9/15- Ca, Phosphorus, Mg Flashcards
What is the “Rule of 3s”?
For the 3 electrolytes: Ca, P, Mg
Controlled by 3 hormones
- Parathyroid hormone (PTH)
- Vitamin D
- Phosphatonins (FGF23)
(- Calcitonin)
Affect 3 target organs
- Bone
- Intestine
- Kidney
How does Parathryoid hormone function?
What stimulates it? Inhibits it?
Stimulated by low Ca; functions to increase Ca!
Stimulated by:
- Low ionized Ca (INactivates Ca sensing receptor, CaSR)
- Increased serum P and low serum Mg
Inhibited by:
- Increase in ionized Ca levels
- Calcitriol (1,25(OH)2D)
- Hypomagnesia is associated with hypocalcemia
- Hypomagnesemia -> increased IC Ca levels, thus inhibiting PTH secretion
- Skeletal PTH receptors are also less sensitive in hypomagnesia
Describe synthesis of PTH?
- Pre-pro PTH -> pro-PTH -> intact PTH (iPTH)
- Catabolized to N-terminal (active) and C-terminal fragments
How does PTH increase serum Ca (broadly: direct and indirect)
- Direct action on bone
- Indirect action on kidney
How does PTH affect bone?
Increases resorption (mobilization of Ca from bone); direct
- Ca and P released
How does PTH affect kidney?
Indirect
Proximal tubule: inhibits posphate reabsorption and stimulation of renal 25(OH)D-1-hydroxylase
- Less phosphate to bind Ca -> more free Ca
- 1,25OH vitamin D reabsorbs Ca from GIT
Distal tubule: increases reabsorption of Ca
Describe the Ca Sensing Receptors (CaSR)
- Location
- Describe pathway (kidney specifics)
Location:
- Kidney
- Parathyroid gland (less PTH produced)
- Intestine
Kidney: thick ascending loop
- Hypercalcemia activates CaSR
- Inhibition of apical K channel
- Ca absorption stops
- End result = mechanism analogous to furosemide or Bartter’s and -> calciuresis (high urine Ca)
Any transporter blocked -> Ca loss
How is hyperparathyroidism treated?
Cinacalcet (Sensipar)- binds to the CaSR
- Tricks the receptor into thinking that Ca level is higher than it really is
Other treatments:
- Calcitriol (1,25 Vitamin D) – feedback inhibition
- Surgical parathyroidectomy
Flowchart of Vitamin D production
What stimulates 1,25OH2 Vitamin D (Calcitriol)? Inhibits?
Stimulated by (1αHydroxylase stimulation):
- PTH (FEEDBACK)
- Low phosphorus / low calcium
- Estrogen, Prolactin, Calcitonin, Growth Hormone
Inhibited by: Calcitriol (1,25-OH2 Vitamin D) (FEEDBACK)
What does Calcitriol do? (1,25OH2 Vitamin D)
- Increases Ca, Mg and Phos reabsorption in the GIT
- Inhibit PTH secretion of parathyroid
What are phosphotonins?
- Secreted by what cells
- High levels when?
Fibroblast GF 23 (FGF-23)
- Tells the kidney to dump phosphorus
- Secreted by the bone cells
- Levels are high in CKD due to phosphorus retention
Role of calcitonin?
Calcitonin “tones down” calcium
- Net effect = lowering serum Ca levels
- Opposite effect on serum Ca as PTH
- Inhibits osteoclast-mediated bone resorption
- Increases renal excretion of Ca
When in calcitonin indicated?
- Hypercalcemia
- Osteoporosis
(Salmon is more potent!)
Not used because:
- High cost
- Inconvenience (nasal, parenteral)
- Resistance development (tachyphylaxis)
Major Ca stores are where?
Bone (99%)
How is Ca found in extracelllar fluid
- Bound to protein (mostly albumin), 45%
- Complexed (bound to anions such as citrate, phosphate, sulfate), 10%
- Free (ionized), 45%
Acidosis -> ____ (increase/decrease) in ionized Ca
Acidosis -> increase in ionized Ca
Alkalosis -> ____ (increase/decrease) in ionized Ca
Alkalosis -> decrease in ionized Ca
How does the nephron handle Ca (renal Ca transport)?
- PCT: reabsorption coupled to Na, convection flow
- DCT: VitD and PTH increase reabsorption (only segment that is hormone dependent)
How does a low sodium diet help with kidney stones?
Kidney trying to maximally reabsorb Na in the proximal tubule and Ca follows (less Ca -> less risk of kidney stones)
How do thiazide diuretics affect Ca levels?
- Thiazide diuretics block apical Na-Cl exchanger
- Cell wants to increase IC Na concentration, so basolateral Na/Ca exchanger kicks up
- Allows Ca to travel over apical membrane through ECaC channels
- Less Ca in lumen/excreted (?)
Lab values for Ca assume what? How can this be corrected?
Values assume normal serum protein
- Must correct for albumin
- Corrected Ca = Ca + (4 - alb) x 0.8
What can cause hypocalcemia?
Absence of PTH gland or function
- Hypoparathyroid
- Hypomagnesemia
Ineffective PTH
- Vit D deficiency
- Intestinal malabsorption of Ca
- Hypogmagnasemia
PTH overwhelmed
- Hyperphosphatemia (e.g. tumor lysis and rhabdomyolysis)
- Ca and P complexing
What is the clinical presentation of hypocalcemia?
Neuromuscular:
- Tetany
- Trousseau’s and Chvostek’s signs
- Seizures
- Neuropsychiatric changes
Cardiovascular
- Prolonged QT inteval
- Arrhythmias
- Hypotension
- Heart failure
Ectodermal
- Coarse scaly skin
- Cataracts
How can hypocalcmia be treated?
Correct underlying disease process
Treat with Ca
- IV Ca: CaCl2 of Ca gluconate
- Oral Ca: complexed either to carbonate, citrate, or acetate
- Vitamin D: Calcitriol (active) or Calcifediol (inactive)
T/F: in assessing for hypercalcemia, must correct lab value for albumin?
True!
Total Ca is protein bound, so must correct abnormal value for albumin
What can cause hypercalcemia?
Bone:
- Hyperparathyroidism
- Acidemia and Ca release
- Immobilization GIT
- Vitamin D and Ca reabsorption
- Milk: alkali (Ca ingestion)
Kidney
- Thiazide diuretics
- Familial hypercalcemia
Other:
- Granulomatous production of 1,25 OH
What is the clinical presentation of hypercalcemia?
“Bones, stones, groans, abdominal moans”
Cardiovascular
- Vasoconstriction
- HTN
- short QT interval
GI
- Ulcers
- Constipation
- Pancreatitis
Neuropsychiatric
- Lethargy
- Obtundation
- Psychosis
- Muscle weakness
Extraskeletal calcifications:
- Dermal
- Ocular
- Vascular (+/- infarction)
- Visceral organs
How can hypercalcemia affect the kidney?
Acute kidney injury
- Vasoconstriction and decreased renal plasma flow and GFR
Nephrogenic Diabetes Insipidus
- Blocks ADH actions at CD and -> inability to concentrate urine Nephrolithiasis Nephrocalcinosis
How to treat hypercalcemia?
Optimize renal excretion of Ca
- Avoid Ca resabsorption at PCT: correct volume depletion by giving salt/saline (remember Na and Ca absorbed together)
- Promote Ca loss at TAL via loop diuretics
Inhibit bone resorption
- Calcitonin
- Bisphosphonates (e.g. pamidronate)
What are the most common causes of hypercalcemia?
- Primary hyperparathyroidism
- Malignancy
What is the most important initial treatment for hypercalcemia?
Aggressive volume replacement
Case)
- 65 yo man presents with altered mental status
- Serum Ca 10 mg/dL and serum albumin is 1.2 mg/dL
- He appears volume depleted and gives a 10 day Hx of polyuria
What is his corrected Ca?
What should be done first?
A. IV fluids (normal saline- salt)
B. Furosemide
C. 1,25 OH Vitamin D
D. Hydrochlorothiazide
What is the most likely diagnosis?
A. Multiple myeloma (bone malignancy)
B. Kidney failure
C. Migraines
D. Sarcoidosis
Corrected Ca = 0.8 x (4 - albumin) + current Ca
= 12.2 mg/dL This is hypercalcemia
What should be done first?
A. IV fluids (normal saline- salt)
B. Furosemide
C. 1,25 OH Vitamin D
D. Hydrochlorothiazide
What is the most likely diagnosis?
A. Multiple myeloma (bone malignancy)
B. Kidney failure
C. Migraines
D. Sarcoidosis
What is the body’s response to hypocalcemia?
Decreased plasma Ca -> inactivation of Ca-sensing receptor
- Decreased fractional renal Ca excretion
- Increased PTH release
- Increased renal 25,hydroxy Vitamin D enzyme
What is the body’s response to hypercalcemia?
Increased plasma Ca -> activation of Ca-sensing receptor
- Increased fractional renal Ca excretion
- Decreased PTH and increased calcitonin release
- Decreased renal 25,hydroxy Vitamin D enzyme
Excretion of Ca (stool vs. urine)? P?
Ca
- Stool: 2/3
- Urine: 1/3
P
- Stool: 1/3
- Urine: 2/3
Describe P absorption in GIT?
- Absorption affected by what
- By region
- What happens to complexed P?
Absorption enhanced by calcitriol
- Duodenum: P absorption coupled to Na
- Jejunum/Ileum: P absorption is passive
Complexed phosphorus (e.g. Ca-P, Mg-P) is not absorbed and is lost in stool
Describe kidney handling of P?
- How much filtered?
- What affects reabsorption?
- Not protein bound, so > 50% enters filtrate
- 55-75% of filtered P is reabsorbed in the proximal tubule
- P reabsorption is inhibited by PTH and FGF-23 via reducing NPT2A (transporter expression)
What can cause hypophosphatemia?
Cell shift:
- Severe alcoholism
- Glucose infusion after starvation
Renal loss
- Elevated PTH
- Fanconi’s syndrome (proximal tubular cell defect)
Malabsorption
- Phosphorus binding antacids
Vitamin D
- Deficiency and decreased GI absorption
- Certain tumors and neoplastic syndrome
How is hypophosphatemia defined?
< 3.5 mg/dL
- Critical hypophosphatemia when < 1 mg/dL
What are the clinical symptoms of hypophosphatemia?
Acute: inadequate ATP production
- Skeletal muscle weakness and necrosis
- Cardiac failure, neurological dysfunction
- Hemolysis, tissue hypoxia
- Impaired platelet and macrophage function
Chronic:
- Increased bone resorption and hypercalcemia
- Bone demineralization and pain
Treatment for hypophosphatemia?
Oral:
- Milk, cheese, eggs
- Na and K phosphate supplements
IV
- Use in emergencies or critical hypophosphatemia (recall: under 1 mg/dL)
- Can cause severe and symptomatic hypocalcemia (complexes with Ca)
What can cause hyperphosphatemia?
Cell shifts
- Tumor lysis
- Rhabdomyolysis
Renal
- Kidney disease
How can hyperphosphatemia be measured/evaluated? What are consequences of hyperphosphatemia?
Calcium phosphorus product: Ca x Phos
- Normal = 30
- Pts with kidney disease = 60-70
Result:
- Ca-Phos deposition in vessels, tissues, visceral organs
- “Calciphylaxis”– VERY high mortality
What can cause secondary hyperparathyroidism?
- Hypocalcemia secondary to Ca x Phos binding -> release of PTH
- Osteitis Fibrosa Cystica and metastatic calcifications
Treatment for hyperphosphatemia?
Correct underlying disease process!
The 3 Ds:
- Diet: Avoid high phos foods
- Dietary Binders: Oral phosphate binding agents (take with meals to bind the P in food)
- Magnesium, aluminum (not for long term use), calcium, and non-calcium based binders
- Dialysis (extra-corporeal removal)
What affects Mg movement (cell efflux/influx)?
Cell efflux of Mg: beta stimulation
Cell influx of Mg:
- Insulin
- Calcitriol
- Vitamin B6
What is the role of Mg in the body?
DNA and protein synthesis
Neurologic:
- Neuronal activity
- Cardiac excitability
- Neuromuscular transmission
- Vasomotor tone and BP
Necessary cofactor for transport systems that affect potassium and calcium levels
- Leaky ROMK channel: low intracellular Mg levels keeps it open
- PTH needs Mg to facilitate calcium release from bone
What are dietary sources of Mg?
Plants (central metal iron in chlorophyll)
Describe renal handling of Mg in the kidney?
tAL: paracellular movement (like Ca)
What can cause hypomagnesemia?
- Malnutrition
- Alcoholism
- GI malabsorpotion
- Renal wasting after nephrotoxic drugs: cisplatin, Amphotericin B, cyclosporin
How can hypogmagnesemia present?
- Muscle weakness, tremors, fasciculations, arrhythmias
- Neuropsychiatric changes
- Hypocalcemia, hypokalemia
Treatment for hypomagnesemia?
- IV or IM supplements
- Oral Mg (side effect is diarrhea, which can -> GI Mg loss!)
What can cause hypermagnesemia?
- Iatrogenic (given to prevent contractions in pregnancy)
- Mg containing antacids in pts with CKD or AKI
Manifestations of hypermagnesemia?
3-5 mg/dL
- Thirst, nausea, vomiting
5-7 mg/dL
- Drowsiness, hypotension, depressed DTR
> 12 mg/dL
- Coma, respiratory paralysis, hypotension, cardiac arrest
What is the treatment for hypermagnesemia?
- Initial treatment: IV Ca (stabilize cardiac membrane)
- Loop diuretics
- Hemodialysis
Putting it all together: CKD
Treatment options in CKD?
Remove phosphorus
- Dietary phosphate reduction
- Dietary binders (bind P and remove via GIT)
- Dialysis (extra-corporeal removal)
Reduce PTH levels
- Cinacalcet
- 1,25 Vitamin D (Calcitriol)
25-Vitamin D supplementation
