Renal II Flashcards
Define: Clearance
the volume of plasma from which a substance is completely cleared ,by the kidneys per unit time
What does the principle of renal clearance emphasize?
the excretory function of the kidneys
it considers only the rate at which a substance is excreted into the urine and not its return to the systemic circulation through the renal vein
Basic Clearance Formula
Cx = (UxV)/Px
Ux = urine concentration of x (mg/ml)
V = urine volume (mL/min)
Px = Plasma concentration of x (mg/mL)
If a substance is present in urine at concentration of 100 mg/mL and urine flow rate is 1 mL/min and the substance has a concentration of 1 mg/mL in plasma, what is the clearance of the substance?
(100 mg/mL X 1 mL/min)/ 1 mg/ml = 100 ml/min
100 mL of plasma is completely cleared of the substance/min
Equation to find GFR using Clearance
GFR = (UwV)/Pw
urinary clearance of w is equal to the GFR
What criteria needs to be met in order for GFR = (UwV)/Pw to be valid?
- W must be
- freely filtrable
- not reabsorbed
- not secreted
- not synthesized by tubules
- not broken down by tubules
What fits the required criteria and can be used to determine GFR using clearance?
Inulin → a polysaccharide
GFR = renal clearance of inulin
Clearance of inulin (Cin) = GFR
What is the issue with using inulin to measure GFR?
inulin is not naturally occurring
What is used in place of inulin in clinical settings? why?
Creatinine
creatinine is freely filterable and not reabsorbed like inulin
there is a direct relationship between plasma creatinine and GFR within limits
What is the relationship between Creatinine and GFR?
a small amount of creatinine is secreted → clearance of creatinine is slightly higher than real GFR
if plasma creatinine is raised, it indicates that renal function, especially GFR, is impaired
GFR decreases → plasma creatine increases
large increase in creatinine → small drop in GFR
What is normal plasma creatinine?
10 mg/L
What happens to plasma creatinine if GFR decreases 50%?
plasma creatinine rises but stabilizes at 20 mg/L
Para-aminohippurate (PAH)
filtered at glomerulus, not reabsorbed, almost totally secreted
PAH approximates renal plasma flow
Equation: Clearance of PAH
CPAH = (UPAHV)/PPAH = ERPF
ERPF = effective renal plasma fluid
What happens to 10-15% of total renal plasma flow?
it supplies non-filtering and non-secreting portions of the kidneys such as (peripelvic fat), and this plasma cannot lose its PAH by secretion
ERPF
0.9RBF
Equation: RBF
RBF = RPF/(1-hematocrit)
hematocrit = % of blood cells
Define: Diffusion
occurs from an area of higher concentration to one of lower concentration (down concentration gradient)
affected by the electrical potential difference across the cell membranes of the renal tubule cells
Define: Facilitated Diffusion
depends on interaction of solute with a specific protein in the membrane that facilitates its movement across the membrane
utilizes transporters to move proteins
Define: Primary Active Transport
the movement of molecules through a mechanism which is directly coupled to energy derived from metabolic processes (consumes ATP)
occurs against the concentration gradient (low to high)
utilizes ATP-dependent transporters or through endocytosis
Define: Endocytosis
transport process where there is invagination of a part of the cell membrane until it completely pinches off and forms a vesicle in the cytoplasm
Define: Secondary Active Transport
occurs when the energy from the downhill movement of a solute provides energy for the uphill movement of another solute
Define: Solvent Drag
occurs when water is reabsorbed and solutes which have been dissolved in the water is reabsorbed with water
Two types of transport mechanisms in reabsorption
Paracellular
Transcellular
Define: Paracellular
movement that goes between two cells
can be by diffusion or solvent drag
Define: Transcellular
movement that goes across the tubular cell → has to pass through the luminal and basolateral membranes
How can lipid soluble substances transverse both membranes?
by diffusion and net passive reabsorption occurring by the transcellular route
How can poorly lipid-soluble substances transverse both membranes?
using active transport
What criteria must be met for a substance to be reabsorbed transcellulary?
1 of its 2 movements has to be active
and the second mode of transport must be different
The generalization for net transcellular reabsorption of a substance requires…
That the luminal and basolateral membranes be asymmetrical for that substance (contain dif channels and/or transporters for the two membranes)
That energy be used for the movement of the substance either from lumen into cell or from cell into interstitial fluid
Define: transport maximum
many active reabsorptive systems in the renal tubule have a limit to the amounts of material they can transport per unit time
What causes transport maximum of reabsorptive systems in the renal tubule?
membrane proteins responsible for the transport become saturated
What does transport maximum represent/refelct?
The maximal transport capacity of both kidneys
In turn it represents the sum of transport capacities of individual functional nephrons
What is the relationship between the amount of substance filtered and the amount reabsorbed?
linear
As Tm is approached, some nephrons have reached their capacity and some substance appears in the urine
Define: Renal Threshold
the plasma concentration where the substance occurs in the urine
What happens as more nephrons exceed their capacity?
the relationship between amount filtered and reabsorbed is not linear (the splay)
Glucose Reabsorption in the Renal System
Glucose is completely reabsorbed → reabsorption rate follows filtered load
renal clearance of glucose is 0 → urinary concentration of glucose is 0
What has to happen to plasma glucose to reach renal threshold?
Plasma glucose has to rise more than double normal levels before renal threshold is reached
What happens to glucose when renal threshold is met?
reabsorption stops and glucose starts appearing in the urine
renal threshold is reached slightly before Tm
Why is renal threshold met slightly before Tm?
as one approaches Tm, there are so few transporters left, that there is a greater chance NOT to get reabsorbed, so glucose molecules are not reabsorbed and pass through nephron and appear in urine
excretion rate now rises in parallel with filtered load
What do tubular secretory processes do?
They transport substances across the tubular epithelium into the lumen
Tubular Secretory Process
begins with diffusion out of peritubular capillaries into the interstitial fluid from which it makes its way into the lumen by crossing either tight junctions (paracellular transport) or in turn, the basolateral luminal membranes of the cell (transcellular)
What is the direction of flow for secretion?
From the peritubular capillary → across tight junctions (paracellular) or membranes (transcellular) → into lumen
What happens to filtered substances when secretion stops?
it is excreted
excretion = secretion + filtered
How are most substances transported?
bidirectionally
How does bidirectional transport work?
active reabsorptive processes tend to establish a concentration lower in the lumen than in the interstitial fluid → concentration difference favors passive paracellular secretion → creates a “pump-leak” system where active transport creates a diffusion gradient that opposes its own action by favoring back diffusion
Where is bidirectional transport particularly prevelant?
the proximal tubule
can also occur if the tubular segment contains opposing pathways
Due to bidirectional transport, reabsorption and/or secretion are…
net processes
Important characteristics of the Proximal Tubule
- Luminal membrane has microvilli which increases surface are available for reabsorption
- Tight junction is relatively leaky.
- leakiness allows some reabsorption to occur passively down osmotic gradient through tight junction
- Na+-K+-ATPase pump in basolateral membrane has greater activity than in most other nephron segments
Reabsorption of sodium is….
mainly an active transcellular process
Reabsorption of chloride is…
both passive (paracellular diffusion) and active (transcellular) but it is either directly or indirectly coupled with sodium reabsorption
Reabsorption of water is…
by diffusion (osmosis) and is secondary to reabsorption of solutes particularly sodium
Low GFR means,
less filtered, less reabsorbed
% of Filtered Load Reabsorbed by Kidneys: Water
99.2%
% of Filtered Load Reabsorbed by Kidneys: Na+
99.4%
% of Filtered Load Reabsorbed by Kidneys: Glucose
100%
% of Filtered Load Reabsorbed by Kidneys: Urea
50%
Cell model for Proximal Tubule Transport
- Two membranes with different permeability characteristics
- luminal membrane with microvilli
- basolateral membrane
- intercellular space between adjacent cells which is open at capillary end and to a lesser degree at the luminal end across from a tight junction
Reabsorption of all organic solutes are coupled by….
Na reabsorption
Na+-K+-ATPase
primary event in the Na+-K+-ATPase is the basolateral membrane
Pump maintains low intracellular Na concentration
steep concentration allows Na to be transported rapidly into cell
Early Portion of Proximal Tubule
movement of Na is linked to co-transport of glucose, amino acids, and phosphate into cell
Na reabsorption occurs via countertransport with hydrogen ions
with each transporter, the favorable inward gradient for Na is sufficient to drive the transport of other solute (20 active transport)
Early Portion Proximal Tubule: How are glucose, amino acids, and phosphate reabsorbed on the basolateral membrane?
via various facilitated diffusion mechanisms
How is Na reabsorption accomplished in later proximal tubule?
via Na/H countertransport mechanisms.
Isoosmotic reabsorption
- in the proximal tubule, sodium and water reabsorption occur to the same degree
- as Na is being reabsorbed (increase concentration of Na) water is also reabsorbed
What is the driving force of water reabsorption?
transtubular osmotic gradient established by solute reabsorption
water reabsorption follows solute reabsorption in proximal tubule
What is the effect of reabsorption of solutes on osmolarity in the proximal tubule?
reabsorption of solutes reduces osmolarity of the tubular fluid and increases osmolarity of the interstitial spaces
osmolarity remains relatively constant throughout the proximal tubule
Why is the proximal tubule highly permeable to water?
because of the expression of aquaporin-1 water channels
How is water reabsorbed in the proximal tubule?
by osmosis down the concentration gradient
paracellularly → tight junctions are permeable to water
Proximal Tubule: Accumulation of solutes and fluid in interstitial space….
increases hydrostatic pressure in this compartment and fluid and solutes are forced into peritubular capillaries
2 mechanisms for movement of fluid into peritubular capillaries
Net diffusion
Bulk Flow of interstitial Fluid
Net filtration pressure across the peritubular capillaries always favors….
net movement into the capillaries
Why does Net filtration pressure across the peritubular capillaries always favor net movement into the capillaries?
Because the peritubular capillary hydrostatic pressure is usually quite low (~13 mmHg)
oncotic pressure of the plasma entering the peritubular capillaries is higher than that of the arterial plasma (plasma proteins are concentrated by loss of protein-free filtrate during passage through the glomerular capillaries)
Relationship between interstitial fluid hydrostatic pressure and oncotic pressure in the proximal tubule?
interstitial fluid hydrostatic pressure usually equals interstitial fluid oncotic pressure in the proximal tubule
Due to the fact that interstitial fluid hydrostatic pressure usually equals interstitial fluid oncotic pressure in the proximal tubule, Reabsorption of fluid from the interstitial space is mostly dependent on…
forces in the peritubular capillary → specifically peritubular capillary oncotic pressure drives reabsorption from the interstitial space into the capillaries, while the capillary hydrostatic pressure opposes this
Reabsorption of Bicarbonate in proximal tubule
bicarbonate is reabsorbed indirectly
- secreted H+ (in exchange for Na) reacts with bicarbonate in filtrate
- carbonic acid forms
- carbonic acid dehydrates to carbon dioxide in presence of carbonic anhydrase
- carbon dioxide (and water) diffuse through the luminal membrane into cell
- CO2 is rehydrated to carbonic acid
- (by intracellular carbonic acid anhydrase)
- intracellular carbonic acid dissociates to HCO3- and H+ ion
- HCO3- exits cell across the basolateral membrane by facilitated diffusion
Net absorption of HCO3- by above mechanism is important for the net reabsorption of Na+
What does reabsorbing Na by the Na+-K+ ATPase pump do to the cell?
it makes it basic
Chloride Reabsorption
a large amount of chloride reabsorption in the proximal tubule occurs by a passive mechanism of bulk flow of water and solute through the tight junction (paracellular reabsorption)
Mechanism of Chloride Reabsorption in Proximal Tubule
- Proximal tubule reabsorbs most of the filtered glucose, amino acids, and bicarbonate by coupled transport with sodium, but a smaller amount of chloride
- chloride ion concentration increases within the proximal tubule compared to plasma
- Tight junction is permeable to chloride
- chloride moved through the tight junction down a concentration gradient
- Na follows to maintain electroneutrality
- chloride moved through the tight junction down a concentration gradient
- Chloride behaves as a permeant ion → luminal fluid has a lower effective osmotic pressure than the intracellular space
- imbalance between osmotic forces across the tight junction causes water to move from lower osmotic pressure of the tubule lumen into high osmotic pressure of the intracellular space
- maintains isosmotic reabsorption of proximal tubule
Chloride reabsorption linked to Formate
- In late proximal tubule, specialized transport devices account for reabsorption of chloride ion
- mechanism is in exchange for formate ion
- formate ion is converted to formic acid (HF) by secreted hydrogen ion
- Formic acid diffuse across the luminal membrane → b/c it is uncharged
- formic acid dissociates to F- and H+ in cell interior
- cell pH is higher than luminal pH
- F- moves back across the luminal membrane in exchange for chloride
- Hydrogen is secreted across the luminal membrane in exchange for sodium
Filtration Fraction
GFR/RBF
Effect of Filtration Fraction on Fluid Reabsorption in the Peritubular Capillaries
Increased sympathetic outflow and/or AII levels → increased arteriolar vasoconstriction → decreases RBF more than GFR → increases filtration fraction → increases peritubular capillary oncotic pressure (w. decreased hydrostatic pressure) → increases fluid movement (reabsorption) into peritubular capillaries
Henle’s Loop
reabsorbs approximately 25% of filtered NaCl and 15% of filtered water
taken as a whole → Henle’s Loop always reabsorbs more sodium and chloride than water
Descending Limb of Henle’s Loop
does not reabsorb sodium but is highly permeable to water → reabsorbs water
Ascending Limb of Henle’s Loop
reabsorbs sodium and chloride but impermeable to water
What does the movement of sodium and chloride out of ascending limbs of Henle’s Loop into interstitial fluid do?
It raises the osmolarity at this location which causes water reabsorption by diffusion from the water permeable descending limb
What is the major transport mechanism in the ascending limb of Henle’s Loop?
Na+-K+-2Cl- cotransporter
Why is Henle’s Loop called the diluting segment?
because of the reabsorption of sodium and water, the fluid that enters distal convoluted tubule is hypoosmotic compared to plasma
Distal Convoluted Tubule and Collecting-Duct System
Distal convoluted tubule and collecting duct reabsorb ~ 10% of the filtered NaCl
secretes variable amounts of K+ and H+
reabsorb a variable amount of water
What kind of cotransporter is found in the initial part of the distal convoluted tube?
Na-Cl
Initial portion of Distal Convoluted Tubule
water reabsorption is low
fluid in this segment becomes more hypoosmotic
Collecting Duct: Principal Cells
reabsorb sodium through Na+ channels.
secrete K+
Collecting Duct: α - intercalated cells
H+ is secreted through an H+-ATPase as well as an H+-K+-ATPase counter transporter
Collecting Duct: β-intercalated cell
secrete HCO3- in exchange for Cl-
reabsorb H+ and Cl-
Water permeability in the collecting ducts
can be very high or very low
under the influence of Vasopressin or Antidiuretic Hormone (ADH)
What effect does ADH have on collecting ducts?
water permeability increases dramatically
there is rapid reabsorption of water by diffusion down its concentration gradient becoming isoosmotic compared to cortical plasma
What happens to water in the medullary collecting duct?
water reabsorption continues
luminal fluid becomes hyperosmotic
produces hyperosmotic urine
What effect does aldosterone have on collecting ducts?
it is secreted by the adrenal cortex
acts in a classic steroid hormone fashion by stimulating protein synthesis in the cell
aldosterone binds to cellular receptors and through the increased synthesis of specific proteins, increases the number of sodium channels in the luminal membrane of the late distal tubule collecting duct
increases activity of the Na+-K+ ATPase pump
What is the effect of reabsorption of Na+ in the late distal tubule and collecting duct?
it generates a lumen negative voltage across the luminal membrane which is the driving force of paracellular reabsorption of Cl-
What is the purpose of the countercurrent multiplier system?
to produce concentrated urine
takes place in the Loops of Henle
What is the Countercurrent Multiplier System dependent on?
- Descending limb of the Loop does not absorb sodium or chloride but reabsorbs water
- high permeability to water but low permeability to sodium and chloride
- Ascending limb reabsorbs sodium and chloride but not water
- segments are permeable to sodium and chloride but less to water
Countercurrent Multiplier System
Step 1: Na, Cl, K are reabsorbed from the thick ascending limb
Step 2: hypertonic interstitium stimulates the reabsorption of water from the thin descending limb
Step 3: flow occurs within the loop so that more isotonic fluid enters the loop from the proximal tubule, and hyperosmotic fluid generated in the thin descending limb is delivered to the ascending limb
Steps 1-3 are repeated until you get the end result of a large vertical osmotic gradient generated but a smaller gradient exists horizontally
THIS IS HOW URINE IS CONCENTRATED
What effect does the Countercurrent Multiplier System have on the medullary interstitium?
it becomes very hyperosmotic
How is the Countercurrent Multiplier System maintained?
by the blood flow in the vasa recta which preserves the hyperosmotic interstitium of the Loop
How can water be reabsorbed in the collecting duct?
by going down its osmotic gradient due to the very high medullary interstitial osmolarity
Rate limiting step in the Countercurrent Multiplier System
Na-K-Cl cotransporter in the thick ascending limb
What happens if the Na-K-Cl cotransporter in the Countercurrent Multiplier System is inhibited?
less NaCl and K is reabsorbed from the thick ascending limb
medullary interstitium will be less hyperosmotic and less water will be reabsorbed from the thin descending limb
more water will remain in the loop → less hyperosmotic
In the collecting tubule/ducts, less water will be reabsorbed because the medullary interstitium is not as hyperosmotic
Role of Interstitial Urea
Urea is important in creating hyperosmolarity in tubular fluid
after filtration, luminal urea concentration rises progressively along the cortical collecting ducts and the outer medullary collecting ducts is reabsorbed
High urea concentration in the inner medullary collecting duct then drives reabsorption in the segment under the influence of ADH
Why is Urea not reabsorbed in the cortical collecting ducts?
tubular segments are impermeable to it
What does simultaneous movement of water out of the inner medullary collecting ducts do?
It maintains high urea concentration within the ducts → net result is that the urea concentration in the inner medulla equilibrates across the interstitial fluid and lumen of duct
concentration in the lumen helps create the high osmolarity of concentrated urine
Sodium reabsorption in the nephron
Proximal tubule reabsorbs 65% of filtered sodium
Thick ascending limbs of Henle’s Loop together - 25%
Distal Convoluted Tubule and Collecting Ducts - remaining 10% so that final urine volume contains less than 1% of total filtered sodium
Essential Event for Transcellular Sodium Reabsorption in the Nephron
primary active transport of sodium from cell to interstitial fluid by the Na-K-ATPase pumps in the basolateral membrane
on the luminal membranes there are many dif transport mechanisms which help reabsorb sodium in dif segments of the nephron
Chloride reabsorption in the nephron: Paracellular transport in the proximal tubule:
Critical step for paracellular reabsorption of Cl is between lumen and interstitium
luminal membrane processes which reabsorb Na, HCO3, phosphate, glucose, amino acids achieve a high enough luminal chloride concentration to cause downhill chloride movement out of the lumen to interstitium
Chloride reabsorption in the nephron: Transcellular transport in the TALH, Distal Convoluted tubule, Collecting Duct:
Most of the transport mechanism for Cl are coupled with Sodium (directly or indirectly)
Cl/bicarbonate transport system is independent of sodium
Where does Cl/bicarbonate transport system occur?
occurs in collecting duct
independent of Na
Where does chloride transport occur?
type B intercalated cells
Where does sodium transport occur?
principal cells
Water reabsorption in nephrons
occurs in the proximal tubule (65% of filtered water)
thin descending limb of Henle’s Loop (10%)
collecting duct system (a few percent to > 24%; depending on ADH levels)
