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 % 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

51. 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.

53. 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

55. 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

56. 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

59. 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

60. 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

61. 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

63. 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

65. 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.

68. 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

70. Secondary Hyperparathyroidism Treatment Options

71. Dietary Restriction of Phosphorus
Phosphate Binders (calcium or non-calcium containing)
Vitamin D Analogues
Calcimimetics
Parathyroidectomy

72. Dietary Phosphate Restriction
800 – 1,000 mg per day
Reverses abnormalities of mineral metabolism
Increases plasma calcitriol
Diminishes PTH levels
Improves Ca2+ intestinal absorption

74. 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

75. 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.

76. Vitamin D Ergocalciferol Limit dose of active Vitamin D analogues:
Paricalcitol
Doxercalciferol
Calcitriol
Dose limited by hypercalcemia and hyperphosphatemia

77. 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

78. 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

79. Treatment Goals in Dialysis Patients
Intact PTH between pg/mL
Serum Phosphate between mg/dL
Serum levels of total corrected Calcium between mg/dL

80. 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

81. References
Brenner, Barry M. Brenner & Rector’s The Kidney. 8th Edition. Saunders Elsevier Pp
Rose, Burton D. and Theodore W. Post. Chapter 6F: Hormonal Regulation of Calcium and Phosphate Balance. Up To Date Pp
Rose, Burton D. and Theodore W. Post. Chapter 6G: Calcium and Phosphate Metabolism in Renal Failure. Up To Date Pp. 1-8.
Qunibi, Wajeh Y. and William L. Henrich. Pathogenesis of Renal Osteodystrophy. Up To Date Pp
Quarles, Darryl L. Bone Biopsy and the Diagnosis of Renal Osteodystrophy. Up To Date Pp
Quarles, Darryl L. and Robert E. Cronin. Management of Secondary Hyperparathyroidism and Mineral Metabolism Abnormalities in Dialysis Patients. Up To Date Pp