Proximal Tubular Dysfunctions and Disorders of Water Balance Flashcards
What are the 2 structural Divisions and 3 functional divisions of the Proximal Tubule?
Structural:
• First 2/3 - PCT
• Last 1/3 - Proximal Straight Tubule
Functional:
• S1 - initial short segement of PCT
• S2 - Remaining PCT and cortical parse Recta
• S3 - Medullary parse recta
In what two functional divisions does excretion happen in the Proximal Tubule?
S2 and S3
What are the 2 pathways of Reabsorptionin the Proximal Tubule?
Trans Cellular
Para Cellular
What is the Primary driver of all transport in the Proximal Tubule?
Na+/K+ ATPase - it moves sodium against its gradient which can then be used to move other substances back in
What are the 3 ways that Proximal Tubule Reabsorption is controlled?
- Glomerulotubular Reabsorption
- Arterial Resistance (Pressure Natriuresis)
- Hormonal
What is Glomerulotubular Balance?
Tubules have INTRINSIC ability to INCREASE tubular uptake in response to Increased tubular load (flow)
What is Pressure Natriuresis?
Increase in Peritubular Capillary Hydrostatic Pressure reduces the net absorption of Na+ and H2O
What Hormones act as regulators in the proximal tubule?
• what do they regulate?
- Angiotensin II - NaCl reabsoption and H+ secretion
* Parathyroid Hormone and FGF23 regulates Pi excretion
Why is the proximal tubule extremely susceptible to ischemia?
- HIGH ATP dependence - ATP is needed for the NKA which creates the gradient for everything that happens in the proximal tubule
- Cells here are also very dependent on cytoskeletal structure to remain in tact because they need to maintain a close relationship to prevent free movement of solutes
What are 6 potential areas for defects in the Proximal Tubule?
- Defective Solute Influx
- Leakage Back into the lumen
- Decreased Solute flux into the blood
- Defective energy generation or transportation
- Increased backflux across tight junctions
- Defective Transporter Recycling
What are the two classifications to Proximal Tubule Dysfunction and their subsets?
- Classification Based on the mechanism of Dysfunction
a. Generalized
b. Isolated Solute Transport disorders - Classification Based on the Mode of Inheritance
a. Genetic
b. Aquired
Differentiate the typical causes of Generalized and isolated solute transport disorders.
Generalized:
• caused by defect in NKA usually or a dysfunction in cellular organelles involved in protein recycling
Isolated:
• Defect in Specific Transport Protein
Hereditary Renal Glucosurea
• Inheritance
• Mutation
• Manifestation
Inheritance:
• Autosomal Recessive
Mutation:
• SGLT2 transporter
Manifestation:
• Mild to Severe increased amounts of glucose in pee
Differentiate the 3 types of Glucoseurea.
Type A:
• Lowered Threshold Value at which Glucose starts to appear in urine (normal = 200 - 220 mg/dL)
Type B:
• Same Threshold, BUT once the threshold is met it approaches the Tm much faster
Type O:
• no presence of channels, you’re always just peeing sugar
Cystinurea
• Inheritance
• Mutation
• Manifestation
Inheritance:
• Autosomal Recessive
Mutation:
• Loss of AA transporter for Cysteine, Arginine, Ornithine, and Lysine
Manifestation:
• Cystals in urine or Kidney stones
What 4 things protein mutations could cause messed up elimination of phosphate?
• aquired or genetic?
Genetic:
• X-linked hypophosphatemia - PHEX gene mutation
- Autosomal Dominant Hypophosphatemic Rickets - FGF-23 gene mutation
- Autosomal Recessive Hypophosphatemic Ricks - increased FGF-23 or mutation in Na/Pi IIc transporter
Aquired:
• Oncogenic Hypophosphatemic Oseomalacia - increased production of FGF-23 by some tumors
What is the function of FGF-23?
Suppresses the Na+/PO4 transporter in the Proximal tubule
What is the most common defect in phosphate reabsorption?
• Inheritance
• Mutation
• manifestation
X-Linked Phosphatemic Rickets
Inheritance:
• X-linked dominant
Mutation:
• PHEX gene - works to down regulate FGF-23 expression. FGF-23 gets over expressed in this disease THERE IS NO Na+/PO4 mutation. FGF-23 levels just stay high and down regulate the transporter in the proximal tubules
Manisfestation:
Rickets in kids; Osteomalacia in adults
- Urinary Phosphate wasting
- Low Serum Phosphorus
- Elevated Serum Alkaline Phosphatase
- Low Ca2+ and Calitriol
Hartnup Disease
• Mutation
• Manifestation
Mutation:
• SLCA19 mutated - this is a neutral amino acid transporter
Manifestation:
• FAILURE TO THRIVE, Nystagmus, Ataxia, Photosensitivity, Tremor
REVIEW PAPER SLIP ON FANCONI SYNDROME
REVIEW PAPER SLIP ON FANCONI SYNDROME
Fanconi Syndrome
• possible causes
- Defective Binding of Na with transport proteins
- Defective insertion of Carriers into the brush border membrane
- Leaky Membrane Tight Junctions
- NKA Impaired
- Mitochondrial Energy Generation Defect
Fanconi Syndrome
• Metabolic Abnormalities
- Aminoaciduria (generalized)
- Glucosuria (with normal serum glucose)
- Hypophosphatemia (multifactorial: decresae phosphate reabsorption from defect in Na/Pi carrier, inhibition of Na/Pi carrier from decreased degradation of parathyroid hormone in PT, decrease in calcitriol synthesis)
- Hyperchloremic metabolic acidosis (due to bicarbonate loss)
- Hypokalemia (along with natriuresis due to bicarbonate loss)
- Uricosuria
Clincial Manifestations of Fanconi Syndrome .
- Polyuria and polydipsia
- Volume depletion
- Cardiac arrhythmias
- Proteinuria
- Growth retardation
- Rickets
- Renal stones and nephrocalcinosis
- Extra renal organ involvement depending on the underline cause
Fanconi Syndrome
• Inherited Causes
• Most important
****Cystinosis**** Hepatorenal tyrosinemia Hereditary fructose intolerance Galactosemia Glycogen storage disease type I Wilson disease Oculocerebral renal (Lowe) syndrome Dent’s disease Mitochondrial disorders (Cytochrome c oxidase deficiency)
