05.15 - Calcium, Phosphate Metab (Kovesdy) - PP, no reading Flashcards
Percent of Phosph Filtered Load that is reabsorbed? What contributes to most of this reabsorption?
80-97%, 80% of this in PT
How does hypocalcemia affect Vit D
Stimulates PTH –> Stimulates 1a-Hydroxylase -> Incr 1,25 production by kidneys
4 Major Consequences of CKD-MBD
Renal Osteodystrophy, Fractures, Calcification, CV Disease
Phosphate and Vit D in secondary HPT in CKD
Vitamin D deficiency –> Phosphate retention (lower capacity to secrete Phosphate in kidney)
FGF-23 directly inhibits
1a-Hydroxylase
How does VDR activation affect PTH levels
Higher activation = Lower PTH
Effect of Vit D on PO4
Incr reabsorption in gut; Decr reabsorption in kidney
Why are FGF19, 21, and 23 unique
Don’t need Heparin, so can circulate and act as endocrine factors (rather than paracrine)
Hereditary Tumoral Calcinosis is disorder of
FGF23 Deficiency
Ratio of Fecal Loss vs Urine Loss of Phosphorus
500 to 900
Disorder of FGF23 excess is called
Hereditary/Acquired Hypo-Phosphatemic Rickets
Change in serum calcium in CKD
Decreases
Hereditary/Acquired Hypo-Phosphatemic Rickets is a disorder of
FGF23 Excess
First, or one of the first, markers in CKD
FGF-23
2 factors that play a role in calcium absorption
Amount of intake, amoung of 1,25(OH)2 Vit D
Pitfalls of Serum Ca2+ measurement
Assay measures total, but 40% of Ca is bound to albumin, and only free and ionized Ca is biologically active
Bones in FGF23 excess vs deficiency
Rickets/Osteomalacia in excess; Hyperosteosis in deficiency
High ___ mileu may potentiate Calcium fluxes in CKD
phosphorus
What is consequence of maintaining 1,25(OH)2 levels with Vit D deficiency
Hypophosphatemia (Osteomalacia)
FGF-23 correlation with Phosphorus in Norma vs CKD/ESRD
in normal, higher fgf-23 = lower PO4; in ckd, higher fgf-23 = higher PO4
Effect of FGF-23 on Heart
LV Hypertrophy
How does bone metabolism affect FGF-23
Osteocytes and osteoblasts secrete FGF-23
FGF-23 is involved in
Phosphate and Vit D homeostasis
T/F: CVD mortality rates are 5 times higher in Stage 5 CKD patients than general population
False, 10-20 times higher
How does 1,25(OH)2 affect FGF-23
Increase FGF-23
Similar to Phosphate, extracellular pool is only ____ proportion of total body Ca
Small
Consequences of Hypercalcemia
CV and Soft Tissue Calcification
Diffuse calcification of tunica media causes what pathophysiology
High pulse wave velocity
T/F: Tubular reabsorption of Phosphate is unsaturable
FALSE
How does PTH affect Vit D
Incr 1a-hydroxylation of Vit D
Urinary Ca excretion in CKD
Marked decr in Ca excretion with advancing states of CKD
1,25(OH)2 in Vit D Deficiency: normal kidney vs CKD
Normal or increase in normal kidney patient; Low in CKD patient
Key regulator of Ca absorption
Active Vit D
Clinical features of FGF23 excess
Low serum Phosphate, Aberrant Vit D, Rickets/Osteomalacia
Phosphate in FGF23 excess vs deficiency
Low in excess, high in deficiency
Main pathophysiology seen in patients on dialysis
Increased pulse wave velocity
The higher the level of Ca in dialysis patients, the higher the
Mortality rate
Most patients with normal kidney fxn who are vit d deficient have what levels of 1,25
Normal or increased (paradoxically, because missing precursor
At what GFR will you see major changes in Phosphorus and Calcium
Not until less than 30 (GFR)
Consequence of Hypocalcemia
Increased neuromuscular excitability
Ratio of Fecal to Renal loss for Calcium
700 mg/dL to 300 mg/dL
How does Calcitrol aka 1,25(OH)2 Vit D affect transcription
Binds with VDR nuclear receptor in cytoplasm, dimerizes with RXR, and both bind Vit D response element
Effect of FGF-23 on RAAS, Klotho, Inflammation
Inc RAAS, Dec Klotho, Inc Inflammation
Klotho is necessary for
FGF23
Effect of FGF23 on PTH, 1a-Hydroxylase
Inhibits both
In Vit D deficiency with CKD, PTH cannot stimulate ___, leading to def in ____
1a-Hydroxylase, deficiency in 1,25(OH)2
Main reason hyperphosphatemia is detrimental
Phenotypically, vascular SM cells turn to bone
Does Ca2+ level affect mortality
Yes, higher Ca2+ means much higher mortality rate
Clinical features of FGF23 deficiency
Hyperphosphatemia, Elevated Calcitrol, Soft tissue calcifications, Hyperosteosis
What percent of phosphorus is in ECV? Soft tissue? Bone?
1%, 14%, 85%
T/F: Albumin-adjusted serum Ca levels correlate well with ionized Ca in CDK and ESRD
False, correlate poorly - don’t adjust for Albumin
Normal Phosp plasma conc.
3-4.5 mg/dL
Serum phosphorus in stage 5 CKD
Predictably elevated
Calcium in what state is actually active
Free (unbound to Albumin) and ionized
With GFR > 40, TmPhosphate ___ with GFR
TmP Varies proportionately with GFR
How does primary decr of Ca affect PTH
Increases PTH
Calcium balance in CKD
If diet is low in calcium, neutral balance; If diet is high in calcium, more positive balance than controls (they are more sensitive)
How does Ca affect PTH
Hypocalcemia stimulates PTH production
Cofactor for FGFs (except 19, 21, 23)
Heparin
Effect of PTH on Bone
Increase reabsorption –> Incr Ca and PO4
Vit D deficiency patients with normal kidney function
Normal 1,25(OH)2 but at expense of Hypophosphatemia (osteomalacia)
PO4 in Vit D deficiency: normal kidney vs CKD
Low in normal patient, high in CKD patient
How and where is Vitamin D3 converted to 25(OH)
In liver by 25-hydroxylase
Change in serum phosphorus in CKD
Increases
First, or one of the first, regulators when GFR lost
FGF-23
With GFR < 40, TmPhosphate ____
Further decreases, but decrease is less than decrease in GFR = Hyperphosphatemia ensues
Effect of Calcitrol supplementation on longevity
Improves
Calcification seen in CKD vs general population
Medial vs Intimal
Vit D in FGF23 excess vs deficiency
Low in excess, high in deficiency
FGF-23 levels in ESRD
Markedly elevated
If you try to explain bone mineral metabolism with PTH, you run into trouble with
Phosphorus - PTH both increases and decreases PO4
Effect of PTH on PO4
Incr thru bone and gut via Vit D, Decr reabsorption in kidney (opposing effects)
Dialysis greatly increases deposits of what in coronary arteries
Calcium
Why do you get Hyperphosphatemia with low GFR
With GFR less than 40, TmPO4 further decreases, but decrease is less than decrease in GFR
Hyperphosphatemia initiates a cascade of events that results in
Calcification of vascular SM cells
How does PTH affect gut absorption
Enhances absorption of Ca and PO4 thru increased Vit D
Association of serum phosphorus to mortality in dialysis patients
Higher mortality with higher phosphate levels (and very low levels)
FGF vs PTH as marker for PTH
Both good, but FGF-23 earlier
PO4, FGF-23, ALP, PTH in CKD, MBD
All increase
Disorder of FGF23 deficiency is called
Hereditary Tumoral Calcinosis
How and where is 25(OH) Vit D converted to 1,25(OH)2 Vit D
By 1a-Hydroxylase most in tissues but also in kidney
Consequences of increased pulse wave velocity due to dialysis calcification
Inc afterload -> LVH; Decr coronary perfusion pressure; Incr Myocardial O2 demand; Incr endothelial dysfunction and atherogenesis
Phosphate imbalance with low GFR
Hyperphosphatemia
