Regulation of Fluid Volumes

and Electrolyte Excretion

Matching fluid/electrolyte output to meet input

Biophysical Journal 90:L01-L03 (2006)
 Potassium

Electrical excitability of cells

Major osmotically active solute in cells

Acid-base balance

The kidneys are the major site in control of

potassium balance
The redistribution of the intracellular
and extracellular K+ is the first line of
defense against changes in
extracellular K+ concentration
 Normal K+ Distribution

K+ intake per day is a significant number

compared to the [K+]p.
 Potassium Balance
Regulatory mechanisms keep plasma potassium in
narrow range
Aldosterone plays a critical role
Hypokalemia
Muscle weakness and failure of respiratory muscles and
the heart
Causes low intake, diarrhea, Conns disease
Hyperkalemia
Can lead to cardiac arrhythmias
Causes include kidney disease, diuretics, Addisons
disease
 Factors that influence K+ redistribution

Insulin (increase cell uptake)

Diabetic patients have higher K+ after meal
Insulin injections helps correct hyperkalemia

Aldosterone (increase excretion)

Conns syndrome (hypokalemia)
Addisons disease (hyperkalemia)
 Factors that influence K+ redistribution

Epinephrine (2-adrenergic stimulation

increase cell uptake)

2-receptors blockers (propranolol) can

cause hyperkalemia (hypertension patients)
 Factors that influence K+ redistribution

Metabolic acidosis (increases extracellular K+)

Metabolic alkalosis (decreases extracellular K+)

Mechanism:
[H+] inhibits Na+-K+ ATPase ( K+
uptake)
 Factors that influence K+ redistribution

Cell lysis (hyperkalemia)

Severe muscle injury

RBC destruction

Strenuous exercise
K+ release from muscle cells (hyperkalemia)

Can be severe in diabetic or -adrenergic

blocker patients
 Factors that influence K+ redistribution

Increased extracellular osmolarity

Cell dehydration concentrates K+ inside cells

leading to diffusion out
Also present in diabetes mellitus
Hypokalemia in Burmese kittens
Renal control of K +
Sites of K+ Reabsorption and Secretion

Control sites

When K+ intake goes up thus increasing filtered load, the

amt. reabsorbed increases but not as much as the amt.
secreted.
Mechanism of K+ Secretion

Na+/K+ pump at
basolateral membrane
of principal cells pumps
K+ into the cell creating
a diffusion gradient to
the tubular lumen
through special K+
channels
K+ secretion responsible for variations in
excretion levels
Main secretion sites
Principal cells (late distal tubules)
Cortical collecting ducts

Secretion and reabsorption depending on

body need
intake secretion (can exceed the filtrate)
intake secretion
 K+ secretion by Principal cells

Since dietary loads of K+ are mainly

secreted by principal cells, the most
important factors causing secretion are:

Increased [K+]p
Increased Aldosterone

Increased tubular flow rate

Increase H+ (acidosis) decrease K+ secretion

Factors regulating K+ secretion
 Increased [K+]p increases secretion

Most important mechanism controlling K+

levels

Three mechanisms:
Na+-K+ ATPase activity
K+ gradient from interstitial fluid to the
interior of the epithelial cells
aldosterone (via Na+-K+ ATPase and
permeability of lumen membrane)
Effect of Aldosterone on K+ Excretion

The sharp
increase in
excretion above
4.1 meq/L due
to direct
stimulation of
Na+/K+ pump to
increase [K+] cell
and diffusion to
lumen
Effect of [K+]p on Aldosterone Release

Note:
Aldosterone
increases
basolateral
Na+/K+
pump
activity and
luminal
border
permeability
to K+
Feedback mechanism for control of
[K+]p by Aldosterone

[K+]p increase
causes
[aldosterone]p
increase which
causes an increase
in K+ excretion
which causes
[K+]p to return to
normal
K+ Excretion Summary

An increase in [K+]p
has a direct effect on
principal cells and an
indirect effect through
aldosterone release.
Both cause increased
secretion by the
principal cells.
Importance of Aldosterone
 Increase in distal tubular flow rate

Causes: volume expansion, Na+ intake,

diuretics (all stimulate K+ secretion)

Mechanism:
K+ in tubular lumen, K+ driving force
across membrane tubular flow flushes
K+ out
Effect of High Na+ Intake on K+ Excretion

The increased
K+ secretion due
to the increased
distal tubular
flow rate is
another example
of gradient time
transport
 Hypokalemia

Reabsorption via intercalated cells

Secretion stops

H+-K+ ATPase in lumen (minor role during

excretion)
Control of extracellular calcium and
excretion
 Disturbances in calcium levels

Hypocalcemia: in excitability of nerve and

muscle cells (spastic skeletal muscle
contraction hypocalcemic tetany )

Hypercalcemia: depression of
neuromuscular excitability and cardiac
arrhythmias
 Dietary calcium

Intake and loss must be balanced

High excretion via feces (900 mg/day of 1000

mg/day intake)

99% stored in bones (reservoir)

1% extracellular fluids and 0.1% intracellular fluids

 Calcium Absorption

Most ingested calcium is lost in feces

Absorption controlled to meet daily need of body

Amount absorbed is dependent on Vitamin D and

Parathyroid hormone
 PTH acts at 3
sites: 1) Bone 2)
Gut and 3)
Kidney. All
work in concert
to keep [Ca++]p
normal

Bone does not have inexhaustible calcium supply, so

intake must balance loss
 Control of calcium renal excretion

Renal calcium excretion=calcium filtered-

calcium reabsorbed
50% undergo filtration
99% filtered reabsorbed , 1% excreted
 65%

4%

30%
Regulation of phosphate excretion
 Regulation of phosphate excretion

Controlled by an overflow mechanism

Tmax=0.1mM/min
Below Tmax, all phosphate reabsorbed
Above Tmax, excess is excreted

Normal diet (milk and meat) contains large

amounts of phosphate and is excreted in
urine
 Role of PTH in phosphate excretion

Promotes bone resorption ( ECF phosphate)

Decreases Tmax in renal tubules (loss via urine)

PTH tubular phosphate reabsorption

excretion

Secondary Hyperparathyroidism
 Secondary Hyperparathyroidism

Chronic renal failure is the most common causes

of secondary hyperparathyroidism. Failing kidneys
do not convert enough Vitamin D to its active
form, and they do not adequately excrete
phosphorus.

Insoluble calcium phosphate forms in the body

and removes calcium from the circulation. Both
processes leads to hypocalcemia and hence
secondary hyperparathyroidism.
Regulation of magnesium excretion
 Regulation of magnesium excretion

More than 50% stored in bones

1.8 mEq/L in plasma (most bound to

proteins)

Less than 1% in extracellular fluid

 Dietary Magnesium

Daily intake 250-300 mg/day

50% absorbed by GI
Kidney excrete 125-150 mg/day
Excretion is controlled via tubular
reabsorption
PT 25%
LH 65%
THE TRANSIENT RECEPTOR
POTENTIAL ION CHANNELS
Transient Receptor Potential Channels

TRPC TRPV TRPM

TRPC1 TRPV1 TRPM1
TRPC2 TRPV2 TRPM2
TRPC3 TRPV3 TRPM3
TRPC4 TRPV4 TRPM4
TRPC5 TRPV5 TRPM5
TRPC6 TRPV6 TRPM6
TRPC7 TRPM7
TRPM8
Chubanov et al., PNAS 2003
 Control of Mg2+ excretion

Increase in Mg2+ excretion:

in extracellular Mg2+ concentration

Extracellular volume expansion

Increasein extracellular calcium

concentration
25%

<5%
65%
 Control of blood volume and ECF

Effect of blood pressure on Na+ and water

excretion! (Most basic and powerful)

Pressure Natriuresis

Pressure Diuresis

Usually parallel to each other

 Pressure Natriuresis

In acute arterial pressure:

30-50mm Hg changes results 2-3 fold Na+
excretion
Independent of sympathetic nervous system,
hormones (ADH, Angiotensin II or aldosterone)

In chronic arterial pressure:

Pressure natriuresis greatly enhanced
Renin suppression ( Angiotensin II and
aldosterone)
The chronic curve is almost vertical indicating a
very high system gain
Basic renal-body fluid feedback mechanism

1
7 8
2

6 5 4
Basic renal-body fluid feedback mechanism

Summary:
Prevents continuous accumulation of salt
and water during increased salt and water
intake
Dependent on functional kidney and
pressure diuresis
Minimal changes in BV, ECF, CO and AP
during large salt and water intake
Precision between blood volume and ECF

Slight in BV in CO

Slight in CO in BP

Slight in BP

in Urine Output
What happens when fluid intake falls
below normal?
 Effect of fluid intake on blood volume

The flatness of the curve tells you that the control of blood
volume is very powerful and the system gain is very high
 When blood volume loss reaches 35-40% of
normal the outcome is usually fatal. Beyond a
certain blood volume, additional fluid simply
passes into the interstitial space (overflow sink)
Nervous & Hormonal Factors and the Renal-
Body Fluid System

Sympathetic Nervous System (blood loss)

Arterial baroreceptors
Low pressure stretch receptors

Angiotensin II (blood loss)

Aldosterone (blood loss)
ADH (restricted dietary intake of H2O)
ANP (congestive heart failure)
 Sympathetic Nervous System

Decrease in blood volume (hemorrhage)

activates pressure sensitive receptors

Increase sympathetic stimulus to kidneys

Constriction of renal artery ( GFR)
tubular reabsorption of salt and water

renin ( angiotensin II and aldosterone)

 Angiotensin II

Angiotensin II formation directly related to

sodium and water intake
sodium intake ( renin and angiotensin II)
sodium and water reabsorption
excretion of sodium and water

The renin-angiotensin system amplifies the

pressure natriuresis mechanism
 Importance of angiotensin on pressure
natriuresis mechanism

The left curve is the basis for the use of ACE inhibitors in
treating hypertension
 Aldosterone

Net effect to increase sodium and water

reabsorption and potassium excretion

sodium intake aldosterone

sodium intake aldosterone

Aid the pressure natriuresis mechanism

Escape effect during oversecretion of
Aldosterone

Conns syndrome

Increase in arterial pressure allows kidneys

to escape the initial sodium and water
retention (Via pressure natriuresis and
diuresis)

Sodium excretion matches intake

 Anti-Diuretic Hormone (ADH)

Water retention with normal salt excretion

24-48 h without water slight decrease in ECF

volume and AP (with ADH)

Without ADH significant decrease in ECF volume

and AP

High ADH levels can cause severe reduction in

extracellular sodium
 Atrial Natriuretic Peptide (ANP)

Released by overstretch of the atria (excess

blood volume)
GFR and sodium reabsorption
excretion of salt and water (compensates
excess blood)
Excess ANP or absence does not cause major
changes in BV (because small changes in BP
via pressure natriuresis)
Conditions that causes large increases in
BV and ECF
Heart disease (congestive failure)
Increased vascular capacity (pregnancy)

Conditions that causes large increases in
ECF but with normal BV

Nephrotic syndrome (urinary loss of plasma

proteins)

Liver cirrhosis (loss of plasma protein

production)

Kidney retain water and sodium to restore

blood volume (similar to hemorrhage)