Topic list
1. Renal handling of glucose & keto-acids
2. Osmotic diuresis
3. Fluid & electrolyte imbalance in diabetes mellitus
4. FM’s acid base problems
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1. Renal handling of glucose & ketoacids
These are examples of “Tm” i.e. “transport maximum” substances
Examples:
glucose, galactose
amino acids
organic acids (acetoacetate,  hydroxybutyrate, lactate, etc.)
*phosphate, *sulfate
vitamin C
*phosphate reabsorption: regulated by parathyroid hormone
*sulfate reabsorption: regulated by kidney; not physiologically important
For all other Tm substances:
kidney excretes excessive plasma concentrations, but is not the
normal regulator of their body concentrations.
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1. Renal handling of glucose & ketoacids
Common features of Tm substances
 reabsorbed from proximal tubule
 transported at the luminal membrane by Na+ linked cotransport (symport)
i.e. secondary active transport (SGLT 2, SGLT 1)
 transported at the basolateral surface by variety of mechanisms
e.g. glucose: facilitated diffusion (passive, carrier mediated)
(GLUT 2, GLUT 1, not GLUT4 - the insulin sensitive one)
e.g. ketoacids: Cl- countertransport (2° active antiport)
 transport at the luminal membrane shows saturation, i.e. has a Tm
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Tm dependent transport mechanisms
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Determination of Tm glucose
Experimental procedure:
give IV infusion of inulin & progressively increasing [glucose]
collect urine over timed clearance periods
take blood sample at mid time of each clearance period
Measure:
glomerular filtration rate (Cin); units: ml/min
filtered load of glucose (GFR x Pglu); units: mg/min
excretion rate of glucose (Uglu x V); units: mg/min
Calculate:
glucose reabsorbed (glucose filtered - glucose excreted)
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Measurement of Tm glucose
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Mr. Murphy’s handling of glucose
Tm for glucose in human is ~ 370 mg/min
(less for FM given his creatinine clearance = 24 ml/min)
Filtered load of glucose = GFR x plasma [glucose]
for Mr. Murphy: = 24 ml/min x 1600 mg/dL
= 384 mg/min
Therefore his filtered load > Tm and he is spilling glucose
The kidney will spill glucose before the Tm is reached (renal threshold)
The renal threshold for glucose in a healthy subject is ~200 mg/dL
Note: Tm units mg/min; plasma threshold units mg/dL
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Topic list
1. Renal handling of glucose & keto-acids
2. Osmotic diuresis
3. Fluid & electrolyte imbalance in diabetes mellitus
4. FM’s acid base problems
8
2. Osmotic diuresis
a.  [glucose] in proximal tubule exerts osmotic effect
b. osmotic pressure of glucose “holds” water in proximal tubule
c.
reabsorption of Na+ occurs without accompanying water (compare
usual situation where Na+ reabsorption accompanied by osmotically
equivalent amount of water, i.e. isosmotic)
d. Na+ concentration in proximal tubule falls
e. Na+ now has to be reabsorbed against its concentration gradient
also, back diffusion of Na+ from interstitial to tubular fluid (paracellular)
f.
proximal Na+ reabsorption (normally 70% of filtered load) is reduced
Net effect:
Decreased Na+ & water reabsorption from proximal tubule
Increased delivery of Na+ & water to collecting duct
Increased excretion of Na+ & water (i.e. osmotic diuresis)
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2. Osmotic diuresis (flow chart)
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2. Consequences of osmotic diuresis
a. Increased water excretion
b. Increased Na+ excretion
c.
Increased K+ excretion
a. Increased water excretion
Mechanism: osmotic diuresis (explained before)
FM’s urinary specific gravity is <1.005 (range 1.003-1.030)
This SG is at the lower end of the range and, given the high rates of
excretion of glucose (urinary [glucose] >1000 mg/dl), Na+ (420 mEq/24
hr), & K+ (260 mEq/24 hr), he must be drinking large volumes of water to
have that low a specific gravity.
Thirst mechanism driven by  vascular volume,  plasma osmolality
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2. Consequences of osmotic diuresis
b. Increased Na+ excretion
In spite of:
reduced plasma [Na+]: 125 mEq/L
reduced vascular volume (bp 100/60 mmHg, pulse 105/min)
Evidence:
FM’s Na+ excretion = 420 mEq/24 hr (on normal diet 150 mEq/24 hr)
Mechanisms:
osmotic diuresis  Na+ reabsorption from proximal tubule
 Na+ delivery to distal nephron  Na+ reabsorption from collecting
duct and  Na+ excretion
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2. Consequences of osmotic diuresis
c. Increased K+ excretion
K+ excretion rate depends on K+ secretion rate by principal cell of
collecting duct
Mechanisms:
i.
Osmotic diuresis
 collecting duct flow rate  tubular fluid [K+]  cell to tubule [K+]
gradient  K+ secretion and excretion
ii.
Vascular volume depletion 
 sympathetic activity and  afferent arteriole bp  renin,
 angiotensin,  aldosterone  K+ secretion and excretion
iii. Unreabsorbable anions in collecting duct (CD)
CD fluid contains acetoacetate &  hydroxybutyrate because they have
exceeded their proximal tubule Tm
Ketoacids not reabsorbed in CD (Cl- is)  CD lumen more negative 
 K+ secretion and excretion
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Topic list
1. Renal handling of glucose & keto-acids
2. Osmotic diuresis
3. Fluid & electrolyte imbalance in diabetes mellitus
4. FM’s acid base problems
14
3. Fluid & electrolyte imbalance in diabetes mellitus
Questions:
a. How are FM’s kidneys doing?
b. Why should you suspect that FM is K+ depleted when his serum [K+]
is 6.9 mEq/L (normal 3.5-5)?
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3. Fluid & electrolyte imbalance in diabetes mellitus
How are FM’s kidneys doing?
Evidence:
serum [creatinine] = 4.3 mg/dl (normal 0.7-1.5)
BUN = 66 mg/dl (normal 10-20)
creatinine clearance = 26 ml/min (normal ~120 ml/min)
Answer:
3 months ago when he was discharged from his previous
hospitalization his serum [creatinine] was 0.9 mg/dl, BUN was 5 mg/dl
Conclusion:
His present impaired renal function is caused by his  vascular volume
which  sympathetic discharge  GFR, i.e. he has pre-renal azotemia
You would expect a BUN/creatinine ratio > normal ~15, but his poor
diet has reduced his body urea content, masking the expected  [BUN]
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3. Fluid & electrolyte imbalance in diabetes mellitus
Why do you think FM is K+ depleted when his serum [K+] is 6.9 mEq/L ?
Answer:
His  serum [K+] is the result of redistribution of K+ from intracellular to
extracellular fluid; his total body K+ content is severely reduced
Causes of K+ efflux from cells
1. Extracellular hyperosmolality; FM’s is 322 mOsm/kg water (1600 mg/dl
glucose has osmolality of ~90 mOsm/kg water) “pulls” water out of
cells causing:
a.  cellular [K+] thus  gradient for [K+] efflux
b. water leaves cells via water channels takes K+ by solvent drag
2. Insulin lack  activity of Na+/K+ pump
Note: K+ efflux not secondary to acidosis because organic acids enter
cells in undissociated form and do not exchange for Na+ & K+
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3. Fluid & electrolyte imbalance in diabetes mellitus
Treatment:
rapid IV isotonic saline (1 L/hr then 500 ml/hr)
purpose: rehydration to increase vascular volume
IV insulin (8 units/hr)
purpose: stimulating glucose uptake by cells
IV K+ (20 mEq/hr then 10 mEq/hr)
purpose: replacing K+ which will enter cells as insulin & glucose
be careful or else you’ll kill him
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Topic list
1. Renal handling of glucose & keto-acids
2. Osmotic diuresis
3. Fluid & electrolyte imbalance in diabetes mellitus
4. FM’s acid base problems
19
4. FM’s acid base problems
Arterial blood gases on admission:
pH 7.06, Pa.CO2 26 mmHg, HCO3- 6.8 mEq/L
Pa.O2 288 mmHg (on 100% O2 by mask)
O2 saturation 99%
Venous blood:
total CO2 8 mEq/L (= HCO3- + 0.03 x Pa.CO2)
Urinary pH 5.8 (range 4.5-7.5)
Urinary titratable acidity 48 mEq/24 hr (normal 20-40)
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4. FM’s acid base problems
Reminder: DRW “absolutely infallible” method of acid base analysis
1. Look at pH (is it acidosis or alkalosis?)
2. Look at HCO3- (is it metabolic acidosis/alkalosis?)
3. Look at Pa.CO2 (is it respiratory acidosis/alkalosis?)
4. See if appropriate compensation has occurred
5. If your diagnosis includes metabolic acidosis, check the anion gap
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4. Applying the AIM to Mr. Murphy
1. Look at pH (is it acidosis or alkalosis?)
pH = 7.06  acidosis
2. Look at HCO3- (is it metabolic acidosis?)
HCO3- = 6.8 mEq/L (normal 22-30)  metabolic acidosis
3. Look at Pa.CO2 (is it respiratory acidosis?)
Pa.CO2 = 25 mmHg (normal 35-45)  not respiratory acidosis
4. See if appropriate compensation has occurred
compensation for metabolic acidosis is hyperventilation
Pa.CO2 = 25 mmHg (normal 35-45)  partial respiratory compensation
5. If your diagnosis includes metabolic acidosis, check the anion gap
Anion gap = [Na+] - [Cl-] - [HCO3-] = 125 - 78 - 7 = 40 (normal ~12)
Partially compensated metabolic acidosis with increased anion gap
(normochloremic)
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4. FM’s acid base problems (additional comments)
Respiratory compensation:
respiration 18/min, “very deep” i.e. Kussmaul breathing
H+ stimulation of peripheral chemoreceptors (aortic, carotid bodies)
Pa.O2 288 mmHg (on 100% O2 by mask); should be >500 mmHg:
FM has COPD (V/Q mismatch); possibly ill fitting mask, too short time.
Anion gap:
unmeasured anions are ketoacids (ketosis) & lactate (hypoperfusion)
Urinary pH 5.8, titratable acidity 48 mEq/24 hr:
kidney is doing well secreting H+, titratable acidity includes ketoacids
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