Calcium, Phosphorus, Magnesium, and Kidney Stones INTRO

Question 1

DISORDERS OF CALCIUM METABOLISM

CALCIUM BACKGROUND

Answer 1

Calcium Background Calcium is mostly bound and associated with bones (~99% of total body calcium, ~1 kg)

Question 2

DISORDERS OF CALCIUM METABOLISM

CALCIUM BACKGROUND

Answer 2

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))

Question 3

DISORDERS OF CALCIUM METABOLISM

CALCIUM BACKGROUND

Answer 3

2. 55% is diffusible (ultrafilterable) 40% to 50% exists as free ionized calcium 10% is complexed (e.g., to bicarbonate, citrate, phosphate anions)

Question 4

DISORDERS OF CALCIUM METABOLISM

CALCIUM BACKGROUND

Answer 4

Intracellular calcium concentration is minute at approximately 100 nmol/L, but may increase up to 10- to 100-fold during various cellular functions.

Question 5

DISORDERS OF CALCIUM METABOLISM

CALCIUM BACKGROUND

Answer 5

Physiologic roles of calcium: skeletal composition, neuromuscular excitation, cardiac and muscle contractility/function

Question 6

Calcium Metabolism

Gastrointestinal (GI)

Answer 6

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.

Question 7

Calcium Metabolism

Gastrointestinal (GI)

Answer 7

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.

Question 8

Calcium Metabolism

Gastrointestinal (GI)

Answer 8

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)

Question 9

Calcium Metabolism

Gastrointestinal (GI)

Answer 9

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.

Question 10

Calcium Metabolism

Gastrointestinal (GI)

Answer 10

Question 11

Calcium Metabolism

Renal Handling

Answer 11

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.

Question 12

Calcium Metabolism

Renal Handling

Answer 12

Proximal tubules: Ca2+ is absorbed via convection (parallels Na+ and water absorption). Any osmotic diuretic agent, for example, mannitol, reduces Ca2+ reabsorption.

Question 13

Calcium Metabolism

Renal Handling

Answer 13

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.

Question 14

Calcium Metabolism

Renal Handling

Answer 14

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.

Question 15

Calcium Metabolism

Renal Handling

Answer 15

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.

Question 16

Calcium Metabolism

Renal Handling

Answer 16

Question 17

Calcium Metabolism

Calcium Regulation

Vitamin D Regulation

Answer 17

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.

Question 18

Calcium Metabolism

Calcium Regulation

Vitamin D Regulation

Answer 18

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.

Question 19

Calcium Metabolism

Calcium Regulation

Vitamin D Regulation

Answer 19

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.

Question 20

Calcium Metabolism

Calcium Regulation

Vitamin D Regulation

Answer 20

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

Question 21

Calcium Metabolism

Calcium Regulation

Vitamin D Regulation

Answer 21

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

Question 22

Calcium Metabolism

Calcium Regulation

Parathyroid Hormone

Answer 22

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.

Question 23

Calcium Metabolism

Calcium Regulation

Parathyroid Hormone

Answer 23

Question 24

Calcium Metabolism

Calcium Regulation

Parathyroid Hormone

Answer 24

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)

Question 25

Calcium Metabolism

Calcium Regulation

Parathyroid Hormone

Answer 25

Reduces 1,25 vitamin D activity via inhibition of 1α-hydroxylase and stimulation of 24-hydroxylase activity

Inhibits PTH

FGF-23 expression is upregulated by increased phosphate “burden” (not necessarily actual hyperphosphatemia) and 1,25 vitamin D.

Question 26

Calcium Metabolism

Calcium Regulation

Parathyroid Hormone

Answer 26

NOTE

In chronic kidney disease (CKD), FGF-23 level increases before PTH.

Question 27

Calcium Intake and Outcomes: “Too Much of a Good Thing May Be Bad…”

Answer 27

Recent prospective longitudinal cohort study revealed that women with dietary calcium intake > 1400 mg/d had increased rate of all-cause-mortality, hazard ratio (HR) 1.4, and increased rate of cardiovascular disease, HR 1.49. All-cause-mortality HR increases to 2.57 if these women also took calcium supplements.

Question 28

Calcium Intake and Outcomes: “Too Much of a Good Thing May Be Bad…”

Answer 28

Recent short-term studies revealed that patients with CKD stage 3 or 4 can develop positive calcium balance when consuming dietary calcium ≥ 2,000 mg/d or receiving calcium carbonate supplement ≥ 1,500 mg daily.