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Lecture Objectives and Outlines-9
Lecture Objectives and Outlines-9
In spite of glomerulotubular balance, the percentage of filtrate reabsorbed here is altered by certain
circumstances and mechanisms.
7. NaCl and NaHCO3 (sodium bicarb) constitute ~90% of all the solute in the extracellular fluid and in the glomerular
filtrate.
a. They account for 90% of the body’s osmolality.
b. Of this 90%, ~20% is NaHCO3 and ~80% is NaCl.
Explain how salt and water are reabsorbed across the epithelium of the proximal tubule. Name the principal
transport proteins found in the proximal tubule. Explain how these, combined with transepithelial electrical forces
and tight junction characteristics, underlie its transport properties.
Early Proximal Convoluted Tubule
1. The first half of the PT
2. Most essential solutes are reabsorbed with Na
a. Glucose, amino acids, HCO3-
3. “Highest priority” reabsorptive work- critical metabolic role of glucose and amino acids and critical buffering role of
HCO3- mean it is super important that they get reabsorbed
4. Luminal membrane has a lot of secondary active transporters that couple Na going down its gradient to bring other
solutes into the cell= Cotransporters
5. There is one countertransporter- Na/H+ Exchanger
a. H is brought out of the cell into the lumen while Na goes into the cellà H combines with HCO3- à converts
it to CO2 and H20 that go into the cellà re-converted back to HCO3 and H+ à HCO3- goes into blood and H
can be pumped back into lumen to do it all over again
6. Lumen-Negative potential difference created by Na/Glc and Na/aa cotransporters
a. Transporters bring net positive charge into the cell and leave negative charge in the lumen
b. The other transporters are electroneutral so they don’t contribute
7. On basolateral membrane
a. Na/K pumps push Na out of cell and into blood
b. Sugars, amino acids and metabolic intermediates diffuse through down their gradients
8. By the time you go halfway down the PT
a. 100% of filtered glucose and amino acids are reabsorbed
b. 85% of filtered HCO3- is reabsorbed
c. most of the filtered phosphate, lactate and citrate are reabsorbed
d. Na has been extensively reabsorbed since it’s coupled to everything above
Isosmotic Reabsorption
1. Water transport is coupled to solute transport- driven by osmosis
a. Uses aquaporins
2. Water and solute are tightly coupled so the reabsorbed fluid is isosmotic
Describe how peritubular forces can alter glomerulotubular balance and net reabsorption rates across the
proximal tubule.
Capillary forces modulate Proximal GT Balance
1. Hypervolemiaà ↓ oncotic pressure and ↑ hydrostatic pressureà ↓ capillary fluid uptakeà ↓ Reabsorption and ↑
Excretionà Hypervolemia is reversed
2. Hypovolemia has opposite effect
a. Concentrates plasma proteins and decrease venous pressureà increase in oncotic pressure and decrease in
hydrostatic pressureà favor reabsorptionà less salt and water are excretedà extracellular volume is
conserved
List the various factors that affect fluid reabsorption in normal proximal tubules.
Urine Concentration and Dilution (The Rest of the Nephron: Forming Hypo- and Hyperosmotic Urine) AND
H2O Homeostasis Thursday
List the key transport properties of each of the remaining major nephron segments.
Name the principal transporters found in each segment: thick ascending limb, distal tubule, and collecting tubule.
Explain how these, combined with transepithelial electrical forces and tight junction characteristics, underlie the
transport functions of each segment.
State the significance of the presence or absence of glomerulotubular balance in each of these remaining
segments.
List the diuretics described in this lecture, and briefly explain their mechanisms and potential side effects.
Describe how regulation of both of GFR and upstream transport are essential for "setting the stage" for fine-tuning
of reabsorption by the collecting duct.
Describe the mechanisms by which urine is concentrated, including counter-current multiplication, the roles of the
vasa recta, and the actions of ADH.
State the routes and rates of daily water turnover.
Understand why the body tends to lose water relatively faster than solute, and its implications for patient
management.
Characterize the mechanisms and feedback loops whereby water balance is regulated in direct response to
changes in osmolality and circulating volume.
Describe the effects of high solute loads or diminished renal capacity on the body’s ability to regulate its water
balance.
Describe the 4 main processes for drug elimination in the kidney: glomerular filtration, active tubular secretion,
passive tubular reabsorption, ion trapping.
Glomerular Filtration
1. GFR ~ 20% of renal blood flow (free drug enters by diffusion)
a. 80% passes on to peritubular capillaries
2. Glomerular Filtration ~ 130 ml min-1 of plasma filtered
3. Passive Process where drugs and other endogenous substances with MW < ~ 5kD and effective radii < 15Å are filtered
a. < 1% of albumin (molecular weight ~ 69kD, is filtered at the glomerulus
4. GFR Assessment with Inulin
a. Not synthesized or metabolized
b. Filters freely through the glomerular barrier
i. Uncharged, not bound to plasma proteins, freely crosses most capillaries but doesn’t traverse cell
membrane, non-toxic
c. Not reabsorbed or secreted
d. Inulin clearance= 125-130 ml/min in humans
5. If Clrenal depends on filtration, ClRenal = GFR x fu
a. fu= unbound fraction of drug since only the unbound drug filters
6. Protein binding: only free fraction of drug crosses glomerulus
a. Protein + Drugfree « Protein-Drugbound
b. In peritubular capillaries: dissociation of bound drug allows for the free drug to diffuse from capillary;
significant amounts of drug (derived from bound fraction) can diffuse from capillary as equilibrium shifts to
the left
2. Definition- Hypothetical volume of plasma from which the blood is completely removed per unit time (L/hour,
ml/min, ect.)
a. It is a constant for each particular drug in normal
b. Cl= rate of elimination / plasma drug concentration
c. Can describe either hepatic blood flow, renal blood flow or total body (systemic)
d. Ex: Renal Clearance- volume of plasma containing the amount of drug that is removed by the kidney in unit
time
i. Depends on GFR, tubular reabsorption and tubular secretion
Describe the role of organic anion and cation transporters for renal drug clearance.
*from above
Identify the target site and uses of carbonic anhydrase inhibitors (Acetazolamide).
1. Act mainly at the proximal convoluted tubule
2. Bicarbonate absorption by the PT is dependent on the activity of carbonic anhydrase (CA).
3. Bicarbonate and H+ come together to form Carbonic Acid in the lumenà CA converts Carbonic Acid to CO2 and H2O in
the lumenà CO2 diffuses into the cells of the PT and is rehydrated back to Carbonic Acid H2CO3 by CAà H2CO3
dissociates to bicarbonate (HCO3-) and H± à HCO3- and H+ get transported out the basolateral side by various
transporters (or the H+ gets reused and pumped out with the Na/H Exchanger again)
4. Inhibiting CA with acetazolamide causes increased urinary loss of sodium bicarbonate Na+ HCO3- (this takes water
along with it) à This interferes with the reabsorption of Na and Clà Basolateral Na/K ATPase maintains low
intracellular Na concentration (necessary for reabsorption of Na) and the PT also facilitates the efflux of Na by the
Na/H Exchanger on the luminal sideà Increased delivery of Na to the collecting duct (because it stays in the lumen
with bicarbonate HCO3-) causes reabsorption of Na (through Na channels) in exchange for increased efflux of Kà Can
cause Hypokalemia
5. “zolamide”= Carbonic Anhydrase Inhibitor
6. Weak diuretic since it acts early in the nephron
a. Can be used as an add-on therapy with loop or thiazide diuretics
b. Most of the fluid loss can be regained later on in the nephron
7. Loss of bicarbonate HCO3- can cause metabolic acidosis
8. Nice video: https://www.youtube.com/watch?v=ueSTQo8041o
Desmopressin
1. Synthetic analog of arginine vasopressin
2. Metabolism is slower than AVP
3. Selectivity for V2 receptors and translocation of AQPNs to luminal surface
a. 10x antidiuretic action f AVP but 1500x less vasoconstrictor action
4. Tx for central diabetes insipidus and primary nocturnal enuresis