5: Renal Handling of Organic Solutes

Question 1

What is the charge of a glucose molecule?

Answer 1

neutral

Question 2

Explain why most waste and foreign substances are secreted by the kidney as opposed to filtered?

Answer 2

Because most waste products are protein bound they cannot be easily filtered and need to be secreted to enter the tubule

Question 3

Where in the nephron are most organic solutes transported?

Answer 3

proximal tubule

Question 4

Explain the general concept of organic solute transport in the proximal tubules

Answer 4

basolateral NaKATPase pumps create a electrochemical gradient favoring entrance of Na into the cell
* neutal or negatively charged organic solutes&raquo_space; enter with sodium via symporters
* cations/positively charged organic solutes&raquo_space; enter via uniporters –> follow negative charge (created by IC Na loss )
* IC concentration of organic solutes increases –> concentration gradient promotes efflux into the interstitial space or luminal space (depending whether it’s secreted or reabsorbed)

Question 5

Explain the reabsorption process of glucose in the tubule

Answer 5

• absolateral NaKATPase pump creates creates electrochemical gradient favoring Na entrance on the luminal side
• Sodium-glucose symporter transports glucose with Na into the cell
• glucose enters interstitium on the basolateral membrane via GLUT uniporters

Question 6

Where are SGLT-1 and SGLT-2 located and how do they differ in the magnitude of their transport and affinity

What is the transports stoichiometry?

Answer 6

SGLT: sodium-glucose symporter
SGLT-2
* high capacity, low-affinity
* in the proximal tubule
* facilitates 90% of the glucose reabsorption
* 1 Na for 1 glucose
SGLT-1
* low capacity, high-affinity
* only in the late proximal tubule
* facilitates remaining 10% reabsorption
* 2 Na for 1 glucose –> the 2 Na provide more energy, which is necessary as glucose will have to move up ints concentration gradient (not much glucose left in the tubular fluid)

Question 7

Is glucose transport in the nephron gradient-limited or tubular maximum-limited?

Answer 7

tubular maximum limited - reaches its limit when transporters are saturated
tight junctions or not permeable to glucose –> cannot back flow into the lumen

Question 8

What percentage of plasma albumin is the concentration in the glomerular filtrate?

Answer 8

0.02% (1 mg/dL of 5 g/dL)

Question 9

How is filtered albumin reabsorbed?

Answer 9

endocytosis of luminal protein –> vesicle formation –> vesicle will merge with intracellular lysosomes containing degradation enzymes –> breaks down albumin into low-molecular weight fragments/amino acids –> exit cells on basolateral side –> interstitium –> reabsorbed into capillaries

Question 10

Is protein transport gradient-limited or tubular maximum-limited?

Answer 10

tubular maximum limited –> endocytic mechanism is saturable

Question 11

What percentage of insulin and growth hormone are filtered in the glomerulus?

Answer 11

100% and 60%

Question 12

How are small peptides reabsorbed in the tubules?

Answer 12

peptidases located on the apical cell surfaces –> catabolixe peptides into amino acids –> reabsorbed

Question 13

Explain the steps of organic cation secretion/excretion in the renal tubles

Answer 13

Na-K-ATPase creates a negative membrane potential of tubular cells –> organic cation enters the tubular cell on the basolateral membrane via an OTC (organic cation transporter) following the negative membrane potential
Cation then exits into the lumen via an antiporter exchanging it for a proton –> electroneutral –> transport is not affected by the membrane potential

Question 14

Explain the steps or organic anion excretion/secretion in the renal tubules

Answer 14

• Na-K-ATPase creates a negative membrane potential and an electrochemical gradient favoring Na to go back into the cell
• Na moves in toghether with alpha-ketoglutarate (alphaKG) on the basolateral membrane via a symporter (sodium-alphaKG symporter, stoichometry 3 Na per alphaKG)
• alphaKG moves back out via an antiporter facilitating movement of the anion into the cell (Organic Anion Transporter, OAT)

Question 15

Why does hepatic conjugation of metabolites facilitate their excretion?

Answer 15

conjugation with either glucuronate or sulfate makes the solute water soluble –> can then be eliminated by the organic-anion secretory pathway in the tubules

Question 16

What is uric acid produced from?

Answer 16

in the liver as product from the metabolic catabolism of pourines

Question 17

what are the clinical consequences of increased plasma urate levels?

Answer 17

urate will precipitate as sodium urate crystals in joints –> gout

Question 18

How is urate reabsorbed?

Answer 18

• urate is initially freely filtered
• antiporter (URAT1) on apical membrane on proximal tubule cells (part of OAT transporter family)
• URAT1 antiporter exchanges absorbed urate for a secreted anion
• exits on the basolateral side via uniporter GLUT9

Question 19

Explain how urine acidifaction and alkalinization affects tubular absorption of weak acids or bases

Answer 19

a more acidic tubular fluid favors reabsorption of weak acids and decreased reabsorption of weak bases

weak acids become protonated (bind to the excess H+) A- + H+ = HA –> diffuses passively and is reabsorbed due to higher permeability

weak bases become protonated –> B +H+ = HB+ –> less permeable and trapped in the lumen

opposite mechanism for urine alkalinization

Question 21

How is urea produced?

Answer 21

protein metabolism

• proteins (either ingested or stored as tissue protein) –> broken down into amino acids
• amino acids are metabolized –> yields nitrogen moiety (ammonium) and carbohydrate moiety
• ammonia is toxic –> livefr immediately converts most to urea and small amount to glutamine

Question 22

From the glomerulus to the collecting ducts, describe the renal urea handling

Answer 22

urea is a small molcule (60Da), water soluble, and filters freely through the glomerulues - glomerular filtrate with same urea cc as plasma

about half (50%) is reabsorbed in the proximal tubules via the paracellular route - tight junctions are permeable to urea - but no transcellular absorption! - urea has a highly polar nature and does not cross lipid bilayers
* absorption is driven by increasing tubular concentration of urea from water and Na loss –> concentration gradient lets urea cross tight junctions
* proportionately more water and Na reabsorbed than urea (66% versus 50%)

thin decending limb of the lopp of Henle lays within the medulla which has a significantly higher interstitial urea cc –> tight junctions here are not permeable to urea anymore but have urea uniporters –> urea secreted back into the tubule

–> tubular fluid back to orignial amount of urea when reaching the **thick ascending limb of the loop of henle ** but higher concentration because most filtered water has been reabsorbed

from the tick ascending limb of of the loop of Henle to the distal tubule and cortical collecting ducts - low urea permeability

very high urea cc fluid flows into the medullary collecting duct –> favor reabsorption via more urea uniporters –> creates a high interstitial urea cc in the medulla –> driving back into the thin descending loop of henle –> urea recycling