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

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.