Ca++, PO4, PTH & VIT D

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.


• 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.


• 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


• 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 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.


• 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


• 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


• 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


• 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


• 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.

Ca++, PO4, PTH & VIT D

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