renal tubular reabsorption stephen p. dibartola department of veterinary clinical sciences college...

Renal tubular reabsorptionRenal tubular reabsorptionRenal tubular reabsorptionRenal tubular reabsorption

Stephen P. DiBartolaStephen P. DiBartola

Department of Veterinary Clinical SciencesDepartment of Veterinary Clinical Sciences

College of Veterinary MedicineCollege of Veterinary Medicine

Ohio State UniversityOhio State University

Columbus OH 43210Columbus OH 43210

What do the kidneys do?What do the kidneys do?

The glomeruli “non-discriminantly” filter the blood, and the The glomeruli “non-discriminantly” filter the blood, and the tubules take back what the body needs leaving the rest as waste tubules take back what the body needs leaving the rest as waste to be excreted. Some wastes also can be actively added to the to be excreted. Some wastes also can be actively added to the tubular fluid.tubular fluid.


• ExcretionExcretion refers to the removal of solutes refers to the removal of solutes and water from the body in urineand water from the body in urine

• ReabsorptionReabsorption (movement from tubular (movement from tubular fluid to peritubular blood) and fluid to peritubular blood) and secretionsecretion (movement from peritubular blood to (movement from peritubular blood to tubular fluid) refer to tubular fluid) refer to directiondirection of of movement of solutes and water across the movement of solutes and water across the renal tubular epitheliumrenal tubular epithelium


• The The luminalluminal cell membranes are cell membranes are those that face the tubular lumen those that face the tubular lumen (“urine” side)(“urine” side)

• The The basolateralbasolateral cell membranes are cell membranes are those are in contact with the lateral those are in contact with the lateral intercellular spaces and peritubular intercellular spaces and peritubular interstitium (“blood” side)interstitium (“blood” side)


• The The transmembranetransmembrane potential potential difference is the electrical potential difference is the electrical potential difference between the inside and difference between the inside and outside of the celloutside of the cell

• The The transepithelialtransepithelial potential potential difference is the electrical potential difference is the electrical potential difference between the tubular lumen difference between the tubular lumen and the peritubular interstitiumand the peritubular interstitium

Renal tubular reabsorptionRenal tubular reabsorptionRenal tubular reabsorptionRenal tubular reabsorption• The term The term transcellulartranscellular refers to refers to

movement of solutes and water through movement of solutes and water through cellscells

• The term The term paracellularparacellular refers to refers to movement of solutes and water between movement of solutes and water between cellscells

• Epithelial cell junctions can be “leaky” Epithelial cell junctions can be “leaky” (proximal tubule) or “tight” (distal (proximal tubule) or “tight” (distal convoluted tubule, collecting duct)convoluted tubule, collecting duct)

TerminologyTerminology

Transepithelial versus Transepithelial versus transmembrane potential transmembrane potential differencedifference

Luminal versus basolateral Luminal versus basolateral membranesmembranes

Transcellular versus paracellular Transcellular versus paracellular transporttransport


• Leaky epithelia Leaky epithelia (proximal)(proximal)• Small Small

transepithelial transepithelial concentration concentration differencedifference

• Small TEPDSmall TEPD• High water High water

permeabilitypermeability

• Tight epithelial Tight epithelial (distal)(distal)• Large Large

transepithelial transepithelial concentration concentration differencedifference

• Large TEPDLarge TEPD• Low water Low water

permeabilitypermeability

Nephro-man says …Nephro-man says …

Luminal surfaceLuminal surface

Basolateral surfaceBasolateral surface

Epithelial tight Epithelial tight junctionsjunctions

Just thinkof it as asix-pack


That renal tubular reabsorption must That renal tubular reabsorption must occur is intuitively obvious because …occur is intuitively obvious because …

The fluid filtered into Bowman’s space is The fluid filtered into Bowman’s space is an ultrafiltrate of plasma containing an ultrafiltrate of plasma containing many vital small molecular weight many vital small molecular weight solutes (e.g., glucose, amino acids, solutes (e.g., glucose, amino acids, bicarbonate) but these solutes do not bicarbonate) but these solutes do not normally appear in urinenormally appear in urine

Renal tubular reabsorptionRenal tubular reabsorptionRenal tubular reabsorptionRenal tubular reabsorption• Solute reaborption in the proximal tubule Solute reaborption in the proximal tubule

is isosmotic (water follows solute is isosmotic (water follows solute osmotically and tubular fluid osmolality osmotically and tubular fluid osmolality remains similar to that of plasma)remains similar to that of plasma)

• 65% of water and solute reabsorption 65% of water and solute reabsorption occurs in the proximal tubuleoccurs in the proximal tubule• 90% of bicarbonate90% of bicarbonate• 99% of glucose & amino acids99% of glucose & amino acids

• Proximal tubules: coarse adjustmentProximal tubules: coarse adjustment• Distal tubules: fine adjustmentDistal tubules: fine adjustment

ClCl-- goes up goes up because Nabecause Na++ is is reabsorbed with reabsorbed with glucose, amino glucose, amino acids, Pacids, Pii and and HCOHCO33

--

Glucose, amino Glucose, amino acids, Pacids, Pii and and HCOHCO33

- - go down go down due to due to reabsorption with reabsorption with NaNa++

Unchanged Unchanged due to due to isosmotic isosmotic reabsorptionreabsorption

Secondary active co-transport Secondary active co-transport (glucose, amino acids, phosphate)(glucose, amino acids, phosphate)


LUMINALLUMINAL BASOLATERALBASOLATERAL

Glucose, PGlucose, Pii amino acidsamino acids

NaNa++

NaNa++

HH++

3 Na3 Na++

2 K2 K++

KK++HCOHCO33-- ++

HH22COCO33

Types of transport processesTypes of transport processesTypes of transport processesTypes of transport processes

• Passive transport (simple diffusion)Passive transport (simple diffusion)

• Facilitated diffusionFacilitated diffusion

• Primary active transportPrimary active transport

• Secondary active transportSecondary active transport

• PinocytosisPinocytosis

• Solvent dragSolvent drag

Passive transport (simple diffusion): Passive transport (simple diffusion): DefinitionDefinition

Passive transport (simple diffusion): Passive transport (simple diffusion): DefinitionDefinition

• Movement of a Movement of a substance across substance across a membrane as a a membrane as a result of random result of random molecular motionmolecular motion

Passive transport (simple Passive transport (simple diffusion): Characteristicsdiffusion): CharacteristicsPassive transport (simple Passive transport (simple diffusion): Characteristicsdiffusion): Characteristics

• No metabolic energy No metabolic energy requiredrequired

• Rate of transfer dependent Rate of transfer dependent on electrochemical gradient on electrochemical gradient across membrane and across membrane and membrane permeability membrane permeability characteristicscharacteristics

• Rate of transfer linearly Rate of transfer linearly related to concentration of related to concentration of diffusion substance (no Vdiffusion substance (no Vmaxmax))

Facilitated diffusion: DefinitionFacilitated diffusion: DefinitionFacilitated diffusion: DefinitionFacilitated diffusion: Definition

• Movement of a substance across Movement of a substance across a membrane down its a membrane down its electrochemical gradient after electrochemical gradient after binding with a specific carrier binding with a specific carrier protein in the membraneprotein in the membrane

Facilitated diffusion: CharacteristicsFacilitated diffusion: CharacteristicsFacilitated diffusion: CharacteristicsFacilitated diffusion: Characteristics

• Saturable (has a VSaturable (has a Vmaxmax))• Structural specificity and affinity of Structural specificity and affinity of

carrier for substance transportedcarrier for substance transported• Transfer may occur in either direction Transfer may occur in either direction

across membraneacross membrane• Does not directly require metabolic Does not directly require metabolic

energyenergy

Facilitated diffusion: ExamplesFacilitated diffusion: ExamplesFacilitated diffusion: ExamplesFacilitated diffusion: Examples

• Glucose, amino acids: Glucose, amino acids: Basolateral membranes of Basolateral membranes of proximal tubulesproximal tubules

• Sodium: luminal membranes of Sodium: luminal membranes of proximal tubulesproximal tubules

Primary active transport: Primary active transport: DefinitionDefinition

Primary active transport: Primary active transport: DefinitionDefinition

• Movement of a substance across Movement of a substance across a membrane in combination with a membrane in combination with a carrier protein but against an a carrier protein but against an electrochemical gradientelectrochemical gradient

Primary active transport: Primary active transport: CharacteristicsCharacteristics

Primary active transport: Primary active transport: CharacteristicsCharacteristics

• Directly requires metabolic Directly requires metabolic energy (i.e. hydrolysis of ATP)energy (i.e. hydrolysis of ATP)

• Saturable (has a VSaturable (has a Vmaxmax))

• Structural specificity and affinity Structural specificity and affinity of the carrier for the substance of the carrier for the substance transportedtransported

Primary active transport: Primary active transport: ExamplesExamples

Primary active transport: Primary active transport: ExamplesExamples

• NaNa++-K-K++ ATPase ATPase

• HH++ ATPase ATPase

• HH++-K-K++ ATPase ATPase

• CaCa+2+2 ATPase ATPase

Secondary active transport: Secondary active transport: DefinitionDefinition

Secondary active transport: Secondary active transport: DefinitionDefinition

• Two substances interact with one Two substances interact with one specific carrier in the cell membrane specific carrier in the cell membrane and both substances are translocated and both substances are translocated across the membraneacross the membrane• Co-transportCo-transport Transported substances Transported substances

move in the same direction across the move in the same direction across the membranemembrane

• Counter-transportCounter-transport Transported Transported substances move in opposite directions substances move in opposite directions across the membraneacross the membrane

Secondary active transport: Secondary active transport: CharacteristicsCharacteristics

Secondary active transport: Secondary active transport: CharacteristicsCharacteristics

• ““Uphill” transport of one substance is linked to Uphill” transport of one substance is linked to “downhill” transport of another substance“downhill” transport of another substance

• Carrier must be occupied by both substances Carrier must be occupied by both substances (or be unoccupied) to be mobile in the (or be unoccupied) to be mobile in the membranemembrane

• Saturable (has a VSaturable (has a Vmaxmax))• Demonstrates specificity and affinity of carrier Demonstrates specificity and affinity of carrier

for substance transportedfor substance transported• ““Uphill” transport occurs without Uphill” transport occurs without directdirect input of input of

metabolic energymetabolic energy

Secondary active transport: Secondary active transport: ExamplesExamples

Secondary active transport: Secondary active transport: ExamplesExamples

• Glucose, amino acids, or Glucose, amino acids, or phosphate with sodium in luminal phosphate with sodium in luminal membranes of proximal tubulesmembranes of proximal tubules

• Sodium and hydrogen ions in Sodium and hydrogen ions in luminal membranes of proximal luminal membranes of proximal tubulestubules

Secondary active transportSecondary active transportSecondary active transportSecondary active transport

• The metabolic energy for secondary The metabolic energy for secondary active transport of Naactive transport of Na++ at the luminal at the luminal membrane in the proximal tubule membrane in the proximal tubule comes from Nacomes from Na++-K-K++ ATPase which ATPase which transports Natransports Na++ out of the cell across out of the cell across the basolateral membrane and the basolateral membrane and maintains a favorable electrochemical maintains a favorable electrochemical gradient for the entry of Nagradient for the entry of Na++ at the at the luminal membraneluminal membrane



LUMINALLUMINAL BASOLATERALBASOLATERAL

Glucose, PGlucose, Pii amino acidsamino acids

NaNa++

NaNa++

HH++

3 Na3 Na++

2 K2 K++

KK++HCOHCO33-- ++

HH22COCO33

PinocytosisPinocytosisPinocytosisPinocytosis

• Definition: Uptake by cells of Definition: Uptake by cells of particles too large to diffuse particles too large to diffuse through the cell membranethrough the cell membrane

• Example: Reabsorption of filtered Example: Reabsorption of filtered proteins in the proximal tubulesproteins in the proximal tubules

Solvent drag: DefinitionSolvent drag: DefinitionSolvent drag: DefinitionSolvent drag: Definition

• A solvent such as water moving A solvent such as water moving across an epithelium by osmosis across an epithelium by osmosis can drag dissolved solutes with itcan drag dissolved solutes with it

Morphologic features of Morphologic features of proximal tubular cellsproximal tubular cells

Morphologic features of Morphologic features of proximal tubular cellsproximal tubular cells

• Large surface area for Large surface area for reabsorption of water reabsorption of water and solutes (brush and solutes (brush border, lateral cellular border, lateral cellular interdigitations)interdigitations)

• Large numbers of Large numbers of mitochondria to provide mitochondria to provide ATPATP

• Leaky epithelial Leaky epithelial junctionsjunctions

Routes of transport across Routes of transport across proximal tubular epitheliumproximal tubular epitheliumRoutes of transport across Routes of transport across proximal tubular epitheliumproximal tubular epithelium

• ParacellularParacellular• 1% of surface area1% of surface area• 5-10% of water transfer5-10% of water transfer• Passive diffusion or Passive diffusion or

solvent drag onlysolvent drag only• Requires favorable Requires favorable

electrochemical electrochemical gradientgradient

• Passive diffusion of Passive diffusion of ions and large non-ions and large non-polar solutespolar solutes

• TranscellularTranscellular• 99% of surface area99% of surface area• 90-95% of water transfer90-95% of water transfer• Passive or active Passive or active

transporttransport• All active transport All active transport

occurs by this routeoccurs by this route

Intrasegmental axial heterogeneity Intrasegmental axial heterogeneity of proximal tubuleof proximal tubule

Intrasegmental axial heterogeneity Intrasegmental axial heterogeneity of proximal tubuleof proximal tubule

• P1: sodium, water, P1: sodium, water, bicarbonate, amino bicarbonate, amino acids, glucose, and acids, glucose, and phosphate reabsorbedphosphate reabsorbed

• P2: sodium, water and P2: sodium, water and chloride reabsorbedchloride reabsorbed

• P3: Organic acids and P3: Organic acids and bases transportedbases transported

Secondary active transportSecondary active transportSecondary active transportSecondary active transport

• Glucose, Amino acidsGlucose, Amino acids• TTmaxmax high and constant (kidney not a high and constant (kidney not a

regulator of plasma glucose and amino regulator of plasma glucose and amino acid concentrations)acid concentrations)

• PhosphatePhosphate• TTmaxmax low and altered by PTH (kidney is a low and altered by PTH (kidney is a

regulator of plasma phosphtate regulator of plasma phosphtate concentration)concentration)

Secondary active transport: Secondary active transport: GlucoseGlucose

Secondary active transport: Secondary active transport: GlucoseGlucose

Secondary active transport: Secondary active transport: PhosphatePhosphate

Secondary active transport: Secondary active transport: PhosphatePhosphate

NaNa++-K-K++ ATPase ATPaseNaNa++-K-K++ ATPase ATPase

• In renal tubular cells found only in In renal tubular cells found only in basolateral membranebasolateral membrane

• When ATP is hydrolyzed, 2 KWhen ATP is hydrolyzed, 2 K++ ions are ions are pumped into the cell and 3 Napumped into the cell and 3 Na++ ions are ions are pumped outpumped out

• Maintains favorable electrochemical Maintains favorable electrochemical gradient for Nagradient for Na++ entry at luminal entry at luminal membranemembrane

• Maintains cell membrane potential Maintains cell membrane potential difference and intracellular osmolalitydifference and intracellular osmolality

PinocytosisPinocytosisPinocytosisPinocytosis

• Endocytosis: Filtered proteins Endocytosis: Filtered proteins adsorbed to sites on luminal adsorbed to sites on luminal membranes that are internalized to form membranes that are internalized to form endosomes. Fusion with lysosomes endosomes. Fusion with lysosomes forms endolysosomes in which forms endolysosomes in which digestion of proteins occursdigestion of proteins occurs

• Hydrolysis of filtered proteins to Hydrolysis of filtered proteins to constituent amino acids by enzymes in constituent amino acids by enzymes in brush border of proximal tubular cellsbrush border of proximal tubular cells

Urea: Passive diffusionUrea: Passive diffusionUrea: Passive diffusionUrea: Passive diffusion

• Urea is passively reabsorbed in the Urea is passively reabsorbed in the proximal tubuleproximal tubule

• More urea is reabsorbed at low tubular More urea is reabsorbed at low tubular flow rates than at high tubular flow flow rates than at high tubular flow ratesrates

• Contributes to BUN increasing out of Contributes to BUN increasing out of proportion to creatinine in dehydrated proportion to creatinine in dehydrated patients even before GFR decreasespatients even before GFR decreases

Calcium homeostasisCalcium homeostasisCalcium homeostasisCalcium homeostasis

• 99% of Ca99% of Ca+2+2 in bone, < 1% in bone, < 1% intracellular, 0.1% extracellularintracellular, 0.1% extracellular

• Much homeostasis achieved by Much homeostasis achieved by altering GI absorption via calcitriolaltering GI absorption via calcitriol

• Only 60% of plasma CaOnly 60% of plasma Ca+2+2 (ionized and (ionized and complexed) is available for complexed) is available for glomerular filtrationglomerular filtration

Renal handling of CaRenal handling of Ca+2+2Renal handling of CaRenal handling of Ca+2+2

• Filtered by glomeruli and reabsorbed Filtered by glomeruli and reabsorbed by tubulesby tubules

• 99% of filtered Ca99% of filtered Ca+2+2 is reabsorbed is reabsorbed (exception: horse)(exception: horse)• Proximal tubule: 60-65%Proximal tubule: 60-65%• Loop of Henle: 25-30%Loop of Henle: 25-30%• Distal tubule & collecting duct: 4-9%Distal tubule & collecting duct: 4-9%

Renal reabsorption of CaRenal reabsorption of Ca+2+2Renal reabsorption of CaRenal reabsorption of Ca+2+2

• Proximal tubule, medullary thick Proximal tubule, medullary thick ascending loop of Henle: passive and ascending loop of Henle: passive and paracellular (favorable electrochemical paracellular (favorable electrochemical gradient)gradient)

• Distal nephron: active and transcellularDistal nephron: active and transcellular• CaCa+2+2 diffuses down electrochemical gradient diffuses down electrochemical gradient

at luminal membraneat luminal membrane• Transported across basolateral membrane by Transported across basolateral membrane by

NaNa++-Ca-Ca+2+2 antiporter and Ca antiporter and Ca+2+2 ATPase ATPase

Factors affecting renal CaFactors affecting renal Ca+2+2 reabsorptionreabsorption


• Proximal tubule: CaProximal tubule: Ca+2+2 reabsorption parallels Nareabsorption parallels Na++ and and water reabsorptionwater reabsorption• Increased by volume depletionIncreased by volume depletion

• Decreased by volume expansionDecreased by volume expansion



• Increased serum PIncreased serum Pii stimulates PTH stimulates PTH release (via decreased serum Carelease (via decreased serum Ca+2+2))

• PTH increases CaPTH increases Ca+2+2 reabsorption and reabsorption and decreases Pdecreases Pii reabsorption in kidney reabsorption in kidney

• Allows retention of CaAllows retention of Ca+2+2 but excretion but excretion of Pof Pii mobilized from bone by PTH and mobilized from bone by PTH and absorbed from gut via calcitriol absorbed from gut via calcitriol



• Metabolic acidosis stimulates Metabolic acidosis stimulates CaCa+2+2 reabsorption in distal reabsorption in distal tubulestubules

• Metabolic alkalosis inhibits Metabolic alkalosis inhibits CaCa+2+2 reabsorption in distal reabsorption in distal tubulestubules

Renal handling of phosphateRenal handling of phosphateRenal handling of phosphateRenal handling of phosphate

• Filtered by glomeruli and Filtered by glomeruli and reabsorbed by tubules but not reabsorbed by tubules but not secretedsecreted

• 75-95% of the filtered load of P75-95% of the filtered load of Pii is is reabsorbed in the proximal tubule reabsorbed in the proximal tubule by co-transport with Naby co-transport with Na++

Renal handling of phosphateRenal handling of phosphateRenal handling of phosphateRenal handling of phosphate

• PPii-rich meal will increase serum P-rich meal will increase serum Pii and filtered load with consequent and filtered load with consequent increase in urinary Pincrease in urinary Pii excretion excretion

• Increased serum PIncreased serum Pii will increase PTH will increase PTH (via decreased serum Ca(via decreased serum Ca+2+2) which will ) which will decrease Tdecrease Tmaxmax for P for Pii reabsorption in reabsorption in proximal tubule and increase urinary proximal tubule and increase urinary PPii excretion excretion

renal tubular reabsorption stephen p. dibartola department of veterinary clinical sciences college...

Documents

tubular fluid

movement of solutes

renal tubular epithelium

peritubular blood

peritubular interstitium

urine reabsorption movement

secretion movement

direction of movement