2 Water travels freely across the cell membranes of most parts of the body. The

cell membrane, however, is only selectively permeable to solutes. The impermeable

solutes are osmotically active and can exert an osmotic pressure that dictates the

distribution of water between fluid compartments. Water moves across the cell

membrane from a region of low osmolality to one of high osmolality. Net water

movement ceases when osmotic equilibrium occurs. Each fluid compartment contains

a major osmotically active solute: potassium in the intracellular space and sodium in

the ECF. The volumes of the two compartments reflect the asymmetrically larger

number of solute particles or osmoles inside the cells.

2,3

The capillary wall separates the interstitial fluid from plasma. Because sodium

moves freely across the capillary wall, its concentration is identical across both

sides of the wall. Therefore, no osmotic gradient is generated, and water distribution

between these two spaces is not affected. Plasma proteins, which are confined in the

vascular space, are the primary osmoles that affect water distribution between the

interstitium and the plasma.

2

In contrast, urea, which traverses both the capillary

walls and most cell membranes, is osmotically inactive.

2,3

Plasma Osmolality

Osmolality is defined as the number of particles per kilogram of water (mOsm/kg). It

is determined by the number of particles in solution and not by particle size or

valence. Nondissociable solutes, such as glucose and albumin, generate 1

mOsm/mmol of particles; and dissociable salts, such as sodium chloride, liberate

two ions in solution to produce 2 mOsm/mmol of salt. The osmolality of body fluid is

maintained between 280 and 295 mOsm/kg. Because all body fluid compartments are

iso-osmotic, plasma osmolality reflects the osmolality of total body water. Plasma

osmolality can be measured by the freezing point depression method, or estimated by

the following equation, which takes into account the osmotic effect of sodium,

glucose, and urea

2,3

:

This equation predicts the measured plasma osmolality within 5 to 10 mOsm/kg.

Although urea contributes to the measured osmolality, it is an ineffective osmole

because it readily traverses cell membranes and, therefore, does not cause significant

fluid shift within the body. Hence, the effective plasma osmolality (synonymous with

tonicity, the portion of total osmolality that has the potential to induce transmembrane

water movement) can be estimated by the following equation:

An osmolal gap exists when the measured and calculated values differ by greater

than 10 mOsm/kg

4

; it signifies the presence of unidentified particles. When the

individual solute has been identified, its contribution to the measured osmolality can

be estimated by dividing its concentration (mg/dL) by one-tenth of its molecular

weight. Calculating the osmolal gap is used to detect the presence of substances, such

as ethanol, methanol, and ethylene glycol, that have high osmolality. Occasionally,

the osmolal gap can also result from an artificial decrease in the serum sodium

secondary to severe hyperlipidemia or hyperproteinemia.

CASE 27-1

QUESTION 1: J.F., a 31-year-old man, is admitted to the inpatient medicine service for methanol intoxication.

Routine laboratory analysis reveals the following:

Sodium (Na), 145 mEq/L

Potassium (K), 3.4 mEq/L

Blood urea nitrogen (BUN), 10 mg/dL

Creatinine, 1.1 mg/dL

Glucose, 90 mg/dL

The blood methanol concentration was 108 mg/dL, and the measured plasma osmolality was 333 mOsm/kg.

What is J.F.’s calculated osmolality? Are other unidentified osmoles present?

Using Equation 27-1, J.F.’s total calculated osmolality is

In J.F., the entire osmolal gap can be accounted for by the presence of the methanol

(because 108 mg/dL of methanol will provide 108/3.2 = 33.7 mOsm/kg). It is

unlikely, therefore, that other unmeasured osmoles are present (e.g., ethylene glycol,

isopropanol, and ethanol). The laboratory determination of osmolality measures the

total number of osmotically active particles but not their permeability across the cell

membrane. Methanol increases plasma osmolality but not tonicity because the cell

membrane is permeable to methanol. Therefore, no net water shift occurs between the

intracellular and extracellular compartments. Conversely, mannitol, which is

confined to the extracellular space, contributes to both plasma osmolality and

tonicity.

Tubular Function of Nephron

The kidney plays an important role in maintaining a constant extracellular

environment by regulating the excretion of water and various electrolytes. The

volume and composition of fluid filtered across the glomerulus are modified as the

fluid passes through the tubules of the nephron.

The renal tubule is composed of a series of segments with heterogeneous structures

and functions: the proximal tubule, the medullary and cortical thick ascending limb of

Henle’s loop, the distal convoluted tubule, and the cortical and medullary collecting

duct

2

(Fig. 27-1). The mechanism for sodium reabsorption is different for each

nephron segment, but it is generally mediated by carrier proteins or channels located

on the luminal membrane of the tubule cell.

2 Na

+

/K+ ATPase (sodium–potassium

adenosine triphosphatase) actively pumps sodium out of the renal tubule cell in

exchange for potassium in a 3:2 ratio. Hence, the intracellular sodium concentration

is kept at a low level. The potassium that is pumped into the cell leaks back out

through potassium channels in the membrane, rendering the cell interior

electronegative. The low intracellular sodium concentration and a negative

intracellular potential produce a favorable gradient for passive sodium entry into the

cell.

3 Na

+

/K+ ATPase also indirectly provides the energy for active sodium transport

and the reabsorption and secretion of other solutes across the luminal membrane of

the renal tubule. The distal segments are mainly involved in the reabsorption of

sodium and chloride ions and the secretion of hydrogen and potassium ions.

2

p. 570

p. 571

Figure 27-1 Sites of tubule salt and water absorption. Sodium is reabsorbed with inorganic anions, amino acids,

and glucose in the proximal tubule against an electrical gradient that is lumen-negative. In the distal part of the

proximal tubule (pars recta), sodium and water are reabsorbed to a lesser extent and organic acids (hippurate,

urate) and urea are secreted into the urine. The electrical potential is lumen-positive in the pars recta. Water, but

not salt, is removed from tubule fluid in the thin descending limb of Henle’s loop, but in the ascending portion salt is

reabsorbed without water, rendering the tubule fluid hyposmotic with respect to the interstitium. Sodium, chloride,

and potassium are reabsorbed by the medullary and cortical portions of the ascending limb; the lumen potential is

positive. Sodium is reabsorbed and potassium and hydrogen ions are secreted in the distal tubule and collecting

ducts. Water absorption in these segments is regulated by antidiuretic hormone (ADH). The electrical potential is

lumen-negative in the corticalsections and positive in the medullary segments. Urea is concentrated in the

interstitium of the medulla and assists in the generation of maximally concentrated urine. (Reprinted with

permission from Chonko AM et al. Treatment of edema states. In: Narins RG, ed. Maxwell & Kleeman’s Clinical

Disorders of Fluid and Electrolyte Metabolism. 5th ed. New York, NY: McGraw-Hill; 1994:545.)

Iso-osmotic reabsorption of the glomerular filtrate occurs in the proximal tubule

such that two-thirds of the filtered sodium and water and 90% of the filtered

bicarbonate are reabsorbed. The Na

+

/H+ antiporter (exchanger) in the luminal

membrane is instrumental in the reabsorption of sodium chloride, sodium

bicarbonate, and water. The reabsorption of most nonelectrolyte solutes, such as

glucose, amino acids, and phosphates, are coupled to sodium transport.

2,5

Both the thick ascending limb of Henle’s loop and the distal convoluted tubule

serve as the diluting segments of the nephron because they are impermeable to water.

Sodium chloride is extracted from the filtrate without water. Sodium transport in both

of these segments is flow-dependent and varies with the amount of sodium ions

delivered from the proximal segments of the nephron. Decreased sodium ions in the

tubular fluid will limit sodium transport in the thick ascending limb of Henle’s loop

and the distal convoluted tubule.

2,6

Reabsorption of sodium in the thick ascending limb of Henle’s loop accounts for

approximately 25% of the total sodium reabsorption. Sodium, chloride, and

potassium are reabsorbed by the medullary and cortical portions of the ascending

limb, but the leakage of reabsorbed potassium ions back into the tubular lumen, via

potassium channels, makes the tubular lumen electropositive. This electrical gradient

promotes the passive reabsorption of cations, such as sodium, calcium, and

magnesium, in the distal convoluted tubules. Because the thick ascending limb of

Henle’s loop is impermeable to water, it contributes to the interstitial osmolality in

the medulla. This high osmolality is key to the reabsorption of water by the medullary

portion of the collecting duct under the influence of antidiuretic hormone (ADH,

vasopressin). Therefore, the thick ascending limb of Henle’s loop is important for

both urinary concentration and dilution.

6

Because, as noted previously, the distal convoluted tubule is also impermeable to

water, the osmolality of the filtrate continues to decline as sodium is being

reabsorbed. In the distal convoluted tubule and collecting duct, sodium is reabsorbed

in exchange for hydrogen ions and potassium. When sodium ions are reabsorbed, the

tubule lumen becomes electronegative, which promotes potassium secretion in the

lumen via potassium channels. Aldosterone enhances sodium reabsorption in the

collecting duct by increasing the number of opened sodium channels.

2,7

The collecting duct is usually impermeable to water. Under the influence of ADH,

however, water permeability is increased through an increase in the number of water

channels along the luminal membrane. The amount of water reabsorbed depends on

the tonicity of the medullary interstitium, which is determined by the sodium

reabsorbed in the thick ascending limb of Henle’s loop and urea.

2,7,8

p. 571

p. 572

Osmoregulation

A reduction of intracellular volume often increases effective plasma osmolality;

conversely, decreased effective plasma osmolality is associated with cellular

hydration. Water homeostasis is important in the regulation of plasma osmolality, and

plasma tonicity is maintained within normal limits through a delicate balance

between the rates of water intake and excretion.

The amount of daily water intake includes the volume of water ingested (sensible

intake), the water content of ingested food, and the metabolic production of water

(insensible intake).

2 To maintain homeostasis, these should be equal to the amount of

water excreted by the kidney and the gastrointestinal (GI) tract (sensible loss) plus

water lost from the skin and respiratory tract (insensible loss).

2,3

Changes in plasma tonicity are detected by osmoreceptors in the hypothalamus,

which also houses the thirst center and is the site for ADH synthesis.

9,10 When the

plasma tonicity falls below 280 mOsm/kg as a result of water ingestion, ADH

release is inhibited,

2 water is no longer reabsorbed in the collecting duct, and a large

volume of dilute urine is excreted. Conversely, when the osmoreceptors in the

hypothalamus sense an increased plasma osmolality, ADH is released to increase

water reabsorption. A small volume of concentrated urine is then excreted. The

threshold for ADH release is 280 mOsm/kg, and maximal ADH secretion occurs

when the plasma osmolality is 295 mOsm/kg.

9 Thus, urine osmolality varies from 50

mOsm/kg in the absence of ADH to 1,200 mOsm/kg during maximal ADH release.

The volume of urine produced depends on the solute load to be excreted, as well as

the urine osmolality

2,3,9,10

:

Therefore, for a typical daily solute load of 600 mOsm:

Although the kidney has a remarkable ability to excrete free water, it is not as

efficient in conserving water. ADH minimizes further water loss, but it cannot correct

water deficits. Therefore, optimal osmoregulation requires increased water intake

stimulated by thirst. Both ADH and thirst can be stimulated by nonosmotic stimuli.

For example, volume depletion is such a strong nonosmotic stimulus for ADH release

that it can override the response to changes in plasma osmolality. Nausea, pain, and

hypoxia are also potent stimuli for ADH secretion.