A lower level of
FGF-23 will result in increased 1-alpha-hydroxylase and de-
creased 24-hydroxylase activities [3, 11].
Weight bearing
Loss of weight bearing almost instantaneously results in
increased osteoclasts and decreased osteoblasts activity
leading to bone demineralization and release of calcium into
the circulation. Besides in non-ambulatory patients, this
phenomenon may become a problem in astronauts who con-
sequently are at risk for development of kidney stones due
to the ensuing hypercalciuria [14]. Indeed most patients will
first develop hypercalciuria and if the kidneys are able to
clear the calcium released from bone they will stay
normocalcemic, but if the released quantity of calcium sur-
passes the kidneys’ ability to excrete it, the patient will de-
velop hypercalcemia. Of note, the above scenario is true for
the newly bedridden patient. In chronic immobilization,
1478
once a new steady state of osteopenia occurs, the patients
may exhibit none of the above perturbations.
As will be detailed later, one can look at hypercalcemia as
either caused by excess PTH activity or from influx of calcium
into the circulation from other reasons, in which case serum
PTH will be suppressed (Fig. 2). In most patients, the hyper-
calcemia is due to excessive osteoclastic activity. Cytokines
such as TNF alpha, IL-1, and IL-6 stimulate the osteoclast
directly. PTH and other osteoclast-stimulating factors interact
with receptors on osteoblasts to increase the expression of
RANKL and to decrease production of osteoprotegerin, which
is a circulating decoy receptor for RANKL. RANKL stimu-
lates activation, migration, differentiation, and fusion of he-
matopoietic cells of the osteoclast lineage to stimulate bone
resorption [15]. In other cases, hypercalcemia can be due to
high levels of vitamin D causing increased intestinal absorp-
tion of the mineral. Less commonly, decreased renal tubular
reabsorption may result in higher serum calcium levels.
Clinical manifestations of hypercalcemia
The clinical features can be nonspecific and hypercalcemia is
often discovered during routine blood work. The symptoms
and signs of hypercalcemia are detailed in Table 1, and to
some degree may go along with the degree of its severity, as
follows:
a) Mild: serum calcium < 12.0 mg/dl. Usually carries
asymptomatic presentation.
b) Moderate: serum calcium 12.0–14.0 mg/dl. The presen-
tation may include fatigue, malaise, anorexia, impaired
mental concentration ability, constipation, polyuria,
polydipsia.
c) Severe: serum calcium > 14.0 mg/dl. The presentation
may include, in addition to the above, nausea, vomiting,
dehydration, pancreatitis, peptic ulcers, arrhythmias, car-
diac arrest, impaired mental capacity, stupor, coma, death.
Naturally, the presentation may include also symptoms of
the underlying disease causing the hypercalcemia like bone
pain, fractures, or urolithiasis in patients with
hyperparathyroidism.
Etiology
The causes of hypercalcemia can be divided between PTH-
mediated and non-PTH-mediated (Fig. 2). Enhanced calcium
mobilization from bone is the most common mechanism lead-
ing to hypercalcemia. In the adult population, the most com-
mon causes of hypercalcemia are hyperparathyroidism and
Pediatr Nephrol (2018) 33:1475–1488
malignancies. In neonates and infants, one should look first
at genetic and iatrogenic etiologies. In children and adoles-
cents, the most common causes of hypercalcemia are primary
hyperparathyroidism, immobilization, and malignancy [13,
16, 17].
I. High serum parathyroid hormone
a) Primary, secondary, and tertiary hyperparathyroidism
Primary hyperparathyroidism is rare during childhood and
represents 1% of hypercalcemia cases. The autonomous se-
cretion of PTH can be due to parathyroid hyperplasia, adeno-
ma (80% of cases), or carcinoma (less than 1% of cases).
Children at presentation are usually symptomatic, having the
above symptoms of moderate hypercalcemia, and in addition
they may have band keratopathy, skeletal manifestations as
subperiosteal resorption, osteopenia, slipped upper femoral
epiphysis and pathologic fractures, and renal involvement
expressed as polyuria, renal failure, kidney stones, or
nephrocalcinosis. Besides high levels of calcium, the elevated
level of PTH induces hyperchloremic metabolic acidosis, ele-
vated serum calcitriol concentration and alkaline phosphatase
activity, and decreased TP/GFR (tubular threshold for phos-
phate per glomerular filtration rate) [18, 19].
In addition to isolated hyperparathyroidism, one should
consider the etiologies of hyperparathyroidism as part of mul-
tiple endocrine neoplasia type I that involves also the pancreas
and anterior pituitary, type II that involves also the adrenal and
thyroid glands, or type IV that involves also the anterior pitu-
itary. Whereas type I can be found in adolescents, the other
two are rare in childhood [11, 20].
Tertiary hyperparathyroidism is the result of advancement
of untreated secondary hyperparathyroidism to an autono-
mous state of uncontrolled release of the hormone in the face
of hypercalcemia. Imaging studies and histopathology will
usually show the glands to be hyperplastic. Tertiary hyper-
parathyroidism can be seen in patients with long-standing
ESRD and poor control of their hyperphosphatemia, and
may continue into the post-transplant period [21]. Less com-
monly, this condition is seen in patients exposed to prolonged
periods of stimulation of the gland by frequent and repeat
episodes of ionized hypocalcemia, as occurs in some patients
with X-linked dominant hypophosphatemic rickets treated
with high oral doses of phosphate [22, 23].
b) Familial hypocalciuric hypercalcemia (FHH)
Various types of genetic mutations transmitted in an auto-
somal dominant mode have been described in FHH resulting
in inactivating mutations or in impaired signaling of the CaSR
[24, 25]. Consequently, the parathyroid glands become less
sensitive to circulating levels of calcium resulting in hypercal-
cemia and either normal or elevated levels of PTH. Naturally,
the Bnormal^ level of PTH is inappropriate for the degree of
Pediatr Nephrol (2018) 33:1475–1488 1479

Fig. 2 Algorithm for evaluation of hypercalcemia

Table 1 Symptoms and signs of hypercalcemia hypercalcemia and practically indicates a higher Bset point^ of
the parathyroid glands to the extracellular calcium concentra-
General tion. In the kidney, the defect leads to an increase in tubular
Weakness calcium and magnesium reabsorption with final result of
Dehydration hypocalciuria manifested by fractional excretion of calcium
Corneal and other ectopic calcification of less than 1% [24, 25].
Central nervous system The diagnosis is made either because of history of an affect-
Impaired mental abilities ed family member or incidentally. Patients present in childhood
Depression with hypercalcemia, inappropriately normal or mildly elevated
Psychosis PTH and very low urine calcium. Affected individuals are usu-
Altered consciousness (confusion, lethargy, stupor, coma) ally asymptomatic although pancreatitis, chondrocalcinosis, or
Gastrointestinal tract mental changes may develop in adulthood. Most patients tend
Anorexia to have normal bone mineral density. This condition usually
Nausea requires no intervention but if indicated may respond well to
Vomiting calcimimetics [12, 19, 26].
Abdominal pain (pancreatitis, peptic ulcer)
Constipation c) Severe neonatal hyperparathyroidism
Renal system
Polydipsia This autosomal recessive disorder is caused by a homozygous
Polyuria inactivating mutation in the CaSR gene (chromosome 3q13.3-
Low urinary specific gravity q21). The genetic anomaly results in a complete or near-
Reduced glomerular filtration rate complete absence of functional CaSR in the parathyroid glands
Nephrolithiasis and other cells in the body. Afflicted patients often have severe
Nephrocalcinosis metabolic bone disease and life-threatening hypercalcemia. The
Cardiovascular system presentation, usually in the first few weeks of life, includes
Hypertension vomiting, feeding difficulties, failure to thrive, respiratory distress
due to muscle hypotonia, elevated PTH in the face of severe
1480
hypercalcemia accompanied by hypophosphatemia, relative
hypocalciuria (although some cases present with hypercalciuria),
bone demineralization (osteopenia), subperiosteal resorption, rick-
ets and fractures. A neck ultrasound will localize a parathyroid
abnormality in only one-third of the cases. Parathyroidectomy has
been the therapeutic approach in cases of life-threatening hyper-
calcemia refractory to medical treatment [27, 28].
d) Maternal hypocalcemia
Chronic maternal hypocalcemia can be seen in the untreated
or undertreated mother with hypoparathyroidism or
pseudohypoparathyroidism, vitamin D deficiency, and renal tu-
bular acidosis. The induced fetal hypocalcemia leads to devel-
opment of secondary hyperparathyroidism and post-natal hy-
percalcemia. The presentation includes hypercalcemia, elevated
PTH, bone deformities, respiratory failure due to rib cage de-
formities, hepatosplenomegaly, and anemia [29, 30]. The sec-
ondary hyperparathyroidism and hypercalcemia usually resolve
spontaneously within a few months [31].
II. Low Serum PTH
(i) Elevated vitamin D metabolites
A Elevated 25(OH)-vitamin D - vitamin D intoxication
Hypervitaminosis D is one of the more common causes of
hypercalcemia in children. It is caused by excessive intake of
vitamin D by either the infant or the breast-feeding mother. The
excess vitamin D leads to increased intestinal calcium and phos-
phate absorption, enhanced bone resorption, and consequently
both hypercalcemia and hyperphosphatemia. Serum levels re-
quired to cause hypercalcemia are believed to need to be quite
high (>250 ng/ml) in order to cause the hypercalcemia due to
decreased affinity of the metabolite to the receptor.
Interestingly, 1,25(OH)2-vitamin D levels in such condition
are not elevated, which is thought to be due to the hypercalce-
mia and suppressed PTH [32]. Due to its liposoluble qualities,
vitamin D overdose leads to long-lasting (weeks to months)
hypercalcemia and hypercalciuria, in contrast to hypercalcemia
seen secondary to ingestion of shorter-acting vitamin D analogs
such as calcitriol or alfacalcidol, which usually last only a few
days because of their short half-lives [33, 34].
B. Elevated 1,25(OH)2-vitamin D
1. Inappropriately high production
a) Granulomatous diseases
In principal, granulomatous diseases can be divided be-
tween infectious and non-infectious, which have an impact
on diagnostic work up, treatment, and prognosis, but the
Pediatr Nephrol (2018) 33:1475–1488
mechanism of hypercalcemia seems to be the same [35, 36].
Granulomas are caused by macrophage activation due either
to an inability to clear the initial source (intracellular bacteria,
foreign material, or inefficient microbial killing in chronic
granulomatous disease) or an abnormality in the processes that
turn off the macrophages, with consequent over-activation of
this phagocytic cells, which leads to endogenous production
of calcitriol (they have an autonomous 1-alpha hydroxylase)
and in turn hypercalcemia develops. While the most studied
granulomatous disease is sarcoidosis, other conditions include
Pneumocystis jirovecii pneumonia, Wegener’s granulomato-
sis, necrobiotic xanthogranuloma, and paraffin-associated
granuloma [37, 38]. The conversion of 25(OH)-vitamin D to
1,25(OH)2-vitamin D is substrate-dependent; namely, a higher
presence of the former will result in higher levels of the latter.
In addition, in contrast to the kidney where production of 1,25
(OH)2 –vitamin D by 1-alpha-hydroxylase is tightly regulated
by Ca, PTH, FGF-23, and 1,25 (OH)2 –vitamin D itself by a
negative feedback loop, it is not regulated in the macrophages.
The treatment of these diseases may take several weeks to
months, and with that the need to manage the hypercalcemia
[35, 36]. In immunocompromised patients, like those follow-
ing kidney transplantation, and hypercalcemia associated with
suppressed PTH, one should be looking for opportunistic in-
fections like the one caused by Pneumocystis jirovecii pneu-
monia [39, 40].
One of the pediatric types of granulomatous diseases is
subcutaneous fat necrosis, which is a form of panniculitis seen
in term infants. Patients develop a violaceous rash composed
of hard, indurated, painful nodules over the trunk, arms, but-
tocks, thighs, and back. It appears that there is a defect in fat
metabolism resulting in granulomatous reaction to the in-
flamed necrotic fat. Hypercalcemia can occur in the first few
weeks of life. The hypercalcemia can be often asymptomatic
but can cause symptoms including irritability, vomiting, fail-
ure to thrive, hypotonia, myopathy, fever, eosinophilia, hyper-
calciuria, nephrocalcinosis, nephrolithiasis, and renal failure
[41–43].
b) Low phosphate intake
Errors in parenteral nutrition manufacturing with low phos-
phate can lead to hypophosphatemia, which in turn promotes
calcitriol production. Hypercalcemia and hypophosphatemia
may occur in premature infants fed a low-phosphate diet or in
full-term infants fed a low-phosphate-containing breast milk
when the mother has known hypophosphatemia, and the met-
abolic abnormalities correct upon addition of phosphate sup-
plementation to the enteral or parenteral nutrition [31, 44, 45].
A clue to this entity will be low serum phosphate accompanied
by very low urine phosphate quantities, namely the TP/GFR is
normal and the intact kidney is avidly reabsorbing the phos-
phate filtered in the glomerulus.
Pediatr Nephrol (2018) 33:1475–1488
c) Phosphate-losing tubulopathies
Caused by homozygous or compound heterozygous mutation
in the SLC34A1 gene (5q35), which encodes for the renal
cotransporter Na-Pi IIa, rendering the latter to be defective. The
resulting renal phosphate wasting induces inappropriate produc-
tion of calcitriol. Besides hypercalcemia, these patients may pres-
ent with hypercalciuria-induced nephrocalcinosis and urolithiasis.
Characteristic to this condition are low serum phosphate concen-
tration and low TP/GFR, in the face of normal FGF-23 [46].
d) Tumors
Hypercalcemia is a common finding in adult with malig-
nancies but relatively rare in children. The hypercalcemia may
be life-threatening and generally requires urgent intervention
[47]. Pediatric malignancies associated with hypercalcemia
include acute lymphoblastic leukemia, Hodgkin and non-
Hodgkin lymphoma, myeloid leukemia, brain tumors, rhab-
domyosarcoma and hepatoblastoma [47, 48]. In children with
leukemia, hypercalcemia is more likely to happen at the time
of initial diagnosis, whereas in patients with solid tumors,
hypercalcemia usually occurs later in the course of the disease.
In malignancy-associated hypercalcemia, PTHrP can be either
normal or elevated, as might be the case with calcitriol, and
PTH will be suppressed [49]. As shown in Fig. 2, there are
three mechanisms of hypercalcemia caused by tumors: (a)
bone invasion of tumor cells causing bone resorption/
destruction due to osteoclasts activated by the tumoral cells,
(b) osteoclastic factors released from tumor cells, mainly
PTHrP and/or other factors/pro-inflammatory cytokines like
leukotrienes, prostaglandin E, IL-1, IL-6, TGF-beta and TNF
alpha, that stimulate osteoclast proliferation through their in-
teraction with RANKL, and (c) increased ectopic production
of 1,25(OH)2-vitamin D, similar to the one described above in
granulomatous disorders. Hypercalcemia has also been de-
scribed during treatment of neuroblastoma as a toxic side ef-
fect from one of the chemotherapy medications, 13 cis-
retinoic acid due to an unknown mechanism [48, 49].
2. Inappropriate degradation of 1,25 (OH)2–vitamin D
a. Idiopathic infantile hypercalcemia (IHH)
Previously named IHH is now known to be an autosomal
recessive disorder caused by inactivating mutation in the
CYP24A1 gene that encodes for vitamin D 24-hydroxylase,
resulting in high serum levels of 1,25(OH)2-vitamin D.
Biallelic disease individuals (homozygous or compound het-
erozygote mutation) are usually symptomatic, whereas pa-
tients with monoallelic mutations can often be asymptomatic.
Hypercalcemia presents between 4 and 12 months of age and
usually resolves spontaneously by age 2 years. Infants
1481
afflicted with this disease can develop significant hypercalce-
mia when supplemented with a standard dose of vitamin D
[34, 50]. Patients have no characteristic dysmorphic features,
and exhibit failure to thrive, vomiting, and dehydration.
Typically, nephrocalcinosis is already present at presentation.
Following normalization of serum calcium, nephrocalcinosis
and hypercalciuria may persist and patients may have reduced
bone mineral density [34, 50].
(ii) Normal-low vitamin D metabolites
A. Elevated parathyroid-hormone related peptide (PTHrP)
a) Tumors
As discussed earlier, elevated PTHrP is commonly seen in
adults with tumor-induced hypercalcemia. Nonetheless, also
in the child, the finding of high PTHrP level requires a thor-
ough investigation to identify or rule out the presence of a
tumor. Interestingly, also benign conditions such as
mesoblastic nephroma and multicystic dysplastic kidney have
been reported to be associated with the development of hyper-
calcemia, suppressed PTH, and elevated PTHrP [51, 52].
Elevated serum PTHrP has also been rarely reported in asso-
ciation with pheochromocytoma [53].
B. Normal parathyroid-hormone related peptide (PTHrP)
a) Maternal hypercalcemia
Maternal hypercalcemia can lead to neonatal calcium over-
load. The source of the maternal hypercalcemia can vary and
may be due to some of the causes detailed in Fig. 2. The
neonatal hypercalcemia will have a tendency to resolve on
its own. Attention should be paid to the possibility that the
parathyroid gland has become temporarily suppressed [31].
b) Williams syndrome
Autosomal dominant condition that is caused by a deletion
on chromosome 7q11.23 that encodes for the elastin gene. The
deletion of the elastin is the culprit of the vascular and con-
nective tissue abnormalities seen in this condition. Most in-
fants are born small for gestational age and may have multi-
system manifestations including depressed nasal bridge,
epicanthal folds, characteristic facial appearance (elfin facies),
dental decay, enamel hypoplasia, neurocognitive problems,
cardiac malformations including supravalvular aortic stenosis
and peripheral pulmonary stenosis. The hypercalcemia, which
is usually mild, presents in 15–40% of patients during infancy/
early childhood, and resolves between 2 and 4 years of age,
and can recur during puberty. There is no exact known specific
mechanism for the hypercalcemia but vitamin D receptor hy-
persensitivity is regarded as a possibility [54, 55].
1482
c) Hypophosphatasia
Autosomal recessive disorder is characterized by a loss-of-
function mutation in the ALPL gene (1p34–36) that encodes
for tissue non-specific alkaline phosphatase. Patients develop
bone and teeth hypo-mineralization. It is classified into several
clinical forms depending on the age at diagnosis and the se-
verity of the symptoms (the most severe presentation is in the
infantile form). Low-alkaline phosphatase impairs skeletal
mineralization and calcium uptake, leading to hypercalcemia,
hypercalciuria, nephrocalcinosis, severe bone demineraliza-
tion, and fractures. Serum PTH, phosphate, and vitamin D
levels are usually within normal range [56].
d) Jansen metaphyseal chondrodysplasia
This autosomal dominant disorder is due to a heterozygous
mutation in the PTHR1 gene encoding type 1 PTH/PTHrP re-
ceptor, which leads to gain-of-function of the receptor in the
kidney, bone, and growth plate. This results in hypercalcemia
in the face of low or undetectable serum PTH presenting as early
as 3 months of age. The abnormal receptor in the growth plate
causes delay chondrocyte differentiation, which results in post-
natal short limbs, short stature (there is usually normal growth
during infancy and short stature becomes apparent during mid-
childhood), and diffuse demineralization. Choanal atresia and rib
fractures may result in respiratory distress after birth. Bone le-
sions seen on plain roentgenograms include rachitic changes,
radiolucencies, and irregular metaphyses of the long bone and
sclerotic changes in the base of the skull [57].
e) Hypervitaminosis A
Receptors for retinoic acid are located on both osteoclasts and
osteoblasts. In vitro, retinoic acid suppresses osteoblast activity
and stimulates osteoclast formation, resulting in increased bone
resorption and decreased bone formation. Vitamin A has been
shown also to stimulate PTH secretion. The clinical presentation
of vitamin A overdose may include anorexia, pruritus, irritability,
bone pain, osteopenia, and fractures [58–60].
f) Immobilization
Immobility-induced hypercalcemia occurs due to uncoupling
of bone remodeling, resulting in a decrease in osteoblastic activ-
ity and increase in osteoclastic activity, which cause calcium and
phosphate release from the skeleton and loss of bone mass.
Serum PTH and calcitriol are usually suppressed. The hypercal-
cemia is observed in acute immobilization cases such as seen in
head injuries, fractures, spinal cord injuries, and burns. Long-
term immobilization leads to decreased bone density and possi-
ble fractures. The hypercalcemia and hypercalciuria resolve with
the onset of weight bearing [61–63].
Pediatr Nephrol (2018) 33:1475–1488
g) Thiazide diuretics
This group of sulfonamide-derivate diuretics act on the
distal tubules to increase calcium reabsorption, an effect that
is useful in the treatment of patients with hypercalciuria,
nephrocalcinosis, and urolithiasis [64]. Hypercalcemia is rare-
ly seen but can be present in patients with an underlying in-
crease in bone resorption such as in patients with hyperpara-
thyroidism, namely the treatment with high-dose thiazide di-
uretic unmasks the endocrinopathy [31].
h) Bartter syndrome
Commonly associated with hypercalciuria. Hypercalcemia
can be seen in infants with homozygous inactivation in the
gene for either the furosemide sensitive Na-K 2Cl
cotransporter NKCC2 (SLC12A1) or the inwardly rectifying
potassium channel ROMK (KCNJ1) [65, 66].
i) Tumors
As discussed earlier, besides the production of humoral
factors such as PTHrP and 1,25 (OH)2–vitamin D that lead
to hypercalcemia, tumors can produce hypercalcemia by di-
rect invasion of the bone and its distraction, releasing calcium
to the circulation. As such, evaluation of children with hyper-
calcemia should include skeletal survey in search for bone
lesions. In acute lymphoblastic leukemia with hypercalcemia,
skeletal survey often shows osteolytic lesions. In some of
these patients, the initial complete blood cell count might be
normal with no blasts seen in the peripheral blood smear, and
only bone marrow aspiration may disclose the malignancy.
The presence of hypercalcemia by itself does not necessarily
indicate a worse oncologic prognosis [12].
Additional, less common causes of hypercalcemia are de-
tailed in Table 2. Due to their rarity and for cost-effectiveness,
one should be looking for them after excluding the more com-
mon etiologies.
Kidney involvement in hypercalcemia
Patients with hypercalcemia are often polyuric due to the de-
velopment of a renal concentrating defect resulting from tu-
bular resistance to the effect of antidiuretic hormone (ADH).
The mechanism likely involves activation of the cortical tu-
bule CaSR that impairs the trafficking and expression of
vasopressin-dependent aquaporin 2 water channel [9].
Consequently, patients are often dehydrated. Since activation
of the CaSR in the TAL results in losses of sodium, replenish-
ment of these patients requires the administration of both wa-
ter and sodium, namely, normal saline [79, 80].
Pediatr Nephrol (2018) 33:1475–1488
Table 2 Rare causes of hypercalcemia (reference)
1. Excessive calcium intake [31]
2. Ovarian tumors [67]
3. Blue diaper syndrome [68]
4. Osteopetrosis [69]
5. Milk-alkali syndrome [31]
6. Congenital lactase deficiency [70]
7. Diabetic ketoacidosis [71]
8. IMAGe syndrome [72]
9. Hypothyroidism and thyrotoxicosis [2]
10. Down syndrome [73]
11. Manganese toxicity [31]
12. Extracorporeal membrane oxygenation, plasmapheresis [74, 75]
13. Primary hyperoxaluria [31]
14. Partial duplication of chromosome 2p [76]
15. Medications – lithium, omeprazole, theophylline, foscarnet [31]
16. Adrenal insufficiency [77]
17. Gum Arabic [78]
Acute kidney injury (AKI) and hypercalcemia can be
pathophysiologically associated in two different ways. (a)
Hypercalcemia can cause AKI, which is typically non-
oliguric. The decrease in GFR is thought to be secondary
to a combination of the aforementioned dehydration and
arterial vasoconstriction caused by the hypercalcemia, as
was demonstrated by Doppler renal ultrasound before and
after alleviation of the hypercalcemia (Fig. 3). As discussed
later, the first step in the treatment of hypercalcemia is the
restoration of intravascular volume by administration of
0.9% normal saline. The AKI is usually reversible once
the hypercalcemia is corrected [81]. (b) On the other hand,
hypercalcemia is at times seen during the recovery phase of
AKI, in particular if the etiology of the AKI was rhabdomy-
olysis. This is due to the fact that during AKI calcium was
settled in soft tissues to be mobilized from them during the
recovery phase. This is usually a transient phenomenon of
mild hypercalcemia that requires no intervention besides
maintenance of adequate hydration [21].
Hypercalcemia can result in more permanent damage to the
kidneys in the form of nephrocalcinosis. The renal calcifica-
tions can result from the high serum calcium itself settling in
the interstitial compartment or from hypercalciuria resulting in
calcium deposits in the tubules. Advanced nephrocalcinosis
can then cause permanent kidney damage.
Evaluation
The investigation of the origin of hypercalcemia and its
management are often done simultaneously. Besides his-
tory and physical examination the laboratory studies
1483
include serum creatinine, electrolytes, phosphate, magne-
sium, alkaline phosphatase, ionized and total calcium, al-
bumin, PTH, 25-hydroxy vitamin D, 1,25(OH)2-vitamin
D, complete blood count, urinalysis with microscopy
and urine calcium, phosphate and creatinine. Routine im-
aging studies include skeletal survey and urinary tract
ultrasound. Second line of the evaluation includes
PTHrP, serum vitamin A, and genetic evaluation.
Additional imaging studies utilizing various techniques
may be directed at specific organs like the parathyroid
glands or lesions like pulmonary infiltrates.
In the interpretation of laboratory data, it is important
to remember to look at blood levels of hormones in the
context of the associated axis and feedback. For example,
in the face of hypercalcemia, Bnormal^ serum PTH is
actually inappropriately high as under normal physiologic
conditions it should be suppressed.
Treatment
The treatment of hypercalcemia proceeds in two avenues
complementing each other; the normalization of serum
calcium and correction of the source of hypercalcemia,
namely the underlying disorder. Symptomatic hypercalce-
mia requires immediate treatment due to potential cardiac
toxicity. In addition, consequences of untreated hypercal-
cemia can include kidney damage and neurologic
sequelae.
The main components of the treatment of hypercalcemia
are detailed in Table 3. In principle, they include enhancement
of urinary calcium excretion and its incorporation to bone, and
when indicated decrease in its absorption from the gut. In the
rare occasion of life-threatening hypercalcemia hemodialysis
or peritoneal dialysis can be considered.
a) Calcium diuresis
Volume expansion with normal saline decreases calcium re-
absorption. As previously discussed, due to hypercalcemia-
induced polyuria, these patients are invariably dehydrated and
volume expansion should always be the immediate first step in
addressing them. Normal saline is the fluid of choice. Not only
does it induce hypercalciuria but by causing volume expansion it
improves kidney perfusion and function [11, 82].
b) Loop diuretics
By blocking the Na-K 2Cl channel in the TAL, loop di-
uretics block sodium reabsorption and with that paracellular
calcium reabsorption. This actually mimics the normal
physiologic response to hypercalcemia that takes place via
1484 Pediatr Nephrol (2018) 33:1475–1488

Fig. 3 Doppler renal ultrasound

in a 7-year-old girl with acute
lymphoblastic leukemia, before
(a) and after (b) correcting her
hypercalcemia (16.2 mg/dl) due
to bone lesions. Note
normalization of abnormal arterial
blood flow, likely due to
hypercalcemia-induced
vasoconstriction (from reference
81 with permission)

the CaSR. In the setting of treatment of hypercalcemia, fu- c) Calcitonin

rosemide should be administered only once the patient is
well hydrated [13, 82]. Chronic furosemide therapy should
be avoided as much as possible due to its known adverse
effects of nephrocalcinosis and urolithiasis [83].
Table 3 Treatment of acute hypercalcemia
Intravenous fluids – Hydration with 0.9% normal saline at 1.5 maintenance
Furosemide – IV 1 mg/kg/dose, q6-8 h
Calcitonin - 3–6 units/kg/dose subcutaneously q6-12 h
Pamidronate - 0.5 to 1 mg/kg/dose (decrease dose by 50% in patients with
impaired renal function); can be repeated after 24–48 h
Zoledronic acid - 0.025 mg/kg/dose (decrease dose by 50% in patients with
impaired renal function); can be repeated after 24–48 h
Calcitonin inhibits bone-resorbing activity of osteoclasts and
inhibits tubular reabsorption of calcium, promoting renal excre-
tion of calcium. Thus, it has a dual beneficial effect in treating
hypercalcemia [84]. Another advantage is its rapid effect within
hours, relative to bisphosphonates that take days. It can be given
intravenously, subcutaneously, intramuscularly, or intranasally.
Its effect on hypercalcemia is moderate, and side effects may
include nausea, flushing, paresthesias, and local inflammation.
It is metabolized by the kidneys so it may accumulate in renal
failure. It cannot be used long term as tachyphylaxis develops,
namely its effect decreases over time presumably due to down-
regulation of the involved receptors [11].
Pediatr Nephrol (2018) 33:1475–1488
d) Bisphosphonates
Targeting the osteoclasts is likely the most effective ap-
proach since in most cases osteoclastic bone resorption is the
cause of hypercalcemia. Bisphosphonates are regarded nowa-
days as the drug of choice in treating hypercalcemia of various
etiologies. Since they act by suppressing osteoclastic activity
the effect on serum calcium is not immediate but may take a
few days to be fully manifested, hence in cases of hypercal-
cemic emergency the immediate treatment is by fluids, loop
diuretics and calcitonin while awaiting the effect of
bisphosphonates that may be delayed by 24–48 h. The
bisphosphonates should be introduced intravenously. Due to
the fact that the drug is cleared through the kidneys and pa-
tients often have a degree of AKI, it is recommended to start
with half the recommended dose. If not enough improvement
is seen in 24–48 h, another dose can be given. The main
potential adverse effects include Bflu-like^ symptoms and de-
velopment of hypocalcemia. The latter is especially true in
cases of Bhungry bones^ [85].
e) Dialysis
Considered in very ill patients in whom there is renal failure or
heart failure, or when hypercalcemia is refractory to other conven-
tional treatment measures. Hemodialysis or peritoneal dialysis
with a low-calcium dialysate should be prescribed.
f) Nutrition and mobilization
IV calcium intake should be assessed and adjusted as
appropriate. The enteral calcium intake should be reviewed,
and calcium and vitamin D supplementation should be
avoided. Low-calcium and vitamin D formulas are avail-
able. It is important to resume recommended vitamin D
supplementation once hypercalcemia and its underlying
disorder have been brought under control. Weight bearing
should be encouraged.
g) Specific treatments
For some specific conditions, additional modes of interven-
tion are helpful as follows.
i. Corticosteroids
Corticosteroids suppress 1-alpha hydroxylase activity, thus
decreasing calcitriol synthesis in conditions where an exces-
sive activation of vitamin D exists, such as seen in granulo-
matous diseases and 1,25(OH)2-vitamin D producing tumors.
In some of these conditions, corticosteroids play a role also in
the treatment of the underlying disease as in sarcoidosis and
lymphoma [13, 82].
1485
ii. Ketoconazole
Like corticosteroids, ketoconazole inhibits 1-alpha hydrox-
ylase activity. The antifungal has been used to treat hypercal-
cemia in infantile idiopathic hypercalcemia, primary hyper-
parathyroidism, granulomatous disorders. Adverse effects in-
clude liver and renal toxicity [86].
iii. Cinacalcet
Calcimimetics modulate the CaSR by lowering its thresh-
old to extracellular calcium resulting in decreased secretion of
PTH, thus lowering Ca concentration. In essence, they can be
used in all cases in which the hypercalcemia is caused by
increased secretion of PTH. This has be shown to be the case
in primary, secondary, and tertiary hyperparathyroidism, in the
face of normal and abnormal kidney function [87, 88]. They
are primarily used to treat chronic hypercalcemia. It is impor-
tant to remember that besides their effect on the CaSR in the
parathyroid glands calcimimetics exert their effect also on the
CaSR in the TAL and may cause hypercalciuria. The latter
responds well to thiazide diuretics [26].
iv. Denosumab
The monoclonal antibody inhibits RANKL, thus suppress-
ing osteoclast activity. It may present as an alternative to
bisphosphonates in controlling the dramatic hypercalcemia
seen at times after bone marrow transplantation [89]. One of
its advantages is its convenient administration by sub-
cutaneous injection.
v. Surgical intervention
In some cases of hyperparathyroidism, parathyroidectomy,
either complete or partial is indicated. Following parathyroid-
ectomy, a Bhungry bone^ syndrome may develop and patients
might require calcium and vitamin D replacement [19].
Key summary points
1. Serum calcium concentration is best assessed by measur-
ing the ionized calcium concentration. If unavailable, then
serum total calcium should be adjusted to that of albumin.
2. Hypercalcemia is mostly caused by increased bone re-
sorption and to a lesser extent by increased intestinal cal-
cium absorption and tubular reabsorption.
3. Severe hypercalcemia can result in cardiac, renal, and
CNS mortality and morbidity.
4. The evaluation of the etiology of hypercalcemia starts
with determination of serum PTH. If normal, serum levels
of 25(OH)-D, 1,25(OH)2D, PTHrP and genetic studies
should follow.
1486
5. Patients with severe hypercalcemia are often polyuric,
dehydrated and at some stage of non-oliguric AKI.
6. Acute treatment should start with IV hydration with 0.9%
normal saline. More sustained control of the hypercalce-
mia can be achieved with bisphosphonates.
Questions: (Answers can be found after the references).
1. Pseudohypercalcemia can be seen in:
a) Low-serum ionized calcium concentration.
b) Hypoalbuminemia.
c) Pseudohypoparathyroidism.
d) Hyperalbuminemia.
e) Severe combined immune deficiency.
2. Elevated Ca concentrations induce the following CaSR-
mediated effect:
a) Water reabsorption is reduced by inhibiting the tubular
response to ADH.
b) Water reabsorption is reduced by inhibiting the CaSR
mesangial transporters.
c) Water reabsorption is enhanced by inhibiting the tubular
response to ADH.
d) Water reabsorption is unaffected.
e) Water reabsorption is reduced by stimulating proximal
tubular sodium reabsorption.
3. Post-renal transplant hypercalcemia may occur as a re-
sult of:
a) Calcineurin inhibitor induced PTH production.
b) Delayed graft function induced 1,25 (OH)2 vitamin D
production.
c) Pre-transplant hyperplastic parathyroid glands.
d) Dietary non-compliance.
e) Hidden parathyroid adenoma.
4. Following hydration, the drug of choice in addressing
most cases of hypercalcemia is:
a) Furosemide.
b) Calcitonin.
c) Corticosteroids.
d) Bisphosphonates.
e) Phosphate.
5. To exert their effect, calcimimetics;
a) Have to have extracellular calcium present.
b) Have to have 1,25 (OH)2 vitamin D present.
c) Have to have an abnormal CaSR present.
d) Have to have high serum phosphate present.
e) Have to be given concomitantly with bisphosphonates.
Acknowledgements We would like to thank Ms. Andrea Fontana for
her administrative assistance. This work was supported by the Sam and
Helen Kaplan Research Fund in Pediatric Nephrology and the Eric
McClure Research Fund in Bone and Mineral Metabolism.
Compliance with ethical standards
Conflict of interest The authors declare no conflict of interest.
Pediatr Nephrol (2018) 33:1475–1488
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Answers to questions:
1d
2a
3c
4d
5a