05.08 - Disorders of PCT, Water (Gosmanova) - PP, No reading Flashcards
Hormonal Function of PT
Final pathway in synthesis of active Vit D
Isolated PT dysfunctions are rare but typically result from
disorder of specific transport proteins
Mutation in AR Hypo-P Rickets
Several leading to increased FGF-23; or Na-Pi Iic transporter
What is Oncogenic Hypo-P Osteomalacia
Inc. production of FGF-23 by some tumors: fibromas, angiosarcomas, hemangiopericytomas
2 ways ADH regulates AQP-2
Short-term: reversibly shuttles channel to luminal membrane; Long-term: inc transcription of AQP-2 gene
Plasma Na ~
(Total Body exchangeable Na and K) / TBW
What causes Vit D-dependent Rickets Type 1
Mutation of 1alpha-Hydroxylase
Mutation in PHEX results in increased
levels of circulating factor FGF-23 (PHEX normally downregulates)
When is Normal Osmolarity Hyponatremia likely to occur
HyperTGemia, Paraproteinemia - when solid phase of plasma is greatly increased
To which is ADH release more senstive, Posm increase or decrease in BV
Posm increase: 1% increase in Posm triggers, but takes 7% decrease in BV to trigger
Hypernatremia usually develops if
Thirst is impaired or limitation in acess to free water
FGF-23 inhibits
Na-Pi cotransporter and alpha-1-hydroxylase
What causes Hartnup Disease
Defect in neutral AA transporter (SLC6A19)
Most important inherited cause of Fanconi Syndrome
Cystinosis - Cysteine not degraded normally
Main defence mechanism against hypernatremia
Thirst
Generalized PT dysfunctions are usually accompanied by
cause-specific extra-renal manifestations
Changes in Plasma Na are mainly determined by changes in
TBW
Normal Posm
285-290 mOsm/kg
When is Dilutional Hyponatremia likely to occur?
Glucose in absence of insulin, Mannitol, Glycine
Polyuria is defined as
Incr in urine volume > 3L/day
__ is always present in True Hyponatremia
Impaired urinary dilution mechanisms
How does increase in peritubular capillary hydrostatic pressure affect net reabsorption of Na and water
Reduces
Glomerulotubular Balance is the intrinsic ability of tubules to increase reabsorption in response to
Incr tubular load
Macro structure of PT epithelial cells
Microvili (brush border); Basolateral surface is thrown into folds - both extend surface area
Inc production of FGF-23 by some tumors
Oncogenic Hypo-P Osteomalacia
Non-osmotic stimuli that stimulate ADH release
Dec ECV, Nausea, Pain, Drugs, Corticosteroid deficiency
In absence of ADH, urinary osmolarity can be lowered to
40-60 mOsm/kg
Ang 2 regulates ___ reabsorption and ___ secretion
NaCl and H20; H+ secretion
How is insulin taken up by PT cells
Pinocytosis
Water Excess =
0.6 x TBW x (1 - [Na]/140)
Most common inherited phosphate wasting disorder
X-Linked Hypophosphatemic Rickets
Osmotic threshold for thirst vs ADH
Slightly higher for thist: 290-295 vs 280-290
Hyponatremia with volume depletion is caused by
Renal, GI, or Skin losses; Third spacing
4 Acquired forms of Nephrogenic DI
(1) Defect in medullary interstitial tonicity; (2) Defect in cAMP generation; (3) AQP-2 downreg; (4) Pregancy
Cause of Cystinuria
Mutation of brush border transporter responsible for cysteine, and other AA’s
Relationship of PHEX, FGF-23, and Na-Pi cotransporter
PHEX inhibits FGF-23, and FGF-23 inhibits Na-Pi cotransporter and Alpha1-Hydroxylase production
Proximal Straight Tubule is aka
Parse Recta
Reabsorption in PT is dependent on
Volume Status
Serum Glucose in Hereditary Renal Glucosuria
Normal
Mutation of brush border transporter responsible for cysteine, and other AA’s
Cause of Cystinuria
2 most important acquired causes of Fanconi Syndrome
Tenofovir, Multiple Myeloma
How does X-Linked Hypophosphatemic Rickes present clinically
Rickets in children; Osteomalacia in adults
Hyperosmolar Hyponatremia is due to
Presence of other osmotically active substances that cause water movement out of cells = Dilutional Hyponatremia
True Hyponatremia occurs as a result of
Incr TBW, either absolute or relative
Mutation in X-linked Hypophosphatemia
PHEX
___ is present in majority of cases of true hyponatremia
Appropriate or inappropriate increase in ADH
Phosphate vs Na: One can be reabsorbed transcellular and para, the other only trans
Phosphate is trancellularly reabsorbed, Na can be either.
3 functional segments of PT
S1-initial short segment; S2-remaining PCT and cortical parse recta; S3-medullary parse recta
Severity of Cystinuria
Relatively benign, rarely causes kidney failure
Hereditary Renal Glucosuria is caused by
mutation of SGLT2 Glucose transporter
FGF-23 normally inhibits
Na-Pi cotransporter
Classifications of PT dysfunction based on mechanism
Generalized vs Isolated Solute Transport Disorders
Inheritance of Hereditary Renal Glucosuria
Autosomal recessive
Water Deficit =
0.6 x TBW x ([Na]/140 - 1)
Hyponatremia with Volume Overload is caused by
Decreased ECV: CHF, Kidney failure, Cirrhosis, Nephrotic
Normal function of PHEX
Downregulate FGF23
Parathyroid hormone regulates what in PT
Pi excretion
Normal osmostic threshold for ADH release
280-290 mOsm/kg
Fanconi Syndrome can be __, but is most commonly ___
Inherited, but most commonly acquired
Susceptibility of PT to ischemia
High
Osmotic threshold for thirst
290-295 mOsm/kg (slight higher than for ADH)
Patient with functional SGLT2 will have glucosuria if
[Glu] exceeds normal threshold
How does pregnancy cause Nephrogenic DI
Placental synthesis of Vasopresinase
Uosm in response to water deprivation in Primary Polydipsia
Increase
Congenital Nephrogenic DI results from mutations in
V2 or Aquaporin 2
Cwater =
V x (1 - Uosm/Posm) = V - Cosm
Normal Osmolarity Hyponatremia is due to
Limitation of some Na assays when Na is measure in the whole plasma while solid phase of plasma is greatly increased (eg. HyperTGemia, Paraproteinemia)
3 inherited causes of Isolated Phosphate Reabsorption defect
(1) X-linked hypophosphatemia; (2) AD Hypophosphatemic Rickets; (3) AR Hypophosphatemic Rickets
Acquired cause of Isolated Phosphate Reabsorption defect
Oncogenic Hypophosphatemic Osteomalacia
Cosm =
Uosm/Posm x V
Most common mutation related to phosphate reabsorption
X-Linked Hypo-P
Why is PT highly susceptible to ischemia
ATP dependence, Polarized structure of cells
K moving paracellularly is an example of
Simple diffusion requiring electrochemical gradient
Mutation in FGF-23
AD Hypo-P Rickets
In PT, 33% of Na is reabsorbed via ___, the rest by
33% via transporter proteins, the rest passively by solvent drug via paracellular route
Most common electrolyte disorder
Hyponatremia
Mitochondria in PT epithelial cells
Rich to provide sufficient energy for mass reabsorption
Where is 100% of glucose reabsorbed
PT
Mutation in AD Hypo-P Rickets
FGF-23
How quickly does ADH insert new AQP-2 channels
within minutes
Hyponatremia with normal volume status is caused by
Too much ADH (SIADH, Glucocorticoid def., Hypothyroidism)
Which are more severe: Generalized or Isolated PT Dysfunctions
Generalized
Hypoosmolar Hyponatremia is due to
Always due to impaired urinary dilution mechanisms
“Generalized” PT dysfunction is usually due to
Defect in energy generation (Na-K ATPase) or dysfunction of cellular organelles affecting transport recycling
25% of Na in PT is reabsorbed by what exchanger
Na-H
mutation of SGLT2 Glucose transporter
Hereditary Renal Glucosuria is caused by
What percent of Phosphorus is reabsorbed in PT
80%
FGF23 regulates what in PT
Pi excretion
