Flashcards in Renal Chapter 5: Renal Handling of Organic Substances Deck (37)
Describe what makes urea unique.
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
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?
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)
Describe the role of the kidney in regulating glucose levels.
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
What is normal plasma glucose level?
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
How and where is glucose normally reabsorbed?
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
What factors are transport of a solute with no back-leak dependent upon?
depends only the characteristics of the rate-limiting transporters (with glucose-the SGLT symporter) and is a Tm limited system
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.
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
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?
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)
Describe the filtration of proteins.
Are they filtered? If so which ones? What happens next?
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
Describe endocytosis of larger proteins.
Discuss the rate of endocytosis.
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
How much protein is found in the urine normally each day?
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
How are very small peptides like angiotensin II handled differently from larger proteins?
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
Describe the active secretory pathway for organic anions in the PT.
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
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?
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
What are the 3 ways by which altered renal function can lead to decreased urate excretion and hence increased plasma urate, as in gout?
1) decreased filtration of urate secondary to decreased GFR
2) excessive re-absorption of urate
3) diminished secretion of urate
Describe active proximal secretion of organic cations.
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.
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?
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)
What happens to the ionized forms of weak acids once in lumen?
cannot diffuse once in lumen...trapped
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?
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)
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?)
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
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?
alkalinize the urine (to trap ionic form in lumen) to enhance excretion
acidify urine if you want to prevent excretion of drug
At any pH how will increasing the urine flow affect excretion of weak acids and bases?
increasing urine flow at any pH will increase excretion of both weak acids and bases
What happens when protein is oxidized for fuel?
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)
Describe urea content in urine.
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)
Describe renal handling of urea (Filtered/reabsorbed/secreted/excreted).
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
Describe urea as a molecule: molecular weight, polar/nonpolar, how transported, conc. in filtrate vs plasma
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
What happens as water is reabsorbed in the PT?
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).
Describe the concentration of urea in interstitium of medulla vs plasma.
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
Describe where/why urea is secreted.
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