Ca++, PO4, PTH & VIT D

1. Ca++, PO4, PTH & VIT D Calcium, Phosphorus & Vitamin D In Chronic Renal Failure By Dr. Rick Hiller

2. 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.

3. 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.

4. 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

5. 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

6. 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.

7. 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.

9. 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.

10. 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

11. 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

13. Calcium Measurement and Balance • Decreased PTH and Vit. D maintain protection against calcium overload by increasing renal excretion and reducing intestinal absorption.

14. 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

16. 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

17. 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

18. 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

20. 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

21. 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

24. 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

27. Regulation of Parathyroid Hormone • Hypocalcemia is more important in stimulating PTH release • Normal or elevated Calcitriol is more important in inhibiting PTH release

28. 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

30. 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

32. 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

34. 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%

35. 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.

36. 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

37. Hypocalcemia • Total Serum Calcium usually decreases during CKD due to: • Phosphate retention • Decreased calcitriol level • Resistance to the calcemic actions of PTH on bone

38. 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

42. 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

43. 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

45. 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

47. Secondary HPT • If phosphate retention is prevented, then secondary hyperparathyroidism does not occur.

48. 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

50. 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