Mineral Metabolism Flashcards
Normal Calcium Homeostasis
a. Calcium is an important divalent ion for cellular function.
b. Normal serum calcium is between 8.4 to 10.4 mg/dl.
c. The serum calcium can be divided into three pools: ionized calcium (50%), complexed to phosphate, citrate, carbonate, and other anions (10%), and protein bounded (40%), which is not filtered by the glomerulus.
d. Majority (99%) of total body calcium is store in bone. Only 1% in serum.
e. Renal calcium excretion balances gastrointestinal calcium absorption.
Renal Handling of Calcium Transport
a. Urinary excretion of calcium is approximately 200 mg per day.
b. The glomerulus freely filters the complexed and ionized calcium.
c. Less than 2% filtered calcium is excreted, and 98% filtered calcium is reabsorbed.
d. Most calcium transport is passive.
e. The major sites of calcium reabsorption are proximal tubules, thick ascending limbs, and distal tubules.
i. Proximal tubule–Reabsorb 65% Ca, 90% passive; 10% active. Parallel to Na reabsorption, influenced by volume status: Depletion: increase Na and Ca reabsorption, Overload: decrease Na and Ca reabsorption.
ii. TAL–Reabsorb 20% Ca, Mainly passive. Paracellular pathway mediated by paracellin-1. Lumen positive charge is the driving force (parallel to Na reabsorption), generated by Na, K,2Cl cotransporter and K channel. Transcellular pathway not identified.
iii. DCT– Reabsorb 10% Ca. Mainly transcellular transport. Active transport. Major regulatory site. Directions of Ca and Na transport tend to be opposite (through Na/Ca exchanger).
Hormonal Regulation of Calcium
a. PTH: PTH increase serum calcium level by increasing:
i. Calcium release from bone.
ii. Calcium reabsorption from the kidney
iii. Conversion of vitamin D to calcitriol by stimulating 1-α hydroxylase, thus indirectly increases GI calcium absorption.
b. Calcitriol i. Increases intestinal calcium absorption ii. Net effect of renal calcium excretion is unclear.
Factors Affecting Renal Calcium Excretion
i) Sodium: Saline infusion increases renal calcium excretion.
ii) Calcium: Dietary calcium increases calcium excretion.
iii) Phosphate: Dietary or IV phosphate increases calcium excretion.
iv) Proton: Acidosis increases calcium excretion.
v) PTH and calcitriol
Normal Phosphate Regulation
a. Majority (85%) of total body calcium is store in bone, 14% is intracellular(non-bone) and only 1% in serum.
b. Serum phosphate is found in both organic and inorganic forms. Only inorganic form (Pi) presents in biologic solution and can be filtered by glomerulus. Organic forms include phospholipids and various organic esters.
c. Normal serum phosphate is between 2.5 to 4.5 mg/dl.
d. Renal phosphate excretion balances gastrointestinal phosphate absorption
Renal Handling of Phosphate Transport
a. Urinary excretion of phosphate is approximately 800 mg per day.
b. About 12% filtered phosphate is excreted, and the remainder is reabsorbed.
c. The renal phosphate reabsorption occurs by an active transcellular pathway in the proximal tubules.
d. Filtered phosphate enter the apical brush border membrane of proximal tubule via the sodium-dependent phosphate cotransporters (type II and Type I) and then cross the basolateral membrane into the blood via the type III sodium-dependent phosphate cotransporter.
Hormonal Regulation of Phosphate
a. PTH.
i. PTH is the principal regulator of renal phosphate reabsorption. It reduces renal phosphate reabsorption by inhibition of type II sodium-dependent phosphate cotransporter. Therefore, it is phosphaturic.
ii. PTH also increases phosphate release from bone.
b. Calcitriol
i. Calcitriol is the principal regulator in the GI. It increases intestinal phosphate absorption by stimulating type IIc sodium-dependent phosphate cotransporter in the brush border membrane of small intestine.
ii) Calcitriol increases renal phosphate reabsorption in proximal tubules.
c. Phosphatonin
i) A group of substances that initially appear to regulate serum P levels in tumor-induced osteomalacia, X-linked hypophosphatemic rickets, and autosomal dominant hypophosphatemic rickets
ii) FGF 23 is one of the major phosphatonins
iii) It inhibits NaPi2a synthesis in proximal tubule and inhibits calcitriol synthesis by inhibiting 1-OHase.
iv) Calcitriol and high phosphate increases FGF23.
Factors Affecting Renal Phosphate Excretion
i. Sodium: Saline infusion increases renal phosphate excretion.
ii. Calcium: hypercalcemia increases phosphate excretion.
iii. Phosphate: Low dietary phosphate decreases phosphate excretion.
iv. Proton: Acute acidosis increases phosphate excretion.
v. Parathyroid hormone, calcitriol, and phosphatonin (FGF23) are the major regulators for phosphate homeostasis.
vi. Decreased glomerular filtration rate is the major cause of hyperphosphatemia for chronic kidney disease, and therefore, is the most important factor to be considered as early prevention for metabolic bone disease.
Chronic Kidney Disease Related Mineral Bone DIsorders
CKD-MBD is defined as a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:
i. Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism
ii. Abnormalities in bone turnover, mineralization, volume, linear growth, or strength
iii. Vascular or other soft tissue calcification
Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism - Secondary Hyperparathyroidism
a. The pathogenesis of secondary hyperparathyroidism in chronic kidney disease is multifactorial, with several different processes contributing to disturbances in the regulation of PTH production and secretion.
b. With the progressive loss of kidney function, active vitamin D production is diminished, phosphorus retention occurs, and levels of ionized extracellular calcium may also decline.
c. The parathyroid gland is highly sensitive to even very small changes in ionized extracellular calcium and rapidly releases PTH in response to a decrease in calcium concentration. This response is mediated by the calcium-sensing receptor, the primary regulator of PTH secretion.
d. Calcitriol inhibits gene transcription of precursors of PTH, and therefore a decline in calcitriol leads to increased PTH production. Decreased calcitriol has also been linked to decreased expression of calcium-sensing receptors in parathyroid tissue, which also contributes to increases in serum PTH levels.
e) Elevated PTH is known to contribute to pathogenesis of renal osteodystrophy and has also been implicated in damage to other systems, including cardiac, cutaneous, endocrine, immunologic, and nervous systems. Associated imbalances in mineral homeostasis probably also contribute to organ system damage.
Vascular Calcification
a. Pathogenesis.
i. Vascular smooth muscle cells can produce “bone”-like proteins in cell culture and forming mineralized nodules in vitro in the presence of phosphorus, identical to the requirements for bone nodule formation from osteoblasts in vitro.
ii. Several nontraditional CKD cardiovascular risk factors can accelerate vascular calcification, including parathyroid hormone (PTH) and PTH-related peptide, calcitriol, advanced glycation end-products, alterations of lipoproteins, and homocysteine.
iii. Inorganic phosphate is a signaling molecule with the ability to initiate both phenotypic change and mineralization in vascular smooth muscle cells.
iv. Calcium phosphate deposition, in the form of bioapatite, is the hallmark of vascular calcification and can occur in the blood vessels, myocardium, and cardiac valves.
v. In humans with CKD, there appears to be a relationship between disorders of mineral metabolism (abnormal levels of serum calcium and phosphorus), abnormal bone (renal osteodystrophy), and vascular calcification.
b. Clinical Consequences of Vascular Calcification
i. Vascular calcification can lead to devastating organ dysfunction depending on its extent and the organ affected.
ii. In heart, calcification of cardiac valve leaflets is recognized as a major mode of failure of native as well as bio prosthetic valves
iii. Calciphylaxis, a necrotizing skin caused by calcific uremic arteriolopathy.
iv. Increased large vessels stiffening and therefore decreased compliance of these vessels
v. Significantly increased cardiovascular mortality.
Abnormalities in bone turnover, mineralization, volume, linear growth, or strength - Renal Osteodystrophy
•”renal osteodystrophy” is exclusively used to define the bone pathology associated with CKD
a. Classification
i. High turnover bone disease or osteitis fibrosa.
ii. Osteomalacia (defective mineralization).
iii. Mixed uremic bone disease (a mixture of high turnover and osteomalacia).
iv. Adynamic bone disease
b. High turnover bone disease
i. High PTH
ii. Increased both osteoclasts and osteoblasts activities.
iii. Resulted as disruption of the structure of bone.
iv. Osteitis fibrosa is characterized by increased bone formation and resorption, increased osteoblast, and osteoclast activation, and extensive peri trabecular fibrosis.
c. Adynamic bone disease
i. Low PTH
ii. Low turnover
iii. Decreased osteoclasts and osteoblasts activities.
iv. No mineralization defect
v. Very low rate of bone formation
d. Osteomalacia.
- Like adynamic bone disease but with mineralization defect
e. Mixed uremic bone disease
- Histologic features of both osteitis fibrosa and osteomalacia.
f. Clinical manifestations.
i. Bone pain
ii. Muscle weakness
iii. Skeletal deformities
iv. Growth retardation in children
Management of CKD-MBD
a. Early prevention is the key
b. Control hyperphosphatemia
i. Control dietary intake
ii. Phosphate binders
iii. Adequate dialysis
c. Control serum calcium level
i. Calcium supplements for low Ca
ii. Low Ca dialysate for high Ca
d. Vitamin D analogs:
i. Directly inhibit PTH synthesis and secretion, indirectly via vitamin-D receptors and hypercalcemia.
e. Calcimimetic agent
i. Cinacalcet (Sensipar) activates Ca sensing receptor and blocks PTH secretion
f. Goal of intact PHT level
i. stage 3 CKD (GFR 30 to 59), less than 70
ii. Stage 4 CKD (GFR15 to 29), less than 110
iii. stage 5 CKD (GFR < 15) or on dialysis, 150 to 300
