Proximal Nephron Na coupled Proximal Nephron Na coupled transport systemstransport systems

Diabetes Mellitus, Diabetes Mellitus, Nephrogenic glucosuria Nephrogenic glucosuria

Diabetes InsipidusDiabetes Insipidus

PHY 423PHY 423University of British ColumbiaUniversity of British Columbia

Linda.peterson@ubc.caLinda.peterson@ubc.ca

What effect does the disorder What effect does the disorder have on renal glucose have on renal glucose excretion?excretion?• Group 1: Diabetes MellitusGroup 1: Diabetes Mellitus

• Group 2: Nephrogenic Glucosuria Group 2: Nephrogenic Glucosuria

• Group 3: Diabetes InsipidusGroup 3: Diabetes Insipidus

What effect does the disorder have on What effect does the disorder have on renal glucose excretion? renal glucose excretion?

What is the underlying cause?What is the underlying cause?

Are there any changes in NaCl, K or water Are there any changes in NaCl, K or water excretion?excretion?

What is the primary defect in each of these disorders?What is the primary defect in each of these disorders?

DisorderDisorder Primary Primary underlying underlying cause of the cause of the problemproblem

Defective Defective Nephron Nephron SegmentSegment

Altered Altered transport transport moleculemolecule

Nephron Nephron

Segment(s)Segment(s)

affectedaffected

Diabetes Diabetes MellitusMellitus

Nephrogenic glucosuria

Diabetes Diabetes InsipidusInsipidus

What effect does the disorder have on the following?What effect does the disorder have on the following?Complete the table, compare to normal and other disordersComplete the table, compare to normal and other disorders

ConditionCondition Glucose Glucose excretion*excretion*

NaCl and NaCl and water water excretion*excretion*

K excretion*K excretion* ECF loss* Urine 24 hrECF loss* Urine 24 hr

NormalNormal

Diabetes Diabetes MellitusMellitus

(Untreated)(Untreated)

Nephrogenic Nephrogenic glucosuriaglucosuria

Diabetes Diabetes Insipidus (water Insipidus (water intake = water intake = water loss)loss)

* vs normal

• Ron is 20 years old and has just gone Ron is 20 years old and has just gone to his family doctor for a health to his family doctor for a health assessment since he is applying to assessment since he is applying to the fire department. Urine dipstick the fire department. Urine dipstick showed the presence of more than a showed the presence of more than a trace of glucose in his urine. His trace of glucose in his urine. His plasma glucose concentration is plasma glucose concentration is normal. Is this OK?normal. Is this OK?

Glucose Reabsorption

Length of the Proximal Tubule

Na-glucose reabsorption-lumen Na-glucose reabsorption-lumen becomes negative- then Cl- and water becomes negative- then Cl- and water are reabsorbed too!are reabsorbed too!

Blood Side

LumenNaCl +glucoseH2

Oglucose

H2O

AQP1

glucose

SGLUT2

GLUT2 H2O

-2 mV

gGlucose

High affinity but low capacity 2Na-glucose cotransporter- last High affinity but low capacity 2Na-glucose cotransporter- last 80% PT80% PTReduces glucose concentration nearly to zero!Reduces glucose concentration nearly to zero!

Blood Side

LumenNaCl +glucoseH2

Oglucose

H2O

AQP1

glucose

SGLUT1

GLUT1 H2O

2

gGlucose

-2 mV

GLUT2 and GLUT1 mediate facilitated GLUT2 and GLUT1 mediate facilitated transport of glucose out of proximal transport of glucose out of proximal tubular cellstubular cells

• GLUT 2 is present on the basolateral GLUT 2 is present on the basolateral membrane of cells in the early part of the membrane of cells in the early part of the PCT that also express SGLUT2PCT that also express SGLUT2

• GLUT1 is expressed in cells of the GLUT1 is expressed in cells of the remaining part of the proximal tubule that remaining part of the proximal tubule that express SLUT1 on the luminal surface. express SLUT1 on the luminal surface.

Facilitated Diffusion is the simplest from of carrier mediated transport

Is this active or passive transport?

Facilitated Diffusion

So what does Ron have?• Ron is 20 years old and has just gone to

his family doctor for a health assessment since he is applying to the fire department. Urine dipstick showed the presence of more than a trace of glucose in his urine. His plasma glucose concentration is normal. Is this OK?

Figure 35-3 Glucose handling by the kidney. The yellow box indicates the fraction of the filtered load that the proximal tubule reabsorbs. The green boxes indicate the fraction of the filtered load that remains in the lumen at various sites. GLUT, glucose

transporter (which mediates facilitated diffusion); PCT, proximal convoluted tubule; PST, proximal straight tubule; SGLT, Na/glucose cotransporter.

Downloaded from: StudentConsult (on 21 September 2006 05:56 PM)

© 2005 Elsevier

So what about Ron?

Ron has nephrogenic or renal glycosuria. The kidney is the source of the problem. It is benign and requires no treatment.

Low capacity-high affinity

High capacity-low affinity

Why is glucose excretion fairly Why is glucose excretion fairly low in patients with low in patients with nephrogenic glucosuria? nephrogenic glucosuria? • Carrier mediated transport systems in the PT are not Carrier mediated transport systems in the PT are not

operating at Vmax i.e. if [S] increases then v increasesoperating at Vmax i.e. if [S] increases then v increases– If a patient has a defect in SGLUT2 (e.g. Vmax is less than If a patient has a defect in SGLUT2 (e.g. Vmax is less than

normal) then [glucose] does not decrease as rapidly as it normal) then [glucose] does not decrease as rapidly as it should. So more glucose is shifted to the next PT segment should. So more glucose is shifted to the next PT segment which has SGLUT1. The higher luminal [glucose] will drive an which has SGLUT1. The higher luminal [glucose] will drive an increase in velocity of transport in this segment- reducing the increase in velocity of transport in this segment- reducing the amount that escapes into the urine. What if the defect was in amount that escapes into the urine. What if the defect was in SGLUT1?SGLUT1?

• Also the patient is able to take advantage of the entire Also the patient is able to take advantage of the entire length of the PT to reabsorb what would normally length of the PT to reabsorb what would normally disappear in the first third of the segmentdisappear in the first third of the segment

• Remember in these patients , glucose delivery to the Remember in these patients , glucose delivery to the PT is normal, its rate of reabsorption is impaired. The PT is normal, its rate of reabsorption is impaired. The reductions in transport efficiency usually only cause a reductions in transport efficiency usually only cause a small but measurable increase in glucose excretion.small but measurable increase in glucose excretion.

Why is glucose excretion in by Why is glucose excretion in by patients with untreated patients with untreated Diabetes Mellitus so high? Part Diabetes Mellitus so high? Part 11• Remember, glucose delivery to the PT is 2-3 Remember, glucose delivery to the PT is 2-3

times higher than normal, there are no defects in times higher than normal, there are no defects in glucose reabsorption.glucose reabsorption.

• The SGLUTs (2 and 1) which normally are not The SGLUTs (2 and 1) which normally are not operating at Vmax become saturated by the operating at Vmax become saturated by the steady high delivery of glucose (2-3 time normal).steady high delivery of glucose (2-3 time normal).– In this situation, [glucose] does not decrease as it In this situation, [glucose] does not decrease as it

normally does, the higher luminal [glucose] drives an normally does, the higher luminal [glucose] drives an increase in velocity of transport of all the SGLUTs. increase in velocity of transport of all the SGLUTs.

• Despite saturation of all SGLUT2 and 1 carriers Despite saturation of all SGLUT2 and 1 carriers along the length of the PT, glucose concentration along the length of the PT, glucose concentration fails to decline and spills into the loop of Henle. fails to decline and spills into the loop of Henle.

Why is glucose excretion in by Why is glucose excretion in by patients with untreated patients with untreated Diabetes Mellitus so high? Part Diabetes Mellitus so high? Part 22• The TAL and DCT, CCD and CD have essentially The TAL and DCT, CCD and CD have essentially

no ability to reabsorb glucose if it is delivered to no ability to reabsorb glucose if it is delivered to these segmentsthese segments

• Thus large amounts are excreted in the urineThus large amounts are excreted in the urine

• We will see that the presence of large amounts of We will see that the presence of large amounts of un-reabsorbed glucose in the PT and downstream un-reabsorbed glucose in the PT and downstream nephron segments will disrupt NaCl , water and nephron segments will disrupt NaCl , water and potassium transportpotassium transport

• We need to look at the mechanism NaCl and We need to look at the mechanism NaCl and water reabsorption that is not coupled to glucose water reabsorption that is not coupled to glucose reabsorption to understand this. Coming soon!reabsorption to understand this. Coming soon!

SummarySummaryThe amount of glucose excretion and the underlying reason The amount of glucose excretion and the underlying reason differ between diabetes mellitus and nephrogenic glucosuriadiffer between diabetes mellitus and nephrogenic glucosuria

DisorderDisorder Primary Primary underlying underlying cause of the cause of the problemproblem

Defective Defective Nephron Nephron Segment(s)Segment(s)

Altered Altered transport transport moleculemolecule

Nephron Nephron

Segment(s) Segment(s)

affectedaffected

Diabetes Diabetes MellitusMellitus

Lack Insulin- Lack Insulin- raises plasma raises plasma [glucose][glucose]

NANA NANA PT, and all PT, and all downstream downstream segmentssegments

Nephrogenic Nephrogenic glucosuriaglucosuria

Defective Defective glucose glucose reabsorptionreabsorption

Proximal Proximal TubuleTubule

SGLUT2, SGLUT2, SGLUT1, or SGLUT1, or GLUT2 or GLUT2 or GLUT1GLUT1

PT PT

SummarySummaryComparison of the primary defect in the three disordersComparison of the primary defect in the three disorders

DisorderDisorder Primary Primary underlying underlying cause of the cause of the problemproblem

Defective Defective Nephron Nephron Segment(s)Segment(s)

Altered Altered transport transport moleculemolecule

Nephron Nephron

Segment(s) Segment(s)

affectedaffected

Diabetes Diabetes MellitusMellitus

Lack Insulin- Lack Insulin- raises plasma raises plasma [glucose][glucose]

NANA NANA PT, and all PT, and all downstream downstream segmentssegments

Nephrogenic Nephrogenic glucosuriaglucosuria

Defective Defective glucose glucose reabsorptionreabsorption

Proximal Proximal TubuleTubule

SGLUT2, SGLUT2, SGLUT1, or SGLUT1, or GLUT2 or GLUT2 or GLUT1GLUT1

PT PT

Diabetes Diabetes InsipidusInsipidus

Lack Lack Antidiuretic Antidiuretic hormone ADHhormone ADH

NANA NA: AQP2 NA: AQP2 expression is expression is absent due to absent due to absence of absence of ADHADH

Entire collecting Entire collecting duct system i.e. duct system i.e. CCD and CCD and downstream . downstream .

Proximal Convoluted Tubule

Recap-First third of the Recap-First third of the proximal tubuleproximal tubule• The lumen potential is negative because of The lumen potential is negative because of

electrogenic Na glucose and some types of electrogenic Na glucose and some types of Na-amino acid reabsorption- which ones? Na-amino acid reabsorption- which ones?

• Any Cl that is reabsorbed is going through Any Cl that is reabsorbed is going through the paracellular pathway driven by the the paracellular pathway driven by the lumen negative potentiallumen negative potential

• There is NaHCOThere is NaHCO33 reabsorption which you reabsorption which you will learn about in the acid base section of will learn about in the acid base section of the coursethe course

Proximal Convoluted TubuleAre there other mechanisms of Are there other mechanisms of reabsorbing NaCl and water in reabsorbing NaCl and water in the last half of the PT?the last half of the PT?• YesYes• **Carrier mediated reabsorption of NaCl- MOST **Carrier mediated reabsorption of NaCl- MOST

is going this way- ACTIVE TRANSPORTis going this way- ACTIVE TRANSPORT• Passive reabsorption of Cl driven by its chemical Passive reabsorption of Cl driven by its chemical

concentration gradient and passive concentration gradient and passive reabsorption of Na driven by the lumen + reabsorption of Na driven by the lumen + potential through the paracellular pathway – potential through the paracellular pathway – THIS IS PASSIVETHIS IS PASSIVE

• Water follows all- i.e. isosmotic NaCl and water Water follows all- i.e. isosmotic NaCl and water reabsorptionreabsorption

Last Half Proximal TubuleMost Na and Cl transport is transcellular and some is paracellular

Transcellular NaCl transport is active

Cl-Cl-

+

Why is NaCl and water reabsorption in Why is NaCl and water reabsorption in the PT disrupted in patients with the PT disrupted in patients with untreated Diabetes Mellitus? untreated Diabetes Mellitus?

• NaCl & water reabsorption in the PT is NaCl & water reabsorption in the PT is disrupted by the creation of a disrupted by the creation of a concentration gradient for Na to leak back concentration gradient for Na to leak back into the lumen. Thus a large amount of into the lumen. Thus a large amount of NaCl and water is delivered downstreamNaCl and water is delivered downstream

How unreabsorbed glucose decreases NaCl How unreabsorbed glucose decreases NaCl and water reabsorption in the PTand water reabsorption in the PT

Gennari and Kassirer, NEJM 291:714-720, Oct 3, 1974 with permission

Read note

Osmotic Diuresis in DMOsmotic Diuresis in DM

• Increased glucose load to the PT exceeds NaGlu reabsorptive capacity. Initially water Increased glucose load to the PT exceeds NaGlu reabsorptive capacity. Initially water follows the NaGlucose, Cl reabsorption thus the glucose concentration in the PT starts to follows the NaGlucose, Cl reabsorption thus the glucose concentration in the PT starts to increase. increase.

• Osmotic pressure of unreabsorbed Glu causes water to remain in the PTOsmotic pressure of unreabsorbed Glu causes water to remain in the PT

• Retained water causes [Na] to decrease in the lumen as NaCl is pumped out by the Retained water causes [Na] to decrease in the lumen as NaCl is pumped out by the mechanism previously described- this creates a [Na] gradient between blood and lumenmechanism previously described- this creates a [Na] gradient between blood and lumen

• Despite maximal rates of NaCl reabsorbed via NaGlu and NaCl coupled mechanism, the Despite maximal rates of NaCl reabsorbed via NaGlu and NaCl coupled mechanism, the gradient causes a back leak of Na Cl and water through the tight junctions. Now the gradient causes a back leak of Na Cl and water through the tight junctions. Now the backleak of NaCl into the tubule equals the rate of NaCl pumpted out. Thus net transport backleak of NaCl into the tubule equals the rate of NaCl pumpted out. Thus net transport stops stops

• This net decrease in NaCl and water reabsorption leads to increased delivery to the distal This net decrease in NaCl and water reabsorption leads to increased delivery to the distal nephron which exceed the capacity of these downstream segments. nephron which exceed the capacity of these downstream segments.

• The increase in delivery of NaCl to the cortical collecting duct (CCD) stimulates K The increase in delivery of NaCl to the cortical collecting duct (CCD) stimulates K secretion. secretion.

• Consequently you will loose NaCl and water = ECF and K into the urine. More on this laterConsequently you will loose NaCl and water = ECF and K into the urine. More on this later

What are the changes in glucose excretion, electrolyte What are the changes in glucose excretion, electrolyte

ConditionCondition Glucose Glucose excretion*excretion*

NaCl and NaCl and water water excretion*excretion*

K excretion*K excretion* ECF loss* Urine 24 hrECF loss* Urine 24 hr

NormalNormal 0 -trace0 -trace NaCl NaCl excretion excretion = NaCl = NaCl intakeintake

Water Water balance is balance is maintainedmaintained

K excretion = K excretion = K intakeK intake

0 1-2 liters0 1-2 liters

Diabetes Diabetes MellitusMellitus

(Untreated)(Untreated)

++++++++++ ++++++++++ ++++++++++++++ +++++ 5 liters+++++ 5 liters

electrolyte electrolyte rich rich

Nephrogenic Nephrogenic glucosuriaglucosuria

++ 00 00 0 normal0 normal

1-2 liters1-2 liters

Diabetes Diabetes Insipidus (water Insipidus (water intake = water intake = water loss)loss)

00 Free water Free water excretion+excretion++++++ +++++ little NaCl little NaCl lossloss

0 virtually no 0 virtually no K lossK loss

0 10-15 liters0 10-15 liters

mostly mostly waterwater

* vs normal

Discussion Questions- next Discussion Questions- next classclassSee Group Assignments See Group Assignments SheetSheet• Three working groupsThree working groups

Group 1 BartterGroup 1 Bartter’’s Syndrome/Disease and s Syndrome/Disease and FurosemideFurosemide

Group 2 GitelmanGroup 2 Gitelman’’s Syndrome/Disease and s Syndrome/Disease and ThiazidesThiazides

Group 3 LiddleGroup 3 Liddle’’s Syndrome/Disease and s Syndrome/Disease and AmilorideAmiloride

http://www2.kumc.edu/ki/physiology/course/six/6_1.htmDr. Bolliger Kanas University Medical Center 1999

Proximal Tubule Length

Cl concentration is increased because it lags behind Na glucose reabsorption and because Na is reabsorbed with bicarbonate in the early part of the PT. Cl diffusion down its concentration gradient through the paracellular pathway creates the lumen + TEP