Download Renal11-ProximalTubularFunctionII

Renal #11
Tue. 3/18/03, 2pm
Dr. Mallet
Paul Duong
Page 1 of 4
Not yet reviewed by Dr Mallet
SESSION 4:Proximal Tubular Handling of Organic Compounds
Berne & Levy: pp. 706-707
Case presentation
•A ten y.o. female is found unconscious in her bedroom and is rushed to the ER.
The attending physician
learns from her parents that the patient has seemed lethargic and sometimes disoriented for the previous 2-3
weeks, and often complained of thirst despite drinking unusually large amounts of water and Dr. Pepper.
She has been urinating frequently and bedwetting, which her parents ascribe to her excessive fluid intake.
A urine specimen is obtained and dipstick reveals 4+ glucosuria; plasma glucose is 700 mg/dl.
•By the end of the lecture you should be able to explain the patient’s polyuria. Why is she thirsty?
•I/ This lecture will consider the basic mechanism of tubular reabsorption of glucose and aa
1.
2.
3.
4.
This is a secondary (gradient coupled) active transport that ultimately depend on Na
reabsorption so it will depend on the Na/K ATP ase.
Glucose reabsorption: a saturable process. If too much glucose is filtered into the nephron
some of the glucose won’t be reabsorbed as the result some glucose will spill into the
urine.
PAH secretion ( an example of organic anions) also is saturable process. PAH clearance
can only use as a measure of renal plasma flow if the renal plasma pH low enough that
the kidney are overwhelmed PAH then the secretion process is saturated.
Secretion of organic acids and bases:
–charged forms: anions and cations will use the Tertiary active transport.
–Uncharged form: move across the epithelium by Passive diffusion. this process can be
effected by the movement of hydrogen ions into the tubular lumen.
II/ Impact of organic nutrient handling
1. Large amounts of nutrients (glucose, amino acids) filtered each day by the nephrons and the
compound must be retained in the body
–Small molecules: freely filtered
–proximal tubule must completely reabsorbed these materials and the reabsorption is occurred
exclusively in the proximal tubule
–No reabsorption of glucose or aa in more distal segments
2.
3.
Normally the Kidneys try to retain as much as they can. The kidneys don’t regulate plasma
concentrations of glucose, amino acids. The liver and endocrine system do: insulin, glucagon, etc.
Basic mechanism of tubular reabsorption
a. The reabsorption of glucose and aa are Secondary active transport. These are small
compounds but they are nor small enough to move between the epithelial cells. So the
compounds only reabsorbed transcellularly. They move through cellular membrane by
specific processes.
b. Uptake of glucose across luminal membrane:
–Against concentration gradient
–Coupled to Na+ entry down its electrochemical gradient
–Ultimately dependent on Na+-K+ ATPase which establish the Na gradient.
c.
Once in the cell, the glucose will Exits cell through basolateral membrane by facilitated
diffusion. This is another example of the polarity of the epithelial cells. The luminal and
basolateral membrane have diff process going on for example: the luminal has Na- Glu
cotransporter and the basolateral has facilitated diffusion. And because the diff process at
diff sides of the cell that enable the unidirectional movement of that substance.
Example: Glucose reabsorption will move from the lumen to the interstitial fluid. (refer to
diagram in the ppt).
Renal #11
Tue. 3/18/03, 2pm
Dr. Mallet
Paul Duong
Page 2 of 4
Not yet reviewed by Dr Mallet
d.
Glucose concentration is pretty low in most cells in the body. Usually the Glucose taken
into the cells will immediately phosphorylated to make glucose 6 phosphate which then
either consumed in glycolysis or put in glycogen reserved.
e. The exception the proximal tubule cells where glucose is accumulated to high
concentration. As the result these epithelial cells are the sweetest cells in the body.
III/ The Glucose reabsorption is saturable because:
1. Limited number of Na+-glucose cotransporters in luminal membrane. If too much glucose
is filtered into the nephrons, some of the glucose won’t be reabsorbed which will spill
into the urine.
2. So If filtered amount (load) of glucose (= GFR  Pglucose) exceeds a certain threshold then:
–Capacity of nephrons to reabsorb all the filtered glucose is exceeded
–Glucose appears in the urine and then we’ll have glucosuria.
3.
4.
Identify a disease in which glucose saturation occurs: diabetes?
Same principles apply to amino acid transport. Instead of glucose you can put aa: alanine,
glutamine, etc for the glucose reabsorption process. There are Na-amino acid
costranpoters just like glucose. There are 20 different transporters for all aa. Certain class
of aa share the same transporters: eg glutamate and aspartate.
5. Refer to the graph in ppt. The graph summarize the glucose filtration, reabsorption and
excretion as a function of plasma glucose concentration. The normal text book values is
about 100mg/dl which is on the left side of the graph. As glucose concentratin incr, the
rate of filtration ( filtration = GFRx Pglucose) will incr. linearly. At low [glucose], the
rate of tubular reabsorption keep pace with the rate of filtration so all of the filtered
glucose will be reabsorbed. But at some point that reabsorption process become saturated
and level off at maximum range which is tubular maximum ( Tm). As the glucose
seretion become saturated you will see some glucose excreted in the urine. And then any
incr. in glucose will produce identical incr. in the rate of glucose excreted.
6. Threshold is the plasma glucose concentration at which glucose will begin to appear in
the urine.
7. Splay refers to the curvature of the reabsorbed graph. Splay reflects the heterogeneity of
the nephrons. There are some nephrons that have fewer glucose transporters than others
so those nephrons will be saturated at a lower plasma glucose. And only when we reach
the Tm ( tubular maximum) then all the nephrons will be saturated.
Questions for discussion
1. Would the filtered load of glucose change if GFR increased but plasma glucose concentration
remained constant? Yes , the filtered load (= GFRxPglucose) increase. GFR is a potential
determinant whether glucose appear in the urine.
2. Would an inhibitor of the renal tubular Na +-K+ ATPase affect reabsorption of glucose? Why?
Yes, the inhibitor will disrupt the gradient of the Na which is established by the Na-K pump which
is the driving force for glucose reabsorption.
3. Urine output increases in diabetes. Why? Yes. In diabetes, glucose acting as a osmotic diuretics.
Glucose remain in the lumen will hold the water with it so the pt will excreted more water. Dr
Mallet performed and excellent example of conveyor belt in the cake factory. The cake is glucose.
As he is the Na-glucose transporter trying to put the cake into the box ( the cell). If there is a large
order from Kroger then more cakes will be in the conveyor belt and Dr Mallet had to try really
hard to put the cake into the boxes. However, after a certain increase then he no longer be able to
put all the cakes in the boxes and some cakes will be dumped which means glucose will be
dumped into the urine.
IV/ PAH secretion is also saturable.
1. PAH is not normally found in the body but was used to illustrated that some compound
secretion is also saturable. Refer to the graph that show the rate of filtration, secretion
and excretion as a function of PAH concentration. All of the filtered Pah will be excreted
Renal #11
Tue. 3/18/03, 2pm
Dr. Mallet
Paul Duong
Page 3 of 4
Not yet reviewed by Dr Mallet
and not reabsorbed anywhere. On top of that amount, some PAH is secreted. And the sum
of those two are the amt excreted. At low PAH, the rate of secretion is great enough that
all the plasma PAH is removed and ultimately excreted in the urine. But at some point
that secretion process reach its tubular maximum and secretion can’t increase anymore.
So any further increase in excretion will run parallel to the amount filtered. The amount
excreted will always be greater than the amount filtered because there is always secretion
of PAH.
2. Refer to the next graph. Because of the saturation, these compounds clearance can very
with the plasma concentration. This graph shows the clearance of inulin, glucose, PAH
vs. plasma concentrations. Inulin is neither reabsorbed or secreted but freely filtered. So
no matter what inulin concentration is the amount of filtered per unit time will always
equal the amt excreted so inulin clearance will equal blood variables, always equal GFR.
Now considering glucose, as normal Pglucose, glucose clearance will be zero. This is due
to the fact that all the glucose filtered will be reabsorbed and the kidneys aren’t removing
any glucose from the plasma. Until the glucose reabsorbed begin to saturate, then some
of the filtered glucose not reabsorbed and being excreted. As the result, the kidneys are
clearing some of the glucose from the plasma. As further increase in glucose
concentration the glucose clearing will continue to increase but will never equal inulin
clearance. That because no matter how much glucose filtered, the amount excreted will
always be at least a little bit less than the amount filtered because there is always some
glucose reabsorbed.
3. For PAH, as low plasma PAH concentration, it is completely removed or cleared from
the plasma. So its clearance is equal to plasma flow = 700ml/min. But as the PAH
secretion process saturated then not all the PAH will be removed from the plasma, some
will remain behind and the PAH clearance will begin to fall, and further increase in the
PAH that clearance level will fall further. But it will be always greater than the GFR=
Inulin clearance because the amount Pah excreted in the urine will always be greater than
the amount it filtered as discussed earlier.
V/ The next topic will be the secretion of organic anions and cations.
For example, PAH is a good organic anions. These compounds are secreted by a tertiary active transport
process. But these processes still ultimately dependent on the Na-K pump. There are a limited number of
these processes so diff cations will compete with each other to be transported. It’s also true for anions.
1. Organic anions and cations are ionized forms of weak acids and bases, respectively
2. Charged forms are highly polar, hydrophilic - cannot readily diffuse through lipid bilayer,
they require an aqueous channel or a transport protein of some sort to get across.
3. But the uncharged molecules are tend to be more lipid soluable since they are less polar,
more lipophilic
4. The relative amount of the charged and uncharged are determined by the H+
concentration in the solution.
VI/ Biochemistry of weak acids and bases
Weak acids are neutral or non charged when protonated:
•
A- + H+  HA
•The neutral form HA will be able to pass through the lipid bilayer.
Weak bases are charged when protonated, so they require the complicated transport mechanism. The
deprotonated form of bases are neutral so they are lipid soluble.
•
B + H+  BH+
•In Acidic solutions with a high H+ concentration, that would favor the formation of weak acid but it
would favor the charged form of the organic cations: the base. On the other hand, basic solutions with a low
H+ concentration, favor the neutral forms of weak base.
Renal #11
Tue. 3/18/03, 2pm
Dr. Mallet
Paul Duong
Page 4 of 4
Not yet reviewed by Dr Mallet
1.
The next figure illustrate how the pH affect the movement of the substances across the
tubular epithelium. When H+ ions are secreted into the tubular lumen. The ions will
combine with the organic anions forming its conjugate acid which is neutral and readily
reabsorbed across tubular cells. With the base when combined with the H+ ions will form
the organic cations and will be excreted.
To summarize that information so far: organic acids & bases
1. Luminal acidification favors reabsorption of organic acids, excretion of bases.
2. Many drugs are weak acids or bases. For eg, Aspirin or acetylsalicylic acid.
3. If patient overdoses on aspirin (acetylsalicylic acid, an organic acid), how can you promote
urinary excretion of aspirin to help eliminate it from his body? Ans: we want less H+ ions to
prevent reabsorption of HA. Because the H+ in the body can combine with aspirin to make it
to neutral forms which will be retained in the body. So you can give the pt HCO3- to lower
the H+ ions. ( which won’t be available to combine with aspirin and won’t be retained in the
body).) For eg, give the pt the baking soda.
Hypothetical scenario
•Several of the patients at your rural F.P. clinic have come down with a life-threatening bacterial
respiratory infection. The antibiotic amoxicillin has proven effective, but supplies are limited, and there
may not be enough to go around. Amoxicillin is an organic anion secreted by the proximal tubule.
•Suggest a strategy using PAH, also an organic anion, to decrease the amoxicillin dosage required to treat
the disease. Because PAH compete with the anions for the transport process to be secreted to the lumen.
And will keep the Amoxicillin longer in the body.
1.
Summary: Proximal tubular handling of organic compounds
•Organic nutrients: reabsorbed by secondary active transport, linked to Na+ reabsorption
•Glucose reabsorption is saturable; glucosuria occurs when filtered load exceeds reabsorptive capacity
of proximal tubular epithelium
•Organic anions, cations secreted by tertiary active transport
•H+ secretion favors reabsorption of organic acids, excretion of organic bases
1.
Case presentation
•A ten y.o. female is found unconscious in her bedroom and is rushed to the ER.
The attending physician
learns from her parents that the patient has seemed lethargic and sometimes disoriented for the previous 2-3
weeks, and often complained of thirst despite drinking unusually large amounts of water and Dr. Pepper.
She has been urinating frequently and bedwetting, which her parents ascribe to her excessive fluid intake.
A urine specimen is obtained and dipstick reveals 4+ glucosuria; plasma glucose is 700 mg/dl.
•Explain the patient’s polyuria.
Why is she thirsty? The pt has polyuria because the glucose in this case
serve as osmotic diuretics. She is thirsty because she is losing water and the glucose also a solute so the
total concentration of solute in the pt will be high and that create sensation of thirst.