1 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

2 1. Renal handling of glucose & ketoacids These are examples of “T m ” 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 T m substances: kidney excretes excessive plasma concentrations, but is not the normal regulator of their body concentrations.

3 1. Renal handling of glucose & ketoacids Common features of T m 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 T m

4 T m dependent transport mechanisms

5 Determination of T m 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 (C in ); units: ml/min filtered load of glucose (GFR x P glu ); units: mg/min excretion rate of glucose (U glu x V); units: mg/min Calculate: glucose reabsorbed (glucose filtered - glucose excreted)

6 Measurement of T m glucose

7 Mr. Murphy’s handling of glucose T m 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 > T m 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: T m units mg/min; plasma threshold units mg/dL

8 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

9 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)

10 2. Osmotic diuresis (flow chart)

11 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 ) 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

12 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

13 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 T m Ketoacids not reabsorbed in CD (Cl - is)  CD lumen more negative   K + secretion and excretion

14 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

15 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)?

16 3. Fluid & electrolyte imbalance in diabetes mellitus How are FM’s kidneys doing? Evidence: serum [creatinine] = 4.3 mg/dl (normal ) 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]

17 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 +

18 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

19 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

20 4. FM’s acid base problems Arterial blood gases on admission: pH 7.06, Pa.CO 2 26 mmHg, HCO mEq/L Pa.O mmHg (on 100% O 2 by mask) O 2 saturation 99% Venous blood: total CO 2 8 mEq/L (= HCO x Pa.CO 2 ) Urinary pH 5.8 (range ) Urinary titratable acidity 48 mEq/24 hr (normal 20-40)

21 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 HCO 3 - (is it metabolic acidosis/alkalosis?) 3.Look at Pa.CO 2 (is it respiratory acidosis/alkalosis?) 4.See if appropriate compensation has occurred 5.If your diagnosis includes metabolic acidosis, check the anion gap

22 4. Applying the AIM to Mr. Murphy 1.Look at pH (is it acidosis or alkalosis?) pH = 7.06  acidosis 2.Look at HCO 3 - (is it metabolic acidosis?) HCO 3 - = 6.8 mEq/L (normal 22-30)  metabolic acidosis 3.Look at Pa.CO 2 (is it respiratory acidosis?) Pa.CO 2 = 25 mmHg (normal 35-45)  not respiratory acidosis 4.See if appropriate compensation has occurred compensation for metabolic acidosis is hyperventilation Pa.CO 2 = 25 mmHg (normal 35-45)  partial respiratory compensation 5.If your diagnosis includes metabolic acidosis, check the anion gap Anion gap = [Na + ] - [Cl - ] - [HCO 3 - ] = = 40 (normal ~12) Partially compensated metabolic acidosis with increased anion gap (normochloremic)

23 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.O mmHg (on 100% O 2 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