HOMEOSTASIS OF CALCIUM AND

DISORDERS
OF CALCIUM METABOLISM

Distribution of Calcium in the

Organism and
Calcium Homeostasis

Most calcium is bound and associated

with
. bone structures (99%)
The majority of free calcium, either in
diffusible (ultrafilterable) nonionized
form or in ionized form (Ca2+), is
found in the intracellular and
.extracellular fluid compartments

Increased calcium absorption is

required in puberty, pregnancy,and
.lactation
In all these states, calcitriol synthesis
.is increased
Intestinal Ca2+ absorption is also
increased in vitamin D excess and
.acromegaly

A decrease in intestinal Ca2+ transport

occurs in a low Ca2+/phosphate ratio in
the food, a high vegetable fiber and fat
content of the diet, corticosteroid
,treatment, estrogen deficiency
advanced age, gastrectomy, intestinal
malabsorption syndromes,diabetes
.mellitus, and renal failure
The decrease in Ca2+ absorption in the
elderly probably results from multiple
factors in addition to lower serum calcitriol
and intestinal VDR levels

The net balance between Ca2+ entry

and exit :fluxes is
positive during skeletal growth inchildren
zero in young adults negative in the elderly-

Ca++

major regulator of calcium

balans

Intestinal, Skeletal, and Renal

Handling of Calcium
Only about 25% of total dietary
calcium is absorbed. Ca2+ transport
across the intestinal wall occurs in
two directions: absorption and
.secretion
Absorption can be subdivided into
transcellular and paracellular flow

Hormonal Regulators
Calcitonin (CT)
Lowers Ca++ in the blood
Inhibits osteoclasts

Parathormone (PTH)
Increases Ca++ in the blood
Stimulates osteoclasts

Vitamin D3 1,25
Increases Ca++ in the blood
Increase Ca++ uptake from the gut
Stimulates osteoclasts

Increase of
calcitonin
hypocalciemia
hypophosphatemia
hyperphosphaturia

Decrease of calcitonin
hypercalciemiahyperphosphatemia hypophosphaturia -

Main regulators of Calcium 2

:and phosphorus
PARATHYROID HORMONE
PTH ( Parathyroid
hormone)
amino peptide 84
Molecular mass if 9.5
kilodalton
no carbohydrate or other
covalently bound molecules
Full biologic activity resides
in the amino terminal third
of the molecule
PTH 1-34 has full biologic
activity while region 25-34
is for receptor binding

.1

Vitamin D
Is a fat soluble steroid
That is present in the diet
and can be synthesized
from the skin

Calcitriol is its most important hormonal

.regulatory factor
After binding to and activating the vitamin D
receptor (VDR),calcitriol increases active
transport by inducing the expression of
TRPV6, calbindin D9k, and Ca2+-ATPase
.(PMCA1b)
Other hormones, including estrogens,
prolactin, growth
hormone, and PTH, also stimulate Ca2+
.absorption, either directly or indirectly

PTH increases Ca
:concentration by

In the presenc e of. 1

permissive amounts of
vitamin D it stimulates
bone
resorptionrelease of
calcium phosphates
Enhances intestinal. 2
Calcium and phosphate
absorption promotes
formation of vit D
It augments renal. 3
calcium reabsorption

PTH
Regulation of Synthesis
Biosynthesis is regulated by levels of calcium
An acute decrease of Ca results in marked increase of PTH
mRNA increase of PTH synthesis
Effects is at the level of gene transciption, MRNA stability, mRNA
translation
Rate of degradation of PTH is low if low calcium and high if calcium
is high
2D3 receptor complex binds with vitamin D in the)OH (25, 1
promoter region of PTH gene and inhibits transcription
decreases the production of PTH
PTH synthesis can be enhanced by the size and number of PTH
producing chief cells in cases of prolonged hypocalcemia

vitamin D metabolism
Cutaneous synthesis on exposure to UV light
converts 7-dehydrocholesterol to vitamin D
.substrate (cholecalciferol)
Cholecalciferol has minimal inherent biologic
activity and requires two hydroxylation
steps
.for full hormonal activity
Hydroxylation occurs in the liver-25
dihydroxyvitamin D-1,25
occurs predominantly in the kidney) calcitriol(

Hydroxylation accepted as a-25

summary measure of vitamin D
.stores

Metabolism and
synthesis of 1,25()H)2Primary Regulators D3 Secondary
Regulators

Hypocalcemia ()
PTH()
Hypophosphatemia()
Calcitriol ()

Estrogen
Androgens
Progesterone
Insulin
Growth Hormone
Prolactin
Thyroid Hormone

The kidneys play a major role in the

;minute-by-minute regulation
the intestine and the skeleton ensure
homeostasis in the
.mid and long term

In the proximal tubule, most of the Ca2+

is reabsorbed by convective flow (as for
)Na+ and water
In the thick ascending loop, the transport
of Ca2+ is primarily passive by the
paracellular route, depending on the
electrical gradient
enhanced by PTH, reduced by an(
increase in extracellular Ca2+ involving
)the Ca2+-sensing receptor

In the distal tubule, Ca2+ transport is

primarily active by the transcellular
route, through TRPV5 located in the
apical membrane and
coupled with a specific basolateral
Ca2+-ATPase (PMCA1b) and a Na+Ca2+ exchanger (NCX1). Both PTH and
calcitriol regulate
distal tubular transport

Clinical manifestations
NEUROPSYCHIATRIC DISTURBANCES -mild
anxiety, depression, and cognitive
.dysfunction
GASTROINTESTINAL ABNORMALITIES
constipation, anorexia, and nausea
RENAL DYSFUNCTION polyuria, resulting
from decreased concentrating ability in the
distal tubule, nephrolithiasis, and acute and
chronic renal insufficiency , type 1 (distal)
.renal tubular acidosis

Diagnostic approach to
hypercalcemia
Serum calcium should be corrected for
albumin and an elevated concentration
should be
confirmed by repeat sampling
Clinical evaluation, including duration of
hypercalcemia, presence or absence of
symptoms, family history, and medications,
may help determine the etiology of
hypercalcemia
Intact parathyroid hormone (PTH)

PTH concentrations below 20 pg/mL in the

setting of hypercalcemia are usually not
consistent with primary hyperparathyroidism
and indicate the need for evaluation for
:other causes of hypercalcemia
PTH-related peptide (PTHrp) and vitamin D
metabolites,thyroid-stimulating hormone
(TSH), serum protein electrophoresis (SPEP),
urine protein electrophoresis (UPEP), and
vitamin A

CARDIOVASCULAR DISEASE Acute hypercalcemia directly

shortens the myocardial action potential, which is reflected in
a shortened QT interval. Although there does not appear to be
any clinically important effect of moderate hypercalcemia on
cardiac conduction or the prevalence of supraventricular or
ventricular arrhythmias in patients with primary
hyperparathyroidism ,arrhythmia has been described in
patients with severe hypercalcemia ,ST-segment elevation
mimicking myocardial infarction has been reported in such
.patients
Long-standing hypercalcemia, as occurs in primary or
secondary hyperparathyroidism, can lead to other cardiac
abnormalities, including deposition of calcium in heart valves,
coronary arteries, and myocardial fibers; hypertension; and
.cardiomyopathy

:MUSCULOSKELETAL SYMPTOMS
muscle weakness
bone pain
reduction in cortical bone mass

Treatment of hypercalcemia
asymptomatic or mildly symptomatic
(eg, constipation) hypercalcemia
(calcium <12 mg/dL [3 mmol/L]) do not
require immediate treatment
to 14 mg/dL (3 to 3.5 mmol/L) may 12
be well-tolerated chronically, and may
not require immediate treatment
mg/dL (3.5 mmol/L) require 14<
treatment, regardless of symptoms

Severe hypercalcemia
calcium >14 mg/dL (3.5 mmol/L) require
more aggressive therapy
Volume expansion with isotonic saline at
an initial rate of 200 to 300 mL/hour that is
then adjusted to maintain the urine output
at 100 to
mL/hour 150
?Furosemide
Administration of salmon calcitonin
Bisphosphonates

Treatment of hypercalcemia
GLUCOCORTICOIDS:
hypercalcemia associated with the excess
administration or ingestion of vitamin D,
or with the endogenous overproduction of
calcitriol (1,25-dihydroxyvitamin D, the
most active metabolite of vitamin D).
Increased calcitriol production can occur
in patients with chronic granulomatous
diseases (eg, sarcoidosis) and in
occasional patients with lymphoma

OTHER THERAPIES
Denosumab (Monoclonal Antibody)
hypercalcemia of malignancy,
particularly in patients with persistent
hypercalcemia despite
bisphosphonates
.Calcimimetics- cinacalcet
Dialysis

Clinical manifestations of
hypocalcemia
Acute
Neuromuscular irritability (Tetany) ,Paresthesias
(peri-oral, extremities)
Muscle twitching ,Carpopedal spasm
Trousseau's sign ,Chvostek's sign,Seizures
,Laryngospasm
.Bronchospasm
Cardiac: Prolonged QT interval
Hypotension ,Heart failure ,Arrhythmia
Papilledema

Clinical manifestations of
hypocalcemia
Chronic
Extrapyramidal signs
Parkinsonism
Dementia
Subcapsular cataracts
Abnormal dentition
Dry skin

management of hypocalcemia
The management of hypocalcemia
depends upon the severity of
. symptoms
In patients with acute symptomatic
hypocalcemia, intravenous calcium
gluconate is the preferred therapy,
whereas chronic hypocalcemia is
treated with oral calcium and vitamin D
supplements

The serum total calcium concentration

falls approximately 0.8 mg/dL for every
1 g/dL reduction in the serum albumin
concentration. Thus, in patients with
hypoalbuminemia, the measured
serum calcium concentration should
be corrected for the abnormality in
albumin

Intravenous calcium
severe symptomatichypocalcemia(carpopedal spasm,
tetany, seizures, decreased cardiac
function, or prolonged QT interval)
require rapid correction of calcium levels
.with IV calcium therapy
IV calcium therapy in asymptomatic
patients with an acute decrease in
.serum corrected calcium to 7.5 mg/dL

Initially, intravenous calcium (1 to 2 g of calcium

gluconate, equivalent to 90 to 180 mg elemental
calcium, in 50 mL of 5 percent dextrose) can be
infused over 10 to 20 minutes. The calcium
should not be given more rapidly, because of the
risk of serious cardiac dysfunction, including
systolic arrest. This dose of calcium gluconate
will raise the serum calcium concentration for
only two or three hours; as a result, it should be
followed by a slow infusion of calcium in patients
with persistent hypocalcemia

Either 10 percent calcium gluconate

(90 mg of elemental calcium per 10
mL) or 10 percent calcium chloride
(270 mg of elemental calcium per 10
mL) can be used to prepare the
. infusion solution
Calcium gluconate is usually preferred
because it is less likely to cause tissue
necrosis if extravasated

An intravenous solution containing 1 mg/mL of

elemental calcium is prepared by adding 11 g of
calcium gluconate (equivalent to 990 mg
elemental calcium) to normal saline or 5 percent
dextrose water to provide a final volume of 1000
mL. This solution is administered at an initial
infusion rate of 50 mL/hour (equivalent to 50
mg/hour). The dose can be adjusted to maintain
the serum calcium concentration at the lower end
of the normal range (with the serum calcium
corrected for any abnormalities in serum albumin
as noted above). Patients typically require 0.5 to
.1.5 mg/kg of elemental calcium per hour

Concurrent hypomagnesemia
Hypomagnesemia is a common cause
of hypocalcemia, both by inducing
resistance to parathyroid hormone
(PTH) and by diminishing its secretion

PHOSPHATE
HOMEOSTASIS

Phosphorus plays a crucial role in cell

.structure and metabolism
Phosphorus is found in the organism as
both mineral phosphate and organic
phosphate
Outside cells, phosphate resides in bone
and teeth as hydroxyapatite; less
.than 1% circulates in serum

Normal serum phosphate levels of 2.5

to 4.5 mg/dl

A young adult requires approximately

.0.5 mmol/kg of phosphate daily
These needs are much higher in the
. child during growth
Phosphates are widely found in milk
products, meat, eggs, and are used
.extensively as food additives

Phosphate entrance into transport

epithelia involves a secondary active
.Na+-phosphate (Na+-Pi) cotransport
Three different Na+-Pi cotransporters
have .been identified and
characterized

The type 1 Na+-Pi family is present in

the renal tubule and may also have
.anion channel function

Type 2 Na+-Pi cotransporters are the

key players in phosphate
homeostasis and include three
members: NPT2a, NPT2b, and NPT2c.
Two of them serve specific epithelial
transport functions in the brush
border of the proximal tubule (NPT2a,
NPT2c) and of the small intestine
(NPT2b)

Type 3 Na+-Pi cotransporters, Pit1 and

Pit2, are
. ubiquitous
Phosphate entry into vascular smooth
muscle cells through Pit1 is believed
to be a necessary first step for
initiation of pathologic smooth
.muscle calcification

The transcellular transport of

phosphate is controlled by metabolic,
hormonal, and autocrine and
paracrine factors,including calcitriol,
growth hormone, insulin-like growth
factor 1, insulin, and thyroid
.hormone

In the kidney, PTH and fibroblast

growth factor (FGF) 23 are major
phosphaturic hormones that promote
. urinary phosphate excretion
Several other phosphatonins have also
been identified subsequently,
including secreted frizzled-related
protein 4 (sFRP-4), matrix extracellular
phosphoglycoprotein, and FGF-7

The klotho protein participates directly

in phosphate homeostasis by
conferring specificity of the
interaction of FGF-23 with its
. receptor FGF-R1
Deletion of klotho in the mouse
induces a hyperphosphatemic
phenotype

intestinal phosphate
absorption

Intestinal absorbtion- 60% to 75% of total

. phosphate intake (15 to 50 mmol/day)
Calcitriol, which stimulates the NPT2b
cotransporter, is the major hormonal
determinant of intestinal phosphat
. absorption
,Cations, such as calcium, magnesium
and aluminum, bind to phosphate in the
gastrointestinal tract, limiting its
absorption

In both animals and humans, ingestion

of a high-phosphate meal results in the
rapid excretion of phosphate in the
urine, without detectable changes in
serum phosphate levels

The kidneys play a major role in controlling

extracellular phosphate homeostasis.
Phosphate is freely filtered in the
glomerulus and reabsorbed primarily in the
. proximal tubule of the kidney
Normally, the daily amount of phosphate
excreted in urine equals that absorbed in
the intestine, usually comprising 5% to
.20% of the ultrafiltered phosphate load

The major fraction of phosphate is

reabsorbed in the proximal convoluted
tubule through NPT2a, which is
modulated by endocrine and metabolic
. factors
PTH,FGF-23, and hyperphosphatemiadownregulate NPT2a, increasing urinary
phosphate excretion whereas
Hypophosphatemia upregulates NPT2a,.decreasing urinary phosphate excretion

Recent attention has focused on FGF23 as a master regulator of

phosphate metabolism. FGF-23
lowers serum phosphate
concentrations by decreasing renal
phosphate reabsorption and by
inhibiting calcitriol production,
thereby reducing phosphate
absorption in the gut

Genetic disruption of FGF-23 in animals

results in hyperphosphatemia, calcitriol
toxicity, vascular calcification,and
.premature death
An identical phenotype is created by
genetic disruption of klotho, which is
needed for FGF-23 to bind its receptor
in the renal proximal tubule and to
enhance phosphate excretion

The net balance of phosphate is

positive during growth, zero in the
, young adult
and negative in the elderly

Causes of hyperphosphatemia
Acute phosphate load
Endogenous :Cell lysis (tumor lysis syndrome, rhabdomyolysis)
Exogenous: Phosphate-containing medications (laxatives, fosphenytoin
Intestinal uptake (vitamin D toxicity)
Cellular shift :Lactic or ketoacidosis
Decreased renal clearance
Reduced glomerular filtration rate
Acute kidney injury
Chronic kidney disease
Increased tubular reabsorption
Hypoparathyroidism or pseudohypoparathyroidism
Acromegaly
Bisphosphonates
Vitamin D toxicity (also increases intestinal absorption)
Familial tumoral calcinosis

Clinical Manifestations
Acute and severe hyperphosphatemia can
induce hypocalcemia,which stimulates
PTH but inhibits renal synthesis of
,calcitriol
which tends to further aggravate
hypocalcemia. Chronic
hyperphosphatemia
is suspected to play a causal role in the
pathogenesis of vascular calcification,
particularly in CKD

Clinical Manifestations
In extreme cases, hyperphosphatemia
can induce tumor-like soft tissue
calcium phosphate deposits or
extensive vascular calcification
within the arteries
of the skin (calciphylaxis or calcific
uremic arteriolopathy

Calcific uremic
arteriolopathy

TREATMENT OF HYPERPHOSPHATEMIA
Acute severe hyperphosphatemia with
symptomatic hypocalcemia can be lifethreatening. The hyperphosphatemia usually
resolves within 6 to 12 hours if renal
function is intact. Phosphate excretion can
be increased by saline infusion, although
this can further reduce the serum calcium
concentration by dilution. Hemodialysis is
often indicated in patients with symptomatic
hypocalcemia, particularly if renal function is
impaired

Major causes of hypophosphatemia

Internal redistribution
Increased insulin secretion, particularly during refeeding
Acute respiratory alkalosis
Hungry bone syndrome

Decreased intestinal absorption

Inadequate intake
Inhibition of phosphate absorption (eg, antacids containing aluminum or
magnesium, niacin)
Steatorrhea and chronic diarrhea
Vitamin D deficiency or resistance

Increased urinary excretion

Primary and secondary hyperparathyroidism
Vitamin D deficiency or resistance
Hereditary hypophosphatemic rickets
Oncogenic osteomalacia
Fanconi syndrome
Other - acetazolamide, tenofovir

Removal by renal replacement therapies

Signs and symptoms of

hypophosphatemia
The manifestations of hypophosphatemia
depend upon the severity and chronicity of
the phosphate depletion. Most symptomatic
patients have a plasma phosphate
. concentration below 1 mg/dL (0.32 mmol/L)
The effects of hypophosphatemia may be
categorized into those that arise from
changes in mineral metabolism and those
due to adenosine triphosphate (ATP)
depletion

Hypophosphatemia-induced changes in mineral

metabolism include a decrease in distal tubular
reabsorption of calcium and magnesium and
increased bone resorption, both resulting in
hypercalciuria. Increased bone resorption is
likely mediated by the phosphate depletioninduced rise in the synthesis of calcitriol (1,25. dihydroxyvitamin D)
Prolonged hypophosphatemia may lead to
rickets and osteomalacia

Decreased intracellular ATP levels may cause

metabolic encephalopathy, impaired myocardial
contractility, respiratory failure due to weakness of
the diaphragm, a proximal myopathy, dysphagia,

. and ileus
Acute hypophosphatemia superimposed upon
preexisting severe phosphate depletion may cause
rhabdomyolysis. Rhabdomyolysis may mask the
underlying hypophosphatemia and therefore protect
against the development of other

. hypophosphatemic symptoms

The hematologic effects of a

hypophosphatemia-induced decrease in
intracellular ATP levels include an increased
predisposition to hemolysis, a decrease in
both phagocytosis and granulocyte
chemotaxis, and defective clot retraction
and thrombocytopenia

TREATMENT
Symptoms of hypophosphatemia rarely
occur unless the serum phosphate
concentration is less than 2 mg/dL
(0.64 mmol/L), some evidence
suggests that even mild
hypophosphatemia may be associated
with poor clinical outcomes

TREATMENT
Hypophosphatemia occurring during the
correction of diabetic ketoacidosis will
correct spontaneously with normal dietary
intake
Patients who have hypophosphatemia due to
gastrointestinal losses should correct spontaneously
once there is resolution of the underlying cause (eg,
diarrhea, chronic antacid therapy, or vitamin D
deficiency which should be treated with vitamin D
. supplementation)

Phosphate repletion regimens

In asymptomatic patients with a serum phosphate
less than 2.0 mg/dL (0.64 mmol/L)-oral phosphate
therapy
symptomatic patients varies with the severity of the
:hypophosphatemia
treat with oral phosphate if the serum phosphate is
1.0 to 1.9 mg/dL (0.32 to 0.63 mmol/L)
treat with intravenous phosphate if the serum
phosphate is less than 1.0 mg/dL (0.32 mmol/L) and
switch to oral replacement when the serum
phosphate exceeds 1.5 mg/dL (0.48 mmol/L)

CKD-MBD

Disturbances of mineral
metabolism are common if not
ubiquitous during the course of
chronic kidney disease (CKD) and
lead
to serious and debilitating
complications unless these
abnormalities are addressed and
. treated

The spectrum of disorders includes

abnormal concentrations of serum
calcium, phosphate, and magnesium
and disorders of parathyroid
hormone (PTH) and
.vitamin D metabolism

Osteitis fibrosa, a manifestation of hyperparathyroidismcharacterized by increased osteoclast and osteoblast

,activity
.peritrabecular fibrosis, and increased bone turnover
Osteomalacia, a manifestation of defectivemineralization
of newly formed osteoid most often caused by
aluminum
.deposition; bone turnover is decreased
Adynamic bone disease, a condition characterized by.abnormally low bone turnover
.Osteopenia or osteoporosisCombinations of these abnormalities termed mixedrenal
.osteodystrophy
Other abnormalities with skeletal manifestations
.(chronic acidosis, b2-microglobulin amyloidosis)

EPIDEMIOLOGY
In patients on hemodialysis, osteitis
fibrosa and
adynamic bone disease now occur with
.almost equal frequency
In contrast, in patients on peritoneal
dialysis, the adynamic bone
.lesion predominates

Osteomalacia represents only a small

fraction
of cases in either group but is more
common in certain ethnic groups,
. particularly Indo-Asians
The abnormalities of the skeleton start
relatively early in the course of CKD

PATHOGENESIS

Osteitis Fibrosa:
Hyperparathyroidism:
High-Turnover Renal Bone
Disease

Elevated levels of PTH in blood and

hyperplasia of the parathyroid
glands are seen early in CKD

Abnormalities of Calcium
Metabolism

Total serum calcium tends to decrease

during the course of CKD as a result of
phosphate retention and decreased
production of 1,25-dihydroxyvitamin D
(calcitriol) from the kidney, decreased
intestinal calcium absorption, and
skeletal resistance to the calcemic action
of PTH, but the levels of free calcium
remain within the normal range in most
patients as a result of compensatory
.hyperparathyroidism

Because calcium is a major regulator

of PTH secretion, persistent
hypocalcemia is a powerful stimulus
for the development of
hyperparathyroidism and also
.contributes to parathyroid growth

Abnormalities of Phosphate
Metabolism
With progressive CKD, phosphate is retained
.by the kidney
However, hyperphosphatemia usually does
not become evidentbefore CKD stage 4.
Until then, compensatory
hyperparathyroidism
and increases in circulating fibroblast growth
factor 23(FGF-23) result in increased
phosphaturia, maintaining serum
.phosphate levels in the normal range

Abnormalities of Vitamin D
Metabolism
The conversion of 25-hydroxyvitamin D
to its active metabolite 1,25dihydroxyvitamin D occurs mainly in
the kidney by the enzyme 1hydroxylase
Renal calcitriol production
progressively declines during the
course of CKD

:Calcitriol production decresed by

reduction in 25-hydroxyvitamin Dlevels
decrease in GFRlimits the delivery of 25-hydroxyvitamin D to the site of the
1-hydroxylase in the proximal
tubule
phosphate retentionPTH-

Low levels of calcitriol directly release

the gene for PTH from suppression by
the
vitamin D receptor and allow increased
PTH secretion
Administration of calcitriol has been
shown to increase the vitamin D
receptor content in the parathyroid
glands coincident
with the suppression of PTH secretion

Low levels of calcitriol may also

promote the development of
hyperparathyroidism :indirectly
reductions in intestinal absorption ofcalcium, leading to hypocalcemia
and stimulation of PTH release
skeletal resistance to the calcemicactions of PTH

Abnormalities of Parathyroid
Gland Function
parathyroid hyperplasia is an earlyfinding in
CKD
decreased expression of vitamin Dreceptors
decreased expression of calciumreceptors

Abnormal Skeletal Response to

Parathyroid Hormone
in CKD, the skeleton is relatively
resistant the calcemic actions of PTH

TREATMENT OF HIGH-TURNOVER
BONE DISEASE
Prevention is the primary goal in the
management of renal
.osteodystrophy
Therapy for hyperparathyroidism
should ideally be initiated in CKD
stage 3 so that parathyroid gland
.hyperplasia can be prevented

Prevention of Hypocalcemia
Control of Phosphate
Use of Vitamin D Metabolites
Calcimimetics
Parathyroidectomy

Prevention of Hypocalcemia
The initial approach to therapy for
hypocalcemia in mild to moderate CKD
is the administration of calcium
supplements such as calcium
carbonate, taken between meals with
increasing doses as required
Assessment of vitamin D status should be
undertaken by measurement
of 25-hydroxyvitamin D, and this should
be corrected if it is below 30 ng/ml

Assessment of efficacy of therapy is by

follow-up determinations of serum
. calcium and PTH
Adjunctive therapy with active vitamin
D sterols should be considered if
hyperparathyroidism or
.hypocalcemia persists

In patients with ESRD, active vitamin D

.sterols are often required
In dialysis patients, the goal is to
achieve levels of iPTH that are
approximately two to nine times
above the upper limit of the assay
.used

Control of Phosphate
Dietary Phosphate Restriction
Phosphate Binders

Approximate potential
phosphate binding
capacities

Calcium carbonate
Calcium acetate
Sevelamer
mg
Lanthanium carbonate
Aluminium hydrixide

1 gr binds 40 mg
1 gr binds 45 mg
1 gr binds 36

1 gr binds 93 mg
1 gr binds 25 mg

Vitamin D Metabolites
Calcitriol and other 1-hydroxylated
vitamin D sterols, such as 1hydroxyvitamin D3 (alfacalcidol), 1hydroxyvitamin D2
and 19-nor-1,25-), doxercalciferol(
,dihydroxyvitamin D2 (paricalcitol)
are effective in the control of
.secondary hyperparathyroidism

Complications of vit D therapy

hypercalcemiaaggravation of hyperphosphatemia-

Calcimimetics
Cinacalcet
In dialysis patients, cinacalcet results
in a
significant fall in PTH levels and when
administered daily can facilitate the
control of hyperparathyroidism

Parathyroidectomy
Parathyroidectomy is indicated for
patients with severe
hyperparathyroidism that cannot be
controlled medically (phosphate
binders, vitamin D sterols, or
).calcimimetic

Indications for PTX

:Severe hyperparathyroidism
With persistent hyperphosphatemiaunresponsive to calcitriol and Cawith hypercalcemiain renal transplantation candidatewith evidence of mtastaticcalcification
Calcifilaxis with HPT

LOW-TURNOVER RENAL OSTEOPATHY

Adynamic bone disease (ABD) describes
the morphologic consequences of lowturnover osteopathy in CKD. As CKD
,progresses
high-turnover renal osteodystrophy initially
develops as an adaptive response to
counteract the increasing skeletal PTH
resistance and phosphate overload
ABD probably results from too rigorous
suppression of this adaptive response

Adynamic bone disease (ABD)

affected >40% in CKD stage 5
association with cardiovascular
calcification
mortality
fracture incidence twice as high in
individuals with low than with high
bone turnover

risk factors of ABD

advanced agediabetes mellitusperitoneal dialysis-

Pathogenesis of Adynamic Bone

Disease
relative resistance of the PTH-1 receptor to its ligand PTH as CKD progresses
inadequately low PTH levels, whichcause suppression or cessation of both
osteoblast
and osteoclast activities, resulting in a
reduced bone formation rate and low
bone mass

Iatrogenic oversuppression of PTH in

:CKD mostly results from
high-dose active vitamin D metabolitetreatment
calcium loading (phosphate binders,high dialysate calcium concentration)
parathyroidectomydiabetes, uremic toxins, malnutrition-

Diagnosis
Low iPTH levels (<100 pg/ml) are
almost always indicative of low bone
turnover in CKD stage 5
However, histologically proven ABD
may occur in many dialysis patients
with iPTH levels of up to 300 pg/ml
and, in exceptions, of up to 600
pg/ml

PTH levels alone are not a sensitive

biomarker
of ABD

Serum levels or activities of alkaline

phosphatase or bone-specific alkaline
;phosphatase are usually normal or low
downward trends may indicate the
development of ABD. Serum calcium
and phosphate can be normal or
elevated, dependent on
the choices of co-treatment (phosphate
binders, vitamin D metabolites) and on
the nutritional status

The gold standard for diagnosis of ABD

is bone biopsy

Treatment of Adynamic Bone

Disease
The key therapeutic approaches in the
treatment of ABD are to avoid PTH
overexpression and to restore
adequate PTH levels, without
triggering the progressive
development of secondary
.hyperparathyroidism

reduction or withdrawal of activevitamin D metabolites

reduction or withdrawal of calcium-containing phosphate binders
reduction of the dialysate calciumconcentration (usually to 1.25
mmol/l)
any aluminum should be withdrawn-

optimized diabetes controlchange from peritoneal dialysis tohemodialysis

administration of recombinant PTH e.g., for patients after total(
)parathyroidectomy
many patients with ABD remain
refractory to treatment

KDIGO, Kidney Disease:

Improving Global Outcomes
In adults, recommend monitoring
serum calcium, phosphorus, PTH,
and ALP levels beginning in CKD
stage 3

KDIGO, Kidney Disease:

Improving Global Outcomes
In children, suggest monitoring serum
,calcium
phosphorus, PTH, and ALP levels
beginning
in CKD stage 2

KDIGO, Kidney Disease:

Improving Global Outcomes
In CKD stages 3-5D, suggestmeasuring
D levels)OH(25
vitamin D deficiency and insufficiencybe corrected using treatment
strategies recommended for the
general population

KDIGO, Kidney Disease:

Improving Global Outcomes
, In patients with CKD stages 3-5D
measurements of serum PTH or bonespecific
ALP can be used to evaluate bone
disease
because markedly high or low values
predict
underlying bone turnover

KDIGO, Kidney Disease:

Improving Global Outcomes
,In CKD stages 3-5 not on dialysis therapy
suggest evaluating patients with PTH
levels
above the upper reference limit of the
assay
for hyperphosphatemia, hypocalcemia,
and
vitamin D deficiency

KDIGO, Kidney Disease:

Improving Global Outcomes
:In CKD stages 3-5
serum phosphorus in the referencerange
serum Ca in reference rangeCa x P <55-

Approximate potential
phosphate binding
capacities

Calcium carbonate
Calcium acetate
Sevelamer
mg
Lanthanium carbonate
Aluminium hydrixide

1 gr binds 40 mg
1 gr binds 45 mg
1 gr binds 36

1 gr binds 93 mg
1 gr binds 25 mg

KDIGO, Kidney Disease:

Improving Global Outcomes
In CKD stage 5D, suggest maintaining
PTH level
in the range of 2-9 times the upper
reference
limit(65 ng/l) for the assay

KDIGO, Kidney Disease:

Improving Global Outcomes
In patients with CKD stage 5D and
:increasing PTH levels
calcitriol,vitamin D analogues,
calcimimetics, or a combination of
calcimimetics and calcitriol or
vitamin D analogues be used to
decrease PTH levels

KDIGO, Kidney Disease:

Improving Global Outcomes
In patients in the immediate post
kidney
transplant period, recommend
measuring
serum calcium and phosphorus at least
weekly until stable