Presentation on theme: "Ca++, PO4, PTH & VIT D Calcium, Phosphorus & Vitamin D"— Presentation transcript:
1Ca++, PO4, PTH & VIT D Calcium, Phosphorus & Vitamin D In Chronic Renal FailureBy Dr. Rick Hiller
2Phosphorus 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.
3Phosphorus 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.
4Phosphorus 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
5Phosphorus Homeostasis 60-70% of dietary phosphorus is absorbed by the GI tract via:Passive transportActive transport stimulated by calcitriol and PTHAntacids, phosphate binders, and calcium bind to phosphorus, decreasing the free amount available for absorption
6Phosphorus 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.
7Phosphorus 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.
9Calcium Measurement and Balance Normal Concentration between 8.5 and 10.5 mg/dLSerum levels are % of extracellular calcium; this is only 1% of total body calciumThe remainder of total body calcium is stored in bone.
10Calcium 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 phosphateIonized 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
11Calcium Measurement and Balance PTH regulates serum ionized calcium byIncreasing bone resorptionIncreasing renal calcium reabsorptionIncreasing the conversion of 25(OH)D to 1,25(OH)2D in the kidney which increases the GI absorption of calcium
13Calcium Measurement and Balance Decreased PTH and Vit. D maintain protection against calcium overload by increasing renal excretion and reducing intestinal absorption.
14Calcium HomeostasisCalcium 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
16Calcium-Sensing Receptor Expressed in organs controlling calcium homeostasis: parathyroid gland, thyroid C cells, intestines, and kidneys.Expression is regulated by 1,25(OH)2D
17Synthesis and Measurement of Vitamin D Vitamin D3 is metabolized in the skin from 7-dehydrocholesterolVitamin D2 (ergocalciferol) is obtained in the diet from plant sourcesVitamin D3 (cholecalciferol) is also obtained in the diet from animal sources
18Synthesis 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
20Physiologic Effects of Vitamin D Facilitates the uptake of calcium in the intestinal and renal epitheliumEnhances the transport of calcium through and out of cellsIs important for normal bone turnover
21Physiologic Effects of Vitamin D Elevated serum PTH increases the hydroxylation of Vitamin D in the kidneyThis causes a rise in serum calcium and feeds back to the parathyroid gland decreasing PTH secretion
24Regulation and Biologic Effects of Parathyroid Hormone Primary function of PTH is to maintain calcium homeostasis by:Increasing bone mineral dissolutionIncreasing renal reabsorption of calcium and excretion of phosphorusIncreasing activity of renal 1-α-hydroxylaseEnhancing GI absorption of calcium and phosphorus
30Measurement of PTH Plasma PTH levels provide: a noninvasive way to initially diagnose renal bone diseaseAllow for monitoring of the disorderProvide a surrogate measure of bone turnover in patients with CKD
32Effects of CKD Chronic Renal Failure disrupts homeostasis by: Decreasing excretion of phosphateDiminishing the hydroxylation of 25(OH)D to calcitriolDecreasing serum calciumLeads to Secondary Hyperparathyroidism
34Secondary HPTInitially, 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%
35Secondary HPTSecondary HPT begins when the GFR declines to <60 ml/min/1.73m2Serum Ca2+ and PO4 levels remain normal until GFR declines to 20 ml/min/1.73m2Low levels of calcitriol occur much earlier, possibly even before elevations in iPTH.
36Secondary HPT Secondary HPT tries to correct: hypocalcemia by increasing bone resorptionCalcitriol deficiency by stimulating 1-hydroxylation of calcidiol (25-hydroxyvitamin D) in the proximal tubule
37Hypocalcemia Total Serum Calcium usually decreases during CKD due to: Phosphate retentionDecreased calcitriol levelResistance to the calcemic actions of PTH on bone
38Hypocalcemia Potent stimulus to the release of PTH Increases mRNA levels via posttranscriptionStimulates proliferation of parathyroid cellsPlays a predominant role via CaSR:Major therapeutic target for suppressing parathyroid gland function
42Decreased Vitamin DDecreases calcium and phosphorus absorption in the GI tract.Directly increases PTH production due to the absence of the normal suppressive effect of calcitriolIndirectly increases secretion of PTH via the GI mediated hypocalcemic stimulus
43Decreased Vitamin DAdministering calcitriol to normalize plasma levels can prevent or reverse secondary HPTCalcitriol deficiency may change the set point between PTH and plasma free calcium
45Mechanisms by which Phosphate Retention may lead to HPT Diminishes the renal production of calcitriolDirectly increases PTH gene expressionHyperphosphatemia, 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
47Secondary HPTIf phosphate retention is prevented, then secondary hyperparathyroidism does not occur.
48If Secondary HPT is not corrected Renal OsteodystrophyOsteitis fibrosa cystica – predominantly hyperparathyroid bone diseaseAdynamic bone disease – diminished bone formation and resorptionOsteomalacia – defective mineralization in association with low osteoclast and osteoblast activitiesMixed uremic osteodystrophy – hyperparathyroid bone disease with a superimposed mineralization defectMetastatic calcification
53Low Bone Turnover Most patients are asymptomatic Increased risk of fracture due to impaired remodelingIncreased risk of vascular calcification due to inability of bone to buffer an acute calcium load
55Metabolic Acidosis and Bone Mineral Disease Stimulates physiochemical mineral dissolution buffering excess hydrogen ionsLeads to a gradual decline in bone calcium storesStimulates cell-mediated bone resorption via stimulating osteoclastic activityAlkali therapy can slow progression of uremic bone disease
56New Classification of Bone Disease Developed to help clarify the interpretation of bone biopsy resultsProvide a clinically relevant description of underlying bone pathologyHelps define pathophysiology and guide treatment
59Vascular Calcification Cardiovascular disease remains the leading cause of morbidity and mortality in CKDDisorders of Mineral MetabolismAccelerated atherosclerosisArterial calcificationIncreased risk of adverse cardiovascular outcomes and death
60Extraosseous Calcification Calcium phosphate precipitation into joints, arteries, soft tissues, and visceraCalciphylaxisWhen the fraction of reabsorbed filtered phosphate declines to 15%, PTH cannot increase phosphate excretion but does continue to release calcium phosphate from bone
61Phosphorus and Calcium in CKD Hyperphosphatemia brings with it a very high population attributable risk of deathCombination of hyperphosphatemia, hypercalcemia, and elevated PTH accounted for 17.5% of observed, explainable mortality in HD patients
63Vascular Calcification Late in the disease, fibrofatty plaques protrude into the arterial lumen, leading to a filling defect on angiographyEarly in the disease, atherosclerosis can be a circumferential lesion without lumen obstruction
65Vascular Calcification Dialysis Patients have calcification scores that are two-to five fold greater than age-matched individuals with normal kidney function and angiographically proven CADDialysis patients have increased arterial calcification (intimal disease and medial layer thickening) in coronary, renal, and iliac arteries.
68Post-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 medicationsPersistence of underlying disordersDevelopment of hyperphosphaturia with hypophosphatemia
74Phosphate Binders Limit the absorption of dietary phosphate Calcium SaltsNon-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
75Phosphate BindersVitamin D will increase the intestinal absorption of calcium: calcium containing binders should be reduced accordinglyPatients with low turnover bone disease will deposit excess calcium in extraskeletal sites because their bones cannot take up the calcium.
76Vitamin D Ergocalciferol Limit dose of active Vitamin D analogues: ParicalcitolDoxercalciferolCalcitriolDose limited by hypercalcemia and hyperphosphatemia
77VITAMIN D ANALOGUESReduce dose of active Vitamin D as PTH levels diminish.Adjust dose every 4-8 weeksDiscontinue calcitriol during hypercalcemiaContraindicated with PTH levels less than 150 pg/ml
78Calcimimetics Increase the sensitivity of the CaSR Decrease PTH gene expressionIncrease Vitamin D receptor expressionCan reduce plasma PTH by more than 50%Cinacalcet (Sensipar)Limited by hypocalcemia
79Treatment Goals in Dialysis Patients Intact PTH between pg/mLSerum Phosphate between mg/dLSerum levels of total corrected Calcium between mg/dL
80Treatment Strategy Reduce Serum Phosphate to normal range Limit Excessive Calcium LoadingUse Calcimimetic for elevated PTH with Ca>9.5Avoid active Vitamin D analogues and if used, reduce dose as treatment progressesPrevent progression of parathyroid diseaseMaintain bone health and prevent fractures
81ReferencesBrenner, Barry M. Brenner & Rector’s The Kidney. 8th Edition. Saunders Elsevier PpRose, Burton D. and Theodore W. Post. Chapter 6F: Hormonal Regulation of Calcium and Phosphate Balance. Up To Date PpRose, 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 PpQuarles, Darryl L. Bone Biopsy and the Diagnosis of Renal Osteodystrophy. Up To Date PpQuarles, Darryl L. and Robert E. Cronin. Management of Secondary Hyperparathyroidism and Mineral Metabolism Abnormalities in Dialysis Patients. Up To Date Pp