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Proximal Nephron Na coupled transport systems Diabetes Mellitus, Nephrogenic glucosuria Diabetes Insipidus PHY 423 University of British Columbia

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Presentation on theme: "Proximal Nephron Na coupled transport systems Diabetes Mellitus, Nephrogenic glucosuria Diabetes Insipidus PHY 423 University of British Columbia"— Presentation transcript:

1 Proximal Nephron Na coupled transport systems Diabetes Mellitus, Nephrogenic glucosuria Diabetes Insipidus PHY 423 University of British Columbia

2 What effect does the disorder have on renal glucose excretion? Group 1: Diabetes Mellitus Group 1: Diabetes Mellitus Group 2: Nephrogenic Glucosuria Group 2: Nephrogenic Glucosuria Group 3: Diabetes Insipidus Group 3: Diabetes Insipidus What effect does the disorder have on renal glucose excretion? What is the underlying cause? Are there any changes in NaCl, K or water excretion?

3 What is the primary defect in each of these disorders? Disorder Primary underlying cause of the problem Defective Nephron Segment Altered transport molecule NephronSegment(s)affected Diabetes Mellitus Nephrogenic glucosuria Diabetes Insipidus

4 What effect does the disorder have on the following? Complete the table, compare to normal and other disorders Condition Glucose excretion* NaCl and water excretion* K excretion* ECF loss* Urine 24 hr Normal Diabetes Mellitus (Untreated) Nephrogenic glucosuria Diabetes Insipidus (water intake = water loss) * vs normal

5 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? 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?

6 Glucose Reabsorption Length of the Proximal Tubule

7 Na-glucose reabsorption-lumen becomes negative- then Cl- and water are reabsorbed too! Blood Side Lumen NaCl +glucose H2OH2O glucose H2OH2O AQP1 glucose SGLUT2 GLUT2 H2OH2O -2 mV gGlucose

8 High affinity but low capacity 2Na-glucose cotransporter- last 80% PT Reduces glucose concentration nearly to zero! Blood Side Lumen NaCl +glucose H2OH2O glucose H2OH2O AQP1 glucose SGLUT1 GLUT1 H2O 2 gGlucose  -2 mV

9 GLUT2 and GLUT1 mediate facilitated transport of glucose out of proximal tubular cells GLUT 2 is present on the basolateral membrane of cells in the early part of the PCT that also express SGLUT2 GLUT 2 is present on the basolateral membrane of cells in the early part of the PCT that also express SGLUT2 GLUT1 is expressed in cells of the remaining part of the proximal tubule that express SLUT1 on the luminal surface. GLUT1 is expressed in cells of the remaining part of the proximal tubule that express SLUT1 on the luminal surface.

10 Facilitated Diffusion is the simplest from of carrier mediated transport Is this active or passive transport? Facilitated Diffusion

11 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?

12 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 :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

13 Why is glucose excretion fairly low in patients with nephrogenic glucosuria? Carrier mediated transport systems in the PT are not operating at Vmax i.e. if [S] increases then v increases Carrier mediated transport systems in the PT are not operating at Vmax i.e. if [S] increases then v increases –If a patient has a defect in SGLUT2 (e.g. Vmax is less than normal) then [glucose] does not decrease as rapidly as it should. So more glucose is shifted to the next PT segment which has SGLUT1. The higher luminal [glucose] will drive an increase in velocity of transport in this segment- reducing the amount that escapes into the urine. What if the defect was in SGLUT1? Also the patient is able to take advantage of the entire length of the PT to reabsorb what would normally disappear in the first third of the segment Also the patient is able to take advantage of the entire length of the PT to reabsorb what would normally disappear in the first third of the segment Remember in these patients, glucose delivery to the PT is normal, its rate of reabsorption is impaired. The reductions in transport efficiency usually only cause a small but measurable increase in glucose excretion. Remember in these patients, glucose delivery to the PT is normal, its rate of reabsorption is impaired. The reductions in transport efficiency usually only cause a small but measurable increase in glucose excretion.

14 Why is glucose excretion in by patients with untreated Diabetes Mellitus so high? Part 1 Remember, glucose delivery to the PT is 2-3 times higher than normal, there are no defects in glucose reabsorption. Remember, glucose delivery to the PT is 2-3 times higher than normal, there are no defects in glucose reabsorption. The SGLUTs (2 and 1) which normally are not operating at Vmax become saturated by the steady high delivery of glucose (2-3 time normal). The SGLUTs (2 and 1) which normally are not operating at Vmax become saturated by the steady high delivery of glucose (2-3 time normal). –In this situation, [glucose] does not decrease as it normally does, the higher luminal [glucose] drives an increase in velocity of transport of all the SGLUTs. Despite saturation of all SGLUT2 and 1 carriers along the length of the PT, glucose concentration fails to decline and spills into the loop of Henle. Despite saturation of all SGLUT2 and 1 carriers along the length of the PT, glucose concentration fails to decline and spills into the loop of Henle.

15 Why is glucose excretion in by patients with untreated Diabetes Mellitus so high? Part 2 The TAL and DCT, CCD and CD have essentially no ability to reabsorb glucose if it is delivered to these segments The TAL and DCT, CCD and CD have essentially no ability to reabsorb glucose if it is delivered to these segments Thus large amounts are excreted in the urine Thus large amounts are excreted in the urine We will see that the presence of large amounts of un- reabsorbed glucose in the PT and downstream nephron segments will disrupt NaCl, water and potassium transport We will see that the presence of large amounts of un- reabsorbed glucose in the PT and downstream nephron segments will disrupt NaCl, water and potassium transport We need to look at the mechanism NaCl and water reabsorption that is not coupled to glucose reabsorption to understand this. Coming soon! We need to look at the mechanism NaCl and water reabsorption that is not coupled to glucose reabsorption to understand this. Coming soon!

16 Summary The amount of glucose excretion and the underlying reason differ between diabetes mellitus and nephrogenic glucosuria Disorder Primary underlying cause of the problem Defective Nephron Segment(s) Altered transport molecule NephronSegment(s)affected Diabetes Mellitus Lack Insulin- raises plasma [glucose] NANA PT, and all downstream segments Nephrogenic glucosuria Defective glucose reabsorption Proximal Tubule SGLUT2, SGLUT1, or GLUT2 or GLUT1 PT

17 Summary Comparison of the primary defect in the three disorders Disorder Primary underlying cause of the problem Defective Nephron Segment(s) Altered transport molecule NephronSegment(s)affected Diabetes Mellitus Lack Insulin- raises plasma [glucose] NANA PT, and all downstream segments Nephrogenic glucosuria Defective glucose reabsorption Proximal Tubule SGLUT2, SGLUT1, or GLUT2 or GLUT1 PT Diabetes Insipidus Lack Antidiuretic hormone ADH NA NA: AQP2 expression is absent due to absence of ADH Entire collecting duct system i.e. CCD and downstream.

18 Proximal Convoluted Tubule Recap-First third of the proximal tubule The lumen potential is negative because of electrogenic Na glucose and some types of Na- amino acid reabsorption- which ones? The lumen potential is negative because of electrogenic Na glucose and some types of Na- amino acid reabsorption- which ones? Any Cl that is reabsorbed is going through the paracellular pathway driven by the lumen negative potential Any Cl that is reabsorbed is going through the paracellular pathway driven by the lumen negative potential There is NaHCO 3 reabsorption which you will learn about in the acid base section of the course There is NaHCO 3 reabsorption which you will learn about in the acid base section of the course

19 Proximal Convoluted Tubule Are there other mechanisms of reabsorbing NaCl and water in the last half of the PT? Yes Yes **Carrier mediated reabsorption of NaCl- MOST is going this way- ACTIVE TRANSPORT **Carrier mediated reabsorption of NaCl- MOST is going this way- ACTIVE TRANSPORT Passive reabsorption of Cl driven by its chemical concentration gradient and passive reabsorption of Na driven by the lumen + potential through the paracellular pathway – THIS IS PASSIVE Passive reabsorption of Cl driven by its chemical concentration gradient and passive reabsorption of Na driven by the lumen + potential through the paracellular pathway – THIS IS PASSIVE Water follows all- i.e. isosmotic NaCl and water reabsorption Water follows all- i.e. isosmotic NaCl and water reabsorption

20 Last Half Proximal Tubule Most Na and Cl transport is transcellular and some is paracellular Transcellular NaCl transport is active Cl - +

21 Why is NaCl and water reabsorption in the PT disrupted in patients with untreated Diabetes Mellitus? NaCl & water reabsorption in the PT is disrupted by the creation of a concentration gradient for Na to leak back into the lumen. Thus a large amount of NaCl and water is delivered downstream NaCl & water reabsorption in the PT is disrupted by the creation of a concentration gradient for Na to leak back into the lumen. Thus a large amount of NaCl and water is delivered downstream

22 How unreabsorbed glucose decreases NaCl and water reabsorption in the PT Gennari and Kassirer, NEJM 291: , Oct 3, 1974 with permission Read note

23 Osmotic Diuresis in DM 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 increase. 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 increase. Osmotic pressure of unreabsorbed Glu causes water to remain in the PT Osmotic 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 mechanism previously described- this creates a [Na] gradient between blood and lumen 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 lumen 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 backleak of NaCl into the tubule equals the rate of NaCl pumpted out. Thus net transport stops 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 backleak of NaCl into the tubule equals the rate of NaCl pumpted out. Thus net transport stops This net decrease in NaCl and water reabsorption leads to increased delivery to the distal nephron which exceed the capacity of these downstream segments. This net decrease in NaCl and water reabsorption leads to increased delivery to the distal nephron which exceed the capacity of these downstream segments. The increase in delivery of NaCl to the cortical collecting duct (CCD) stimulates K secretion. The increase in delivery of NaCl to the cortical collecting duct (CCD) stimulates K secretion. Consequently you will loose NaCl and water = ECF and K into the urine. More on this later Consequently you will loose NaCl and water = ECF and K into the urine. More on this later

24 What are the changes in glucose excretion, electrolyte Condition Glucose excretion* NaCl and water excretion* K excretion* ECF loss* Urine 24 hr Normal 0 -trace NaCl excretion = NaCl intake Water balance is maintained K excretion = K intake liters Diabetes Mellitus (Untreated) liters electrolyte rich electrolyte rich Nephrogenic glucosuria normal 1-2 liters 1-2 liters Diabetes Insipidus (water intake = water loss) 0 Free water excretion little NaCl loss 0 virtually no K loss liters mostly water mostly water * vs normal

25 Discussion Questions- next class See Group Assignments Sheet Three working groups Three working groups Group 1 Bartter’s Syndrome/Disease and Furosemide Group 2 Gitelman’s Syndrome/Disease and Thiazides Group 3 Liddle’s Syndrome/Disease and Amiloride

26 Dr. 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


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