Calcium, Phosphorus, Magnesium, and Kidney Stones INTRO Flashcards
DISORDERS OF CALCIUM METABOLISM
CALCIUM BACKGROUND
Calcium Background Calcium is mostly bound and associated with bones (~99% of total body calcium, ~1 kg)
DISORDERS OF CALCIUM METABOLISM
CALCIUM BACKGROUND
Extracellular calcium concentration range: 9.0 to 10.6 mg/dL 1. 40% to 50% is protein bound (mostly albumin). Corrected total serum calcium concentration (SCa) for patients with hypoalbuminemia may be estimated as: Measured SCa (mg/dL) + 0.8 × (4.0 − serum albumin concentration (g/dL))
DISORDERS OF CALCIUM METABOLISM
CALCIUM BACKGROUND
- 55% is diffusible (ultrafilterable) 40% to 50% exists as free ionized calcium 10% is complexed (e.g., to bicarbonate, citrate, phosphate anions)
DISORDERS OF CALCIUM METABOLISM
CALCIUM BACKGROUND
Intracellular calcium concentration is minute at approximately 100 nmol/L, but may increase up to 10- to 100-fold during various cellular functions.
DISORDERS OF CALCIUM METABOLISM
CALCIUM BACKGROUND
Physiologic roles of calcium: skeletal composition, neuromuscular excitation, cardiac and muscle contractility/function
Calcium Metabolism
Gastrointestinal (GI)
Dietary calcium intake is approximately 1 g/d. Twenty percent is absorbed by the GI tract.
Paracellular absorption does not depend on vitamin D, but the favorable intraluminal gradient at the jejunum and ileum when calcium intake is high.
Calcium Metabolism
Gastrointestinal (GI)
Transcellular absorption occurs primarily in the duodenum when calcium intake is low:
a. Apical uptake by enterocytes is via the transient receptor potential TRPV6 calcium channel.
b. Cytoplasmic Ca2+ is taken up into mitochondria or endoplasmic reticulum, or transported into the basolateral side via Ca2+-ATPase, or in the presence of high intracytoplasmic Ca2+concentration, via the Na+-Ca2+ exchanger.
c. Calbindin D9k mediates Ca2+ transport across enterocytes into circulation.
Calcium Metabolism
Gastrointestinal (GI)
Hormonal regulations of GI absorption:
a. Calcitriol (1,25 vitamin D): 1,25 vitamin D binds to its receptor (VDR) to increase TRPV6 expression, calbindin D9k, and Ca2+-ATPase, all acting in concert to increase Ca2+absorption.
b. Other hormones that may contribute to increased GI absorption of calcium: estrogens, prolactin, growth hormone, parathyroid hormone (PTH)
Calcium Metabolism
Gastrointestinal (GI)
Intestinal Ca2+ absorption may be
a. Increased in acromegaly and excess vitamin D ingestion
b. Decreased in patients whose diet has low Ca2+/PO42− ratio, high vegetable fiber, or high fat content, older patients, patients with estrogen deficiency, corticosteroid use, or various medical conditions including diabetes, kidney failure, gastrectomy/bowel malabsorption.
Calcium Metabolism
Gastrointestinal (GI)
Calcium Metabolism
Renal Handling
Glomerular filtration: 8 to 10 g/d
a. Ultrafilterable Ca2+ load is determined by glomerular filtration rate (GFR), glomerular surface, ultrafiltration coefficient Kf, and ultrafilterable calcium load. PTH reduces Kf.
b. Respiratory and metabolic acidosis increase plasma ionized Ca2+, hence increased ultrafilterable Ca2+ load and wasting.
c. Metabolic acidosis enhances bone release of Ca2+, hence increased ultrafilterable Ca2+ load and wasting.
Calcium Metabolism
Renal Handling
Proximal tubules: Ca2+ is absorbed via convection (parallels Na+ and water absorption). Any osmotic diuretic agent, for example, mannitol, reduces Ca2+ reabsorption.
Calcium Metabolism
Renal Handling
Thick ascending limb of Henle loop: paracellular reabsorption, facilitated by claudin 16/19 and positive tubular lumen (created by K+ recycling via ROMK)
a. PTH enhances paracellular reabsorption.
b. Activation of calcium-sensing receptors (CaSR) by high extracellular Ca2+ or calcimimetics inhibits ROMK, hence reduced intraluminal K+ recycling and the associated positively charged lumen that drives paracellular Ca2+ reabsorption.
c. Loop diuretics reduce paracellular Ca2+ reabsorption due to reduced NKCC activity and subsequent ROMK activity. Downstream effect is similar to above.
Calcium Metabolism
Renal Handling
Distal tubules: luminal uptake is via the apical TRPV5 calcium channel, followed by reabsorption into the basolateral side via Ca2+-ATPase and Na+-Ca2+ exchanger.
a. Both PTH and calcitriol increase distal calcium reabsorption.
b. Thiazides and amiloride increase Ca2+ reabsorption in distal tubules.
Calcium Metabolism
Renal Handling
Despite the high amount of glomerular filtration of calcium, daily urinary excretion is minimal, <0.3 g/d, due to its effective reabsorption along the entire nephron.
Calcium Metabolism
Renal Handling
Calcium Metabolism
Calcium Regulation
Vitamin D Regulation
Vitamin D Metabolism
UV light (skin exposure) converts 7-dehydrocholesterol to cholecaliferol.
Liver hydroxylates cholecalciferol at the 25 carbon position to 25-OH vitamin D.
Kidney hydroxylates 25-OH vitamin D (via 1α-hydroxylase) to 1,25 (OH)2 vitamin D. This is the most biologically active form of vitamin D.
Calcium Metabolism
Calcium Regulation
Vitamin D Regulation
24-hydroxylation of 1,25 or 25 vitamin D (by 24-hydroxylase) to 1,24,25 or 24,25 vitamin D respectively renders the vitamin D inactive.
a. Overactivity of 24-hydroxylase leads to 1,25 vitamin D deficiency.
b. Underactivity of 24-hydroxylase (e.g., loss of function mutation of the enzyme) leads to 1,25 vitamin D excess.
Calcium Metabolism
Calcium Regulation
Vitamin D Regulation
c. Regulation of vitamin D-24-hydroxylase
1. PTH decreases 24-hydroxylase activity.
2. Vitamin D receptor (VDR) agonist (VDRA) (e.g., 1,25 vitamin D) increases 24-hydroxylase activity.
3. The fibroblast growth factor-23 (FGF-23) increases 24-hydroxylase activity while decreasing1α-hydroxylase activity. The former results in increased inactivation of 1,25-vitamin D while the latter leads to lower 1,25-vitamin D formation.
Calcium Metabolism
Calcium Regulation
Vitamin D Regulation
Of note, 1,25 vitamin D synthesis increases during puberty, pregnancy, and lactation.
Physiologic effects of 1,25 vitamin D:
a. Increases GI absorption of calcium and phosphate
b. Stimulates FGF-23 and 24-hydroxylase
Calcium Metabolism
Calcium Regulation
Vitamin D Regulation
c. Provides negative feedback on PTH via
1. Reducing PTH gene transcription
2. Increasing VDR and CaSR expressions on parathyroid cells
3. Reducing parathyroid cell proliferation
Maintains healthy bone formation and mineral homeostasis
Calcium Metabolism
Calcium Regulation
Parathyroid Hormone
Parathyroid Hormone
Primary function is to increase ionized calcium level in response to hypocalcemia
Increases 1,25 vitamin D:
a. Stimulates 1-α hydroxylase
b. Inhibits 24-hydroxylase
Increases calcium reabsorption at distal tubules
Phosphaturic effect: PTH induces phosphaturia.
Calcium Metabolism
Calcium Regulation
Parathyroid Hormone
Calcium Metabolism
Calcium Regulation
Parathyroid Hormone
Fibroblast Growth Factor-23 (FGF-23)
FGF-23 is a peptide produced by osteocytes and osteoblasts.
Induces phosphaturia by suppressing NPT2a and NPT2b (genes encoding two different sodium phosphate transporters in renal proximal tubules)
