Renal Chapter 5: Renal Handling of Organic Substances

Question 1

Describe what makes urea unique.

Answer 1

it is a waste product that must be excreted to prevent accumulation, however, it also plays a key role in renal regulation of water balance

Question 2

Describe the transport of freely filterable substances like glucose, amino acids, acetate, Krebs cycle intermediates, certain water-soluble vitamins,
lactate, acetoacetate, beta-hydroxybutyrate, and many others.

What is the “uphill” step?

What type of systems are most of these substances?

Answer 2

actively transported (can be reabsorbed up their respective electrochemical gradients) …specificity!! given transporter selectively takes up one or a few substrates and ignores all others (some similar compounds can share transporters tho)

“uphill” step is across the luminal membrane, usually via a symporter with sodium

Tm systems (have an upper limit at which they can transport)

Question 3

Describe the role of the kidney in regulating glucose levels.

Answer 3

bc there is no opportunity to vary the amount excreted (there is none), the kidneys do not help regulate their levels in the body

(under abnormal conditions like diabetes, the plasma concentration of glucose/acetoacetate/B-hydroxybutyrate substances may increase so much that the filtered load exceeds reabsorptive Tm and large quantities are excreted in the urine

Question 4

What is normal plasma glucose level?

In meals?

Severe diabetes?

Answer 4

about 90mg/dL (5mmol/L)

it rises transiently to well over 100mg/dL during meals and can reach levels of over 1000 mg/dL (over 44mmol/L) in severe diabetes

Question 5

How and where is glucose normally reabsorbed?

Answer 5

in PT by removing glucose from tubular lumen along with sodium via a sodium-dependent glucose symporter (SGLUT) across the apical membrane of proximal convoluted tubule cells, followed by its exit across the basolateral membrane into the interstitium via a GLUT uniporter

-no back-leak as glucose is removed from lumen and as luminal concentration falls bc tight junctions are not specifically permeable to glucose

Question 6

What factors are transport of a solute with no back-leak dependent upon?

Answer 6

depends only the characteristics of the rate-limiting transporters (with glucose-the SGLT symporter) and is a Tm limited system

Question 7

At what amount does glucose exceed its re-absorptive capacity?

Draw a graph with plasma glucose (mg/dL) on the horizontal axis and glucose flux (mg/min) on the vertical axis. Label Tm and filtered load. Use dotted lines to draw reabsorbed/excreted.

Answer 7

bc glucose reabsorption is a Tm system, abnormally high filtered loads overwhelm the re-absorptive capacity (exceed Tm) …occurs when plasma glucose rises above roughly 300mg/dL

(any glucose not reabsorbed is an osmole in the tubule that has consequences for water re-absorption)

graph p 75

Question 8

Given GFR of 125mL/min (1.25dL/min) and plasma glucose of 90mg/dL what is the filtered load?

What is the filtered load when plasma glucose is 300mg/dL?

Answer 8

filtered load = GFR x Px
1.25dL/min x 90mg/dL = 112.5mg/min

300mg/dL x 1.25dL/min= 375mg/min
- at this point, the proximal convoluted tubule fails to reabsorb all the filtered glucose and some begins to spill into the urine
(will have consequences for water re-absorption)

Question 9

Describe the filtration of proteins.

Are they filtered? If so which ones? What happens next?

Describe albumin.

Answer 9

small and medium-sized proteins (angiotensin, insulin) are filtered in considerable qualities

although movement of large plasma proteins across glomerular filtration barrier is extremely limited, a small amount does make it through into Bowmans’s space

for albumin the concentration if filtrate is normally about 10mg/L but bc of huge volume filtered everyday, the total amount of filtered protein is negligible

PT can take up filtered albumin and other proteins.. proteins are degraded into aa before being transported into the cortical interstitum

Question 10

Describe endocytosis of larger proteins.

Discuss the rate of endocytosis.

Answer 10

initial step for uptake of larger proteins is endocytosis at the luminal membrane. This energy-requiring process is triggered by the binding of filtered protein molecules to specific receptors on the luminal membrane

so rate of endocytosis is increased in proportion to the concentration of protein in the glomerular filtrate until a maximal rate of vesicle formation, and thus the Tm for protein uptake is reached

pinched-off intracellular vescicles resulting from endocytosis merge with lysosomes, whose enzymes degrade the protein to low-molecular weight fragments, mainly individual amino acids- these end products exit cells across basolateral membrane into the interstitial fluid and then gain entry into PT capillaries

Question 11

How much protein is found in the urine normally each day?

Answer 11

almost all filtered protein is taken up, so excretion of protein in the urine is normally only 100mg/day

however, the endocytic mechanism by which protein is taken up is easily saturated; any large increase in filtered protein resulting from increased glomerular permeability can cause the excretion of large quantities of protein

Question 12

How are very small peptides like angiotensin II handled differently from larger proteins?

Answer 12

end result is same: catabolism of peptide and preservation of its amino acids

but the very small peptides are completely filterable at the renal corpsules and are then catabolized mainly into aa within the proximal tubular lumen by peptidases located on the luminal surface of the plasma membrane
-the aa are then re-absorbed by the same transporters that normally reabsorb filtered amino acids

Question 13

Describe the active secretory pathway for organic anions in the PT.

Answer 13

active transporters for the anions at the BL membrane of the tubular epithelial cells that are the rate-limiting step in overall transport

transport out of the cell across the apical membrane into the lumen is via facilitated diffusion on a variety of uniporters or more specific sodium-dependent antiporters

not significantly permeable through tight junctions or membranes, so transport is char. by a tubular maximum

Question 14

What is urate? How is it filtered/reabsorbed/secreted?

What can elevated levels of urate in the blood cause?

What happens if plasma urate begins to increase because of increased urate production?

Answer 14

the base form of uric acid

urate is not protein bound so it is freely filterable. almost all filtered urate is reabsorbed early in PT; however, further on in the PT, urate undergoes active tubular secretion. Then, in the straight portion, urate is once again reabsorbed. Total rate of tubular reabsorption is normally much greater than the rate of tubular secretion, and so the mass of urate excreted per unit time is only a small fraction of the mass filtered.

elevated levels of urate can cause gout.

if plasma urate begins to increase because of increased urate production,
the active proximal secretion of urate is stimulated, thereby increasing urate
excretion.

Question 15

What are the 3 ways by which altered renal function can lead to decreased urate excretion and hence increased plasma urate, as in gout?

Answer 15

1) decreased filtration of urate secondary to decreased GFR
2) excessive re-absorption of urate
3) diminished secretion of urate

Question 16

Describe active proximal secretion of organic cations.

Answer 16

large number of transporters so substantial amt of foreign and endogenous substances are transported, cations compete for transport (and there is a Tm limitation)

Organic cations enter across the
basolateral membrane via one of several uniporters, members of the OCT family
(organic cation transporter), and exit into the lumen via an antiporter, which
exchanges a proton for the organic cation

The proximal secretion of organic cations, as for organic anions, is particularly
critical for the excretion of those cations extensively bound to plasma proteins
and not filterable at the renal corpuscle.

Question 17

At a given pH describe the weak acids/bases of kidney.

How do weak acids change at low/high pH?

Which form is most permeable in lipid membranes?

Answer 17

at given pH, split between neutral form and ionized form

many weak acids are neutral at low pH (acid form) and dissociated into anion and proton and higher pH

(neutral forms are more permeable in lipid membranes)

Question 18

What happens to the ionized forms of weak acids once in lumen?

Answer 18

cannot diffuse once in lumen…trapped

Question 19

What happens if tubular fluid becomes acidified relative to the plasma (which it does on a normal diet)?’

How will a highly acidic urine affect passive reabsoprtion of weak acids?

Answer 19

relatively more will be converted to neutral free acid form and therefore become more permeable

this factors diffusion out of the lumen (reabsorption).

So a highly acidic urine (low PH) tends to increase passive reabsorption of weak acids (and promote less excretion)

Question 20

At low pH describe the formation of weak bases.

What happens as urine becomes more acidified? (What form is the weak base in? How is reabsorption/excretion affected?)

Answer 20

at low pH they are protonated cations (trapped in lumen) whereas at high pH they are converted to neutral free base.

as urine becomes acidified, more is converted to the impermeable charged form and is trapped in the lumen. Less is reabsorbed passively, and more is excreted

Question 21

If you wanted to enhance the excretion of a drug that is a weak acid will you want to acidify or alkalinize the urine?

What if you wanted to prevent excretion of the drug?

Answer 21

alkalinize the urine (to trap ionic form in lumen) to enhance excretion

acidify urine if you want to prevent excretion of drug

Question 22

At any pH how will increasing the urine flow affect excretion of weak acids and bases?

Answer 22

increasing urine flow at any pH will increase excretion of both weak acids and bases

Question 23

What happens when protein is oxidized for fuel?

Answer 23

protein is first split into its constituent amino acids. Those are then separated into a nitrogen moitey (ammonium) and a carbohydrate moiety.

The carbohydrate goes on to further metabolic processing, but the ammonium cannot be further oxidized and is a waste product (ammonium is toxic to tissues except medullary interstitum, so liver converts it to urea and small amount of glutamine)

Question 24

Describe urea content in urine.

Answer 24

its about half of normal solute content of urine.

normal level is variable (3mmol/L-9mmol/L)
over days to weeks renal urea excretion must match hepatic production otherwise plasma levels would rise to pathological range (uremia)

Question 25

Describe renal handling of urea (Filtered/reabsorbed/secreted/excreted).

Draw.

Answer 25

urea is freely filtered. About half is reabsorbed in the proximal
tubule (by paracellular route). An amount equal to that reabsorbed is then secreted back into the loop of Henle. Finally, about half is reabsorbed again in the medullary collecting duct. The net result is that about half the filtered load is excreted

p. 82

Question 26

Describe urea as a molecule: molecular weight, polar/nonpolar, how transported, conc. in filtrate vs plasma

Answer 26

urea is small (molecular weight, 60 Da)

water soluble, freely filtered

highly polar nature so does not permeate lipid bilayers but a set of uniporters (UT family) transport urea in various places in kidney and other sites like RBC

bc urea is freely filtered, filtrate contains urea at a concentration identical to that in plasma

Question 27

What happens as water is reabsorbed in the PT?

Answer 27

as water is reabsorbed (about 2/3 of the filtered water is reabsorbed in the PT), solutes in the lumen that are not reabsorbed by the transcellular route become concentrated

urea is prominent among these solutes, as urea becomes concentrated it is driven passively through the leaky tight junctions, by time tubular fluid enters Loop of Henle, about half of filtered urea has been reabsorbed

By the time the tubular fluid enters the loop of Henle, about half the filtered urea has been reabsorbed, and the urea concentration has
increased to a little more than its value in the filtrate (because proportionally more water than urea was reabsorbed).

Question 28

Describe the concentration of urea in interstitium of medulla vs plasma.

Answer 28

The interstitium of the medulla has a considerably higher urea concentration than plasma. The concentration increases from the outer to the inner medulla

peak value in the inner
medulla depends on hydration status and levels of antidiuretic hormone

Question 29

Describe where/why urea is secreted.

Answer 29

the medullary urea concentration is greater
than in the tubular fluid entering the loop of Henle, so there is a concentration
gradient favoring secretion into the lumen.

The tight junctions in the loop of Henle are no longer permeable, but the epithelial membranes of the thin regions of the Henle loops express urea uniporters, members of the UT family. This permits secretion of urea

Question 30

What happens when tubular fluid enters the thick ascending limb? How does amount of urea in lumen compare with filtered load? Describe lumenal content of urea.

Answer 30

when tubular fluid enters the thick ascending limb, the amount in the lumen is at least as large as filtered load. Bc about 80% of the filtered water has now been reabsorbed, the luminal urea concentration is now several times greater than in the plasma.

Beginning with the thick ascending limb and continuing all the way to the medullary collecting
ducts (through the distal tubule and cortical collecting ducts), the luminal membrane urea permeability (and the tight junction permeability) is essentially zero. Therefore, a large amount (roughly the filtered load or more) of urea is still within the tubular lumen and flowing from the cortical into the medullary collecting ducts. The concentration is now much greater than in the plasma

Question 31

What does the gradient for urea favor in the inner medulla?

Answer 31

We indicated earlier that the urea concentration in the medullary interstitium is also greater than in plasma, but the luminal concentration is a little higher, so the gradient favors reabsorption
in the inner medulla. Therefore, urea is reabsorbed for the second time. In fact, this reabsorbed urea increases medullary interstitial urea concentration and is the
source of urea that is secreted into the loop of Henle

Question 32

If 50% of a person’s nephrons were destroyed, which of the following compounds
would be likely to show increased blood concentration?
A. Urea
B. Creatinine
C. Uric acid
D. Most amino acids
E. Glucose

Answer 32

The answers are A, B, and C. These waste products are all normally
excreted in large amounts; a decreased GFR would cause their plasma
concentrations to increase until the filtered load was increased enough
to reestablish normal excretion. In contrast, the reabsorption Tms for
glucose, amino acids, and many other organic compounds that are not
waste products are usually so high relative to normal filtered loads that,
even with a 50% loss of nephrons, virtually all the filtered loads are
reabsorbed. Accordingly, their plasma concentrations are virtually independent
of renal function (ie, the kidneys do not participate in the
setting of their plasma concentrations).

Question 33

The concentration of urea in urine is always much higher than the concentration in
plasma. Is this because the overall tubular handling of urea is secretion?

Answer 33

The answer is no. The overall tubular handling of urea is reabsorption.
Urinary urea concentration is higher than that of plasma because relatively
more water has been reabsorbed than urea, thereby concentrating
the urea in the tubular fluid leaving the kidney.

Question 34

If the concentration of protein in the glomerular filtrate was 0.005 g/100 mL and
none was reabsorbed, how much protein would be excreted per day (assuming a
normal GFR)?

Answer 34

This is simply the GFR (180 L/day) times the concentration in the filtrate:
180 L/day x 0.005 g/dL x 10 dL/L x 9 g/day.

Question 35

Suppose there is an excessively high filtered load of glucose, and only half is reabsorbed
in the proximal tubule. How much of the remaining half now flowing into
the loop of Henle is reabsorbed from this point on?
A. None
B. About half, leaving one quarter of the filtered load to be excreted
C. The amount is variable, depending on hydration status

Answer 35

The answer is A. The luminal membranes of nephron segments beyond
the proximal tubule do not express glucose transporters, so no further
reabsorption occurs regardless of conditions.

Question 36

If you wished to increase your patient’s excretion of quinine, a weak organic base,
what change in urinary pH would you try to induce?

Answer 36

Decreased pH (acidify the urine). Weak bases like quinine become protonated,
and thus less permeable, at low pH. This would prevent its
passive reabsorption and increase its excretion.

Question 37

How much of the filtered load of urea remains at the following sites: (a) beginning
of the loop of Henle, (b) end of the loop of Henle, and (c) end of the cortical collecting
duct?

Answer 37

(a) About 50%; (b) about 100% (due to secretion in the thin limbs);
(c) about 50%