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)
What are there so many drugs that can cause Fanconi Syndrome?
Proximal Tubule is often the first thing to come into contact with drugs on their way out of the body
Fanconi Syndrome
• Drugs that can cause
Cancer Drugs:
• Ifosfamide
• Cisplatin
Hep B protease Inhibitors
• Cidofovir
• Tenofovir
Others • Outdated Tetracyclines • Aminoglycosides • Cisplatin • Ranitidine
Fanconi Syndrome
• Heavy Metals that can cause
• Toxins that can cause
• Dysproteinemias that can cause
Heavy Metals
• Lead
• Cadmium
Toxins
• Toluene, Paraquat, Aristolochic Acid
Dysproteinemias
• Multiple Myeloma
• Light chain deposition disease
**Note: Acute tubular necrosis can also cause this
Who is Inherited Fanconi Most Commonly Seen in?
• Acquired?
Inherited:
• Typically seen in children and usually more severe
Aquired:
• Typically seen in Adults usually more mild
What is the difference between effective and ineffective osmoles?
•give two examples of each
Effective:
• Na+ and K+; these do not easily permeate any membrane
Ineffective:
• Urea and Glucose; these can easily travel between body compartment
How is plasma Osmolarity Calculated?
Posm = 2 x [Na]
What is the formula for plasma Na?
•What are changes in Plasma sodium concentration indicative of?
Plasma Na = Total Body Exchangable Na and K / Total body H2O
Changes in Total Body Water = only thing that really matters because Na concentration is never really going to change
How much of a change in plasma osmolarity does there need to be to trigger ADH secretion?
• what about change in blood volume?
- Change in Posm as little as 1% Stimulates ADH secretion
* Greater than 7% decrease in blood volume stimulates ADH secretion
ADH
• what does it act on?
• In what ways does it act?
ADH is released from the pituitary and acts on the COLLECTING DUCT
Acts in 2 ways:
1. Short-term: there is a Rapid and Reversible increase in AQP-2 that is sent to the luminal surface
- Long-term: AQP-2 GENE EXPRESSION is upregulated, takes LONGER THAN 24hrs
• Not Readily Reversible
How do you determine if water is in XS or deficit?
• Formulas for calculating the amount?
If in XS Excess:
• Low Pna - sodium is diluted
• XS = 0.6 TBwt. x (1 - [Na]obs/140)
If in Deficit:
• High Pna - sodium is concentrated
• Deficit = 0.6 TBwt. x ([Na]obs/140 -1)
What is the most common type of electrolyte disorder?
Hyponatremic Disorders
What are the 3 types of Hyponatremic disorders?
• what ion are they typically associated with?
Most often associated with Na
3 types:
• Hyperosmolar Hyponatremia
• Normal Osmolarity Hyponatremia
• Decreased Osmolarity Hyponatremia
What is Hyperosmolar Hypnatremia?
• causes?
- Presence of other osmotically active substances that cause water movement OUT of cells
- Since sodium resides OUTside of cells this dilutes Na concentration
Causes:
• Glucose - in absence of insulin
• Mannitol
• Glycine
What is Normal osmolality Hyponatremia (pseudohyponatremia)?
• causes?
- Occurs due to limitation of some Na assays when Na is measured in the WHOLE PLASMA while solid phase of Plasma is Greatly increased
- Hypertriglyceridemia or Paraproteinemia may cause this misreading
What is Hypoosmolar Hyponatremia aka TRUE HYPONATREMIA?
• causes?
- ALWAYS due to impaired Urinary Dilution Mechanisms
* Appropriate or Inappropriate increase in ADH is present in the majority of cases of true hyponatremia
Causes of True Hyponatremia with Volume Depletion?
Hyponatremia with volume depletion:
- renal losses (diuretics, aldosterone deficit)
- gastrointestinal losses (diarrhea, vomiting, bleeding)
- skin losses (excessive sweating while ingesting some free water)
- third spacing (pancreatitis, bowel obstruction, burns)
Causes of True Hyponatremia with normal Volume status?
Hyponatremia with normal volume status:
- Syndrome of inappropriate ADH release (drugs, tumors, pain, any lung or brain diseases)
- Glucocorticoid deficiency (loss of negative feedback stimulates corticotropin releasing hormone which in turn stimulates ADH)
- Hypothyroidism (increase ADH possibly due to low cardiac output state and impaired urine dilution from decreased GFR)
Causes of True Hyponatremia with Volume Overload?
Hyponatremia with volume overload (however, effective circulating volume is usually decreased):
- Congestive heart failure - Acute and Chronic kidney failure - Cirrhosis - Nephrotic syndrome
