Regulation of Extracellular Fluid

Osmolarity and Sodium Concentration

Changes in Osmolarity of the
Renal Tubular Fluid

Figure 28-7; Guyton and Hall

Concentration and
Dilution of the Urine

• Maximal urine concentration

= 1200 - 1400 mOsm / L
(specific gravity ~ 1.030)

• Minimal urine concentration

= 50 - 70 mOsm / L
(specific gravity ~ 1.003)
 Relationship Between Urine Osmolarity and Specific Gravity
1400

1200

1000

Urine
Influenced by
Osmolarity 800 • glucose in urine
(mOsm/L) • protein in urine
600

400

200

1.010 1.020 1.030 1.040

Copyright © 2006 by Elsevier, Inc. Urine Specific Gravity
Water diuresis
in a human
after ingestion
of 1 liter of
water
 Formation of a Dilute
Urine
• Continue electrolyte
reabsorption
• Decrease water
reabsorption

Mechanism:
decreased ADH
release and reduced
water permeability
in distal and
collecting tubules
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
 Formation of a Concentrated Urine when
Antidiuretic Hormone (ADH) Levels are High

Figure 28-4; Guyton and Hall

 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 = 0.5 L/day

1200 mOsm/L
 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
= 2.0 L/day
300 mOsm/L
Maximum Urine Concentration
of Different Animals
Animal Max. Urine Conc. (mOsm /L)
Beaver 500
Pig 1,100
Human 1,400
Dog 2,400
White Rat 3,000
Kangaroo Mouse 6,000
Australian Hopping Mouse 10,000
 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)
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
into interstitium
• Diffusion of only small amounts of water into medullary
interstitium
Medullary Collecting Duct Transport

Figure 27-11; Guyton and Hall

Recirculation of Urea Absorbed from Medullary
Collecting Duct into Interstitial Fluid

Figure 28-5; Guyton and Hall

 Summary of Tubule Characteristics

Tubule Active NaCl Permeability

Segment Transport H 2O NaCl Urea

Proximal ++ +++ + +
Thin Desc. 0 +++ + +
Thin Ascen. 0 0 + +
Thick Ascen. +++ 0 0 0
Distal + +ADH 0 0
Cortical Coll. + +ADH 0 0
Inner Medullary + +ADH 0 +ADH
Coll.
Countercurrent Multiplier System
in the Loop of Henle
 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.
 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.
 The Vasa Recta Preserve
Hyperosmolarity of Renal Medulla

• The vasa recta

serve as
countercurrent
exchangers
• Vasa recta blood
flow is low
(only 1-2 % of
total renal
blood flow)

Figure 28-3; Guyton and Hall

Changes in Osmolarity of the
Renal Tubular Fluid

Figure 28-7; Guyton and Hall

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
“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 = -
 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
 Control of Extracellular Osmolarity
(NaCl Concentration)

• ADH
] ADH -Thirst Osmoreceptor System
• Thirst

Mechanism:
increased extracellular osmolarity (NaCl) stimulates
ADH release, which increases H2O reabsorption,
and stimulates thirst (intake of water)
 Osmoreceptor–
antidiuretic hormone
(ADH) feedback
mechanism for
regulating extracellular
fluid osmolarity
 ADH synthesis in the
magnocellular neurons of
hypothalamus, release by
the posterior pituitary,
and action on the kidneys
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
 The effect of
increased plasma
osmolarity
or decreased
blood volume

Figure 28-10;
Guyton and Hall
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)
Stimuli for Thirst

• Increased osmolarity
• Decreased blood volume
(cardiopulmonary reflexes)
• Decreased blood pressure
(arterial baroreceptors)
• Increased angiotensin II
• Other stimuli:
- dryness of mouth
Factors that Decrease Thirst

• Decreased osmolarity
• Increased blood volume
(cardiopulmonary reflexes)
• Increased blood pressure
(arterial baroreceptors)
• Decreased angiotensin II
• Other stimuli:
-Gastric distention
Chapter 29:
 Normal Potassium Intake,
Distribution, and Output from the Body

<2% > 98 %
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
Renal Tubular Sites of Potassium
Reabsorption and Secretion

Figure 29-2; Guyton and Hall

Internal Distribution of K+
• Factors That Promote Hypokalemia
- aldosterone
- insulin
-alkalosis

• Factors That Promote Hyperkalemia

- cell lysis
- acidosis
- strenuous exercise
K+ Secretion by Principal cells
 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
Effect of Aldosterone on K+ Excretion
4

3
Urinary K+
Excretion 2
(x normal)
1

0
1 2 3 4 5
Plasma Aldosterone (x normal
 K+ Intake

Plasma K+ Aldosterone
Concentration

K+ Secretion Cortical
Collecting Tubules

K+
Excretion
 Effect of Changes in K+ Intake on Plasma
K+ After Blocking Aldosterone System

4.6

4.4
Plasma normal
K+ Conc. 4.2
(mEq/L)
Aldosterone
4.0 System blocked
3.8
30 60 90 120 150 180 210
K+ Intake ( mEq/day)
 Mechanisms of Hydrogen Ion
Regulation
[H+] is precisely regulated at 3 - 5 x 10 -8 moles/L
(pH range 7.2 -7.4)
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-
Buffer Systems in the body

Bicarbonate: most important ECF buffer

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

Normal H+ concentration = 0.00004 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

 Bicarbonate Buffer System
carbonic
anhydrase
H2O + CO2 H2CO3 H+ + HCO3 -

HCO3 -  = 0.03
pH = pK + log
pCO2 pK = 6.1
Effectiveness of buffer system depends on:
• concentration of reactants
• pK of system and pH of body fluids
Titration Curve for Bicarbonate
Buffer System
 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
Respiratory Regulation of Acid-Base Balance

Alveolar
[H ]
+
Ventilation

pCO2

H2O + CO2 H2CO3 H+ + HCO3 -

Effects of Blood pH on Alveolar
Ventilation
Renal Regulation of Acid-Base Balance

• Kidneys eliminate non-volatile

acids (H2SO4, H3PO4)

• Secretion of H+

• Reabsorption of HCO3-

• Production of new HCO3-

 Renal Tubular Reabsorption
of Bicarbonate (and H+ secretion)

Key point:
For each HCO3-
reabsorbed, there
must be a H+
secreted
Mechanism of HCO3- Reabsorption and Na+ - H+ Exchange In
Proximal Tubule and Thick Loop of Henle
HCO3- Reabsorption and H+ secretion in Intercalated cells of late distal
and collecting tubules

Figure 30-6; Guyton and Hall

 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
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
Importance of Renal Tubular Buffers

Minimum urine pH = 4.5

= 10 -4.5
= 3 x 10 -5 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:
60 mmol
= 2000 L per day !!!
.03mmol/L
Buffering of Secreted H+ by Filtered Phosphate
(NaHPO4-) and Generation of “New” HCO3-

“New” HCO3-
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
Phosphate and Ammonium
Buffering In Chronic Acidosis
500
- -
H2PO4 + HSO4
400 +
NH 4
Acid
Excretion 300
(mmoles/day)
200

100

0
Normal Acidosis for 4 Days
Production and Secretion of NH4+ and HCO3- by
Proximal, Thick Loop of Henle,and Distal Tubules

H++NH3

“New” HCO3-
Buffering of Hydrogen Ion Secretion by Ammonia
(NH3) in the Collecting Tubules

“New” HCO3-

Figure 30-9; Guyton and Hall

 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)
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
Classification of Acid Base Disorders from Plasma pH;PCO2 and HCO3-

H2O + CO2 H2CO3 H+ + HCO3 -

HCO3 -
pH = pK + log
α pCO2
Acidosis: pH < 7.4
- metabolic: HCO3 -
- respiratory: pCO2
Alkalosis: pH > 7.4
- metabolic: HCO3 -
- respiratory: pCO2
Simple Analysis of Acid-Base Disorders

Figure 30-10;
Guyton and Hall
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
Renal Responses to Respiratory Acidosis

H2O + CO2 H2CO3 H+ + HCO3 -

Respiratory acidosis: pH pCO2 HCO3-

PCO2 H+ secretion complete HCO3- reabs.

+
excess tubular H+
pH Buffers (NH4+, NaHPO4-)

H+ Buffers -
+
new HCO3-
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-
 Renal Response to Respiratory Alkalosis

Respiratory alkalosis: pH pCO2 HCO3-

PCO2 H+ secretion HCO3- reabs.

+
excess tubular HCO3-
pH

HCO3- excretion
+
+ excretion
H
 Renal Response to Metabolic Alkalosis

Metabolic alkalosis: pH pCO2 HCO3-

HCO3 - HCO3- excess tubular HCO3-

filtration
HCO3- reabs.
pH

HCO3- excretion
+
H+ excretion
 Classification of Acid Base Disturbance

Plasma
Disturbance pH HCO3- pCO2 Compensation
ventilation
metabolic renal HCO3
acidosis production
respiratory renal HCO3
acidosis production
ventilation
metabolic renal HCO3
alkalosis excretion

respiratory renal HCO3

alkalosis excretion
 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 -
pH = pK + log HCO 3
-

pCO2