Tubular Reabsorption and Secretion

Question 1

Reabsorption

Answer 1

• the movement of filtered solutes and water from the tubular fluid across the epithelial cell tubule into the peritubular capillaries and the circulation
• the reabsorption of filtered solutes and water is regulated to maintain the homestatic balance matching solute and water excretion to a variable solute and water consumption

Question 2

Secretion

Answer 2

• the movement of solutes from the circulation via the peritubular capillaries across the epithelial cell tubule into the tubular fluid
• secretion provides another mechanism, in addition to filtration, by which solutes may be added to the tubular fluid and excreted in the urine
• renal handling of solute NOT synthesized by the kidney: excreted = filtered + secreted - reabsorbed

Question 3

General transport in kidneys

Answer 3

• concentration of inorganic/organic is same in plasma and in tubular ultrafiltrate
• as they go through nephron most of the solutes and water is reabsorbed and returned to the circulation
• urine is formed by the solutes and water not reabsorbed and by solutes secreted into the tubular fluid
• most solute transport from lumen to peritubular space is active transport primary or secondary
• some solute transport from lumen to peritubular space across the tubular epithelium is passive
• water transport from lumen to peritubular space across the tubular epithelium is passive and occurs by osmosis
• water transport follows solute transport

Question 4

Renal Epithelial Transport

Answer 4

• the transport pathway of solutes and water across the renal tubular epithelium
  1) Transcellular, occurring by uptake into and efflux from the cell in either the reabsorptive or secretory direction
  2) Paracellular- occurring by movement of solute and water through junctions of contiguous cell in either the reabsorptive or secretory direction

Question 5

Transcellular Transport

Answer 5

• dependent on solute specific transporters in the apical membrane (facing tubular fluid in the lumen) and basolateral membrane (facing the peritubular space and peritubular capillaries)
• solute-specific and nephron specific transporters mediate water and solute transport in different segments of the nephron
• Na+-K+ ATPase is restricted to the basolateral membrane of all renal epithelial cells in all segments of the nephron where it maintains a steady state concentration difference or gradient of Na and K across the luminal and basolateral membrane
• active transport against a solute electrochemical potential gradient
• primary active transport capture and transduce the energy of ATP hydrolysis to the energy stored in the formation of a solute electrochemical gradient

Question 6

Secondary Active Transport

Answer 6

• transduce energy stored in the electrochemical potential gradient of one solute into the energy stored in the formation of an electrochemical potential gradient of a second solute
• secondary active co-transporters couple transport of the driving and driven in the same direction. Driving solute is usually Na inward
• secondary active counter-transporters couple transport the driving and driven solute in the opposite direction across the membranes

Question 7

Passive transport

Answer 7

• mediate solute transport across the cell membrane down a solute electrochemical potential gradient in either the inward or outward direction and do NOT require coupling to a source of energy
• passive transport mechanisms, either carrier or channel, mediate “facilitated diffusion” of solute equilibration across the membrane

Question 8

Paracellular transport

Answer 8

• passive and driven by a transepithelial solute electrochemical potential gradient
• depends on the tightness of intercellular junctions. The ability of epithelia to maintain a transepithelial voltage difference or an osmotic gradient is determined by cell to cell junctional resistance
• movement of water from the tubular lumen across the intercellular junctions to the peritublar space occurs by osmosis and may entrain the movement of solute by a process of solvent drag, which contributes to transtubular solute reabsorption or secretion
• bidirectional;

Question 9

Renal Epithelial Transport

Answer 9

• transport from the luminal fluid across the cells to the pertubular fluid is absorption
• transport from the peritubular fluid across the cell to the luminal fluid is secretion
• diffusion
• co-transport
• counter transport
• paracellular pathway

Question 10

Functional Properties of Transcellular Transepithelial Transport

Answer 10

• the coordinate function of solutes-specific active and passive transporters in series, in opposing members mediates bidirectional transcellular transepithelial transfer of solutes between the tubular fluid and peritubular space
• tubular reabsorption: active uptake at luminal membrane and passive efflux at basolateral membrane or passive uptake at luminal membrane and active at basolateral
• tubular secretion: active uptake at basolateral membrane and passive efflux at luminal membrane or passive uptake at basolateral membrane and active at luminal
• tanscellular reabsorption and secretion is saturable and a maximum rate is achieved at defined, solute-specific, plasma and/or tubular fluid solute concentrations
• transcellular reabsorption and secretion is inhibitable by drugs (diuretics) and circulating metabolites

Question 11

Renal Handling of Glucose

Answer 11

• filtration and reabsorption but not se4cretion
• the amount of glucose excreted in the urine is a function only of the amount filtered and the amount reabsorbed
• because the first tubular segment of the nephron, the proximal tubule, is the only segment of the nephron where glucose reabsorption occurs, all glucose escaping reabsorption in the proximal tubule will be excreted in the urine
• Reabsorbed glucose = Filtered Glucose - Excreted Glucose
• Excreted Glucose = Filtered Glucose- Reabsorbed Glucose
• Reabsorbed Glucose = Pglu x GFR - Uglu x V urine

Question 12

Glucose Reabsorption

Answer 12

• reabsorbed and not secreted, as a function of plasma glucose concentration
• circulating glucose 75 mg/dL to 170
• glucose is freely filtered from the plasma at the glomerulus and at normal circulating levels all the filtered glucose is reabsorbed by the proximal tubule
• the nephron segments beyond the proximal tubule do not have the capacity to transport glucose and all glucose not reabsorbed by the proximal tubule appears in the urine
• the clearance of glucose is zero at normal circulating level of gluxose and begins to increase at plasma levels of approximately 200 mg/dL. There is is threshold plasma concentration at which glucose begins appearing in urine (Diabetes mellitus)
• Tm is the tubular reabsorptive maximum defining the maximum solute reabsorptive rate or capacity for tubular solute reabsorption. As plasma solute concentration increases and approaches the Tm the cell membrane transport mechanisms mediating transcellular solute reabsorption become saturated and solute begins to appear in urine

Question 13

Membrane Transport Mechanisms Mediating Transcellular Gluxose Reabsorption

Answer 13

Lumenal membrane

• Na+-glucose cotransporters mediate the concentrative accumulation of glucose inside the cell driven by the inwardly directed Na+ electrochemical potential gradient
• the Na+ to glucose transport stoichiometry or coupling ratio is 1 to 2 to 1 resulting in net positive charge transfer with each glucose transported. This property makes Na+-glucose cotransport electrogenic and sensitive to membrane potential as an additional driving force increasing concentrative glucose accumulation

Basolateral membrane
-passive efflux of intracellular glucose mediated by facilitated diffusion (uniporter)

• 98% of the glucose is reabsorbed in early proximal tubule
• nephron segments beyond the PST reabsorb the remaining 2%
• SGLT2 can accumulate glucose to a [glucose]/[glucose]lumen as high as 70
• late proximal tubule: SGLT1 which couples glucose to two Na+, can establish a ratio as high as 4900

Question 14

Renal Handling of PO4

Answer 14

• the filtered load (PPO4 x GFR) of monobasic and dibasic phosphate is approximately 250 mMole/day which is more than 10x the total extracellular pool of phosphates
• phosphate reabsorption occurs in the proximal tubule where approximately 90% of the filtered load is returned to the circulation
• as shown above,proximal tubular phosphate reabsorption increases with increasing filtered load of phosphate and approaches a tubular maximum of phosphate reabsorption where the process of transcellular phosphate transport becomes saturated and the rate of phosphate reabsorption becomes maximal and constant
• the renal handling of phosphate at normal physiological levels results in virtually complete reabsorption of the filtered load of phosphate and a small but important amount of phosphate remains in the tubular fluid and is excreted in the urine

Question 15

Where is phosphate reabsorpton

Answer 15

• proximal tubule
• for individuals on a low Pi diet, Pi excretion is minimal
• 10% of filtered load remaining

Question 16

Transcellular Phosphate Reabsorption

Answer 16

• Lumenal membrane:
• Na+ - PO4 cotransporters mediate the concentrative accumulation of PO4 inside the cell driven the inwardly directed Na+ electrochemical potential gradient
• the Na+ to PO4 transport stoichiometry or coupling ratio is 2 or 3 to resulting in net positive charge transfer with each PO4 transported
• this property makes Na+ - PO4 cotransport electogenic positive and sensitive to membrane potential as an additional driving force increasing concentrative intracellular PO4 accumulation
• titration of dibasic to monobasic PO4 by increasing tubular fluid acidity inhibits PO4 transport by decreasing the concentration of dibasic PO4 and the transport of dibasic PO4

Basolateral membrane
-passive efflux of intracellular PO4 mediated by facilitated diffusion

Question 17

The Renal Handling of Amino Acids

Answer 17

• Excreted AA = Filtered AA- Reabsorbed AA
• Reabsorbed AA = Filtered AA- Excreted AA
• Reabsorb AA = Paa x GFR - Uaa x Vurine
• circulating levels of amino acids arise from GI absorption, protein catabolism and de novo synthesis
• AA’s are freely filtered at the glomerulus and are completely (>98%) reabsorbed across the proximal tubule by AA-specific, transcellular transport mechanisms mediating active uptake at the luminal membrane (Na-symport) and passive efflux at the basolateral membrane (facilitated diffusion)
• the luminal and basolateral membrane transport mechanisms mediating transcellular AA transport across the proximal tubule are saturable and above a threshold plasma AA concentration, AA will be excreted in the urine (aminoaciduria) due to a maximal capacity to reabsorb AA. This occurs because the proximal tubule is the only segment of the nephron where AA’s are reabsorbed and beyond the proximal tubule no other nephron segments reabsorbs AA
• the clearance of AA is essentially zero at normal circulating levels of AA and the role of the kidney in maintaining AA homeostasis is to return filtered AA to the circulation except when plasma AA levels are excessively high or when a tubule defect in AA reabsorption exists resulting in hyperaminoaciduria

Question 18

Secretion

Answer 18

• in addition to filtration at the glomerulus, many blood born solutes enter the tubular fluid by transcellular secretion from the peritubular space to the tubular lumen across various segments of the nephron. These include organic and inorganic solutes:
• foreign to the body (ingested drugs or toxins)
• metabolized by the kidney for excretion by the kidney
• metabolized by the liver (gluconidation, sulfation, carboxylation) for excretion by the kidney
• regulated in blood (H+ and K+ concentration)

Question 19

The Renal Handling of p-Aminohippuric Acid (PAH)

Answer 19

• Excreted PAH= Filtered PAH + Secreted PAH
• Secreted PAH = Excreted PAH- Filtered PAH
• Secreted PAH = Upah x Vurine - Ppah x GFR
• the renal handling of PAH is an example of solute which is secreted into the tubular fluid
• accordingly, the amount of PAH excreted in the urine is a function of the amount filtered (filtered load) as well as the amount secreted by the tubule.
• contrast the renal handling of PAH with the renal handling of glucose and other solutes, which are reabsorbed but not secreted
• PAH is an exogenous monovalent organic anion freely filtered at the glomerulus. At low PAH concentrations PAH is effectively secreted by the proximal tubule that its clearance from the renal circulation is complete and no PAH exits the kidney in the renal vein. The clearance of PAH from the plasma is dependent upon both filtration and secretion of PAH

Question 20

Tm for tubular secretion of PAH

Answer 20

• Tm is the tubular secretion maximum defining the maximum solute secretion rate or capacity for tubular solute secretion
• as plasma solute concentration increases and approaches the Tm, the cellular transport processes mediating solute secretion become saturated and plasma solute concentration begins to increase
• when the plasma PAH concentration is increased sufficiently, the Tm for PAH secretion is achieved indicating the luminal and basolateral transport mechanisms mediating transcellular secretion of PAH are saturated and PAH will begin to appear in the renal vein
• at increasing plasma PAH concentrations where secretion becomes saturated, the secretory Tm for PAH is achieved and PAH secretion becomes a progressively small fraction of the amount of PAH in the urine and PAH filtration becomes a progressively larger fraction of the amount of PAH in the urine

Question 21

Transcellular PAH Secretion in the Proximal Tubule

Answer 21

• Basolateral membrane:
• Na+-Dicarboxylate cotransporter mediates the concentrative accumulation of dicarboxylate (ketoglutarate) inside the cell driven by the inwardly directed Na+ electrochemical potential gradient
• an organicanion antiporter (OAT1 or OAT3) mediates the concentrative exchange of intracellular ketoglutarate for extracellular PAH. The ketoglutarate to PAH transport stoichiometery or coupling ratio is 1 to 1 resulting in exchange of a divalent anion doe a monovalent anion and net negative charge transfer out of the cell with each PAH transported. This property makes the organic anion antiport electrogenic negative and sensitive to membrane potential as an additional driving force increasing concentrative PAH accumulation

Lumenal membrane:

• efflux of intracellular PAH may occur passively mediated by facilitated diffusion (uniporter)
• efflux of intracellular PAH may occur actively mediated by anion gradient driven antiport

Question 22

Excretion of PAH Measures Renal Plasma Flow

Answer 22

• the rate of plasma solute entry into the kidney in the renal artery is equal to the rate of solute exit from the kidney in the urine and in the renal vein
• rate of PAH enters the kidney in the renal artery = RPF x Ppah
• rate of PAH exits kidney in the renal vein and urine = RPFvein x Pvein + Upah x V
• rate of PAH entering the kidney= rate PAH leaving the kidney: RPF x Ppah= RPFvein x PveinPAH + Upahx V
• where all the PAH entering peritubular capillaries is secreted into the tubular fluid- none exits the kidney in the renal vein

Question 23

The Renal Handling of Salicylate

Answer 23

• salicylate circulates in plasma and is filtered in its neutral weak acid form (HA) and its conjugate base form (A-)
• Secretion:
• Active (basolateral) and passive (luminal) transport of the conjugate base (A-) across the proximal tubule
• PAH and Salicylate are substrates of the same active (basolateral) and passive (luminal) transporters mediating transcellular secretion
• Reabsorption:
• occurs primarily by the passive process of nonionic diffusion across the distal nephron
• decreases with increased tubular fluid pH and flow rates
• increases with decreasing tubular fluid pH and flow rates

Question 24

Effect of Luminal Fluid pH on the Renal Handling of Salicylate

Answer 24

• pH dependence of salicylate absorption from the distal tubular fluid back into the general circulation resulting from nonionic diffusion of salicylate
• where tubular fluid pH is low and nonionic diffusion of salicylate out of the tubular fluid is high, the clearance of salicylate from the circulation is reduced, due to increased return of filtered salicylate to the circulation and reduced renal excretion of salicylate
• where tubular fluid pH is high, nonionic diffusion of salicylate out of the tubular fluid is decrased and the clearance of salicylate from the circulation is increased, due to decreased return of filtered salicylate to the circulation and increased renal excretion of salicylate
• therapeutic strategy may be used to promote a more rapid renal excretion of anionic drugs, where drug overdose is clinically indicated, by IV infusion of bicarbonate, at sufficiently high concentrations to saturate, renal proximal tubular bicarbonate reabsorption, causing an increase in the pH of the distal tubular fluid
• this alkalinization of the distal tubular fluid inhibits the process of nonionic diffusion and reabsorption of anion drugs, promoting a more rapid clearance of the drug from the circulation by increasing renal excreation of the drug