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 1-
hydroxylation 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 age-matched 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
• 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.