Ca++, PO4, PTH & VIT D
Calcium, Phosphorus & Vitamin D
In Chronic Renal Failure
By Dr. Rick Hiller
Phosphorus Measurement and
Balance
• Normal concentration between 2.5 and 4.5
mg/dl.
• 85% of total body stores are contained in
bone (hydroxyapatite), 14% is intracellular,
and 1% extracellular.
Phosphorus Measurement and
Balance
• 70% of the extracellular phosphorus is organic
(phospholipids) and the remaining 30% is
inorganic.
• 15% of the inorganic is protein bound; the
remaining is complexed with sodium, magnesium,
or calcium or circulates as free monohydrogen or
dihydrogen forms.
• This freely circulating phosphorus is what is
measured.
Phosphorus Measurement and
Balance
• 2/3 of ingested phosphorus is excreted in
urine; the remaining in stool.
• Foods high in phosphorus are also high in
protein.
• Three organs are involved in phosphate
homeostasis: intestine, kidney, and bone.
• Major hormones involved are Vit. D and
PTH
Phosphorus Homeostasis
• 60-70% of dietary phosphorus is absorbed
by the GI tract via:
– Passive transport
– Active transport stimulated by calcitriol and
PTH
• Antacids, phosphate binders, and calcium
bind to phosphorus, decreasing the free
amount available for absorption
Phosphorus Homeostasis
• Inorganic phosphorus is freely filtered by
the glomerulus.
• 70-80% is then reabsorbed in the proximal
tubule. The remaining is reabsorbed in the
distal tubule.
• Phosphorus excretion can be increased
primarily by increasing plasma phosphorus
concentration and PTH.
Phosphorus Homeostasis
• Phosphorus excretion can also be increased
to a lesser degree by volume expansion,
metabolic acidosis, glucocorticoids, and
calcitonin.
• This regulation occurs in the proximal
tubule via the sodium-phosphate
cotransporter.
Calcium Measurement and
Balance
• Normal Concentration between 8.5 and 10.5
mg/dL
• Serum levels are 0.1-0.2% of extracellular
calcium; this is only 1% of total body
calcium
• The remainder of total body calcium is
stored in bone.
Calcium Measurement and
Balance
• Ionized calcium is physiologically active
and is 40% of total serum calcium.
• Non-ionized calcium is bound to albumin,
citrate, bicarbonate, and phosphate
• Ionized calcium can be corrected from total
calcium by adding 0.8 mg/dL for every 1
mg decrease in serum albumin below 4
mg/dL
Calcium Measurement and
Balance
• PTH regulates serum ionized calcium by
– Increasing bone resorption
– Increasing renal calcium reabsorption
– Increasing the conversion of 25(OH)D to
1,25(OH)2D in the kidney which increases the
GI absorption of calcium
Calcium Measurement and
Balance
• Decreased PTH and Vit. D maintain
protection against calcium overload by
increasing renal excretion and reducing
intestinal absorption.
Calcium Homeostasis
• Calcium absorption primarily occurs in the
duodenum through Vit. D dependent and
Vit. D independent pathways.
• 60-70% of calcium is reabsorbed passively
in the proximal tubule, with another 10%
reabsorbed in the thick ascending limb
Calcium-Sensing Receptor
• Expressed in organs controlling calcium
homeostasis: parathyroid gland, thyroid C
cells, intestines, and kidneys.
• Expression is regulated by 1,25(OH)2D
Synthesis and Measurement of
Vitamin D
• Vitamin D3 is metabolized in the skin from
7-dehydrocholesterol
• Vitamin D2 (ergocalciferol) is obtained in
the diet from plant sources
• Vitamin D3 (cholecalciferol) is also
obtained in the diet from animal sources
Synthesis and Measurement of
Vitamin D
• In the Liver, Vitamins D2 and D3 are
hydroxylated to 25(OH)D (calcidiol)
• Calcidiol then travels to the kidney where it
is converted to 1,25(OH)2D
Physiologic Effects of Vitamin D
• Facilitates the uptake of calcium in the
intestinal and renal epithelium
• Enhances the transport of calcium through
and out of cells
• Is important for normal bone turnover
Physiologic Effects of Vitamin D
• Elevated serum PTH increases the
hydroxylation of Vitamin D in the kidney
• This causes a rise in serum calcium and
feeds back to the parathyroid gland
decreasing PTH secretion
Regulation and Biologic Effects of
Parathyroid Hormone
• Primary function of PTH is to maintain
calcium homeostasis by:
– Increasing bone mineral dissolution
– Increasing renal reabsorption of calcium and
excretion of phosphorus
– Increasing activity of renal 1-α-hydroxylase
– Enhancing GI absorption of calcium and
phosphorus
Regulation of Parathyroid Hormone
• Hypocalcemia is more important in
stimulating PTH release
• Normal or elevated Calcitriol is more
important in inhibiting PTH release
Regulation of Parathyroid Hormone
• Increased PTH in Secondary
Hyperparathyroidism is due to:
–
–
–
–
–
Loss of renal mass
Low 1,25(OH)2D
Hyperphosphatemia
Hypocalcemia
Elevated FGF-23
Measurement of PTH
• Plasma PTH levels provide:
– a noninvasive way to initially diagnose renal
bone disease
– Allow for monitoring of the disorder
– Provide a surrogate measure of bone turnover
in patients with CKD
Effects of CKD
• Chronic Renal Failure disrupts homeostasis
by:
– Decreasing excretion of phosphate
– Diminishing the hydroxylation of 25(OH)D to
calcitriol
– Decreasing serum calcium
• Leads to Secondary Hyperparathyroidism
Secondary HPT
• Initially, the hypersecretion of PTH is
appropriate to normalize plasma Ca2+ and
phosphate concentrations.
• Chronically, it becomes maladaptive,
reducing the fraction of filtered phosphate
that is reabsorbed from 80-95% to 15%
Secondary HPT
• Secondary HPT begins when the GFR
declines to <60 ml/min/1.73m2
• Serum Ca2+ and PO4 levels remain normal
until GFR declines to 20 ml/min/1.73m2
• Low levels of calcitriol occur much earlier,
possibly even before elevations in iPTH.
Secondary HPT
• Secondary HPT tries to correct:
– hypocalcemia by increasing bone resorption
– Calcitriol deficiency by stimulating 1hydroxylation of calcidiol (25-hydroxyvitamin
D) in the proximal tubule
Hypocalcemia
• Total Serum Calcium usually decreases
during CKD due to:
– Phosphate retention
– Decreased calcitriol level
– Resistance to the calcemic actions of PTH on
bone
Hypocalcemia
• Potent stimulus to the release of PTH
– Increases mRNA levels via posttranscription
– Stimulates proliferation of parathyroid cells
• Plays a predominant role via CaSR:
• Major therapeutic target for suppressing
parathyroid gland function
Decreased Vitamin D
• Decreases calcium and phosphorus
absorption in the GI tract.
• Directly increases PTH production due to
the absence of the normal suppressive effect
of calcitriol
• Indirectly increases secretion of PTH via
the GI mediated hypocalcemic stimulus
Decreased Vitamin D
• Administering calcitriol to normalize
plasma levels can prevent or reverse
secondary HPT
• Calcitriol deficiency may change the set
point between PTH and plasma free calcium
Mechanisms by which Phosphate
Retention may lead to HPT
• Diminishes the renal production of calcitriol
• Directly increases PTH gene expression
• Hyperphosphatemia, hypocalcemia, and
elevated PTH account for ~17.5% of
observed, explainable mortality risk in HD
patients with the major cause of death being
cardiovascular events
Secondary HPT
• If phosphate retention is
prevented, then secondary
hyperparathyroidism does
not occur.
If Secondary HPT is not corrected
• Renal Osteodystrophy
– Osteitis fibrosa cystica – predominantly
hyperparathyroid bone disease
– Adynamic bone disease – diminished bone formation
and resorption
– Osteomalacia – defective mineralization in association
with low osteoclast and osteoblast activities
– Mixed uremic osteodystrophy – hyperparathyroid bone
disease with a superimposed mineralization defect
• Metastatic calcification
Renal Osteodystrophy
• Serum intact PTH Predicts severity of HPT,
but not necessarily bone disease
• PTH < 100 pg/mL – adynamic bone disease
• PTH > 450 pg/mL – hyperparathyroid bone
disease and/or mixed osteodystrophy
• PTH < 200 pg/mL – increased risk of
fracture
Renal Osteodystrophy
• Low serum bone-specific alkaline
phosphatase (<= 7 ng/mL) and a low serum
PTH suggests a low remodeling disorder
• Elevated alkaline phosphatase (>= 20
ng/mL) alone or with increased serum PTH
(>200 pg/mL) suggests high turnover bone
disease.
Low Bone Turnover
• Most patients are asymptomatic
• Increased risk of fracture due to impaired
remodeling
• Increased risk of vascular calcification due
to inability of bone to buffer an acute
calcium load
Metabolic Acidosis and Bone
Mineral Disease
• Stimulates physiochemical mineral
dissolution buffering excess hydrogen ions
• Leads to a gradual decline in bone calcium
stores
• Stimulates cell-mediated bone resorption
via stimulating osteoclastic activity
• Alkali therapy can slow progression of
uremic bone disease
New Classification of Bone Disease
• Developed to help clarify the interpretation
of bone biopsy results
• Provide a clinically relevant description of
underlying bone pathology
• Helps define pathophysiology and guide
treatment
Vascular Calcification
• Cardiovascular disease remains the leading
cause of morbidity and mortality in CKD
• Disorders of Mineral Metabolism
– Accelerated atherosclerosis
– Arterial calcification
– Increased risk of adverse cardiovascular
outcomes and death
Extraosseous Calcification
• Calcium phosphate precipitation into joints,
arteries, soft tissues, and viscera
• Calciphylaxis
• When the fraction of reabsorbed filtered phosphate
declines to 15%, PTH cannot increase phosphate
excretion but does continue to release calcium
phosphate from bone
Phosphorus and Calcium in CKD
• Hyperphosphatemia brings with it a very
high population attributable risk of death
• Combination of hyperphosphatemia,
hypercalcemia, and elevated PTH accounted
for 17.5% of observed, explainable
mortality in HD patients
Vascular Calcification
• Late in the disease, fibrofatty plaques
protrude into the arterial lumen, leading to a
filling defect on angiography
• Early in the disease, atherosclerosis can be a
circumferential lesion without lumen
obstruction
Vascular Calcification
• Dialysis Patients have calcification scores
that are two-to five fold greater than agematched individuals with normal kidney
function and angiographically proven CAD
• Dialysis patients have increased arterial
calcification (intimal disease and medial
layer thickening) in coronary, renal, and
iliac arteries.
Post-Renal Transplant Bone Disease
• Kidney Transplantation returns patients to
CKD and to CKD-MBD.
• Disorders of mineral metabolism occur post
transplant and include:
– Effects of medications
– Persistence of underlying disorders
– Development of hyperphosphaturia with
hypophosphatemia
TREATMENT
Secondary
Hyperparathyroidism
Treatment Options
• Dietary Restriction of Phosphorus
• Phosphate Binders (calcium or non-calcium
containing)
• Vitamin D Analogues
• Calcimimetics
• Parathyroidectomy
Dietary Phosphate Restriction
• 800 – 1,000 mg per day
• Reverses abnormalities of mineral
metabolism
– Increases plasma calcitriol
– Diminishes PTH levels
– Improves Ca2+ intestinal absorption
Phosphate Binders
• Limit the absorption of dietary phosphate
• Calcium Salts
• Non-calcium containing (sevelamer and
lanthanum carbonate)
• Calcium containing binders should be limited to
<1500 mg of elemental calcium per day to keep
total calcium intake <2000 mg per day
Phosphate Binders
• Vitamin D will increase the intestinal
absorption of calcium: calcium containing
binders should be reduced accordingly
• Patients with low turnover bone disease will
deposit excess calcium in extraskeletal sites
because their bones cannot take up the
calcium.
Vitamin D
•
•
•
•
•
•
Ergocalciferol
Limit dose of active Vitamin D analogues:
Paricalcitol
Doxercalciferol
Calcitriol
Dose limited by hypercalcemia and
hyperphosphatemia
VITAMIN D ANALOGUES
• Reduce dose of active Vitamin D as PTH
levels diminish.
• Adjust dose every 4-8 weeks
• Discontinue calcitriol during hypercalcemia
• Contraindicated with PTH levels less than
150 pg/ml
Calcimimetics
•
•
•
•
•
•
Increase the sensitivity of the CaSR
Decrease PTH gene expression
Increase Vitamin D receptor expression
Can reduce plasma PTH by more than 50%
Cinacalcet (Sensipar)
Limited by hypocalcemia
Treatment Goals in Dialysis
Patients
• Intact PTH between 150-300 pg/mL
• Serum Phosphate between 3.5-5.5 mg/dL
• Serum levels of total corrected Calcium
between 8.4-9.5 mg/dL
Treatment Strategy
• Reduce Serum Phosphate to normal range
• Limit Excessive Calcium Loading
• Use Calcimimetic for elevated PTH with
Ca>9.5
• Avoid active Vitamin D analogues and if
used, reduce dose as treatment progresses
• Prevent progression of parathyroid disease
• Maintain bone health and prevent fractures
References
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Brenner, Barry M. Brenner & Rector’s The Kidney. 8th Edition. Saunders Elsevier 2008.
Pp. 1784-1809.
Rose, Burton D. and Theodore W. Post. Chapter 6F: Hormonal Regulation of Calcium
and Phosphate Balance. Up To Date 2010. Pp. 1-10.
Rose, Burton D. and Theodore W. Post. Chapter 6G: Calcium and Phosphate
Metabolism in Renal Failure. Up To Date 2010. Pp. 1-8.
Qunibi, Wajeh Y. and William L. Henrich. Pathogenesis of Renal Osteodystrophy. Up
To Date 2010. Pp. 1-15.
Quarles, Darryl L. Bone Biopsy and the Diagnosis of Renal Osteodystrophy. Up To
Date 2010. Pp. 1-17.
Quarles, Darryl L. and Robert E. Cronin. Management of Secondary
Hyperparathyroidism and Mineral Metabolism Abnormalities in Dialysis Patients. Up
To Date 2010. Pp. 1-21.