Calcium physiology, hypercalemia, renal secondary hyperparathyroidism Flashcards
Chronic kidney disease mineral and bone disorders can be manifested in one of three ways. Name them.
- Laboratory abnormalities indicative of disturbed mineral/bone metabolism
- Calcification of the vasculature and soft tissues
- Abnormalities in skeletal morphology (renal osteodystrophy)
99% of the calcium in the body is stored in the bone in what form?
Hydroxyapatite
What percent of the plasma calcium is in a free, ionized form under normal conditions?
55%
In the presence of acidemia, what happens to the protein bound and ionized calcium concentrations in the blood?
Calcium and hydrogen ions compete for the negatively-charged protein binding sites
Therefore, protein bound calcium decreases and ionized calcium increases with acidemia
What are the major functions of PTH?
- Stimulates calcium reabsorption from the renal tubules (distal convoluting)
- Stimulates calcitriol synthesis
- Enhances mobilization of calcium from the bone
- Increases FGF23 production from the bone
- Stimulates phosphorus excretion in the kidneys
What is the effect of FGF23 on PTH synthesis?
FGF23 inhibits PTH synthesis and secretion - negative feed back loop
What are the major functions of FGF23?
- Potent phosphaturic hormone
- Stimulates renal tubular reabsorption of calcium
- Inhibits calcitriol production
What are the major functions of calcitriol?
- Inhibits PTH synthesis
- Increases transcellular calcium reabsorption from the intestines
- Increases transcellular calcium reabsorption from the distal convoluted tubule
Under normal conditions, what percent of filtered calcium is reabsorbed in the renal tubules?
98%
- Proximal tubule 60-70%
What is the paracellular pathway of calcium reabsorption in the renal tubules?
Movement of calcium through tight junctions between epithelial cells
- Primary method of calcium reabsorption in the proximal tubule and thick ascending limb
- Driven by passive diffusion or solvent drag down an electrochemical gradient
What is the transcellular pathway of calcium reabsorption in the renal tubules
Calcium transport through tubular epithelial cells
- Primary method of calcium reabsorption in the distal convoluted tubule (5-10% of calcium reabsorption)
- Crucial to the fine regulation of calcium reabsorption, where hormones act
When dietary calcium intake is low, what absorption method predominates? How does it occur?
Active, hormonal-dependent, transcellular absorption
- Occurs in the duodenum
- Via vitamin D receptors that are highly expressed under the influence of calcitriol
Passive paracellular calcium diffusion occurs when the dietary intake is higher. Where does it occur?
Throughout the small intestine, cecum, and proximal colon
How does calcitriol enhance calcium absorption in the intestines?
Calcitriol binds to the vitamin D receptor (transcription factor) => transcription of genes encoding for:
- The transient receptor potential vanilloid subtype 6: absorbs calcium on the intraluminal surface of the cell
- Calcium ATPase and sodium-calcium exchangers - on the basolateral membrane to move calcium into the blood
What cell in the parathyroid gland synthesizes PTH?
Parathyroid chief cells
What stimulates PTH release?
- Ionized hypocalcemia
- Phosphate retention
- Decreased calcitriol synthesis
How does PTH promote bone resorption?
Indirectly activates osteoclasts through increased expression of RANKL on the osteoblasts and osteocytes
What factors increase the activity of 1-alpha-hydroxylase activity in the kidneys, leading to increased calcitriol production?
PTH, calcitonin, low extracellular calcium and phosphate
Where is FGF23 produced?
Osteocytes and osteoblasts in the bone
What stimulates FGF23 production?
Calcitriol, PTH, increased phosphorus
How does FGF23 lead to increased renal excretion of phosphorus?
Decreases expression of the renal sodium phosphate cotransporters
FGF23 exerts its biological function by interacting with what receptor complex?
alpha-Klotho-FGF receptor complex
How does membrane-bound alpha-Klotho affect FGF23?
Acts as a co-factor to enhance ligand-receptor affinity
Where is calcitonin produced?
Parafollicular cells of the thyroid gland
What stimulates calcitonin production?
Increased blood calcium concentrations
What are the primary effects of calcitonin?
- Inhibits osteoclastic bone resorption
- Antagonizes PTH
How does calcitriol reduce PTH synthesis?
- Directly inhibits mRNA synthesis for the production of PTH
- Increases the number of calcium channels on the cell to increase responsiveness to extracellular calcium concentrations
What is the half life of PTH and how does that effect it’s function?
3-5 minutes - allows PTH to be involved in the minute to minute, fine tuning of iCa concentrations
How is hypercalcemia toxic to cells?
Alters cell membrane permeability, alters cell membrane calcium pump activity, reduces energy production, derangements in cellular functions result
What are the most common clinical signs of hypercalcemia?
PU/PD, anorexia, lethargy, weakness
What are uncommon signs of hypercalcemia?
Constipation, cardiac arrhythmias, seizures, AKI, calcium urolithiasis
The severity of clinical signs from hypercalcemia depends on what factors?
- Magnitude of hypercalcemia
- Rate of development - signs are most severe when hypercalcemia develops rapidly
- Duration - clinical signs more likely the longer hypercalcemia goes on
Soft tissue mineralization occurs when the product of calcium x phosphorus is greater than what?
60
How does hypercalcemia lead to an AKI?
- Ionized hypercalcemia can result in renal vasoconstriction
- Can decrease the permeability coefficient of the glomerulus
- Can cause acute tubular necrosis from ischemic and toxic effects
If the thick ascending limb is not damaged, hypercalcemia can result in hyposthenuria through what means?
Causes nephrogenic diabetes insipidus - hypercalcemia can affect aquaporin expression and delivery to the membrane of the tubular cells in the collecting duct
In one study of 109 dogs, what was the most common cause of hypercalcemia?
Neoplasia - 58%
What percent of dogs with hypoadrenocorticism have hypercalcemia?
~30% (another study says 42% total, 22% ionized hypercalcemia)
What is the PTH concentration in dogs with hypoadrenocorticism and hypercalcemia?
Normal to low
How quickly does hypercalcemia resolve in dogs with hypoadrenocorticism?
Rapidly - within 1-2 day of corticosteroids and fluids
Patients with CRF often have a total hypercalcemia and elevated PTH. What is their ionized calcium?
- Normal or low - helps you distinguish from primary hyperparathyroidism
- In one study, less than 10% of these dogs had ionized hypercalcemia
- Ionized hypercalcemia more common in cats
Why are clinical signs of hypercalcemia uncommon in CRF patients?
Clinical signs are due to ionized hypercalcemia, and in CRF, ionized calcium is typically normal to low
Of 490 dogs with CRF, what percent had ionized hypercalcemia? Hypocalcemia?
Hypercalcemia - 9%
Normocalcemia - 55%
Hypocalcemia - 36%
Of 102 cats with CRF, what percent had ionized hypercalcemia? Hypocalcemia?
Hypercalcemia - 29%
Normocalcemia - 61%
Hypocalcemia - 10%
In renal secondary hyperparathyroidism, elevated PTH (not necessarily calcium) contributes to what?
Disease progression
The use of low dose calcitriol to reduce PTH concentrations has what effects on CRF patients?
- Reduces toxic concentrations of PTH
- Improves QOL
- Reduces disease progression and prolongs survival
- Low doses typically do not lead to excessive intestinal absorption of calcium
If hypercalcemia develops while on calcitriol therapy, what dosing scheme can be used?
Twice weekly - still suppresses PTH without intestinal absorption of calcium
In dogs with CRF, total hypercalcemia, and normal ionized calcium, what is driving the increase in total calcium?
Increased in complexed calcium - calcium bound to organic anions (citrate, phosphates, lactate, oxalates)
What does tertiary hyperparathyroidism refer to?
Patients with CRF that develop ionized hypercalcemia and excessive PTH secretion that is not inhibited by hypercalcemia - likely a progression of secondary hyperparathyroidism
Why is the parathyroid gland secreting more PTH in cases of tertiary hyperparathyroidism?
Likely not autonomous secretion. Rather, it takes more ionized calcium to inhibit PTH secretion (higher “set point”) due to a lack of calcitriol and reduced expression of calcium receptors
What are the characteristic clinicopathologic findings in patients with humoral hypercalcemia of malignancy?
- Hypercalcemia
- Hypophosphatemia
- Hypercalciuria
- Increased fractional excretion of phosphorus
What mechanisms are responsible for hypercalcemia in humoral hypercalcemia of malignancy?
- Increased osteoclastic bone resorption
- PTHrP stimulates renal calcium resorption
- Some forms, but not all, increase calcitriol as well
What two neoplasias are most responsible for hypercalcemia of malignancy in the cat?
Lymphoma, squamous cell carcinoma
What cytokines may synergize with PTHrP to induce hypercalcemia?
IL-1, TNF-alpha, TGF-alpha or beta - can stimulate bone resorption too
What percent of dogs with lymphoma are hypercalcemic?
20-40%
What percent of dogs with AGASACA are hypercalcemic?
30-50%
What percent of primary hyperparathyroidism cases are caused by an adenoma? Carcinoma?
Adenoma 90%
Carcinoma 5%
Hyperplasia 5%
What is the mean age of dogs diagnosed with primary hyperparathyroidism?
10-11 years
What dog breed is over-represented among cases of primary hyperparathyroidism?
Keeshonds - 36% of cases in one study
What percent of dogs with primary hyperparathyroidism develop calcium containing uroliths?
30%
What substance can be infused to enhance visualization of the parathyroids intra-operatively? What are the potential side effects?
Methylene blue
Can cause hemolytic anemia and AKI - only used if really needed
What is the success rate of surgical removal of a parathyroid adenoma?
Resolution of hypercalcemia in 94% of cases, usually 1-6 days post op
What is the success rate of ethanol ablation of a parathyroid adenoma? Of radio frequency heat ablation?
Ethanol 72%
Heat ablation 90%
How does hypercalcemia result from granulomatous disease?
Macrophages can synthesize calcitriol - express 1-alpha-hydroxylase when stimulated by interferons or LPS
In cats with idiopathic hypercalcemia, what is the PTH concentration?
Usually in the lower half of the reference range
Hypercalcemia has been detected in 93% of dogs with AKI due to ingestion of what toxin?
Grapes/raisins
Why is 0.9% NaCl the fluid treatment of choice for hypercalcemia?
- Results in slight expansion of the ECF => increased GFR and increased filtered load of calcium
- Increased sodium ions leads to reduced resorption of calcium in the renal tubules => calciuresis
- Fluid itself is devoid of calcium
Why is furosemide used in hypercalcemic cases? What method of delivery is more effective?
Increases calciuresis
CRI causes 1.6x more calcicuresis than intermittent boluses
What other electrolyte can drop rapidly with furosemide therapy and should be monitored during treatment?
Magnesium
Is glucocorticoid therapy effective at reducing hypercalcemia in patients with primary hyperparathyroidism?
No - only effective for neoplastic causes, vitamin D toxicity, granulomatous disease, Addison’s, and idiopathic hypercalcemia in cats
Is glucocorticoid therapy effective at reducing hypercalcemia in patients with primary hyperparathyroidism?
No - only effective for neoplastic causes, vitamin D toxicity, granulomatous disease, Addison’s, and idiopathic hypercalcemia in cats
How do steroids reduce calcium levels?
- Reduce bone resorption by impairing osteoclast maturation
- Decrease intestinal calcium absorption by antagonizing vitamin D
- Increase renal calcium excretion
If you suspect an animal has lymphoma and do not want to give prednisone until a diagnosis is reached, what drug can be given to reduce hypercalcemia?
L-asparaginase - disrupts tumor metabolism without causing cytolysis, so you can still find the lymphoma cells
If calcium normalizes within 72 hours, occult lymphoma is likely
What is the maximal decrease in tCa that can be expected with calcitonin administration?
3 mg/dL
How does administration of calcitonin reduce hypercalcemia?
Reduces the activity and formation of osteoclasts - acts rapidly
What are the downsides to using calcitonin?
Expensive
Short lived (hours)
Resistance mediated by receptor down regulation occurs within a few days of treatment - can discontinue therapy for 24-48 hours to restore effectiveness
What is the mechanism of action of bisphosphonates?
- Decrease osteoclast activity and function
- Interfere with hydroxyapatite dissolution
- Result in osteoclast apoptosis
How long after administering a bisphosphonate is bone resorption inhibited?
1-2 days
What is the most potent bisphosphonate?
Zoledronate
How can bisphosphonates lead to AKI?
Precipitation of insoluble calcium-bisphosphonate salts in the renal tubules => AKI
More common after multiple doses, with dehydration, and in patients with pre-existing CKD
What are calcimimetic drugs?
Activate the calcium receptor, decreasing PTH secretion
Ex: cinacalcet (Sensipar)
Why are calcimimetic drugs contraindicated in CKD patients?
Can cause hyperphosphatemia
What are the common clinical signs of hypocalcemia?
Muscle tremors, facial rubbing, muscle cramping, behavioral change (aggression, anxiety, disorientation), seizures in which partial consciousness is retained
How does hypocalcemia result in clinical signs?
Causes increased excitability of neuromuscular tissue
In its most severe form, hypocalcemia can result in death from what mechanisms?
Hypotension, decreased myocardial contraction, paralysis of the respiratory muscles
What causes hypocalcemia in CKD?
- Mostly decreased production of calcitriol from diseased kidneys
- Some small contribution from mass law interactions of calcium with markedly increased phosphorus
What does hypocalcemia correlate with in CKD patients?
Degree of azotemia - worse CRF = worse hypocalcemia
Does total calcium accurately predict iCa in patients with CKD?
No - tCa underestimates the number of patients with ionized hypocalcemia
In IRIS stage I CKD, what percent of dogs had already developed renal secondary hyperparathyroidism (low or normal calcium with an elevated PTH)?
36%
In IRIS stage II CKD, what percent of dogs had developed renal secondary hyperparathyroidism? Stage III?
Stage II - 50%
Stage III - 96%
What causes hypocalcemia in critical illness?
Decreased PTH secretion, increased calcitonin secretion, altered calcium binding to proteins. May be related to inflammatory cytokines or complexes with lactate in some cases
What are the proposed mechanisms of hypocalcemia in acute pancreatitis?
- Sequestration of calcium into peri- pancreatic fat (saponification)
- Increased free fatty acids
- Increased calcitonin secondary to hyperglucagonemia
- PTH resistance or deficit from hypomagnesemia
What clinicopathologic abnormalities are noted with acute tumor lysis syndrome?
Hyperkalemia, hyperphosphatemia, hyperuricemia. Hypocalcemia can result from calcium-phosphate salts deposited into soft tissues
What causes nutritional secondary hyperparathyroidism?
Vitamin D deficiency, low calcium and/or high phosphorus concentration in the diet, or severe GI disease preventing absorption of calcium and vitamin D
What are the clinicopathologic abnormalities with nutritional secondary hyperparathyroidism?
-Initially leads to low iCa and increased PTH secretion
- High PTH tends to return iCa to normal, but may cause low phosphorus
How does renal secondary hyperparathyroidism affect the bones differently from nutritional secondary hyperparathyroidism?
Renal: preferentially affects the bones of the face (fibrous osteodystrophy)
Nutritional: causes osteopenia of the long bones and vertebrae
What is type 2 vitamin D dependent Ricketts?
End organ resistance to calcitriol - affected puppies/kittens develop hypocalcemia with an increased PTH and increased calcitriol (nutritional secondary) - do not respond at all to calcitriol supplementation
What is type 1 vitamin D dependent Ricketts?
Deficiency of 1-alpha-hydroxylase - display hypocalcemia, elevated PTH, and low calcitriol levels - respond to calcitriol therapy
In 68 dogs with hyperadrenocorticism, what percent had elevated PTH above the reference range?
92% - normalizes with trilostane
No changes in iCa though
What is thought to the mechanism behind increased PTH in hyperadrenocorticism?
Glucocorticoids decrease intestinal absorption of calcium and increase renal excretion of calcium - may lead to a negative calcium balance => increased PTH
What is the primary cause of hypoparathyroidism in dogs? In cats?
- Dogs: usually idiopathic chronic inflammation (likely immune mediated, but not proven)
- In cats, surgical removal or injury to the thyroid parathyroid glands during thyroidectomy for hyperthyroidism is most common
Is primary hypoparathyroidism more common in female or male dogs?
Female (62%)
What clinicopathologic changes are seen with primary hypoparathyroidism?
Low PTH despite ionized hypocalcemia, hyperphosphatemia, and decreased calcitriol
How does hyperphosphatemia affect calcitriol concentrations?
Phosphorus is a potent inhibitor of 1-alpha-hydroxylase => low calcitriol
What percent of dogs become hypocalcemic after surgical removal of a parathyroid adenoma (primary hyperparathyroidism)? When does hypocalcemia occur and how long can it take to resolve?
50% - 3-6 days post-operatively
Takes 8-12 weeks for the remaining parathyroid tissue to hypertrophy and return iCa to normal
Mild, acute hypomagnesemia results in increased PTH secretion. What does severe hypomagnesemia cause?
Decreased PTH secretion, increased end organ resistance to PTH, may impair calcitriol synthesis
How does ethylene glycol cause hypocalcemia?
Chelates calcium and leads to calcium deposition in soft tissues
An ECG should be closely monitored when injecting calcium salts. What should you be monitoring for?
- Bradycardia - may signal the onset of cardiotoxicity from rapid infusion
- Sudden elevation of the ST segment or shortening of the QT interval
Calcitriol supplementation exerts effects on the intestines within what time frame?
3-4 hours
What should the goal be in treating primary hypoparathyroidism?
To achieve calcium just below the reference range - minimize clinical signs while also minimizing calciuresis (due to the lack of PTH) - can cause uroliths
Describe the pathogensis of renal secondary hyperparathyroidism
Decreased GFR => phosphorus retention => increased FGF23 => decreased calcitriol synthesis => hypocalcemia => increased serum PTH
In early CKD, what hormone increases before increased serum phosphorus and PTH?
FGF23
FGF23 initially inhibits PTH production. Why does this inhibition stop in later stages of CKD?
Downregulation of the FGF23 receptor and it’s co-receptor, alpha-Klotho, occur
Why do calcitriol concentrations initially decrease in early CKD patients? Why do they decrease in later stage CKD patients?
Initial decline is due to the inhibitory effects of increasing FGF23 and hyperphosphatemia
Later decline is due to declining functional renal mass and decreased production by nephrons
How does FGF23 lead to a decrease in calcitriol concentrations?
Downregulates 1-alpha-hydroxylase and stimulates renal expression of 24-hydroxylase
Name 3 consequences of metabolic bone disorder (secondary renal hyperparathyroidism)
- Progressive CKD
- Parathyroid hyperplasia
- Extraskeletal calcification
An increase in serum phosphorus of 1mg/dL increases the risk of CKD progression by what?
42%
Aluminum hydroxide should not be administered with what substance? Why?
Citrate - increases aluminum absorption and the risk of aluminum toxicity
What clinicopathologic abnormality can result from aluminum toxicity?
Microcytic anemia
What is alpha klotho?
The co-receptor for FGF23 - needed for most of FGF23’s actions. FGF23 binds to alpha-klotho and then to the FGF-1 receptor
How do FGF23 and PTH increase renal excretion of phosphorus?
Downregulates two sodium-linked phosphate transporters in the proximal tubule of the kidney (NPT2a and NPT2c)
What is occurring in fibrous osteodystrophy?
Demineralized bone is replaced with fibrous tissue
What are the clinical signs of fibrous osteodystrophy in CKD dogs?
Osseous swelling of the maxilla and mandible, facial deformity, bone malleability (“rubber jaw”)
Why are young dogs more prone to developing fibrous osteodystrophy?
Incomplete skeletal maturation - require higher calcium concentrations, bones more easily demineralized
Why does systemic hypertension develop in humans with CKD?
Mineralization/calcification of the vascular walls occurs - unknown if this occurs in dogs/cats
What are calcimimetic drugs and how do they work?
Act on the calcium sensing receptor in the parathyroid gland to reduce PTH secretion. Cinacalcet is the most commonly used
After controlling hyperphosphatemia with diet and phosphate binders, what laboratory test should be performed?
Check PTH concentration
If PTH is still high after correcting hyperphosphatemia, what medications are indicated?
If iCa is low - calcitriol
If iCa is high - cinacalcet
If iCa is normal, could try either with close monitoring (JD likes cinacalet)
What form of phosphorus may be detrimental to renal health?
Soluble, inorganic phosphates - more bioavailable than organic or insoluble phosphates
In normophosphatemic dogs with CKD, a serum FGF-23 > 528 pg/mL was associated with what?
Shorter time to development of hyperphosphatemia and CKD progression
Cats with early CKD developed what when fed a low protein, low phosphorus diet?
Hypercalcemia and elevated FGF-23
Did not occur on a moderate protein, moderate phosphorus diet - may be more appropriate for early CKD
In a retrospective study of 37 dogs: Compared to healthy dogs, what forms of vitamin D were decreased in dogs with IRIS stage I and II CKD? Stages III and IV CKD?
Stage I and II - no difference
Stage III and IV - All of them were decreased- calcidiol, calcitriol, 24,25(OH)2D
What is the sensitivity and specificity for total calcium to predict ionized calcium in CKD cats?
Sensitivity is 27%
Specificity is 100%
So if they have total hypercalcemia, they likely have ionized hypercalcemia. But if the total is normal, who knows what the ionized is doing
What other clinicopathologic change caused total calcium to underestimate ionized calcium in CKD cats?
Low serum bicarbonate (acidosis => increased iCa)
What are the strongest independent predictors of FGF-23 concentration in CKD dogs?
Creatinine (worse IRIS stage = higher FGF23) and phosphorus
What factors were independent predictors of survival time and CKD progression in a study of 200 CKD cats?
FGF-23 and age
What changes were noted in the bone of dogs with CKD vs healthy dogs?
- Decreased lacunae size
- Increased resorption cavity density
- Increased overall porosity
All changes were relatively mild and unlikely to cause clinical signs
In dogs with CKD, supplementation with calcifediol lead to what clinicopathologic changes?
- Increased levels of all vitamin D metabolites
- No difference in calcium, phosphorus, PTH
- Increased FGF-23
Long term bisphosphonate use in cats can lead to what rare side effect?
Osteonecrosis of the jaw
What predicts post-operative hypocalcemia in dogs undergoing surgical treatment of hyperparathyroidism?
Pre-operative hypercalcemia - moderate correlation with post-operative hypocalcemia. Dogs with iCa >1.7 were more likely to be hypocalcemia
