Urea and the Osmolality–Tonicity Paradox

Four terms that measure solute concentration differently

Plasma holds many dissolved solutes, and the word chosen to describe their concentration matters, because only some of them move water across cell membranes. Four related terms separate these ideas.

An osmole is a number of moles of dissolved solute. For a substance that does not dissociate into sub-particles, the osmole and the mole are equal; for a substance that does dissociate, the osmole is the mole multiplied by the number of particles formed.

Osmolarity measures solute per unit volume of solution. It is a colligative property, meaning it depends on the number of particles rather than on their nature, and because it is defined per volume, it depends on the temperature and pressure of the solution.

Osmolality measures osmoles of solute per kilogram of solvent. It is also colligative. It is preferred for body fluids because it is defined per mass rather than per volume, and mass does not change with temperature or pressure; the reported value can be calculated from

$Plasma\ osmolality = 2 \times [Na^+] + [Glucose] + [Urea]$

or measured in the laboratory from the freezing-point depression of plasma. Glucose and urea contribute little to plasma osmolality in health, but their contribution grows in diabetes mellitus and in reduced kidney function.

Tonicity, or effective osmolality, counts only the solutes that cannot cross the semipermeable membrane, because only those exert osmotic pressure. From this follow two definitions that are often confused. An iso-osmolar solution has a total osmolarity, effective and ineffective solutes together, equal to that of the body fluids. An iso-tonic solution has an effective osmolarity equal to that of the body fluids. Dextrose 5% is iso-osmolar and yet hypotonic: its solute crosses the cell membrane easily, so its water stays in the blood and acts as free water.

Urea, one of the terms in the osmolality formula, crosses the cell membrane freely, so it is left out of the tonicity formula:

$Plasma\ tonicity = 2 \times [Na^+] + [Glucose]$

Why the distinction matters in kidney failure

Urea raises plasma osmolality but not plasma tonicity. In kidney failure, urea accumulates in the extracellular fluid (ECF) and crosses cell membranes freely, but its movement across the blood–brain barrier is slower than across other membranes and takes longer to equilibrate. This becomes a problem during hemodialysis, when urea is removed from the blood and the ECF faster than it can equilibrate with the brain cells. For a time the blood osmolality is low while the brain-cell osmolality is still high, so water moves into the brain cells and can cause neurological damage.