1. Regulation of Extracellular Fluid Osmolarity and Sodium Concentration

2. Changes in Osmolarity of the Renal Tubular Fluid
Figure 28-7; Guyton and Hall

3. Minimal urine concentration
Concentration and
Dilution of the Urine
Maximal urine concentration
= mOsm / L
(specific gravity ~ 1.030)
Minimal urine concentration
= mOsm / L
(specific gravity ~ 1.003)

4. Urine Specific Gravity
Relationship Between Urine Osmolarity and Specific Gravity
1400
1200
1000
Influenced by
glucose in urine
protein in urine
Urine
Osmolarity
(mOsm/L)
800
600
400
200
Urine Specific Gravity
Copyright © 2006 by Elsevier, Inc.

5. Water diuresis in a human after ingestion of 1 liter of water

6. Formation of a Dilute Urine
Continue electrolyte reabsorption
Decrease water reabsorption
Mechanism: decreased ADH release and reduced water permeability in distal and collecting tubules

7. Formation of a Concentrated Urine
Continue electrolyte reabsorption
Increase water reabsorption
Mechanism:
Increased ADH release which increases water
permeability in distal and collecting tubules
High osmolarity of renal medulla
Countercurrent flow of tubular fluid

8. Formation of a Concentrated Urine when Antidiuretic Hormone (ADH) Levels are High
Figure 28-4; Guyton and Hall

9. Obligatory Urine Volume
The minimum urine volume in which the excreted
solute can be dissolved and excreted.
Example:
If the max. urine osmolarity is 1200 mOsm/L,
and 600 mOsm of solute must be excreted each
day to maintain electrolyte balance, the
obligatory urine volume is:
600 mOsm/d
1200 mOsm/L
= L/day

10. Obligatory Urine Volume
In renal disease the obligatory urine volume may be
increased due to impaired urine concentrating ability.
Example:
If the max. urine osmolarity = 300 mOsm/L,
If 600 mOsm of solute must be excreted each
day to maintain electrolyte balance
obligatory urine volume = ?
600 mOsm/d
= L/day
300 mOsm/L

11. Maximum Urine Concentration of Different Animals
Animal Max. Urine Conc. (mOsm /L)
Beaver
Pig 1,100
Human 1,400
Dog 2,400
White Rat 3,000
Kangaroo Mouse ,000
Australian Hopping Mouse ,000

12. Formation of a Concentrated Urine when Antidiuretic Hormone (ADH) Levels are High
Continue electrolyte
reabsorption
Increase water reabsorption
Increased ADH
High osmolarity
of renal medulla
(countercurrent
multiplier)

13. Factors That Contribute to Buildup of Solute in Renal Medulla - Countercurrent Multiplier
Active transport of Na+, Cl-, K+ and other ions from thick
ascending loop of Henle into medullary interstitium
Active transport of ions from medullary collecting ducts
into interstitium
Passive diffusion of urea from medullary collecting ducts
Diffusion of only small amounts of water into medullary
interstitium

14. Medullary Collecting Duct Transport
Figure 27-11; Guyton and Hall

15. Recirculation of Urea Absorbed from Medullary Collecting Duct into Interstitial Fluid
Figure 28-5; Guyton and Hall

16. Summary of Tubule Characteristics
Permeability
Tubule
Active NaCl
Segment
Transport
H2O NaCl Urea
Proximal
Thin Desc
Thin Ascen
Thick Ascen
Distal + +ADH 0 0
Cortical Coll. + +ADH 0 0
Inner Medullary + +ADH 0 +ADH
Coll.

17. Countercurrent Multiplier System in the Loop of Henle

18. Net Effects of Countercurrent Multiplier
1. More solute than water is added to the renal medulla
(i.e., solutes are “trapped” in the renal medulla).
2. Fluid in the ascending loop is diluted.
3. Most of the water reabsorption occurs in the cortex
(i.e., in the proximal tubule and in the distal
convoluted tubule) rather than in the medulla.
4. Horizontal gradient of solute concentration established
by the active pumping of NaCl is “multiplied” by countercurrent flow of fluid.

19. Urea Recirculation Urea is passively reabsorbed in proximal tubule.
In the presence of ADH, water is reabsorbed in distal and collecting tubules, concentrating
urea in these parts of the nephron.
The inner medullary collecting tubule is highly
permeable to urea, which diffuses into the
medullary interstitium.
ADH increases urea permeability of medullary
collecting tubule.

20. The Vasa Recta Preserve Hyperosmolarity of Renal Medulla
serve as
countercurrent
exchangers
Vasa recta blood
flow is low
(only 1-2 % of
total renal
blood flow)
Figure 28-3; Guyton and Hall

21. Changes in Osmolarity of the Renal Tubular Fluid
Figure 28-7; Guyton and Hall

22. Summary of Water Reabsorption and Osmolarity in Different Parts of the Tubule
Proximal Tubule: 65 % reabsorption, isosmotic
Desc. loop: 15 % reasorption, osmolarity increases
Asc. loop: 0 % reabsorption, osmolarity decreases
Early distal: 0 % reabsorption, osmolarity decreases
Late distal and coll. tubules: ADH dependent
water reabsorption and tubular osmolarity
Medullary coll. ducts: ADH dependent water reabsorption and tubular osmolarity

23. “Free” Water Clearance (CH2O)
CH2O = V -
Uosm x V
Posm
where:
Uosm = urine osmolarity
V = urine flow rate
P = plasma osmolarity
If: Uosm < Posm, CH2O = +
If: Uosm > Posm, CH2O = -

24. Disorders of Urine Concentrating Ability
Failure to produce ADH: “Central” diabetes insipidus
Failure to respond to ADH: “nephrogenic” diabetes insipidus
- impaired loop NaCl reabs. (loop diuretics)
- drug induced renal damage: lithium, analgesics
- malnutrition (decreased urea concentration)
- kidney disease: pyelonephritis, hydronephrosis,
chronic renal failure

25. Control of Extracellular Osmolarity (NaCl Concentration)
ADH
Thirst ]
ADH -Thirst Osmoreceptor System
Mechanism:
increased extracellular osmolarity (NaCl) stimulates ADH release, which increases H2O reabsorption, and stimulates thirst (intake of water)

26. Osmoreceptor– antidiuretic hormone (ADH) feedback mechanism for regulating extracellular fluid osmolarity

27. ADH synthesis in the magnocellular neurons of hypothalamus, release by the posterior pituitary, and action on the kidneys

28. Stimuli for ADH Secretion
Increased osmolarity
Decreased blood volume (cardiopulmonary reflexes)
Decreased blood pressure (arterial baroreceptors)
Other stimuli :
- input from cerebral cortex (e.g. fear)
- angiotensin II ?
- nausea
- nicotine
- morphine

29. The effect of increased plasma osmolarity or decreased blood volume
Figure 28-10;
Guyton and Hall

30. Factors that Decrease ADH Secretion
Decreased osmolarity
Increased blood volume (cardiopulmonary reflexes)
Increased blood pressure (arterial baroreceptors)
Other factors:
- alcohol
- clonidine (-2 adrenergic agonist)
- haloperidol (antipsychotic, tics,Tourette’s)

31. Stimuli for Thirst Increased osmolarity Decreased blood volume
(cardiopulmonary reflexes)
Decreased blood pressure
(arterial baroreceptors)
Increased angiotensin II
Other stimuli:
- dryness of mouth

32. Factors that Decrease Thirst
Decreased osmolarity
Increased blood volume
(cardiopulmonary reflexes)
Increased blood pressure
(arterial baroreceptors)
Decreased angiotensin II
Other stimuli:
-Gastric distention

34. Chapter 29:

35. Normal Potassium Intake, Distribution, and Output from the Body
< 2 %
> 98 %

36. Effects of severe hyperkalemia
Partial depolarization of cell membranes
Cardiac toxicity
ventricular fibrillation or asystole
Effects of severe hypokalemia
Hyperpolarization of cell membranes
Fatigue, muscle weakness
hypoventilation
delayed ventricular repolarization

37. Renal Tubular Sites of Potassium Reabsorption and Secretion
Figure 29-2; Guyton and Hall

38. Internal Distribution of K+
Factors That Promote Hypokalemia
aldosterone
insulin
alkalosis
Factors That Promote Hyperkalemia
cell lysis
acidosis
strenuous exercise

39. K+ Secretion by Principal cells

40. Control of Cortical Collecting Tubule (Principal Cells) K+ Secretion
Aldosterone : increases K+ secretion
Extracellular K+ concentration : increases
K+ secretion
Acid - base status:
- acidosis : decreases K+ secretion
- alkalosis : increases K+ secretion

41. Effect of Changes in K+ Intake on Plasma K+
4.6
4.4
Plasma
K+ Conc.
4.2
(mEq/L)
4.0
3.8
K+ Intake ( mEq/day)

42. Effect of Aldosterone on K+ Excretion4 3
Urinary K+
Excretion
(x normal) 2 1 1 2 3 4 5
Plasma Aldosterone (x normal

43. K+ Intake
Plasma K+
Concentration
Aldosterone
K+ Secretion Cortical
Collecting Tubules
K+ Excretion

44. Effect of Changes in K+ Intake on Plasma
K+ After Blocking Aldosterone System
3.8
4.0
4.2
4.4
4.6
Aldosterone
System blocked
Plasma
normal
K+ Conc.
(mEq/L)
210
K+ Intake ( mEq/day)

46. Mechanisms of Hydrogen Ion Regulation
[H+] is precisely regulated at x moles/L
(pH range )
1. Body fluid chemical buffers (rapid but temporary)
bicarbonate - ammonia
proteins - phosphate
2. Lungs (rapid, eliminates CO2)
[H+] ventilation CO2 loss
3. Kidneys (slow, powerful); eliminates non-volatile acids
- secretes H+
- reabsorbs HCO3-
- generates new HCO3-

47. Bicarbonate: most important ECF buffer
Buffer Systems in the body
Bicarbonate: most important ECF buffer
Phosphate: important renal tubular buffer
HPO4-- + H H2PO 4 -
Ammonia: important renal tubular buffer
NH3 + H+ NH4+
Proteins: important intracellular buffers
H+ + Hb HHb
H2O + CO2 H2CO3 H+ + HCO3 -
(60-70% of buffering is in the cells)

48. Normal H+ concentration = 0.00004 mmol/L
Importance of Buffer System
Normal H+ concentration = mmol/L
Amount of non-volatile acid produced
~ 80 mmol/day
80 mmol /42 L = 1.9 mmol/L
= 47,500 times > normal H+ concentration

49. Bicarbonate Buffer System
carbonic
anhydrase
H2O + CO2 H2CO3 H+ + HCO3 -
HCO3 -
pCO2
 = 0.03
pK = 6.1
pH = pK + log
Effectiveness of buffer system depends on:
concentration of reactants
pK of system and pH of body fluids

50. Titration Curve for Bicarbonate Buffer System

51. Bicarbonate Buffer System
Is the most important buffer in extracellular fluid even though the concentration of the components are low and pK of the system is 6.1, which is not very close to normal extracellular fluid pH (7.4).
Reason: the components of the system (CO2 and HCO3-) are closely regulated by the lungs and the kidneys

52. Respiratory Regulation of Acid-Base Balance
[H+]
Alveolar
Ventilation
pCO2
H2O + CO2 H2CO3 H+ + HCO3 -

53. Effects of Blood pH on Alveolar
Ventilation

54. Renal Regulation of Acid-Base Balance
Kidneys eliminate non-volatile
acids (H2SO4, H3PO4)
Secretion of H+
Reabsorption of HCO3-
Production of new HCO3-

55. Renal Tubular Reabsorption of Bicarbonate (and H+ secretion)
Key point:
For each HCO3-
reabsorbed, there
must be a H+
secreted

56. Mechanism of HCO3- Reabsorption and Na+ - H+ Exchange In Proximal Tubule and Thick Loop of Henle

57. and collecting tubules
HCO3- Reabsorption and H+ secretion in Intercalated cells of late distal
and collecting tubules
Figure 30-6; Guyton and Hall

58. Regulation of H+ secretion
Increased pCO2 increases H+ secretion
i.e. respiratory acidosis
Increased extracellular H+ increases H+
secretion
i.e. metabolic or respiratory acidosis
Increased tubular fluid buffers increases H+
secretion
i.e. metabolic or respiratory acidosis

59. increased H+ secretion increased HCO3- reabsorption
Renal Compensations for Acid-Base Disorders
Acidosis:
increased H+ secretion
increased HCO3- reabsorption
production of new HCO3-
Alkalosis:
decreased H+ secretion
decreased HCO3- reabsorption
loss of HCO3- in urine

60. i.e. the maximal [H+] of urine is 0.03 mmol/L
Importance of Renal Tubular Buffers
Minimum urine pH = 4.5 =
= 3 x moles/L
i.e. the maximal [H+] of urine is 0.03 mmol/L
Yet, the kidneys must excrete, under normal
conditions, at least 60 mmol non-volatile acids
each day. To excrete this as free H+ would require:
.03mmol/L
= L per day !!!
60 mmol

61. Buffering of Secreted H+ by Filtered Phosphate (NaHPO4-) and Generation of “New” HCO3-

62. Phosphate as a Tubular fluid buffer
There is a high concentration of phosphate in the tubular fluid; pK = 6.8
Phosphate normally buffers about 30 mmol/day H+ (about 100 mmol/day phosphate is filtered but 70 % is reabsorbed)
Phosphate buffering capacity does not change much with acid-base disturbances (phosphate is not the major tubular buffer in chronic acidosis
NaHPO4- + H NaH2PO4

63. Phosphate and Ammonium Buffering In Chronic Acidosis
500 - - H PO
+ HSO4 2 4
400 + NH 4
Acid
Excretion
(mmoles/day)
300
200
100
Normal
Acidosis for 4 Days

64. Production and Secretion of NH4+ and HCO3- by Proximal, Thick Loop of Henle,and Distal Tubules
H++NH3
“New” HCO3-

65. Buffering of Hydrogen Ion Secretion by Ammonia (NH3) in the Collecting Tubules
“New” HCO3-
Figure 30-9; Guyton and Hall

66. Quantification of Normal Renal Acid-Base Regulation
Total H+ secretion = 4380 mmol/day
= HCO3- reabsorption (4320 mmol/d)
+ titratable acid (NaHPO4-) (30 mmol/d)
+ NH4+ excretion (30 mmol/d)
Net H+ excretion = 59 mmol/day
= titratable acid (30 mmol/d)
+ NH4+ excretion (30 mmol/d)
- HCO3- excretion (1 mmol/d)

67. Normal Renal Acid-Base Regulation
Net addition of HCO3- to body
(i.e., net loss of H+)
Titratable acid = 30 mmol/day
+ NH4+ excretion = 30 mmol/day
- HCO3- excretion = 1 mmol/day
Total = 59 mmol/day

68. H2O + CO2 H2CO3 H+ + HCO3 - HCO3 - pH = pK + log α pCO2
Classification of Acid Base Disorders from Plasma pH;PCO2 and HCO3-
H2O + CO2 H2CO3 H+ + HCO3 -
HCO3 -
α pCO2
pH = pK + log
Acidosis: pH < 7.4
- metabolic: HCO3 -
- respiratory: pCO2
Alkalosis: pH > 7.4
- metabolic: HCO3 -
- respiratory: pCO2

69. Simple Analysis of Acid-Base Disorders
Figure 30-10; Guyton and Hall

70. increased H+ excretion increased HCO3- reabsorption
Renal Compensation of Acid-Base Disorders
Acidosis:
increased H+ excretion
increased HCO3- reabsorption
production of new HCO3-
Alkalosis
decreased H+ excretion
decreased HCO3- reabsorption
loss of HCO3- in urine

71. Renal Responses to Respiratory Acidosis
H2O + CO2 H2CO3 H+ + HCO3 -
Respiratory acidosis:
pH pCO2 HCO3-
H+ secretion pH
PCO2
complete HCO3-
reabs. +
excess tubular H+
Buffers (NH4+, NaHPO4-) H+
Buffers - +
new HCO3-

72. Metabolic acidosis: pH pCO2 HCO3- HCO3- HCO3- complete HCO3- reabs.
Renal Responses to Metabolic Acidosis
Metabolic acidosis:
pH pCO2 HCO3-
HCO3-
HCO3-
complete HCO3-
reabs.
filtration +
excess tubular H+ pH
Buffers (NH4+, NaHPO4-) H+
Buffers - +
new HCO3-

73. Respiratory alkalosis: pH pCO2 HCO3-
Renal Response to Respiratory Alkalosis
Respiratory alkalosis:
pH pCO2 HCO3-
H+ secretion pH
PCO2
HCO3-
reabs. +
excess tubular HCO3-
HCO3- + H+
excretion

74. + Metabolic alkalosis: pH pCO2 HCO3- HCO3- excess tubular HCO3- HCO3-
Renal Response to Metabolic Alkalosis
Metabolic alkalosis:
pH pCO2 HCO3-
HCO3-
excess tubular HCO3-
HCO3-
filtration
HCO3-
reabs. pH H+
excretion
HCO3- +
excretion

75. Disturbance pH HCO3- pCO2 Compensation
Classification of Acid Base Disturbance
Plasma
Disturbance pH HCO3- pCO Compensation
ventilation
metabolic
acidosis
renal HCO3
production
respiratory
acidosis
renal HCO3
production
ventilation
metabolic
alkalosis
renal HCO3
excretion
respiratory
alkalosis
renal HCO3
excretion

76. Acid-Base Disturbances
Metabolic Acidosis: HCO3- / pCO2 in plasma
( pH, HCO3- )
aspirin poisoning ( H+ intake)
diabetes mellitus ( H+ production)
diarrhea (HCO3- loss)
renal tubular acidosis ( H+ secretion, HCO3- reabs.)
carbonic anhydrase inhibitors ( H+ secretion)
H2O + CO2 H2CO3 H+ + HCO3 -
HCO3 -
pH = pK + log
pCO2